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Sample records for leukemia drug imatinib

  1. Exploring chronic myeloid leukemia patients' reasons for not adhering to the oral anticancer drug imatinib as prescribed.

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    Eliasson, Lina; Clifford, Sarah; Barber, Nick; Marin, David

    2011-05-01

    Nonadherence has been shown to be frequent amongst chronic myeloid leukemia (CML) patients prescribed imatinib, which results in reduced clinical response and increased healthcare costs. However, little is known about the reasons why CML patients frequently do not take their imatinib as prescribed. The current study explored CML patients' experience of taking, or not taking, imatinib therapy through in-depth interviews with twenty-one patients. Their adherence had been previously measured using a medication events monitoring device. The interviews were recorded, transcribed and analysed in accordance with established techniques. Patients revealed a variety of reasons for their nonadherence. Major themes that emerged from the data were the intentional and unintentional reasons for nonadherence. Furthermore, as a result of information received from health care professionals, several patients felt inappropriately reassured that their nonadherence would not have a detrimental effect on their clinical response. Factors that seemed to favour adherence were finding ways to deal with side effects and using prompts as reminders to take the medicine. This study forms a basis on which to build future adherence research and may help to develop interventions designed to ensure that patients with CML and other cancers adhere optimally to their oral drugs treatment. Copyright © 2010 Elsevier Ltd. All rights reserved.

  2. Time-series analysis in imatinib-resistant chronic myeloid leukemia K562-cells under different drug treatments.

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    Zhao, Yan-Hong; Zhang, Xue-Fang; Zhao, Yan-Qiu; Bai, Fan; Qin, Fan; Sun, Jing; Dong, Ying

    2017-08-01

    Chronic myeloid leukemia (CML) is characterized by the accumulation of active BCR-ABL protein. Imatinib is the first-line treatment of CML; however, many patients are resistant to this drug. In this study, we aimed to compare the differences in expression patterns and functions of time-series genes in imatinib-resistant CML cells under different drug treatments. GSE24946 was downloaded from the GEO database, which included 17 samples of K562-r cells with (n=12) or without drug administration (n=5). Three drug treatment groups were considered for this study: arsenic trioxide (ATO), AMN107, and ATO+AMN107. Each group had one sample at each time point (3, 12, 24, and 48 h). Time-series genes with a ratio of standard deviation/average (coefficient of variation) >0.15 were screened, and their expression patterns were revealed based on Short Time-series Expression Miner (STEM). Then, the functional enrichment analysis of time-series genes in each group was performed using DAVID, and the genes enriched in the top ten functional categories were extracted to detect their expression patterns. Different time-series genes were identified in the three groups, and most of them were enriched in the ribosome and oxidative phosphorylation pathways. Time-series genes in the three treatment groups had different expression patterns and functions. Time-series genes in the ATO group (e.g. CCNA2 and DAB2) were significantly associated with cell adhesion, those in the AMN107 group were related to cellular carbohydrate metabolic process, while those in the ATO+AMN107 group (e.g. AP2M1) were significantly related to cell proliferation and antigen processing. In imatinib-resistant CML cells, ATO could influence genes related to cell adhesion, AMN107 might affect genes involved in cellular carbohydrate metabolism, and the combination therapy might regulate genes involved in cell proliferation.

  3. An analysis of strategic treatment interruptions during imatinib treatment of chronic myelogenous leukemia with imatinib-resistant mutations.

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    Paquin, Dana; Sacco, David; Shamshoian, John

    2015-04-01

    Chronic myelogenous leukemia (CML) is a cancer of the white blood cells that results from increased and uncontrolled growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. The most common form of treatment for CML is imatinib, a tyrosine kinase inhibitor. Although imatinib is an effective treatment for CML and most patients treated with imatinib do attain some form of remission, imatinib does not completely eradicate all leukemia cells, and if treatment is stopped, all patients eventually relapse (Cortes, 2005). In Kim (2008), the authors developed a mathematical model for the dynamics of CML under imatinib treatment that incorporates the anti-leukemia immune response, and in Paquin (2011), the authors used this mathematical model to study strategic treatment interruptions as a potential therapeutic strategy for CML patients. Although the authors presented the results of several numerical simulations in Paquin (2011), the studies in that work did not include the possibility of imatinib-resistant mutations or an initial population of imatinib-resistant leukemia cells. As resistance is a significant consideration in any drug treatment, it is important to study the efficacy of the strategic treatment interruption plan in the presence of imatinib resistance. In this work, we modify the delay differential equations model of Kim (2008), Paquin (2011) to include the possibility of imatinib resistance, and we analyze strategic treatment interruptions as a potential therapeutic tool in the case of patients with imatinib-resistance leukemia cells.

  4. Lichenoid drug eruption due to imatinib mesylate.

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    Bhatia, Anuradha; Kanish, Bimal; Chaudhary, Paulina

    2015-01-01

    Imatinib mesylate is a selective tyrosinase kinase inhibitor which has revolutionized the treatment of chronic myeloid leukemia. It is also used in gastrointestinal stromal tumors and dermatofibrosarcoma protruberans. Cutaneous adverse reactions are the most common nonhematological side effects secondary to imatinib. Nonlichenoid reactions are common, while lichenoid reactions are rare. We report a case of lichenoid drug eruption due to imatinib. As the indications and use of imatinib are increasing, the incidences of adverse effects, including cutaneous ones, are likely to increase. Some of the reactions may be severe enough to warrant discontinuation of the drug. The physicians should be aware of this morphological entity, which is usually benign and does not warrant withdrawal of the drug.

  5. Profile of imatinib in pediatric leukemia

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    Burke MJ

    2014-02-01

    Full Text Available Michael J BurkeDepartment of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, USAAbstract: Using targeted therapy for treatment of cancer has become the paradigm to which clinical trials aspire. Imatinib, the BCR-ABL1 tyrosine kinase inhibitor (TKI, was the first of its kind to specifically target and inhibit the underlying Philadelphia chromosome (Ph+ oncogene found to be driving chronic myeloid leukemia in adults, and has since become standard of care for the treatment of chronic myeloid leukemia in children. Imatinib, with its ability to target Ph+ leukemia, has been successfully incorporated into the treatment of not only pediatric chronic myeloid leukemia but also Ph+ acute lymphoblastic leukemia. With the incorporation of imatinib into combination chemotherapy for pediatric Ph+ acute lymphoblastic leukemia, current survival rates are far higher than at any other time for this once dreadful disease. With more children today receiving treatment with imatinib for either chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia, knowledge is accumulating surrounding the short-term and long-term toxicities observed in children, adolescents, and young adults treated with this TKI. In summary, the TKI imatinib has made a historic impact in the treatment of pediatric Ph+ leukemias, transforming what were once very high-risk diseases with considerable morbidity and mortality into ones that are now very treatable but with a new awareness surrounding the long-term toxicities that may come with this price for cure.Keywords: imatinib, leukemia, lymphoblastic leukemia, chronic myeloid leukemia, pediatric

  6. In vitro effect of imatinib mesylate loaded on polybutylcyanoacrylate nanoparticles on leukemia cell line K562.

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    Hasandoost, Leyla; Akbarzadeh, Azim; Attar, Hossein; Heydarinasab, Amir

    2017-05-01

    The study aimed to prepare imatinib mesylate-loaded polybutylcyanoacrylate (PBCA) nanoparticles and evaluate their efficacy on leukemia cell line K562. The formulation was prepared by miniemulsion polymerization technique. Nanoparticles were characterized by dynamic light scattering (DLS), spectrophotometry, Fourier transform infrared spectroscopy (FTIR), dialysis membrane, and 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) techniques. Nanoscale particles with high encapsulation efficiency (86%) and physical entrapment of drug were observed. In addition, nanoparticles showed suitable drug retention capability and potentiate the cytotoxicity effects of imatinib mesylate. Findings of study suggested PBCA nanoparticles are promising carrier for imatinib mesylate delivery to leukemia cell line K562.

  7. Therapeutic drug monitoring for imatinib: Current status and Indian experience.

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    Arora, Brijesh; Gota, Vikram; Menon, Hari; Sengar, Manju; Nair, Reena; Patial, Pankaj; Banavali, S D

    2013-07-01

    Imatinib is the current gold standard for treatment of chronic myeloid leukemia (CML). Recent pharmacokinetic studies have shown considerable variability in trough concentrations of imatinib due to variations in its metabolism, poor compliance, or drug-drug interactions and highlighted its impact on clinical response. A trough level close to 1000 ng/mL, appears to be correlated with better cytogenetic and molecular responses. Therapeutic Drug Monitoring (TDM) for imatinib may provide useful added information on efficacy, safety and compliance than clinical assessment alone and help in clinical decision making. It may be particularly helpful in patients with suboptimal response to treatment or treatment failure, severe or rare adverse events, possible drug interactions, or suspected nonadherence. Further prospective studies are needed to confirm relationship between imatinib plasma concentrations with response, and to define effective plasma concentrations in different patient populations.

  8. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia

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    Saglio, Giuseppe; Kim, Dong-Wook; Issaragrisil, Surapol

    2010-01-01

    Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.......Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase....

  9. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Saglio, Giuseppe; Kim, Dong-Wook; Issaragrisil, Surapol

    2010-01-01

    Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase....

  10. First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib

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    Rafiyath Shamudheen

    2010-11-01

    Full Text Available Abstract Imatinib, a tyrosine kinase inhibitor (TKI of BCR-ABL, was the standard first-line therapy for chronic myeloid leukemia (CML for almost 10 years. Dasatinib and nilotinib, two newer drugs with higher potency than imatinib against BCR-ABL and activity against most imatinib-resistant BCR-ABL mutations, have each shown superior efficacy compared with imatinib for first-line treatment of chronic-phase CML in randomized phase 3 trials. With 14 months follow-up time, available data suggest no obvious differences in efficacy between dasatinib and nilotinib. Compared with imatinib, dasatinib is associated with higher rates of pleural effusion and thrombocytopenia, but lower rates of edema, gastrointestinal AEs, musculoskeletal AEs, and rash. Nilotinib is associated with higher rates of dermatologic toxicity, headache, and biochemical abnormalities associated with hepatic and pancreatic toxicity compared with imatinib, but lower rates of edema, gastrointestinal AEs, muscle spasm, and neutropenia. Several studies have shown that poor adherence to imatinib detrimentally affects responses and should be considered in patients with a suboptimal response. The different dosing requirements of dasatinib (once daily with or without food and nilotinib (twice daily with fasting may be an additional factor in selecting frontline agents. This review compares and contrasts the three FDA approved first line TKI agents.

  11. Chronic Myeloid Leukemia with Variant Chromosomal Translocations: Results of Treatment with Imatinib Mesylate

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    Rohan Bhise

    2013-01-01

    Full Text Available Objective: To evaluate the efficacy of imatinib in chronic myeloid leukemia patients with variant translocations. Methods: Forty eight chronic myeloid leukemia patients carrying variant translocations and treated with imatinib at our institute were considered for the study. Survival and response rates were evaluated. Results: The median follow up was 48 months(m. Forty three (89.58% patients achieved complete hematologic response. Thirty one (64.58% patients achieved complete cytogenetic response and 19(39.58% achieved major molecular response anytime during their follow up period. Only 18.75% of the patients achieved complete cytogenetic response and major molecular response within the stipulated time frames.The estimated overall survival at 48 m median follow up was 81.2%.The progression free survival was also 81.2% and the event free survival was 79.1%.There was no significant survival difference between low vs intermediate and high risk sokal group. Conclusion: We report suboptimal responses to imatinib in chronic myeloid leukemia with variant translocations. Further studies with imatinib and the newer more active drugs dasatinib and nilotinib are justified.

  12. Adherence to imatinib therapy in gastrointestinal stromal tumors and chronic myeloid leukemia.

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    Al-Barrak, Jasem; Cheung, Winson Y

    2013-08-01

    The number of anticancer drugs available in oral formulation has risen sharply in the past few years and this is expected to continue to increase over the next several decades. For patients, the convenience of self-administration constitutes a major benefit associated with oral therapy. For clinicians, however, the transition from parenteral to oral therapy has resulted in concerns about adherence to therapy, its monitoring, and its effects on clinical outcomes. Several studies have demonstrated that imatinib is effective at improving overall survival and/or recurrence-free survival in patients with gastrointestinal stromal tumors and chronic myeloid leukemia (primary and metastatic disease). Despite the survival benefit and the favorable toxicity profile of imatinib, however, adherence to imatinib remains poor. Herein, we review the evidence showing the effects of nonadherence on patient outcomes as well as data indicating that adherence to imatinib (and oral anticancer therapy in general) is suboptimal. We also highlight factors that may contribute to nonadherence and suggest key steps that can be implemented by the multidisciplinary medical team to overcome the daily challenges of adherence. Improving adherence to imatinib depends on open communication and comprehensive patient education. All of this is essential to maximize benefits from therapy and improve clinical outcomes for our patients.

  13. Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec®, Gleevec™

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    Martin Henkes

    2008-03-01

    Full Text Available 1Martin Henkes, 2Heiko van der Kuip, 1Walter E Aulitzky12nd Department of Internal Medicine, Oncology and Hematology, Robert Bosch Hospital, Auerbachstr. 110, Stuttgart, Germany; 2Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, Stuttgart, and University of Tuebingen, GermanyAbstract: Treatment options for chronic myeloid leukemia (CML have changed dramatically during the last decades. Interferon-α treatment and stem cell transplantation (SCT clearly improved survival over conventional chemotherapy and offered the possibility of complete and durable responses. With the advent of the small molecule inhibitor imatinib mesylate (Glivec®, GleevecTM targeting the causative Bcr-Abl oncoprotein, the era of molecular cancer therapy began with remarkable success especially in chronic phase patients. Today, imatinib is the first-line treatment for CML. However, imatinib does not appear to be capable to eliminate all leukemia cells in the patients and pre-existing as well as acquired resistance to the drug has been increasingly recognized. To overcome these problems, several strategies involving dose escalation, combinations with other agents, and novel Bcr-Abl inhibitors have been developed.Keywords: CML therapy, imatinib, SCT, novel kinase inhibitors

  14. Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia

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    Roberta Bitencourt

    2011-12-01

    Full Text Available The development of point mutations in the BCR-ABL kinase domain is the main reason for imatinib resistance in chronic myeloid leukemia. Different detection methods are used in chronic myeloid leukemia monitoring, such as direct sequencing, denaturing high performance liquid chromatography and allele specific polymerase chain reaction. Mutation analysis has become mandatory during patient workup of chronic myeloid leukemia in order for the physician to choose the most suitable tyrosine kinase inhibitor. This article, a review of possible therapies used to overcome imatinib resistance, investigates the current position by searching the PubMed electronic database using the following keywords: imatinib, dasatinib, nilotinib, aurora kinase, SRC kinase, mutation, treatment, drugs and resistance. New tyrosine kinase inhibitors include BCR-ABL kinase selective inhibitors, dual ABL/SRC kinase inhibitors and aurora kinase inhibitors. Awareness of the spectrum of new drugs against mutations, in particular the T315I mutation, makes it possible to properly select the best therapy for each patient.

  15. O tratamento da Leucemia Mielóide Crônica com mesilato de imatinibe Therapy of Chronic Myeloid Leukemia with imatinib mesylate

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    Vaneuza M. Funke

    2008-04-01

    Full Text Available O mesilato de imatinibe é atualmente o tratamento de escolha para pacientes com Leucemia mielóide Crônica (LMC recém-diagnosticados. Desde os primeiros estudos clínicos em 1998 até o estudo IRIS, que comparou o uso em primeira linha de imatinibe com interferon + ara-C, esta droga vem se consolidando em segurança e eficácia. Ainda há, entretanto questionamentos sobre a melhor dose inicial, a identificação dos pacientes que mais se beneficiariam e a melhor abordagem frente a respostas sub-ótimas e resistência. Os principais estudos clínicos publicados com mesilato de imatinibe são revisados no presente artigo, e discutidos sob a perspectiva da realidade brasileira.Imatinib mesylate is currently the gold-standard therapy for patients with newly diagnosed Chronic Myelogenous Leukemia. From the clinical trials in 1998 to the IRIS study, which compared first line imatinib treatment with interferon and low dose ara-C, this drug has been consolidated in regards to its safety and efficacy. There are still some questions to answer. Which would be the best initial dose? Are there any patients who benefit more than others? What is the best approach to suboptimal response and resistance? The most important published clinical studies are reviewed in the current article and discussed from a Brazilian perspective.

  16. Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells

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    Xing-Xiang Peng; Amit K. Tiwari; Hsiang-Chun Wu; Zhe-Sheng Chen

    2012-01-01

    Imatinib,a breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) tyrosine kinase inhibitor (TKI),has revolutionized the treatment of chronic myelogenous leukemia (CML).However,development of multidrug resistance(MDR) limits the use of imatinib.In the present study,we aimed to investigate the mechanisms of cellular resistance to imatinib in CML.Therefore,we established an imatinib-resistant human CML cell line (K562-imatinib) through a stepwise selection process.While characterizing the phenotype of these cells,we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells.In addition,these cells were cross-resistant to second- and third-generation BCR-ABL TKIs.Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein (P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells.In addition,accumulation of [14C]6-mercaptopurine (6-MP) was decreased,whereas the ATP-dependent efflux of [14C] 6-MP and [3H]methotrexate transport were increased in K562-imatinib cells.These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.

  17. In vitro effects of imatinib on CD34+ cells of patients with chronic myeloid leukemia in the megakaryocytic crisis phase

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    MENG, FANKAI; ZENG, WEN; HUANG, LIFANG; QIN, SHUANG; MIAO, NINGNING; SUN, HANYING; LI, CHUNRUI

    2014-01-01

    Imatinib is a tailored drug for the treatment of chronic myeloid leukemia (CML), and has substantial activity and a favorable safety profile when used as a single agent in patients with CML in myeloid blast crisis. The megakaryocytic blast crisis in CML occurs rarely and carries a poor prognosis. The aim of the present study was to investigate the effects of imatinib on cluster of differentiation (CD)34+ cells from patients with CML in the megakaryocytic crisis phase. Bone marrow mononuclear cells (BMNCs) were isolated from patients with CML in the megakaryocytic crisis phase. CD34+ cells were selected from BMNCs by positive immunomagnetic column separation. Imatinib significantly induced G1 arrest, reduced the phosphorylation of cyclin-dependent kinase 1 and retinoblastoma proteins and inhibited the proliferation of CD34+ cells from patients with CML in the megakaryocytic crisis phase. Annexin V/propidium iodide and caspase-3 activity showed that imatinib induced apoptosis. Western blot analysis and protein tyrosine kinase activity assays showed that imatinib inhibited BCR-ABL protein tyrosine kinase activity. The in vitro data thus markedly indicate a potential clinical application of imatinib for patients with CML in the megakaryocytic crisis phase. PMID:24527087

  18. In vitro effects of imatinib on CD34(+) cells of patients with chronic myeloid leukemia in the megakaryocytic crisis phase.

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    Meng, Fankai; Zeng, Wen; Huang, Lifang; Qin, Shuang; Miao, Ningning; Sun, Hanying; Li, Chunrui

    2014-03-01

    Imatinib is a tailored drug for the treatment of chronic myeloid leukemia (CML), and has substantial activity and a favorable safety profile when used as a single agent in patients with CML in myeloid blast crisis. The megakaryocytic blast crisis in CML occurs rarely and carries a poor prognosis. The aim of the present study was to investigate the effects of imatinib on cluster of differentiation (CD)34(+) cells from patients with CML in the megakaryocytic crisis phase. Bone marrow mononuclear cells (BMNCs) were isolated from patients with CML in the megakaryocytic crisis phase. CD34(+) cells were selected from BMNCs by positive immunomagnetic column separation. Imatinib significantly induced G1 arrest, reduced the phosphorylation of cyclin-dependent kinase 1 and retinoblastoma proteins and inhibited the proliferation of CD34(+) cells from patients with CML in the megakaryocytic crisis phase. Annexin V/propidium iodide and caspase-3 activity showed that imatinib induced apoptosis. Western blot analysis and protein tyrosine kinase activity assays showed that imatinib inhibited BCR-ABL protein tyrosine kinase activity. The in vitro data thus markedly indicate a potential clinical application of imatinib for patients with CML in the megakaryocytic crisis phase.

  19. Preliminary comparison of efficacy and safety of dasatinib and imatinib in newly diagnosed chronic myeloid leukemia

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    周励

    2013-01-01

    Objective To compare the efficacy and safety of dasatinib and imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia(CML-CP).Methods37CML-CP patients were randomized to receive

  20. Successful pregnancy in a patient with chronic myeloid leukemia under treatment with imatinib.

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    Tsuzuki, Motohiro; Inaguma, Youko; Handa, Kousuke; Hasegawa, Akio; Yamamoto, Yukiya; Watanabe, Masato; Mizuta, Syuichi; Maruyama, Fumio; Okamoto, Masataka; Emi, Nobuhiko

    2009-01-01

    Contraception is recommended during imatinib therapy based on the teratogenicity data in rats. However, patients may become pregnant and here we describe a successful pregnancy and labor without any congenital anomaly in a patient with chronic myeloid leukemia (CML) under treatment with imatinib. The patient had received imatinib for 53 months before she became pregnant, with a complete cytogenetic response achieved after 6 months of therapy and a major molecular response (MMR) after 28 months. CML was in MMR at discovery of pregnancy and the fetus had been exposed to imatinib for 5 weeks. Treatment was discontinued, but MMR persisted during gestation.

  1. Imatinib in the treatment of chronic myeloid leukemia: current perspectives on optimal dose

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    Waclaw J

    2015-09-01

    Full Text Available Joanna Waclaw,1 Tomasz Sacha,1 Tomasz Stoklosa,21Department of Hematology, Jagiellonian University Collegium Medicum, Kraków, 2Department of Immunology, Medical University of Warsaw, Warsaw, Poland Abstract: Imatinib was the first tyrosine kinase inhibitor (TKI, successfully used in a clinical setting. It inhibits activity of BCR-ABL1 oncogenic tyrosine kinase which is crucial in the pathogenesis of chronic myeloid leukemia (CML. The safety and efficacy of imatinib dose 400 mg daily was established in several clinical studies. Nevertheless, imatinib dose escalation (≥600 mg daily has been widely explored as an option to improve clinical outcomes. Results of the meta-analysis comparing frontline therapy with imatinib 400 mg daily vs high dose (HD, ≥600 mg daily in patients with chronic phase CML (CML-CP showed that the rate of complete cytogenetic response as well as major molecular response (MMR at 12 months was significantly higher in HD imatinib group. However, HD imatinib does not improve overall survival and progression-free survival. Thus, the routine use of HD imatinib as frontline treatment for CML-CP is not recommended. In patients with CML-CP resistant to standard dose, HD imatinib does not significantly improve patient outcomes without a prior cytogenetic response. Therefore, in second-line therapy, the current CML-CP treatment guidelines do not recommend imatinib dose escalation but the use of second-or third-generation TKIs. In the therapy of TKI-naïve patients with accelerated or blastic phase of CML, HD imatinib (400 mg twice daily is one of the recommended standards. In case of disease progression while on imatinib, second- or third-generation TKIs should be administered. Keywords: imatinib, standard dose, dose escalation, chronic myeloid leukemia, BCR-ABL1, high dose

  2. Imatinib-induced postoperative periorbital purpura: GASP (Gleevec-Associated Surgical Purpura) in a woman with imatinib-treated chronic myelogenous leukemia.

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    Anzalone, C Lane; Cohen, Philip R; Kurzrock, Razelle; Cortes, Jorge E

    2014-01-15

    Imatinib mesylate is a selective tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia. Ocular side effects of imatinib include periorbital edema, which may become so severe as to obstruct the visual field. The purpose of this case study is to describe the clinical characteristics of imatinib- induced postoperative periorbital purpura. We retrospectively reviewed the medical literature using PubMed, searching the terms edema, Gleevec, imatinib, periorbital, postoperative and purpura. Patient reports and previous reviews of the subject were critically assessed and the salient features are presented. Three patients have undergone surgery to reduce the imatinib-induced periorbital edema; two of these individuals have developed imatinib-induced postoperative periorbital purpura. We recommend discontinuing imatinib usage one week prior to periorbital surgery and not resuming therapy until the eighth postoperative day.

  3. An uneventful pregnancy and delivery, in a case with chronic myeloid leukemia on imatinib

    OpenAIRE

    2011-01-01

    The concomitant occurrence of pregnancy and chronic myelogenous leukemia is uncommon. We describe the successful management of a 24-year-old woman in the first trimester of her pregnancy with chronic myelogenous leukemia (CML) in the chronic phase, who was on treatment with imatinib, which was stopped by 10 th week of pregnancy. Until, she completed full term of pregnancy she was on hydroxyurea. The use of imatinib did not have adverse effects on the fetus. The patient had a normal vaginal de...

  4. Generalized lichenoid drug eruption associated with imatinib mesylate therapy

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    Sudip Kumar Ghosh

    2013-01-01

    Full Text Available Imatinib mesylate (IM, an anticancer drug, has been widely used to treat chronic myeloid leukemia (CML, gastrointestinal stromal tumors (GIST, and dermato-fibrosarcoma protuberans. Cutaneous reactions to IM have been reported to occur in varying number of patients in different case series. Non-lichenoid cutaneous reactions secondary to IM have been well-documented in the literature and are the commonest non-hematologic adverse reactions associated with its use. Lichenoid drug eruption (LDE associated with IM therapy has rarely been reported in the literature. A case of a generalized LDE associated with IM therapy has been described here for its rarity and interesting clinical presentation. As the clinical usage of IM is increasing, one might expect an increasing number of similar patients in the future. It is thus important to realize the potential of IM to produce LDE and to differentiate this entity from idiopathic lichen planus. In the present article, the reports of IM-associated LDE, described in the PubMed and Medline database (in English language literature, have also been reviewed.

  5. Generalized lichenoid drug eruption associated with imatinib mesylate therapy.

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    Ghosh, Sudip Kumar

    2013-09-01

    Imatinib mesylate (IM), an anticancer drug, has been widely used to treat chronic myeloid leukemia (CML), gastrointestinal stromal tumors (GIST), and dermato-fibrosarcoma protuberans. Cutaneous reactions to IM have been reported to occur in varying number of patients in different case series. Non-lichenoid cutaneous reactions secondary to IM have been well-documented in the literature and are the commonest non-hematologic adverse reactions associated with its use. Lichenoid drug eruption (LDE) associated with IM therapy has rarely been reported in the literature. A case of a generalized LDE associated with IM therapy has been described here for its rarity and interesting clinical presentation. As the clinical usage of IM is increasing, one might expect an increasing number of similar patients in the future. It is thus important to realize the potential of IM to produce LDE and to differentiate this entity from idiopathic lichen planus. In the present article, the reports of IM-associated LDE, described in the PubMed and Medline database (in English language literature), have also been reviewed.

  6. Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era.

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    Zafar Iqbal

    Full Text Available BACKGROUND: BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. METHODS: We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. RESULTS: Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48, all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. CONCLUSION: Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid

  7. Maternal, Fetal, and Neonatal Imatinib Levels With Treatment of Chronic Myeloid Leukemia in Pregnancy.

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    Burwick, Richard M; Kuo, Kelly; Brewer, Diana; Druker, Brian J

    2017-05-01

    Pregnant women with chronic myeloid leukemia (CML) can be treated effectively with the tyrosine-kinase inhibitor imatinib, but data regarding fetal and neonatal exposure and safety are limited. We present a patient with newly diagnosed CML in early pregnancy. Leukapheresis and interferon-α were initiated in the second trimester with limited benefit. Imatinib was subsequently started at 28 weeks of gestation with complete hematologic response within 4 weeks. No significant maternal or neonatal adverse effects were noted, but imatinib and its primary active metabolite concentrated in maternal breast milk and neonatal urine. Imatinib is effective for CML in pregnancy, but caution is warranted in light of potentially unrecognized fetal and neonatal effects.

  8. Drugs Approved for Leukemia

    Science.gov (United States)

    This page lists cancer drugs approved by the FDA for use in leukemia. The drug names link to NCI's Cancer Drug Information summaries. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  9. An uneventful pregnancy and delivery, in a case with chronic myeloid leukemia on imatinib.

    Science.gov (United States)

    Martin, Jovita; Ramesh, Anita; Devadasan, Lalitha; Palaniappan; Martin, Jude J

    2011-04-01

    The concomitant occurrence of pregnancy and chronic myelogenous leukemia is uncommon. We describe the successful management of a 24-year-old woman in the first trimester of her pregnancy with chronic myelogenous leukemia (CML) in the chronic phase, who was on treatment with imatinib, which was stopped by 10(th) week of pregnancy. Until, she completed full term of pregnancy she was on hydroxyurea. The use of imatinib did not have adverse effects on the fetus. The patient had a normal vaginal delivery and gave birth to a healthy 2500 g girl at 37 weeks of gestation. We conclude that imatinib in the first trimester of pregnant lady with CML, though has particular concern regarding the potential teratogenic and other adverse effects, has shown evidences of safe conception, pregnancy and delivery in ladies with CML.

  10. An uneventful pregnancy and delivery, in a case with chronic myeloid leukemia on imatinib

    Directory of Open Access Journals (Sweden)

    Jovita Martin

    2011-01-01

    Full Text Available The concomitant occurrence of pregnancy and chronic myelogenous leukemia is uncommon. We describe the successful management of a 24-year-old woman in the first trimester of her pregnancy with chronic myelogenous leukemia (CML in the chronic phase, who was on treatment with imatinib, which was stopped by 10 th week of pregnancy. Until, she completed full term of pregnancy she was on hydroxyurea. The use of imatinib did not have adverse effects on the fetus. The patient had a normal vaginal delivery and gave birth to a healthy 2500 g girl at 37 weeks of gestation. We conclude that imatinib in the first trimester of pregnant lady with CML, though has particular concern regarding the potential teratogenic and other adverse effects, has shown evidences of safe conception, pregnancy and delivery in ladies with CML.

  11. Philadelphia chromosome-positive mixed phenotype acute leukemia in the imatinib era.

    Science.gov (United States)

    Shimizu, Hiroaki; Yokohama, Akihiko; Hatsumi, Nahoko; Takada, Satoru; Handa, Hiroshi; Sakura, Toru; Nojima, Yoshihisa

    2014-10-01

    Although the introduction of imatinib dramatically improved the outcomes for patients with Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph + BCP-ALL), the survival benefit of imatinib has not been assessed in the context of Ph + mixed phenotype acute leukemia (Ph + MPAL). To clarify this important issue, we studied 42 Ph+ acute leukemia (Ph + AL) patients who received intensive chemotherapy and concurrent administration of imatinib. Of the 42 Ph + AL patients, 13 (31%) patients were categorized as Ph + MPAL (positive for both myeloid and B-cell lineage), 27 (64%) were categorized as Ph + BCP-ALL, and two (5%) were categorized as Ph + acute myeloid leukemia. The complete remission rates after the initial induction therapy were not significantly different when comparing Ph + MPAL and Ph + BCP-ALL patients (100% vs. 85%, respectively, P = 0.14). Likewise, there were no significant differences in the 5-yr overall survival (OS) or disease-free survival (DFS) rates when comparing the MPAL and BCP-ALL groups (OS: 55% vs. 53%, respectively, P = 0.87, DFS: 46% vs. 42%, respectively, P = 0.94). These findings suggest that concurrent imatinib administration with chemotherapy improved the outcomes of Ph + MPAL patients to the level seen in Ph+BCP-ALL patients and should, therefore, be considered as the standard therapy for these patients. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Twin pregnancy in a patient of chronic myeloid leukemia on imatinib therapy.

    Science.gov (United States)

    Meera, V; Jijina, Farah; Shrikande, Mitu; Madkaikar, Manisha; Ghosh, K

    2008-10-01

    Imatinib is a tyrosine kinase inhibitor and is now used regularly in chronic myeloid leukaemia therapy in chronic phase with great success. This drug due its very nature of action is suspected to be teratogenic hence the patients are counseled not to get pregnant while on this drug. However in world literature few normal pregnancies have been reported in patients on Imatinib therapy, though no twin pregnancy has been reported on this medication. We report here the birth of normal mono-ovular mono-chorionic twin while the patient is on imatinib during conception and early pregnancy for chronic myeloid leukaemia.

  13. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump

    NARCIS (Netherlands)

    H. Burger (Herman); H. van Tol; A.W.M. Boersma (Anton); M. Brok (Mariël); E.A.C. Wiemer (Erik); G. Stoter (Gerrit); K. Nooter (Kees)

    2004-01-01

    textabstractImatinib mesylate (STI571), a potent tyrosine kinase inhibitor, is successfully used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. However, the intended chronic oral administration of imatinib may lead to development of cellular

  14. Determination of serum levels of imatinib mesylate in patients with chronic myeloid leukemia: validation and application of a new analytical method to monitor treatment compliance.

    Science.gov (United States)

    Rezende, Vinícius Marcondes; Rivellis, Ariane Julio; Gomes, Melissa Medrano; Dörr, Felipe Augusto; Novaes, Mafalda Megumi Yoshinaga; Nardinelli, Luciana; Costa, Ariel Lais de Lima; Chamone, Dalton de Alencar Fisher; Bendit, Israel

    2013-01-01

    The goal of this study was to monitor imatinib mesylate therapeutically in the Tumor Biology Laboratory, Department of Hematology and Hemotherapy, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (USP). A simple and sensitive method to quantify imatinib and its metabolite (CGP74588) in human serum was developed and fully validated in order to monitor treatment compliance. The method used to quantify these compounds in serum included protein precipitation extraction followed by instrumental analysis using high performance liquid chromatography coupled with mass spectrometry. The method was validated for several parameters, including selectivity, precision, accuracy, recovery and linearity. The parameters evaluated during the validation stage exhibited satisfactory results based on the Food and Drug Administration and the Brazilian Health Surveillance Agency (ANVISA) guidelines for validating bioanalytical methods. These parameters also showed a linear correlation greater than 0.99 for the concentration range between 0.500 µg/mL and 10.0 µg/mL and a total analysis time of 13 minutes per sample. This study includes results (imatinib serum concentrations) for 308 samples from patients being treated with imatinib mesylate. The method developed in this study was successfully validated and is being efficiently used to measure imatinib concentrations in samples from chronic myeloid leukemia patients to check treatment compliance. The imatinib serum levels of patients achieving a major molecular response were significantly higher than those of patients who did not achieve this result. These results are thus consistent with published reports concerning other populations.

  15. Successful pregnancy outcome in a patient of chronic myeloid leukemia on imatinib therapy

    Directory of Open Access Journals (Sweden)

    Manisha Singhal

    2016-03-01

    Full Text Available Pregnancy and cancer is a complex situation. The coincidence chronic myeloid leukemia (CML and pregnancy is an uncommon event, in part because CML occurs mostly in older age group. The management of CML, during pregnancy is a difficult problem because of potential effects of therapy on the mother and foetus. Imatinib, a tyrosine kinase inhibitor induces dramatic hematologic and cytogenetic responses in CML, but it is not recommended for use in pregnancy or if the patient plans to conceive. In literature there are very few reports of successful outcome of pregnancy while on imatinib. In this report we describe a successful pregnancy and labor under treatment with imatinib in a known case of CML. [Int J Reprod Contracept Obstet Gynecol 2016; 5(3.000: 913-915

  16. Imatinib-induced decompensated heart failure in an elderly patient with chronic myeloid leukemia: case report and literature review

    Institute of Scientific and Technical Information of China (English)

    Hai-Hong Ran; Ran Zhang; Xue-Chun Lu; Bo Yang; Hui Fan; Hong-Li Zhu

    2012-01-01

    Because it is safe and well tolerated, imatinib is a standard first-line therapy for chronic myeloid leukemia (CML). Although there have been sporadic reports of imatinib-induced cardiotoxicity, including left ventricle (LV) dysfunction and heart failure, the evidence for it is contradictory. Here, we reported a case of an 88-year-old male patient with CML developed decompensated heart failure following imatinib therapy. Four days after the initiation of imatinib, the patient developed orthopnea, edema and a pleural effusion accompanied by abdominal distension, nausea and vomiting. The chest X-ray film showed an enlarged cardiac profile. The echocardiogram demonstrated a decreased LV ejection fraction and enlarged left-side cardiac chambers. B-type natriuretic peptide concentrations were markedly increased. The patient recovered soon after the withdrawal of imatinib and introduction of comprehensive therapy for heart failure. Imatinib-induced cardiotoxicity in elderly patients is a potentially serious complication that merits further evaluation.

  17. Influence of late treatment on how chronic myeloid leukemia responds to imatinib

    Directory of Open Access Journals (Sweden)

    Ana Carolina Costa Scerni

    2009-01-01

    Full Text Available INTRODUCTION: In Brazil, patients with chronic myeloid leukemia (CML in the chronic phase were not given first-line imatinib treatment until 2008. Therefore, there was a long period of time between diagnosis and the initiation of imatinib therapy for many patients. This study aims to compare the major molecular remission (MMR rates of early versus late imatinib therapy in chronic phase CML patients. METHODS: Between May 2002 and November 2007, 44 patients with chronic phase CML were treated with second-line imatinib therapy at the Hematology Unit of the Ophir Loyola Hospital (Belém, Pará, Brazil. BCR-ABL transcript levels were measured at approximately six-month intervals using quantitative polymerase chain reaction. RESULTS: The early treatment group presented a 60% probability of achieving MMR, while the probability for those patients who received late treatment was 40%. The probability of either not achieving MMR within one year of the initiation of imatinib therapy or losing MMR was higher in patients who received late treatment (79%, compared with patients who received early treatment (21%, odds ratio=5.75, P=0.012. The probability of maintaining MMR at 30 months of treatment was 80% in the early treatment group and 44% in the late treatment group (P=0.0005. CONCLUSIONS: For CML patients in the chronic phase who were treated with second-line imatinib therapy, the probability of achieving and maintaining MMR was higher in patients who received early treatment compared with those patients for whom the time interval between diagnosis and initiation of imatinib therapy was longer than one year.

  18. Nilotinib and imatinib are comparably effective in reducing growth of human eosinophil leukemia cells in a newly established xenograft model.

    Directory of Open Access Journals (Sweden)

    Daniel Wicklein

    Full Text Available We developed a xenograft model of human Chronic Eosinophilic Leukemia (CEL to study disease progression and remission-induction under therapy with tyrosine kinase inhibitors using imatinib and nilotinib as examples. The FIP1L1/PDGFRA+ human CEL cell lineEOL-1 was injected intravenously into scid mice, and MR imaging and FACS analysis of mouse blood samples were performed to monitor disease development and the effects of imatinib and nilotinib. Organ infiltration was analyzed in detail by immunohistochemistry after sacrifice. All animals developed CEL and within one week of therapy, complete remissions were seen with both imatinib and nilotinib, resulting in reduced total tumor volumes by MR-imaging and almost complete disappearance of EOL-1 cells in the peripheral blood and in tissues. The new model system is feasible for the evaluation of new tyrosine kinase inhibitors and our data suggest that nilotinib may be a valuable additional targeted drug active in patients with FIP1L1/PDGFRA+ CEL.

  19. Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital

    Directory of Open Access Journals (Sweden)

    Samuel Roosevelt Campos dos Reis

    2013-06-01

    Full Text Available Objetive: The aim of this study was to identify the reasons for failure in adherence to imatinib mesylate treatment in chronic myeloid leukemia. Methods: A retrospective review was performed of 100 non-electronic records of patients with Ph+ chronic myeloid leukemia treated with imatinib mesylate. The study period was from January 2001 to January2011. Data were analyzed by Chi-Square and Correspondence analysis using the Statistical Analysis System software package. Results: At the beginning of treatment 41% of patients were in advanced stages of the disease. The unavailability of the drug (44.8% and myelotoxicity (25.7% were the most frequent reasons for interruption. The adherence rate was 95% induced complete cytogenetic response, major cytogenetic response and major molecular response. Conclusion: The population of this study obtained lower-than-expected therapeutic responses compared to other studies.

  20. The in-vitro antiproliferative effect of PRI-2191 and imatinib applied in combined treatment with cisplatin, idarubicin, or docetaxel on human leukemia cells.

    Science.gov (United States)

    Switalska, Marta; Nasulewicz-Goldeman, Anna; Opolska, Aleksandra; Maciejewska, Magdalena; Kutner, Andrzej; Wietrzyk, Joanna

    2012-01-01

    Imatinib mesylate (Gleevec, STI571) is a specific inhibitor of the Bcr/Abl fusion tyrosine kinase that exhibits potent antileukemic effects in chronic myelogenous leukemia. Bcr/Abl-positive K562 and Bcr/Abl-negative HL-60 human leukemia cells were used to investigate the effect of PRI-2191, a calcitriol analog, on the biological effects of imatinib combined with other anticancer drugs. The results show that PRI-2191 enhances the antiproliferative effect of imatinib on HL-60 cells. When these two agents together are applied with either docetaxel or cisplatin, but not with idarubicin, the antiproliferative effect could still be enhanced. Moreover, when the interaction between the chemotherapy agents was antagonistic or additive, PRI-2191 could even shift it to synergism. This effect correlated with an accumulation of HL-60 cells in the G0/G1 phase of the cell cycle and a decrease in the percentage of cells in the G2/M and S stage in the ternary combinations used. PRI-2191 did not influence apoptosis induced by imatinib alone or in ternary combinations with all the chemotherapy agents used. These results may suggest that the stronger antiproliferative effect of the combined treatment with PRI-2191 on HL-60 cells is related to cell cycle arrest rather than to the induction of apoptosis.

  1. Platelet Dysfunction in Patients with Chronic Myeloid Leukemia: Does Imatinib Mesylate Improve It?

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    Olga Meltem Akay

    2016-05-01

    Full Text Available Objective: The aim of this study was to investigate the effects of imatinib mesylate on platelet aggregation and adenosine triphosphate (ATP release in chronic myeloid leukemia patients. Materials and Methods: Platelet aggregation and ATP release induced by 5.0 mM adenosine diphosphate, 0.5 mM arachidonic acid, 1.0 mg/ mL ristocetin, and 2 µg/mL collagen were studied by whole blood platelet lumi-aggregometer in 20 newly diagnosed chronic myeloid leukemia patients before and after imatinib mesylate treatment. Results: At the time of diagnosis, 17/20 patients had abnormal platelet aggregation results; 8 (40% had hypoactivity, 6 (30% had hyperactivity, and 3 (15% had mixed hypo- and hyperactivity. Repeat platelet aggregation studies were performed after a mean of 19 months (min: 5 months-max: 35 months in all patients who received imatinib mesylate during this period. After therapy, 18/20 (90% patients had abnormal laboratory results; 12 (60% had hypoactive platelets, 4 (20% had mixed hypo- and hyperactive platelets, and 2 (10% had hyperactive platelets. Three of the 8 patients with initial hypoactivity remained hypoactive, while 2 developed a mixed picture, 2 became hyperactive, and 1 normalized. Of the 6 patients with initial hyperactivity, 4 became hypoactive and 2 developed a mixed pattern. All of the 3 patients with initial hypo- and hyperactivity became hypoactive. Finally, 2 of the 3 patients with initial normal platelets became hypoactive while 1 remained normal. There was a significant decrease in ristocetin-induced platelet aggregation after therapy (p0.05. Conclusion: These findings indicate that a significant proportion of chronic myeloid leukemia patients have different patterns of platelet function abnormalities and imatinib mesylate has no effect on these abnormalities, with a significant impairment in ristocetin-induced platelet aggregation.

  2. Integrative genomic analysis in K562 chronic myelogenous leukemia cells reveals that proximal NCOR1 binding positively regulates genes that govern erythroid differentiation and Imatinib sensitivity.

    Science.gov (United States)

    Long, Mark D; van den Berg, Patrick R; Russell, James L; Singh, Prashant K; Battaglia, Sebastiano; Campbell, Moray J

    2015-09-01

    To define the functions of NCOR1 we developed an integrative analysis that combined ENCODE and NCI-60 data, followed by in vitro validation. NCOR1 and H3K9me3 ChIP-Seq, FAIRE-seq and DNA CpG methylation interactions were related to gene expression using bootstrapping approaches. Most NCOR1 combinations (24/44) were associated with significantly elevated level expression of protein coding genes and only very few combinations related to gene repression. DAVID's biological process annotation revealed that elevated gene expression was uniquely associated with acetylation and ETS binding. A matrix of gene and drug interactions built on NCI-60 data identified that Imatinib significantly targeted the NCOR1 governed transcriptome. Stable knockdown of NCOR1 in K562 cells slowed growth and significantly repressed genes associated with NCOR1 cistrome, again, with the GO terms acetylation and ETS binding, and significantly dampened sensitivity to Imatinib-induced erythroid differentiation. Mining public microarray data revealed that NCOR1-targeted genes were significantly enriched in Imatinib response gene signatures in cell lines and chronic myelogenous leukemia (CML) patients. These approaches integrated cistrome, transcriptome and drug sensitivity relationships to reveal that NCOR1 function is surprisingly most associated with elevated gene expression, and that these targets, both in CML cell lines and patients, associate with sensitivity to Imatinib.

  3. Determination of serum levels of imatinib mesylate in patients with chronic myeloid leukemia: validation and application of a new analytical method to monitor treatment compliance

    Directory of Open Access Journals (Sweden)

    Vinícius Marcondes Rezende

    2013-01-01

    Full Text Available OBJECTIVE: The goal of this study was to monitor imatinib mesylate therapeutically in the Tumor Biology Laboratory, Department of Hematology and Hemotherapy, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (USP. A simple and sensitive method to quantify imatinib and its metabolite (CGP74588 in human serum was developed and fully validated in order to monitor treatment compliance. METHODS: The method used to quantify these compounds in serum included protein precipitation extraction followed by instrumental analysis using high performance liquid chromatography coupled with mass spectrometry. The method was validated for several parameters, including selectivity, precision, accuracy, recovery and linearity. RESULTS: The parameters evaluated during the validation stage exhibited satisfactory results based on the Food and Drug Administration and the Brazilian Health Surveillance Agency (ANVISA guidelines for validating bioanalytical methods. These parameters also showed a linear correlation greater than 0.99 for the concentration range between 0.500 µg/mL and 10.0 µg/mL and a total analysis time of 13 minutes per sample. This study includes results (imatinib serum concentrations for 308 samples from patients being treated with imatinib mesylate. CONCLUSION: The method developed in this study was successfully validated and is being efficiently used to measure imatinib concentrations in samples from chronic myeloid leukemia patients to check treatment compliance. The imatinib serum levels of patients achieving a major molecular response were significantly higher than those of patients who did not achieve this result. These results are thus consistent with published reports concerning other populations.

  4. Evaluation of the Safety of Imatinib Mesylate in 200 Iraqi Patients with Chronic Myeloid Leukemia in the Chronic Phase: Single-Center Study

    Directory of Open Access Journals (Sweden)

    Bassam Francis Matti

    2013-12-01

    Full Text Available OBJECTIVE: Imatinib mesylate, a tyrosine kinase inhibitor, is presently the drug of choice for chronic myeloid leukemia (CML. During therapy, a few patients may develop hematological and non-hematological adverse effects. METHODS: The aim of this study was to evaluate the safety of imatinib therapy in patients with CML. Between December 2007 and October 2009 two hundred patients with CML in chronic phase were included in the study. Written informed consent was obtained from all patients prior to the start of the study. Imatinib was started at 400 mg orally daily. Patients were monitored carefully for any adverse effects. Complete blood count, liver, and renal function tests were done once in 2 weeks during the first month and on a monthly basis during follow-up. Toxicities that encountered were graded as per the National Cancer Institute common toxicity criteria version 2. Both hematologic and non-hematologic toxicities were managed with short interruptions of treatment and supportive measures, but the daily dose of imatinib was not reduced below 300 mg/day. RESULTS: Two hundred CML patients in chronic phase were included in this study; the male: female ratio was 0.7: 1 with mean age 39.06±13.21 years (ranged from 15-81 years. The study showed that the commonest hematological side effects were grade 2 anemia (12.5% followed by leukopenia (8% and thrombocytopenia (4%, while the most common non-hematological adverse effects were superficial edema and weight gain (51.5%, followed by musculoskeletal pain (35.5%, then gastro-intestinal symptoms (vomiting, diarrhea (19%. Fluid retention was the commonest side effect, which responded to low-dose diuretics. The drug was safe and well tolerated. There were no deaths due to toxicity. CONCLUSION: Imatinib mesylate a well-tolerated drug, and all undesirable effects could be ameliorated easily. The most common hematological and non-hematological side effects were anemia and fluid retention, respectively.

  5. Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

    Science.gov (United States)

    Wassmann, Barbara; Pfeifer, Heike; Stadler, Michael; Bornhaüser, Martin; Bug, Gesine; Scheuring, Urban J; Brück, Patrick; Stelljes, Matthias; Schwerdtfeger, Rainer; Basara, Nadezda; Perz, Jolanta; Bunjes, Donald; Ledderose, Georg; Mahlberg, Rolf; Binckebanck, Anja; Gschaidmeier, Harald; Hoelzer, Dieter; Ottmann, Oliver G

    2005-07-15

    In adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), minimal residual disease (MRD) after stem cell transplantation (SCT) is associated with a relapse probability exceeding 90%. Starting imatinib in the setting of MRD may decrease this high relapse rate. In this prospective multicenter study, 27 Ph+ ALL patients received imatinib upon detection of MRD after SCT. Bcr-abl transcripts became undetectable in 14 (52%) of 27 patients, after a median of 1.5 months (0.9-3.7 months) ((early)CR(mol)). All patients who achieved an (early)CR(mol) remained in remission for the duration of imatinib treatment; 3 patients relapsed after imatinib was discontinued. Failure to achieve polymerase chain reaction (PCR) negativity shortly after starting imatinib predicted relapse, which occurred in 12 (92%) of 13 patients after a median of 3 months. Disease-free survival (DFS) in (early)CR(mol) patients is 91% +/- 9% and 54% +/- 21% after 12 and 24 months, respectively, compared with 8% +/- 7% after 12 months in patients remaining MRD+ (P < .001). In conclusion, approximately half of patients with Ph+ ALL receiving imatinib for MRD positivity after SCT experience prolonged DFS, which can be anticipated by the rapid achievement of a molecular complete remission (CR). Continued detection of bcr-abl transcripts after 2 to 3 months on imatinib identifies patients who will ultimately experience relapse and in whom additional or alternative antileukemic treatment should be initiated.

  6. Aurora kinase inhibitors: which role in the treatment of chronic myelogenous leukemia patients resistant to imatinib?

    Directory of Open Access Journals (Sweden)

    Giovanni Martinelli

    2009-02-01

    Full Text Available At present, there are no compounds in clinical development in the field of chronic myeloid leukemia (CML or Philadelphia-positive (Ph+ acute lymphoblastic leukemia (ALL that have been documented to harbor significant activity against the imatinib-resistant T315I mutation. Recent reports on the pre-clinical activity of some emerging tyrosine kinase inhibitors such as ON012380, VX-680 and PHA-739358 promise possible clinical efficacy against this specific Bcr-Abl mutant form. Here, we focus on the role of aurora kinase inhibitor VX-680 and PHA-739358 in blocking the leukemogenic pathways driven by wild-type and T315I-Bcr-Abl in CML or Ph+ ALL by reviewing recent research evidence. We also discuss the possibility of employing aurora kinase inhibitors as a promising new therapeutic approach in the treatment of CML and Ph+ ALL patients resistant to first and second generation TK inhibitors.

  7. Chronic myeloid leukemia with pregnancy: Successful management of pregnancy and delivery with hydroxyurea and imatinib continued till delivery

    Directory of Open Access Journals (Sweden)

    Usha Yadav

    2013-01-01

    Full Text Available The concomitant occurrence of pregnancy and chronic myeloid leukemia is uncommon. We describe the successful management of a 30-year-old G3 P0, A2 woman who was diagnosed to have chronic myelogenous leukemia (CML in the third trimester of her pregnancy with intra-uterine growth retardation and oligohydroamnios. She was started on hydroxyurea and imatinib, and was continued till delivery and beyond. The use of imatinib did not have any adverse effects on the fetus, except for low birth weight and low APGAR at birth, but the later progress of the child was normal. We conclude that imatinib and hydroxyurea can be continued even at the third trimester in a pregnant lady with CML, if necessary.

  8. Chronic myeloid leukemia with pregnancy: Successful management of pregnancy and delivery with hydroxyurea and imatinib continued till delivery.

    Science.gov (United States)

    Yadav, Usha; Solanki, Sohan Lal; Yadav, Rupesh

    2013-01-01

    The concomitant occurrence of pregnancy and chronic myeloid leukemia is uncommon. We describe the successful management of a 30-year-old G3 P0, A2 woman who was diagnosed to have chronic myelogenous leukemia (CML) in the third trimester of her pregnancy with intra-uterine growth retardation and oligohydroamnios. She was started on hydroxyurea and imatinib, and was continued till delivery and beyond. The use of imatinib did not have any adverse effects on the fetus, except for low birth weight and low APGAR at birth, but the later progress of the child was normal. We conclude that imatinib and hydroxyurea can be continued even at the third trimester in a pregnant lady with CML, if necessary.

  9. Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia

    NARCIS (Netherlands)

    Deenik, W.; van der Holt, B.; Verhoef, G.E.G.; Smit, W.M.; Kersten, M.J.; Kluin-Nelemans, Hanneke; Verdonck, L.F.; Ferrant, A.; Schattenberg, A.V.M.B.; Janssen, J.J.W.M.; Sonneveld, P.; Kooy, M.V.; Wittebol, S.; Willemze, R.; Wijermans, P.W.; Westveer, P.H.M.; Beverloo, H.B.; Valk, P.; Lowenberg, B.; Ossenkoppele, G.J.; Cornelissen, J.J.

    2008-01-01

    The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1-7) in conjunction with im

  10. 伊马替尼耐药或不耐受的 CML 患者更换二代 TKI治疗的疗效观察及相关因素分析%The curative effect observation and relevant factors analysis of the second generation TKI drugs after imatinib resistance or intolerance in chronic myeloid leukemia patients

    Institute of Scientific and Technical Information of China (English)

    安福润; 杨明珍; 曾庆曙; 王永庆; 葛健; 王霖; 阮敏; 陈莹莹; 顾悦

    2015-01-01

    Objective To observe the curative effect of second generation TKI drugs and analyze the influence of relevant factors in chronic myeloid leukemia (CML) patients with imatinib resistance or intolerance. Methods The patients with Imatinib resistance or intolerance and had switched to the second generation TKI drugs, were se-lected randomly 25 each group. Then, monitored their BCR/ ABL fusion gene quantitative results in the 3rd month or 6th month, analyzed the relationship between achieving BCR/ ABL≤10% within 6 months and relevant factors, including the reason, phase and hematologic remission status while changing drug, and the adherence after the changing. Results There were 16 imatinib resistance patients (41. 0% ) and 9 Imatinib intolerance patients (81. 8% ) who had achieved BCR/ ABL≤10% within 6 months after changing. There were 23 patients(76. 7% ) in chronic phase (CP) and 2 patients(10. 0% ) in advanced phase(blastic phase BP or accelerated phase AP) while changing, who had achieved BCR/ ABL≤10% within 6 months. 16 patients(72. 7% ) had changed drug with complete hematologic remission (CHR) and 9 patients(32. 1% ) without CHR, then achieved BCR/ ABL≤10% within 6 months. 23 patients(74. 2% ) with good adherence of the second generation TKI drugs and 2 patients (10. 5% ) with bad adherence, had achieved BCR/ ABL≤10% within 6 months. Conclusion There is a certain effect on imatinib-resistant or intolerant CML patients who have switched to second-generation TKI drugs. And the difference between the efficacy of these two second-generation TKI drugs (Dasatinib, Nilotinib) is not statistically significant. The imatinib intolerance patients get better effect than the imatinib resistance patients. The patients in CP get better effect than the patients in advanced phase, while changing drug, the patients with CHR get better effect than the patients without CHR. The patients with good adherence of the second generation TKI drugs get bet-ter effect than the

  11. Lack of non-hematological cross intolerance of dasatinib to imatinib in imatinib-intolerant patients with Philadelphia chromosome positive chronic myeloid leukemia or acute lymphatic leukemia: a retrospective safety analysis.

    Science.gov (United States)

    Kobayashi, Yukio; Sakamaki, Hisashi; Fujisawa, Shin; Ando, Kiyoshi; Yamamoto, Kazuhito; Okada, Masaya; Ishizawa, Kenichi; Nagai, Tadashi; Miyawaki, Syuichi; Motoji, Toshiko; Usui, Noriko; Iida, Shinsuke; Taniwaki, Masafumi; Uoshima, Nobuhiko; Seriu, Taku; Ohno, Ryuzo

    2011-06-01

    The aim of this retrospective study was to evaluate the toxicity profiles of dasatinib in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) or acute lymphatic leukemia (ALL) who were intolerant to imatinib, and who had been enrolled in our previous clinical trials to evaluate efficacy of dasatinib in patients resistant or tolerant to imatinib therapy. Twenty-four patients with CML and four with ALL were enrolled in the clinical studies to evaluate the efficacy according to the eligibility criteria related to intolerance to imatinib therapy. The toxicities reported during imatinib therapy were non-hematological toxicities in 23 patients and hematological toxicities in six patients. Patients were administered dasatinib 50-70 mg BID or 100 mg QD. Cross intolerance was observed in four patients who showed hematological toxicity after dasatinib treatment. However, it was possible to successfully continue therapy with only temporary interruption. No cross intolerance in non-hematological toxicity was found with the exception of one patient who showed cross intolerance, which did not result in treatment interruption. Dasatinib can be safely administered to imatinib-intolerant CML or Ph-positive ALL patients.

  12. Leucemia Mielóide Crônica: causas de falha do tratamento com mesilato de imatinibe Chronic Myeloid Leukemia: causes of treatment failure with imatinib

    Directory of Open Access Journals (Sweden)

    Katia B. B. Pagnano

    2008-04-01

    Full Text Available O mesilato de imatinibe (MI é atualmente o tratamento de escolha da Leucemoa Mielóide Crônica (LMC, mas, apesar dos excelentes resultados, não é capaz de erradicar completamente a doença, podendo ocorrer resistência ao tratamento. O mecanismo mais conhecido de resistência é o desenvolvimento de mutações do BCR-ABL, que impedem a ação ligação adequada do imatinibe à quinase, além de amplificação gênica e evolução clonal. No entanto, há uma série de outros mecanismos envolvidos e ainda pouco estudados, como alterações na absorção, efluxo e influxo de droga para o interior das células. Devem-se também considerar outros fatores, como aderência ao tratamento e uso de medicamentos concomitantes que podem interferir com imatinibe, diminuindo sua ação. O entendimento desses mecanismos poderá contribuir no desenvolvimento de novas estratégias para o tratamento dos casos resistentes.Imatinib is currently the treatment of choice of CML, but despite of the excellent results, it is not able to completely eradicate the disease and resistance may occur. The most studied mechanism is the presence of ABL kinase mutations that interfere with imatinib binding and action, gene amplification and clonal evolution. However, there are other mechanisms involved and less studied such as drug absorption and influx and efflux of imatinib. Besides the true causes of resistance, compliance is always a concern and also drug interaction should be checked. An understanding of these mechanisms will certainly contribute to develop new strategies for the treatment of resistant cases.

  13. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remissio...

  14. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit;

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-a may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission...

  15. Imatinib treatment induces CD5+ B lymphocytes and IgM natural antibodies with anti-leukemic reactivity in patients with chronic myelogenous leukemia.

    Directory of Open Access Journals (Sweden)

    Silvia Catellani

    Full Text Available Imatinib mesylate is a first line treatment of Chronic Myelogenous Leukemia and of a rare form of gastrointestinal stromal cancer, where the response to the drug is also linked to the immune system activation with production of antineoplastic cytokines. In this study, forty patients in the chronic phase of disease, treated with imatinib mesylate, were analyzed. Bone marrow aspirates were drawn at diagnosis, after 3, 6, 12, 18 months for haematological, cytofluorimetric, cytogenetic, biomolecular evaluation and cytokine measurement. Responder and non responder patients were defined according to the European LeukemiaNet recommendations. In responder patients (n = 32, the percentage of bone marrow CD20(+CD5(+sIgM(+ lymphocytes, and the plasma levels of IgM, were significantly higher, at 3 months and up to 9 months, than in non responders. These IgM reacted with O-linked sugars expressed by leukemic cells and could induce tumor cell apoptosis. In responder patients the stromal-derived factor-1 and the B-lymphocyte-activating factor of the tumor necrosis factor family significantly raised in the bone marrow after imatinib administration, together with the bone morphogenetic proteins-2 and -7. All patients with high number of CD20(+CD5(+sIgM(+ cells and high stromal-derived factor-1 and B lymphocyte activating factor levels, underwent complete cytogenetic and/or molecular remission by 12 months. We propose that CD20(+CD5(+sIgM(+ lymphocytes producing anti-carbohydrate antibodies with anti-tumor activity, might contribute to the response to imatinib treatment. As in multivariate analysis bone marrow CD20(+CD5(+sIgM(+ cells and stromal-derived factor-1 and B-lymphocyte-activating factor levels were significantly related to cytogenetical and molecular changes, they might contribute to the definition of the pharmacological response.

  16. A phase I study of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients.

    Science.gov (United States)

    Hebb, Jonathan; Assouline, Sarit; Rousseau, Caroline; Desjardins, Pierre; Caplan, Stephen; Egorin, Merrill J; Amrein, Lilian; Aloyz, Raquel; Panasci, Lawrence

    2011-09-01

    The tyrosine kinase inhibitor, imatinib, has the potential to indirectly inhibit DNA repair. This mechanism of action has been shown to mediate sensitization to chlorambucil in chronic lymphocytic leukemia (CLL). To evaluate this effect in vivo, we performed a phase I study of chlorambucil combined with imatinib in relapsed CLL patients. The three dose levels studied included imatinib at 300, 400, or 600 mg/day. Imatinib was given on days 1-10, and chlorambucil (8 mg/m(2) daily) was given on days 3-7 of a 28-day cycle (up to 6 cycles). Eleven patients participated in this study. Low-grade gastrointestinal toxicities were observed in a dose-dependent manner. Forty-five percent of patients responded (two unconfirmed CRs and three PRs). Two responding patients were fludarabine refractory. The in vitro IC(50) of chlorambucil alone or in the presence of 5 μM imatinib in CLL lymphocytes correlated with the decrease in lymphocyte counts on day 15. Imatinib plasma concentrations achieved in patients were in the range of those effective in in vitro sensitization studies. The combination of chlorambucil and imatinib in patients with previously treated CLL was well tolerated and showed evidence of clinical efficacy. Based on our results, we recommend the 400 mg daily dose of imatinib on days 1-10 with 8 mg/m(3) chlorambucil on days 3-7 every 28 days as the phase II dose. This represents the first clinical trial examining the potential synergy between a tyrosine kinase inhibitor and a conventional alkylating agent for the treatment of CLL.

  17. Pregnancy and Accelerated Phase of Myeloid Chronic Leukemia Treated with Imatinib: A Case Report from a Developing Country.

    Science.gov (United States)

    Ngolet, Lydie Ocini; Kocko, Innocent; Elira Dokekias, Alexis

    2016-01-01

    Background. Chronic myeloid leukemia is a hematological malignancy caused by expression of BCR-ABL tyrosine kinase oncogene, product of the t(9;22) Philadelphia translocation. Accelerated phase of this disease marks the onset of advanced rapidly progressive disease unresponsive to many therapies. Pregnancy limits broad number of therapies on patients because of their potential teratogenic effects. We report the case of a pregnant 34-year-old patient on accelerated phase successively managed by imatinib. She achieved a safe pregnancy and delivered at 39 weeks a healthy baby without congenital abnormalities. Our case is unusual because of the accelerated phase of the disease. Case Presentation. A 34-year-old African female with history of chronic phase of myeloid leukemia on imatinib, lost to follow-up for 4 months, presented to the hematological department for abdominal discomfort. Accelerated phase of chronic myeloid leukemia was diagnosed. Complete hematological response was achieved on high doses of imatinib. At the completion of 39 weeks, she delivered a healthy child without congenital anomalies. Conclusion. Despite its teratogenic and embryotoxic effects, front line imatinib is the only effective, well-tolerated treatment for patient on accelerated phase that can be offered to patients in sub-Saharan countries.

  18. Pregnancy and Accelerated Phase of Myeloid Chronic Leukemia Treated with Imatinib: A Case Report from a Developing Country

    Directory of Open Access Journals (Sweden)

    Lydie Ocini Ngolet

    2016-01-01

    Full Text Available Background. Chronic myeloid leukemia is a hematological malignancy caused by expression of BCR-ABL tyrosine kinase oncogene, product of the t(9;22 Philadelphia translocation. Accelerated phase of this disease marks the onset of advanced rapidly progressive disease unresponsive to many therapies. Pregnancy limits broad number of therapies on patients because of their potential teratogenic effects. We report the case of a pregnant 34-year-old patient on accelerated phase successively managed by imatinib. She achieved a safe pregnancy and delivered at 39 weeks a healthy baby without congenital abnormalities. Our case is unusual because of the accelerated phase of the disease. Case Presentation. A 34-year-old African female with history of chronic phase of myeloid leukemia on imatinib, lost to follow-up for 4 months, presented to the hematological department for abdominal discomfort. Accelerated phase of chronic myeloid leukemia was diagnosed. Complete hematological response was achieved on high doses of imatinib. At the completion of 39 weeks, she delivered a healthy child without congenital anomalies. Conclusion. Despite its teratogenic and embryotoxic effects, front line imatinib is the only effective, well-tolerated treatment for patient on accelerated phase that can be offered to patients in sub-Saharan countries.

  19. Lichenoid drug eruption caused by imatinib mesylate in a Chinese patient with gastrointestinal stromal tumor.

    Science.gov (United States)

    Luo, Jing-Ru; Xiang, Xiao-Jun; Xiong, Jian-Ping

    2016-09-01

    Imatinib mesylate, the first agent approved for the treatment of unresectable or metastatic gastrointestinal stromal tumor, is a tyrosine kinase inhibitor targeting (KIT) and the platelet-derived growth factor receptor-α and -β. However, imatinib administration can be accompanied by various adverse events. Here we report a case of Lichenoid drug eruption (LDE) that appeared 24 weeks after commencement of imatinib in a 73-year-old man with gastrointestinal stromal tumor (GIST). The skin lesions were distributed over his face, trunk and limbs, which improved only after discontinuation of imatinib therapy. To the best of our knowledge, this is the first report of imatinib-induced LDE in the Chinese population.

  20. New HPLC-MS method for the simultaneous quantification of the antileukemia drugs imatinib, dasatinib, and nilotinib in human plasma.

    Science.gov (United States)

    De Francia, Silvia; D'Avolio, Antonio; De Martino, Francesca; Pirro, Elisa; Baietto, Lorena; Siccardi, Marco; Simiele, Marco; Racca, Silvia; Saglio, Giuseppe; Di Carlo, Francesco; Di Perri, Giovanni

    2009-06-15

    A new method using high performance liquid chromatography coupled with electrospray mass spectrometry is described for the quantification of plasma concentration of tyrosine kinase inhibitors imatinib, dasatinib and nilotinib. A simple protein precipitation extraction procedure was applied on 250 microl of plasma aliquots. Chromatographic separation of drugs and Internal Standard (quinoxaline) was achieved with a gradient (acetonitrile and water + formic acid 0.05%) on a C18 reverse phase analytical column with 20min of analytical run, at flow rate of 1 ml/min. Mean intra-day and inter-day precision for all compounds were 4.3 and 11.4%; mean accuracy was 1.5%; extraction recovery ranged within 95 and 114%. Calibration curves ranged from 10,000 to 62.5 ng/ml. The limit of quantification was set at 78.1 ng/ml for imatinib and at 62.5 ng/ml for dasatinib and nilotinib. This novel developed methodology allows a specific, sensitive and reliable simultaneous determination of the three tyrosine kinase inhibitors imatinib, dasatinib and nilotinib in a single chromatographic run, useful for drugs estimation in plasma of patients affected by chronic myeloid leukemia.

  1. Increased peroxisome proliferator-activated receptor-gamma activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells.

    Science.gov (United States)

    Wang, Jueqiong; Lu, Liu; Kok, Chung H; Saunders, Verity A; Goyne, Jarrad M; Dang, Phuong; Leclercq, Tamara M; Hughes, Timothy P; White, Deborah L

    2017-02-02

    Imatinib is actively transported by OCT-1 influx transporter, and low OCT-1 activity in diagnostic chronic myeloid leukemia blood mononuclear cells is significantly associated with poor molecular response to imatinib. Here we report that, in diagnostic chronic myeloid leukemia mononuclear cells and BCR-ABL1+ cell lines, peroxisome proliferator-activated receptor gamma agonists (GW1929, rosiglitazone, pioglitazone) significantly decrease OCT-1 activity; conversely, peroxisome proliferator-activated receptor gamma antagonists (GW9662, T0070907) increase OCT-1 activity. Importantly, these effects can lead to corresponding changes in sensitivity to Bcr-Abl kinase inhibition. Results were confirmed in peroxisome proliferator-activated receptor gamma-transduced K562 cells. Furthermore, we identified a strong negative correlation between OCT-1 activity and peroxisome proliferator-activated receptor gamma transcriptional activity in diagnostic chronic myeloid leukemia patients (n=84; preceptor gamma activation has a negative impact on the intracellular uptake of imatinib and consequent Bcr-Abl kinase inhibition. The inter-patient variability of peroxisome proliferator-activated receptor gamma activation likely accounts for the heterogeneity observed in patient OCT-1 activity at diagnosis. Recently, the peroxisome proliferator-activated receptor gamma agonist pioglitazone was reported to act synergistically with imatinib targeting the residual chronic myeloid leukemia stem cell pool. Our findings suggest that peroxisome proliferator-activated receptor gamma ligands have differential effects on circulating mononuclear cells compared to stem cells. Since the effect of peroxisome proliferator-activated receptor gamma activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, caution should be applied when combining these therapies, especially in patients with high peroxisome proliferator-activated receptor gamma

  2. Pristimerin induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation by blocking NF-κB signaling and depleting Bcr-Abl

    Directory of Open Access Journals (Sweden)

    Cao Qi

    2010-05-01

    Full Text Available Abstract Background Chronic myelogenous leukemia (CML is characterized by the chimeric tyrosine kinase Bcr-Abl. Bcr-Abl-T315I is the notorious point mutation that causes resistance to imatinib and the second generation tyrosine kinase inhibitors, leading to poor prognosis. CML blasts have constitutive p65 (RelA NF-κB transcriptional activity, and NF-κB may be a potential target for molecular therapies in CML that may also be effective against CML cells with Bcr-Abl-T315I. Results In this report, we discovered that pristimerin, a quinonemethide triterpenoid isolated from Celastraceae and Hippocrateaceae, inhibited growth and induced apoptosis in CML cells, including the cells harboring Bcr-Abl-T315I mutation. Additionally, pristimerin inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Pristimerin blocked the TNFα-induced IκBα phosphorylation, translocation of p65, and expression of NF-κB-regulated genes. Pristimerin inhibited two steps in NF-κB signaling: TAK1→IKK and IKK→IκBα. Pristimerin potently inhibited two pairs of CML cell lines (KBM5 versus KBM5-T315I, 32D-Bcr-Abl versus 32D-Bcr-Abl-T315I and primary cells from a CML patient with acquired resistance to imatinib. The mRNA and protein levels of Bcr-Abl in imatinib-sensitive (KBM5 or imatinib-resistant (KBM5-T315I CML cells were reduced after pristimerin treatment. Further, inactivation of Bcr-Abl by imatinib pretreatment did not abrogate the TNFα-induced NF-κB activation while silencing p65 by siRNA did not affect the levels of Bcr-Abl, both results together indicating that NF-κB inactivation and Bcr-Abl inhibition may be parallel independent pathways. Conclusion To our knowledge, this is the first report to show that pristimerin is effective in vitro and in vivo against CML cells, including those with the T315I mutation. The mechanisms may involve inhibition of NF-κB and Bcr-Abl. We concluded that pristimerin could be a lead compound for

  3. Combination of Rapamycin and Imatinib in Treating Refractory Chronic Myeloid Leukemia Myeloid Blast Crisis: a Case Report

    Institute of Scientific and Technical Information of China (English)

    Jing Xie; Xiang Zhang; Bao-zhi Fang; Guang-sheng He; Yun Zhao; De-pei Wu

    2013-01-01

    CHRONIC myeloid leukemia (CML) is character-ized by the presence of the BCR/ABL fusiongene, which is the resultof a reciprocal translo-cation betweenchromosomes 9 and 22, calledPhiladelphia (Ph) chromosome. Imatinib mesylate (imatinib), a specific small molecularinhibitor of BCR/ABL,couldimprove the prognosis of CML and is now the standard drugapplied in all phases of this disease.1 Despite the efficacy ofimatinib,the development of resistance and the persistence of minimal residual disease haveseriously impaired the efficiency of this medicine. Resistance may developthrough several differentmechanisms, such asmutations in the Abl kinase domain, BCR/ABL overexpression, or compensatory phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian targetof rapamycin (mTOR) activation.2,3Rapamycin, with mTOR asapotential therapeutic target, has been studied in patients with hematologic malignancies. Herewe report a case ofrefractory CML myeloid blast crisis successfully treated by the combination of rapamycin and imatinib.

  4. [Successful induction of complete cytogenetic response with low-dose imatinib mesylate in an accelerated phase chronic myelogenous leukemia patient who developed severe bone marrow aplasia following standard-dose imatinib mesylate therapy].

    Science.gov (United States)

    Nakazato, Tomonori; Suzuki, Kazuhito; Mihara, Ai; Sanada, Yukinari; Kakimoto, Tsunayuki

    2010-03-01

    A 58-year-old female presented with massive splenomegaly, leukocytosis and anemia. Bone marrow appearance was consistent with CML-AP, and t (9;22) (q34;q11) was detected on karyotyping. 600 mg daily imatinib mesylate (imatinib) was started and achieved complete hematological remission. However, pancytopenia was evident. Despite dose reduction and subsequent drug withdrawal, the pancytopenia worsened and she became transfusion dependent. Grade 4 pancytopenia persisted for 8 months after discontinuing imatinib. Bone marrow biopsy showed severe bone marrow aplasia with no morphological evidence of disease progression. Karyotyping showed minor cytogenetic response with no clonal evolution. Signs of hematological recovery appeared 8 months after stopping imatinib. The patient was re-started on imatinib at a dose of 100 mg/day. The dose was increased to 200 mg/day without hematological toxicity. Complete cytogenetic response (CCyR) was achieved 5 months after the re-administration of imatinib. The patient maintained CCyR with 200 mg of imatinib per day. Prolonged severe bone marrow aplasia has rarely been reported as a complication of imatinib therapy. This case also suggests that low-dose imatinib would be tolerable and effective for some CML patients who are intolerant of a standard dose of imatinib.

  5. [Prolonged molecular response induced by imatinib in Philadelphia positive acute lymphoblastic leukemia A case report and brief review].

    Science.gov (United States)

    Raissi, Abderrahim; Bouaouad, Majdouline; Drideb, Noufissa Alami; Jennane, Selim; Mahtat, El Mahdi; Doghmi, Kamal; Mikdame, Mohammed

    2015-01-01

    Philadelphia or BCR-ABL positive acute lymphoblastic leukemia (PH+ ALL) is the most common and severe of adult ALL. The only potentially curator treatment remains allogeneic hematopoietic stem cells transplantation (SCT) in first complete remission. The use of imatinib has revolutionized the treatment of chronic myeloid leukemia. Its incorporation into PH + ALL protocols also improved the prognosis of this disease giving better complete remission rates compared to chemotherapy alone. The treatment of patients not eligible for SCT remains controversial. Prolonged use of high dose tyrosine kinase inhibitors (TKI) (ie: imatinib at 600 or 800 mg/j) as maintenance therapy seems to be a reasonable approach. We present a case of prolonged molecular remission of PH+ ALL under TKI alone as maintenance therapy.

  6. Development of a specific and sensitive enzyme-linked immunosorbent assay for the quantification of imatinib.

    Science.gov (United States)

    Saita, Tetsuya; Shin, Masashi; Fujito, Hiroshi

    2013-01-01

    Imatinib is an oral tyrosine kinase inhibitor used for first-line treatment of chronic myeloid leukemia. Therapeutic drug monitoring targeting trough plasma levels of about 1000 ng/mL may help to optimize imantinib's therapeutic effect. This paper reports a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for a pharmacokinetic evaluation of imatinib. Anti-imatinib antibody was obtained by immunizing rabbits with an antigen conjugated with bovine serum albumin and succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. Enzyme labeling of imatinib with horseradish peroxidase was similarly performed using succinimidyl 4-{(4-methyl-1-piperazinyl)methyl}-benzoate. A simple ELISA for imatinib was developed using the principle of direct competition between imatinib and the enzyme marker for anti-imatinib antibody which had been adsorbed by the plastic surface of a microtiter plate. Serum imatinib concentrations lower than 40 pg/mL were reproducibly measurable using the ELISA. This ELISA was specific to imatinib and showed very slight cross-reactivity (1.2%) with a major metabolite, N-desmethyl imatinib. Using this assay, drug levels were easily measured in the blood of mice after their oral administration of imatinib at a single dose of 50 mg/kg. The specificity and sensitivity of the ELISA for imatinib should provide a valuable new tool for use in therapeutic drug monitoring and pharmacokinetic studies of imatinib.

  7. ELN 2013 response status criteria: relevance for de novo imatinib chronic phase chronic myeloid leukemia patients?

    Science.gov (United States)

    Etienne, Gabriel; Dulucq, Stéphanie; Lascaux, Axelle; Schmitt, Anna; Bidet, Audrey; Fort, Marie-Pierre; Lippert, Eric; Bureau, Caroline; Adiko, Didier; Hayette, Sandrine; Reiffers, Josy; Nicolini, Franck-Emmanuel; Mahon, François-Xavier

    2015-01-01

    The response definitions proposed by the European Leukemia Net (ELN) have been recently modified. We evaluated the new criteria for de novo imatinib (400 mg/d) chronic phase chronic myeloid leukemia (CP-CML) patients. Response status according to the 2009 and 2013 criteria were determined in 180 unselected patients. Outcome of the subgroups of patients were then compared. The 180 patients were classified as optimal responders (OR2009; n = 113, 62.7%), suboptimal responders (SOR2009; n = 47, 26.1%) and failures (FAIL2009; n = 20, 11.1%) according to the 2009 ELN criteria and optimal responders (OR2013; n = 77, 42.7%), warnings (WAR2013; n = 59, 32.7%), and failures (FAIL2013; n = 44, 24.4%) according to the 2013 ELN criteria. No difference in terms of outcome was observed between OR2009 patients who became WAR2013 when compared with OR2013 patients. When compared with FAIL2009 patients, SOR2009 patients who became WAR2013 had better EFS, FFS, PFS, and OS. No difference was observed in PFS or OS in SOR2009 patients who became FAIL2013. The 2013 ELN response status criteria have improved patients classification in terms of response status. However, in our patient population this improvement is related to a better definition of failure rather than that of optimal response for CP-CML patients treated with IM frontline therapy.

  8. Quantification of imatinib in human serum: validation of a high-performance liquid chromatography-mass spectrometry method for therapeutic drug monitoring and pharmacokinetic assays

    Directory of Open Access Journals (Sweden)

    Rezende VM

    2013-08-01

    Full Text Available Vinicius Marcondes Rezende,1 Ariane Rivellis,1 Mafalda Megumi Yoshinaga Novaes,1 Dalton de Alencar Fisher Chamone,2 Israel Bendit1,21Laboratory of Tumor Biology, 2Department of Hematology, School of Medicine, University of São Paulo, São Paulo, BrazilBackground: Imatinib mesylate has been a breakthrough treatment for chronic myeloid leukemia. It has become the ideal tyrosine kinase inhibitor and the standard treatment for chronic-phase leukemia. Striking results have recently been reported, but intolerance to imatinib and noncompliance with treatment remain to be solved. Molecular monitoring by quantitative real-time polymerase chain reaction is the gold standard for monitoring patients, and imatinib blood levels have also become an important tool for monitoring.Methods: A fast and cheap method was developed and validated using high-performance liquid chromatography-mass spectrometry for quantification of imatinib in human serum and tamsulosin as the internal standard. Remarkable advantages of the method includes use of serum instead of plasma, less time spent on processing and analysis, simpler procedures, and requiring reduced amounts of biological material, solvents, and reagents. Stability of the analyte was also studied. This research also intended to drive the validation scheme in clinical centers. The method was validated according to the requirements of the US Food and Drug Administration and Brazilian National Health Surveillance Agency within the range of 0.500–10.0 µg/mL with a limit of detection of 0.155 µg/mL. Stability data for the analyte are also presented.Conclusion: Given that the validated method has proved to be linear, accurate, precise, and robust, it is suitable for pharmacokinetic assays, such as bioavailability and bioequivalence, and is being successfully applied in routine therapeutic drug monitoring in the hospital service.Keywords: imatinib, high-performance liquid chromatography-mass spectrometry, therapeutic

  9. Regulatory network analysis of microRNAs and genes in imatinib-resistant chronic myeloid leukemia.

    Science.gov (United States)

    Soltani, Ismael; Gharbi, Hanen; Hassine, Islem Ben; Bouguerra, Ghada; Douzi, Kais; Teber, Mouheb; Abbes, Salem; Menif, Samia

    2016-09-16

    Targeted therapy in the form of selective breakpoint cluster region-abelson (BCR/ABL) tyrosine kinase inhibitor (imatinib mesylate) has successfully been introduced in the treatment of the chronic myeloid leukemia (CML). However, acquired resistance against imatinib mesylate (IM) has been reported in nearly half of patients and has been recognized as major issue in clinical practice. Multiple resistance genes and microRNAs (miRNAs) are thought to be involved in the IM resistance process. These resistance genes and miRNAs tend to interact with each other through a regulatory network. Therefore, it is crucial to study the impact of these interactions in the IM resistance process. The present study focused on miRNA and gene network analysis in order to elucidate the role of interacting elements and to understand their functional contribution in therapeutic failure. Unlike previous studies which were centered only on genes or miRNAs, the prime focus of the present study was on relationships. To this end, three regulatory networks including differentially expressed, related, and global networks were constructed and analyzed in search of similarities and differences. Regulatory associations between miRNAs and their target genes, transcription factors and miRNAs, as well as miRNAs and their host genes were also macroscopically investigated. Certain key pathways in the three networks, especially in the differentially expressed network, were featured. The differentially expressed network emerged as a fault map of IM-resistant CML. Theoretically, the IM resistance process could be prevented by correcting the included errors. The present network-based approach to study resistance miRNAs and genes might help in understanding the molecular mechanisms of IM resistance in CML as well as in the improvement of CML therapy.

  10. Lack of Association of Multidrug Resistance Gene-1 Polymorphisms with Treatment Outcome in Chronic Myeloid Leukemia Patients Treated with Imatinib

    Directory of Open Access Journals (Sweden)

    Yaya Kassogue

    2015-10-01

    Full Text Available Background: Despite the impressive results obtained with imatinib, inadequate response or resistance are observed in certain patients. It is known that imatinib is a substrate of a multidrug resistance gene (MDR1. Thus, interindividual genetic differences linked to single nucleotide polymorphisms in MDR1 may influence the metabolism of imatinib. The present study has aimed to examine the impact of MDR1 polymorphisms on the hematologic and cytogenetic responses in 70 chronic myeloid leukemia patients who received imatinib. Methods: We used a polymerase chain reaction followed by restriction fragment length polymorphism to identify different profiles of 1236C>T, 2677G>T and 3435C>T in MDR1. Results: The distribution of the three SNPs in responders and poor responders did not show any particular trend (P>0.05. The T allele was slightly higher in responders, but not significantly regardless of the type of SNP (40.3% vs. 33.8% for 1236C>T; 25% vs. 14.7% for 2677G>T and 33.3% vs. 22% for 3435C>T. The dominant model showed a similar trend (P>0.05. Diplotypes composed by the T allele in different exons were frequent in responders. Haplotype analysis showed that 1236C-2677G-3435C was slightly higher in poor responders (60.02% compared to responders (50.42%. However, 1236T-2677T-3435T was frequent in responders (16.98% compared to poor responders (13.1%. Overall, none of the haplotypes were associated with IM response in our cohort (global haplotype association test, P=0.39. Conclusion: The identification of 1236C>T, 2677G>T and 3435C>T polymorphisms may not be advantageous to predict imatinib response for our chronic myeloid leukemia patients.

  11. Pregnancy outcomes in patients with chronic myeloid leukemia treated with imatinib mesylate: short report from a developing country.

    Science.gov (United States)

    Iqbal, Javaid; Ali, Zafar; Khan, Aruj-Un-Nisa; Aziz, Zeba

    2014-09-01

    Treatment of chronic myeloid leukemia (CML) is challenging in patients who want to conceive. We followed 809 patients with CML treated with imatinib mesylate (IM). We observed outcomes in 90 pregnancies from 61 patients (21 females, 40 males) who conceived while on IM. Information was obtained on duration of exposure to IM, pregnancy termination and congenital abnormalities. Hematologic and cytogenetic responses were also recorded. Twenty-eight pregnancies occurred among females, while 62 were reported from male patients. Among female patients, 19 (67.9%) pregnancies were uneventful while six (21.4%) ended in adverse events. Only 12 (57%) females reported their pregnancies. Three (4.4%) adverse events were reported from male patients. Pregnancy is an important part of life in our young patients due to cultural and societal pressures. It is paramount to counsel pregnant patients to switch to drugs with no adverse effect on the developing fetus. However, lack of communication is a major factor preventing physicians from counseling patients about conception.

  12. Effect of VE-cadherin on sentitivity to Imatinib in Sup-B15 Philadelphia chromosome positive acute lymphoblastic leukemia cells

    Institute of Scientific and Technical Information of China (English)

    张焕新

    2013-01-01

    Objective To investigate the sensitivity of imatinib mesylate (IM) on Sup-B15 Ph+acute lymphoblastic leukemia (ALL) cells knockdown of VE-cadherin (CD144) ,and to further explore its mechanism.Methods CD144in Sup-B15 leukemia cells was stably knockdowned via lentivirus-mediated RNA interference (named as

  13. Implication of the Autologous Immune System in BCR-ABL Transcript Variations in Chronic Myelogenous Leukemia Patients Treated with Imatinib.

    Science.gov (United States)

    Clapp, Geoffrey D; Lepoutre, Thomas; El Cheikh, Raouf; Bernard, Samuel; Ruby, Jérémy; Labussière-Wallet, Hélène; Nicolini, Franck E; Levy, Doron

    2015-10-01

    Imatinib and other tyrosine kinase inhibitors (TKI) have improved treatment of chronic myelogenous leukemia (CML); however, most patients are not cured. Deeper mechanistic understanding may improve TKI combination therapies to better control the residual leukemic cell population. In analyzing our patients' data, we found that many patients who otherwise responded well to imatinib therapy still showed variations in their BCR-ABL transcripts. To investigate this phenomenon, we applied a mathematical model that integrates CML and an autologous immune response to the patients' data. We define an immune window or a range of leukemic loads for which the autologous immune system induces an improved response. Our modeling results suggest that, at diagnosis, a patient's leukemic load is able to partially or fully suppress the autologous immune response developed in a majority of patients, toward the CML clone(s). Imatinib therapy drives the leukemic population into the "immune window," allowing the patient's autologous immune cells to expand and eventually mount an efficient recognition of the residual leukemic burden. This response drives the leukemic load below this immune window, allowing the leukemic population to partially recover until another weaker immune response is initiated. Thus, the autologous immune response may explain the oscillations in BCR-ABL transcripts regularly observed in patients on imatinib. ©2015 American Association for Cancer Research.

  14. Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia.

    Science.gov (United States)

    Deenik, Wendy; van der Holt, Bronno; Verhoef, Gregor E G; Smit, Willem M; Kersten, Marie J; Kluin-Nelemans, Hanneke C; Verdonck, Leo F; Ferrant, Augustin; Schattenberg, Anton V M B; Janssen, Jeroen J W M; Sonneveld, Pieter; van Marwijk Kooy, Marinus; Wittebol, Shulamit; Willemze, Roelof; Wijermans, Pierre W; Westveer, Petra H M; Beverloo, H Berna; Valk, Peter; Löwenberg, Bob; Ossenkoppele, Gert J; Cornelissen, Jan J

    2008-03-01

    The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m(2)) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m(2)). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO-2001-03.

  15. The study of resistant mechanisms and reversal in an imatinib resistant Ph+ acute lymphoblastic leukemia cell line.

    Science.gov (United States)

    Xing, Hongyun; Yang, Xi; Liu, Ting; Lin, Juan; Chen, Xiaoyi; Gong, Yuping

    2012-04-01

    In this study, we established an imatinib resistant Ph+ acute lymphoblastic leukemia (ALL) cell line SUP-B15/RI in vitro and studied the mechanism of imatinib resistance. Our results showed that the BCR-ABL1 fusion gene and the mdr1 gene were 6.1 times and 1.7 times, respectively, as high as that of parental SUP-B15 cell line. We found no mutation in the Abl kinase domain of SUP-B15/RI. Furthermore, the detection of cell signaling pathway of PI3K/AKT/mTOR, RAS/RAF, NF-κB, JNK and STAT showed the up-regulation of phosphorylation of AKT, mTOR, P70S6K, and RAF, ERK, and MEK, down-regulation of PTEN and 4EBP-1, and no change in other cell signaling pathways in SUP-B15/RI. However, dasatinib and nilotinib showed partial resistance. Interestingly, bortezomib had no resistance. Imatinib combination with rapamycin had synergistic effect on overcoming the resistance. Altogether, over-expression of BCR-ABL1 and mdr1 gene were involved in the resistance mechanisms, and up-regulation of the cell signaling pathways of PI3K/AKT/mTOR, RAS/RAF in SUP-B15/RI cell line may be correlated with them. The SUP-B15/RI cell line was also resistant to the second generation tyrosine kinase, dasatinib, and nilotinib, not bortezomib. The combination of imatinib with rapamycin can partially overcome the resistance and blockade of the ubiquitin-proteasome can be also a promising pathway to overcome imatinib resistance. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Real-time analysis of imatinib- and dasatinib-induced effects on chronic myelogenous leukemia cell interaction with fibronectin.

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    Adam Obr

    Full Text Available Attachment of stem leukemic cells to the bone marrow extracellular matrix increases their resistance to chemotherapy and contributes to the disease persistence. In chronic myelogenous leukemia (CML, the activity of the fusion BCR-ABL kinase affects adhesion signaling. Using real-time monitoring of microimpedance, we studied in detail the kinetics of interaction of human CML cells (JURL-MK1, MOLM-7 and of control BCR-ABL-negative leukemia cells (HEL, JURKAT with fibronectin-coated surface. The effect of two clinically used kinase inhibitors, imatinib (a relatively specific c-ABL inhibitor and dasatinib (dual ABL/SRC family kinase inhibitor, on cell binding to fibronectin is described. Both imatinib and low-dose (several nM dasatinib reinforced CML cell interaction with fibronectin while no significant change was induced in BCR-ABL-negative cells. On the other hand, clinically relevant doses of dasatinib (100 nM had almost no effect in CML cells. The efficiency of the inhibitors in blocking the activity of BCR-ABL and SRC-family kinases was assessed from the extent of phosphorylation at autophosphorylation sites. In both CML cell lines, SRC kinases were found to be transactivated by BCR-ABL. In the intracellular context, EC50 for BCR-ABL inhibition was in subnanomolar range for dasatinib and in submicromolar one for imatinib. EC50 for direct inhibition of LYN kinase was found to be about 20 nM for dasatinib and more than 10 µM for imatinib. Cells pretreated with 100 nM dasatinib were still able to bind to fibronectin and SRC kinases are thus not necessary for the formation of cell-matrix contacts. However, a minimal activity of SRC kinases might be required to mediate the increase in cell adhesivity induced by BCR-ABL inhibition. Indeed, active (autophosphorylated LYN was found to localize in cell adhesive structures which were visualized using interference reflection microscopy.

  17. Os desafios no tratamento da Leucemia mielóide crônica na era do mesilato de imatinibe Challenges in current chronic myeloid leukemia therapy of imatinib era

    Directory of Open Access Journals (Sweden)

    Cármino Antônio de Souza

    2004-12-01

    Full Text Available Um progresso dramático no tratamento da LMC foi conquistado com o surgimento do inibidor da tirosina quinase BCR/ABL mesilato de imatinib. O imatinib induz altas taxas de resposta citogenética e molecular. A mobilização e coleta de células progenitoras periféricas para transplante autólogo após terapia com imatinib é possível e recentemente houve ressurgimento do interesse neste procedimento. Os autores discutem o atual e futuro papel do transplante autólogo no tratamento da LMC e as aplicações clínicas deste método. Provavelmente esse procedimento inicialmente será restrito aos pacientes que falharem na terapia com imatinib. Estudos clínicos serão necessários para definir a melhor aplicação desse método.A dramatic progress in treatment of chronic myeloid leukemia (CML has been achieved with the BCR-ABL tyrosine kinase imatinib. Imatinib induces high rates of cytogenetic and even molecular remissions in CML patients. The collection of Ph negative progenitor blood stem cells (PBSC for autologous hematopoietic cell transplantation (AHCT after imatinib treatment is possible and the interest of this procedure has emerged. The authors discuss the current and future role of autologous transplantation in CML therapy and the clinical applications of this method. Methods for additional purging of the graft are also discussed. It is likely that this procedure will be limited initially to patients who have failed imatinib therapy. Clinical trials are necessary to define the best application of this method.

  18. Structural Biology Contributions to the Discovery of Drugs to Treat Chronic Myelogenous Leukemia

    Science.gov (United States)

    Cowan-Jacob, Sandra W.; Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W.

    This case study illustrates how the determination of multiple co-crystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery efforts leading to the design of nilotinib, a newly approved therapy for imatinib-intolerant and - resistant chronic myelogenous leukemia. Chronic myelogenous leukemia (CML) results from the BCR-Abl onco-protein, which possesses a constitutively activated Abl tyrosine kinase domain. Although many chronic-phase CML patients treated with imatinib as first-line therapy maintain excellent, durable responses, patients who have progressed to advanced-stage CML frequently fail, or lose their response to therapy, often due to the emergence of drug-resistant mutants of the protein. More than 60 such point mutations have been detected in imatinib-resistant patients. We determined the crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small molecule Abl inhibitors, with the aim of understanding the molecular basis for resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way this information is used to support drug discovery.

  19. SPARC expression in CML is associated to imatinib treatment and to inhibition of leukemia cell proliferation

    Directory of Open Access Journals (Sweden)

    Giallongo Cesarina

    2013-02-01

    Full Text Available Abstract Background SPARC is a matricellular glycoprotein with growth-inhibitory and antiangiogenic activity in some cell types. The study of this protein in hematopoietic malignancies led to conflicting reports about its role as a tumor suppressor or promoter, depending on its different functions in the tumor microenvironment. In this study we investigated the variations in SPARC production by peripheral blood cells from chronic myeloid leukemia (CML patients at diagnosis and after treatment and we identified the subpopulation of cells that are the prevalent source of SPARC. Methods We evaluated SPARC expression using real-time PCR and western blotting. SPARC serum levels were detected by ELISA assay. Finally we analyzed the interaction between exogenous SPARC and imatinib (IM, in vitro, using ATP-lite and cell cycle analysis. Results Our study shows that the CML cells of patients at diagnosis have a low mRNA and protein expression of SPARC. Low serum levels of this protein are also recorded in CML patients at diagnosis. However, after IM treatment we observed an increase of SPARC mRNA, protein, and serum level in the peripheral blood of these patients that had already started at 3 months and was maintained for at least the 18 months of observation. This SPARC increase was predominantly due to monocyte production. In addition, exogenous SPARC protein reduced the growth of K562 cell line and synergized in vitro with IM by inhibiting cell cycle progression from G1 to S phase. Conclusion Our results suggest that low endogenous SPARC expression is a constant feature of BCR/ABL positive cells and that IM treatment induces SPARC overproduction by normal cells. This exogenous SPARC may inhibit CML cell proliferation and may synergize with IM activity against CML.

  20. Synergy between proteasome inhibitors and imatinib mesylate in chronic myeloid leukemia.

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    Zheng Hu

    Full Text Available BACKGROUND: Resistance developed by leukemic cells, unsatisfactory efficacy on patients with chronic myeloid leukemia (CML at accelerated and blastic phases, and potential cardiotoxity, have been limitations for imatinib mesylate (IM in treating CML. Whether low dose IM in combination with agents of distinct but related mechanisms could be one of the strategies to overcome these concerns warrants careful investigation. METHODS AND FINDINGS: We tested the therapeutic efficacies as well as adverse effects of low dose IM in combination with proteasome inhibitor, Bortezomib (BOR or proteasome inhibitor I (PSI, in two CML murine models, and investigated possible mechanisms of action on CML cells. Our results demonstrated that low dose IM in combination with BOR exerted satisfactory efficacy in prolongation of life span and inhibition of tumor growth in mice, and did not cause cardiotoxicity or body weight loss. Consistently, BOR and PSI enhanced IM-induced inhibition of long-term clonogenic activity and short-term cell growth of CML stem/progenitor cells, and potentiated IM-caused inhibition of proliferation and induction of apoptosis of BCR-ABL+ cells. IM/BOR and IM/PSI inhibited Bcl-2, increased cytoplasmic cytochrome C, and activated caspases. While exerting suppressive effects on BCR-ABL, E2F1, and beta-catenin, IM/BOR and IM/PSI inhibited proteasomal degradation of protein phosphatase 2A (PP2A, leading to a re-activation of this important negative regulator of BCR-ABL. In addition, both combination therapties inhibited Bruton's tyrosine kinase via suppression of NFkappaB. CONCLUSION: These data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment.

  1. Pilot study of Bortezomib for Patients with Imatinib-Refractory Chronic Myeloid Leukemia in Chronic or Accelerated Phase

    Science.gov (United States)

    Santos, Fabio P S; Kantarjian, Hagop; McConkey, David; O'Brien, Susan; Faderl, Stefan; Borthakur, Gautam; Ferrajoli, Alessandra; Wright, John; Cortes, Jorge

    2015-01-01

    Background Proteasome inhibitors are anticancer compounds that disrupt the proteolytic activity of the proteasome and lead to tumor cell growth arrest and apoptosis. Bortezomib is a proteasome inhibitor that is currently approved for use in multiple myeloma and mantle cell lymphoma. It induces apoptosis of chronic myeloid leukemia (CML) cells in vitro, but the activity of bortezomib in patients with imatinib-resistant CML is unknown. Methods We conducted a pilot trial to evaluate the activity of single agent bortezomib in CML. Seven patients with imatinib-refractory CML were treated with bortezomib at a dose of 1.5 mg/m2 on days 1, 4, 8 and 11 every 3 weeks. Results The median number of cycles received was 2. No patient had a hematologic or cytogenetic response. Three patients had a temporary decrease in basophil counts associated with therapy with bortezomib. Six patients developed grade 3-4 nonhematological toxicities. Conclusion Bortezomib had minimal efficacy and considerable toxicity in patients with imatinib-refractory CML. Further studies should focus on alternative approaches to employ proteasome inhibitors in the treatment of CML, such as in combination with tyrosine kinase inhibitors or as a strategy to eradicate leukemic stem cells. PMID:21816374

  2. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

    Science.gov (United States)

    Wassmann, Barbara; Pfeifer, Heike; Goekbuget, Nicola; Beelen, Dietrich W; Beck, Joachim; Stelljes, Matthias; Bornhäuser, Martin; Reichle, Albrecht; Perz, Jolanta; Haas, Rainer; Ganser, Arnold; Schmid, Mathias; Kanz, Lothar; Lenz, Georg; Kaufmann, Martin; Binckebanck, Anja; Brück, Patrick; Reutzel, Regina; Gschaidmeier, Harald; Schwartz, Stefan; Hoelzer, Dieter; Ottmann, Oliver G

    2006-09-01

    The best strategy for incorporating imatinib in front-line treatment of Ph+ acute lymphoblastic leukemia (ALL) has not been established. We enrolled 92 patients with newly diagnosed Ph+ ALL in a prospective, multicenter study to investigate sequentially 2 treatment schedules with imatinib administered concurrent to or alternating with a uniform induction and consolidation regimen. Coadministration of imatinib and induction cycle 2 (INDII) resulted in a complete remission (CR) rate of 95% and polymerase chain reaction (PCR) negativity for BCR-ABL in 52% of patients, compared with 19% in patients in the alternating treatment cohort (P = .01). Remarkably, patients with and without a CR after induction cycle 1 (INDI) had similar hematologic and molecular responses after concurrent imatinib and INDII. In the concurrent cohort, grades III and IV cytopenias and transient hepatotoxicity necessitated interruption of induction in 87% and 53% of patients, respectively; however, duration of induction was not prolonged when compared with patients receiving chemotherapy alone. No imatinib-related severe hematologic or nonhematologic toxicities were noted with the alternating schedule. In each cohort, 77% of patients underwent allogeneic stem cell transplantation (SCT) in first CR (CR1). Both schedules of imatinib have acceptable toxicity and facilitate SCT in CR1 in the majority of patients, but concurrent administration of imatinib and chemotherapy has greater antileukemic efficacy.

  3. Stability-indicating HPTLC determination of imatinib mesylate in bulk drug and pharmaceutical dosage form.

    Science.gov (United States)

    Vadera, N; Subramanian, G; Musmade, P

    2007-01-17

    A simple, selective, precise and stability-indicating high-performance thin-layer chromatographic method of analysis of imatinib mesylate both as a bulk drug and in formulations was developed and validated. The method employed HPTLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of chloroform:methanol (6:4, v/v). The system was found to give compact spot for imatinib mesylate (R(f) value of 0.53+/-0.02). Densitometric analysis of imatinib mesylate was carried out in the absorbance mode at 276 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r(2)=0.9966+/-0.0013 with respect to peak area in the concentration range 100-1000 ng per spot. The mean value+/-S.D. of slope and intercept were 164.85+/-0.72 and 1168.3+/-8.26 with respect to peak area. The method was validated for precision, recovery and robustness. The limits of detection and quantitation were 10 and 30 ng per spot, respectively. Imatinib mesylate was subjected to acid and alkali hydrolysis, oxidation and thermal degradation. The drug undergoes degradation under acidic, basic, oxidation and heat conditions. This indicates that the drug is susceptible to acid, base hydrolysis, oxidation and heat. Statistical analysis proves that the method is repeatable, selective and accurate for the estimation of said drug. The proposed developed HPTLC method can be applied for identification and quantitative determination of imatinib mesylate in bulk drug and dosage forms.

  4. Stability-Indicating HPTLC Determination of Imatinib Mesylate in Bulk Drug and Pharmaceutical Dosage

    Science.gov (United States)

    Musmade, P.; Vadera, N.; Subramanian, G.

    A simple, selective, precise and stability-indicating high-performance thin-layer chromatographic method of analysis of imatinib mesylate both as a bulk drug and in formulations was developed and validated. The method employed HPTLC aluminum plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of chloroform:methanol (6:4, v/v). The system was found to give compact spot for imatinib mesylate (R f value of 0.53 ± 0.02). Densitometric analysis of imatinib mesylate was carried out in the absorbance mode at 276 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r 2 = 0.9966 ± 0.0013 with respect to peak area in the concentration range 100-1,000 ng per spot. The mean value ± SD of slope and intercept were 164.85 ± 0.72 and 1168.3 ± 8.26, respectively, with respect to peak area. The method was validated for precision, recovery, and robustness. The limits of detection and quantitation were 10 and 30 ng per spot, respectively. Imatinib mesylate was subjected to acid and alkali hydrolysis, and oxidation and thermal degradation. The drug undergoes degradation under acidic, basic, oxidation, and heat conditions. This indicates that the drug is susceptible to acid, base hydrolysis, oxidation, and heat. Statistical analysis proves that the method is repeatable, selective, and accurate for the estimation of the said drug. The proposed developed HPTLC method can be applied for identification and quantitative determination of imatinib mesylate in bulk drug and dosage forms.

  5. Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells

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    Juan Liu

    2016-04-01

    Full Text Available Although dasatinib is effective in most imatinib mesylate (IMT-resistant chronic myeloid leukemia (CML patients, the underlying mechanism of its effectiveness in eliminating imatinib-resistant cells is only partially understood. This study investigated the effects of dasatinib on signaling mechanisms driving-resistance in imatinib-resistant CML cell line K562 (K562RIMT. Compared with K562 control cells, exsomal release, the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt/ mammalian target of rapamycin (mTOR signaling and autophagic activity were increased significantly in K562RIMT cells and mTOR-independent beclin-1/Vps34 signaling was shown to be involved in exosomal release in these cells. We found that Notch1 activation-mediated reduction of phosphatase and tensin homolog (PTEN was responsible for the increased Akt/mTOR activities in K562RIMT cells and treatment with Notch1 γ-secretase inhibitor prevented activation of Akt/mTOR. In addition, suppression of mTOR activity by rapamycin decreased the level of activity of p70S6K, induced upregulation of p53 and caspase 3, and led to increase of apoptosis in K562RIMT cells. Inhibition of autophagy by spautin-1 or beclin-1 knockdown decreased exosomal release, but did not affect apoptosis in K562RIMT cells. In summary, in K562RIMT cells dasatinib promoted apoptosis through downregulation of Akt/mTOR activities, while preventing exosomal release and inhibiting autophagy by downregulating expression of beclin-1 and Vps34. Our findings reveal distinct dasatinib-induced mechanisms of apoptotic response and exosomal release in imatinib-resistant CML cells.

  6. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors

    Science.gov (United States)

    Cortes, Jorge E.; Kim, Dong-Wook; Khoury, H. Jean; Brümmendorf, Tim H.; Porkka, Kimmo; Martinelli, Giovanni; Durrant, Simon; Leip, Eric; Kelly, Virginia; Turnbull, Kathleen; Besson, Nadine; Gambacorti-Passerini, Carlo

    2014-01-01

    Bosutinib is an oral, dual SRC/ABL tyrosine kinase inhibitor (TKI) with clinical activity in Philadelphia chromosome–positive (Ph+) leukemia. We assessed the safety and tolerability of bosutinib 500 mg per day in a phase 1/2 study in chronic-phase (CP) chronic myeloid leukemia (CML) or advanced Ph+ leukemia following resistance/intolerance to imatinib and possibly other TKIs. Patient cohorts included second-line CP CML (n = 286), third-/fourth-line CP CML (n = 118), and advanced leukemia (n = 166). Median bosutinib duration was 11.1 (range, 0.03-83.4) months. Treatment-emergent adverse events (TEAEs) in each cohort were primarily gastrointestinal (diarrhea [86%/83%/74%], nausea [46%/48%/48%], and vomiting [37%/38%/43%]). Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppression TEAEs were reported in 41% of patients; among affected patients, 46% were managed with bosutinib interruption and 32% with dose reduction. Alanine aminotransferase elevation TEAEs occurred in 17% of patients (grade 3/4, 7%); among patients managed with dose interruption, bosutinib rechallenge was successful in 74%. Bosutinib demonstrated acceptable safety with manageable toxicities in Ph+ leukemia. This trial (NCT00261846) was registered at www.ClinicalTrials.gov (this manuscript is based on a different data snapshot from that in ClinicalTrials.gov). PMID:24345751

  7. Children and Adolescents with Newly Diagnosed Chronic Phase CML or with Ph+ Leukemias Resistant to or Intolerant to Imatinib | EU Clinical Trials Register [EU Clinical Trials Register

    Lifescience Database Archive (English)

    Full Text Available t-2010) Studio di fase II con Dastinib in bambini e adolescenti con leucemia mieloide cronica in fase corica... or with Ph+ Leukemias Resistant to or Intolerant to Imatinib Bambini ed adolescenti con leucemia... mieloide cronica in fase cronica di nuova diagnosi o con leucemia Ph+ resistenti o intoller

  8. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia : 2-year follow-up from a randomized phase 3 trial (DASISION)

    NARCIS (Netherlands)

    Kantarjian, Hagop M.; Shah, Neil P.; Cortes, Jorge E.; Baccarani, Michele; Agarwal, Mohan B.; Soledad Undurraga, Maria; Wang, Jianxiang; Kassack Ipina, Juan Julio; Kim, Dong-Wook; Ogura, Michinori; Pavlovsky, Carolina; Junghanss, Christian; Milone, Jorge H.; Nicolini, Franck E.; Robak, Tadeusz; Van Droogenbroeck, Jan; Vellenga, Edo; Bradley-Garelik, M. Brigid; Zhu, Chao; Hochhaus, Andreas

    2012-01-01

    Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259

  9. Immunoglobulin D multiple myeloma, plasma cell leukemia and chronic myelogenous leukemia in a single patient treated simultaneously with lenalidomide, bortezomib, dexamethasone and imatinib

    Directory of Open Access Journals (Sweden)

    Naveed Ali

    2016-03-01

    Full Text Available Multiple myeloma (MM is a neoplastic lymphoproliferative disorder characterized by uncontrolled monoclonal plasma cell proliferation. Among different isotypes of MM, immunoglobulin D (IgD MM is very rare, representing only 1 to 2% of all isotypes. Chronic myelogenous leukemia (CML is a neoplastic myeloproliferative disorder of pluripotent hematopoietic stem cell, which is characterized by the uncontrolled proliferation of myeloid cells. An 88-year-old male was diagnosed simultaneously with IgD kappa MM and CML. A distinctive feature in this patient was the progression to plasma cell leukemia without any symptomatic myeloma stage. He was treated simultaneously with lenalidomide, bortezomib and imatinib. Synchronous occurrence of these rare hematological malignancies in a single patient is an exceedingly rare event. Multiple hypotheses to explain co-occurrence of CML and MM have been proposed; however, the exact etiological molecular pathophysiology remains elusive.

  10. Impact of low-grade adverse events on health-related quality of life in adult patients receiving imatinib or nilotinib for newly diagnosed Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase.

    Science.gov (United States)

    Guérin, Annie; Chen, Lei; Ionescu-Ittu, Raluca; Marynchenko, Maryna; Nitulescu, Roy; Hiscock, Robert; Keir, Christopher; Wu, Eric Qiong

    2014-11-01

    Chronic myeloid leukemia (CML) treatment relies on tyrosine kinase inhibitors (TKIs), but their use can be associated with low-grade adverse events (AEs). This analysis aimed to identify the low-grade AEs which significantly impact the Health Related Quality of Life (HRQoL) of CML patients in chronic phase (CP) and to compare the incidence of such AEs among nilotinib- and imatinib-treated patients. Data from the 48 month ENESTnd trial were used (N = 593 patients). HRQoL was assessed using generic (SF-36) and leukemia-specific (FACT-Leu) HRQoL surveys. AEs were categorized into 26 system organ classes. In the adjusted regression model, five low-grade AE categories - gastrointestinal disorders, blood and lymphatic system disorders, general disorders and administration site conditions, musculoskeletal disorders, and psychiatric disorders - significantly impaired at least one HRQoL score. The incidence rate of these five AE categories was either significantly lower for nilotinib than imatinib or not different between the two drugs. The AE categories with lower incidence for both nilotinib 300 mg BID and 400 mg BID versus imatinib 400 mg daily were gastrointestinal, blood and lymphatic system, and musculoskeletal; nilotinib 300 mg BID had lower incidence than imatinib for general disorders. Low-grade AEs were grouped and analyzed by system organ class category, so the effect of some rare individual AEs on HRQoL may have been missed. The impact of low-grade AEs on HRQoL should be taken into account, along with other factors, when selecting the optimal treatment for patients newly diagnosed with CML-CP.

  11. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study.

    Science.gov (United States)

    Rea, Delphine; Henry, Guylaine; Khaznadar, Zena; Etienne, Gabriel; Guilhot, François; Nicolini, Franck; Guilhot, Joelle; Rousselot, Philippe; Huguet, Françoise; Legros, Laurence; Gardembas, Martine; Dubruille, Viviane; Guerci-Bresler, Agnès; Charbonnier, Aude; Maloisel, Frédéric; Ianotto, Jean-Christophe; Villemagne, Bruno; Mahon, François-Xavier; Moins-Teisserenc, Hélène; Dulphy, Nicolas; Toubert, Antoine

    2017-08-01

    Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56(dim) subset than had relapsing patients, while CD56(bright) natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56(dim) natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1(+) leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier

  12. Imatinib induces H2AX phosphorylation and apoptosis in chronic myelogenous leukemia cells in vitro via caspase-3/Mst1 pathway

    Institute of Scientific and Technical Information of China (English)

    Yan-jun ZHANG; Lian-ning DUAN; Cheng-rong LU; Yan CAO; Yuan LUO; Rong-feng BAO; Shu YAN; Mei XUE; Feng ZHU; Zhe WANG

    2012-01-01

    Aim:Histone H2AX is a novel tumor suppressor and its phosphorylation at the C terminus (Ser139 and Tyr142)is required for tumor cell apoptosis.The aim of the present study was to elucidate the mechanisms underlying imatinib-induced C-terminal phosphorylation of H2AX in chronic myelogenous leukemia cells in vitro.Methods:BCR-ABL-positive K562 cells were used.Microscopy,Western blotting and flow cytometry were used to study the signaling pathways that regulate imatinib-induced H2AX phosphorylation and the apoptotic mechanisms.Results:Treatment of K562 cells with imatinib (1-8 μmol/L)induced phosphorylation of H2AX at Ser139 and Tyr142 in time-and dose-dependent manners.In contrast,imatinib at the same concentrations did not affect H2AX acetylation at Lys 5,and the acetylated H2AX maintained a higher level in the cells.Meanwhile,imatinib (1-8 μmol/L)activated caspase-3 and its downstream mammalian STE20-like kinase 1 (Mst1),and induced apoptosis of K562 cells.The caspase-3 inhibitor Z-VAD (40 μmol/L)reduced imatinibinduced H2AX phosphorylation at Ser139 and Tyr142 and blocked imatinib-induced apoptosis of K562 cells.Imatinib (4 μmol/L)induced expression of Williams-Beuren syndrome transcription factor (WSTF),but not wild-type p53-induced phosphatase 1 (Wip1)in K562 cells.Conclusion:The caspase-3/Mst1 pathway is required for H2AX C-terminal phosphorylation at Ser139 and Tyr142 and subsequent apoptosis in Bcr-Abl-positive K562 cells induced by imatinib.

  13. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).

    Science.gov (United States)

    Ottmann, Oliver G; Wassmann, Barbara; Pfeifer, Heike; Giagounidis, Aristoteles; Stelljes, Matthias; Dührsen, Ulrich; Schmalzing, Marc; Wunderle, Lydia; Binckebanck, Anja; Hoelzer, Dieter

    2007-05-15

    Elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) have a poor prognosis, with a low complete remission (CR) rate, high induction mortality, and short remission duration. Imatinib (IM) has a favorable toxicity profile but limited antileukemic activity in advanced Ph+ALL. Imatinib in combination with intensive chemotherapy has yielded promising results as front-line therapy, but its value as monotherapy in newly diagnosed Ph+ALL is not known. Patients with de novo Ph+ALL were randomly assigned to induction therapy with either imatinib (Ind(IM)) or multiagent, age-adapted chemotherapy (Ind(chemo)). Imatinib was subsequently coadministered with consolidation chemotherapy. In all, 55 patients (median age, 68 years) were enrolled. The overall CR rate was 96.3% in patients randomly assigned to Ind(IM) and 50% in patients allocated to Ind(chemo) (P = .0001). Nine patients (34.6%) were refractory and 2 patients died during Ind(chemo); none failed imatinib induction. Severe adverse events were significantly more frequent during Ind(chemo) (90% vs 39%; P = .005). The estimated overall survival (OS) of all patients was 42% +/- 8% at 24 months, with no significant difference between the 2 cohorts. Median disease-free survival was significantly longer in the 43% of patients (21 of 49 evaluable) in whom BCR-ABL transcripts became undetectable (18.3 months vs 7.2 months; P = .002). In elderly patients with de novo Ph+ALL, imatinib induction results in a significantly higher CR rate and lower toxicity than induction chemotherapy. With subsequent combined imatinib and chemotherapy consolidation, this initial benefit does not translate into improved survival compared with chemotherapy induction. (c) 2007 American Cancer Society

  14. Patan hospital experience in treating philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukemia patients with gleevec (imatinib mesylate; the first generation specific tyrosine kinase inhibitor

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    Zimmerman Mark

    2010-12-01

    Full Text Available Abstract Background Chronic Myeloid Leukemia (CML is caused by the abnormal fusion protein BCR-ABL1, a constitutively active tyrosine kinase and product of the Philadelphia chromosome. Gleevec (Imatinib mesylate is a selective inhibitor of this kinase. Treatment with this agent is known to result in hematologic, cytogenetic, and molecular responses. Patan hospital (Patan, Nepal is one of the Gleevec International Patient Assistance Program (GIPAP centers for patients with CML. Methods A total of 106 Philadelphia positive CML patients were enrolled in our center between Feb 2003 and Jun 2008, and 103 of them were eligible for cytogenetic and/or hematologic response analyses. Results Out of 103 patients, 27% patients underwent cytogenetic analysis. Imatinib induced major cytogenetic responses in 89% and complete hematologic responses in almost 100% of the patients with confirmed CML. After a mean follow up of 27 months, an estimated 90% of the patients on imatinib remained in hematologic remission and more than 90% of the patients are still alive. About 30% of patients developed some form of manageable myelosuppression. A few patients developed non-hematologic toxic side effects such as edema and hepatotoxicity. Conclusions Our study demonstrates that imatinib is safe to use in a developing country. Furthermore, we demonstrate that imatinib is very effective and induced long lasting responses in a high proportion of patients with Ph chromosome/BCR-ABL1 positive CML. Imatinib is well tolerated by our patients. The lack of cytogenetic analysis in the majority of our patients hindered our ability to detect inadequate responses to imatinib and adjust therapy appropriately.

  15. FIP1L1-PDGFRA-Positive Chronic Eosinophilic Leukemia: A Low-Burden Disease with Dramatic Response to Imatinib - A Report of 5 Cases from South India

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    Anıl Kumar N.

    2014-12-01

    Full Text Available OBJECTIVE: Eosinophilia associated with FIP1L1-PDGFRA rearrangement represents a subset of chronic eosinophilic leukemia and affected patients are sensitive to imatinib treatment. This study was undertaken to learn the prevalence and associated clinicopathologic and genetic features of FIP1L1-PDGFRA rearrangement in a cohort of 26 adult patients presenting with profound eosinophilia (>1.5x109/L. METHODS: Reverse-transcriptase polymerase chain reaction and gel electrophoresis were used for the detection of FIP1L1-PDGFRA rearrangement. RESULTS: Five male patients with splenomegaly carried the FIP1L1-PDGFRA gene rearrangement. All patients achieved complete hematological response within 4 weeks of starting imatinib. One patient had previous deep vein thrombosis and 1 patient had cardiomyopathy, which improved with steroids and imatinib. Conventional cytogenetics was normal in all these patients. No primary resistance to imatinib was noted. CONCLUSION: This study indicates the need to do the FIP1L1-PDGFRA assay in patients with hypereosinophilic syndrome. Prompt treatment of this condition with imatinib can lead to complete hematological response and resolution of the organ damage that can be seen in this setting.

  16. [Nilotinib in patients with chronic myeloid leukemia without response to imatinib].

    Science.gov (United States)

    Báez-de la Fuente, Enrique; Arellano-Severiano, Baltazar

    2014-01-01

    INTRODUCCIÓN: la resistencia e intolerancia al imatinib en pacientes con leucemia mieloide crónica requiere el uso de otros fármacos, como el nilotinib. El objetivo de este informe es presentar los resultados obtenidos en un grupo de pacientes con leucemia mieloide crónica que recibió tratamiento de segunda línea con nilotinib. MÉTODOS: se incluyeron 16 pacientes con diagnóstico de leucemia mieloide crónica que recibieron tratamiento de segunda línea con nilotinib, después de que no respondieron adecuadamente al imatinib. El cambio de fármaco se debió a intolerancia, resistencia o progresión de la leucemia.

  17. [Pregnancy and myeloid leukemia treated with imatinib. Development and monitoring of a patient].

    Science.gov (United States)

    Báez-de la Fuente, Enrique; Arellano-Severiano, Baltazar

    2014-01-01

    INTRODUCCIÓN: el tratamiento con imatinib ha modificado la historia natural de la leucemia mieloide crónica, y ha permitido que las mujeres con este padecimiento puedan embarazarse. El objetivo de este reporte es describir el curso y desenlace de un embarazo en una paciente con diagnóstico previo de leucemia mieloide crónica, que recibía tratamiento con imatinib. CASO CLÍNICO: mujer de 32 años con leucemia mieloide crónica de 11 años de evolución. Al diagnóstico se inició tratamiento estándar, pero debido a poca adherencia terapéutica, a los dos años se le prescribió imatinib. Debido al deseo de procrear, la paciente decidió suspender el medicamento. Un mes después acudió a la consulta con amenorrea de seis semanas de evolución; se confirmó embarazo. Durante 10 meses que permaneció sin tratamiento, no tuvo síntomas de progresión de la leucemia. El embarazo se interrumpió por cesárea a las 35.5 semanas de gestación. El neonato aparentemente se encontraba sano. En el transcurso del puerperio quirúrgico, la paciente acudió a consulta; los resultados de la biometría hemática indicaron hemoglobina de 8.7 g/dL, hematócrito de 25 %, leucocitos de 22 000/mL y plaquetas de 170 000/mL. Ese día se reinició tratamiento con 600 mg/día de imatinib.

  18. Efeitos adversos e resposta citogenética em pacientes com leucemia mieloide crônica tratados com imatinibe Adverse events and cytogenetc response in patients with chronic myeloid leukemia treated with imatinib

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    Tatiana F. Alvarenga

    2010-01-01

    pacientes.Chronic myeloid leukemia (CML is a clonal myeloproliferative disorder characterized cytogenetically by the Philadelphia chromosome (Ph. Therapeutic options of this disease are: hydroxyurea, interferon-a, allogeneic HSCT and more recently imatinib. This latter therapy demonstrated efficacy in the treatment of CML, particularly in the chronic phase. However some studies have demonstrated that there are additional chromosomal alterations related to resistance while others have reported undesirable clinical manifestations during imatinib therapy such as headache, nausea and vomiting. Because of the importance of this new molecular target therapy, it may be necessary to analyze the response of this treatment in respect to the quality of life of patients. The aim of this study was to analyze the clinical manifestations and the cytogenetic response during imatinib therapy in fifty-one patients with CML who had previously been treated using interferon-a. Cytogenetic analysis was performed in bone marrow cells using GTG-banding. The commonest clinical manifestations were mild to moderate: headache (37%, nausea (37%, vomiting (33% and edema (33%. Patients that achieved major cytogenetic response had a significantly longer median survival than patients without response (p=0.007. Eight patients evolved to death; none of them exhibited cytogenetic responses to imatinib. Our results show the importance of the clinical (analyzing the degree of tolerance to the drug and cytogenetic follow-up, where the presence of additional chromosomal alterations showed a distinct biological pattern that is not identifiable by molecular techniques, and so cytogenetic analysis is an important tool for the diagnosis and monitoring of this group of patientss.

  19. Association of The Common CYP1A1*2C Variant (Ile462Val Polymorphism with Chronic Myeloid Leukemia (CML in Patients Undergoing Imatinib Therapy

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    Samyuktha Lakkireddy

    2015-10-01

    Full Text Available Objective: Cytochrome P450 is one of the major drug metabolizing enzyme families and its role in metabolism of cancer drugs cannot be less emphasized. The association between single nucleotide polymorphisms (SNPs in CYP1A1 and pathogenesis of chronic myeloid leukemia (CML has been investigated in several studies, but the results observed vary based on varied risk factors. The objective of this study was to investigate the risk factors associated with the CYP1A1*2C [rs1048943: A>G] polymorphism in CML patients and its role in therapeutic response to imatinib mesylate (IM affecting clinico-pathological parameters, in the Indian population. Materials and Methods: In this case-control study, CYP1A1*2C was analysed in CML patients. After obtaining approval from the Ethics Committee of oncology hospital, we collected blood samples from 132 CML patients and 140 matched controls. Genomic DNA was extracted and all the samples were analysed for the presence of the CYP1A1*2C polymorphism using allele-specific polymerase chain reaction, and we examined the relationship of genotypes with risk factors such as gender, age, phase of the disease and other clinical parameters. Results: We observed a significant difference in the frequency distribution of CYP1A1*2C genotypes AA (38 vs. 16%, P=0.0001, AG (57 vs. 78%, P=0.0002 and GG (5 vs. 6%, P=0.6635 between patients and controls. In terms of response to IM therapy, significant variation was observed in the frequencies of AA vs AG in major (33 vs 67% and poor (62 vs 31% hematological responders, and AA vs AG in major (34 vs. 65% and poor (78 vs. 22% cytogenetic responders. However, the patients with the GG homozygous genotype did not show any significant therapeutic outcome. Conclusion: The higher frequency of AG in controls indicates that AG may play a protective role against developing CML. We also found that patients with the AG genotype showed favorable treatment response towards imatinib therapy, indicating

  20. Switching to nilotinib in patients with chronic myeloid leukemia in chronic phase with molecular suboptimal response to frontline imatinib: SENSOR final results and BIM polymorphism substudy.

    Science.gov (United States)

    Miyamura, Koichi; Miyamoto, Toshihiro; Tanimoto, Mitsune; Yamamoto, Kazuhito; Kimura, Shinya; Kawaguchi, Tatsuya; Matsumura, Itaru; Hata, Tomoko; Tsurumi, Hisashi; Saito, Shigeki; Hino, Masayuki; Tadokoro, Seiji; Meguro, Kuniaki; Hyodo, Hideo; Yamamoto, Masahide; Kubo, Kohmei; Tsukada, Junichi; Kondo, Midori; Aoki, Makoto; Okada, Hikaru; Yanada, Masamitsu; Ohyashiki, Kazuma; Taniwaki, Masafumi

    2016-12-01

    Optimal management of patients with chronic myeloid leukemia in chronic phase with suboptimal molecular response (MR) to frontline imatinib is undefined. We report final results from SENSOR, which evaluated efficacy/safety of nilotinib in this setting. A substudy assessed whether BIM polymorphisms impacted response to nilotinib. In this single-arm, multicenter study, Japanese patients with suboptimal MR per European LeukemiaNet 2009 criteria (complete cytogenetic response, but not major MR [MMR]) after ≥18 months of frontline imatinib received nilotinib 400mg twice daily for 24 months. MR, BCR-ABL1 mutations/variants, and BIM polymorphisms were evaluated in a central laboratory. Primary endpoint was the MMR rate at 12 months (null hypothesis of 40%). Of 45 patients (median exposure, 22.08 months), 39 completed the study and six discontinued. At 12 and 24 months, 51.1% (95% CI, 35.8%-66.3%) and 66.7% (95% CI, 51.0%-80.0%) achieved MMR, respectively. Cumulative MMR incidence by 24 months was 75.6%. Of 40 patients analyzed, 10 of 12 (83.3%) with and 17 of 28 (60.7%) without BIM polymorphisms achieved MMR at 24 months. The safety profile was manageable with dose reductions and interruptions. Nilotinib provided clinical benefit for patients with suboptimal response to imatinib, and BIM polymorphisms did not influence MMR achievement. ClinicalTrials.gov: NCT01043874.

  1. Is Adherence to Imatinib Mesylate Treatment Among Patients with Chronic Myeloid Leukemia Associated with Better Clinical Outcomes in Qatar?

    Science.gov (United States)

    Al-Dewik, Nader I.; Morsi, Hisham M.; Samara, Muthanna M.; Ghasoub, Rola S.; Gnanam, Cinquea C.; Bhaskaran, Subi K.; Nashwan, Abdulqadir J.; Al-Jurf, Rana M.; Ismail, Mohamed A.; AlSharshani, Mohammed M.; AlSayab, Ali A.; Ben-Omran, Tawfeg I.; Khatib, Rani B.; Yassin, Mohamed A.

    2016-01-01

    BACKGROUND Despite the revolutionary success of introducing tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), for treating chronic myeloid leukemia (CML), a substantial proportion of patients’ treatments fail. AIM This study investigates the correlation between patient adherence and failure of TKIs’ treatment in a follow-up study. METHODS This is a follow-up study of a new cohort of CML patients. Adherence to IM is assessed using the Medication Event Monitoring System (MEMS 6 TrackCap, AARDEX Ltd). The 9-item Morisky Medication Adherence Scale, medication possession ratio (MPR) calculation, and the electronic medical records are used for identifying potential factors that influence adherence. Clinical outcomes are assessed according to the European Leukemia Net 2013 guidelines via reverse transcriptase quantitative polymerase chain reaction measurement of the level of BCR-ABL1 transcripts in peripheral blood. Response is classified at the hematological, cytogenetic, and molecular levels into optimal, suboptimal, or failure. RESULTS A total of 36 CML patients (5 citizens and 31 noncitizen residents) consented to participate in the study. The overall mean MEMS score was 89. Of the 36 patients, 22 (61%) were classified as adherent (mean: 95) and 14 (39%) were classified as nonadherent (mean: 80.2). Adherent patients were significantly more likely to obtain optimal response (95%) compared to the nonadherent group (14.3%; P health-care teams, doctors, nurses, pharmacists, and patients are essential components for maximizing the benefits of TKI therapy and could rectify this problem. The preliminary results show that patients’ response to treatment may be directly linked to patients’ adherence to treatment. However, further in-depth and specific analysis may be necessary in a larger cohort. PMID:27721664

  2. Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with imatinib mesylate against chronic myelogenous leukemia cell lines

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    Xin P

    2017-04-01

    Full Text Available Pengliang Xin, Chuntuan Li, Yan Zheng, Qunyi Peng, Huifang Xiao, Yuanling Huang, Xiongpeng Zhu Department of Haematology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Licheng, Quanzhou, Fujian Province, China Background: Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR pathway is a therapy target of cancer. We aimed to confirm the effect of dual PI3K/mTOR inhibitor NVP-BEZ235 on proliferation, apoptosis, and autophagy of chronic myelogenous leukemia (CML cells and sensitivity of tyrosine kinase inhibitor in vitro.Methods: Two human CML cell lines, K562 and KBM7R (T315I mutant strain, were used. The proliferation of CML cells was detected by MTS (Owen’s reagent assay. Cell cycle and apoptosis assay were examined by flow cytometric analysis. The phosphorylation levels and the expression levels were both evaluated by Western blot analysis. NVP-BEZ235 in combination with imatinib was also used to reveal the effect on proliferation and apoptosis.Results: NVP-BEZ235 significantly inhibited the proliferation in a time- and dose-dependent manner, and the half-maximal inhibitory concentration values of NVP-BEZ235 inhibiting the proliferation of K562 and KBM7R were 0.37±0.21 and 0.43±0.27 µmol/L, respectively, after 48 h. Cell apoptosis assay showed that NVP-BEZ235 significantly increased the late apoptotic cells. Cell cycle analysis indicated that the cells were mostly arrested in G1/G0 phase after treatment by NVP-BEZ235. In addition, results also found that, after treatment by NVP-BEZ235, phosphorylation levels of Akt kinase and S6K kinase significantly reduced, and the expression levels of cleaved caspase-3 significantly increased; meanwhile, the expression levels of caspase-3, B-cell lymphoma-2, cyclin D1, and cyclin D2 significantly decreased, and the ratio of LC3II/LC3I was significantly increased with increased LC3II expression level. Moreover, imatinib in combination with NVP-BEZ235

  3. Leucemia Mielóide Crônica: causas de falha do tratamento com mesilato de imatinibe Chronic Myeloid Leukemia: causes of treatment failure with imatinib

    OpenAIRE

    Katia B.B. Pagnano

    2008-01-01

    O mesilato de imatinibe (MI) é atualmente o tratamento de escolha da Leucemoa Mielóide Crônica (LMC), mas, apesar dos excelentes resultados, não é capaz de erradicar completamente a doença, podendo ocorrer resistência ao tratamento. O mecanismo mais conhecido de resistência é o desenvolvimento de mutações do BCR-ABL, que impedem a ação ligação adequada do imatinibe à quinase, além de amplificação gênica e evolução clonal. No entanto, há uma série de outros mecanismos envolvidos e ainda pouco ...

  4. Imatinib Mesylate Effectiveness in Chronic Myeloid Leukemia with Additional Cytogenetic Abnormalities at Diagnosis among Black Africans

    Science.gov (United States)

    Aïssata, Tolo Diebkilé; Sawadogo, Duni; Nanho, Clotaire; Kouakou, Boidy; Meité, N'dogomo; Emeuraude, N'Dhatz; Roméo, Ayémou; Yassongui Mamadou, Sekongo; Kouéhion, Paul; Mozart, Konan; Koffi, Gustave; Sanogo, Ibrahima

    2013-01-01

    Imatinib mesylate provides good results in the treatment of CML in general. But what about the results of this treatment in CML associated with additional cytogenetic abnormalities at diagnosis among black Africans? For this, we retrospectively studied 27 cases of CML associated with additional cytogenetic abnormalities, diagnosed in the department of clinical hematology of the University Hospital of Yopougon in Côte d'Ivoire, from May 2005 to October 2011. The age of patients ranged from 13 to 68 years, with a mean age of 38 years and a sex ratio of 2. Patients were severely symptomatic with a high Sokal score of 67%. CML in chronic phase accounted for 67%. The prevalence of additional cytogenetic abnormalities was 29.7%. There were variants of the Philadelphia chromosome (18.5%), trisomy 8 (14.8%), complex cytogenetic abnormalities (18.5%), second Philadelphia chromosome (14.8%), and minor cytogenetic abnormalities (44.4%). Complete hematologic remission was achieved in 59%, with 52% of major cytogenetic remission. The outcome was fatal in 37% of patients. Death was related in 40% to hematologic toxicity and in 30% to acutisation. The median survival was 40 months. PMID:23802015

  5. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study.

    Science.gov (United States)

    Ottmann, Oliver; Dombret, Hervé; Martinelli, Giovanni; Simonsson, Bengt; Guilhot, Francois; Larson, Richard A; Rege-Cambrin, Giovanna; Radich, Jerald; Hochhaus, Andreas; Apanovitch, Anne Marie; Gollerkeri, Ashwin; Coutre, Steven

    2007-10-01

    Patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.

  6. Prediction of outcomes in patients with Ph+ chronic myeloid leukemia in chronic phase treated with nilotinib after imatinib resistance/intolerance

    Science.gov (United States)

    Jabbour, Elias; le Coutre, Philipp D.; Cortes, Jorge; Giles, Francis; Bhalla, Kapil N.; Pinilla-Ibarz, Javier; Larson, Richard A.; Gattermann, Norbert; Ottmann, Oliver G.; Hochhaus, Andreas; Hughes, Timothy P.; Saglio, Giuseppe; Radich, Jerald P.; Kim, Dong-Wook; Martinelli, Giovanni; Reynolds, John; Woodman, Richard C.; Baccarani, Michele; Kantarjian, Hagop M.

    2014-01-01

    The purpose was to assess predictive factors for outcome in patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP) treated with nilotinib after imatinib failure. Imatinib-resistant and -intolerant patients with CML-CP (n = 321) were treated with nilotinib 400 mg twice daily. Of 19 baseline patient and disease characteristics and two response end points analyzed, 10 independent prognostic factors were associated with progression-free survival (PFS). In the multivariate analysis, major cytogenetic response (MCyR) within 12 months, baseline hemoglobin ≥120 g/l, baseline basophils <4%, and absence of baseline mutations with low sensitivity to nilotinib were associated with PFS. A prognostic score was created to stratify patients into five groups (best group: 0 of 3 unfavorable risk factors and MCyR by 12 months; worst group: 3 of 3 unfavorable risk factors and no MCyR by 12 months). Estimated 24-month PFS rates were 90%, 79%, 67% and 37% for patients with prognostic scores of 0, 1, 2 and 3, respectively (no patients with score of 4). Even in the presence of poor disease characteristics, nilotinib provided significant clinical benefit in patients with imatinib-resistant or -intolerant CML. This system may yield insight on the prognosis of patients. PMID:23174881

  7. A Multi-centric Bioequivalence Trial in Ph+ Chronic Myeloid Leukemia Patients to Assess Bioequivalence and Safety Evaluation of Generic Imatinib Mesylate 400 mg Tablets

    Science.gov (United States)

    Arora, Rachna; Sharma, Manju; Monif, Tausif; Iyer, Sunil

    2016-01-01

    Purpose This study was designed to characterize the pharmacokinetic profile and to assess bioequivalence of the sponsor’s test formulation (imatinib mesylate 400 mg tablets) with an innovator product (Gleevec 400 mg tablets, Novartis Pharmaceuticals) under fed conditions, in adult patients of Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) stabilized on imatinib mesylate 400 mg. In addition, the aim of this study was to monitor the safety profile of investigational medicinal products (IMPs). Materials and Methods A multicenter, randomized, open label, two-period, crossover, single dose bioequivalence study was designed for conduct under fed conditions in 42 adult Ph+ CML patients already stabilized on imatinib 400 mg tablets. Pharmacokinetic parameters Tmax, Cmax, and AUC0-24 were calculated using a non-compartmental model on validated WinNonlin software. Validated SAS software was used for statistical evaluation of data. The safety profile of investigational products was monitored during the course of study by applying a clinical process for recording observed untoward effects postadministration of investigational products. Results The 90% confidence intervals for the test/reference mean ratios of the ln-transformed PK variables Cmax (99.0%) and AUC0-24 (99.2%) were within an acceptable range of 80%-125%, as per bioequivalence assumptions. Both formulations were well tolerated after oral administration of IMPs. Conclusion The test product was found to be bioequivalent and safe, and thus can be used interchangeably in clinical practice. PMID:26875198

  8. Long-term safety and efficacy of dasatinib in the treatment of chronic-phase chronic myeloid leukemia patients resistant or intolerant to imatinib

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    Shoumariyeh K

    2014-09-01

    Full Text Available Khalid Shoumariyeh, Nikolas von BubnoffDepartment of Hematology, Oncology and Stem Cell Transplantation, University Hospital Freiburg, Freiburg, Germany Abstract: Treatment of chronic myeloid leukemia (CML has undergone dramatic changes in the last decade. Dissecting the molecular pathways that lead to the development of this disease resulted in the development of targeted therapy against the molecular driver of CML, namely the aberrantly activated tyrosine kinase BCR-ABL1. By introducing the tyrosine kinase inhibitor imatinib to the treatment repertoire, the natural course of the disease has been dramatically altered and overall survival of patients with CML prolonged substantially. Nevertheless, a significant number of patients are primarily resistant, acquire resistance during the course of their disease, or do not tolerate the intake of imatinib due to adverse effects. Second-generation tyrosine kinase inhibitors were developed in an attempt to overcome these problems. Dasatinib is a potent oral kinase inhibitor that was originally developed as an Src-kinase inhibitor but exhibited promising potency against BCR-ABL1 as well. Phase I and II trials demonstrated efficacy in patients failing imatinib, and thus dasatanib was approved in 2006 for the treatment of imatinib-resistant or -intolerant patients with chronic-phase CML harboring the BCR-ABL1 fusion protein. It has since shown promising efficacy and good overall tolerability in subsequent clinical trials, including the Phase III first-line DASISION trial that led to the extension of its approval for first-line treatment of chronic-phase CML. The following review summarizes the available data on the long-term efficacy and safety of dasatinib as a second-line therapy in chronic-phase CML. Keywords: BCR-ABL1, TKI, CML-CP, second-line treatment

  9. Effect of imatinib on the biochemical parameters of the reproductive function in male Swiss albino mice

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    A M Prasad

    2011-01-01

    Full Text Available Background: Treatment of cancers with cytotoxic agents such as tyrosine kinase inhibiting drugs often, but not always, result in transient to permanent testicular dysfunction. Germ cells are important targets of many chemicals. Most of the drugs are genotoxins and induce irreversible effect on genetic makeup. These mutagenic changes are proportionally related to carcinogenesis. This is alarmingly dangerous in youth and children, since these effects last longer, affecting fertility or forming basis for carcinogenesis. There is paucity of reports on planned studies of imatinib on the testicular function. Hence, the study was planned to assess the effects of imatinib on biochemical markers of testicular functions in male Swiss albino mice. Materials and Methods: Male Swiss albino mice were treated with imatinib and sacrificed at the end of first, second, fourth, fifth, seventh, and tenth week after the last exposure to imatinib. The testis were removed, weighed, and processed for biochemical analysis. Results: The intratesticular testosterone level was significantly (P<0.001 reduced in treated groups and severe effect was observed on week 4 and 5. The intratesticular lactate dehydrogenase (LDH level was significantly increased by imatinib in all treated groups up to week 5. Conclusion: Imatinib does affect testosterone and LDH level significantly, but this effect is reversible once the drug is withdrawn. This finding may help the clinicians to plan and address the fertility-related issues in young patients of reproductive age who are being treated with imatinib for gastrointestinal tumors and chronic myeloid leukemia.

  10. Effects of Imatinib Mesylate in Patients with Chronic Myeloid Leukemia%甲磺酸伊马替尼治疗慢性粒细胞白血病的循征评价

    Institute of Scientific and Technical Information of China (English)

    耿素霞; 杜欣

    2007-01-01

    @@ 1 文献类型 治疗. 2 证据水平 1b. 3 文献来源 ① O'Brien SG, Guilhot F, Larson RA, et al.Imatinib compared with interferon and low-dose Cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia [J]. N Engl J Med, 2003,348:994-1004.

  11. Doxorubicin Differentially Induces Apoptosis, Expression of Mitochondrial Apoptosis-Related Genes, and Mitochondrial Potential in BCR-ABL1-Expressing Cells Sensitive and Resistant to Imatinib

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    Ewelina Synowiec

    2015-01-01

    Full Text Available Imatinib resistance is an emerging problem in the therapy of chronic myeloid leukemia (CML. Because imatinib induces apoptosis, which may be coupled with mitochondria and DNA damage is a prototype apoptosis-inducing factor, we hypothesized that imatinib-sensitive and -resistant CML cells might differentially express apoptosis-related mitochondrially encoded genes in response to genotoxic stress. We investigated the effect of doxorubicin (DOX, a DNA-damaging anticancer drug, on apoptosis and the expression of the mitochondrial NADH dehydrogenase 3 (MT-ND3 and cytochrome b (MT-CYB in model CML cells showing imatinib resistance caused by Y253H mutation in the BCR-ABL1 gene (253 or culturing imatinib-sensitive (S cells in increasing concentrations of imatinib (AR. The imatinib-resistant 253 cells displayed higher sensitivity to apoptosis induced by 1 μM DOX and this was confirmed by an increased activity of executioner caspases 3 and 7 in those cells. Native mitochondrial potential was lower in imatinib-resistant cells than in their sensitive counterparts and DOX lowered it. MT-CYB mRNA expression in 253 cells was lower than that in S cells and 0.1 μM DOX kept this relationship. In conclusion, imatinib resistance may be associated with altered mitochondrial response to genotoxic stress, which may be further exploited in CML therapy in patients with imatinib resistance.

  12. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

    Science.gov (United States)

    Pfeifer, Heike; Wassmann, Barbara; Pavlova, Anna; Wunderle, Lydia; Oldenburg, Johannes; Binckebanck, Anja; Lange, Thoralf; Hochhaus, Andreas; Wystub, Silvia; Brück, Patrick; Hoelzer, Dieter; Ottmann, Oliver G

    2007-07-15

    Acquired imatinib resistance in advanced Philadelphia-positive acute lymphoblastic leukemia (Ph(+) ALL) has been associated with mutations in the kinase domain (KD) of BCR-ABL. We examined the prevalence of KD mutations in newly diagnosed and imatinib-naive Ph(+) ALL patients and assessed their clinical relevance in the setting of uniform frontline therapy with imatinib in combination with chemotherapy. Patients enrolled in the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) trial ADE10 for newly diagnosed elderly Ph(+) ALL were retrospectively examined for the presence of BCR-ABL KD mutations by denaturing high-performance liquid chromatography (D-HPLC), cDNA sequencing, and allele-specific polymerase chain reaction (PCR). A KD mutation was detected in a minor subpopulation of leukemic cells in 40% of newly diagnosed and imatinib-naive patients. At relapse, the dominant cell clone harbored an identical mutation in 90% of cases, the overall prevalence of mutations at relapse was 80%. P-loop mutations predominated and were not associated with an inferior hematologic or molecular remission rate or shorter remission duration compared with unmutated BCR-ABL. BCR-ABL mutations conferring high-level imatinib resistance are present in a substantial proportion of patients with de novo Ph(+) ALL and eventually give rise to relapse. This provides a rationale for the frontline use of kinase inhibitors active against these BCR-ABL mutants.

  13. [Effect of tyrosine kinase inhibitor Imatinib mesylate on proliferation, differentiation and apoptosis of Kasumi-1 leukemia cell line].

    Science.gov (United States)

    Wang, Li-Hong; Rao, Qing; Wang, Min; Wang, Jian-Xiang

    2005-08-01

    To explore the effect of Imatinib mesylate on proliferation, differentiation and apoptosis of leukemic Kasumi-1 cells bearing c-kit mutation. Kasumi-1 cells were treated with Imatinib at different concentrations in culture. Cell proliferation was assayed by MTT assay, expressions of c-kit antigen, surface myeloid antigen and cell cycle by flow cytometry, cell apoptosis by annexin V staining and agarose gel electrophoresis. Western blot was used to analyze the level of c-kit protein tyrosine phosphorylation. Imatinib treatment caused a time- and dose-dependent inhibition of the cell proliferation, with a 72 h IC50 of 4.45 micromol/L. Imatinib treatment induced a decrease in the mean fluorescence value of c-kit antigen, a progressive decline in S-phase cell fraction and an increase in G0/G1 cells. Treatment with 5.00 micromol/L of imatinib for 72 h induced an increase in expression of myeloid surface protein CD11, CD13 and CD15, and for 24 h induced an increase in early apoptosis cells [from 9.04% to 86.84% (P Kasumi-1 cells which bear a c-kit mutation, induce differentiation, apoptosis and G0/G1 cells accumulation.

  14. Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia.

    Science.gov (United States)

    Zeng, Xian; Zhao, Hui; Li, Yubin; Fan, Jiajun; Sun, Yun; Wang, Shaofei; Wang, Ziyu; Song, Ping; Ju, Dianwen

    2015-01-01

    The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL(+) CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL(+) CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL(+) cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL(+) cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.

  15. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia

    NARCIS (Netherlands)

    K. Porkka (Kimmo); P. Koskenvesa (Perttu); T. Lundan (Tuija); J. Rimpiläinen (Johanna); S. Mustjoki (Satu); R. Smykla (Richard); R. Wild (Robert); R. Luo (Roger); M. Arnan (Montserrat); B. Brethon (Benoit); L. Eccersley (Lydia); H. Hjorth-Hansen (Henrik); M. Höglund (Martin); H. Klamova (Hana); H. Knutsen (Håvar); S. Parikh (Suhag); E. Raffoux (Emmanuel); F. Gruber (Franz); F. Brito-Babapulle (Finella); H. Dombret (Hervé); R.F. Duarte (Rafael); E. Elonen (Erkki); R. Paquette (Ron); C.M. Zwaan (Christian Michel); F.Y.F. Lee (Francis)

    2008-01-01

    textabstractAlthough imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a

  16. Monitoração molecular da Leucemia Mielóide Crônica na era do imatinibe Molecular monitoring of Chronic Myeloid Leukemia in the imatinib era

    Directory of Open Access Journals (Sweden)

    Israel Bendit

    2008-04-01

    Full Text Available Nos últimos dez anos, o tratamento da leucemia mielóide crônica (LMC passou por uma grande mudança com a introdução da terapia alvo, onde o mesilato de imatinibe (MI atua inibindo a atividade tirosina quinase do transcrito BCR-ABL produto este do cromossomo Filadélfia (Ph. Esta revolução terapêutica obrigou que técnicas moleculares, até então de uso restrito na oncohematologia, como a reação em cadeia da polimerase em tempo real (RQ-PCR, fossem necessárias para monitorar o sucesso terapêutico ou a detecção precoce da perda de resposta ao MI. Nesta revisão estão delineados, de forma resumida, os principais procedimentos quanto à monitoração dos pacientes com LMC em tratamento com o MI segundo o Consenso Brasileiro de LMC.Treatment of chronic myeloid leukemia (CML has changed since the introduction of imatinib mesylate (IM 10 years ago. IM acts as a target therapy against the BCR-ABL gene by inhibiting its tyrosine kinase activity. This revolution in treating CML compels the introduction of molecular techniques, such as real time quantitative polymerase chain reaction (RQ-PCR to monitor the response to IM by providing an accurate measurement of the degree to which the BCR-ABL transcript is reduced or an early detection of loss of response identified by a rising level of BCR-ABL. In this review, we summarize the Brazilian CML consensus regarding the main procedures used to monitor CML patients treated with IM.

  17. Therapy of chronic myeloid leukemia with imatinib mesylate in Brazil: a study of 98 cases Tratamento da leucemia mielóide crônica com imatinib mesilato no Brasil: estudo de 98 casos

    Directory of Open Access Journals (Sweden)

    Vaneuza A. M. Funke

    2005-09-01

    Full Text Available Chronic Myeloid Leukemia (CML is a clonal disease characterized by balanced translocation between chromosomes 9 and 22 (Philadelphia chromosome. The resulting BCR-ABL gene has tyrosine kinase activity which stimulates cellular growth. Imatinib mesylate is a potent and specific inhibitor of all ABL related kinases. Ninety-eight CML patients were treated with imatinib mesylate from October 2000 to January 2003. Disease stage was: late chronic phase resistant or intolerant to alpha-interferon (CP: 28; accelerated phase (AP: 55; blastic phase (BP: 15 patients. Dose: 400 mg for CP and 600 mg for AP or CB. The objectives were to evaluation the efficacy, safety and survival with imatinib mesylate therapy in all phases of CML. The median follow up time was 545 days (range: 7-862, complete hematologic response was 86% in CP, 47% in AP and 13% in BP. Complete cytogenetic response was 61%, 24% and 0% respectively. BCR-ABL was not detected by nested RT-PCR in 9% of patients. Grade 3-4 hematologic toxicity was seen in 21% of CP, 74% of AP and 87% of BP patients. Grade 3-4 non-hematologic toxicity was observed in 11% of CP, 51% of AP and 53% of BP patients. Two-year overall survival was 64% for all patients, 96% for CP and 36% for AP patients. All BP patients died within a median of 60 days. Imatinib mesylate induced cytogenetic responses in Brazilian patients with previously treated CML in chronic and accelerated phase. Adverse events are similar to those reported in the literature, except for lower rates of gastrointestinal symptoms and muscle cramps in our study group.INTRODUÇÃO: A Leucemia Mielóide Crônica (LMC é uma doença clonal caracterizada pela presença da translocação entre os cromossomos 9 e 22 (cromossomo Philadelphia. O gene resultante BCR-ABL possui atividade de tirosino-quinase, que estimula o crescimento celular. O mesilato de imatinibe é um inibidor potente e específico de todas as quinases relacionadas ao ABL. PACIENTES E M

  18. Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

    Science.gov (United States)

    2016-12-28

    B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; BCR-ABL1 Fusion Protein Expression; Minimal Residual Disease; Philadelphia Chromosome Positive; T Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  19. H2AX phosphorylation regulated by p38 is involved in Bim expression and apoptosis in chronic myelogenous leukemia cells induced by imatinib.

    Science.gov (United States)

    Dong, Yaqiong; Xiong, Min; Duan, Lianning; Liu, Ze; Niu, Tianhui; Luo, Yuan; Wu, Xinpin; Xu, Chengshan; Lu, Chengrong

    2014-08-01

    Increasing evidence suggests that histone H2AX plays a critical role in regulation of tumor cell apoptosis and acts as a novel human tumor suppressor protein. However, the action of H2AX in chronic myelogenous leukemia (CML) cells is unknown. The detailed mechanism and epigenetic regulation by H2AX remain elusive in cancer cells. Here, we report that H2AX was involved in apoptosis of CML cells. Overexpression of H2AX increased apoptotic sensitivity of CML cells (K562) induced by imatinib. However, overexpression of Ser139-mutated H2AX (blocking phosphorylation) decreased sensitivity of K562 cells to apoptosis. Similarly, knockdown of H2AX made K562 cells resistant to apoptotic induction. These results revealed that the function of H2AX involved in apoptosis is strictly related to its phosphorylation (Ser139). Our data further indicated that imatinib may stimulate mitogen-activated protein kinase (MAPK) family member p38, and H2AX phosphorylation followed a similar time course, suggesting a parallel response. H2AX phosphorylation can be blocked by p38 siRNA or its inhibitor. These data demonstrated that H2AX phosphorylation was regulated by p38 MAPK pathway in K562 cells. However, the p38 MAPK downstream, mitogen- and stress-activated protein kinase-1 and -2, which phosphorylated histone H3, were not required for H2AX phosphorylation during apoptosis. Finally, we provided epigenetic evidence that H2AX phosphorylation regulated apoptosis-related gene Bim expression. Blocking of H2AX phosphorylation inhibited Bim gene expression. Taken together, these data demonstrated that H2AX phosphorylation regulated by p38 is involved in Bim expression and apoptosis in CML cells induced by imatinib.

  20. FIP1L1-PDGFRα alone or with other genetic abnormalities reveals disease progression in chronic eosinophilic leukemia but good response to imatinib

    Institute of Scientific and Technical Information of China (English)

    WANG Lin-na; CHEN Sai-juan; PAN Qin; FU Jian-fei; SHI Jing-yi; JIN Jie; LI Jun-ming; HU Jiong; ZHAO Wei-li; CHEN Zhu

    2008-01-01

    Background The FIP1L1-PDGFRα fusion gene plays an important role in the pathogenesis of chronic eosinophilic leukemia (CEL) and is a direct therapeutic target of the tyrosine kinase inhibitor imatinib mesylate.Methods In 24 hypereosinophilic syndromes (HES) patients, using reverse transcriptase-polymerase chain reaction (RT-PCR), nested PCR and sequence analysis, we investigated the frequency of FIPIL1-PDGFRα and other abnormalities of tyrosine kinase family genes like PDGFRα, PDGFRβ, C-KIT, FGFR1, ABL and FLT3 as well as gene mutation "hotspots", like MPL515 and JAK2V617F, frequently involved in myeloproliferative diseases. Fluorescence in situ hybridization was used to confirm the 4q12 deletion.Results The FIPILI-PDGFRα fusion transcript was found in 8 (33%) of 24 patients with HES, corresponding to the chromosome 4q12 deletion identified by FISH. The FIP1L1-PDGFRα-associated patients diagnosed with CEL, frequently had hepatosplenomegaly, eosinophil-related tissue damage, anemia, thrombocytopenia, myelofibrosis and a short overall survival time. Nevertheless, imatinib mesylate induced rapid and complete hematological responses in treated FIP1L1-PDGFRα cases, followed by molecular remission and reversal of myelofibrosis. FIP1L1-PDGFRα fusion could co-exist with other mutations of tyrosine kinase family genes, like FLT3 or PDGFRβ. We also demonstrated that the SNPs of PDGFRβ were associated with selective splicing of exon 19 in case 20.Conclusions Correlating the CEL genotype with phenotype, FIPIL 1-PDGFRα emerges as a relatively homogeneous clinicobiological entity that co-exists with other abnormalities of tyrosine kinase family genes. It reflects the disease progression and there is a good response to imatinib. Detection of the FIP1L1-PDGFRα fusion gene is valid for both CEL diagnosis and therapy surveillance.

  1. Follow-up of the tumor load in patients with de novo chronic myeloid leukemia and in complete cytogenetic remission treated with imatinib in Colombia

    Directory of Open Access Journals (Sweden)

    Guevara, Gonzalo

    2012-12-01

    Full Text Available Objective: To evaluate the hematological, cytogenetic, and molecular responses in Colombian patients with CML chronic myeloid leukemia (CML treated with imatinib.Methods: Two groups of patients, one with the novo diagnostic and another in state of complete cytogenetic remission were followed for 12 months with quantitative PCR evaluations every three months and with chromosomal analysis every 6 months.Results: The group with the novo diagnosis showed 50% of complete cytogenetic remission at 12 months while the other 50% were considered to have primary resistance. Respect the molecular analysis, 10.5% of the patients reached undetectable BCR-ABL transcripts at 12 months. In the complete cytogenetic remission group, 10.6% lost the state of complete cytogenetic remission at 12 months, 50% reached undetectable BCR-ABL transcripts but 10% showed levels higher than 10%, which in our standardization was equal to no molecular response. Conclusions: Despite having received the conventional dosages of 400 mg/day of imatinib, the cytogenetic and molecular responses obtained in our group of Colombian patients with CML, were lower than those in other international studies

  2. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results

    Science.gov (United States)

    Giles, Francis J.; Bhalla, Kapil N.; Pinilla-Ibarz, Javier; Larson, Richard A.; Gattermann, Norbert; Ottmann, Oliver G.; Hochhaus, Andreas; Radich, Jerald P.; Saglio, Giuseppe; Hughes, Timothy P.; Martinelli, Giovanni; Kim, Dong-Wook; Shou, Yaping; Gallagher, Neil J.; Blakesley, Rick; Baccarani, Michele; Cortes, Jorge; le Coutre, Philipp D.

    2011-01-01

    Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure. This trial was registered at www.clinicaltrials.gov as #NCT00109707. PMID:21098399

  3. [A female chronic myeloid leukemia patient who gave birth after stopping imatinib intentionally but who maintained a major molecular response with interferon].

    Science.gov (United States)

    Osawa, Tomohiro; Takahashi, Takeshi; Yasuda, Masahiro; Umeda, Michi; Nagaya, Katsuhiro; Tachi, Tomoya; Goto, Hideko; Kasahara, Senji; Teramachi, Hitomi; Goto, Chitoshi

    2015-04-01

    Imatinib was administrated to a 38-year-old woman with chronic myeloid leukemia(CML). A major molecular response (MMR)(≤5 copies/0.5 μgRNA in Amp-CML detected using the transcription mediated amplification/hybridization protection assay(TMA/HPA)method)was achieved in 18 months. She maintained MMR for 10 months, and wished to become pregnant. Imatinib was stopped intentionally because she wished to plan a pregnancy, but we prescribed interferon alpha (IFN-a)due to the likelihood of the CML recurring after pregnancy. The nausea caused by IFN-a was improved by administrating it during the night, and she gave birth to a healthy baby by a normal delivery, whilst maintaining MMR. In this case, IFN-a treatment gave good clinical results, the patient's prognosis was improved, and she could maintain a good quality of life. We consider this to be an informative example of IFN-a therapy for CML during pregnancy.

  4. Slow desensitization of imatinib-induced nonimmediate reactions and dynamic changes of drug-specific CD4(+)CD25(+)CD134(+) lymphocytes.

    Science.gov (United States)

    Klaewsongkram, Jettanong; Thantiworasit, Pattarawat; Sodsai, Pimpayao; Buranapraditkun, Supranee; Mongkolpathumrat, Pungjai

    2016-11-01

    Imatinib is a tyrosine kinase inhibitor indicated for the treatment of gastrointestinal stromal tumors (GISTs) and certain neoplastic diseases; however, nonimmediate adverse reactions are common. To describe the process of imatinib slow desensitization in patients who experienced nonimmediate reactions to imatinib and the dynamic change in drug-specific CD4(+)CD25(+)CD134(+) T-lymphocyte percentages. Five patients diagnosed as having GISTs and with a recent history of imatinib-induced nonimmediate reactions (maculopapular exanthema with eosinophilia, exfoliative dermatitis, palmar-plantar erythrodysesthesia, and drug rash with eosinophilia and systemic symptoms) were desensitized using a slow desensitization protocol. The reintroduced imatinib dosage was stepped up every week starting from 10 mg/d and increasing to 25, 50, 75, 100, 150, 200, and 300 mg/d until the target dose of 400 mg/d was achieved. Prednisolone of up to 30 mg/d was allowed if allergic reactions recurred. The percentages of CD4(+)CD25(+)CD134(+) T cells present after incubating peripheral blood mononuclear cells with imatinib, at baseline and after successful desensitization, were analyzed using flow cytometric analysis. By using a slow desensitization technique, all patients were able to receive 400 mg/d of imatinib, and prednisolone was gradually tapered off. The percentages of imatinib-induced CD4(+)CD25(+)CD134(+) T cells decreased from a mean (SD) of 11.3% (6.5%) and 13.4% (7.3%) at baseline to 3.2% (0.7%) and 3.0% (1.1%) after successful desensitization, when stimulating peripheral blood mononuclear cells with 1 and 2 μM of imatinib, respectively. Slow desensitization is a helpful procedure in treating patients with imatinib-induced nonimmediate reactions other than simple maculopapular exanthema. The reduced percentages of imatinib-induced CD4(+)CD25(+)CD134(+) T cells in these patients may be associated with immune tolerance. Copyright © 2016 American College of Allergy, Asthma

  5. The Effect of Imatinib Mesylate for Newly Diagnosed Philadelphia Chromosome-Positive, Chronic-Phase Myeloid Leukemia in Sub-Saharan African Patients: The Experience of Côte d'Ivoire

    Directory of Open Access Journals (Sweden)

    K. G. Koffi

    2010-01-01

    Full Text Available Imatinib mesylate, showed encouraging activity in chronic myelogenous leukemia. However, there are few data regarding his efficacy and response monitoring in Sub-Saharan African patients. Our objective was to assess response to imatinib mesylate (Glivec in Côte d’Ivoire patients with newly diagnosed Chronic Myeloid Leukemia (CML. From May 2005 to September 2009, we treated 42 patients (40 years; range 16–69 with Philadelphia chromosome (Ph+ positive in chronic phase CML with oral imatinib mesylate at daily doses of 400 mg. Overall survival (OS and frequency of complete or major cytogenetic remission (CCR/MCR were evaluated. At a median follow up of 32 (range 7.6–113 months, the CHR rate in our study group was 76%. A major CR was found in 19 patients (45% with 17% and 29% complete and partial CR respectively. There were no significant differences in the incidence of major cytogenetic response by known prognostics factors. Median time to CHR was 8 months (range 0.4–25, and 16 months (range: 0.1–36 for CR. Projected 5-year OS rate was 72% (95%CI 42–88. We conclude that imatinib therapy sub-Saharan African CML patients is very promising and has favorably changed the prognosis for black African patients with CML.

  6. Successful Peripheral Blood Stem Cells Collection in Imatinib Pretreated and Nilotinib-Treated Chronic Myeloid Leukemia Patient

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    Samuel Vokurka

    2010-01-01

    Full Text Available We report a case of a successful mobilization and harvest of the peripheral blood stem cells (PBSCs in imatinib-pretreated and nilotinib treated 52-year-old woman diagnosed with Philadelphia chromosome-positive and BCR-ABL (b2a2 positive chronic phase CML in 2/2002. She failed interferon-alfa and imatinib treatment. She achieved her first complete molecular remission after 16 months of nilotinib treatment and later on was mobilized with filgrastim at a dose of 10 ug/kg/day applied subcutaneously once daily. The total number of 2.98×106 CD34+ cells/kg was harvested on the fourth day of the mobilization. The autologous graft of the stem cells was cryopreserved and tested for the residual disease: the FISH revealed negative results and the RT-PCR was positive (BCR-ABL/ABL ratio 0,0017 in RQ-PCR. To our knowledge, this is the first report of successful PBSC harvest in a patient significantly pretreated with imatinib and nilotinib.

  7. Differential expression and alternative splicing of cell cycle genes in imatinib-treated K562 cells.

    Science.gov (United States)

    Liu, Jing; Lin, Jin; Huang, Lin-Feng; Huang, Bo; Xu, Yan-Mei; Li, Jing; Wang, Yan; Zhang, Jing; Yang, Wei-Ming; Min, Qing-Hua; Wang, Xiao-Zhong

    2015-09-01

    Cancer progression often involves the disorder of the cell cycle, and a number of effective chemotherapeutic drugs have been shown to induce cell cycle arrest. The purpose of this study was to comprehensively investigate the effects of imatinib on the expression profile of cell cycle genes in the chronic myeloid leukemia (CML) K562 cell line. In addition, we also investigated alternative splicing of the cell cycle genes affected by imatinib, since an important relationship has been shown to exist between RNA splicing and cell cycle progression. Exon array analysis was performed using total RNA purified from normal and imatinib-treated K562 cells. We identified 185 differentially expressed genes and 277 alternative splicing events between the two cell groups. A detailed analysis by reverse transcription-PCR (RT-PCR) of key genes confirmed the experimental results of the exon array. These results suggested that treatment of K562 cells with imatinib shifts the expression and alternative splicing profiles of several cell cycle-related genes. Importantly, these findings may help improve imatinib treatment strategies in patients with CML and may be useful for imatinib resistance research and CML drug development.

  8. Imatinib-induced fatal acute liver failure

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Imatinib mesylate is a drug that has been approved for treatment of chronic myeloid leukemia (CML) in blast crisis, accelerated or chronic phase, and also for advanced gastrointestinal stromal tumors. Severe hepatic toxicity and three deaths from hepatic failure have been reported. We report the case of a 51-year-old woman who was admitted to our institution with severe acute hepatitis. She was diagnosed with CML and began treatment with imatinib mesylate at a dose of 400 mg/d.Five months after beginning treatment, she developed severe hepatitis associated with coagulopathy, and was admitted to our institution. She had been consuming acetaminophen 500-1000 mg/d after the onset of symptoms. She had a progressive increase in bilirubin level and a marked decrease of clotting factor Ⅴ. Five days after admission, grade Ⅱ encephalopathy developed and she was referred for liver transplantation. Her clinical condition progressively deteriorated, and 48 h after being referred for transplantation she suffered a cardiac arrest and died. This report adds concern about the possibility of imatinib-mesylate-induced hepatotoxicity and liver failure, particularly in the case of concomitant use with acetaminophen. Liver function tests should be carefully monitored during treatment and, with the appearance of any elevation of liver function tests, treatment should be discontinued.

  9. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance.

    Science.gov (United States)

    Kantarjian, Hagop; le Coutre, Phillipp; Cortes, Jorge; Pinilla-Ibarz, Javier; Nagler, Arnon; Hochhaus, Andreas; Kimura, Shinya; Ottmann, Oliver

    2010-06-01

    : INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance. : A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. : INNO-406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and

  10. 甲磺酸伊马替尼治疗慢性粒细胞白血病疗效观察%Efficacy of imatinib in the treatment of chronic myeloid leukemia

    Institute of Scientific and Technical Information of China (English)

    黄敬青

    2009-01-01

    目的 探讨甲磺酸伊马替尼治疗慢性粒细胞白血病(CML)的体会.方法 40例CML患者接受甲磺酸伊马替尼治疗,其中慢性期(CP)20例,加速期(AP)8例,急变期(BC)12例.甲磺酸伊马替尼用法:CP患者400 mg/d,AP和BC患者600 mg/d,均为餐后1次顿服.治疗前全面查体,查血象、骨髓象、Ph染色体和(或)bcr/abl融合基因.治疗期间第1个月每周查血象2次,1个月后每周或2周1次.每2~4周查一次肝、肾功能.待血液学取得完全缓解(CR)后择期复查骨髓、Ph染色体和(或)bcr/abl基因.根据血象和患者对药物耐受情况及时调整药物剂量.结果 经中位时间20个月(12~24个月)随访,20例CML CP期患者均取得血液学CR,其中7例(35%)Ph染色体转阴,8例AP患者中6例(75%)回到CP,12例BC患者中4例(33.3%)回到CP.药物不良反应有造血功能抑制、眶周和下肢轻度水肿、全身肌肉关节酸痛和恶心、呕吐、低热(37.5~38.5℃)、皮疹、胆红素升高等.结论 甲磺酸伊马替尼对CML有较好疗效,药物不良反应可耐受.%Objective To explore the management experience of imatinib in the treatment of chronic myeloid leuke-mia (CML). Methods There were 40 CML. 20 patients in chronic phase(CP), 8 patients in accelerated phase(AP) and 12 patients in blast crisis(BC). The dosage of imatinib was 400 mg/d for CP patients and 600 mg/d for AP and BC patients. The prescribed dose was administrated orally, once daily after a meal with a large glass of water. Before starting the imatinib administration, all the patients had thorough physical examination as well as blood and bone marrow examination. Ph chromo-some and or the bcr/abl fusion- gene detection again when they achieved a hematological response(CR). Dose was adjusted from time to time according to the results of blood examination and the patients tolerance to the drug. Results After a median 20 - month period of follow - up, all the 20 CP patients achieved complete

  11. Downregulated microRNA-148b in circulating PBMCs in chronic myeloid leukemia patients with undetectable minimal residual disease: a possible biomarker to discontinue imatinib safely

    Directory of Open Access Journals (Sweden)

    Ohyashiki JH

    2014-08-01

    Full Text Available Junko H Ohyashiki,1 Kazushige Ohtsuki,1 Izuru Mizoguchi,2 Takayuki Yoshimoto,2 Seiichiro Katagiri,3 Tomohiro Umezu,1,4 Kazuma Ohyashiki3,4 1Department of Molecular Oncology, Institute of Medical Science, 2Department of Immunoregulation, Institute of Medical Science, 3Department of Hematology, 4Department of Molecular Science, Tokyo Medical University, Tokyo, Japan Background: A subset of patients with chronic myeloid leukemia (CML can sustain a complete molecular response after discontinuing imatinib mesylate (IM. We focused on microRNAs (miRNAs, with the aim of finding a molecular biomarker to discriminate which patients can safely and successfully discontinue IM use. Methods: To identify miRNAs that showed altered expression in patients who had discontinued IM (STOP-IM group, we first screened miRNA expression of peripheral blood mononuclear cells by using a TaqMan miRNA array on samples from five unselected patients from the STOP-IM group, seven CML patients receiving IM (IM group, and five healthy volunteers. We then performed miRNA quantification in 49 CML patients with deep molecular response. Mann–Whitney U and chi-square tests were used to determine statistical significance for comparisons between the control (healthy volunteers and test groups (STOP-IM and IM groups. Multiple groups were compared by one-way analysis of variance. Results: Downregulation of miR-148b was noted in patients in the STOP-IM group and in a subset of the IM group. We then subdivided the IM patients into two groups: one with downregulated miR-148b expression (IM-1; less than the cut-off value and the other without downregulated miR-148b expression (IM-2; greater than the cut-off value. The number of patients who had a sustained stable molecular response was significantly lower in IM-2 group. This group also had a significantly lower percentage of natural killer cells. Conclusion: Downregulated miR-148 may contribute to immune surveillance in STOP-IM patients

  12. Efficacy of Dasatinib in Treatment of Imatinib-Resistant BCR/ABL Positive Leukemia%达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病的临床研究

    Institute of Scientific and Technical Information of China (English)

    朱雨; 潘良琴; 钱思轩; 宋萍; 于慧; 张苏江; 葛峥; 洪鸣; 田甜

    2013-01-01

    imatinib-resistant BCR/ABL positive leukemia cases,with a median follow-up of 54 (3-75) months.After the dasatinib treatment,88.8% of all the 27 cases achived complete hematologic response (CHR),29.6% of them achived major cytogenetic response (mCyR),37% of all achived complete cytogenetic response (CCyR) and 18.5% cases achived major molecular response (MMR).Patients who received dasatinib in progress of disease (CML-AP,CML-BC and bone marrow relapse Ph+ ALL) had a lower CCyR rate than those in stable disease (CML-CP and bone marrow remission Ph + ALL) (P =0.0377),and 3-4 grade adverse events occured more frequently in progress of disease than that in stable disease.Overall survival of the patients who achived CCyR after dasatinib therapy was statistically longer than those who did not achive CCyR (63 m vs 9 m,P =0.0126).The most common grade 3-4 adverse events during dasatinib therapy including hematology events such as thrombocytopenia (51.8%),neutropenia (48.1%),anemia (33.3%),and non-hematologic events such as pleural effusion (18.5 %),pulmonary infection (18.5 %),pericardial effusion (11.1%).The 3-4 grade adverse events occared within 12 months from dasatinib therapy,and were mainly observed in patients with progress of disease.It is concluded that dasatinib is an effective drug in imatinib-resistant BCR/ABL positive leukemia patients,the better curative effect and better tolerance has been observed in patients who received dasatinib in stable disease.

  13. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study.

    Science.gov (United States)

    Baccarani, Michele; Druker, Brian J; Branford, Susan; Kim, Dong-Wook; Pane, Fabrizio; Mongay, Lidia; Mone, Manisha; Ortmann, Christine-Elke; Kantarjian, Hagop M; Radich, Jerald P; Hughes, Timothy P; Cortes, Jorge E; Guilhot, François

    2014-01-01

    The TOPS trial evaluated high- (800 mg/day; n = 319) versus standard-dose (400 mg/day; n = 157) imatinib in patients newly diagnosed with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. Patients had a minimum follow-up of 42 months or discontinued early. Major molecular response (MMR) rates were similar between arms at (51.6 vs 50.2 % for 400 and 800 mg/day, respectively; P = 0.77) and by (75.8 vs 79.0 %; P = 0.4807) 42 months. There were no differences in event-free survival (EFS), progression-free survival(PFS), or overall survival (OS) between arms. The estimated rates of PFS on treatment and OS at 42 months were significantly higher in patients with MMR at 6, 12, and 18 months compared with those without MMR.Adverse events were more frequent with high-dose imatinib. Patients with B1 treatment interruption (vs [1) and those able to maintain imatinib C600 mg/day (vs\\600 mg/day) in the first year of treatment had faster and higher response rates, but no improvement in EFS or PFS. Adherence to prescribed dose without interruption may be more important than initiation of therapy with higher doses of imatinib. Achievement of MMR correlated with longterm clinical outcomes.

  14. Effects of Formulation Variables on the Particle Size and Drug Encapsulation of Imatinib-Loaded Solid Lipid Nanoparticles.

    Science.gov (United States)

    Gupta, Biki; Poudel, Bijay Kumar; Pathak, Shiva; Tak, Jin Wook; Lee, Hee Hyun; Jeong, Jee-Heon; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2016-06-01

    Imatinib (IMT), an anticancer agent, inhibits receptor tyrosine kinases and is characterized by poor aqueous solubility, extensive first-pass metabolism, and rapid clearance. The aims of the current study are to prepare imatinib-loaded solid lipid nanoparticles (IMT-SLN) and study the effects of associated formulation variables on particle size and drug encapsulation on IMT-SLN using an experimental design. IMT-SLN was optimized by use of a "combo" approach involving Plackett-Burman design (PBD) and Box-Behnken design (BBD). PBD screening resulted in the determination of organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), and amount of Tween® 20 (Tw20) as three significant variables for particle size (S z), drug loading (DL), and encapsulation efficiency (EE) of IMT-SLN, which were used for optimization by BBD, yielding an optimized criteria of O/A = 0.04, D/L = 0.03, and Tw20 = 2.50% w/v. The optimized IMT-SLN exhibited monodispersed particles with a size range of 69.0 ± 0.9 nm, ζ-potential of -24.2 ± 1.2 mV, and DL and EE of 2.9 ± 0.1 and 97.6 ± 0.1% w/w, respectively. Results of in vitro release study showed a sustained release pattern, presumably by diffusion and erosion, with a higher release rate at pH 5.0, compared to pH 7.4. In conclusion, use of the combo experimental design approach enabled clear understanding of the effects of various formulation variables on IMT-SLN and aided in the preparation of a system which exhibited desirable physicochemical and release characteristics.

  15. Imatinib Use in Pregnancy

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    Michael J Webb

    2012-12-01

    Full Text Available The outcome in patients with chronic myeloid leukemia (CML has dramatically improved over the last decade due to the widespread use of novel tyrosine kinase inhibitors such as imatinib. As overall survival has improved, the number of women with CML that wish to become pregnant has increased. As such, attending physicians are faced with a dilemma-continue life-prolonging medication to treat the cancer, or interrupt its use due to its potential teratogenicity. Herein we describe 2 CML patients that gave birth. Case 1 was managed via substitution of imatinib with interferon. The patient’s child underwent genetic evaluation at age 3 years, achieved normal developmental milestones, and despite being shorter than his peers was proportional. In terms of morphology, the child had clinodactyly, short fifth fingers, and slightly downward slanting palpebral fissures, but otherwise appeared normal. In case 2 imatinib was continued throughout the pregnancy. This patient’s child underwent postpartum evaluation by a geneticist and was observed to be morphologically normal, except for clinodactyly and low-set ears.

  16. PROGNOSTIC FACTORS FOR OUTCOMES IN ALLOGENEIC TRANSPLANTATION FOR ADVANCED PHASES OF CHRONIC MYELOID LEUKEMIA IN THE IMATINIB ERA: A CIBMTR ANALYSIS

    Science.gov (United States)

    Khoury, Hanna J; Kukreja, Manisha; Goldman, John M.; Wang, Tao; Halter, Jorg; Arora, Mukta; Gupta, Vikas; Rizzieri, David A.; George, Biju; Keating, Armand; Gale, Robert Peter; Marks, David I.; McCarthy, Philip L.; Woolfrey, Ann; Szer, Jeffrey; Giralt, Sergio A.; Maziarz, Richard T.; Cortes, Jorge; Horowitz, Mary M.; Lee, Stephanie J

    2013-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment, albeit in a minority of patients with accelerated (AP) or blast phase (BP) chronic myeloid leukemia (CML). Imatinib (IM) has transient but significant activity in advanced phases of CML, which may permit early allografting for responding patients. To identify prognostic factors in allograft recipients previously treated with IM, we analyzed 449 allogeneic HSCT performed between 1999–2004 in advanced phase CML using data reported to the Center for International Blood and Marrow Transplant Research. CML patients in second chronic phase (CP2, n=184), AP (n=185), and BP (n=80) received HLA-identical sibling (27%), related (3%), or matched or mismatched unrelated donor (70%), peripheral blood (47%) or bone marrow (53%) HSCT after myeloablative (78%) or non-myeloablative (22%) conditioning. 52% in CP2, 49% in AP, and 46% in BP received IM pre-HSCT. Disease-free survival was 35–40% for CP2, 26–27% for AP and 8–11% for BP. Cumulative incidence of acute and chronic GVHD and TRM were not affected by stages of CML or pre-HSCT IM exposure. Multivariate analyses showed that conventional prognostic indicators remain the strongest determinants of transplant outcomes. In conclusion, there are no new prognostic indicators of outcomes of allogeneic HSCT for advanced phase CML in the IM era. PMID:21986636

  17. Isolated Ocular Manifestation of Relapsed Chronic Myelogenous Leukemia Presenting as Myeloid Blast Crisis in a Patient on Imatinib Therapy: A Case Report and Review of the Literature

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    Rohit Gulati

    2015-01-01

    Full Text Available Blast phase in chronic myelogenous leukemia (CML has rarely been reported to involve extramedullary sites like skin, lymph nodes, and central nervous system. Clinical history, characteristic hematologic findings (elevated leukocyte counts, myelocytic predominance, and basophilia, and Philadelphia chromosome are of high diagnostic significance especially in isolated extramedullary presentations. We describe a unique case of CML relapse with blast phase involving the eye. A 66-year-old man with a known diagnosis of CML on imatinib and in molecular remission for 3 years presented with a painful blind eye. Histologic examination revealed diffuse involvement of choroid, iris, vitreous humor, and the optic nerve by blast cells. The blasts expressed CD34, aberrant TdT, and a myeloid phenotype (CD13, CD33, and CD117. Fluorescence in situ hybridization (FISH of vitreous fluid detected BCR-ABL1 gene rearrangement. Additionally, trisomy 8 and gains of 9 and 22 were seen which were not present in the initial diagnostic marrow study 3 years ago. At relapse, the bone marrow, peripheral blood, and the cerebrospinal fluid were not involved by CML. Patient received induction chemotherapy and single dose prophylactic intrathecal methotrexate and was maintained on antityrosine kinase therapy and eventually underwent allogenic stem cell transplantation.

  18. Leucemia Mielóide Crônica: novas drogas em desenvolvimento Chronic Myeloid Leukemia: development of new drugs

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    Cármino A. de Souza

    2008-04-01

    Full Text Available A LMC é um modelo de investigação biológica e clinica que deve ser seguido nesta nova fase da oncologia moderna. A resposta terapêutica ao uso do imatinibe como droga de primeira linha mudou os conceitos e paradigmas e criou uma expectativa que drogas mais potentes possam ser desenvolvidas no futuro. Infelizmente nem todos conseguem atingir essa situação ideal. Por esta razão, Baccarani M sugeriu que a falência de resposta subótima, precaução ou alerta fossem estudadas no sentido de serem desenvolvidas intervenções terapêuticas diferenciadas mais precoces. A resistência ao imatinibe existe e depende de vários mecanismos. Tanto mais tardia a introdução do imatinibe e mais avançada for a fase evolutiva da doença maior a freqüência de resistência. Do ponto de vista biológico, a superexpressão do BCR-ABL, os defeitos genéticos adicionais e as mutações que podem atingir várias regiões da molécula - a alça de fosfato, a alça de ativação, o domínio da quinase são os mais importantes fatores associados à resistência ao imatinibe. Por esta razão, são necessárias outras opções terapêuticas e hoje há o desenvolvimento de um grande número de drogas para um número maior de alvos. Inicialmente temos o dasatinibe, já aprovado nos EUA, na Europa e também no Brasil; o nilotinibe, em fase avançada de estudos clínicos (inclusive de fase III, e também já aprovado para uso nos EUA; o bosutinibe, o INNO - 406 bem como outras drogas que atuam em alvos como as aurora-quinases ou inibidores de histona-deacetilases.Chronic Myeloid Leukemia (CML is a model of clinical and biological investigation that may be useful for other neoplastic diseases. The therapeutic response to imatinib as the front line therapy has changed concepts and procedures in CML and has created hope concerning new more potent drugs for this and other oncological diseases that have a similar mechanism of action. However, not all patients achieve

  19. MPT0B169, a New Antitubulin Agent, Inhibits Bcr-Abl Expression and Induces Mitochondrion-Mediated Apoptosis in Nonresistant and Imatinib-Resistant Chronic Myeloid Leukemia Cells.

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    Shuit-Mun Wong

    Full Text Available Chronic myeloid leukemia (CML is a clonal disorder of hematopoietic stem/progenitor cells that is caused by the Bcr-Abl oncoprotein. Clinical resistance to the Bcr-Abl inhibitor imatinib is a critical problem in treating CML. This study investigated the antitumor effect and mechanism of MPT0B169, a new antitubulin agent, in K562 CML cells and their derived imatinib-resistant cells, IMR2 and IMR3. IMR2 and IMR3 cells showed complete resistance to imatinib-induced growth inhibition and apoptosis. Resistance involved ERK1/2 overactivation and MDR1 overexpression. MPT0B169 inhibited the growth of K562, IMR2, and IMR3 cells in a dose- and time-dependent manner. MPT0B169 substantially inhibited the mRNA and protein levels of Bcr-Abl, followed by its downstream pathways including Akt, ERK1/2, and STAT3 in these cells. MPT0B169 treatment resulted in a decrease in the polymer form of tubulin according to Western blot analysis. It triggered cell cycle arrest at the G2/M phase before apoptosis, which was related to the upregulation of the mitotic marker MPM2 and the cyclin B1 level, and a change in the phosphorylation of Cdk1. MPT0B169 induced apoptosis in nonresistant and imatinib-resistant cells via a mitochondrion-mediated caspase pathway. Further study showed that the agent led to a decrease in the antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 and an increase in the apoptotic protein Bax. Taken together, our results suggest that MPT0B169 might be a promising agent for overcoming imatinib resistance in CML cells.

  20. MPT0B169, a New Antitubulin Agent, Inhibits Bcr-Abl Expression and Induces Mitochondrion-Mediated Apoptosis in Nonresistant and Imatinib-Resistant Chronic Myeloid Leukemia Cells.

    Science.gov (United States)

    Wong, Shuit-Mun; Liu, Fu-Hwa; Lee, Yueh-Lun; Huang, Huei-Mei

    2016-01-01

    Chronic myeloid leukemia (CML) is a clonal disorder of hematopoietic stem/progenitor cells that is caused by the Bcr-Abl oncoprotein. Clinical resistance to the Bcr-Abl inhibitor imatinib is a critical problem in treating CML. This study investigated the antitumor effect and mechanism of MPT0B169, a new antitubulin agent, in K562 CML cells and their derived imatinib-resistant cells, IMR2 and IMR3. IMR2 and IMR3 cells showed complete resistance to imatinib-induced growth inhibition and apoptosis. Resistance involved ERK1/2 overactivation and MDR1 overexpression. MPT0B169 inhibited the growth of K562, IMR2, and IMR3 cells in a dose- and time-dependent manner. MPT0B169 substantially inhibited the mRNA and protein levels of Bcr-Abl, followed by its downstream pathways including Akt, ERK1/2, and STAT3 in these cells. MPT0B169 treatment resulted in a decrease in the polymer form of tubulin according to Western blot analysis. It triggered cell cycle arrest at the G2/M phase before apoptosis, which was related to the upregulation of the mitotic marker MPM2 and the cyclin B1 level, and a change in the phosphorylation of Cdk1. MPT0B169 induced apoptosis in nonresistant and imatinib-resistant cells via a mitochondrion-mediated caspase pathway. Further study showed that the agent led to a decrease in the antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 and an increase in the apoptotic protein Bax. Taken together, our results suggest that MPT0B169 might be a promising agent for overcoming imatinib resistance in CML cells.

  1. Evolution of T-cell clonality in a patient with Ph-negative acute lymphocytic leukemia occurring after interferon and imatinib therapy for Ph-positive chronic myeloid leukemia

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    Yang Lijian

    2010-04-01

    Full Text Available Abstract Introduction The development of Philadelphia chromosome (Ph negative acute leukemia/myelodysplastic syndrome (MDS in patients with Ph-positive chronic myeloid leukemia (CML is very rare. The features of restrictive usage and absence of partial T cell clones have been found in patients with CML. However, the T-cell clonal evolution of Ph-negative malignancies during treatment for CML is still unknown. Objective To investigate the dynamic change of clonal proliferation of T cell receptor (TCR Vα and Vβ subfamilies in one CML patient who developed Ph-negative acute lymphoblastic leukemia (ALL after interferon and imatinib therapy. Methods The peripheral blood mononuclear cells (PBMC samples were collected at the 3 time points (diagnosis of Ph-positive chronic phase (CP CML, developing Ph-negative ALL and post inductive chemotherapy (CT for Ph-negative ALL, respectively. The CDR3 size of TCR Vα and Vβ repertoire were detected by RT-PCR. The PCR products were further analyzed by genescan to identify T cell clonality. Results The CML patient who achieved complete cytogenetic remission (CCR after 5 years of IFN-α therapy suddenly developed Ph-negative ALL 6 months following switch to imatinib therapy. The expression pattern and clonality of TCR Vα/Vβ T cells changed in different disease stages. The restrictive expression of Vα/Vβ subfamilies could be found in all three stages, and partial subfamily of T cells showed clonal proliferation. Additionally, there have been obvious differences in Vα/Vβ subfamily of T cells between the stages of Ph-positive CML-CP and Ph-negative ALL. The Vα10 and Vβ3 T cells evolved from oligoclonality to polyclonality, the Vβ13 T cells changed from bioclonality to polyclonality, when Ph-negative ALL developed. Conclusions Restrictive usage and clonal proliferation of different Vα/Vβ subfamily T cells between the stages of Ph-positive CP and Ph-negative ALL were detected in one patient. These changes

  2. The impact assessment of anticancer drug imatinib on the feeding behavior of rotifers with an integrated perspective: Exposure, post-exposure and re-exposure.

    Science.gov (United States)

    Yan, Zhengyu; Yan, Kun; He, Xingliang; Liu, Yanhua; Zhang, Jie; Lopez Torres, Oscar; Guo, Ruixin; Chen, Jianqiu

    2017-10-01

    The anticancer drugs are getting increasing attention as an emerging contaminant in the aquatic environments. In the present study, feeding behavior of the rotifer Brachionus calyciflorus under the impact of anticancer drug imatinib was evaluated. Traditional toxicological studies usually focus on dose-effect relationship at a given exposure time, while ignore the possible impact after the exposure. Thus, how the impact varied in the post-exposure and re-exposure was also considered in the present study. The feeding depression of the rotifers was attributed to the increased concentration of imatinib. Although the filtration and ingestion rate of the rotifers recovered to a certain extent after the exposure, the significant feeding inhibition still persisted even if the exposure was ended. In the re-exposure period, the feeding behavior was less depressed than those of the exposure period, which implied that rotifers might develop a tolerance to the same toxics. The activities of acetylcholine esterase (AchE) and the levels of reactive oxygen species (ROS) in rotifers were also detected. Imatinib inhibited the activities of AchE in the exposure and re-exposure while ROS levels increased significantly in the re-exposure period. Our present study provided an integrated assessment the potential environmental risks of imatinib at a new perspective. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. 伊马替尼治疗幼儿慢性粒细胞白血病一例并文献复习%Imatinib is effective in a 12-month-old boy with chronic myelogenous leukemia: case report and literature review

    Institute of Scientific and Technical Information of China (English)

    潘玉夏; 温树鹏; 田金满; 吕朝霞; 杜志芳; 杨琳

    2015-01-01

    Objective To summarize the clinical characteristics of an infant with chronic myelogenous leukemia (CML) and the effects of imatinib on the case.Method The clinical features of an infant with CML,who was treated with imatinib in the Norman Bethune International Peace Hospital at June 2009,were retrospectively analyzed and the reports in literature were reviewed.The 1-year-old boy suffered from recurrent low-degree fever and pallor.He had a moderate anemia,distended abdomen and marked splenomegaly.Bone marrow aspiration revealed CML in chronic phase (CP).The t (9; 22) (q34; q11) could be detected and BCR-ABL (p210) was positive.The boy was diagnosed as CML-CP and treated with imatinib 100 mg per day.There were 10 related papers and more than 100 child CML patients were reported as retrieved from CNKI (from its establishment to August 2014) and Wanfang Database (from its establishment to August 2014) when "Child","Chronic" and " Leukemia" were used as keywords.And there were 30 related papers including 400 cases from PubMed Database (from its establishment to August 2014) and one detailed report of an infant with CML was retrieved when "childhood" and "chronic myeloid leukemia imatinib" were used as keywords.The clinical effects of imatinib in infant CML cases were analyzed and summarized based on the literature.Result The boy obtained a complete hematologic response (CHR)at the 6th week of diagnosis,a complete cytogenetic response (CCyR) at the 3rd month and a complete molecular response (CMR) at the 12th month without side effect.This boy grows very well and after a 62-month follow-up,his disease was stable.According to the domestic literature,5 children CML cases aged 6-12 years were treated with imatinib without side effects and got complete hematologic response (CHR) after 2-month-therapy.The dose,metabolic characteristics and clinical observation of imatinib can be found in foreign literature and imatinib showed good response with good tolerance in children

  4. Imatinib Mesylate Exerts Anti-Proliferative Effects on Osteosarcoma Cells and Inhibits the Tumour Growth in Immunocompetent Murine Models

    Science.gov (United States)

    Ory, Benjamin; Charrier, Céline; Brion, Régis; Blanchard, Frederic; Redini, Françoise; Heymann, Dominique

    2014-01-01

    Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients

  5. Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

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    Bérengère Gobin

    Full Text Available Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma, a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1. Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma and POS-1 (undifferentiated osteosarcoma. Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R, appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor

  6. Imatinib resistance mutation analysis: experience from a tertiary oncology center

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    Mallekavu Suresh Babu

    2015-01-01

    Full Text Available Purpose: BCR-ABL kinase domain (KD mutations account for 50-90% of the imatinib resistance observed in patients of CML-chronic phase. In CML-CP patients receiving imatinib first-line, mutation analysis is recommended in case of failure or suboptimal response using European LeukemiaNet (ELN criteria. The present study was carried out at a tertiary oncology centre in south India to assess which mutations accounted for resistance to imatinib among patients of chronic phase CML being treated with imatinib.Methods: This was a retrospective observational study. We analyzed patients who were tested for imatinib resistance mutation in view of suboptimal responses while on imatinib or imatinib failure. Direct sequencing of the BCR-ABL transcript by the Sanger method was used for IRMA testing.Results: Out of 120 tested for IRMA, 36 (30% had detectable mutations. We observed a higher frequency of mutations at amino acids T315, F359 and M351T.Conclusions: Among the patients who were tested for imatinib resistance mutation in view of suboptimal responses while on imatinib or imatinib failure, 30% had IRMA +ve mutations. The high incidence of imatinib resistance in present study may be attributed to the fact that our patients were given higher dose of imatinib (600 mg, if they failed to achieve CCyR at 12 months or CHR at 3 months as they could not afford second generation TKIs.

  7. Myc induced miR-144/451 contributes to the acquired imatinib resistance in chronic myelogenous leukemia cell K562

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    Liu, Li, E-mail: liuli029@yahoo.cn [Department of Hematology, Tangdu Hospital, The Fourth Military Medical University, Xi' an 710038 (China); Wang, Sitao; Chen, Renan; Wu, Yanlan; Zhang, Bei; Huang, Siyong; Zhang, Jingyi; Xiao, Fang; Wang, Meng; Liang, Yingmin [Department of Hematology, Tangdu Hospital, The Fourth Military Medical University, Xi' an 710038 (China)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Increased c-myc expression in imatinib resistant CML cells. Black-Right-Pointing-Pointer c-myc contributes the imatinib resistance in CML cells. Black-Right-Pointing-Pointer c-myc transcriptionally reduces the expression of miR-144/451 in K562R cells. Black-Right-Pointing-Pointer Restoration of miR-144/451 reverses the resistance of K562R cells to imatinib. -- Abstract: Imatinib resistance remains the big hurdle for CML therapy. Previous study reveals that c-myc is important for bcr-abl CML cell proliferation, while its role in imatinib resistance is largely unknown. In this study, we first found that c-myc expression is upregulated in imatinib resistant K562R cells, which in turn enhances the expression of miR-144/451. Knockdown of c-myc or restoration of miR-144/451 in the K562R cells sensitizes K562R cells to imatinib therapy. Our study here reveals an regulatory pathway between myc and miR-144/451 and highlights that targeting either myc or miR-144/451 might be valuable for eliminating the imatinib resistant CML cells.

  8. Two different point mutations in ABL gene ATP-binding domain conferring Primary Imatinib resistance in a Chronic Myeloid Leukemia (CML patient: A case report

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    Iqbal Zafar

    2004-01-01

    Full Text Available Imatinib (Gleevec is the effective therapy for BCR-ABL positive CML patients. Point mutations have been detected in ATP-binding domain of ABL gene which disturbs the binding of Gleevec to this target leading to resistance. Detection of mutations is helpful in clinical management of imatinib resistance. We established a very sensitive (ASO PCR to detect mutations in an imatinib-resistant CML patient. Mutations C944T and T1052C were detected which cause complete partial imatinib resistance, respectively. This is the first report of multiple point mutations conferring primary imatinib resistance in same patient at the same time. Understanding the biological reasons of primary imatinib resistance is one of the emerging issues of pharmacogenomics and will be helpful in understanding primary resistance of molecularly-targeted cancer therapies. It will also be of great utilization in clinical management of imatinib resistance. Moreover, this ASO-PCR assay is very effective in detecting mutations related to imatinib resistance.

  9. Pregnancy and Accelerated Phase of Myeloid Chronic Leukemia Treated with Imatinib: A Case Report from a Developing Country

    OpenAIRE

    2016-01-01

    Background. Chronic myeloid leukemia is a hematological malignancy caused by expression of BCR-ABL tyrosine kinase oncogene, product of the t(9;22) Philadelphia translocation. Accelerated phase of this disease marks the onset of advanced rapidly progressive disease unresponsive to many therapies. Pregnancy limits broad number of therapies on patients because of their potential teratogenic effects. We report the case of a pregnant 34-year-old patient on accelerated phase successively managed b...

  10. Leukemia stem cells in drug resistance and metastasis

    Institute of Scientific and Technical Information of China (English)

    DENG Chao-hua; ZHANG Qiu-ping

    2010-01-01

    Objective To review the central role of leukemia stem cells (LSCs) in drug resistance and metastasis, aiming to provide key insights into leukemogenic pathology and developing novel therapeutic strategies against the relapse of leukemia.Data sources The data used in this review were obtained mainly from the studies reported in PubMed using the key terms "tumor-initiating cells", "leukemia stem cells", "drug resistance" and "metastasis".Study selection Relevant articles on studies of leukemia stem cells were selected.Results Increasing numbers of studies have suggested the importance of cancer stem cells (CSCs) in the initiation and maintenance of cancer, especially in leukemia. This review has summarized the origin, characteristics, isolation and identification of LSCs. It highlights the crucial role of LSCs in drug resistance and metastasis of leukemia by illustrating possible mechanisms and aims to provide novel therapeutic strategies for LSCs-targeted treatment.Conclusion LSCs play a crucial role in drug resistance and metastasis of leukemia and new promising LSCs-targeted therapies warrant investigation in both experimental models and clinical practice.

  11. The long-term clinical implications of clonal chromosomal abnormalities in newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib mesylate.

    Science.gov (United States)

    Lee, Sung-Eun; Choi, Soo Young; Bang, Ju-Hee; Kim, Soo-Hyun; Jang, Eun-Jung; Byeun, Ji-Young; Park, Jin Eok; Jeon, Hye-Rim; Oh, Yun Jeong; Kim, Myungshin; Kim, Dong-Wook

    2012-11-01

    The aim of this study was to evaluate the long-term clinical significance of an additional chromosomal abnormality (ACA), variant Philadelphia chromosome (vPh) at diagnosis, and newly developed other chromosomal abnormalities (OCA) in patients with chronic myeloid leukemia (CML) on imatinib (IM) therapy. Sequential cytogenetic data from 281 consecutive new chronic phase CML patients were analyzed. With a median follow-up of 78.6 months, the 22 patients with vPh (P = 0.034) or ACA (P = 0.034) at diagnosis had more events of IM failure than did the patients with a standard Ph. The 5-year overall survival (OS), event-free survival (EFS), and failure-free survival (FFS) rates for patients with vPh at diagnosis were 77.8%, 75.0%, and 53.3%, respectively; for patients with ACA at diagnosis, 100%, 66.3%, and 52.1%, respectively; and for patients with a standard Ph, 96.0%, 91.3%, and 83.7%, respectively. During IM therapy, eight patients developed an OCA, which had no impact on outcomes as a time-dependent covariate in our Cox proportional hazards regression models. This study showed that vPh was associated with poor OS and FFS and that ACA had adverse effects on EFS and FFS. In addition, no OCA, except monosomy 7, had any prognostic impact, suggesting that the development of OCA may not require a change in treatment strategy. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Guggulsterone of Commiphora mukul resin reverses drug resistance in imatinib-resistant leukemic cells by inhibiting cyclooxygenase-2 and P-glycoprotein.

    Science.gov (United States)

    Xu, Hong-Bin; Xu, Lu-Zhong; Mao, Xia-Ping; Fu, Jun

    2014-06-15

    The purpose of this study was to investigate the effects of guggulsterone on cyclooxygenase-2 and P-glycoprotein mediated drug resistance in imatinib-resistant K562 cells (K562/IMA). MTT cytotoxicity assay, flow cytometry, western blot analysis, and ELISA were performed to investigate the anti-proliferative effect, the reversal action of drug resistance, and the inhibitory effect on cyclooxygenase-2, P-glycoprotein, BCR/ABL kinase, and PGE2 release in K562/IMA cells by guggulsterone. The results showed that co-administration of guggulsterone resulted in a significant increase in chemo-sensitivity of K562/IMA cells to imatinib, compared with imatinib treatment alone. Rhodamine123 accumulation in K562/IMA cells was significantly enhanced after incubation with guggulsterone (60, 120 μM), compared with untreated K562/IMA cells (pP-glycoprotein and prostaglandin E2. However, guggulsterone had little inhibitory effect on the activity of BCR/ABL kinase. The present study indicates guggulsterone induces apoptosis by inhibiting cyclooxygenase-2 and down-regulating P-glycoprotein expression in K562/IMA cells.

  13. Assessment of fibrosis and vascularization of bone marrow stroma of chronic myeloid Leukemia patients treated with imatinib mesylate and their relationship with the cytogenetic response

    Directory of Open Access Journals (Sweden)

    Caroline Regina de Jesus

    2011-06-01

    Full Text Available Chronic Myeloid Leukemia (CML is a myeloproliferative disease characterized by the presence of the Philadelphia chromosome (translocation between chromosomes 9 and 22, resulting in the formation of the hybrid BCR-ABL protein. Currently, the treatment of CML patients is performed with imatinib mesylate (IM, which promotes the elimination of leukemic cells by inhibiting the kinase activity of BCR-ABL. This study evaluated the effectiveness of IM by monitoring 22 CML patients in a chronic phase treated at the CEPON/SC with IM for a minimum follow-up period of two years. Cytogenetic Response (CR and bone marrow biopsies (BMB were evaluated before and after IM treatment. BMB were evaluated by detection of reticulin degree and vascularization. The results were correlated to the CR. Mean time to achieve CR was 9 months and was attained by 77.27% of the patients. The results from the initial BMB analysis showed that 59.09% presented reticulin of between 2+ and 4+ whereas after treatment, only 27.17% presented this degree. With regard to vascularization of the initial sample, 90.91% were graded between II and IV, whereas after treatment, 40.91% had this degree. The results suggest a positive correlation of degree of reticulin and vascularization with CR.A Leucemia Mielóide Crônica (LMC é uma doença mieloproliferativa caracterizada pela presença do cromossomo Filadélfia (translocação entre os cromossomos 9 e 22, que resulta na formação da proteína híbrida BCR-ABL. Atualmente o tratamento de pacientes com LMC é realizado com mesilato de imatinibe (MI, o qual promove a eliminação das células leucêmicas pela inibição da atividade quinase de BCR-ABL. O presente estudo avaliou a eficácia do MI por meio do acompanhamento de pacientes portadores de LMC em fase crônica, atendidos no CEPON/SC tratados com MI pelo tempo mínimo de dois anos. Foram avaliadas a Resposta Citogenética (RC e as biópsias de medula óssea (BMO antes e após o

  14. Acompanhamento farmacoterapêutico dos pacientes com leucemia mieloide crônica em uso de mesilato de imatinibe na Universidade Federal do Ceará The pharmacotherapeutic follow- up of patients with chronic myeloid leukemia (CML on imatinib mesylate therapy

    Directory of Open Access Journals (Sweden)

    Sterfen S. Aquino

    2009-01-01

    Full Text Available Leucemia mieloide crônica (LMC é uma desordem genética de etiologia desconhecida, caracterizada por crescimento aumentado e não regulado de células precursoras mieloides na medula óssea. LMC está associada com uma característica translocação cromossômica chamada de cromossoma Philadelphia. Esse é um estudo observacional descritivo de pacientes com LMC do Hospital Universitário Walter Cantídio, Universidade Federal de Ceará, Brasil. O objetivo foi estudar a eficácia e a frequência de efeitos colaterais da terapia com mesilato de imatinibe. Vinte e seis pacientes foram incluídos: 09 em fase crônica (34,61%, 06 em fase acelerada (23,08% e 11 em crise blástica (42,31 %. Os casos em fase crônica tiveram intolerância prévia para interferon alfa (IFN- α. Resposta hematológica completa foi observada em sete pacientes, cinco em fase crônica, um em acelerada e um em crise blástica. Durante o primeiro ano de tratamento, quatro pacientes em fase crônica mostraram resposta citogenética completa. Um destes pacientes perdeu a resposta posteriormente. Nenhum paciente em fase acelerada ou crise blástica mostrou resposta citogenética completa. Entre os 18 pacientes que estavam vivos no fim do estudo, apenas quatro (22,22% não tiveram nenhuma queixa. Os mais comuns efeitos adversos foram: edema (50%, adinamia (33,33%, dor óssea e/ou articular (33,33%, cefaléia (27,78%, cãimbra (16,67%, diarreia (16,67%, insônia (16,67%, prurido (16,67%, equimoses (11,11%, náuseas (11,11%, dor epigástrica (5,55%, eritema (5,55%, lacrimejamento (5,55%, ressecamento da pele e lábios (5,55%, rush (5,55%, sudorese (5,55%. Uma minoria de pacientes desenvolveu resistência ao imatinibe. Para superar a resistência e aumentar a resposta positiva aos inibidores de tirosino- quinase novos fármacos e testes estão sendo utilizados e pesquisados.Chronic myeloid leukemia (CML is a genetic disorder of unknown etiology characterized by increased and

  15. Imatinib induced melasma-like pigmentation: Report of five cases and review of literature

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    Sneha Ghunawat

    2016-01-01

    Full Text Available Imatinib mesylate is a cytotoxic agent that targets tyrosine kinase. Common side effects of this drug include nausea, edema and maculopapular rash. Hypopigmentation is a commonly reported side effect of this drug while hyperpigmentation has rarely been described. We describe five cases of melasma-like pigmentation induced by this anti-cancer drug. Four of the patients were diagnosed with gastrointestinal stromal tumor while one had chronic myeloid leukemia. Patients received imatinib mesylate in a dose of 400 mg daily. Over an average period of 3 months, well defined hyperpigmented macules appeared over the convexities of the face. One of the patients also developed similar pigmentation on the forearm. Other causes of hyperpigmentation were excluded in each patient.

  16. Imatinib induced melasma-like pigmentation: Report of five cases and review of literature.

    Science.gov (United States)

    Ghunawat, Sneha; Sarkar, Rashmi; Garg, Vijay Kumar

    2016-01-01

    Imatinib mesylate is a cytotoxic agent that targets tyrosine kinase. Common side effects of this drug include nausea, edema and maculopapular rash. Hypopigmentation is a commonly reported side effect of this drug while hyperpigmentation has rarely been described. We describe five cases of melasma-like pigmentation induced by this anti-cancer drug. Four of the patients were diagnosed with gastrointestinal stromal tumor while one had chronic myeloid leukemia. Patients received imatinib mesylate in a dose of 400 mg daily. Over an average period of 3 months, well defined hyperpigmented macules appeared over the convexities of the face. One of the patients also developed similar pigmentation on the forearm. Other causes of hyperpigmentation were excluded in each patient.

  17. UV Differentially Induces Oxidative Stress, DNA Damage and Apoptosis in BCR-ABL1-Positive Cells Sensitive and Resistant to Imatinib

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    Ewelina Synowiec

    2015-08-01

    Full Text Available Chronic myeloid leukemia (CML cells express the active BCR-ABL1 protein, which has been targeted by imatinib in CML therapy, but resistance to this drug is an emerging problem. BCR-ABL1 induces endogenous oxidative stress promoting genomic instability and imatinib resistance. In the present work, we investigated the extent of oxidative stress, DNA damage, apoptosis and expression of apoptosis-related genes in BCR-ABL1 cells sensitive and resistant to imatinib. The resistance resulted either from the Y253H mutation in the BCR-ABL1 gene or incubation in increasing concentrations of imatinib (AR. UV irradiation at a dose rate of 0.12 J/(m2·s induced more DNA damage detected by the T4 pyrimidine dimers glycosylase and hOGG1, recognizing oxidative modifications to DNA bases in imatinib-resistant than -sensitive cells. The resistant cells displayed also higher susceptibility to UV-induced apoptosis. These cells had lower native mitochondrial membrane potential than imatinib-sensitive cells, but UV-irradiation reversed that relationship. We observed a significant lowering of the expression of the succinate dehydrogenase (SDHB gene, encoding a component of the complex II of the mitochondrial respiratory chain, which is involved in apoptosis sensing. Although detailed mechanism of imatinib resistance in AR cells in unknown, we detected the presence of the Y253H mutation in a fraction of these cells. In conclusion, imatinib-resistant cells may display a different extent of genome instability than their imatinib-sensitive counterparts, which may follow their different reactions to both endogenous and exogenous DNA-damaging factors, including DNA repair and apoptosis.

  18. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib

    Science.gov (United States)

    Shah, Neil P.; Kim, Dong-Wook; Kantarjian, Hagop; Rousselot, Philippe; Llacer, Pedro Enrique Dorlhiac; Enrico, Alicia; Vela-Ojeda, Jorge; Silver, Richard T.; Khoury, Hanna Jean; Müller, Martin C.; Lambert, Alexandre; Matloub, Yousif; Hochhaus, Andreas

    2010-01-01

    Background Dasatinib 100 mg once daily achieves intermittent BCR-ABL kinase inhibition and is approved for chronic-phase chronic myeloid leukemia patients resistant or intolerant to imatinib. To better assess durability of response to and tolerability of dasatinib, data from a 2-year minimum follow-up for a dose-optimization study in chronic-phase chronic myeloid leukemia are reported here. Design and Methods In a phase 3 study, 670 chronic-phase chronic myeloid leukemia patients with resistance, intolerance, or suboptimal response to imatinib were randomized to dasatinib 100 mg once-daily, 50 mg twice-daily, 140 mg once-daily, or 70 mg twice-daily. Results Data from a 2-year minimum follow-up demonstrate that dasatinib 100 mg once daily achieves major cytogenetic response and complete cytogenetic response rates comparable to those in the other treatment arms, and reduces the frequency of key side effects. Comparable 2-year progression-free survival and overall survival rates were observed (80% and 91%, respectively, for 100 mg once daily, and 75%–76% and 88%–94%, respectively, in other arms). Complete cytogenetic responses were achieved rapidly, typically by 6 months. In patients treated with dasatinib 100 mg once daily for 6 months without complete cytogenetic response, the likelihood of achieving such a response by 2 years was 50% for patients who had achieved a partial cytogenetic response, and only 8% or less for patients with minor, minimal, or no cytogenetic response. Less than 3% of patients suffered disease transformation to accelerated or blast phase. Conclusions Intermittent kinase inhibition can achieve rapid and durable responses, indistinguishable from those achieved with more continuous inhibition. PMID:20139391

  19. Interaction of imatinib mesylate with human serum transferrin: The comparative spectroscopic studies

    Science.gov (United States)

    Śliwińska-Hill, Urszula

    2017-02-01

    Imatinib mesylate (Imt) is a tyrosine kinase inhibitor mainly used in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (Ph + CML). Human serum transferrin is the most abundant serum protein responsible for the transport of iron ions and many endogenous and exogenous ligands. In this study the mechanism of interactions between the imatinib mesylate and all states of transferrin (apo-Tf, Htf and holo-Tf) has been investigated by fluorescence, ultraviolet-visible (UV-vis), circular dichroism (CD) and zeta potential spectroscopic methods. Based on the experimental results it was proved that under physiological conditions the imatinib mesylate binds to the each form of transferrin with a binding constant c.a. 105 M- 1. The thermodynamic parameters indicate that hydrogen bonds and van der Waals were involved in the interaction of apo-Tf with the drug and hydrophobic and ionic strength participate in the reaction of Htf and holo-Tf with imatinib mesylate. Moreover, it was shown that common metal ions, Zn2 + and Ca2 + strongly influenced apo-Tf-Imt binding constant. The CD studies showed that there are no conformational changes in the secondary structure of the proteins. No significant changes in secondary structure of the proteins upon binding with the drug and instability of apo-Tf-Imt system are the desirable effects from pharmacological point of view.

  20. Imatinib mesylate in idiopathic and postpolycythemic myelofibrosis.

    Science.gov (United States)

    Hasselbalch, Hans Carl; Bjerrum, Ole Weiss; Jensen, Bjarne Anker; Clausen, Nielsaage Tøffner; Hansen, Per Boye; Birgens, Henrik; Therkildsen, Marianne Hamilton; Ralfkiaer, Elisabeth

    2003-12-01

    Imatinib mesylate targets the adenosine triphosphate (ATP)-binding sites of the protein tyrosine kinase domains associated with Bcr-abl, the platelet-derived growth factor (PDGF) and c-kit. In idiopathic myelofibrosis (IMF) PDGF is considered to be one of the growth factors responsible for the development of bone marrow fibrosis. Recently, it has been shown that imatinib has antifibrogenic effect on bone marrow fibrosis in chronic myelogenous leukemia. Treatment with imatinib alone in IMF has been associated with significant side effects. In this study, the safety and efficacy of imatinib therapy in IMF, either administered as a single agent or in combination with hydroxyurea (HU) and/or alpha-interferon (IFN-alpha) are evaluated. Eleven patients (median age, 63 years; range, 33-82 years) with IMF (n = 8) or postpolycythemic myelofibrosis (PPMF) (n = 3) were studied All patients had been treated with HU (n = 9) and/or IFN (n = 7) before study entry. In all but one patient, treatment with these agents was discontinued when imatinib therapy was instituted. One patient continued IFN when treatment with imatinib was started. Imatinib was given at a dose of 400 mg/day. Nine patients were in an advanced disease phase. The patients have been followed for a median period of 2 months (range, 0.5-12 months). Treatment with imatinib has been stopped in six patients (55%), because of overt side effects (n = 4), recurrence of transitory dizziness and visual defects owing to a rising platelet count (n = 1), or the occurrence of an acute subdural hemorrhage that was evacuated without neurological deficits (n = 1). In nine patients imatinib treatment was followed by a rise in leukocyte and platelet counts that required combination with HU or IFN. The combined treatment modalities were followed by a rapid decrease in cell counts and were well tolerated apart from IFN side effects. A beneficial effect of imatinib was documented in three patients. It is concluded that leukocytosis

  1. 达沙替尼治疗伊马替尼耐药的 BCR/ABL阳性白血病%Dasatinib in treatment of imatinib-resistant BCR/ABL positive leukemia

    Institute of Scientific and Technical Information of China (English)

    严红; 赵海军

    2014-01-01

    This study was aimed to evaluate the efficacy and safety of dasatinib in BCR /ABL positive leukemia patients with resistance to imatinib.Method 9 patients with imatinib -resistant chronic myelogenous leukemia ( CML) or Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ALL) received 100~140 mg· d-1 dasatinib orally.Their overall survival and tolerance were evalua-ted.Results After the dasatinib treatment ,2 patients with CML in chronic phase achieved complete hematologic response ( CHR) ,one of them achieved complete cytogenetic response (CCyR);4 of 5 patients with CML in blast crisis achieved CHR and partly cytogenetic response (PCyR);one patient had no response .Treated with dasatinib,one patient with Ph +ALL,presented with E255V mutation,a-chieved CHR and PCyR .The other died of infection .Conlusion Receiving therapy of dasatinib , patients with resistance to imatinib could achieve CHR ,even PCyR .%目的:评价达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病的疗效和安全性。方法对9例伊马替尼耐药的慢性髓系白血病( CML)或Ph阳性急性淋巴细胞白血病( Ph+ALL)患者,给予达沙替尼100~140 mg· d-1口服治疗,评估疗效和耐受情况。结果9例伊马替尼耐药的BCR/ABL阳性白血病,2例CML-CP患者均获得CHR,1例达CCyR;5例CML-BC患者中4例获得CHR和PCyR,1例NR;2例Ph+ALL患者中1例检测到E255V突变,采用达沙替尼治疗达CHR和PCyR,1例诱导缓解时,同时行VDP方案化疗,继发严重感染死亡。结论达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病患者可获得血液学甚至细胞遗传学缓解,且耐受性好。

  2. MDM2 promoter polymorphism and p53 codon 72 polymorphism in chronic myeloid leukemia: the association between MDM2 promoter genotype and disease susceptibility, age of onset, and blast-free survival in chronic phase patients receiving imatinib.

    Science.gov (United States)

    Liu, Yi-Chang; Hsiao, Hui-Hua; Yang, Wen-Chi; Liu, Ta-Chih; Chang, Chao-Sung; Yang, Ming-Yu; Lin, Pai-Mei; Hsu, Jui-Feng; Lee, Ching-Ping; Lin, Sheng-Fung

    2014-12-01

    The genetic or functional inactivation of the p53 pathway plays an important role with regards to disease progression from the chronic phase (CP) to blast phase (BP) and imatinib treatment response in chronic myeloid leukemia (CML). Two functional single nucleotide polymorphisms (SNPs), p53 R72P and MDM2 SNP309, are associated with alternation of p53 activity, however the association regarding CML susceptibility and BP transformation under imatinib treatment is unclear. The MDM2 SNP309 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing from 116 CML patients, including 104 in the CP at diagnosis, and 162 healthy Taiwanese controls. The p53 R72P polymorphism was examined in all CML patients. The SNP309 G/G genotype was associated with an increased risk of CML susceptibility (OR: 1.82, 95% CI: 1.03-3.22, P = 0.037), and an earlier age of disease onset (log-rank P = 0.005) compared with the T/T + T/G genotypes. Higher MDM2 mRNA expression was found in G/G genotype compared with T/T (P = 0.034) and T/T + T/G (P = 0.056) genotypes. No associations were found between the p53 R72P genotypes and clinical parameters and survival outcomes. Among 62 CP patients receiving imatinib as first-line therapy, the G/G genotype was associated with a shorter blast-free survival (log-rank P = 0.048) and more clonal evolution compared with the T/T + T/G genotypes. In patients with advanced diseases at diagnosis, the G/G genotype was associated with a poor overall survival (log-rank P = 0.006). Closely monitoring CML patients harboring the G/G genotype and further large-scale studies are warranted.

  3. Imatinib and nilotinib inhibit hematopoietic progenitor cell growth, but do not prevent adhesion, migration and engraftment of human cord blood CD34+ cells.

    Directory of Open Access Journals (Sweden)

    Ludovic Belle

    Full Text Available BACKGROUND: The availability of tyrosine kinase inhibitors (TKIs has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more potent than imatinib towards BCR-ABL in vitro. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation, differentiation, adhesion, migration and engraftment capacities of human cord blood CD34(+ cells. DESIGN AND METHODS: After a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD/SCID/IL-2Rγ (null mice. RESULTS: TKIs did not affect LTC-IC frequencies despite in vitro inhibition of CFC formation due to inhibition of CD34(+ cell cycle entry. Adhesion of CD34(+ cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations. Migration through a SDF-1α gradient was not changed by cell culture in the presence of TKIs. Finally, bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model. No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for KIT. CONCLUSIONS: These data suggest that combining non-myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe.

  4. 75 FR 76017 - Determination That GLEEVEC (Imatinib Mesylate) Capsules, 50 Milligrams and 100 Milligrams, Were...

    Science.gov (United States)

    2010-12-07

    ... HUMAN SERVICES Food and Drug Administration Determination That GLEEVEC (Imatinib Mesylate) Capsules, 50... determined that GLEEVEC (imatinib mesylate) Capsules, 50 milligrams (mg) and 100 mg, were not withdrawn from... new drug applications (ANDAs) for imatinib mesylate capsules, 50 mg and 100 mg, if all other legal and...

  5. Imatinib enhances functional outcome after spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Mathew B Abrams

    Full Text Available We investigated whether imatinib (Gleevec®, Novartis, a tyrosine kinase inhibitor, could improve functional outcome in experimental spinal cord injury. Rats subjected to contusion spinal cord injury were treated orally with imatinib for 5 days beginning 30 minutes after injury. We found that imatinib significantly enhanced blood-spinal cord-barrier integrity, hindlimb locomotor function, sensorimotor integration, and bladder function, as well as attenuated astrogliosis and deposition of chondroitin sulfate proteoglycans, and increased tissue preservation. These improvements were associated with enhanced vascular integrity and reduced inflammation. Our results show that imatinib improves recovery in spinal cord injury by preserving axons and other spinal cord tissue components. The rapid time course of these beneficial effects suggests that the effects of imatinib are neuroprotective rather than neurorestorative. The positive effects on experimental spinal cord injury, obtained by oral delivery of a clinically used drug, makes imatinib an interesting candidate drug for clinical trials in spinal cord injury.

  6. Rewired Metabolism in Drug-resistant Leukemia Cells

    Science.gov (United States)

    Stäubert, Claudia; Bhuiyan, Hasanuzzaman; Lindahl, Anna; Broom, Oliver Jay; Zhu, Yafeng; Islam, Saiful; Linnarsson, Sten; Lehtiö, Janne; Nordström, Anders

    2015-01-01

    Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid β-oxidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics and RNA expression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies. PMID:25697355

  7. Mycophenolic Acid Overcomes Imatinib and Nilotinib Resistance of Chronic Myeloid Leukemia Cells by Apoptosis or a Senescent-Like Cell Cycle Arrest

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    Claire Drullion

    2012-01-01

    Full Text Available We used K562 cells sensitive or generated resistant to imatinib or nilotinib to investigate their response to mycophenolic acid (MPA. MPA induced DNA damage leading to cell death with a minor contribution of apoptosis, as revealed by annexin V labeling (up to 25%. In contrast, cell cycle arrest and positive staining for senescence-associated β-galactosidase activity were detected for a large cell population (80%. MPA-induced cell death was potentialized by the inhibition of autophagy and this is associated to the upregulation of apoptosis. In contrast, senescence was neither decreased nor abrogated in autophagy deficient K562 cells. Primary CD34 cells from CML patients sensitive or resistant to imatinib or nilotinib respond to MPA although apoptosis is mainly detected. These results show that MPA is an interesting tool to overcome resistance in vitro and in vivo mainly in the evolved phase of the disease.

  8. Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

    Science.gov (United States)

    Gotta, V; Widmer, N; Decosterd, L A; Chalandon, Y; Heim, D; Gregor, M; Benz, R; Leoncini-Franscini, L; Baerlocher, G M; Duchosal, M A; Csajka, C; Buclin, T

    2014-12-01

    This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

  9. Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.

    Science.gov (United States)

    2016-10-07

    Leukemia; Leukemia,Pediatric; Leukemia, Myleiod; Leukemia, Mylegenous, Chronic; Leukemia, Mylegenous, Accelerated; BCR-ABL Positive; Myeloproliferative Disorder; Bone Marrow Disease; Hematologic Diseases; Neoplastic Processes; Imatinib; Dasatinib; Enzyme Inhibitor; Protein Kinase Inhibitor

  10. Proteomics analysis of cellular imatinib targets and their candidate downstream effectors.

    Science.gov (United States)

    Breitkopf, Susanne B; Oppermann, Felix S; Keri, Gyorgy; Grammel, Markus; Daub, Henrik

    2010-11-05

    Inhibition of deregulated protein kinases by small molecule drugs has evolved into a major therapeutic strategy for the treatment of human malignancies. Knowledge about direct cellular targets of kinase-selective drugs and the identification of druggable downstream mediators of oncogenic signaling are relevant for both initial therapy selection and the nomination of alternative targets in case molecular resistance emerges. To address these issues, we performed a proof-of-concept proteomics study designed to monitor drug effects on the pharmacologically tractable subproteome isolated by affinity purification with immobilized, nonselective kinase inhibitors. We applied this strategy to chronic myeloid leukemia cells that express the transforming Bcr-Abl fusion kinase. We used SILAC to measure how cellular treatment with the Bcr-Abl inhibitor imatinib affects protein binding to a generic kinase inhibitor resin and further quantified site-specific phosphorylations on resin-retained proteins. Our integrated approach indicated additional imatinib target candidates, such as flavine adenine dinucleotide synthetase, as well as repressed phosphorylation events on downstream effectors not yet implicated in imatinib-regulated signaling. These included activity-regulating phosphorylations on the kinases Btk, Fer, and focal adhesion kinase, which may qualify them as alternative target candidates in Bcr-Abl-driven oncogenesis. Our approach is rather generic and may have various applications in kinase drug discovery.

  11. Using 2 nd generation tyrosine kinase inhibitors in frontline management of chronic phase chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Vishal Jayakar

    2014-01-01

    Full Text Available Choices in medicine come with responsibility. With several TKI′s (Tyrosine kinase inhibitors available for front-line management of CML (Chronic Myeloid Leukemia, an astute clinician has to personalise, rationalise and take a pragmatic approach towards selection of the best drug for the ′patient in question′. Though it is hotly debated as to which TKI will triumph, the truth of this debate lies in individualising treatment rather than a general ′all size fits all′ approach with imatinib. I personally believe that the second generation TKI′s will suit most patient clinical profiles rather than prescribing imatinib to all and I have strived to make a strong case for them in front line treatment of CML. Though Imatinib may remain the first line choice for some patients, my efforts in this debate are mainly geared towards breaking the myth that imatinib is the sole ′block buster′ on the CML landscape

  12. ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF SOLID DOSAGE FORM OF ANTINEOPLASTIC DRUG IMATINIB MESILATE BY RP HPLC.

    Directory of Open Access Journals (Sweden)

    G. Sathwik

    2015-04-01

    Full Text Available A simple and sensitive High Performance Liquid Chromatographic method has been established and validated for Imatinib Mesylate in pharmaceutical dosage form, separation was performed on a C18, 150×4.6 mm, 5μ column in isocratic mode, with mobile phase containing a mixture of buffer: acetonitrile (72:28 v/v. The mobile phase was pumped at a flow rate of 1.0 ml/min and eluents were monitored at 265 nm. Linearity was found to be in the range of levels 80% to 120% and retention time was 3.63 min. The statistical validation parameters such as linearity, accuracy, precision, and specificity, limit of detection, limit of quantification were checked. The samples were prepared in water and the stability of Imatinib mesylate in aqueous solution at 30°C was studied. The results were satisfactory with good stability after 24 h at 30°C. The proposed method can be used for the related substances of Imatinib mesylate.

  13. Tratamento da recidiva da leucemia mielóide crônica após transplante de medula óssea alogênico utilizando mesilato de imatinibe: relato de três casos Treatment of chronic myelogenous leukemia relapse after allogeneic bone marrow transplantation with imatinib mesylate: report of three cases

    Directory of Open Access Journals (Sweden)

    Ronald Pallotta

    2006-06-01

    Full Text Available O mesilato de imatinibe (MI, inibidor seletivo da tirosinoquinase envolvido na patogênese da leucemia mielóide crônica (LMC, tem se constituído como terapia farmacológica de primeira linha para o tratamento desta doença. A infusão de linfócitos do doador (DLI tem sido considerada como tratamento padrão para recidiva da LMC após transplante de medula óssea (TMO alogênico, apesar de estar freqüentemente associado à ocorrência de doença do enxerto contra hospedeiro e mielossupressão. Por apresentar resultados satisfatórios e boa tolerabilidade no tratamento da LMC, os autores empregaram o mesilato de imatinib como terapêutica alternativa à DLI em pacientes que sofreram recidiva após o TMO. Obtiveram sucesso em dois casos, sendo que em um houve retorno comprovado do quimerismo do doador. No terceiro caso houve progressão da doença e o paciente foi encaminhado para segundo TMO. Desta forma, devido ao caráter recente do tema, este estudo descritivo sugere que esta opção terapêutica possa ser estudada como alternativa na recaída pós-TMO.Imatinib mesylate (MI, a selective tyrosine kinase inhibitor involved in the pathogenesis of chronic myelogenous leukemia (CML, has become the first-line treatment for this disease. Donor lymphocyte infusion (DLI has been considered as the standard treatment for relapse after allogeneic bone marrow transplantation (BMT, even though it is frequently associated with graft versus host disease and myelosuppression. Because of the satisfactory results and tolerance of the treatment of CML, the authors used MI as an alternative therapy for DLI in patients that relapsed after BMT. They obtained cytogenetic remission in two cases, with, in one case, proven conversion to the donor chimera. The third case evolved with progression of the disease and a second BMT was required. Since this is a new alternative, this descriptive study suggests it should be considered as an alternative therapy for relapse

  14. Imatinib treatment for gastrointestinal stromal tumour (GIST).

    Science.gov (United States)

    Lopes, Lisandro F; Bacchi, Carlos E

    2010-01-01

    Gastrointestinal stromal tumour (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. GISTs are believed to originate from intersticial cells of Cajal (the pacemaker cells of the gastrointestinal tract) or related stem cells, and are characterized by KIT or platelet-derived growth factor receptor alpha (PDGFRA) activating mutations. The use of imatinib has revolutionized the management of GIST and altered its natural history, substantially improving survival time and delaying disease progression in many patients. The success of imatinib in controlling advanced GIST led to interest in the neoadjuvant and adjuvant use of the drug. The neoadjuvant (preoperative) use of imatinib is recommended to facilitate resection and avoid mutilating surgery by decreasing tumour size, and adjuvant therapy is indicated for patients at high risk of recurrence. The molecular characterization (genotyping) of GISTs has become an essential part of the routine management of the disease as KIT and PDGFRA mutation status predicts the likelihood of achieving response to imatinib. However, the vast majority of patients who initially responded to imatinib will develop tumour progression (secondary resistance). Secondary resistance is often related to secondary KIT or PDGFRA mutations that interfere with drug binding. Multiple novel tyrosine kinase inhibitors may be potentially useful for the treatment of imatinib-resistant GISTs as they interfere with KIT and PDGFRA receptors or with the downstream-signalling proteins.

  15. Combinations of Novel Histone Deacetylase and Bcr-Abl Inhibitors in the Therapy of Imatinib Mesylate-Sensitive and -Refractory Bcr-Abl Expressing Leukemia

    Science.gov (United States)

    2008-12-01

    Anderson Cancer Center, Houston (H.K., F.G., S.O., J.C.); J.W. Goethe Universität, Frankfurt, Germany (L.W., B.W., D.H., O.G.O.); Moffitt Cancer...3Department of Leukemia, H L Moffitt Cancer Center, Tampa, FL, USA and 4Department of Leukemia, JW Goethe Universitat, Frankfurt, Germany Most studies test...Capistrano, CA, USA b Department of Leukemia, M.D. Anderson Cancer Center, University of Texas, Houston, TX, USA c Department of Leukemia, JW Goethe

  16. Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: a case report.

    Science.gov (United States)

    Prodduturi, Prathima; Perry, Anamarija M; Aoun, Patricia; Weisenburger, Dennis D; Akhtari, Mojtaba

    2012-12-01

    Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.

  17. CLINICAL EFFICACY OF IMATINIB CHA NILE UNITED 12- O- TETRADECANE ACID PHORBOL-13- ACETATE (TPA) IN TREATMENT OF IMATINIB (GLEEVEC) -RESISTANT CHRONIC MYELOID LEUKEMIA (CML) CML PATIENTS%尼勒替尼联合TPA治疗伊马替尼耐药的慢性粒细胞白血病急变期患者的临床疗效

    Institute of Scientific and Technical Information of China (English)

    薛芙蕖

    2011-01-01

    [Objective] To observed clinical efficacy and toxicity of Imatinib Cha Nile United 12 - 0 - tetradecane acid phorbol-13-acetate (TPA) in treatment of imatinib (Gleevec) -resistant chronic myeloid leukemia (CML) CML patients. [Methods] Conventional dose imatinib resistant CML patients with the acute phase 72 patients were randomly divided into two groups, and treated with mesnil or mesnil Imatinib combined TPA, respectively. The liver and kidney function were reviewed each week, and peripheral blood smear were review each week after one month of treatment Blood and bone marrow cells were performed morphological examination every 3 months, cytogenetic and recording adverse events during treatment were observed, and we also recorded hematologic remission rate and cell genetic school response rate. [Results] 6 cases in treatment group showed complete hematologic remission (CHR), 12 cases showed partial hematologic remission (PHR), 12 cases returned to chronic phase, 6 cases failed. The hematologic response rate (including the CHR and PHR) was 50%. 6 cases showed complete cytogenetic remission (CCR), 10 cases showed partial cytogenetic response (PCR), and the total genetic response rate (including the CCR and PCR) was 50% and 44%, respectively. 8 cases in the treatment group shwed complete hematologic remission (CHR), 18 cases showed partial hematologic remission (PHR), 8 cases returned to chronic phase, 2 cases failed, and the hematologic response rate (including the CHR and PHR) was 72.2%. 8 cases showed complete cytogenetic response, 16 cases showed partial cytogenetic response (PCR), and the total rate of genetic response rate was 67%, which was higher than the single use mesnil imatinib treatment group. Between the two groups, the total effective rates of the hematologic remission and cytogenetic response was significant difference. There was no statistical difference in the adverse reactions between the two groups. [Conclusion] Imatinib combined TPA mesnil

  18. Análise de pacientes com leucemia mieloide crônica com resistência primária ou secundária ao mesilato de imatinibe Analysis of chronic myelogenous leukemia patients with primary or secondary resistance to imatinib mesylate

    Directory of Open Access Journals (Sweden)

    Rita de Cássia S. Alves

    2009-01-01

    Full Text Available O mesilato de imatinibe, como terapia alvo, se revelou altamente eficiente na leucemia mielóide crônica. Um desafio é a resistência primária ou secundária, principalmente nas fases avançadas da doença. Na secundária, as mutações pontuais no domínio quinase ABL são o mecanismo mais frequente. Estudou-se no período de outubro de 2000 a dezembro de 2005, 112 pacientes no Serviço de Hematologia e Hemoterapia da Santa Casa de São Paulo. O objetivo foi caracterizar o perfil dos resistentes e pesquisar a presença de mutação. Encontrou-se maior porcentagem de resistentes nas fases mais avançadas. Foram fatores de risco para resistência na fase crônica o número de plaquetas superior a 450.000/mm³ pré-imatinibe ou plaquetas inferior a 50.000/mm³ durante o tratamento. A taxa de resposta hematológica completa e o tempo para obtenção foram semelhantes entre os resistentes e não resistentes. Observou-se menor sobrevida global nos resistentes. Destacaram-se dez pacientes resistentes com resposta citogenética completa pós 12 meses, "responsivos tardios", cuja freqüência de resposta hematológica e citogenética foi semelhante aos não resistentes (100%. A sobrevida livre de progressão foi similar até aos 40 meses e a sobrevida global até aos 70 meses. A sobrevida global e as respostas foram superiores aos demais resistentes. Referente à pesquisa de mutação, analisou-se 22 resistentes, dos quais oito apresentaram mutação (36,4%. Caracterizou-se maior risco para a condição de mutação, a presença de blastos no sangue periférico ao diagnóstico nos pacientes em fase crônica.Imatinib mesylate, as target therapy, is highly efficient in chronic myelogenous leukemia. A challenge is primary and secondary resistance, particularly in the advanced phases of the disease. In secondary resistance, point mutations in the ABL dominion are the most common mechanism. From October 2000 to December 2005, 112 patients were

  19. An ultra-specific and sensitive sandwich ELISA for imatinib using two anti-imatinib antibodies.

    Science.gov (United States)

    Saita, Tetsuya; Yamamoto, Yuta; Hosoya, Kazuhisa; Yamamoto, Yutaro; Kimura, Sakiko; Narisawa, Yutaka; Shin, Masashi

    2017-05-29

    The development of an immunoassay for a low-molecular-weight drug first requires the identification of specific antibodies that do not cross-react with the drug's metabolites. If two antibodies can simultaneously recognize the entire structure of the drug, we can then utilize them to establish an ultra-specific sandwich ELISA, free from interference due to the metabolic products of the drug. This paper reports an ultra-specific and sensitive sandwich ELISA for determination of the tyrosine kinase inhibitor imatinib using two anti-imatinib antibodies. The anti-imatinib antibodies were obtained by two partial structures of imatinib as haptens (2-(5-amino-2-methylanilino)-4-(3-pyridyl)pyrimidine and 4-{(4-methyl-1-piperazinyl)-methyl}-benzoate). Under optimized conditions, this sandwich ELISA shows a linear detection range from 64 pg mL(-1) to 8 ng mL(-1), and a limit of detection of approximately 64 pg mL(-1) for 100-μL samples. The ELISA is specific to imatinib and while there was no cross-reactivity with the major metabolite N-desmethyl-imatinib, slight cross-reactivity was found with metabolite pyridine-N-oxide-imatinib. This assay demonstrated significantly lower cross-reactivity with metabolites than competitive ELISAs. Using this assay, drug levels were easily measured in rat blood after oral administration of imatinib via a single dose of 30 mg kg(-1) or 100 mg kg(-1). The levels in rat serum measured by this ELISA were comparable with those measured by HPLC, and there was a strong correlation between the values determined by the two methods (y = 0.983x + 0.081, R(2) = 0.948). Thus, we have successfully developed the first specific and sensitive sandwich ELISA for imatinib using two anti-imatinib antibodies. This sandwich ELISA will be a valuable tool for therapeutic drug monitoring and pharmacokinetic studies of imatinib. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Exploiting mitochondrial dysfunction for effective elimination of imatinib-resistant leukemic cells.

    Directory of Open Access Journals (Sweden)

    Jérome Kluza

    Full Text Available Challenges today concern chronic myeloid leukemia (CML patients resistant to imatinib. There is growing evidence that imatinib-resistant leukemic cells present abnormal glucose metabolism but the impact on mitochondria has been neglected. Our work aimed to better understand and exploit the metabolic alterations of imatinib-resistant leukemic cells. Imatinib-resistant cells presented high glycolysis as compared to sensitive cells. Consistently, expression of key glycolytic enzymes, at least partly mediated by HIF-1α, was modified in imatinib-resistant cells suggesting that imatinib-resistant cells uncouple glycolytic flux from pyruvate oxidation. Interestingly, mitochondria of imatinib-resistant cells exhibited accumulation of TCA cycle intermediates, increased NADH and low oxygen consumption. These mitochondrial alterations due to the partial failure of ETC were further confirmed in leukemic cells isolated from some imatinib-resistant CML patients. As a consequence, mitochondria generated more ROS than those of imatinib-sensitive cells. This, in turn, resulted in increased death of imatinib-resistant leukemic cells following in vitro or in vivo treatment with the pro-oxidants, PEITC and Trisenox, in a syngeneic mouse tumor model. Conversely, inhibition of glycolysis caused derepression of respiration leading to lower cellular ROS. In conclusion, these findings indicate that imatinib-resistant leukemic cells have an unexpected mitochondrial dysfunction that could be exploited for selective therapeutic intervention.

  1. 应用遗传学和分子生物学分析评价伊马替尼和常规化疗治疗慢性粒细胞白血病的疗效%Efficiency evaluation of imatinib and traditional chemical therapy in patients with chronic myeloid leukemia by analysis of cytogenetics and molecular genetics

    Institute of Scientific and Technical Information of China (English)

    李莉; 闫金松; 康志杰; 武克宇

    2012-01-01

    To compare the efficiency of imatinib mesylate (imatinib) and traditional chemical therapy in patients with chronic myeloid leukemia (CML) in chronic phase. [ Methods] Collecting 20 patients with chronic myeloid leukemia in chronic phase, 11 patients were treated with imatinib, while the other 9 were treated with traditional chemical therapy. Karyotypes were analyzed by chromosome G banding in 20 cases who were monitored the level of bcr - abl fusion gene by RT - PCR before and after administrating imatinib or traditional chemical therapy. Evaluate the rates of CHR, CyR, MoR. [Results] All the patients treated with imatinib got complete hematological response (CHR) , 9 of which had negative ph chromosome and bcr - abl fusion gene. The cytogenetic response ( CyR) response rate is 81%. To patients with traditional chemical therapy, CHR rate is 100% , but no one got CyR. [Conclusion] Imatinib significantly improves cytogenetic and molecular response rates of patients with chronic myeloid leukemia, which is better than traditional chemical therapy.%[目的]比较伊马替尼和常规化疗治疗慢性粒细胞白血病的疗效.[方法]收集20例慢性粒细胞白血病患者,其中11例应用伊马替尼治疗,9例应用常规化疗.采用常规染色体显带技术和半定量RT - PCR技术对细胞遗传学及分子遗传学进行动态监测,评价两种不同治疗方法的血液学、遗传学、分子生物学缓解率.[结果]应用伊马替尼治疗的患者均达血液学缓解,其中9例患者Ph染色体和bcr - abl融合基因消失,遗传学缓解率为81%.应用常规化疗的患者均能达到血液学缓解,但无一例达遗传学缓解.[结论]伊马替尼治疗慢性粒细胞白血病能达到部分或完全细胞遗传学缓解及分子生物学水平的缓解,优于常规化学药物治疗.

  2. Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01–08)

    Science.gov (United States)

    Wen, Patrick Y.; Yung, W.K. Alfred; Lamborn, Kathleen R.; Norden, Andrew D.; Cloughesy, Timothy F.; Abrey, Lauren E.; Fine, Howard A.; Chang, Susan M.; Robins, H. Ian; Fink, Karen; DeAngelis, Lisa M.; Mehta, Minesh; Di Tomaso, Emmanuelle; Drappatz, Jan; Kesari, Santosh; Ligon, Keith L.; Aldape, Ken; Jain, Rakesh K.; Stiles, Charles D.; Egorin, Merrill J.; Prados, Michael D.

    2009-01-01

    Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently coexpressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary end point was 6-month progression-free survival (6M-PFS). Patients requiring enzyme-inducing antiepileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptable toxicities. Plasma concentrations of imatinib and its active metabolite, CGP74588, were assessed. Twenty-three heavily pre-treated patients were enrolled into the study (13 benign, 5 atypical, and 5 malignant meningiomas), of whom 22 were eligible. The study was closed prematurely due to slow accrual. Tissue was available only from a minority of patients, but in these specimens there was uniform distribution of PDGFR, the drug target. Imatinib was generally well tolerated. Of 19 patients evaluable for response, 10 progressed at the first scan, and 9 were stable. There were no complete or partial responses. Overall median PFS was 2 months (range, 0.7–34 months); 6M-PFS was 29.4%. For benign meningiomas, median PFS was 3 months (range, 1.1–34 months); 6M-PFS was 45%. For atypical and malignant meningiomas, median PFS was 2 months (range, 0.7–3.7 months); 6M-PFS was 0%. Cycle 1 trough concentrations of imatinib and CGP74588 were 2,129 ± 1,600 ng/ml and 517 ± 326 ng/ml, respectively. Single-agent imatinib was well tolerated but had no significant activity in recurrent meningiomas. Trough plasma concentrations of imatinib exceeded those associated with imatinib activity in

  3. Mouse models for pre-clinical drug testing in leukemia.

    Science.gov (United States)

    Bhatia, Sanil; Daschkey, Svenja; Lang, Franziska; Borkhardt, Arndt; Hauer, Julia

    2016-11-01

    The development of novel drugs which specifically target leukemic cells, with the overall aim to increase complete remission and to reduce toxicity and morbidity, is the most important prerequisite for modern leukemia treatment. In this regard, the current transition rate of potential novel drugs from bench to bedside is remarkably low. Although many novel drugs show promising data in vitro and in vivo, testing of these medications in clinical phase I trials is often sobering with intolerable toxic side effects leading to failure in FDA approval. Areas covered: In this review, the authors discuss the development of murine model generation in the context of targeted therapy development for the treatment of childhood leukemia, aiming to decrease the attrition rate of progressively complex targeted therapies ranging from small molecules to cell therapy. As more complex therapeutic approaches develop, more complex murine models are needed, to recapitulate closely the human phenotype. Expert opinion: Combining xenograft models for efficacy testing and GEMMs for toxicity testing will be a global approach for pre-clinical testing of complex therapeutics and will contribute to the clinical approval of novel compounds. Finally, this approach is likely to increase clinical approval of novel compounds.

  4. Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

    OpenAIRE

    Eriksson, Anna; Österroos, Albin; Hassan, Sadia Bashir; Gullbo, Joachim; Rickardson, Linda; Jarvius, Malin; Nygren, Peter; Fryknäs, Mårten; Höglund, Martin; Larsson, Rolf

    2015-01-01

    To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 mu M drug concentration. Only one of these compounds, quinacrine, showed low...

  5. Which method better evaluates the molecular response in newly diagnosed chronic phase chronic myeloid leukemia patients with imatinib treatment, BCR-ABL(IS) or log reduction from the baseline level?

    Science.gov (United States)

    Qin, Ya-Zhen; Jiang, Qian; Jiang, Hao; Li, Jin-Lan; Li, Ling-Di; Zhu, Hong-Hu; Lai, Yue-Yun; Lu, Xi-Jing; Liu, Yan-Rong; Jiang, Bin; Huang, Xiao-Jun

    2013-09-01

    The molecular response of chronic myeloid leukemia (CML) patients to tyrosine kinase inhibitor treatment can be evaluated either by BCR-ABL mRNA levels on international scale (IS) or by log reduction from the baseline level of the laboratory. Both methods were compared in 248 newly diagnosed chronic phase CML patients treated with imatinib. The major molecular responses (MMR) obtained by both methods predict progression-free survival (PFS, all Plog reduction method, had the same PFS as MMR patients identified by both methods. The molecular responses of patients at 3 and 6 months, as evaluated by the two methods, have similar predictive values on their cytogenetic responses at 12 months and on their molecular responses at 18 months. Both ≤ 10%(IS) and ≥ 1 log reduction at 3 months and ≤ 1%(IS) at 6 months were significantly associated with PFS (P=0.0011, 0.0090, and 0.0064). The percentages of patients with BCR-ABL(IS) of ≤ 1%, >1-10%, and of >10% at 3 months and 6 months in the German CML Study IV were similar with those with corresponding BCR-ABL(IS) in our center, but was significantly different with those evaluated by the log reduction method. Therefore, the molecular response evaluated by BCR-ABL(IS) has similar trends in PFS and in response prediction, but can better differentiate patients than that by the log reduction method. Furthermore, the IS method allows comparison among molecular response results from different laboratories.

  6. Switching to second-generation tyrosine kinase inhibitor improves the response and outcome of frontline imatinib-treated patients with chronic myeloid leukemia with more than 10% of BCR-ABL/ABL ratio at 3 months

    Science.gov (United States)

    Casado, Luis-Felipe; García-Gutiérrez, José-Valentín; Massagué, Isabel; Giraldo, Pilar; Pérez-Encinas, Manuel; de Paz, Raquel; Martínez-López, Joaquín; Bautista, Guiomar; Osorio, Santiago; Requena, María-José; Palomera, Luis; Peñarrubia, María-Jesús; Calle, Carmen; Hernández-Rivas, José-Ángel; Burgaleta, Carmen; Maestro, Begoña; García-Ormeña, Nuria; Steegmann, Juan-Luis

    2015-01-01

    Chronic myeloid leukemia patients display heterogeneous responses to imatinib. Survival depends on baseline clinical characteristics (including prognostic scoring systems) and on early response (such as >10% BCR-ABL/ABL ratio at 3 months of therapy). The results of switching to second-generation tyrosine kinase inhibitors (2GTKIs) may contain a bias since, in the majority of these studies, patients who switch treatment due to intolerance or failure are censored or excluded. We analyzed the Spanish Registry data on switching in an intention-to-treat analysis of patients in standard clinical practice. Switching to 2GTKIs improves responses from 45% to 75% of complete cytogenetic response (CCyR) and from 15% to 45% of major molecular response (MMR) in the group without molecular response 1 (MR1) at 3 months and from 70% to 87% in CCyR and from 52% to 87% in MMR in the group with MR1. The final response rate is poorer in the group with no MR1 at 3 months. Nevertheless, the differences in the rates of response were not translated into differences in major events (transformations or deaths), and the final progression-free survival and overall survival were similar. PMID:25756742

  7. A V530I Mutation in c-KIT Exon 10 Is Associated to Imatinib Response in Extraabdominal Aggressive Fibromatosis

    Directory of Open Access Journals (Sweden)

    Jean-Emmanuel Kurtz

    2010-01-01

    Full Text Available Aggressive fibromatosis (AF or desmoid tumor is a rare condition, characterized by deep tissue invasion by a monoclonal fibroblastic neoplasm, developed from musculoaponeurotic structures. Surgery is the treatment of choice, but negative margins can hardly been achieved in large tumors, and can lead to major functional disability. AF medical therapy includes nonsteroids anti-inflammatory drugs, tamoxifen, with inconsistent results. Several reports of imatinib efficacy in AF appear in the literature. Here, we describe for the first time a V530I KIT exon 10 mutant that was associated to a dramatic imatinib response in an extraabdominal aggressive fibromatosis. The previously discovered V530I substitution was characterized in the core binding factor AML, but had never been reported in any other condition, so far. In this paper, we discuss the KIT exon 10 mutations or polymorphisms that have been described in a variety of KIT-related conditions, including acute myelogenous leukemia, mastocytosis, and aggressive fibromatosis.

  8. Clinical relative factors analysis of imatinib on treatment of chronic myeloid leukemia%伊马替尼治疗慢性髓系白血病临床疗效的相关影响因素分析

    Institute of Scientific and Technical Information of China (English)

    陈莹莹; 曾庆曙; 杨明珍; 王永庆; 夏海龙; 江慧敏; 安福润

    2014-01-01

    Objective To analyse the relationship between the clinical efficacy of imatinib treatment on chronic myeloid leukemia in chronic phaseand risk stratification. Methods 98 imatinib-treated patients were enrolled, and before taking imatinib Sokal and Hasford score were used to assess risk stratification to compare if it has statistical significance between different groups. Results In the 98 cases, 89 cases (97.8%) achieved complete hematologic remission(CHR),76 cases(86.4%) achieved partial cytogenetic remission(PCyR) after three months, 63 cases (82.9%) achieved complete cytogenetic response(CCyR) after six months and 24 cases(54.5%) achieved major molecular response ( MMR ) after twelve months. Risk stratification was assessed according to Sokal score. After three months the rate of groups at low, intermediate and high risk categories which achieved PCyR were 94.4%, 82.6% and 66.7%, respectively(P=0.104), after six months the rate of different groups which achieved CCyR were 88.2%,76.9% and 100%, respectively(P=0.319), and after twelve months the rate of different groups at low and intermediate risk categories which achieved MMR were 52.4% and 65.0%( P=0.412 ).According to the patients' condition, before taking imatinib,46 patients were stratified by Hasford, among which 21 at low risk cate-gorie,23 at intermediate risk categorie and 2 at high risk categorie.After three months the rate of groups at low, in-termediate and high risk categories which achieved PCyR were 90.5%, 91.3% and 50%, respectively ( P =0.191),after six months the rate of different groups which achieved CCyR were 83.3%,94.4% and 100%,respec-tively(P=0.528),and after twelve months the rate of different groups at low and intermediate risk categories which achieved MMR were 45.5% and 58.3% ( P=0.842 ) . Conclusion Imatinib mesylate treatment of chronic mye-loid leukemia is good. Patients belonged to low and intermediate risk groups are more likely to get better clinical ef-ficacy than the high

  9. Outcome of Short Period and Intermittent ImatinibPhased Chemotherapy (Northern Italy Leukemia Group Protocol 09/00) as Therapy for Ph+ ALL%短程、间歇伊马替尼联合传统化疗(N ILG09/00方案)在Ph+ ALL治疗中的作用

    Institute of Scientific and Technical Information of China (English)

    杜欣; 凌伟

    2011-01-01

    1 文献来源Renato B,Giuseppe R,Enrico MP,et al.Chemotherapy-phased Imatinib pulses improve longterm outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia:Northern Italy leukemia group protocol 09/00[J].J Clin Oncol,2010,28(22):3644-3652.2 证据水平3a.3背景·作为一种ABL1酪氨酸激酶抑制剂,伊马替尼在费城染色体(Philadelphia chromosome,Ph)阳性急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)患者的治疗中担当重要角色.%Department of Hemalology, Cancer Center, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China

  10. Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  11. Observation on the therapeutic effects of imatinib mesylate in treatment of 43 cases with advanced chronic myelogenous leukemia%甲磺酸伊马替尼治疗43例慢性粒细胞白血病进展期患者的疗效观察

    Institute of Scientific and Technical Information of China (English)

    朱晓明; 程辉; 游泳

    2013-01-01

    目的:探讨甲磺酸伊马替尼(STI571,格列卫)治疗慢性粒细胞白血病(CML)进展期(即加速期、急变期)患者的临床疗效.方法:43例疾病进展期CML患者口服格列卫治疗,评价其血液学、细胞遗传学及分子遗传学疗效.结果:43例患者的完全血液学反应(CHR)率、完全细胞遗传学反应(CCyR)率和完全分子遗传学反应(CMR)率分别为44.2%、30.0%和21.9%,观察期内总病死率为25.6%,均于12个月内死亡,不同年龄(≤25岁,>25岁)患者之间病死率有统计学意义(P<0.05).结论:格列卫对慢性粒细胞白血病进展期患者有一定的疗效,但耐药现象较普遍,年轻患者的预后可能较差.%Objective: To investigate the effects of imatinib mesylate in treatment of advanced chronic myelogenous leukemia. Methods: To observe the hematologic, cytogenetic and molecular genetic effect of Gleevic in treatment of 43 cases with advanced chronic myelogenous leukemia. Results; The complete hematologic response, complete cytogenetic response and complete molecular genetic response was 44. 2% , 30. 0% and 21. 9% , respectively. Total mortality during observation was 25.6% , and those were dead in 12 months. There was statistically difference in different ages ( ≤25 yeas and >25 years). Conclusions; Gleevic had effects in patients with advanced chronic myelogenous leukemia, but the drug resistance is common, and young patients might have bad prognosis.

  12. Clinical Observation of Domestic Imatinib Mesylate Tablet in the Treatment of Chronic Myeloid Leukemia%国产甲磺酸伊马替尼片治疗慢性粒细胞白血病的临床观察

    Institute of Scientific and Technical Information of China (English)

    祝文娟; 尹大伟; 李琚; 江娟

    2016-01-01

    OBJECTIVE:To observe therapeutic efficacy and safety of domestic Imatinib mesylate tablet in the treatment of chronic myeloid leukemia(CML). METHODS:16 CML patients were selected,including 7 newly diagnosed CML patients and 9 patients diagnosed as CML more than 12 months. Imatinib mesylate tablet 400 mg,qd were used in all patients. Blood routine, bone marrow cytology,ph chromosome Evaluate efficacy,and observed peripheral blood fusion gene,Bcr-Abl/Abl gene mutation and ADR were all detected. RESULTS:After treatment,16 patients achieved complete hematologic remission (CHR);12 cases were pavtial cytogenetic response(MCyR),of which 2 cases achieved complete cytogenetic response(CCyR),2 cases were cyto-genelic remission. 15 patients'Bcr-Abl/Abl transcript levels were less than 10%,and only one case was more than 10%. No ADR difficult to tolerate was found in 16 patients. CONCLUSIONS:Domestic Imatinib mesylate tablet shows definite early therapeutic efficacy and high safety.%目的:观察国产甲磺酸伊马替尼片治疗慢性粒细胞白血病(CML)患者的疗效及安全性.方法:选取CML患者16例,其中初诊CML即给予甲磺酸IM治疗者7例,诊断CML超过12个月后再给予甲磺酸IM治疗者9例,所有患者均长期口服甲磺酸伊马替尼片400 mg,qd.治疗后3个月通过检测所有患者血常规、骨髓细胞学、费城染色体(Ph染色体)评估疗效,并观察外周血Bcr-Abl/Abl融合基因突变及不良反应发生情况.结果:治疗后,16例患者均达到完全血液学缓解(CHR);12例患者获得部分细胞遗传学缓解(PCyR),2例患者获得完全细胞遗传学缓解(CCyR),2例患者无细胞遗传学缓解;15例患者Bcr-Abl/Abl转录水平10%.16例患者均未出现难以耐受的不良反应.结论:国产甲磺酸伊马替尼片早期疗效确切,安全性高.

  13. The teratogenic effects of imatinib mesylate on rat fetuses

    Directory of Open Access Journals (Sweden)

    M.M. El Gendy

    2015-01-01

    Full Text Available Imatinib mesylate, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukemia and gastrointestinal stromal tumors. The aim of the present study is to investigate the effects of imatinib mesylate on the pregnant rats and their fetuses. Pregnant rats were divided into three groups; the first group served as a control group. The second and third groups were orally administered imatinib at doses of 36 mg/kg body weight or 54 mg/kg b.wt. on gestation days (SDs 6 through 13 or SDs 13 through 19, respectively. All animals were sacrificed on the 20th day of gestation. Treatment with imatinib caused a reduction of maternal body weight gain, uterine and placental weights, increased rate of abortion and fetal resorptions. High dose of imatinib caused fetal congenital deformities represented in harelip, contraction of the fore limbs, and paralysis of the hind limbs, exencephaly, encephalocoele and distended abdominal wall, besides occurrence of wavy ribs and absence of other ribs in addition to skeletal growth retardation and lack of ossification of the most skeletal elements. The present work concluded that imatinib is teratogenic when given orally to pregnant rats at 54 mg/kg b.wt. and causes direct maternal or developmental toxicity.

  14. Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia.

    Directory of Open Access Journals (Sweden)

    Matthew J Cooper

    Full Text Available Protein kinases play key roles in oncogenic signaling and are a major focus in the development of targeted cancer therapies. Imatinib, a BCR-Abl tyrosine kinase inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML. However, resistance to imatinib may be acquired by BCR-Abl mutations or hyperactivation of Src family kinases such as Lyn. We have used multiplexed kinase inhibitor beads (MIBs and quantitative mass spectrometry (MS to compare kinase expression and activity in an imatinib-resistant (MYL-R and -sensitive (MYL cell model of CML. Using MIB/MS, expression and activity changes of over 150 kinases were quantitatively measured from various protein kinase families. Statistical analysis of experimental replicates assigned significance to 35 of these kinases, referred to as the MYL-R kinome profile. MIB/MS and immunoblotting confirmed the over-expression and activation of Lyn in MYL-R cells and identified additional kinases with increased (MEK, ERK, IKKα, PKCβ, NEK9 or decreased (Abl, Kit, JNK, ATM, Yes abundance or activity. Inhibiting Lyn with dasatinib or by shRNA-mediated knockdown reduced the phosphorylation of MEK and IKKα. Because MYL-R cells showed elevated NF-κB signaling relative to MYL cells, as demonstrated by increased IκBα and IL-6 mRNA expression, we tested the effects of an IKK inhibitor (BAY 65-1942. MIB/MS and immunoblotting revealed that BAY 65-1942 increased MEK/ERK signaling and that this increase was prevented by co-treatment with a MEK inhibitor (AZD6244. Furthermore, the combined inhibition of MEK and IKKα resulted in reduced IL-6 mRNA expression, synergistic loss of cell viability and increased apoptosis. Thus, MIB/MS analysis identified MEK and IKKα as important downstream targets of Lyn, suggesting that co-targeting these kinases may provide a unique strategy to inhibit Lyn-dependent imatinib-resistant CML. These results demonstrate the utility of MIB/MS as a tool to identify

  15. Characterization of Drug Effect on Leukemia Cells Through Single Cell Assay With Optical Tweezers and Dielectrophoresis.

    Science.gov (United States)

    Hou, Jundi; Luo, Tao; Ng, Ka Lam; Leung, Anskar Y H; Liang, Raymond; Sun, Dong

    2016-12-01

    One of the greatest challenges in acute myeloid leukemia (AML) treatment is preventing relapse. Leukemia cells can hide in bone marrow niche or vascular niche. Hence, many chemical drugs cannot kill these cells. To characterize migration and adhesion properties of leukemia cells in specific niches, CXCR4/SDF- 1α signal pathway has been widely used for investigation. AMD3100 is treated as one of the most common chemical drugs that can inhibit this signal. In the current study, we particularly investigate the effect of AMD3100 on the adhesion property of leukemia cells on stromal cells by using engineering tools, namely, optical tweezers (OT) and dielectrophoresis (DEP), to probe single cell property. AMD3100 not only inhibits the CXCR4/SDF- 1α signal pathway but also reduces gene expression of CXCR4 and VLA-4 on leukemia cells. The drug also softens leukemia cells. This work provides a new way to investigate cell behavior under drug treatment. The use of combined engineering tools will benefit drug discovery and assessment for leukemia treatment.

  16. [Modern therapy of chronic myeloid leukemia: an example for paradigma shift in hemato-oncology].

    Science.gov (United States)

    Leitner, A A; Hehlmann, R

    2011-02-01

    Chronic myeloid leukemia (CML) is exceptional amongst neoplasias since its underlying pathomechanism has been elucidated, and potent well tolerated targeted drugs, the tyrosine kinase inhibitors (TKI), are available for treatment. They convincingly improve prognosis while retaining good quality of life. Aims of therapy are complete remissions as well as prolongation of life and cure. Imatinib 400 mg per day is current standard therapy. There are hints for a better outcome with a higher initial imatinib dose or with combination therapy. Even after achievement of complete molecular response continuous therapy might be necessary in most cases. In case of imatinib intolerance or failure, the second generation TKI dasatinib and nilotinib and allogeneic stem cell transplantation are available. The use of second generation TKI as first line treatment might further improve prognosis. The therapeutic response should be regularly monitored according to international recommendations.

  17. Shortcomings in the clinical evaluation of new drugs: acute myeloid leukemia as paradigm

    OpenAIRE

    Walter, Roland B.; Appelbaum, Frederick R.; Tallman, Martin S.; Weiss, Noel S.; Larson, Richard A.; Estey, Elihu H.

    2010-01-01

    Drugs introduced over the past 25 years have benefitted many patients with acute myeloid leukemia (AML) and provided cure for some. Still, AML remains difficult to treat, and most patients will eventually die from their disease. Therefore, novel drugs and drug combinations are under intense investigation, and promising results eagerly awaited and embraced. However, drug development is lengthy and costs are staggering. While the phase 1–phase 2–phase 3 sequence of clinical drug testing has rem...

  18. 伊马替尼治疗慢性粒细胞白血病135例远期疗效观察%Investigation of long-term follow-up results of 135 patients with chronic myeloid leukemia receiving imatinib

    Institute of Scientific and Technical Information of China (English)

    周可树; 王翠翠; 赵耀中; 邢立杰; 钱林生; 于珍; 齐军元; 王建祥; 邱录贵

    2010-01-01

    Objective To evaluate the efficacy and safety of imatinib in chronic myeloid leukemia (CML) patients and analyse the factors affecting the survival. Methods 135 CML patients receiving imatinib were evaluated for hematologic, cytogenetic, and molecular responses and adverse events. Results The median follow-up was 20 (range 3-67) months. The rate of cumulative complete hematological response (CHR), major cytogenetic response (MCyR), complete cytogenetic response( CCyR ) and complete molecular response (CMoR) in chronic phase CML patients were 97.9 %, 78.3 %, 72.2 % and 35.1%, respectively.These rates were significantly higher in chronic phase than in accelerated phase and blastic phase (P <0.001).The rate of CCyR in low-risk patients was significantly higher than high-risk patients (P =0.048). The estimated overall survival (OS) rate at 1, 3 and 5 year for chronic phase patients were (97.8±1.5) %, (95.2±2.4) % and (91.9±3.2) %, respectively. The estimated progression-free (PFS) survival rate at 1, 3 and 5 year were (92.6±2.7) %, (85.5±3.7) % and (81.3±4.3) %, respectively. The OS rate for accelerated phase patients at 6, 12 and 24 month were (93.8±6.1) %, (72.5±11.8) % and (64.5±12.9) %, the PFS rate were (92.3±7.4) %,(64.5±14.7) %, (53.7±15.7) %, respectively. The OS rate for blastic phase patients at 6, 12 and 19 month were (86.4±7.3) %, (45.4±11.4) %, (19.4±9.8) %, the PFS rate were (70.1±12.6) %, (37.6±15.6) % and (18.8±15.4) %, respectively. The OS and PFS of patients in chronic phase who achieved CCyR or CMoR were better than patients only achieved CHR (P ≤0.001). Multivariate analysis for survival of chronic phase patients indicated that imatinib resistance was the unfavourable factor for PFS (P =0.000, RR =46.744) and OS(P =0.007, RR =20.270). The non-hematological toxicity of imatinib was slight and tolerable, severe hematological toxicity was the major reason for dose reduction or drug discontinuation. Conclusion The efficacy of

  19. Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity.

    Directory of Open Access Journals (Sweden)

    Ruth J Napier

    2015-03-01

    Full Text Available Imatinib mesylate (Gleevec inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics "emergency hematopoiesis," a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.

  20. TCGA researchers identify potential drug targets, markers for leukemia risk

    Science.gov (United States)

    Investigators for The Cancer Genome Atlas (TCGA) Research Network have detailed and broadly classified the genomic alterations that frequently underlie the development of acute myeloid leukemia (AML), a deadly cancer of the blood and bone marrow. Their wo

  1. Effects of imatinib and nilotinib on the whole transcriptome of cultured murine osteoblasts.

    Science.gov (United States)

    Kirschner, Gyöngyi; Balla, Bernadett; Horváth, Péter; Kövesdi, Andrea; Lakatos, Gergely; Takács, István; Nagy, Zsolt; Tóbiás, Bálint; Árvai, Kristóf; Kósa, János Pál; Lakatos, Péter

    2016-09-01

    Numerous clinical observations have confirmed that breakpoint cluster region-abelson fusion oncoprotein tyrosine kinase inhibitors used in leukemia treatment alter bone physiology in a complex manner. The aim of the present study was to analyze the whole transcriptome of cultured murine osteoblasts and determine the changes following treatment with imatinib and nilotinib using Sequencing by Oligonucleotide Ligation and Detection next generation RNA sequencing. This study also aimed to identify candidate signaling pathways and network regulators by multivariate Ingenuity Pathway Analysis. Based on the right-tailed Fisher's exact test, significantly altered pathways including upstream regulators were defined for each drug. The correlation between these pathways and bone metabolism was also examined. The preliminary results suggest the two drugs have different mechanisms of action on osteoblasts, and imatinib was shown to have a greater effect on gene expression. Data also indicated the potential role of a number of genes and signaling cascades that may contribute to identifying novel targets for the treatment of metabolic bone diseases.

  2. Insufficient bilateral femoral subtrochanteric fractures in a patient receiving imatinib mesylate.

    Science.gov (United States)

    Yang, Kyu-Hyun; Park, Si-Young; Park, Sang-Won; Lee, Soon-Hyuck; Han, Seung-Beom; Jung, Woong-Kyo; Kim, Suk-Jin

    2010-11-01

    We present a case of insufficient bilateral femoral subtrochanteric fractures in a patient who was treated with imatinib mesylate, an anticancer drug, for 1 year after a diagnosis of chronic myelogenous leukemia (CML). A 60-year-old woman presented with bilateral thigh pain for 6 months. A plain radiograph revealed bilateral progressive insufficient fractures on the subtrochanteric areas of the femurs. MRI of the femurs revealed incomplete stress fractures and no evidence of bone metastasis on either femur. Bone densitometry showed normal T-scores around the hip joint and spine. The patient had normal serum levels of calcium, vitamin D derivatives, and thyroid hormones. Serum phosphate levels were decreased, and parathyroid hormone levels were increased. Serum osteocalcin and urinary N-telopeptide of collagen cross-links (NTx) were both decreased. A bone biopsy demonstrated normocellular marrow without leukemic cells. A histomorphometric evaluation of her bones revealed reduced bone turnover despite secondary hyperparathyroidism. The serum markers for bone metabolism and histomorphometric evaluations in this patient suggest that the drug may have an effect on bone metabolism. These effects could be seen for both bone formation and resorption: this could result in impaired bone mineralization, a severely suppressed bone turnover rate, insufficient fractures, and bone necrosis, which are sometimes seen with long-term use of bisphosphonates. To our knowledge, this is the first case of an insufficient bilateral femoral shaft fracture that is potentially related to the use of imatinib mesylate in a patient with CML. Careful examination of bone metabolism should be performed in patients with CML because imatinib mesylate treatment is a lifelong process.

  3. IMATINIB MESYLATE IN THE TREATMENT OF CHRONIC MYELOGENOUS LEUKEMIA: AN EFFICACY AND SAFETY EVALULATION%伊马替尼治疗慢性粒细胞白血病有效性和安全性观察

    Institute of Scientific and Technical Information of China (English)

    雷媚; 赵洪国; 杨颉

    2012-01-01

    目的 观察甲磺酸伊马替尼治疗慢性粒细胞白血病(CML)的有效性与安全性.方法 51例CML病人给予伊马替尼治疗,观察其血液学、细胞遗传学、分子学反应以及不良反应、总生存和疾病进展情况.结果 CML慢性期病人治疗3个月时97.8%(45/46)获得完全血液学缓解;用药1年后,79,4%(27/34)获得完全细胞遗传学缓解,5.9%(2/34)获得部分细胞遗传学缓解,2.9%(1/34)获得次要细胞遗传学缓解,5.9%(2/34)获得微小细胞遗传学缓解,5.9%(2/34)未获得遗传学反应,29.4%(10/34)获得完全分子遗传学缓解;1、2、3年总生存率分别为100.0%、97.0%、91.6%,疾病无进展生存率分别为100.0%、85.3%、73.1%.3例CML加速期病人1例获得完全血液学缓解,1例获得完全细胞遗传学缓解,1例获得部分细胞遗传学缓解.2例CML急变期病人均死亡,总病程分别为9、15个月.结论 伊马替尼治疗CML慢性期病人,完全血液学缓解率和细胞遗传学缓解率高,且不良反应少,但对加速期和急变期病人疗效欠佳.%Objective To assess the efficacy and safety of imatinib mesylate in the treatment of patients with chronic my-elogenous leukemia (CML). Methods Fifty-one CML patients were treated with imatinib. The responses in hematology, cyto-genetics, molecule and adverse reactions, total survival and progression of the disease were observed. Results After three months of therapy, 97. 8% (45/46) of the patients in chronic phase achieved complete hematologic response (CHR)I After one year of medication, 79.4% (27/34) reached complete cytogenetic response, 5. 9% (2/34) achieved partial cytogenetic response, 2. 9% (1/34) obtained minor cytogenetic response, 5. 9% (2/34) got minimal cytogenetic response, 5. 9% (2/34) did not get cytogenetic response, and patients with complete molecular response accounted for 29. 4% (10/34). The total one-, two-and three-year survival rates were 100. 0%, 97. 0%, and 91

  4. Formulation and characterization of microspheres loaded with imatinib for sustained delivery.

    Science.gov (United States)

    Ramazani, F; Chen, W; Van Nostrum, C F; Storm, G; Kiessling, F; Lammers, T; Hennink, W E; Kok, R J

    2015-03-30

    The aim of this study was the development of imatinib-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with high loading efficiency which can afford continuous release of imatinib over a prolonged period of time. Imatinib mesylate loaded PLGA microspheres with a size of 6-20 μm were prepared by a double emulsion (W1/O/W2) method using dichloromethane as volatile solvent. It was found that the microspheres were spherical with a non-porous surface; imatinib loading efficiency (LE) was highly dependent on the pH of the external water phase (W2). By increasing the pH of W2 phase above the highest pKa of imatinib (pKa 8.1), at which imatinib is mainly uncharged, the LE increased from 10% to 90% (pH 5.0 versus pH 9.0). Conversely, only 4% of its counter ion, mesylate, was retained in the microspheres at the same condition (pH 9.0). Since mesylate is highly water soluble, it is unlikely that it partitions into the organic phase. We demonstrated, using differential scanning calorimetry (DSC), that imatinib was molecularly dispersed in the polymeric matrix at loadings up to 8.0%. At higher drug loading, imatinib partially crystallized in the matrix. Imatinib microspheres released their cargo during three months by a combination of diffusion through the polymer matrix and polymer erosion. In conclusion, we have formulated imatinib microspheres with high LE and LC. Although we started with a double emulsion of imatinib mesylate, the obtained microspheres contained imatinib base which was mainly molecularly dispersed in the polymer matrix. These microspheres release imatinib over a 3-month period which is of interest for local treatment of cancer.

  5. Combination of imatinib with CXCR4 antagonist BKT140 overcomes the protective effect of stroma and targets CML in vitro and in vivo.

    Science.gov (United States)

    Beider, Katia; Darash-Yahana, Merav; Blaier, Orly; Koren-Michowitz, Maya; Abraham, Michal; Wald, Hanna; Wald, Ori; Galun, Eithan; Eizenberg, Orly; Peled, Amnon; Nagler, Arnon

    2014-05-01

    Functional role of CXCR4 in chronic myelogenous leukemia (CML) progression was evaluated. Elevated CXCR4 significantly increased the in vitro survival and proliferation in response to CXCL12. CXCR4 stimulation resulted in activation of extracellular signal-regulated kinase (Erk)-1/2, Akt, S6K, STAT3, and STAT5 prosurvival signaling pathways. In accordance, we found that in vitro treatment with CXCR4 antagonist BKT140 directly inhibited the cell growth and induced cell death of CML cells. Combination of BKT140 with suboptimal concentrations of imatinib significantly increased the anti-CML effect. BKT140 induced apoptotic cell death, decreasing the levels of HSP70 and HSP90 chaperones and antiapoptotic proteins BCL-2 and BCL-XL, subsequently promoting the release of mitochondrial factors cytochrome c and SMAC/Diablo. Bone marrow (BM) stromal cells (BMSC) markedly increased the proliferation of CML cells and protected them from imatinib-induced apoptosis. Furthermore, BMSCs elevated proto-oncogene BCL6 expression in the CML cells in response to imatinib treatment, suggesting the possible role of BCL6 in stroma-mediated TKI resistance. BKT140 reversed the protective effect of the stroma, effectively promoted apoptosis, and decreased BCL6 levels in CML cells cocultured with BMSCs. BKT140 administration in vivo effectively reduced the growth of subcutaneous K562-produced xenografts. Moreover, the combination of BKT140 with low-dose imatinib markedly inhibited tumor growth, achieving 95% suppression. Taken together, our data indicate the importance of CXCR4/CXCL12 axis in CML growth and CML-BM stroma interaction. CXCR4 inhibition with BKT140 antagonist efficiently cooperated with imatinib in vitro and in vivo. These results provide the rational basis for CXCR4-targeted therapy in combination with TKI to override drug resistance and suppress residual disease.

  6. Renal dysfunction in a renal transplant patient treated concurrently with cyclosporine and imatinib.

    Science.gov (United States)

    Mulder, Karen E; Egorin, Merrill J; Sawyer, Michael B

    2012-12-01

    Imatinib mesylate has proven activity in treating locally advanced or metastatic gastrointestinal stromal tumors (GIST). Drug interactions are particularly concerning as imatinib is extensively metabolized by the cytochrome P450 enzyme system. We describe the clinical course of a 72 year-old male with a cadaveric renal transplant requiring cyclosporine that presented with a metastatic GIST and was started on imatinib at the standard dose of 400 mg daily. Imatinib initiation resulted in a decline in renal function with the serum creatinine increasing from 123 μmol/L to 196 μmol/L and an elevation in whole blood cyclosporine concentrations from 79 μg/L to 139 μg/L. No other imatinib toxicities were reported. With discontinuation of imatinib, the serum creatinine returned to baseline as did the whole blood cyclosporine levels. Ultimately, decreasing both the cyclosporine and imatinib dosing was associated with stabilized renal function (serum creatinine 150-186 μmol/L) and cyclosporine concentrations (53-97 μg/L). A prolonged partial response to therapy for 19 months was maintained despite low imatinib trough concentrations measured on two separate occasions (127.1 ng/ml and 139 ng/ml). In our patient, imatinib initiation resulted in renal toxicity most likely due to its interaction with cyclosporine resulting in elevation of the whole blood cyclosporine concentration.

  7. Analysis of related factors in 70 chronic myeloid leukemia patients treated with imatinib mesylate%甲磺酸伊马替尼对慢性髓系白血病患者效果的相关因素研究

    Institute of Scientific and Technical Information of China (English)

    王良妥; 张湘兰; 司徒健瑜; 黄远颖

    2016-01-01

    Objective The aim of this study was to investigate the related factors of imatinib mesylate on myeloid leukemia patients. Methods 70 CML patients received imatinib mesylate at a dose of 400 ~600 mg orally per day and we evaluated their complete he-matologic response (CHR),complete cytogenetic response (CCyR),major cytogenetic response (MCyR)and complete molecular re-sponse (CMoR),etc.in patients of chronic phase (CP)(early chronic phase and chronic phase),accelerated phase (AP)and blast crisis (BC).And then analyzed the related factors of imatinib mesylate on chronic myeloid leukemia.Results Until the February 2015 in our hospital,55 cases of the 70 chronic myeloid leukemia patients are in chronic phase (CP)(30 cases of early chronic phase,25 cases of late chronic phase);11 cases are in accelerated phase (AP);9 cases are in blast crisis (BC).(1)After a median follow up of 15 months,all the 70 cases of CML patients reached a 100% CHR.Among primary treated group,the CHR rate was 100%,CCyR rate 80.8%,MCyR rate 71.9% and CMoR 74.9%.And in retreated group,the CHR rate,CCyR,MCyR and CMoR were 100%,45.8%,79.1% and 53.9%,respectively,and there was no significant difference.(2)The CHR rate,CCyR,MCyR and CMoR in low-risk CML patients were 100%,63.7%,78.9% and 56.3%,respectively.The rates in intermediate risk CML pa-tients were 100%,76.1%,79.6% and 47.9%,respectively.The rates in high-risk CML patients were 100%,49.8%,76.3% and 46.8%,respectively and there was no significant difference.(3)Before treatment,the WBC count was less than 100 ×109 ·L -1 ,the Hb level was much more than 130 g·L -1 ,and the rate of basophil count in peripheral blood was less than 0.05.This indicated that CML patients were susceptible to the beneficial rates of CHR,CCyR,MCyR or CMoR.(4)Chronic phase (30 patients of early chronic phase,30 cases of late chronic phase)with a median follow -up of 15 months,overall CHR rate was 90.9%,CCyR rate 85.5%, MCyR rate 69.1%,and CMoR rate 63.6%.Among the total

  8. 中国慢性髓性白血病伊马替尼耐药或不耐受患者采用达沙替尼治疗的临床疗效及安全性研究%Research of clinical effect and safety by dasatinib in the treatment of imatinib resistance or intolerance in Chinese chronic myelogenous leukemia patients

    Institute of Scientific and Technical Information of China (English)

    朱琳

    2016-01-01

    ObjectiveTo research application value by dasatinib in the treatment of imatinib resistance or intolerance in chronic myelogenous leukemia(CML).MethodsA total of 90 CML patients with imatinib resistance or intolerance were divided by different medication into control group (nilotinib for treatment) and observation group (dasatinib for treatment), with 45 cases in each group. Observation was made on complete cytogenetic remission (CCyR), complete hematologic remission (CHR), main molecular biology remission (MMR)/complete molecular biology remission (CMR) rates and incidence of adverse reactions in the two groups.Results Comparing with the control group, the observation group had higher CCyR remission rate in chronic period and higher CHR, MMR/CMR rates in acceleration period. The observation group had lower mortality rate and progression rate in in acceleration period and less adverse reaction in treatment. The differences all had statistical significance (P<0.05).ConclusionDasatinib provides remarkable effect and tolerance in treating patients with imatinib resistance or intolerance in chronic myelogenous leukemia. It is worth promoting.%目的:研究达沙替尼在慢性髓性白血病(CML)伊马替尼耐药或不耐受患者中的应用价值。方法根据用药不同将90例CML伊马替尼耐药或不耐受患者随机分为对照组(尼洛替尼治疗)和观察组(达沙替尼治疗),各45例。观察两组完全细胞遗传学(CCyR)、完全血液学(CHR)、主要生物分子学(MMR)/完全分子生物学(CMR)缓解率及不良反应发生率。结果与对照组比较,观察组慢性期患者CCyR缓解率及加速期患者CHR、MMR/CMR缓解率均更高,加速期死亡率及进展率更低,治疗期间不良反应更少,差异均有统计学意义(P<0.05)。结论达沙替尼治疗慢性髓性白血病伊马替尼耐药或不耐受患者的临床疗效优,患者更耐受,值得推广。

  9. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia

    DEFF Research Database (Denmark)

    Göllner, Stefanie; Oellerich, Thomas; Agrawal-Singh, Shuchi

    2017-01-01

    In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of h...

  10. Quantitative determination of two polymorphic forms of imatinib mesylate in a drug substance and tablet formulation by X-ray powder diffraction, differential scanning calorimetry and attenuated total reflectance Fourier transform infrared spectroscopy.

    Science.gov (United States)

    Bellur Atici, Esen; Karlığa, Bekir

    2015-10-10

    Imatinib has been identified as a tyrosine kinase inhibitor that selectively inhibits the Abl tyrosine kinases, including Bcr-Abl. The active substance used in drug product is the mesylate salt form of imatinib, a phenylaminopyrimidine derivative and chemically named as N-(3-(4-(pyridin-3-yl) pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl) methyl)-benzamide methanesulfonic acid salt. It exhibits many polymorphic forms and most stable and commercialized polymorphs are known as α and β forms. Molecules in α and β polymorphic forms exhibit significant conformational differences due to their different intra- and intermolecular interactions, which stabilize their molecular conformations and affect their physicochemical properties such as bulk density, melting point, solubility, stability, and processability. The manufacturing process of a drug tablet included granulation, compression, coating, and drying may cause polymorphic conversions. Therefore, polymorphic content of the drug substance should be controlled during quality control and stability testing. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) methods were evaluated for determination of the polymorphic content of the drug substance and drug product; and PXRD was the most accurate technique and selected as preferred method and validated. Prior to development of a quantification method, pure α and β polymorphs were characterized and used throughout the method development and validation studies. Mixtures with different ratios of α and β forms were scanned using X-ray diffractometer with a scan rate of 0.250°/min over an angular range of 19.5-21.0° 2θ and the peak heights for characteristic peak of β form at 20.5 ± 0.2° 2θ diffraction angle were used to generate a calibration curve. The detection limit of β polymorph in α form imatinib mesylate tablets was found as 4% and

  11. Sensitivity of imatinib-resistant T315I BCR-ABL CML to a synergistic combination of ponatinib and forskolin treatment.

    Science.gov (United States)

    Oaxaca, Derrick M; Yang-Reid, Sun Ah; Ross, Jeremy A; Rodriguez, Georgialina; Staniswalis, Joan G; Kirken, Robert A

    2016-09-01

    Tyrosine kinase inhibitors (TKIs) have dramatically improved the life expectancy of patients suffering from chronic myeloid leukemia (CML); however, patients will eventually develop resistance to TKI therapy or adverse side effects due to secondary off-target mechanisms associated with TKIs. CML patients exhibiting TKI resistance are at greater risk of developing an aggressive and drug-insensitive disease. Drug-resistant CML typically arises in response to spontaneous mutations within the drug binding sites of the targeted oncoproteins. To better understand the mechanism of drug resistance in TKI-resistant CML patients, the BCR-ABL transformed cell line KCL22 was grown with increasing concentrations of imatinib for a period of 6 weeks. Subsequently, a drug-resistant derivative of the parental KCL22 cell line harboring the T315I gatekeeper mutation was isolated and investigated for TKI drug sensitivity via multi-agent drug screens. A synergistic combination of ponatinib- and forskolin-reduced cell viability was identified in this clinically relevant imatinib-resistant CML cell line, which also proved efficacious in other CML cell lines. In summary, this study provides new insight into the biological underpinnings of BCR-ABL-driven CML and potential rationale for investigating novel treatment strategies for patients with T315I CML.

  12. Effect and Prognostic Analysis of Treatment for Acute Myeloid Leukemia Using Chinese Drugs Combined with Chemotherapy

    Institute of Scientific and Technical Information of China (English)

    胡晓梅; 刘锋; 郑春梅; 李柳; 刘池; 张姗姗; 肖海燕; 杨晓红; 王洪志; 许勇钢; 胡乃平; 麻柔

    2009-01-01

    Objective:To observe the clinical efficacy of Chinese drugs combined with chemotherapy in the treatment of acute myeloid leukemia(AML) and to investigate the prognostic relevance of the main parameters in AML treated with integrative medicine.Methods:Forty AML patients hospitalized at the authors' hospital were treated with Chinese drugs and chemotherapy.The routine examination,immunophenotype and karyotype analyses were carried out.The clinical efficacy was observed and the prognostic factors were analy...

  13. Patients Taking Imatinib for CML Have Similar Risk of Death as General Population

    Science.gov (United States)

    In an international study, the risk of death for chronic myelogenous leukemia patients treated with imatinib (Gleevec) who had been in remission for at least 2 years was not different from that of the general population, according to an article in the March 21, 2011 issue of the Journal of the National Cancer Institute.

  14. Quantitative Phenotyping-Based In Vivo Chemical Screening in a Zebrafish Model of Leukemia Stem Cell Xenotransplantation

    Science.gov (United States)

    Zhang, Beibei; Shimada, Yasuhito; Kuroyanagi, Junya; Umemoto, Noriko; Nishimura, Yuhei; Tanaka, Toshio

    2014-01-01

    Zebrafish-based chemical screening has recently emerged as a rapid and efficient method to identify important compounds that modulate specific biological processes and to test the therapeutic efficacy in disease models, including cancer. In leukemia, the ablation of leukemia stem cells (LSCs) is necessary to permanently eradicate the leukemia cell population. However, because of the very small number of LSCs in leukemia cell populations, their use in xenotransplantation studies (in vivo) and the difficulties in functionally and pathophysiologically replicating clinical conditions in cell culture experiments (in vitro), the progress of drug discovery for LSC inhibitors has been painfully slow. In this study, we developed a novel phenotype-based in vivo screening method using LSCs xenotransplanted into zebrafish. Aldehyde dehydrogenase-positive (ALDH+) cells were purified from chronic myelogenous leukemia K562 cells tagged with a fluorescent protein (Kusabira-orange) and then implanted in young zebrafish at 48 hours post-fertilization. Twenty-four hours after transplantation, the animals were treated with one of eight different therapeutic agents (imatinib, dasatinib, parthenolide, TDZD-8, arsenic trioxide, niclosamide, salinomycin, and thioridazine). Cancer cell proliferation, and cell migration were determined by high-content imaging. Of the eight compounds that were tested, all except imatinib and dasatinib selectively inhibited ALDH+ cell proliferation in zebrafish. In addition, these anti-LSC agents suppressed tumor cell migration in LSC-xenotransplants. Our approach offers a simple, rapid, and reliable in vivo screening system that facilitates the phenotype-driven discovery of drugs effective in suppressing LSCs. PMID:24454867

  15. Optimizing Adherence to Adjuvant Imatinib in Gastrointestinal Stromal Tumor

    Science.gov (United States)

    Tetzlaff, Eric D.; Davey, Monica P.

    2013-01-01

    The increasing use of patient-administered oral anticancer drugs is paralleled by new challenges in maintaining treatment adherence. These challenges are particularly significant with adjuvant therapies for prevention of disease recurrence, where the benefits of ongoing treatment are not readily apparent to patients. Nurse practitioners and physician assistants (collectively referred to as advanced practitioners) play integral roles in providing education on disease and treatment to patients that can increase adherence to oral therapies and ideally improve outcomes. For patients with gastrointestinal stromal tumor (GIST), the oral targeted therapy imatinib has become the mainstay of treatment for advanced and recurrent disease and as adjuvant therapy following surgical resection. Recent data indicate significantly improved overall survival with 3 years vs. 1 year of adjuvant imatinib therapy. Continuous dosing with imatinib is needed for optimal efficacy and to limit additional health-care costs associated with management of disease progression in GIST. However, longer duration of therapy increases the risk of nonadherence. Imatinib adherence rates, as well as factors contributing to nonadherence to adjuvant therapy in routine clinical practice, are discussed in this review. Also explored are practical approaches for improving adherence to adjuvant imatinib therapy through greater patient education, in light of the increased duration of therapy in select patients. PMID:25032004

  16. The role of microenvironment and immunity in drug response in leukemia.

    Science.gov (United States)

    Bakker, Emyr; Qattan, Malak; Mutti, Luciano; Demonacos, Constantinos; Krstic-Demonacos, Marija

    2016-03-01

    Leukemia is a cancer of the white blood cells, with over 54,000 new cases per year diagnosed worldwide and a 5-year survival rate below 60%. This highlights a need for research into the mechanisms behind its etiology and causes of therapy failure. The bone marrow microenvironment, in which adult stem cells are maintained in healthy individuals, has been implicated as a source of chemoresistance and disease relapse. Here the various ways that the microenvironment can contribute to the resistance and persistence of leukemia are discussed. The targeting of the microenvironment by leukemia cells to create an environment more suitable for cancer progression is described. The role of soluble factors, drug transporters, microvesicles, as well as the importance of direct cell-cell contact, in addition to the effects of inflammation and immune surveillance in microenvironment-mediated drug resistance are discussed. An overview of the clinical potential of translating research findings to patients is also provided. Understanding of and further research into the role of the bone marrow microenvironment in leukemia progression and relapse are crucial towards developing more effective treatments and reduction in patient morbidity. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

  17. Unilateral Gynaecomastia in a Young Man with Chronic Myeloid Leukemia.

    Science.gov (United States)

    Jain, Ankur; Varma, Subhash; Garg, Rashi; Malhotra, Pankaj

    2017-09-01

    Male reproductive issues are frequently overlooked in patients of chronic myeloid leukemia (CML) on imatinib therapy. Current article describes a young man with CML on imatinib mesylate since 13 years who presented to us with painful left sided breast swelling. Mammography and fine needle aspiration cytology confirmed the diagnosis of gynaecomastia and hormone profile revealed low testosterone levels. Gynaecomastia was attributed to imatinib related hypogonadism. Gynaecomastia improved after hormone replacement therapy. Need for long term monitoring of reproductive hormones in patients of CML on imatinib therapy is emphasized in this report.

  18. Experience of imatinib in the treatment of chronic myelogenous leukemia%甲磺酸伊马替尼治疗慢性粒细胞白血病的临床观察

    Institute of Scientific and Technical Information of China (English)

    梁蓉; 陈协群; 白庆咸; 杨岚; 张涛; 张永清; 朱华锋; 顾宏涛; 高广勋

    2011-01-01

    目的:总结甲磺酸伊马替尼(IM)治疗Ph阳性慢性粒细胞白血病(CML)患者的临床观察体会.方法:收集110例Ph阳性CML慢性期(CP)患者、6例加速期(AP)患者和4例急变期(BC)患者分别口服IM 400、600或800 mg/d.通过血液学、细胞遗传学和分子遗传学指标来判断疗效.结果:CP患者完全血液学反应(CHR)率、主要细胞遗传学反应(MCyR)率和完全细胞遗传学反应(CCyR)率分别为98.2%、90.9%和80.9%;AP分别为66.7%、33.3%和16.7%,P值分别为0.002、0.000和0.000.其中CP患者中肝肾功能不全的患者需减少IM剂量.27例经干扰素治疗失败的CP患者IM治疗仍有效.第1年高随访(1次/月)CP患者CCyR达81.9%,非高随访则为63.6%,P=0.005 2.服药前肾功能不全和肝功能不全较脏器功能正常的CP患者服药6个月内发生3~4级血液学毒副反应概率增高,服药6个月后有所减少.结论:IM对CP患者包括干扰素治疗失败的有较高疗效,对AP和BC患者有一定近期疗效.肝肾功能不全的患者易出现血液学毒副反应,需要药物剂量调整.%OBJECTIVE: To summarize the experience of imatinib mesylate (IM) in the treatment of patients with Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia(CML). METHODS: Totally 110 patients with Ph-positive CML in chronic phase(CP) were treated with IM 400 mg/d; 6 CML patients of accelerated phase(AP) and 4 CML patients with blastcrisis (BC) were treated with IM 600 mg/d and 800 mg/d respectively. RESULTS: Overall complete hematological response(CHR) rate, major cytogenetic response (MCyR) rate and complete cytogenetic response (CCyR) rate of CP were 98. 2%, 90.9% and 80. 9% respectively; while those of AP were 66. 7%, 33. 3% and 16. 7% (P were 0.002,0.000 and 0. 000). Dose reductions were performed in of 97 patients with renal and liver dysfunction. IM was effective in 27 patients with CP who failed in previous IFN-α therapy. CCyR of CP patients with

  19. Managing inadequate responses to frontline treatment of chronic myeloid leukemia: a case-based review.

    Science.gov (United States)

    Bixby, Dale L

    2013-05-01

    The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib are the standard of care for treating patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML). Compared with interferon-based treatment, the previous standard of care, imatinib is associated with significantly higher cytogenetic response rates and prolonged overall survival. Nilotinib and dasatinib, both newer and more potent TKIs, significantly improve cytogenetic and molecular response rates compared with imatinib. Despite significant advances in CML treatment enabled by the TKIs, a fraction of patients who receive frontline treatment with a TKI demonstrate inadequate response. The reasons for this vary, but in many cases, inadequate response can be attributed to non-adherence to the treatment regimen, intolerance to the drug, intrinsic or acquired resistance to the drug, or a combination of reasons. More often than not, strategies to improve response necessitate a change in treatment plan, either a dose adjustment or a switch to an alternate drug, particularly in the case of drug intolerance or drug resistance. Improved physician-patient communication and patient education are effective strategies to address issues relating to adherence and intolerance. Because inadequate response to TKI treatment correlates with poor long-term outcomes, it is imperative that patients who experience intolerance or who fail to achieve appropriate responses are carefully evaluated so that appropriate treatment modifications can be made to maximize the likelihood of positive long-term outcome.

  20. Drugs under preclinical and clinical study for treatment of acute and chronic lymphoblastic leukemia

    OpenAIRE

    Jacob JA; Salmani JMM; Chen B

    2016-01-01

    Joe Antony Jacob, Jumah Masoud Mohammad Salmani, Baoan Chen Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China Abstract: Targeted therapy has modernized the treatment of both chronic and acute lymphoblastic leukemia. The introduction of monoclonal antibodies and combinational drugs has increased the survival rate of patients. Preclinical studies with various agents have resulted in positive outputs...

  1. High Throughput Drug Sensitivity Assay and Genomics- Guided Treatment of Patients With Relapsed or Refractory Acute Leukemia

    Science.gov (United States)

    2016-11-14

    Acute Leukemia of Ambiguous Lineage; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  2. Imatinib mesylate therapy for patients with chronic myeloid leukemia:long-term out-come from a single center in China%伊马替尼一线治疗慢性粒细胞白血病慢性期患者-单中心十年回顾性分析

    Institute of Scientific and Technical Information of China (English)

    李菲; 张晓洁; 张荣艳; 肖承京; 卢炜; 饶佳; 周玉兰; 陈国安; 杨赣萍

    2016-01-01

    Objective:Imatinib is extensively used as a first-line therapeutic agent for patients with chronic myeloid leukemia (CML) at the chronic phase (CP). Although CML patients undergoing imatinib treatment are enrolled mainly in the Glivec International Patient Assistance Program (GIPAP) in China since 2003, limited data have been reported on the long-term outcome of these patients. This study aims to compare the treatment response and prognosis of CML-CP patients who received different treatments from January 2003 to December 2013 in the First Affiliated Hospital of Nanchang University. Methods:A total of 295 patients were enrolled, includ-ing 185, 30, 50, and 30 patients for imatinib, interferon-alpha (IFN-α) plus Ara-C, hydroxycarbamide (HU), or allogeneic hematopoietic stem cell transplantation (Allo-HSCT) treatments, respectively. Results:Patients in imatinib and Allo-HSCT groups achieved excellent complete hematologic remission (CHR) (i.e., 96.7%vs. 96.7%), complete cytogenetic response (CCyR) (i.e., 89.7%vs. 93.3%), and com-plete molecular remission (CMoR) (i.e., 49.7%vs. 83.3%, P=0.001). However, significantly low rates of CHR, CCyR, McyR, and CMoR were observed in IFN-αand HU groups. Moreover, patients from imatinib group showed longer overall survival (OS) time than patients from other groups (P<0.001), even patients in Allo-HSCT group (10-year OS, 89.0%vs. 67.0%, P<0.001) because of high risk of Allo-HSCT-related complication. Multivariate analysis showed that receiving imatinib treatment (HR=5.267, 95%CI:1.054-1.940, P=0.022) and achieving CCyR (HR=9.541, 95%CI:1.692-10.513, P=0.002) were independent predictors for OS. Conclusion:Imatinib treatment may be an optimal first-line choice for Chinese patients with CML-CP who have not received any previous treatments.%目的:总结以伊马替尼为一线治疗的慢性粒细胞白血病(chronic myeloid leukemia,CML)初治患者的疗效和生存。方法:回顾性分析

  3. Combination therapy of imatinib and donor lymphocyte infusion for chronic myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation%伊马替尼联合供者淋巴细胞输注治疗造血干细胞移植后慢性粒细胞白血病复发

    Institute of Scientific and Technical Information of China (English)

    钱思轩; 李建勇; 吴汉新; 张晓艳; 张苏江; 洪鸣; 张闰; 孙雪梅

    2008-01-01

    Objective To evaluate the efficiency of combination therapy of imatinib and donor lymphocyte infusion (DLI) for chronic myeloid leukemia (CML) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods Patient 1 received peripheral blood stem cell transplantation from her HLA-identical sister, patient 2 received bone marrow transplantation from her HLA-identical brother and patient 3 received the transplantation of bone marrow in combined with peripheral blood stem cells following a conditioning regimen. For the prophylaxis of graft-versus-host disease (GVHD), patient 1 was treated with cyclosporine A (CsA) and mycophenolate mofetil (MMF), patient 2 with CsA, short course methotrexate (MTX), anti-thymocyte globulin and anti-CD25 monoclonal antibody,and patient 3 with CsA, MTX and MMF. They were treated with imatinib and DLI in hematologic relapse after HSCT. Results Patient 1 was treated with DLI on day + 30,+ 50 and + 70 after allo-HSCT,with CD3+ T lymphocyte cells of 0. 5 × 107 /kg,1.0×107 /kg and 2. 0 × 107 /kg respectively. She obtained a full donor ehimerism on short tandem repeats polymerase chain reaction (STR-PCR). She was treated with imatinib 400 nag daily and DLI with CD3+ T lymphocyte cells of 2. 5×107 /kg on day + 120 days for progression of disease. The bone marrow on day + 180 showed a full donor chimerism on STR-PCR. She died of extramedullary relapse 17 months after alloHSCT. For patient 2,cytogenetic analysis of bone marrow showed a male karyotype of 46,XY without any cytogenetic abnormalities, 100% cells on interphase nuclei revealed the XY genotype in the sex chromosome fluorescence in site hybridization(FISH) analysis and BCR-ABL fusion gene was negative on day + 35 after alIo-HSCT. Patient 2 relapsed on day + 100 after allo-HSCT,CsA was withdrawn and DLI with CD3+ T lymphocyte cells of 3. 9 × 107 /kg in combination with imatinib 500 mg was given daily. After treatment with DLI and imatinib for 30 days

  4. Population Analysis of Pharmacogenetic Polymorphisms Related to Acute Lymphoblastic Leukemia Drug Treatment

    Directory of Open Access Journals (Sweden)

    Marcela A. Chiabai

    2012-01-01

    Full Text Available This study aimed to evaluate in the Brazilian population, the genotypes and population frequencies of pharmacogenetic polymorphisms involved in the response to drugs used in treatment of acute lymphoblastic leukemia (ALL, and to compare the data with data from the HapMap populations. There was significant differentiation between most population pairs, but few associations between genetic ancestry and SNPs in the Brazilian population were observed. AMOVA analysis comparing the Brazilian population to all other populations retrieved from HapMap pointed to a genetic proximity with the European population. These associations point to preclusion of the use of genetic ancestry as a proxy for predicting drug response. In this way, any study aiming to correlate genotype with drug response in the Brazilian population should be based on pharmacogenetic SNP genotypes.

  5. Exploring the binding of two potent anticancer drugs bosutinib and imatinib mesylate with bovine serum albumin: spectroscopic and molecular dynamic simulation studies.

    Science.gov (United States)

    Pawar, Suma K; Naik, Roopa S; Seetharamappa, J

    2017-08-29

    Bosutinib (BST) and imatinib mesylate (IMT) are tyrosine kinase inhibitors (TKIs). In view of the importance of these inhibitors in cancer treatment, we investigated the mechanism of interaction between BST/IMT and bovine serum albumin (BSA) using various spectroscopic and molecular docking methods. Fluorescence studies indicated that BST/IMT interacted with BSA without affecting the microenvironment around the residue Trp213 of BSA. The quenching mechanism associated with the BST-BSA and IMT-BSA interactions was determined by performing fluorescence measurements at different temperatures. These results suggested that BST and IMT quenched the fluorescence intensity of BSA through static and dynamic processes, respectively, which was confirmed by time-resolved fluorescence measurements. Evaluation of the thermodynamic parameters ∆H°, ∆S°, and ∆G° suggested that hydrophobic and electrostatic interactions played significant roles in the BST-BSA interaction, while IMT-BSA was stabilized by hydrophobic forces. Competitive experimental results revealed that the primary binding sites for BST and IMT on BSA were sites II and I, respectively. This was supported by the results of molecular docking and dynamic simulation studies. The change in the secondary structure of BSA upon binding with BST/IMT was investigated by 3D fluorescence, absorption, and CD spectroscopic studies. In addition, the influences of β-cyclodextrin and metal ions (Cu(2+) and Zn(2+)) on the binding affinities of BST and IMT to BSA were examined. Graphical abstract Binding of BST and IMT in BSA at site II and site I respectively.

  6. [Watermelon stomach: Chronic renal failure and/or imatinib?].

    Science.gov (United States)

    Montagnac, Richard; Blaison, Dominique; Brahimi, Saïd; Schendel, Adeline; Levasseur, Thomas; Takin, Romulus

    2015-11-01

    Watermelon stomach or gastric antral vascular ectasia (GAVE) syndrome is an uncommon cause of sometimes severe upper gastro-intestinal bleeding. Essentially based on a pathognomonic endoscopic appearance, its diagnosis may be unrecognised because mistaken with portal hypertensive gastropathy, while treatment of these two entities is different. Its etiopathogeny remains still unclear, even if it is frequently associated with different systemic illnesses as hepatic cirrhosis, autoimmune disorders and chronic renal failure. The mechanism inducing these vascular ectasia may be linked with mechanical stress on submucosal vessels due to antropyloric peristaltic motility dysfunction modulated by neurohormonal vasoactive alterations. Because medical therapies are not very satisfactory, among the endoscopic modalities, argon plasma coagulation seems to be actually the first-line treatment because the most effective and safe. However, surgical antrectomy may be sometimes necessary. Recently GAVE syndrome appeared as a new adverse reaction of imatinib mesylate, one of the tyrosine kinase inhibitors used in chronic myeloid leukemia, and we report here the observation of such a pathology in one patient treated at the same time by haemodialysis and by imatinib mesylate for chronic myeloid leukemia.

  7. Computational analysis of ABL kinase mutations allows predicting drug sensitivity against selective kinase inhibitors.

    Science.gov (United States)

    Kamasani, Swapna; Akula, Sravani; Sivan, Sree Kanth; Manga, Vijjulatha; Duyster, Justus; Vudem, Dashavantha Reddy; Kancha, Rama Krishna

    2017-05-01

    The ABL kinase inhibitor imatinib has been used as front-line therapy for Philadelphia-positive chronic myeloid leukemia. However, a significant proportion of imatinib-treated patients relapse due to occurrence of mutations in the ABL kinase domain. Although inhibitor sensitivity for a set of mutations was reported, the role of less frequent ABL kinase mutations in drug sensitivity/resistance is not known. Moreover, recent reports indicate distinct resistance profiles for second-generation ABL inhibitors. We thus employed a computational approach to predict drug sensitivity of 234 point mutations that were reported in chronic myeloid leukemia patients. Initial validation analysis of our approach using a panel of previously studied frequent mutations indicated that the computational data generated in this study correlated well with the published experimental/clinical data. In addition, we present drug sensitivity profiles for remaining point mutations by computational docking analysis using imatinib as well as next generation ABL inhibitors nilotinib, dasatinib, bosutinib, axitinib, and ponatinib. Our results indicate distinct drug sensitivity profiles for ABL mutants toward kinase inhibitors. In addition, drug sensitivity profiles of a set of compound mutations in ABL kinase were also presented in this study. Thus, our large scale computational study provides comprehensive sensitivity/resistance profiles of ABL mutations toward specific kinase inhibitors.

  8. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.

    Science.gov (United States)

    Kantarjian, Hagop; Giles, Francis; Wunderle, Lydia; Bhalla, Kapil; O'Brien, Susan; Wassmann, Barbara; Tanaka, Chiaki; Manley, Paul; Rae, Patricia; Mietlowski, William; Bochinski, Kathy; Hochhaus, Andreas; Griffin, James D; Hoelzer, Dieter; Albitar, Maher; Dugan, Margaret; Cortes, Jorge; Alland, Leila; Ottmann, Oliver G

    2006-06-15

    Resistance to imatinib mesylate can occur in chronic myelogenous leukemia (CML). Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50. In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily. Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes. Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response; of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response; 11 of 12 patients with the chronic phase had a complete hematologic remission. Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML. (ClinicalTrials.gov number, NCT00109707 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.

  9. Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes But Not Normal Lymphocytes.

    Science.gov (United States)

    Zhelev, Zhivko; Ivanova, Donika; Bakalova, Rumiana; Aoki, Ichio; Higashi, Tatsuya

    2017-01-01

    The present study demonstrates specific sensitization of leukemia lymphocytes towards anticancer drugs using melatonin and clarifies the role of reactive oxygen species (ROS) for induction of apoptosis. The study covers four conventional and 11 new-generation anticancer drugs. Four parameters were analyzed simultaneously in leukemia and normal lymphocytes treated with drug, melatonin, or their combination: cell viability, induction of apoptosis, level of reactive oxygen species (ROS), and level of protein-carbonyl products. Almost all investigated combinations of melatonin with new-generation anticancer drugs were characterized by synergistic cytotoxicity towards leukemia lymphocytes, while the combinations with conventional drugs exhibited additive or antagonistic effects on cell viability. In leukemia lymphocytes, the additive cytotoxicity of doxorubicin plus melatonin was accompanied by low levels of ROS and protein-carbonyl products, as well as by suppression of apoptosis. In normal lymphocytes, none of the studied parameters changed significantly compared to cells treated with doxorubicin only. The combinations of everolimus plus melatonin and barasertib plus melatonin exhibited impressive synergistic cytotoxic effects on leukemia lymphocytes but did not affect the viability of normal lymphocytes. In leukemia cells, the synergistic cytotoxicity was accompanied by strong induction of apoptosis but a decrease of ROS to a level below that of the control. In normal lymphocytes, these combinations did not affect the level of ROS nor of protein-carbonyl products, and did not induce apoptosis. The data suggest that melatonin is a promising supplementary component in chemotherapy which allows the therapeutic doses of anticancer drugs to be reduced, minimizing their side-effects.

  10. Relationship between triterpenoid anticancer drug resistance, autophagy, and caspase-1 in adult T-cell leukemia

    Directory of Open Access Journals (Sweden)

    Tsukasa Nakanishi

    2016-05-01

    Full Text Available We previously reported that the inflammasome inhibitor cucurbitacin D (CuD induces apoptosis in human leukemia cell lines. Here, we investigated the effects of CuD and a B-cell lymphoma extra-large (Bcl-xL inhibitor on autophagy in peripheral blood lymphocytes (PBL isolated from adult T-cell leukemia (ATL patients. CuD induced PBL cell death in patients but not in healthy donors. This effect was not significantly inhibited by treatment with rapamycin or 3-methyladenine (3-MA. The Bcl-xL inhibitor Z36 induced death in primary cells from ATL patients including that induced by CuD treatment, effects that were partly inhibited by 3-MA. Similarly, cell death induced by the steroid prednisolone was enhanced in the presence of Z36. A western blot analysis revealed that Z36 also promoted CuD-induced poly(ADP ribose polymerase cleavage. Interestingly, the effects of CuD and Z36 were attenuated in primary ATL patient cells obtained upon recurrence after umbilical cord blood transplantation, as compared to those obtained before chemotherapy. Furthermore, cells from this patient expressed a high level of caspase-1, and treatment with caspase-1 inhibitor-enhanced CuD-induced cell death. Taken together, these results suggest that rescue from resistance to steroid drugs can enhance chemotherapy, and that caspase-1 is a good marker for drug resistance in ATL patients.

  11. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors.

    Science.gov (United States)

    Agaram, Narasimhan P; Wong, Grace C; Guo, Tianhua; Maki, Robert G; Singer, Samuel; Dematteo, Ronald P; Besmer, Peter; Antonescu, Cristina R

    2008-10-01

    BRAF and NRAS are commonly mutated in cancer and represent the most frequent genetic events in malignant melanoma. More recently, a subset of melanomas was shown to overexpress KIT and harbor KIT mutations. Although most gastrointestinal stromal tumors (GISTs) exhibit activating mutations in either KIT or PDGFRA, about 10% of the cases lack mutations in these genes. It is our hypothesis following the melanoma model that mutations in BRAF or NRAS may play a role in wild-type GIST pathogenesis. Alterations in RAS/MEK/ERK pathway may also be involved in development of imatinib resistance in GIST, particularly in tumors lacking secondary KIT or PDGFRA mutations. Imatinib-naive wild-type GISTs from 61 patients, including 15 children and 28 imatinib-resistant tumors without secondary KIT mutations were analyzed. Screening for hot spots mutations in BRAF (exons 11 and 15) and NRAS (exons 2 and 3) was performed. A BRAF exon 15 V600E was identified in 3 of 61 GIST patients, who shared similar clinical features, being 49- to 55-years-old females and having their tumors located in the small bowel. The tumors were strongly KIT immunoreactive and had a high risk of malignancy. An identical V600E BRAF mutation was also identified in one of 28 imatinib resistant GIST lacking a defined mechanism of drug resistance. In conclusion, we identified a primary BRAF V600E mutations in 7% of adult GIST patients, lacking KIT/PDGFRA mutations. The BRAF-mutated GISTs show predilection for small bowel location and high risk of malignancy. A secondary V600E BRAF mutation could represent an alternative mechanism of imatinib resistance. Kinase inhibitors targeting BRAF may be effective therapeutic options in this molecular GIST subset.

  12. Decreased PARP and procaspase-2 protein levels are associated with cellular drug resistance in childhood acute lymphoblastic leukemia.

    Science.gov (United States)

    Holleman, Amy; den Boer, Monique L; Kazemier, Karin M; Beverloo, H Berna; von Bergh, Anne R M; Janka-Schaub, Gritta E; Pieters, Rob

    2005-09-01

    Drug resistance in childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is associated with impaired ability to induce apoptosis. To elucidate causes of apoptotic defects, we studied the protein expression of Apaf-1, procaspases-2, -3, -6, -7, -8, -10, and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) in cells from children with acute lymphoblastic leukemia (ALL; n = 43) and acute myeloid leukemia (AML; n = 10). PARP expression was present in all B-lineage samples, but absent in 4 of 15 T-lineage ALL samples and 3 of 10 AML cases, which was not caused by genomic deletions. PARP expression was a median 7-fold lower in T-lineage ALL (P < .001) and 10-fold lower in AML (P < .001) compared with B-lineage ALL. PARP expression was 4-fold lower in prednisolone, vincristine and L-asparaginase (PVA)-resistant compared with PVA-sensitive ALL patients (P < .001). Procaspase-2 expression was 3-fold lower in T-lineage ALL (P = .022) and AML (P = .014) compared with B-lineage ALL. In addition, procaspase-2 expression was 2-fold lower in PVA-resistant compared to PVA-sensitive ALL patients (P = .042). No relation between apoptotic protease-activating factor 1 (Apaf-1), procaspases-3, -6, -7, -8, -10, and drug resistance was found. In conclusion, low baseline expression of PARP and procaspase-2 is related to cellular drug resistance in childhood acute lymphoblastic leukemia.

  13. miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1.

    Science.gov (United States)

    Lu, Fei; Zhang, Jingru; Ji, Min; Li, Peng; Du, Yahui; Wang, Hongchun; Zang, Shaolei; Ma, Daoxin; Sun, Xiulian; Ji, Chunyan

    2014-07-01

    Multidrug resistance (MDR) remains the major cause of disease relapse and poor prognosis in adults with acute myeloid leukemia (AML). Emerging evidence shows that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to elucidate the mechanisms through which AML patients develop drug resistance. MicroRNAs have been shown to play an important role in regulating the chemotherapy resistance in AML. A detailed understanding of the mechanisms of microRNA that are clinically relevant in AML may enhance our ability to predict and overcome drug resistance. Here, we demonstrated, for the first time, that miR-181b was decreased significantly in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-181b increased the sensitivity of leukemia cells to cytotoxic chemotherapeutic agents and promoted drug-induced apoptosis. Moreover, miR-181b inhibited HMGB1 and Mcl-1 expression by direct binding to their 3'-untranslated regions. In addition, HMGB1 was expressed at high levels in relapsed/refractory AML patients and suppression of HMGB1 via RNA interference sensitized multidrug-resistant leukemia cells to chemotherapy and induced apoptosis. In conclusion, these results provide a strong rationale for the development of miR-181b-based therapeutic strategies for the enhancement of efficacy in AML treatment.

  14. Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein.

    LENUS (Irish Health Repository)

    Elzinga, Baukje M

    2013-06-01

    Chronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. Autophagy has been associated with the clearance of large macromolecular signaling complexes and abnormal proteins, however, the contribution of autophagy to the turnover of Bcr-Abl protein in imatinib treated cells is unknown. In this study, we show that following imatinib treatment, Bcr-Abl is sequestered into vesicular structures that co-localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1\\/ATG7). Pharmacological inhibition of autophagy also reduced Bcr-Abl\\/LC3 co-localization in both K562 and CML patient cells. Bcr-Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down-regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib.

  15. Combined liver transplantation plus imatinib for unresectable metastases of gastrointestinal stromal tumours.

    Science.gov (United States)

    Serralta, Alfonso S; Sanjuan, Fernando R; Moya, Angel H; Orbis, Francisco C; López-Andújar, Rafael; Pareja, Eugenia I; Vila, Juan C; Rayón, Miguel; Juan, Manuel B; Mir, José P

    2004-11-01

    Therapeutic options for treating unresectable hepatic metastases of leiomyosarcomas were scarce until a few years ago. Recent advances in the study of the biology of intestinal tumours have radically changed our knowledge of their pathogenesis. Many of the tumours previously considered as leiomyosarcomas are now identified as gastrointestinal stromal tumours (GISTs). The introduction of imatinib (an antineoplasic drug that specifically acts on the pathogenesis of these tumours) has shown promising results in patients with advanced GISTs. We present three patients with the initial diagnosis of unresectable hepatic metastases of leiomyosarcomas. They received liver transplants. All three had tumour recurrences after transplantation. Histological re-evaluation identified a stromal origin of the tumours, and the patients were treated with imatinib therapy (400 mg/day). Recurrence occurred in all patients after a mean of 38.3 months, but imatinib treatment achieved control of the tumours. The current survival times with the combination of transplantation and imatinib are 92, 48 and 46 months for the three patients. This series is small and inconclusive, but imatinib treatment showed promising results. The treatment options for patients with unresectable metastases of GISTs must be defined, as in these three patients liver transplantation achieved a disease-free status but all had tumour recurrences before starting the imatinib treatment.

  16. Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice.

    Science.gov (United States)

    Sanford, David S; Wierda, William G; Burger, Jan A; Keating, Michael J; O'Brien, Susan M

    2015-07-01

    Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.

  17. Evidence that high-migration drug-surviving MOLT4 leukemia cells exhibit cancer stem cell-like properties.

    Science.gov (United States)

    Huang, Xiaoxing; Xiong, Meng; Jin, Yujie; Deng, Chaohua; Xu, Hui; An, Changqing; Hao, Ling; Yang, Xiangyong; Deng, Xinzhou; Tu, Zhenbo; Li, Xinran; Xiao, Ruijing; Zhang, Qiuping

    2016-07-01

    Leukemia represents a spectrum of hematological malignancies threatening human health. Resistance to treatments and metastasis of leukemia are the main causes of death in patients. Leukemia stem cells (LSCs) are the initiating cells of leukemia as well as the main source of drug resistance, invasion and metastasis. Consequently, eliminating LSCs is a prerequisite to eradicate leukemia. Preliminary studies in our laboratory have shown that chemokines and their related receptors play an important role in the drug resistance and metastasis of leukemic cells. In this study, we obtained high migration drug-surviving (short term) MOLT4 cells (hMDSCs-MOLT4) with treatment of doxorubicin (DOX) after Transwell assay. Then we detected stem cell-associated molecular markers on hMDSCs-MOLT4 cells and the parental MOLT4 cells by FCM, QPCR, western blotting, H&E staining and immunohisto-chemistry experimental techniques in vitro and in vivo. Moreover, we explored its impact on drug resistance and tumor formation. Then we found that compared with the parental MOLT4 cells, the mRNA expression levels of stem cell-related factors Sox2, Oct4, C-myc, Klf4, Nanog, Bmi-1, CXCR4 are increased in hMDSCs-MOLT4 cells, together with the protein expression levels of Sox2, Oct4, Klf4, Nanog, CXCR4 and CD34. Our results indicated that hMDSCs-MOLT4 cells exhibited strong drug resistance and certain cancer stem cell-like characteristics. It is the first indication that the targeting stemness factors such as Sox2, Oct4, Klf4, Nanog and CXCR4 may represent plausible options for eliminating T-ALL stem-like cells. The present findings shed light on the relationship between drug-tolerant leukemic cells and cancer stem cells.

  18. The conformational control inhibitor of tyrosine kinases DCC-2036 is effective for imatinib-resistant cells expressing T674I FIP1L1-PDGFRα.

    Directory of Open Access Journals (Sweden)

    Yingying Shen

    Full Text Available The cells expressing the T674I point mutant of FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα in hypereosinophilics syndrome (HES are resistant to imatinib and some second-generation tyrosine kinase inhibitors (TKIs. There is a desperate need to develop therapy to combat this acquired drug resistance. DCC-2036 has been synthesized as a third-generation TKI to combat especially the Bcr-Abl T315I mutant in chronic myeloid leukemia. This study evaluated the effect of DCC-2036 on FIP1L1-PDGFRα-positive cells, including the wild type (WT and the T674I mutant. The in vitro effects of DCC-2036 on the PDGFRα signal pathways, proliferation, cell cycling and apoptosis of FIP1L1-PDGFRα-positive cells were investigated, and a nude mouse xenograft model was employed to assess the in vivo antitumor activity. We found that DCC-2036 decreased the phosphorylated levels of PDGFRα and its downstream targets without apparent effects on total protein levels. DCC-2036 inhibited proliferation, and induced apoptosis with MEK-dependent up-regulation of the pro-apoptotic protein Bim in FIP1L1-PDGFRα-positive cells. DCC-2036 also exhibited in vivo antineoplastic activity against cells with T674I FIP1L1-PDGFRα. In summary, FIP1L1-PDGFRα-positive cells are sensitive to DCC-2036 regardless of their sensitivity to imatinib. DCC-2036 may be a potential compound to treat imatinib-resistant HES.

  19. Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression.

    Science.gov (United States)

    Akram, Afia Muhammad; Iqbal, Zafar; Akhtar, Tanveer; Khalid, Ahmed Mukhtar; Sabar, Muhammad Farooq; Qazi, Mahmood Hussain; Aziz, Zeba; Sajid, Nadia; Aleem, Aamer; Rasool, Mahmood; Asif, Muhammad; Aloraibi, Saleh; Aljamaan, Khaled; Iqbal, Mudassar

    2017-04-03

    BCR-ABL kinase domain (KD) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-KD mutations in chronic phase (n = 41), late chronic phase (n = 33) and accelerated phase (n = 16) imatinib responders. Direct sequencing analysis was used for this purpose. Eleven patients (12.22%) in late-CP CML were detected having total 24 types of point mutations, out of which 8 (72.72%) harbored compound mutated sites. SH2 contact site mutations were dominant in our study cohort, with E355G (3.33%) being the most prevalent. Five patients (45%) all having compound mutated sites, progressed to advanced phases of disease during follow up studies. Two novel silent mutations G208G and E292E/E were detected in combination with other mutants, indicating limited tolerance for BCR-ABL1 kinase domain for missense mutations. However, no patient in early CP of disease manifested mutated ABL-KD. Occurrence of mutations was found associated with elevated platelet count (p = 0.037) and patients of male sex (p = 0.049). The median overall survival and event free survival of CML patients (n = 90) was 6.98 and 5.8 y respectively. The compound missense mutations in BCR-ABL kinase domain responsible to elicit disease progression, drug resistance or disease relapse in CML, can be present in yet Imatinib sensitive patients. Disease progression observed here, emphasizes the need of ABL-KD mutation screening in late chronic phase CML patients for improved clinical management of disease.

  20. Imatinib treatment of chronic myeloid leukemia in chronic phase: clinical effect assessment of 69 cases%伊马替尼治疗69例慢性粒细胞白血病慢性期患者的临床效果评价

    Institute of Scientific and Technical Information of China (English)

    钟敏; 苏群豪; 胡敏; 陶石

    2015-01-01

    目的:评价慢性粒细胞白血病慢性期患者接受伊马替尼治疗的临床效果及不良反应.方法:慢性粒细胞白血病慢性期患者114例,随机分为观察组(69例)和对照组(45例)两组.观察组患者采用伊马替尼进行治疗,对照组则采用干扰素进行治疗,对比两组患者的临床治疗效果.结果:观察组患者治疗3个月完全血液学缓解率(95.65%)、6个月部分细胞遗传学缓解率(82.61%)、12个月完全细胞遗传学缓解率(79.71%)、18个月主要分子学缓解率(68.12%)与对照组(75.55%、33.33%、22.22%、0%)比较差异具有统计学意义(P<0.05).两组不良反应比较,观察组的不良反应较轻,安全性要高于对照组,差异具有统计学意义(P<0.05).观察组五年的总生存率为97.10%,无事件生存率为91.30%,与对照组的82.22%、73.33%比较,差异具有统计学意义(P<0.05).结论:伊马替尼治疗能明显提高慢性粒细胞白血病慢性期患者的细胞遗传学和分子学疗效,不良反应少,可延长无疾病进展生存期.%Objective: To investigate the clinical effect imatinib treatment of patients with chronic myeloid leukemia in chronic phase. Methods: 114 patients with chronic myeloid leukemia in chronic phase were randomly divided into an observation group (69 cases) and a control group (45 cases). The observation group was treated with imatinib and the control group was treated with interferon. The clinical treatment effect of the two groups was compared. Results: Regarding the observation group, the rate of the complete hematologic response (CHR) of patients treated for 3 months was 95.65%, the rate of the part cytogenetic response (PCyR) of patients treated for 6 months was 82.61%, the rate of the complete cytogenetic response (CCyR) of patients treated for 12 months was 79.71%, and the rate of the main molecular response (MMR) was 68.12%. Regarding the control group, the rate of the complete hematologic response, the part cytogenetic

  1. Imatinib triggers mesenchymal-like conversion of CML cells associated with increased aggressiveness

    Institute of Scientific and Technical Information of China (English)

    Alexandre Puissant; Yann Chéli; Jill-Patrice Cassuto; Sophie Raynaud; Laurence Legros; Jean-Max Pasquet; Francois-Xavier Mahon; Frédéric Luciano; Patrick Auberger; Maeva Dufies; Nina Fenouille; Issam Ben Sahra; Arnaud Jacquel; Guillaume Robert; Thomas Cluzeau; Marcel Deckert; Mélanie Tichet

    2012-01-01

    Chronic myelogenous leukemia (CML) is a cytogenetic disorder resulting from the expression of p210BCR-ABL Imatinib,an inhibitor of BCR-ABL,has emerged as the leading compound to treat CML patients.Despite encouraging clinical results,resistance to imatinib represents a major drawback for therapy,as a substantial proportion of patients are refractory to this treatment.Recent publications have described the existence of a small cancer cell population with the potential to exhibit the phenotypic switch responsible for chemoresistance.To investigate the existence of such a chemoresistant cellular subpopulation in CML,we used a two-step approach of pulse and continuous selection by imatinib in different CML cell lines that allowed the emergence of a subpopulation of adherent cells (IM-R Adh) displaying an epithelial-mesenchymal transition (EMT)-like phenotype.Overexpression of several EMT markers was observed in this CML subpopulation,as well as in CD34+ CML primary cells from patients who responded poorly to imatinib treatment.In response to imatinib,this CD44high/CD24low IM-R Adh subpopulation exhibited increased adhesion,transmigration and invasion in vitro and in vivo through specific overexpression of the αVβ3 receptor.FAK/Akt pathway activation following integrin β3 (ITGβ3) engagement mediated the migration and invasion of IM-R Adh cells,whereas persistent activation of ERK counteracted BCR-ABL inhibition by imatinib,promoting cell adhesion-mediated resistance.

  2. Imatinib Case: Technical and Legal Analysis of Patent Prosecution in Colombia

    Directory of Open Access Journals (Sweden)

    Luisa Fernanda Díaz Pinilla

    2016-12-01

    Full Text Available Imatinib –marketed as Gleevec™ or Glivec™– is a drug mainly used to treat a condition called Acute myeloid leukemia (AML. Its patent protection in Colombia, as a polymorphic entity of mesylate salt –called Beta polymorphous–, exhibits a divergent procedure due to differences between Colombian Patent Office (SIC and State Council judgment given in order to deny patent right in 2003 and then revoking such denial and ordering patent grant in 2012, respectively. This paper evaluates technical regards associated with each institution arguments and legal topics considered to conclude the instance. Findings show that studies carried out in relation to testimonial evidence and expert advice –that were submitted by two experts –one of them– directly related to the patent application– guided Colombian State Council in order to grant the polymorphous patent, even when there was no clear evidence of inventive step, especially referred as a compound surprising technical effect. Furthermore, the paper includes some comparisons related to legal instances that are in charge of studying patent office decisions in other jurisdictions and protection given –or not– to polymorphous entities in other countries.

  3. Chronic myelogenous leukemia: molecular monitoring in clinical practice

    Directory of Open Access Journals (Sweden)

    N. R. Ryabchikova

    2013-01-01

    Full Text Available Use of tyrosine kinase inhibitor imatinib has led to significant progress in chronic myeloid leukemia (CML treatment. To date, genetic monitoring is a mandatory attribute of therapy with tyrosine kinase inhibitors. The purpose of this study was to access the imatinib therapy efficacy in CML patients using complete molecular genetic monitoring by standard cytogenetics, realtime polymerase chain reaction and mutational analysis. Correlation between cytogenetic and molecular response was shown. Heterogeneity of molecular response in each patient group was revealed by expression of BCR-ABL. Kinase domain mutations were detected in 32 % of CML patients resistant to imatinib.

  4. A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

    DEFF Research Database (Denmark)

    Marstrand, T T; Borup, R; Willer, A

    2010-01-01

    regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost...

  5. Imatinib and nilotinib reverse multidrug resistance in cancer cells by inhibiting the efflux activity of the MRP7 (ABCC10.

    Directory of Open Access Journals (Sweden)

    Tong Shen

    Full Text Available BACKGROUND: One of the major mechanisms that could produce resistance to antineoplastic drugs in cancer cells is the ATP binding cassette (ABC transporters. The ABC transporters can significantly decrease the intracellular concentration of antineoplastic drugs by increasing their efflux, thereby lowering the cytotoxic activity of antineoplastic drugs. One of these transporters, the multiple resistant protein 7 (MRP7, ABCC10, has recently been shown to produce resistance to antineoplastic drugs by increasing the efflux of paclitaxel. In this study, we examined the effects of BCR-Abl tyrosine kinase inhibitors imatinib, nilotinib and dasatinib on the activity and expression of MRP7 in HEK293 cells transfected with MRP7, designated HEK-MRP7-2. METHODOLOGY AND/OR PRINCIPAL FINDINGS: We report for the first time that imatinib and nilotinib reversed MRP7-mediated multidrug resistance. Our MTT assay results indicated that MRP7 expression in HEK-MRP7-2 cells was not significantly altered by incubation with 5 microM of imatinib or nilotinib for up to 72 hours. In addition, imatinib and nilotinib (1-5 microM produced a significant concentration-dependent reversal of MRP7-mediated multidrug resistance by enhancing the sensitivity of HEK-MRP7-2 cells to paclitaxel and vincristine. Imatinib and nilotinib, at 5 microM, significantly increased the accumulation of [(3H]-paclitaxel in HEK-MRP7-2 cells. The incubation of the HEK-MRP7-2 cells with imatinib or nilotinib (5 microM also significantly inhibited the efflux of paclitaxel. CONCLUSIONS: Imatinib and nilotinib reverse MRP7-mediated paclitaxel resistance, most likely due to their inhibition of the efflux of paclitaxel via MRP7. These findings suggest that imatinib or nilotinib, in combination with other antineoplastic drugs, may be useful in the treatment of certain resistant cancers.

  6. Nose-to-brain transport of imatinib mesylate: A pharmacokinetic evaluation.

    Science.gov (United States)

    Hada, Nobuko; Netzer, William Joseph; Belhassan, Fanny; Wennogle, Lawrence Paul; Gizurarson, Sveinbjörn

    2017-02-24

    The delivery of drugs to the brain is a constant challenge due to limitations imposed by the blood-brain barrier (BBB). Various methods of bypassing the BBB are under investigation. One approach is intranasal administration, where the olfactory region of the nasal cavity extends up to the cranial cavity and provides direct access to the brain. The pharmacokinetics of this transport and factors that determine transport rates and capacity is of vital importance for evaluating the clinical value of this route. Here, the pharmacokinetics of intranasally administered imatinib has been explored. Imatinib is distributed into the brain following intravenous administration, and then rapidly removed. Following intravenous administration, the brain/plasma ratio for imatinib was calculated to be 2% and remained at this ratio for 30min. The brain/plasma ratio following intranasal administration, however, was found to be 5.3% and remained at this ratio for up to 90min. Imatinib was found to be rapidly transported into the brain via the olfactory region, by shutting down the nose-to-blood-to-brain transport with epinephrine. The increased brain concentration of imatinib (0.33μg/g tissue) achieved by intranasal administration, compared with an IV injection, is likely to provide a model for developing a wide range of CNS active molecules that were previously removed from consideration as drug candidates due to their lack of CNS access. Furthermore, brain imatinib levels were increased by co-administration of the p-gp substrates, elacridar and pantoprazole, showing that both compounds were able to inhibit the elimination of imatinib from the brain.

  7. Quantitative phenotyping-based in vivo chemical screening in a zebrafish model of leukemia stem cell xenotransplantation.

    Directory of Open Access Journals (Sweden)

    Beibei Zhang

    Full Text Available Zebrafish-based chemical screening has recently emerged as a rapid and efficient method to identify important compounds that modulate specific biological processes and to test the therapeutic efficacy in disease models, including cancer. In leukemia, the ablation of leukemia stem cells (LSCs is necessary to permanently eradicate the leukemia cell population. However, because of the very small number of LSCs in leukemia cell populations, their use in xenotransplantation studies (in vivo and the difficulties in functionally and pathophysiologically replicating clinical conditions in cell culture experiments (in vitro, the progress of drug discovery for LSC inhibitors has been painfully slow. In this study, we developed a novel phenotype-based in vivo screening method using LSCs xenotransplanted into zebrafish. Aldehyde dehydrogenase-positive (ALDH+ cells were purified from chronic myelogenous leukemia K562 cells tagged with a fluorescent protein (Kusabira-orange and then implanted in young zebrafish at 48 hours post-fertilization. Twenty-four hours after transplantation, the animals were treated with one of eight different therapeutic agents (imatinib, dasatinib, parthenolide, TDZD-8, arsenic trioxide, niclosamide, salinomycin, and thioridazine. Cancer cell proliferation, and cell migration were determined by high-content imaging. Of the eight compounds that were tested, all except imatinib and dasatinib selectively inhibited ALDH+ cell proliferation in zebrafish. In addition, these anti-LSC agents suppressed tumor cell migration in LSC-xenotransplants. Our approach offers a simple, rapid, and reliable in vivo screening system that facilitates the phenotype-driven discovery of drugs effective in suppressing LSCs.

  8. Efficacy and Safety of High-dose Imatinib in the Treatment of Chronic Myeloid Leukemia in Chronic Phrase:A Meta -analysis%高剂量伊马替尼治疗慢性髓细胞白血病慢性期疗效与安全性的Meta分析

    Institute of Scientific and Technical Information of China (English)

    李浩; 付美兰

    2015-01-01

    Objective To compare the efficacy and safety between high -dose imatinib( IM,≥600 mg/d)and standard-dose imatinib(400 mg/d)in the treatment of chronic myeloid leukemia in chronic phrase(CML-CP). Methods We made computer-based retrieval in PubMed,EMBase,CNKI,CBM,Wanfang database and VIP for randomized controlled trials( RCTs)which trial group was administrated with high-dose imatinib and control group was administrated with standard-dose imatinib. The Cochrane Collaboration′s tool for assessing risk of bias was employed to evaluate the quality of included literatures,and the RevMan 5. 2 software of Cochrane Collaboration was used to make statistic analysis. The subjects taking high-dose IM and those taking standard IM were compared in CCyR,MMR,OS,PFS and adverse reaction. Results Two groups were not significantly different in the CCyR incidence 3 months after intervention〔RR=2. 08,95%CI(0. 73,5. 90),P=0. 17〕. Trial group was higher than control group in CCyR 6 months and 12 months after intervention〔RR =1. 34,95%CI (1. 20,1. 49),P<0. 001;RR=1. 16,95%CI(1. 07,1. 25),P<0. 001〕. Trial group was higher than control group in MMR 3 months,6 months and 12 months after intervention〔RR =2. 97,95%CI(1. 75,5. 05),P <0. 01;RR =2. 02, 95%CI(1. 38,2. 93),P <0. 001;RR =1. 28,95%CI(1. 14,1. 44),P <0. 001〕. Two groups were not significantly different in OS〔RR=1. 00,95%CI(0. 98,1. 02),P=0. 86〕. Trial group was higher than control group in PFS〔RR=1. 04,95%CI(1. 00,1. 09),P =0. 04〕. Trial group was higher than control group in the incidence of neutropenia and thrombocytopenia〔RR =1. 55,95%CI(1. 13,2. 11),P =0. 006;RR =1. 92,95%CI(1. 28,2. 86),P =0. 001〕. Trial group was higher than control group in the incidence of myalgia,adverse reaction in digestive system〔RR=2. 89,95%CI (1. 17,7. 14),P<0. 05;RR =3. 46,95%CI(1. 34,8. 97),P <0. 05〕. Conclusion High - dose imatinib in the treatment of CML - CP patients may increase PFS and the incidence of CCyR and MMR

  9. Imatinib as preoperative therapy in Chinese patients with recurrent or metastatic GISTs

    Institute of Scientific and Technical Information of China (English)

    Chunmeng Wang; Biqiang Zheng; Yong Chen; Xi Cao; Ruining Zhang; Yingqiang Shi

    2013-01-01

    Imatinib has dramatically altered the options for management of patients with gastrointestinal stromal tumours.However,it has become clear that secondary resistance to the drug develops during long-term therapy.The purpose of our study was to retrospectively analyze safety and long-term outcomes in Chinese patients with recurrent or metastatic GISTs treated with imatinib preoperatively.Methods:Between June 2003 and June 2011,22 patients underwent surgery for recurrent or metastatic GISTs after preoperative treatment with imatinib.Results:Complete resection was accomplished in 8 of the 10 responsive disease (RD) patients (80%),and in 3 of the 12 patients (25%) who had progression disease (PD).The amount of blood loss during the operation in PD patients was higher than in RD patients.There was 1 hospital death in PD group related to surgery,while the other patients recovered with conservative therapy because complications were mild.The difference in median PFS between patients with RD and those with PD was significant (24.8 vs.2.81 months,P<0.001).The difference in 2-year OS rate between patients with RD and those with PD was not significant (100% vs.87.5%,P>0.05).Conclusions:Our study indicates that surgical intervention can improve the PFS of Chinese patients with recurrent or metastatic GISTs responsive to imatinib,but does not prolong OS as well as in patients who develop imatinib resistance.Surgical resection following imatinib treatment is feasible and can be considered for patients with advanced GISTs responsive to imatinib.

  10. Molecular response to imatinib & its correlation with mRNA expression levels of imatinib influx & efflux transporters in patients with chronic myeloid leukaemia in chronic phase

    Directory of Open Access Journals (Sweden)

    Hemant Malhotra

    2015-01-01

    Full Text Available Background & objectives: Imatinib is the standard first-line treatment for chronic myeloid leukaemia (CML patients. About 20 to 30 per cent patients develop resistance to imatinib and fail imatinib treatment. One of the mechanisms proposed is varying expression levels of the drug transporters. This study was aimed to determine the expression levels of imatinib transporter genes (OCT1, ABCB1, ABCG2 in CML patients and to correlate these levels with molecular response. Methods: Sixty three CML chronic phase patients who were on 400 mg/day imatinib for more than two years were considered for gene expression analysis study for OCT1, ABCB1 and ABCG2 genes. These were divided into responders and non-responders. The relative transcript expression levels of the three genes were compared between these two categories. The association between the expression values of these three genes was also determined. Results: No significant difference in the expression levels of OCT1, ABCB1 and ABCG2 was found between the two categories. The median transcript expression levels of OCT1, ABCB1 and ABCG2 genes in responders were 26.54, 10.78 and 0.64 versus 33.48, 7.09 and 0.53 in non-responders, respectively. A positive association was observed between the expression of the ABCB1 and ABCG2 transporter genes (r=0.407, P<0.05 while no association was observed between the expression of either of the ABC transporter genes with the OCT1 gene. Interpretation & conclusions: Our findings demonstrated that the mRNA expression levels of imatinib transporter genes were not correlated with molecular response in CML patients. Further studies need to be done on a large sample of CML patients to confirm these findings.

  11. Clinical efficacy of imatinib on chronic myeloid leukemia in chronic phase%伊马替尼治疗慢性髓细胞白血病慢性期临床疗效观察

    Institute of Scientific and Technical Information of China (English)

    朱晓峰; 蔡晓燕

    2015-01-01

    目的:分析甲磺酸伊马替尼(IM)治疗慢性髓系白血病(CML)慢性期的临床疗效及影响疗效的因素。方法随访观察74例 CML 慢性期患者,IM中位治疗剂量为400(200~600)mg·d -1,评估其临床疗效,总生存时间和疾病无进展生存时间,并对相关疗效影响因素进行分析。结果中位随访时间为20(6~72)个月,累积达到血液学缓解(CHR)为98.6%,血液学中位缓解时间1(1~3)月;63例(85.1%)达到主要细胞遗传学缓解(MCyR),中位达 MCyR 时间为9(5~24)个月;53例(71.6%)达完全细胞遗传学缓解(CCyR),41例(55.4%)达到主要分子生物学缓解(MMR);6例(8.1%)达到完全分子生物学缓解(CMR);初治组及复治组应用 IM治疗后 CHR 及 MCyR 差异无统计学意义,但 CCyR 及 MMR 差异均有统计学意义(P <0.016);由 EUTOS 评分区分的低危组与高危组应用 IM治疗后 CHR 差异无统计学意义,但 MCyR、CCyR 及 MMR 差异均有统计学意义(P <0.020);其中初治组与复治组及 EUTOS 评分低危组与高危组 OS 差异无统计学意义,但其 PFS 差异均有统计学意义(P 分别为0.021和0.004)。结论IM用于 CML 慢性期患者治疗可获得极高的血液学缓解率和较高细胞遗传学缓解率,不良反应少,提高了患者生存质量,延长患者的生存时间;在 CML 确诊早期应用可提高疗效,IM治疗前时间大于6个月或EUTOS 评分高危组可影响 IM疗效。%Objective To explore the clinical efficacy and influence factors of imatinib mesylate(IM)treatment of chronic myeloid leu-kemia(CML)in chronic phase.Methods We followed up 74 cases of patients with chronic phase CML,IM median dose being 400 (200 ~600)mg·d -1 ,to assess its clinical efficacy,overall survival and progression -free survival,and to analyze the related factors affecting the efficacy

  12. Optimal Duration of Imatinib Mesylate Therapy in Metastatic Gastrointestinal Stromal Tumours

    Directory of Open Access Journals (Sweden)

    Ruth Gauden

    2011-04-01

    Full Text Available While current literature provides evidence that imatinib mesylate has significant activity in patients with advanced and metastatic gastrointestinal stromal tumour (GIST, and highlights the potential for the development of anticancer drugs based on specific molecular abnormalities present in cancers, specific recommendations concerning the optimal duration of therapy remain controversial. This case presents the favourable outcome of a patient who originally presented almost 9 years ago with widespread, bulky, metastatic GIST involving the abdomen and pelvis. A sustained, complete response was achieved with imatinib and prompted an interruption in treatment 7 years after initial presentation. The disease reoccurred extensively within 9 months of treatment interruption, but once again rapidly completely responded to the recommencement of imatinib, with that response being now maintained for over 9 months. This report suggests that dramatic and durable responses to imatinib can be achieved in individual cases despite the lack of specific guidelines in the literature with respect to defining how long treatment with imatinib should be continued in the absence of evidence of tumour progression.

  13. Imatinib enchances the sensitivity of gastrointestinal stromal tumors to topoisomerase II inhibitors

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    S. V. Boichuk

    2015-01-01

    Full Text Available Objective: to study the sensitivity of gastrointestinal stromal tumors (GISTs to the topoisomerases type II inhibitors and ability of imatinib to enhance GISTs sensitivity to the chemotherapeutic drugs indicated above.Subjects and Methods. We studied the sensitivity of gastrointestinal stromal tumors (GISTs to the topoisomerases II inhibitors and ability of imatinib to enhance GISTs sensitivity to these chemotherapeutic agents. The expression of DNA damage and repair (DDR markers was examined by western-blotting. Cleaved forms of poly (ADP-rybose polymerase and caspase-3 were served as an apoptotic markers measured by western blotting. Amount of apoptotic cells was counted by flow cytometry analysis by using a propidium iodide DNA staining procedure and counting the numbers of hypodiploid cells.Results. We observed the sensitivity of GISTs to topoisomerase II inhibitors – doxorubicine and etoposide inducing DNA double-strand breaks and apoptotic cell death. Imatinib enhances GISTs sensitivity to topoisomerase II inhibitors. This might be due to reduced ability of GISTs to repair DNA damage by homologous recombination. Imatinib-induced reduction of Rad51 recombinase might be due to increased proteasome-dependent degradation.Conclusion. GIST cells are sensitive to topoisomerase II inhibitors (etoposide and doxorubicin in vitro. Imatinib enhances GISTs sensitivity to the chemotherapeutic agents indicated above.

  14. Profile of bosutinib and its clinical potential in the treatment of chronic myeloid leukemia

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    Keller-von Amsberg G

    2013-03-01

    Full Text Available Gunhild Keller-von Amsberg,1 Steffen Koschmieder21Department of Hematology and Oncology, University Cancer Center Hamburg, University Hospital Hamburg Eppendorf, 2Department of Medicine (Hematology, Oncology, and Stem Cell Transplantation, University Medical Center of Aachen and RWTH Aachen University, Aachen, GermanyAbstract: Bosutinib (SKI-606 is an orally available, once-daily, dual Src and Abl kinase inhibitor with promising clinical potential in first-, second-, and third-line treatment of chronic myeloid leukemia (CML. Bosutinib effectively inhibits wild-type BCR-ABL and most imatinib-resistant BCR-ABL mutations except for V299L and T315I. Low hematologic toxicity is a remarkable characteristic of this novel second-generation tyrosine kinase inhibitor, and this has been ascribed to its minimal activity against the platelet-derived growth factor receptor and KIT. Low-grade, typically self-limiting diarrhea, which usually appears within the first few weeks after treatment initiation, represents the predominant toxicity of bosutinib. Other treatment-associated adverse events are mostly mild to moderate. Bosutinib has been approved by the US Food and Drug Administration for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive CML in adult patients with resistance or intolerance to prior therapy. This review summarizes the main properties of bosutinib and the currently available data on its clinical potential in the treatment of CML.Keywords: bosutinib, chronic myeloid leukemia, BCR-ABL, Src/Abl kinase inhibitor, point mutation, imatinib resistance

  15. Effect of Imatinib on the Oogenesis and Pituitary -Ovary Hormonal Axis in Female Wistar Rat

    OpenAIRE

    Parichehreh Yaghmaei; Kazem Parivar; Fatemeh Jalalvand

    2009-01-01

    Background: Imatinib mesylate, a small-molecular analog of adenosine triphosphate (ATP)that potently inhibits tyrosine kinase activities of Bcr–Abl, PDGFR-β, PDGFR-α, c-Fms, Argand c-kit, is one of the novel molecularly targeted drugs being introduced into cancer therapy.We tested the effect of imatinib on the ovarian histological structure and the concentration ofestrogen and progesterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH)in the serum of female Wistar rats.Mater...

  16. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment

    NARCIS (Netherlands)

    A. Holleman (Amy); C. Cheng (Cheng); C.H. Pui (Ching-Hon); W.E. Evans (William); M.V. Relling (Mary); R. Pieters (Rob); G.E. Janka-Schaub (Gritta); M.H. Cheok (Meyling); M.L. den Boer (Monique); W. Yang; A.J. Veerman; K.M. Kazemier (Karin); D. Pei (Deqing)

    2004-01-01

    textabstractBACKGROUND: Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown. METHODS: We tested leukemia cells from 173

  17. Long-term outcomes of nilotinib treatment for chonic myelogenous leukemia patients with imatinib resistance or intolerance%尼洛替尼治疗伊马替尼耐药或不耐受的慢性粒细胞白血病的长期随访研究

    Institute of Scientific and Technical Information of China (English)

    魏永强; 张贤; 陈伟伟; 曹睿; 阴常欣; 冯茹; 刘启发; 孟凡义

    2012-01-01

    目的 评价对伊马替尼耐药或不耐受的慢性粒细胞白血病(CML)患者接受尼洛替尼治疗的远期疗效和安全性.方法 26例对伊马替尼耐药或不耐受CML患者接受尼洛替尼400~800 mg/d治疗,随访观察近5年,定期监测血液学、细胞遗传学及分子生物学指标,记录用药后患者临床表现及各项生化指标,评价其疗效、不良反应.结果 26例对伊马替尼耐药或不耐受的CML患者,尼洛替尼中位治疗时间17个月,中位随访时间51个月.累计获得完全血液学缓解(CHR)16例(61.5%),获得主要细胞遗传学缓解(MCyR)13例(50.0%),获得完全细胞遗传学缓解(CCyR)9例(34.6%),获得主要分子生物学缓解(MMR)7例(26.9%).尼洛替尼治疗相关的非血液学不良反应多为1~2级,主要为胆红素升高(69 2%)和皮疹(57 7%).3~4级血液学不良反应包括血小板减少(53.8%)、中性粒细胞减少和贫血(分别为26.9%和19.2%).相比进展期患者,尼洛替尼对慢性期和缓解期的患者疗疗效更佳、血液学副作用更少.结论 尼洛替尼为对伊马替尼耐药和不耐受的CML患者提供了一个有效并安全的治疗选择,尤其对非进展期CML患者更为安全和有效.%Objective To evaluate the long-term clinical efficacy and safety of nilotinib in the treatment of chronic myelogenous leukemia (CML) patients with imatinib resistance or intolerance. Methods Twenty-six CML patients with imatinib resistance or intolerance received nilotinib treatment at the dose of 400 mg once or twice daily. The patients were followed up for nearly 5 years with regular monitoring of the hematologic, cytogenetic and molecular biological markers and recording of the clinical manifestations and biochemical indicators to evaluate the therapeutic effect and adverse events. Results The median duration of nilotinib therapy was 17 (1-56) months, and the patients were follow up for a median of 51 months. At the last follow-up, 16

  18. Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

    NARCIS (Netherlands)

    D.A. Reardon; G. Dresemann; S. Taillibert; M. Campone (Mario); M.J. van den Bent (Martin); P.M.J. Clement (Paul); E. Blomquist; L. Gordower; H. Schultz; J. Raizer; P. Hau (Peter); J. Easaw; M. Gil (Miguel); J. Tonn; A. Gijtenbeek; U. Schlegel; P. Bergström (Per); S. Green; A.E. Weir (Angela); Z. Nikolova

    2009-01-01

    textabstractBackground: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). Methods: A total of 231 patients with GBM at first recurrence from 21 institutio

  19. Imatinib

    Science.gov (United States)

    ... blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop the ... or cause blurred vision. Do not drive a car or operate machinery until you know how this ...

  20. Dasatinib treatment based on BCR-ABL mutation detection in imatinib-resistant patients with chronic myeloid leukemia%BCR-ABL突变检测指导下的达沙替尼治疗伊马替尼耐药的慢性髓性白血病疗效分析

    Institute of Scientific and Technical Information of China (English)

    江倩; 秦亚溱; 赖悦云; 江浩; 石红霞

    2016-01-01

    Objective To evaluate the efficiency of dasatinib as the second-or third-line tyrosine kinase inhibitor(TKI)in imatinib-resistant patients with chronic myeloid leukemia(CML)based on BCR-ABL mutation detection. Methods 122 CML patients received dasatinib treatment, including 83 with imatinib-resistance and 39 with both imatinib-and nilotinib-resistance, 55 in the chronic-phase(CP), 21 in the accelerated-phase (AP) and 46 in the blast-phase (BP). Those harboring dasatinib highly-resistant mutations(T315I/A, F317L/V/C and V299L)were excluded based on BCR-ABL kinase domain mutation screening by Sanger sequencing at baseline. Hematologic, cytogenetic and molecular responses were evaluated regularly, and rates of progression-free-survival(PFS)and overall survival(OS)were analyzed. BCR-ABL mutation detection was performed once the patients failed on dasatinib. Results In the CP patients, the rates of complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response(MMR)and molecular response 4.5(MR4.5)were 92.7%, 53.7%, 29.6%and 14.8%, respectively. 4-year PFS and OS rates were 84.4%and 89.5%, respectively. In the AP patients, HR and CCyR rates were 81.0%and 35.0%;and 3-year PFS and OS rates were 56.1%and 59.3%, respectively. In the BP patients, HR and CCyR rates were 63.0%and 21.4%;and 1-year PFS and OS rates were 43.6%and 61.8%, respectively. Outcomes were similar when dasatinib was used as the second-line TKI or thethird-line TKI. Of the 75 patients who were resistant to dasatinib, 37(48.7%)developed new mutation(s), and T315I(59.5%)was the most common mutation type. The patients who already harbored mutation(s) before dasatinib therapy achieved similar responses and outcomes to those with no mutation at baseline. However, they had higher likelihood of developing additional mutations associated with resistance to dasatinib(65.7%vs 34.1%, P=0.006). Conclusions Dasatinib was proved to be effective in the treatment of imatinib

  1. Lymphoblastic leukemia in pregnancy

    OpenAIRE

    Rojas Castrillo, Yaoska; Guevara González, José Guillermo

    2015-01-01

    Acute Leukemia occurs mainly in age groups of children under 5 years and in elderly patients, however; can also be seen in women of reproductive age. The prevalence of adult acute leukemia in young pregnant women is very rare, one case in 75,000 pregnancies and only 28% of them correspond to Lymphoblastic Leukemia occurs. The association between Acute Lymphocytic Leukemia and pregnancy poses a complex situation where you should not take or delay treatment, but the use of antineoplastic drug c...

  2. Imatinib-induced hyperbilirubinemia with UGT1A1 (*28) promoter polymorphism: first case series in patients with gastrointestinal stromal tumor

    Science.gov (United States)

    Saif, Muhammad Wasif; Smith, Melissa Hennessey; Maloney, Antonia; Diasio, Robert B.

    2016-01-01

    Imatinib, an orally administered protein-tyrosine kinase inhibitor (TKI) is indicated for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). Severe hepatotoxicity associated with imatinib is rare, and relationship to polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) expression and related frequency of hyperbilirubinemia or toxicity are not well known. We present a case series patients who developed hyperbilirubinemia while on oral administration imatinib for treatment of GIST. Genetic testing for polymorphism of UGT1A1 showed the first patient to be homozygous for the UGT1A1 TA7 (*28) polymorphism and the second patient heterozygous for the UGT1A1 TA1 (*28) polymorphism. The first patient had to stop imatinib due to severe and persistent hyperbilirubenemia peaking >3 despite reducing imatininb to only 100 mg every other day while the second patient improved at this dose. Our case series represent the first data associating UGT1A1 polymorphism and imatinib in patients being treated for GIST. Given the prevalence of Gilbert’s syndrome and the increasing use of imatinib, we encourage physicians to be aware of this possible toxicity as hepatotoxicity can be fatal if not managed in a timely fashion. This association is also timely due to recent FDA requirement for testing UGT1A1 polymorphism for nilotinib, another TKI. PMID:27708529

  3. Parameter estimation and sensitivity analysis for a mathematical model with time delays of leukemia

    Science.gov (United States)

    Cândea, Doina; Halanay, Andrei; Rǎdulescu, Rodica; Tǎlmaci, Rodica

    2017-01-01

    We consider a system of nonlinear delay differential equations that describes the interaction between three competing cell populations: healthy, leukemic and anti-leukemia T cells involved in Chronic Myeloid Leukemia (CML) under treatment with Imatinib. The aim of this work is to establish which model parameters are the most important in the success or failure of leukemia remission under treatment using a sensitivity analysis of the model parameters. For the most significant parameters of the model which affect the evolution of CML disease during Imatinib treatment we try to estimate the realistic values using some experimental data. For these parameters, steady states are calculated and their stability is analyzed and biologically interpreted.

  4. Compound list: imatinib, methanesulfonate salt [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available imatinib, methanesulfonate salt IMA 00186 ftp://ftp.biosciencedbc.jp/archive/open-t...ggates/LATEST/Rat/in_vivo/Liver/Single/imatinib%2C_methanesulfonate_salt.Rat.in_vivo.Liver.Single.zip ...

  5. Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model.

    Science.gov (United States)

    Nassar, Inthisham; Pasupati, Thanikachalam; Judson, John Paul; Segarra, Ignacio

    2010-06-01

    Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.

  6. Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia

    NARCIS (Netherlands)

    Daniels, J. M. A.; Vonk-Noordegraaf, A.; Janssen, J. J. W. M.; Postmus, P. E.; van Altena, R.

    Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB. There are

  7. Abacavir, an anti–HIV-1 drug, targets TDP1-deficient adult T cell leukemia

    OpenAIRE

    Tada, K; Kobayashi, M.; Takiuchi, Y.; Iwai, F.; Sakamoto, T; Nagata, K.; Shinohara, M.; Io, K.; Shirakawa, K.; Hishizawa, M.; Shindo, K.; Kadowaki, N.; Hirota, K; Yamamoto, J.; Iwai, S.

    2015-01-01

    Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chrom...

  8. Imatinib mesylate inhibits proliferation and exerts an antifibrotic effect in human breast stroma fibroblasts.

    Science.gov (United States)

    Gioni, Vassiliki; Karampinas, Theodoros; Voutsinas, Gerassimos; Roussidis, Andreas E; Papadopoulos, Savvas; Karamanos, Nikos K; Kletsas, Dimitris

    2008-05-01

    Tumor stroma plays an important role in cancer development. In a variety of tumors, such as breast carcinomas, a desmoplastic response, characterized by stromal fibroblast and collagen accumulation, is observed having synergistic effects on tumor progression. However, the effect of known anticancer drugs on stromal cells has not been thoroughly investigated. Imatinib mesylate is a selective inhibitor of several protein tyrosine kinases, including the receptor of platelet-derived growth factor, an important mediator of desmoplasia. Recently, we have shown that imatinib inhibits the growth and invasiveness of human epithelial breast cancer cells. Here, we studied the effect of imatinib on the proliferation and collagen accumulation in breast stromal fibroblasts. We have shown that it blocks the activation of the extracellular signal-regulated kinase and Akt signaling pathways and up-regulates cyclin-dependent kinase inhibitor p21(WAF1), leading to the inhibition of fibroblast proliferation, by arresting them at the G(0)/G(1) phase of the cell cycle. Imatinib inhibits more potently the platelet-derived growth factor-mediated stimulation of breast fibroblast proliferation. By using specific inhibitors, we have found that this is due to the inhibition of the Akt pathway. In addition, imatinib inhibits fibroblast-mediated collagen accumulation. Conventional and quantitative PCR analysis, as well as gelatin zymography, indicates that this is due to the down-regulation of mRNA synthesis of collagen I and collagen III-the main collagen types in breast stroma-and not to the up-regulation or activation of collagenases matrix metalloproteinase 2 and matrix metalloproteinase 9. These data indicate that imatinib has an antifibrotic effect on human breast stromal fibroblasts that may inhibit desmoplastic reaction and thus tumor progression.

  9. [Chronic myeloid leukemia: "archetype" of the impact of targeted therapies].

    Science.gov (United States)

    Nasr, R; Bazarbachi, A

    2012-08-01

    Chronic myeloid leukemia (CML) is a chronic blood disorder characterized by a reciprocal translocation between chromosomes 9 and 22, leading to the creation of a chimeric gene encoding the BCR-ABL fusion protein with a constitutive tyrosine kinase activity. Although long known as a disease with an inexorable progression to acute leukemia, CML history has been significantly improved by the use of imatinib, a tyrosine kinase inhibitor. Imatinib has revolutionized the treatment of CML by transforming it from an invariably fatal disease to a chronic but manageable condition. In fact, the discovery of this class of targeted therapy had an impact not only on the survival of CML patients but also on other scientific and medical fields. This review illustrates the impact of imatinib, the first example of tyrosine kinase inhibitors on the treatment of CML, on the treatment of other cancers, the impact on health systems and on the scientific research in general.

  10. Nilotinib-Induced Acute Pancreatitis in a Patient with Chronic Myeloid Leukemia

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    Vihang Patel

    2017-05-01

    Full Text Available Nilotinib, a second-generation tyrosine kinase inhibitor, is used for treatment of chronic myeloid leukemia (CML; it has been widely used especially for imatinib-resistant CML. Despite being a novel drug in this therapeutic class, it has the potential to be harmful. We present the case of an elderly woman who developed life-threatening acute pancreatitis as an adverse event after having started the drug. There is only one reported case in the literature of nilotinib-induced acute pancreatitis. The purpose of this case report is to educate physicians who prescribe this medication to be aware of potential life-threatening adverse events. As more and more therapies are available, physicians should be aware of potential effects of cancer treatment that could be life-threatening to patients.

  11. Approval summary: imatinib mesylate in the adjuvant treatment of malignant gastrointestinal stromal tumors.

    Science.gov (United States)

    Cohen, Martin H; Cortazar, Patricia; Justice, Robert; Pazdur, Richard

    2010-01-01

    On December 19, 2008, the U.S. Food and Drug Administration approved imatinib mesylate tablets for oral use (Gleevec(R); Novartis Pharmaceuticals Corporation, East Hanover, NJ) for the adjuvant treatment of adult patients following complete gross resection of Kit(+) (CD117(+)) gastrointestinal stromal tumor (GIST). A randomized, double-blind, placebo-controlled study enrolling 713 patients was submitted. The primary objective of the clinical trial was to compare the recurrence-free survival (RFS) intervals of the two groups. Overall survival (OS) was a secondary endpoint. Eligible patients were > or =18 years of age with a histological diagnosis of GIST (Kit(+)), resected tumor size > or =3 cm, and a complete gross resection within 14-70 days prior to registration. Imatinib, 400 mg orally, was administered once daily for 1 year. The study was terminated after completion of the third protocol-specified interim analysis. At that time, 100 RFS events were confirmed by a blinded central independent review. With a median follow-up of 14 months, 30 RFS events were observed in the imatinib group and 70 were observed in the placebo group (hazard ratio, 0.398; 95% confidence interval, 0.259-0.610; two-sided p-value or =3 adverse reactions. The most frequently reported adverse reactions (> or =20%) were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. Drug was discontinued for adverse reactions in 17% and 3% of the imatinib and placebo-treated patients, respectively.

  12. An Integrated Analysis of Heterogeneous Drug Responses in Acute Myeloid Leukemia That Enables the Discovery of Predictive Biomarkers.

    Science.gov (United States)

    Chen, Weihsu C; Yuan, Julie S; Xing, Yan; Mitchell, Amanda; Mbong, Nathan; Popescu, Andreea C; McLeod, Jessica; Gerhard, Gitte; Kennedy, James A; Bogdanoski, Goce; Lauriault, Stevan; Perdu, Sofie; Merkulova, Yulia; Minden, Mark D; Hogge, Donna E; Guidos, Cynthia; Dick, John E; Wang, Jean C Y

    2016-03-01

    Many promising new cancer drugs proceed through preclinical testing and early-phase trials only to fail in late-stage clinical testing. Thus, improved models that better predict survival outcomes and enable the development of biomarkers are needed to identify patients most likely to respond to and benefit from therapy. Here, we describe a comprehensive approach in which we incorporated biobanking, xenografting, and multiplexed phospho-flow (PF) cytometric profiling to study drug response and identify predictive biomarkers in acute myeloid leukemia (AML) patients. To test the efficacy of our approach, we evaluated the investigational JAK2 inhibitor fedratinib (FED) in 64 patient samples. FED robustly reduced leukemia in mouse xenograft models in 59% of cases and was also effective in limiting the protumorigenic activity of leukemia stem cells as shown by serial transplantation assays. In parallel, PF profiling identified FED-mediated reduction in phospho-STAT5 (pSTAT5) levels as a predictive biomarker of in vivo drug response with high specificity (92%) and strong positive predictive value (93%). Unexpectedly, another JAK inhibitor, ruxolitinib (RUX), was ineffective in 8 of 10 FED-responsive samples. Notably, this outcome could be predicted by the status of pSTAT5 signaling, which was unaffected by RUX treatment. Consistent with this observed discrepancy, PF analysis revealed that FED exerted its effects through multiple JAK2-independent mechanisms. Collectively, this work establishes an integrated approach for testing novel anticancer agents that captures the inherent variability of response caused by disease heterogeneity and in parallel, facilitates the identification of predictive biomarkers that can help stratify patients into appropriate clinical trials.

  13. Cerebral relapse of metastatic gastrointestinal stromal tumor during treatment with imatinib mesylate: Case report

    Directory of Open Access Journals (Sweden)

    Waring Paul

    2004-10-01

    Full Text Available Abstract Background The management of unresectable or metastatic gastrointestinal stromal tumors (GISTs has previously been difficult as they are resistant to conventional chemotherapy and radiation. The development of imatinib mesylate has made a major impact on the management of advanced GISTs. It is apparent that there are sanctuary sites such as the central nervous system where imatinib does not achieve adequate concentrations. We describe the case of a man with metastatic GIST who experienced multiple cerebral relapses of disease while systemic disease progression appeared to be controlled by imatinib. Case presentation A 47-year-old man presented in July 1999 with a jejunal GIST with multiple hepatic metastases. The jejunal primary was resected and after unsuccessful cytoreductive chemotherapy, the liver metastases were also resected in December 1999. The patient subsequently relapsed in August 2001 with symptomatic hepatic, subcutaneous gluteal, left choroidal and right ocular metastases all confirmed on CT and PET scanning. Biopsy confirmed recurrent GIST. MRI and lumbar puncture excluded central nervous system involvement. The patient was commenced on imatinib 400 mg bd in September 2001 through a clinical trial. The symptoms improved with objective PET and CT scan response until December 2002 when the patient developed a right-sided foot drop. MRI scan showed a left parasagittal tumor which was resected and confirmed histologically to be metastatic GIST. Imatinib was ceased pre-operatively due to the trial protocol but recommenced in February 2003 on a compassionate use program. The left parasagittal metastasis recurred and required subsequent re-excision in September 2003 and January 2004. Control of the systemic GIST was temporarily lost on reduction of the dose of imatinib (due to limited drug supply but on increasing the dose back to 800 mg per day, systemic disease was stabilized for a period of time before generalised progression

  14. Chronic myeloid leukemia data from India

    Directory of Open Access Journals (Sweden)

    Shweta Bansal

    2013-01-01

    Full Text Available In an effort to collaborate the data of chronic myeloid leukemia (CML patient from all over India,meeting was conceived by ICON ( Indian Cooperative Oncology Network in 2010. This article presents the summarized picture of the data presented in the meeting. In the meeting 8115 patients data was presented and 18 centres submitted their manuscripts comprising of 6677 patients. This data represents large series of patients from all over the country treated on day to day clinical practice and presents the actual outcomes of CML patients in India. The compilation of data confirms the younger age at presentation, increased incidence of resistance and poor outcomes in patients with late chronic phase. It also addresses the issues like Glivec versus Generic drug outcomes, safety of Imatinib during pregnancy and mutational analysis among resistant patients. It concludes that survival and quality of life of CML patients in India has improved over the years especially when treated in early chronic phase. The generic drug is a good option where original is unable to reach the patient due to various reasons. Hopefully, this effort will provide a platform to conduct systematic studies in learning the best treatment options among CML patients in Indian settings.

  15. RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Houcai; Yu, Jing; Zhang, Lixia; Xiong, Yuanyuan; Chen, Shuying; Xing, Haiyan; Tian, Zheng; Tang, Kejing; Wei, Hui; Rao, Qing; Wang, Min; Wang, Jianxiang, E-mail: wangjx@ihcams.ac.cn

    2014-04-18

    Highlights: • RPS27a expression was up-regulated in advanced-phase CML and AL patients. • RPS27a knockdown changed biological property of K562 and K562/G01 cells. • RPS27a knockdown affected Raf/MEK/ERK, P21 and BCL-2 signaling pathways. • RPS27a knockdown may be applicable for new combination therapy in CML patients. - Abstract: Ribosomal protein S27a (RPS27a) could perform extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. The high expression level of RPS27a was reported in solid tumors, and we found that the expression level of RPS27a was up-regulated in advanced-phase chronic myeloid leukemia (CML) and acute leukemia (AL) patients. In this study, we explored the function of RPS27a in leukemia cells by using CML cell line K562 cells and its imatinib resistant cell line K562/G01 cells. It was observed that the expression level of RPS27a was high in K562 cells and even higher in K562/G01 cells. Further analysis revealed that RPS27a knockdown by shRNA in both K562 and K562G01 cells inhibited the cell viability, induced cell cycle arrest at S and G2/M phases and increased cell apoptosis induced by imatinib. Combination of shRNA with imatinib treatment could lead to more cleaved PARP and cleaved caspase-3 expression in RPS27a knockdown cells. Further, it was found that phospho-ERK(p-ERK) and BCL-2 were down-regulated and P21 up-regulated in RPS27a knockdown cells. In conclusion, RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells. It appears that drugs targeting RPS27a combining with tyrosine kinase inhibitor (TKI) might represent a novel therapy strategy in TKI resistant CML patients.

  16. Phase I study of gemcitabine, docetaxel and imatinib in refractory and relapsed solid tumors

    Science.gov (United States)

    Chugh, Rashmi; Karantza, Vassiliki; Mehnert, Janice; Moss, Rebecca A.; Savkina, Nelli; Stein, Mark N.; Baker, Laurence H.; Chenevert, Thomas; Poplin, Elizabeth A.

    2017-01-01

    Summary Purpose In a phase I study, the combination of gemcitabine and imatinib was well tolerated with broad anticancer activity. This phase I trial evaluated the triplet of docetaxel, gemcitabine and imatinib. Experimental Design Imatinib was administered at 400 mg daily on days 1–5, 8–12 and 15–19. Gemcitabine was started at 600 mg/m2 at a rate of 10 mg/min on days 3 and 10 and docetaxel at 30 mg/m2 on day 10, on a 21-day cycle. Diffusion and dynamic contrast-enhanced perfusion MRI was performed in selected patients. Results Twenty patients with relapsed/ refractory solid tumors were enrolled in this IRB-approved study. The mean age was 64, and mean ECOG PS was 1. Two patients were evaluated by diffusion/perfusion MRI. After two grade 3 hematological toxicities at dose level 1, the protocol was amended to reduce the dose of imatinib. MTDs were 600 mg/ m2 on days 3 and 10 for gemcitabine, 30 mg/ m2 on day 10 for docetaxel, and 400 mg daily on days 1–5 and 8–12 for imatinib. Dose limiting toxicities after one cycle were neutropenic fever, and pleural and pericardial effusions. The best response achieved was stable disease, for six cycles, in one patient each with mesothelioma and non small cell lung cancer (NSCLC) at the MTD. Two patients with NSCLC had stable disease for four cycles. Discussion An unexpectedly low MTD for this triplet was identified. Our results suggest drug-drug interactions that amplify toxicities with little evidence of improved tumor control. PMID:20697775

  17. Effect of Imatinib on the Oogenesis and Pituitary -Ovary Hormonal Axis in Female Wistar Rat

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    Parichehreh Yaghmaei

    2009-01-01

    Full Text Available Background: Imatinib mesylate, a small-molecular analog of adenosine triphosphate (ATPthat potently inhibits tyrosine kinase activities of Bcr–Abl, PDGFR-β, PDGFR-α, c-Fms, Argand c-kit, is one of the novel molecularly targeted drugs being introduced into cancer therapy.We tested the effect of imatinib on the ovarian histological structure and the concentration ofestrogen and progesterone, luteinizing hormone (LH and follicle stimulating hormone (FSHin the serum of female Wistar rats.Materials and Methods: Two groups of rats (180 ± 15 grams were gavaged with doses of 50and 100 mg/kg body weight imatinib dissolved in distilled water for 14 days. The control groupreceived sterile water. On day 7, after termination of the treatment, blood serum concentrationwas measured with the radioimmunoassay (RIA method. Also, sections (5 μm thick of ovariesstained with hematoxylin and eosin (H&E were investigated histologically.Results: Progesterone concentration in the experimental groups was increased (p<0.001,estrogen and FSH concentrations were decreased (p<0.01, and the LH concentration decreasedbut was not statistically different in comparison with the control group. The weight of ovaries andnumber of atretic follicles in the experimental groups was increased compared with the controlgroup (p<0.05. The diameter of corpus lutea were increased but the number of corpus luteadecreased in both experimental groups (p<0.01.Conclusion: These findings suggest that administration of imatinib may have profound effects onfemale fertility.

  18. Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia

    Directory of Open Access Journals (Sweden)

    Govindarajan Baskaran

    2012-07-01

    Full Text Available Abstract Tuberous sclerosis (TS is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS.

  19. Behandling af ideopatisk hypereosinofilt syndrom med imatinib

    DEFF Research Database (Denmark)

    Sørensen, Anne Louise; Larsen, Herdis

    2008-01-01

    We here report a case of idiopathic hypereosinophilic syndrome with prompt response to treatment with imatinib. The patient presented with chest pain, myalgias, fatigue and weakness. Blood tests and bone marrow examination revealed striking eosinophilia. Clonal or reactive disorders were excluded...

  20. MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia

    NARCIS (Netherlands)

    D. Schotte (Diana); R.X. de Menezes (Renee); F. Akbari Moqadam (Farhad); L.M. Khankahdani (Leila Mohammadi); E.A.M. Lange-Turenhout (Ellen); C. Chen (Caifu); R. Pieters (Rob); M.L. den Boer (Monique)

    2011-01-01

    textabstractBackground MicroRNA regulate the activity of protein-coding genes including those involved in hematopoietic cancers. The aim of the current study was to explore which microRNA are unique for seven different subtypes of pediatric acute lymphoblastic leukemia. Design and Methods Expression

  1. Inhibition of c-Myc overcomes cytotoxic drug resistance in acute myeloid leukemia cells by promoting differentiation.

    Directory of Open Access Journals (Sweden)

    Xiao-Na Pan

    Full Text Available Nowadays, drug resistance still represents a major obstacle to successful acute myeloid leukemia (AML treatment and the underlying mechanism is not fully elucidated. Here, we found that high expression of c-Myc was one of the cytogenetic characteristics in the drug-resistant leukemic cells. c-Myc over-expression in leukemic cells induced resistance to chemotherapeutic drugs, enhanced colony formation capacity and inhibited cell differentiation induced by all-trans retinoic acid (ATRA. Meanwhile, inhibition of c-Myc by shRNA or specific c-Myc inhibitor 10058-F4 rescued the sensitivity to cytotoxic drugs, restrained the colony formation ability and promoted differentiation. RT-PCR and western blotting analysis showed that down-regulation of C/EBPβ contributed to the poor differentiation state of leukemic cells induced by c-Myc over-expression. Importantly, over-expression of C/EBPβ could reverse c-Myc induced drug resistance. In primary AML cells, the c-Myc expression was negatively correlated with C/EBPβ. 10058-F4, displayed anti-proliferative activity and increased cellular differentiation with up-regulation of C/EBPβ in primary AML cells. Thus, our study indicated that c-Myc could be a novel target to overcome drug resistance, providing a new approach in AML therapy.

  2. Morphological Changes in Bone Marrow Post Imatinib Therapy in Chronic Phase CML: A Follow up Study on Sequential Bone Marrow Aspirates and Biopsies.

    Science.gov (United States)

    Narang, Neha Chopra; Rusia, Usha; Sikka, Meera; Kotru, Mrinalini

    2017-04-01

    Imatinib mesylate is used extensively for first line treatment of Chronic Myeloid Leukemia (CML). However, not many studies have documented morphological changes in bone marrow biopsies produced during Imatinib therapy with reference to myelofibrosis. To document the morphological changes produced in the bone marrow during Imatinib therapy. This longitudinal study followed up 75 Philadelphia Chromosome Positive Chronic Myeloid Leukemia with chronic phase(Ph+ CML- CP) patients sequentially, receiving 400-600mg Imatinib over a period of 12 or more months. Haematologic parameters were measured at admission, 2 weeks, 1 month, 3 months, 6 months and 12 or more months. Morphologic changes in bone marrow aspirate and biopsy were evaluated at admission, 6 months and ≥12 months of treatment in accordance with National Comprehensive Cancer Network(NCCN) guidelines. Complete Haematologic Response (CHR) was seen in 47.1%, 80%, 85.4%, 90.4% at ≥1 month, 3 months, 6 months and 12 months respectively after therapy. It was noted that patients not showing CHR by 3 months were less likely to show CHR at 6 months and beyond. Bone marrow aspirates and biopsies showed reduction in cellularity and myeloid precursors with regeneration of erythroid precursors in 70-83% at ≥12 months. A significant decrease in myelofibrosis (p-value< 0.04) was noted as early as 6 months. Mild to moderate hypoplasia was noted in 31.8% of biopsies within 6 months. Pseudo gaucher cells and benign lymphoid nodules were also seen. Sequential analysis showed that Imatinib reduced the grade of myelofibrosis significantly (p-value< 0.04). It also prevented development of myelofibrosis in patients who did not have it at presentation. Hence Imatinib is effective when used early in the course of CML-CP.

  3. Effects of tyrosine kinase inhibitors on spermatogenesis and pituitary gonadal axis in males with chronic myeloid leukemia

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    Yassin MA

    2014-08-01

    Full Text Available Objective: The introduction of several classes of targeted therapeutics for the treatment of chronic myelogenous leukemia (CML raises the question of whether male fertility is affected and the degree of this affection, if any, among the different generations of tyrosine kinase inhibitors (TKIs. Additionally, when two drugs are equally effective, the drug with less toxic effect on fertility is favourable. Our aims were to evaluate semen parameters and pituitary gonadal function before and four months after starting TKIs namely, dasatinib, nilotinib, and imatinib in patients with CML. Design: Prospective study. Setting, patients and interventions: We studied the effect of TKIs' first generation (imatinib and second generation (dasatinib and nilotinib on semen parameters and endocrine functions in 20 eugonadal male patients with CML, aged between 35 to 51 years. They were receiving imatinib (400 mg once daily, dasatinib (100 mg once daily or nilotinib (300 mg twice daily as upfront therapy. We assessed the serum gonadotropins (LH and FSH and testosterone (T secretion and sperm parameters before and after four months of using these TKIs. Results: Four months after starting TKIs, serum testosterone, LH and FSH concentrations decreased significantly. The total sperm count (SC, total and rapid progressive sperm motility, and % sperms with normal morphology decreased significantly versus pre-treatment. After 4 months of therapy, dasatinib had comparatively the least deleterious effects on SC, ejaculate volume (SV, sperm motility and % of sperms with normal morphology (%NM compared to imatinib and nilotinib. Significant correlations were found between serum T concentrations and semen parameters before and after TKIs therapy including SC (r = 0.658 and r = 0.73 respectively, p < 0.001, rapid progressive motility (r = 0.675 and r = 0.758, respectively; p < 0.001, and the % NM (r = 0.752 and r = 0.834, respectively; p < 0.001. After TKIs therapy, LH were

  4. HnRNP K contributes to drug resistance in acute myeloid leukemia through the regulation of autophagy.

    Science.gov (United States)

    Zhang, JinFang; Liu, XiaoLi; Lin, YuDeng; Li, YuLing; Pan, JianWei; Zong, Sa; Li, YongKang; Zhou, Yang

    2016-09-01

    The goal of this study was to explore the role of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in drug resistance through the regulation of autophagy in acute myeloid leukemia (AML). First, we used fluorescence quantitative polymerase chain reaction (PCR) to verify the connection between the expression level of hnRNP K and the level of drug resistance in AML. We then used Western blotting to determine the expression level of the autophagy-related proteins microtubule-associated protein light chain 3 I and II (LC3 I/II) after the modulation of hnRNP K by ribonucleic acid (RNA) interference. Finally, an analysis of adriamycin drug sensitivity was conducted before and after the modulation of hnRNP K expression. hnRNP K and LC3 I/II were significantly overexpressed in the bone marrow of nonremission patients and in drug-resistant cell lines; however, the expression of LC3 I/II was decreased when the expression of hnRNP K was reduced and drug sensitivity to adriamycin could be restored. hnRNP K may be involved in the development of adriamycin resistance in AML through the regulation of autophagy.

  5. Structural identification of imatinib cyanide adducts by mass spectrometry and elucidation of bioactivation pathway.

    Science.gov (United States)

    Li, Austin C; Yu, Erya; Ring, Steven C; Chovan, James P

    2014-01-15

    Recent publications have reported that imatinib forms cyanide and methoxylamine adducts in vitro but without detail structural identification. The current work reports the identification of seven cyanide adducts that elucidate the bioactivation pathways and may provide hints for observed clinical adverse effects of the drug. Imatinib was incubated with human liver microsomal proteins in the presence of a NADPH-regeneration system and the trapping agents reduced GSH, potassium cyanide and methoxylamine. Samples were analyzed by high-performance liquid chromatography (HPLC) coupled with a LTQ-Orbitrap data collection system. Chemical structures were determined and/or postulated based on data-dependent high-resolution tandem mass spectrometric (MS(n)) exact mass measurements in both positive and negative scan modes, as well as in combination with hydrogen-deuterium exchange (HDX). GSH and methoxylamine conjugates were either not detected or were in insufficient quantities for characterization. However, seven cyanide conjugates were identified, indicating that the piperazine and p-toluidine partial structures in imatinib can become bioactivated and subsequently trapped by the nucleophile cyanide ion. The reactive intermediates were postulated as imine and imine-carbonyl conjugate (α,β-unsaturated) structures on the piperazine ring, and imine-methide on the p-toluidine partial structure. Chemical structures of seven cyanide adducts of imatinib have been identified or proposed based on high-resolution MS/MS data. Mechanisms for the formation of the conjugates were also proposed. The findings may help to understand the mechanism of hepatotoxicity of imatinib in humans. Copyright © 2013 John Wiley & Sons, Ltd.

  6. PPAR-gamma in overcoming kinase resistance in chronic myeloid leukemia.

    Science.gov (United States)

    Yousefi, B; Shafiei-Irannejad, V; Azimi, A; Samadi, N; Zarghami, N

    2016-07-31

    Peroxisome proliferator-activated receptor gamma (PPARγ) plays key roles in regulating cellular differentiation, proliferation and apoptosis pathways. As such, they are considered promising targets for anticancer drug development, especially for breast cancer, multiple myeloma and hematologic malignancies. Chronic myeloid leukemia (CML) is a myeloproliferative disorder arising from an oncogenic Bcr-Abl tyrosine kinase. Inhibitors of this oncogene by small molecules such as imatinib are effective only in 75% of the patient's population. One of the potential strategies to overcome this resistance is to devise combination therapy protocols with other therapeutic agents including PPAR ligands. Since PPAR ligands are potentially interesting in different hematologic malignancies, this article will review the potential of PPAR ligands for use in CML treatment.

  7. Pharmacokinetic modeling of an induction regimen for in vivo combined testing of novel drugs against pediatric acute lymphoblastic leukemia xenografts.

    Directory of Open Access Journals (Sweden)

    Barbara Szymanska

    Full Text Available Current regimens for induction therapy of pediatric acute lymphoblastic leukemia (ALL, or for re-induction post relapse, use a combination of vincristine (VCR, a glucocorticoid, and L-asparaginase (ASP with or without an anthracycline. With cure rates now approximately 80%, robust pre-clinical models are necessary to prioritize active new drugs for clinical trials in relapsed/refractory patients, and the ability of these models to predict synergy/antagonism with established therapy is an essential attribute. In this study, we report optimization of an induction-type regimen by combining VCR, dexamethasone (DEX and ASP (VXL against ALL xenograft models established from patient biopsies in immune-deficient mice. We demonstrate that the VXL combination was synergistic in vitro against leukemia cell lines as well as in vivo against ALL xenografts. In vivo, VXL treatment caused delays in progression of individual xenografts ranging from 22 to >146 days. The median progression delay of xenografts derived from long-term surviving patients was 2-fold greater than that of xenografts derived from patients who died of their disease. Pharmacokinetic analysis revealed that systemic DEX exposure in mice increased 2-fold when administered in combination with VCR and ASP, consistent with clinical findings, which may contribute to the observed synergy between the 3 drugs. Finally, as proof-of-principle we tested the in vivo efficacy of combining VXL with either the Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, or arsenic trioxide to provide evidence of a robust in vivo platform to prioritize new drugs for clinical trials in children with relapsed/refractory ALL.

  8. Maintenance therapy of childhood acute lymphoblastic leukemia revisited—Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Nersting, Jacob; Nielsen, Stine Nygaard

    2016-01-01

    BACKGROUND: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on do...

  9. Cell-based evaluation of changes in coagulation activity induced by antineoplastic drugs for the treatment of acute myeloid leukemia.

    Science.gov (United States)

    Tsunaka, Misae; Shinki, Haruka; Koyama, Takatoshi

    2017-01-01

    Idarubicin (IDR), cytarabine (AraC), and tamibarotene (Am80) are effective for treatment of acute myeloid leukemia (AML). In acute leukemia, the incidence of venous thromboembolism or disseminated intravascular coagulation is associated with induction chemotherapy. Procoagulant effects of IDR, AraC, and Am80 were investigated in a vascular endothelial cell line EAhy926 and AML cell lines HL60 (AML M2), NB4 (AML M3, APL), and U937 (AML M5), focusing on tissue factor (TF), phosphatidylserine (PS), and thrombomodulin (TM). IDR induced procoagulant activity on the surface of vascular endothelial and AML cell lines. Expression of TF antigen, TM antigen, and PS were induced by IDR on the surface of each cell line, whereas expression of TF and TM mRNAs were unchanged. Conversely, Am80 decreased TF exposure and procoagulant activity, and increased TM exposure on NB4 cells. In NB4 cells, we observed downregulation of TF mRNA and upregulation of TM mRNA. These data suggest IDR may induce procoagulant activity in vessels by apoptosis through PS exposure and/or TF expression on vascular endothelial and AML cell lines. Am80 may suppress blood coagulation through downregulation of TF expression and induction of TM expression. Our methods could be useful to investigate changes in procoagulant activity induced by antineoplastic drugs.

  10. Wogonoside induces growth inhibition and cell cycle arrest via promoting the expression and binding activity of GATA-1 in chronic myelogenous leukemia cells.

    Science.gov (United States)

    Li, Hui; Hui, Hui; Xu, Jingyan; Yang, Hao; Zhang, Xiaoxiao; Liu, Xiao; Zhou, Yuxin; Li, Zhiyu; Guo, Qinglong; Lu, Na

    2016-06-01

    GATA-1, a zinc finger transcription factor, has been demonstrated to play a key role in the progression of leukemia. In this study, we investigate the effects of wogonoside, a naturally bioactive flavonoid derived from Scutellaria baicalensis Georgi, on cell growth and cell cycle in chronic myeloid leukemia (CML) cells, and uncover its underlying mechanisms. The experimental design comprised CML cell lines K562, imatinib-resistant K562 (K562r) cells, and primary CML cells, treated in vitro or in vivo, respectively, with wogonoside; growth and cell cycle were then evaluated. We found that wogonoside could induce growth inhibition and G0/G1 cell cycle arrest in both normal and K562r cells. Wogonoside promotes the expression of GATA-1 and facilitates the binding to methyl ethyl ketone (MEK) and p21 promoter, thus inhibiting MEK/extracellular signal-regulated kinase signaling and cell cycle checkpoint proteins, including CDK2, CDK4, cyclin A, and cyclin D1, and increasing p21 expression. Furthermore, in vivo studies showed that administration of wogonoside decreased CML cells and prolonged survival in NOD/SCID mice with CML cell xenografts. In conclusion, these results clearly revealed the inhibitory effect of wogonoside on the growth in CML cells and suggested that wogonoside may act as a promising drug for the treatment of imatinib-resistant CML.

  11. Intermittent targeted therapies and stochastic evolution in patients affected by chronic myeloid leukemia

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    Pizzolato, N.; Persano Adorno, D.; Valenti, D.; Spagnolo, B.

    2016-05-01

    Front line therapy for the treatment of patients affected by chronic myeloid leukemia (CML) is based on the administration of tyrosine kinase inhibitors, namely imatinib or, more recently, axitinib. Although imatinib is highly effective and represents an example of a successful molecular targeted therapy, the appearance of resistance is observed in a proportion of patients, especially those in advanced stages. In this work, we investigate the appearance of resistance in patients affected by CML, by modeling the evolutionary dynamics of cancerous cell populations in a simulated patient treated by an intermittent targeted therapy. We simulate, with the Monte Carlo method, the stochastic evolution of initially healthy cells to leukemic clones, due to genetic mutations and changes in their reproductive behavior. We first present the model and its validation with experimental data by considering a continuous therapy. Then, we investigate how fluctuations in the number of leukemic cells affect patient response to the therapy when the drug is administered with an intermittent time scheduling. Here we show that an intermittent therapy (IT) represents a valid choice in patients with high risk of toxicity, despite an associated delay to the complete restoration of healthy cells. Moreover, a suitably tuned IT can reduce the probability of developing resistance.

  12. New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia

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    Moorman, Anthony V.

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is a heterogeneous disease at the genetic level. Chromosomal abnormalities are used as diagnostic, prognostic and predictive biomarkers to provide subtype, outcome and drug response information. t(12;21)/ETV6-RUNX1 and high hyper-diploidy are good-risk prognostic biomarkers whereas KMT2A (MLL) translocations, t(17;19)/TCF3-HLF, haploidy or low hypodiploidy are high-risk biomarkers. t(9;22)/BCR-ABL1 patients require targeted treatment (imatinib/dasatinib), whereas iAMP21 patients achieve better outcomes when treated intensively. High-risk genetic biomarkers are four times more prevalent in adults compared to children. The application of genomic technologies to cases without an established abnormality (B-other) reveals copy number alterations which can be used either individually or in combination as prognostic biomarkers. Transcriptome sequencing studies have identified a network of fusion genes involving kinase genes - ABL1, ABL2, PDGFRB, CSF1R, CRLF2, JAK2 and EPOR. In vitro and in vivo studies along with emerging clinical observations indicate that patients with a kinase-activating aberration may respond to treatment with small molecular inhibitors like imatinib/dasatinib and ruxolitinib. Further work is required to determine the true frequency of these abnormalities across the age spectrum and the optimal way to incorporate such inhibitors into protocols. In conclusion, genetic biomarkers are playing an increasingly important role in the management of patients with ALL. PMID:27033238

  13. Imatinib and gastrointestinal stromal tumor (GIST: a selective targeted therapy Imatinib y tumor del estroma gastrointestinal (GIST: un tratamiento selectivo frente a una diana molecular

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    A. Fernández

    2004-10-01

    Full Text Available Gastrointestinal stromal tumors are the most frequent mesenchymal tumors in the gastrointestinal tract. They originate from the interstitial cells of Cajal and are characterized by an anomalous receptor for a growth factor with tyrosine-kinase activity (c-kit. This anomaly causes a permanent activation of the receptor and uncontrolled cell growth. These tumors show a poor response to traditional chemotherapy drugs, and are thus associated with low survival in cases of advanced disease. Imatinib, a tyrosine kinase inhibitor, is an example of selective targeted oncologic therapy that induces improved survival in these patients. We discuss two cases of metastatic gastrointestinal stromal tumors with a good response to imatinib, and also review the pathophysiology and treatment-related outcome of this type of tumors. We include results from clinical phase-III studies.Los tumores del estroma gastrointestinal son los tumores mesenquimales más frecuentes del tracto digestivo y se originan de las células intersticiales de Cajal. Se caracterizan por presentar un receptor para el factor de crecimiento con actividad tirosin kinasa (c-kit anómalo que condiciona su activación permanente y un crecimiento celular incontrolado. Tienen una baja supervivencia en casos de enfermedad avanzada, con escasa respuesta a los agentes quimioterápicos tradicionales. El imatinib es un fármaco inhibidor de la tirosín kinasa y un ejemplo de terapia oncológica selectiva que condiciona un importante aumento en la supervivencia de estos pacientes. Se presentan 2 casos de enfermedad metastásica con buena respuesta a imatinib, así como una revisión sobre la fisiopatología y evolución en el tratamiento de este tipo de tumores, incluyendo resultados de estudios en fase III.

  14. Chemotherapy drug scheduling for the induction treatment of patients with acute myeloid leukemia.

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    Pefani, E; Panoskaltsis, N; Mantalaris, A; Georgiadis, M C; Pistikopoulos, E N

    2014-07-01

    Leukemia is an immediately life-threatening cancer wherein immature blood cells are overproduced, accumulate in the bone marrow (BM) and blood and causes immune and blood system failure. Treatment with chemotherapy can be intensive or nonintensive and can also be life-threatening since only relatively few patient-specific and leukemia-specific factors are considered in current protocols. We have already presented a mathematical model for one intensive chemotherapy cycle with intravenous (i.v.) daunorubicin (DNR), and cytarabine (Ara-C). This model is now extended to nonintensive subcutaneous (SC) Ara-C and for a standard intensive chemotherapy course (four cycles), consistent with clinical practice. Model parameters mainly consist of physiological patient data, indicators of tumor burden and characteristics of cell cycle kinetics. A sensitivity analysis problem is solved and cell cycle parameters are identified to control treatment outcome. Simulation results using published cell cycle data from two acute myeloid leukemia patients are presented for a course of standard treatment using intensive and nonintensive protocols. The aim of remission-induction therapy is to debulk the tumor and achieve normal BM function; by treatment completion, the total leukemic population should be reduced to at most 10(9) cells, at which point BM hypoplasia is achieved. The normal cell number should be higher than that of the leukemic, and a 3-log reduction is the maximum permissible level of population reduction. This optimization problem is formulated and solved for the two patient case studies. The results clearly present the benefits from the use of optimization as an advisory tool for treatment design.

  15. Dasatinib in chronic myeloid leukemia: a review

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    Dolly G Aguilera

    2009-03-01

    Full Text Available Dolly G Aguilera1, Apostolia M Tsimberidou21Department of Hematology-Oncology and Stem Cell Transplantation, Children’s Memorial Hospital, Northwestern University, Chicago, IL, USA; 2Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston Texas USAAbstract: Deregulated BCR-ABL tyrosine kinase (TK activity is the molecular marker for chronic myeloid leukemia (CML, which provides an identifiable target for developing therapeutic agents. Imatinib mesylate, a BCR-ABL TK inhibitor, is the frontline therapy for CML. Despite the stunning efficacy of this agent, a small number of patients develop a suboptimal response or resistance to imatinib. In newly diagnosed patients with chronic phase CML, the rate of resistance to imatinib at 4 years was up to 20%, increasing to 70% to 90% for patients in the accelerated/blastic phase. Resistance to imatinib led to the development of novel TK inhibitors such as dasatinib. Several clinical trials have reported more durable complete hematologic and cytogenetic responses with this agent in patients who are resistant or intolerant to imatinib. Dasatinib is well tolerated and has broad efficacy, resulting in durable responses in patients with any BCR-ABL mutation except for T3151 and mutations in codon 317 – most commonly F317L – including mutations that were highly resistant to imatinib, such as L248, Y253, E255, F359, and H396. Dasatinib is recommended for CML in chronic, blastic or accelerated phase that is resistant or intolerant to imatinib. Dasatinib was approved by the FDA at 100 mg once daily as the starting dose in patients with chronic phase CML and at 70 mg twice daily in patients with accelerated or blastic phase CML. Various clinical trial results provided evidence that resistance to one TK inhibitor can be reversed with the use of a different TK inhibitor (TKI. Other second-generation TKIs with activity in CML include nilotinib, bosutinib and

  16. Impact of oncology pharmacist-managed oral anticancer therapy in patients with chronic myelogenous leukemia.

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    Lam, Masha Sh; Cheung, Nathan

    2016-12-01

    Studies have identified non-adherence as one of the major contributing factors to treatment failure in chronic myelogenous leukemia (CML) patients receiving imatinib. Published literature has demonstrated a unique role of oncology pharmacists, as part of a multidisciplinary team, in contributing to overall positive outcomes for patients. To evaluate the impact of an oncology pharmacist-managed oral anticancer therapy program on oral medication adherence in CML patients versus usual care. Electronic refill history and medical records of patients diagnosed with CML treated with oral tyrosine kinase inhibitors (TKIs) managed by oncology pharmacists during a 6-year period, were retrospectively reviewed. Imatinib adherence rate, as the primary endpoint, was compared with the rate for those in the usual care group within the same organization. The secondary endpoints were descriptive to characterize pharmacist interventions for all TKIs. A total of 56 patients including 45 who were treated with imatinib, were evaluated. The group managed by oncology pharmacists resulted in a higher percentage of imatinib adherence rate compared to usual care (88.6% vs 65.8%, p = 0.0046). A total of 3432 pharmacist encounters were reviewed, and 567 interventions of six categories including side effect monitoring/management (n = 95; 16.8%); drug interaction detection (n = 109; 19.2%); TKI dose adjustment (n = 82; 14.5%); laboratory monitoring (n = 200; 35.3%); non-CML related drug choice (n = 74; 13.1%); and copay assistance (n = 7; 1.2%), were documented. This resulted in a mean of 10.1 interventions per patient. Our oncology pharmacist-managed oral anticancer therapy program significantly improved TKI adherence rates in CML patients. We attribute the success of our program to consistent follow-up by utilizing routine phone, and secure email follow-ups, that allowed our oncology pharmacists to build a close and trustworthy relationship with patients and

  17. Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy.

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    Bibi, Siham; Arslanhan, Melis Dilara; Langenfeld, Florent; Jeanningros, Sylvie; Cerny-Reiterer, Sabine; Hadzijusufovic, Emir; Tchertanov, Luba; Moriggl, Richard; Valent, Peter; Arock, Michel

    2014-03-01

    Chronic myeloid leukemia and systemic mastocytosis are myeloid neoplasms sharing a number of pathogenetic and clinical features. In both conditions, an aberrantly activated oncoprotein with tyrosine kinase activity, namely BCR-ABL1 in chronic myeloid leukemia, and mutant KIT, mostly KIT D816V, in systemic mastocytosis, is key to disease evolution. The appreciation of the role of such tyrosine kinases in these diseases has led to the development of improved therapies with tyrosine kinase-targeted inhibitors. However, most drugs, including new KIT D816V-blocking agents, have failed to achieve long-lasting remissions in advanced systemic mastocytosis, and there is a similar problem in chronic myeloid leukemia, where imatinib-resistant patients sometimes fail to achieve remission, even with second- or third-line BCR-ABL1 specific tyrosine kinase inhibitors. During disease progression, additional signaling pathways become activated in neoplastic cells, but most converge into major downstream networks. Among these, the AKT and STAT5 pathways appear most critical and may result in drug-resistant chronic myeloid leukemia and systemic mastocytosis. Inhibition of phosphorylation of these targets has proven their crucial role in disease-evolution in both malignancies. Together, these observations suggest that STAT5 and AKT are key drivers of oncogenesis in drug-resistant forms of the diseases, and that targeting STAT5 and AKT might be an interesting approach in these malignancies. The present article provides an overview of our current knowledge about the critical role of AKT and STAT5 in the pathophysiology of chronic myeloid leukemia and systemic mastocytosis and on their potential value as therapeutic targets in these neoplasms.

  18. Incidences of hematological adverse reactions in 435 patients with chronic myeloid leukemia treated by imatinib mesylate%慢性粒细胞白血病435例甲磺酸伊马替尼治疗后血液学不良反应

    Institute of Scientific and Technical Information of China (English)

    王娟; 高松坤; 李珍; 李梦娟; 张莉; 宋永平

    2015-01-01

    Objective To explore the hematology adverse reactions of imatinib mesylate (IM) in the treatment of chronic phase (CP) of chronic myeloid leukemia (CML).Methods The clinical data of 435 CML-CP patients treated with IM were analyzed respectively in the Affiliated Cancer Hospital of Zhengzhou University from Jan 2013 to Jan 2015.The hematology adverse reactions were followed up regularly and the incidences in different groups with various factors were compared.Results Until the end of follow-up,74 (17.0 %) patients had hematology adverse reactions.61 (14.02 %) patients had neutropenia,including 9 (14.75 %) patients who had level Ⅲ-Ⅳ neutropenia.60 (13.79 %) cases had thrombocytopenia including 11 (18.33 %) patients with level Ⅲ-Ⅳ thrombocytopenia.Anemia occurred in 50 (11.49 %) patients,of whom 5 (10.00 %) cases were grade Ⅲ-Ⅳ anemia.33 (7.59 %) cases experienced pancytopenia.The incidence of hematology adverse reactions was influenced by nine factors,including the course before treatment,the size of spleen,Sokal scores,the use of interferon,fusion genes,chromosomes,complete cytogenetic response,main molecular reaction and Karnofsky scores (all P < 0.05),while it was not influenced by age,gender,BMI,smoking and drinking (all P > 0.05).Conclusions During the initial treatment of CML-CP,if patients experienced level Ⅰ-Ⅱ hematology adverse reactions,they can continue to taking IM.However,when level Ⅲ-Ⅳ hematology adverse reactions happened,they need to reduce the dose or stop taking,and one month later,hemocyte will get well.In the long-term treatment of CML,once level Ⅲ-Ⅳ hematology adverse reactions occur,the patients need to receive some related inspections,such as bone marrow morphology and molecular biology detection,to clear the disease stage.When it is necessary,the patients can take the second generation of tyrosine kinase inhibitors.%目的 探讨甲磺酸伊马替尼(IM)治疗慢性粒细胞白血病(CML)慢性期

  19. Monitoring of plasma concentration of imatinib mesylate in patients with chronic myeloid leukemia%甲磺酸伊马替尼治疗慢性髓系白血病的临床研究及血药浓度监测

    Institute of Scientific and Technical Information of China (English)

    陈晨; 王文; 徐从高; 侯明; 王鲁群; 刘传方; 宋强; 纪春岩

    2011-01-01

    Objective To analyze the clinical efficacy of imatinib mesylate (IM) for Ph-positive or BCR-ABL positive chronic myeloid leukemia( CML) to couple the trough plasma concentrations(Cmins) of IM with clinical responses and adverse events (AEs).Methods One hundred and one CML patients received IM therapy, and Cmins of IM were determmined in 30 patients.Results ①Cumulative complete hematological response( CHR) , major cytogenetic response ( MCyR ), complete cytogenetic response ( CCyR ) and negative BCR/ABL fusion gene rates were 96.6% , 86.5% ,77.5% and 47.2% , respectively, in CMLCP patients.In accelerated and blastic phases(AP and BC) patients, CHR, MCyR, CCyR and negative BCR-ABL fusion gene rates were 58.3% , 25.0% , 25.0% , 8.3%, respectively.②Mean Cmins of IM was significantly higher in the CCyR at 1 year[( 1472 ±482) μg/L]group than in the non-CCyR at 1 years group[(1067 ±373)μg/L](P<0.05), and higher in the MMR at 1 year group than in the non-MMR at 1 years group[( 1624 ±468) μg/L as (1137 ±404) μg/L, P <0.05].Conclusion IM significantly improves cytogenetic and molecular response, envent-free survival, and overall survival for patients with Ph-positive CML.The Cmins of IM exerts a significant impact on clinical response (CCyR and MMR at 1 year).%目的 观察甲磺酸伊马替尼(IM)治疗慢性髓系白血病(CML)的疗效,并分析血浆药物谷浓度水平与临床疗效及不良反应的关系.方法 观察101例CML患者接受IM治疗的疗效,并采用液相色谱-串联质谱法检测其中30例CML-慢性期(CP)患者IM血浆药物谷浓度.结果 ①89例CML-CP患者总的完全血液学缓解率(CHR)、主要细胞遗传学缓解率(MCyR)、完全细胞遗传学缓解率(CCyR)和BCR-ABL融合基因转阴率分别为96.6%、86.5%、77.5%和47.2%;12例CML进展期(加速期和急变期)患者的CHR、MCyR、CCyR、BCR-ABL转阴率分别为58.3%、25.0%、25.0%、8.3%.②服用IM 1年时获得CCyR患者

  20. Assessment of Drug Sensitivity in Hematopoietic Stem and Progenitor Cells From Acute Myelogenous Leukemia and Myelodysplastic Syndrome Ex Vivo.

    Science.gov (United States)

    Knorr, Katherine L B; Finn, Laura E; Smith, B Douglas; Hess, Allan D; Foran, James M; Karp, Judith E; Kaufmann, Scott H

    2016-11-07

    : Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples. Utilizing a multicolor flow cytometry antibody panel for identification of hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, granulocyte-monocyte progenitors, and megakaryocyte-erythroid progenitors present in mononuclear cell fractions isolated from bone marrow aspirates, we compare stem and progenitor cell counts after treatment for 24 hours with drug versus diluent. We demonstrate that MLN4924 exerts a cytotoxic effect on MDS and AML stem and progenitor cell populations, whereas cytarabine has more limited effects. Further application of this method for evaluating drug effects on these populations ex vivo and in vivo may inform rational design and selection of therapies in the clinical setting.

  1. A new disposable electrode for electrochemical study of leukemia K562 cells and anticancer drug sensitivity test.

    Science.gov (United States)

    Yu, Chunmei; Zhu, Zhenkun; Wang, Li; Wang, Qiuhong; Bao, Ning; Gu, Haiying

    2014-03-15

    Developing cost-effective and simple analysis tools is of vital importance for practical applications in bioanalysis. In this work, a new disposable electrochemical cell sensor with low cost and simple fabrication was proposed to study the electrochemical behavior of leukemia K562 cells and the effect of anticancer drugs on cell viability. The analytical device was integrated by using ITO glass as the substrate of working electrodes and paper as the electrolytic cell. The cyclic voltammetry of the K562 cells at the disposable electrode exhibited an irreversible anodic peak and the peak current is proportional to the cell number. This anodic peak is attributed to the oxidation of guanine in cells involving two protons per transfer of two electrons. For the drug sensitivity tests, arsenic trioxide and cyclophosphamide were added to cell culture media. As a result, the electrochemical responses of the K562 cells decreased significantly. The cytotoxicity curves and results obtained corresponded well with the results of CCK-8 assays. In comparison to conventional methods, the proposed method is simple, rapid and inexpensive. More importantly, the developed sensor is supposed to be a single-use disposable device and electrodes were prepared "as new" for each experiment. We think that such disposable electrodes with these characteristics are suitable for experimental study with cancer cells or other types of pathogens for disease diagnosis, drug selection and on-site monitoring.

  2. Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia.

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    Tada, Kohei; Kobayashi, Masayuki; Takiuchi, Yoko; Iwai, Fumie; Sakamoto, Takashi; Nagata, Kayoko; Shinohara, Masanobu; Io, Katsuhiro; Shirakawa, Kotaro; Hishizawa, Masakatsu; Shindo, Keisuke; Kadowaki, Norimitsu; Hirota, Kouji; Yamamoto, Junpei; Iwai, Shigenori; Sasanuma, Hiroyuki; Takeda, Shunichi; Takaori-Kondo, Akifumi

    2015-04-01

    Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chromosomal DNA of ATL cells. DSBs persisted over time in ATL cells but not in other cell lines, suggesting impaired DNA repair. We found that the reduced expression of tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme, is attributable to the cytotoxic effect of abacavir on ATL cells. We also showed that TDP1 removes abacavir from DNA ends in vitro. These results suggest a model in which ATL cells with reduced TDP1 expression are unable to excise abacavir incorporated into genomic DNA, leading to irreparable DSBs. On the basis of the above mechanism, we propose abacavir as a promising chemotherapeutic agent for ATL.

  3. Chronic myeloid leukemia in case of Klinefelter syndrome

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    Vasundhara Chennuri

    2014-01-01

    Full Text Available Klinefelter syndrome (KS is a sex chromosome disorder and has been reported to be associated with increased risk for malignancies. We report a 22-year-old male patient who was diagnosed to have chronic myeloid leukemia in chronic phase. Bone marrow cytogenetic examination revealed karyotype 47, XXY, t (9; 22(q34, q11 suggestive of KS with presence of Philadelphia chromosome. The patient was treated with oral imatinib mesylate (400 mg/day. Complete hematological response was achieved after 2 months of therapy. The bcr-abl/abl transcript percentage measured from peripheral blood at baseline, 1 and 2 years after imatinib were 97%, 1.99%, 0.007%, respectively. He remains in complete hematological and major molecular remission after 2 years of continued imatinib therapy.

  4. Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

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    Ottmann, Oliver G; Wassmann, Barbara

    2005-01-01

    Philadelphia chromosome positive (Ph(+)) acute lymphoblastic leukemia (ALL) includes at least one-quarter of all adults with ALL. Until recently, conventional chemotherapy programs that have been effective in other precursor B-cell ALL cases have been unable to cure patients with this diagnosis. Allogeneic stem cell transplantation early in first remission has been the recommended therapy. The availability of imatinib mesylate and other tyrosine kinase inhibitors and small molecules that affect the BCR/ABL signaling pathways may be changing the treatment paradigm and the prognosis for these patients. The results from clinical trials using imatinib in the frontline setting and in relapsed patients as well as preliminary experience treating imatinib-resistant Ph(+) ALL will be described.

  5. Multiple drug resistance protein (MDR-1, multidrug resistance-related protein (MRP and lung resistance protein (LRP gene expression in childhood acute lymphoblastic leukemia

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    Elvis Terci Valera

    Full Text Available CONTEXT: Despite the advances in the cure rate for acute lymphoblastic leukemia, approximately 25% of affected children suffer relapses. Expression of genes for the multiple drug resistance protein (MDR-1, multidrug resistance-related protein (MRP, and lung resistance protein (LRP may confer the phenotype of resistance to the treatment of neoplasias. OBJECTIVE: To analyze the expression of the MDR-1, MRP and LRP genes in children with a diagnosis of acute lymphoblastic leukemia via the semiquantitative reverse transcription polymerase chain reaction (RT-PCR, and to determine the correlation between expression and event-free survival and clinical and laboratory variables. DESIGN: A retrospective clinical study. SETTING: Laboratory of Pediatric Oncology, Department of Pediatrics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil. METHODS: Bone marrow aspirates from 30 children with a diagnosis of acute lymphoblastic leukemia were assessed for the expression of messenger RNA for the MDR-1, MRP and LRP genes by semi-quantitative RT-PCR. RESULTS: In the three groups studied, only the increased expression of LRP was related to worsened event-free survival (p = 0.005. The presence of the common acute lymphoblastic leukemia antigen (CALLA was correlated with increased LRP expression (p = 0.009 and increased risk of relapse or death (p = 0.05. The relative risk of relapse or death was six times higher among children with high LRP expression upon diagnosis (p = 0.05, as confirmed by multivariate analysis of the three genes studied (p = 0.035. DISCUSSION: Cell resistance to drugs is a determinant of the response to chemotherapy and its detection via RT-PCR may be of clinical importance. CONCLUSIONS: Evaluation of the expression of genes for resistance to antineoplastic drugs in childhood acute lymphoblastic leukemia upon diagnosis, and particularly the expression of the LRP gene, may be of clinical relevance, and should be the

  6. Imatinib treatment causes substantial transcriptional changes in adult Schistosoma mansoni in vitro exhibiting pleiotropic effects.

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    Christin Buro

    2014-06-01

    Full Text Available BACKGROUND: Schistosome parasites cause schistosomiasis, one of the most important infectious diseases worldwide. For decades Praziquantel (PZQ is the only drug widely used for controlling schistosomiasis. The absence of a vaccine and fear of PZQ resistance have motivated the search for alternatives. Studies on protein kinases (PKs demonstrated their importance for diverse physiological processes in schistosomes. Among others two Abl tyrosine kinases, SmAbl1 and SmAbl2, were identified in Schistosoma mansoni and shown to be transcribed in the gonads and the gastrodermis. SmAbl1 activity was blocked by Imatinib, a known Abl-TK inhibitor used in human cancer therapy (Gleevec/Glivec. Imatinib exhibited dramatic effects on the morphology and physiology of adult schistosomes in vitro causing the death of the parasites. METHODOLOGY/PRINCIPAL FINDINGS: Here we show modeling data supporting the targeting of SmAbl1/2 by Imatinib. A biochemical assay confirmed that SmAbl2 activity is also inhibited by Imatinib. Microarray analyses and qRT-PCR experiments were done to unravel transcriptional processes influenced by Imatinib in adult schistosomes in vitro demonstrating a wide influence on worm physiology. Surface-, muscle-, gut and gonad-associated processes were affected as evidenced by the differential transcription of e.g. the gynecophoral canal protein gene GCP, paramyosin, titin, hemoglobinase, and cathepsins. Furthermore, transcript levels of VAL-7 and egg formation-associated genes such as tyrosinase 1, p14, and fs800-like were affected as well as those of signaling genes including a ribosomal protein S6 kinase and a glutamate receptor. Finally, a comparative in silico analysis of the obtained microarray data sets and previous data analyzing the effect of a TGFβR1 inhibitor on transcription provided first evidence for an association of TGFβ and Abl kinase signaling. Among others GCP and egg formation-associated genes were identified as common

  7. Mathematical modeling of genesis and treatment of chronic myeloid leukemia.

    Science.gov (United States)

    Horn, Matthias; Loeffler, Markus; Roeder, Ingo

    2008-01-01

    Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder induced by translocation of chromosomes 9 and 22, resulting in an overproduction of myeloid blood cells. CML-specific characteristics include a latency time of several years, a period of coexistence of malignant and normal cells and an eventual dominance of the malignant clone. Different drug therapies are available, most notably imatinib, which inhibits the oncogenic BCR-ABL1 tyrosine kinase. Although the chromosomal aberration causing CML is well known, the resulting dynamic effects on the system behavior are not sufficiently understood yet. Here, we apply an already established mathematical model of hematopoietic stem cell organization. Based on parameter estimates for normal hematopoiesis, we systematically explore the changes in these parameters necessary to reproduce CML-specific characteristics regarding emergence and course of disease as well as a variety of qualitative and quantitative clinical data on CML treatment. Our results indicate that 1 or more of the following mechanisms are compatible with the induction of a dominant clone in the proposed model: a retarded differentiation process, a reduced turnover time or a defective cell-microenvironment interaction of the neoplastic cells. However, in order to explain the massive overproduction of malignant cells, an unregulated and abnormal activation of leukemia stem cells into cycle has to be assumed additionally. Based on our simulation results we conclude that CML dynamics can most appropriately be explained by a modulation of the cell-microenvironment interactions of leukemia stem cells, including both the process of stem cell silencing and activation into cycle.

  8. The Effect of Apigenin on Pharmacokinetics of Imatinib and Its Metabolite N-Desmethyl Imatinib in Rats

    Directory of Open Access Journals (Sweden)

    Xian-yun Liu

    2013-01-01

    Full Text Available The purpose of this study was to determine the effect of apigenin on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Healthy male SD rats were randomly divided into four groups: A group (the control group, B group (the long-term administration of 165 mg/kg apigenin for 15 days, C group (a single dose of 165 mg/kg apigenin, and D group (a single dose of 252 mg/kg apigenin. The serum concentrations of imatinib and N-desmethyl imatinib were measured by HPLC, and pharmacokinetic parameters were calculated using DAS 3.0 software. The parameters of AUC(0-t, AUC(0−∞, Tmax, Vz/F, and CLz/F for imatinib in group B were different from those in group A (P<0.05. Besides, MRT(0−t and MRT(0−∞ in groups C and D differed distinctly from those in group A as well. The parameters of AUC(0-t and Cmax for N-desmethyl imatinib in group C were significantly lower than those in group A (P<0.05; however, compared with groups B and D, the magnitude of effect was modest. Those results indicated that apigenin in the short-term study inhibited the metabolism of imatinib and its metabolite N-desmethyl imatinib, while in the long-term study the metabolism could be accelerated.

  9. [The idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia].

    Science.gov (United States)

    Chrobák, L; Voglová, J

    2005-12-01

    Idiopathic hypereosinophilic syndrome is a heterogenous group of hematological disorders characterized by eosinophilia (> 1.5 x 10(9)/l) persistent for more than 6 months, exclusion of reactive eosinophilia from other causes, such as parasitic infections or allergy, and evidence of end-organ damage. According to World Health Organization the exclusion includes all neoplastic disorders in which eosinophils are part of the neoplastic clone. Excluded should be also T cell population with aberant phenotype and abnormal cytokine production, recently considert also as "lymphocytic" variants of the HES [42]. HES has to be reclassified as chronic eosinophilic leukemia (CEL) when there is evidence for clonality based on the presence of chromosomal abnormalities or inactivation of X-chromosome in female patients. The successful empiric treatment of patients with tyrosine kinase inhibitor imatinib (Glivec) suggested the presence of an imatinib-sensitive tyrosine kinase inhibitor. The identification of a specific intersticial chromosome deletion del(4)(q12;q12) creating the FIP1L1-PDGFRA fusion gene confirmed this hypothesis. Patients carrying this gene should be reclassified as CEL and detection of this gene is a positive predictor for response to imatinib therapy. Effective doses of imatinib are 100 mg/day. The side effects are minimal. The only exception is an acute left ventricular dysfunction which has been reported in three patients within the first week of treatment with imatinib. Imatinib has been successfully used also in some patients with the constitutively activated thyrosine kinase ETV6-PDGFRbeta [1] and in systemic mast cell disease associated with eosinophilia. Other therapeutical options for HES/CEL have been mentioned. The resistence to imatinib and the possibilities how to overcome it are discussed.

  10. Chronic myelocytic leukemia in pregnancy: a case report describing successful treatment using multimodal therapy.

    Science.gov (United States)

    Eskander, Ramez N; Tarsa, Maryam; Herbst, Kenneth D; Kelly, Thomas F

    2011-11-01

    Leukemia during pregnancy is rare, posing a complex series of questions, including appropriate therapy and maternal counseling. Management of chronic myelocytic leukemia (CML) during pregnancy is limited. Our patient presented at 30 weeks' gestation with anemia, leukocytosis, and a non-productive cough. Polymerase chain reaction performed on a peripheral blood sample confirmed presence of the breakpoint cluster region-Abl1 chromosomal translocation and the diagnosis of CML. Therapy included acute leukocytapheresis, followed by α-interferon and imatinib mesylate. The patient responded to treatment and delivered a viable female infant at term weighing 2613 g. Continued imatinib mesylate chemotherapy post-delivery resulted in complete clinical remission. Successful antepartum management of newly diagnosed CML is possible utilizing leukocytapheresis, α-interferon and, more recently, imatinib mesylate. Definitive treatment should not be delayed due to pregnancy.

  11. Redox modulation of adjacent thiols in VLA-4 by AS101 converts myeloid leukemia cells from a drug-resistant to drug-sensitive state.

    Science.gov (United States)

    Layani-Bazar, Adi; Skornick, Itai; Berrebi, Alain; Pauker, Maor H; Noy, Elad; Silberman, Alon; Albeck, Michael; Longo, Dan L; Kalechman, Yona; Sredni, Benjamin

    2014-06-01

    Interaction between the integrin VLA-4 on acute myelogenous leukemia (AML) cells with stromal fibronectin is a decisive factor in chemotherapeutic resistance. In this study, we provide a rationale for a drug repositioning strategy to blunt integrin activation in AML cells and restore their sensitivity to chemotherapy. Specifically, we demonstrate that the nontoxic tellurium compound AS101, currently being evaluated in clinical trials, can abrogate the acquired resistance of AML. Mechanistic investigations revealed that AS101 caused redox inactivation of adjacent thiols in the exofacial domain of VLA-4 after its ligation to stromal fibronectin. This effect triggered cytoskeletal conformational changes that decreased PI3K/Akt/Bcl2 signaling, an obligatory step in chemosensitization by AS101. In a mouse xenograft of AML derived from patient leukemic cells with high VLA-4 expression and activity, we demonstrated that AS101 abrogated drug resistance and prolonged survival in mice receiving chemotherapy. Decreased integrin activity was confirmed on AML cells in vivo. The chemosensitizing activity of AS101 persisted in hosts with defective adaptive and innate immunity, consistent with evidence that integrin deactivation was not mediated by heightening immune attack. Our findings provide a mechanistic rationale to reposition the experimental clinical agent, AS101, to degrade VLA-4-mediated chemoresistance and improve clinical responses in patients with AML.

  12. Chaetominine reduces MRP1-mediated drug resistance via inhibiting PI3K/Akt/Nrf2 signaling pathway in K562/Adr human leukemia cells

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    Yao, Jingyun; Wei, Xing [State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai (China); Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai (China); Lu, Yanhua, E-mail: luyanhua@ecust.edu.cn [State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai (China); Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai (China)

    2016-05-13

    Drug resistance limits leukemia treatment and chaetominine, a cytotoxic alkaloid that promotes apoptosis in a K562 human leukemia cell line via the mitochondrial pathway was studied with respect to chemoresistance in a K562/Adr human resistant leukemia cell line. Cytotoxicity assays indicated that K562/Adr resistance to adriamycin (ADR) did not occur in the presence of chaetominine and that chaetominine increased chemosensitivity of K562/Adr to ADR. Data show that chaetominine enhanced ADR-induced apoptosis and intracellular ADR accumulation in K562/Adr cells. Accordingly, chaetominine induced apoptosis by upregulating ROS, pro-apoptotic Bax and downregulating anti-apoptotic Bcl-2. RT-PCR and western-blot confirmed that chaetominine suppressed highly expressed MRP1 at mRNA and protein levels. But little obvious alternation of another drug transporter MDR1 mRNA was observed. Furthermore, inhibition of MRP1 by chaetominine relied on inhibiting Akt phosphorylation and nuclear Nrf2. In summary, chaetominine strongly reverses drug resistance by interfering with the PI3K/Akt/Nrf2 signaling, resulting in reduction of MRP1-mediated drug efflux and induction of Bax/Bcl-2-dependent apoptosis in an ADR-resistant K562/Adr leukemia cell line. - Highlights: • Chaetominine enhanced chemosensitivity of ADR against K562/Adr cells. • Chaetominine increased intracellular ADR levels via inhibiting MRP1. • Chaetominine induced apoptosis of K562/Adr cells through upregulation of ROS and modulation of Bax/Bcl-2. • Inhibition of MRP1 and Nrf2 by chaetominine treatment was correlative with blockade of PI3K/Akt signaling.

  13. Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in pregnancy.

    Science.gov (United States)

    Mainor, Candace B; Duffy, Alison P; Atkins, Kristin L; Kimball, Amy S; Baer, Maria R

    2016-04-01

    BCR-ABL inhibitors administered in conjunction with chemotherapy have significantly improved outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia but, for patients diagnosed during pregnancy, data on risks to the fetus are limited. We report a woman treated with chemotherapy and imatinib mesylate who delivered a healthy baby at 30 weeks, and we discuss available data.

  14. Impact of age, leukocyte count and day 21-bone marrow response to chemotherapy on the long-term outcome of children with philadelphia chromosome-positive acute lymphoblastic leukemia in the pre-imatinib era: results of the FRALLE 93 study

    Directory of Open Access Journals (Sweden)

    Debre Marianne

    2009-01-01

    Full Text Available Abstract Background We explored the heterogeneity of philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL in a study of the effect of early features on prognosis in children. Here we report the long-term results of the FRALLE 93 study conducted in the era before the use of tyrosine kinase inhibitors. Methods Between 1993 and 1999, 36 children with Ph1-ALL were enrolled into the FRALLE 93 protocol. After conventional four-drug induction, children were stratified by availability of an HLA-matched sibling. Results Complete remission (CR was observed in 26 children (72%, of which 13 underwent allogeneic bone marrow transplantation (BMT. Thirty-one children were good responders to prednisone, defined on day 8, and 21 were good responders to chemotherapy, defined by day-21 bone marrow (M1. Overall five-year disease-free survival (DFS was 42 ± 9.7%. Based on multivariate analysis, two groups showed marked differences in five-year outcome: children with age3 and day-21 M1 marrow had a more favorable prognosis (14 pts: 100% CR, event free survival [EFS]: 57%, overall survival [OS]: 79%, than the high-risk group (22 patients: 55% CR, EFS: 18%, OS: 27% (p Conclusion Age, leukocyte count and early response to treatment defined by the D21 bone marrow response provide an accurate model for outcome prediction. The combination of available tools such as minimal residual disease assessment with determination of these simple factors could be useful for refining indications for BMT in the current era of tyrosine-kinase inhibitor-based therapy.

  15. Enhancing in vivo Bioavailability in Beagle Dogs of GLM-7 as a Novel Anti-Leukemia Drug through a Self-Emulsifying Drug Delivery System for Oral Delivery.

    Science.gov (United States)

    Wang, Yuli; Yu, Ning; Guo, Rui; Yang, Meiyan; Shan, Li; Huang, Wei; Gong, Wei; Shao, Shuai; Chen, Xiaoping; Gao, Chunsheng

    2016-01-01

    GLM-7 is a novel anti-leukemia drug in the pre-clinical study. The previous study shows that GLM-7 is a poorly water-soluble drug with low oral bioavailability. In this study, we employed the self-emulsifying drug delivery system (SEDDS) to improve the oral bioavailability of GLM-7. The GLM-7 SEDDS formulation was prepared using MCT as oil, ovolecithin as surfactant and Transcutol as co-surfactant, and the formulation parameters were optimized by the response surface methodology. The optimized GLM-7 SEDDS formulation showed a stable liquid state, and can automatically emulsify to form the isotropic emulsion once exposure to the water phase. The generated emulsion showed the spherical shape, and had an average size of about 399 nm and a zeta potential of about -42 mV. Compared to the GLM-7 dissolution less than 1.4% from pure GLM-7 powder (reference), the GLM-7 SEDDS formulation could remarkably enhance the in vitro dissolution to 83% in the medium of 0.1N HCL. The in vivo oral bioavailability of GLM-7 SEDDS formulation was investigated in beagle dogs. The results demonstrated that the GLM-7 SEDDS formulation significantly enhanced the plasma concentrations of GLM-7, and the Cmax reached to 878 ng/ml and was 9.2 folds as high as the Cmax 95.85 ng/ml of reference. Moreover, the area under the curve (AUC) of GLM-7 SEDDS formulation was 13.6 times higher than that of reference, which suggested that the SEDDS formulation remarkably increased the oral bioavailability of GLM-7.

  16. BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: using guidelines to make rational treatment choices.

    Science.gov (United States)

    Kantarjian, Hagop; Cortes, Jorge

    2008-03-01

    The success of the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib in improving prognosis in chronic myeloid leukemia (CML) has led to its wide use as first-line therapy at a standard dose of 400 mg daily. As more patients have undergone therapy, the development of molecular and clinical resistance to imatinib has raised further therapeutic challenges. The 2 main approaches to overcoming resistance are imatinib dose escalation and the use of alternative more potent TKIs, such as dasatinib or nilotinib. The phase II SRC/ABL Tyrosine Kinase Inhibition Activity Research Trials (START) of dasatinib have established dasatinib as potent and effective in overcoming imatinib resistance or intolerance in all phases of CML. The most recent treatment guidelines by the National Comprehensive Cancer Network now contain recommendations for using dasatinib in this setting. The issue of when to change from imatinib to an alternative agent in preference to imatinib dose escalation is keenly debated, particularly as new clinical evidence emerges, which highlights the importance of achieving early cytogenetic and molecular responses for a good long-term outcome. Identifying patients in whom a change to dasatinib or nilotinib is more appropriate than imatinib dose escalation is therefore important.

  17. Treatments for chronic myeloid leukemia: a qualitative systematic review

    Directory of Open Access Journals (Sweden)

    Ferdin

    2012-08-01

    Full Text Available Roxanne Ferdinand,1 Stephen A Mitchell,2 Sarah Batson,2 Indra Tumur11Pfizer, Tadworth, UK; 2Abacus International, Bicester, UKBackground: Chronic myeloid leukemia (CML is a myeloproliferative disorder of blood stem cells. The tyrosine kinase inhibitor (TKI imatinib was the first targeted therapy licensed for patients with chronic-phase CML, and its introduction was associated with substantial improvements in response and survival compared with previous therapies. Clinical trial data are now available for the second-generation TKIs (nilotinib, dasatinib, and bosutinib in the first-, second-, and third-line settings. A qualitative systematic review was conducted to qualitatively compare the clinical effectiveness, safety, and effect on quality of life of TKIs for the management of chronic-, accelerated-, or blast-phase CML patients.Methods: Included studies were identified through a search of electronic databases in September 2011, relevant conference proceedings and the grey literature.Results: In the first-line setting, the long-term efficacy (up to 8 years of imatinib has been confirmed in a single randomized controlled trial (International Randomized Study of Interferon [IRIS]. All second-generation TKIs reported lower rates of transformation, and comparable or superior complete cytogenetic response (CCyR, major molecular response (MMR, and complete molecular response rates compared with imatinib by 2-year follow-up. Each of the second-generation TKIs was associated with a distinct adverse-event profile. Bosutinib was the only second-generation TKI to report quality-of-life data (no significant difference compared with imatinib treatment. Data in the second- and third-line setting confirmed the efficacy of the second-generation TKIs in either imatinib-resistant or -intolerant patients, as measured by CCyR and MMR rates.Conclusion: Data from first-line randomized controlled trials reporting up to 2-year follow-up indicate superior response

  18. Regulation of HtrA2 on WT1 gene expression under imatinib stimulation and its effects on the cell biology of K562 cells.

    Science.gov (United States)

    Zhang, Lixia; Li, Yan; Li, Xiaoyan; Zhang, Qing; Qiu, Shaowei; Zhang, Qi; Wang, Min; Xing, Haiyan; Rao, Qing; Tian, Zheng; Tang, Kejing; Wang, Jianxiang; Mi, Yingchang

    2017-09-01

    The aim of the present study was to investigate the regulation of Wilms Tumor 1 (WT1) by serine protease high-temperature requirement protein A2 (HtrA2), a member of the Htr family, in K562 cells. In addition, the study aimed to observe the effect of this regulation on cell biological functions and its associated mechanisms. Expression of WT1 and HtrA2 mRNA, and proteins following imatinib and the HtrA2 inhibitor 5-[5-(2-nitrophenyl) furfuryl iodine]-1, 3-diphenyl-2-thiobarbituric acid (UCF-101) treatment was detected with reverse transcription-quantitative polymerase chain reaction and western blot analysis. Subsequent to treatment with drugs and UCF-101, the proliferative function of K562 cells was detected using MTT assays, and the rate of apoptosis was detected using Annexin V with propidium iodide flow cytometry in K562 cells. The protein levels in the signaling pathway were analyzed using western blotting following treatment with imatinib and UCF-101. In K562 cells, imatinib treatment activated HtrA2 gene at a transcription level, while the WT1 gene was simultaneously downregulated. Following HtrA2 inhibitor (UCF-101) treatment, the downregulation of WT1 increased gradually. At the protein level, imatinib induced the increase in HtrA2 protein level and concomitantly downregulated WT1 protein level. Subsequent to HtrA2 inhibition by UCF-101, the WT1 protein level decreased temporarily, but eventually increased. Imatinib induced apoptosis in K562 cells, but this effect was attenuated by the HtrA2 inhibitor UCF-101, resulting in the upregulation of the WT1 protein level. However; UCF-101 did not markedly change the proliferation inhibition caused by imatinib. Imatinib activated the p38 mitogen activated protein kinase (p38 MAPK) signaling pathway in K562 cells, and UCF-101 affected the activation of imatinib in the p38 MAPK signaling pathway. Imatinib inhibited the extracellular signal-related kinase (ERK1/2) pathway markedly and persistently, but UCF-101

  19. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts

    Science.gov (United States)

    Abboud, Camille; Berman, Ellin; Cohen, Adam; Cortes, Jorge; DeAngelo, Daniel; Deininger, Michael; Devine, Steven; Druker, Brian; Fathi, Amir; Jabbour, Elias; Jagasia, Madan; Kantarjian, Hagop; Khoury, Jean; Laneuville, Pierre; Larson, Richard; Lipton, Jeffrey; Moore, Joseph O.; Mughal, Tariq; O’Brien, Susan; Pinilla-Ibarz, Javier; Quintas-Cardama, Alfonso; Radich, Jerald; Reddy, Vishnu; Schiffer, Charles; Shah, Neil; Shami, Paul; Silver, Richard T.; Snyder, David; Stone, Richard; Talpaz, Moshe; Tefferi, Ayalew; Van Etten, Richard A.; Wetzler, Meir; Abruzzese, Elisabetta; Apperley, Jane; Breccia, Massimo; Byrne, Jenny; Cervantes, Francisco; Chelysheva, Ekaterina; Clark, R. E.; de Lavallade, Hugues; Dyagil, Iryna; Gambacorti-Passerini, Carlo; Goldman, John; Haznedaroglu, Ibrahim; Hjorth-Hansen, Henrik; Holyoake, Tessa; Huntly, Brian; le Coutre, Philipp; Lomaia, Elza; Mahon, Francois-Xavier; Marin-Costa, David; Martinelli, Giovanni; Mayer, Jiri; Milojkovic, Dragana; Olavarria, Eduardo; Porkka, Kimmo; Richter, Johan; Rousselot, Philippe; Saglio, Giuseppe; Saydam, Guray; Stentoft, Jesper; Turkina, Anna; Vigneri, Paolo; Zaritskey, Andrey; Aguayo, Alvaro; Ayala, Manuel; Bendit, Israel; Maria Bengio, Raquel; Best, Carlos; Bullorsky, Eduardo; Cervera, Eduardo; DeSouza, Carmino; Fanilla, Ernesto; Gomez-Almaguer, David; Hamerschlak, Nelson; Lopez, Jose; Magarinos, Alicia; Meillon, Luis; Milone, Jorge; Moiraghi, Beatriz; Pasquini, Ricardo; Pavlovsky, Carolina; Ruiz-Arguelles, Guillermo J.; Spector, Nelson; Arthur, Christopher; Browett, Peter; Grigg, Andrew; Hu, Jianda; Huang, Xiao-jun; Hughes, Tim; Jiang, Qian; Jootar, Saengsuree; Kim, Dong-Wook; Malhotra, Hemant; Malhotra, Pankaj; Matsumura, Itaru; Melo, Junia; Ohnishi, Kazunori; Ohno, Ryuzo; Saikia, Tapan; Schwarer, Anthony P.; Takahashi, Naoto; Tam, Constantine; Tauchi, Tetsuzo; Usuki, Kensuke; Wang, Jianxiang; Abdel-Rahman, Fawzi; Deeb Saeed Aljurf, Mahmoud; Bazarbachi, Ali; Ben Yehuda, Dina; Chaudhri, Naeem; Durosinmi, Muheez; Kamel, Hossam; Louw, Vernon; Francis Matti, Bassam; Nagler, Arnon; Raanani, Pia; Salem, Ziad

    2013-01-01

    As a group of more than 100 experts in chronic myeloid leukemia (CML), we draw attention to the high prices of cancer drugs, with the particular focus on the prices of approved tyrosine kinase inhibitors for the treatment of CML. This editorial addresses the multiple factors involved in cancer drug pricing and their impact on individual patients and health care policies, and argues for the need to (1) lower the prices of cancer drugs to allow more patients to afford them and (2) maintain sound long-term health care policies. PMID:23620577

  20. Imatinib Reverses Doxorubicin Resistance by Affecting Activation of STAT3-Dependent NF-κB and HSP27/p38/AKT Pathways and by Inhibiting ABCB1

    Science.gov (United States)

    Sims, Jonathan T.; Ganguly, Sourik S.; Bennett, Holly; Friend, J. Woodrow; Tepe, Jessica; Plattner, Rina

    2013-01-01

    Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis. PMID:23383209

  1. Systematic in-vitro evaluation of the NCI/NIH Developmental Therapeutics Program Approved Oncology Drug Set for the identification of a candidate drug repertoire for MLL-rearranged leukemia

    Directory of Open Access Journals (Sweden)

    Hoeksema KA

    2011-09-01

    Full Text Available Kimberley A Hoeksema1, Aarthi Jayanthan1, Todd Cooper2, Lia Gore3, Tanya Trippett4, Jessica Boklan6, Robert J Arceci5, Aru Narendran11Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB, Canada; 2Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA; 3Center for Cancer and Blood Disorders, Children's Hospital, University of Colorado Denver, Aurora, CO, USA; 4Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 5Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA; 6Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USAAbstract: Despite significant progress made in the overall cure rate, the prognosis for relapsed and refractory malignancies in children remains extremely poor. Hence, there is an urgent need for studies that enable the timely selection of appropriate agents for Phase I clinical studies. The Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC is systematically evaluating libraries of known and novel compounds for activity against subsets of high-risk pediatric malignancies with defined molecular aberrations for future clinical development. In this report, we describe the in-vitro activity of a diverse panel of approved oncology drugs against MLL-rearranged pediatric leukemia cell lines. Agents in the Approved Oncology Drug Set II (National Cancer Institute/National Institutes of Health Developmental Therapeutics Program were evaluated by in-vitro cytotoxicity assays in pediatric acute lymphoblastic leukemia and acute myeloid leukemia cell lines with MLL gene rearrangements. Validation studies were carried out with patient leukemia cells in culture. Comparative analysis for toxicity against nonmalignant cells was evaluated in normal bone marrow stromal cells and normal human lymphocytes. Results from this study show that 42 of the 89 agents tested have

  2. LAM Pilot Study with Imatinib Mesylate (LAMP-1)

    Science.gov (United States)

    2015-10-01

    AD______________ AWARD NUMBER: W81XWH-14-1-0132 TITLE: LAM Pilot Study with Imatinib Mesylate ( LAMP -1) PRINCIPAL INVESTIGATOR: Charlie...AND SUBTITLE LAM Pilot Study with Imatinib Mesylate ( LAMP -1) 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0132 5c. PROGRAM ELEMENT...AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The LAMP -1 study is

  3. Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Seshadri Ramakrishnan

    2009-01-01

    Full Text Available Aim : To study the role of neoadjuvant imatinib mesylate in downsizing tumors in patients with locally advanced nonmetastatic gastrointestinal stromal tumors (GISTs, thus improving the possibility of complete resection. Materials and Methods : We used neoadjuvant imatinib in six patients with locally advanced GISTs, at a dose of 400 mg daily, given orally in all patients for a median period of 3.5 months (range 1-20 months. All patients had a computerized tomography scan (CT scan once before starting the treatment and a repeat CT scan 1 month after starting imatinib. Some patients had another CT scan done at 3 months. The tumor volume was calculated using the formula V=4/3 πr 3 . Results : Following imatinib therapy, the median reduction in the tumor volume was 40% (range 20-50%. Four of the six patients underwent successful complete resection of the tumor following neoadjuvant imatinib for a median period of 2 months, and are disease free after a median follow-up of 10.5 months (range 3-20 months. Two patients in whom the tumors were deemed to be operable after downsizing refused surgery and are continuing imatinib. Imatinib did not produce serious toxicity in any patient. Conclusion : Neoadjuvant imatinib can be used successfully in patients with locally advanced nonmetastatic GISTs to improve the rates of complete resection and reduce the chance of tumor spill. The optimal duration of neoadjuvant treatment needs to be tailored based on response assessment at frequent intervals to identify the ideal window period for surgery.

  4. Increased financial burden among patients with chronic myelogenous leukaemia receiving imatinib in Japan: a retrospective survey

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    Kodama Yuko

    2012-04-01

    Full Text Available Abstract Background The financial burden of medical expenses has been increasing for cancer patients. We investigated the relationship between household income and financial burden among patients with chronic myelogenous leukaemia (CML who have been treated with imatinib. Methods A questionnaire was distributed to 1200 patients between May and August 2009. We retrospectively surveyed their household incomes, out-of-pocket medical expenses, final co-payments after refunds, and the perceived financial burden of their medical expenses in 2000, 2005 and 2008. Results A total of 577 patients completed the questionnaire. Their median age was 61 years (range, 15–94. A financial burden was felt by 41.2 % (28 of 68 of the patients treated with imatinib in 2000, 70.8 % (201 of 284 in 2005, and 75.8 % (400 of 528 in 2008. Overall, 182 patients (31.7 % considered its discontinuation because of the financial burden and 15 (2.6 % temporarily stopped their imatinib prescription. In 2000, 2005 and 2008, the patients’ median annual household incomes were 49,615 US Dollars (USD, 38,510 USD and 36,731 USD, respectively, with an average currency exchange rate of 104 Yen/USD in 2008. Their median annual out-of-pocket expenses were 11,548, 12,067 and 11,538 USD and their median final annual co-payments were 4,375, 4,327 and 3,558 USD, respectively. Older patients (OR = 0.96, 95 % CI: 0.95–0.98, p ≪ 0.0001 for 1-year increments, and patients with higher household incomes (OR = 0.92, 95 % CI: 0.85–0.99, p = 0.03 for 10,000 USD-increments were less likely to have considered discontinuing their imatinib treatment. Conversely, patients with higher annual final co-payments (OR = 2.21, 95 % CI: 1.28–4.28, p = 0.004 for 10,000 USD-increments were more likely to have considered discontinuing their imatinib treatment. Conclusions The proportion of CML patients who sensed a financial burden increased between 2000 and 2008

  5. Serum α1-acid glycoprotein, imatinib concentration and efficacy in chronic myeloid leukemia patients%慢性粒细胞白血病患者血清α1-酸性糖蛋白、伊马替尼浓度与疗效关系

    Institute of Scientific and Technical Information of China (English)

    钟健生; 孟凡义; 徐丹; 戴敏; 魏永强; 周红升

    2011-01-01

    目的 研究慢性粒细胞白血病(CML)患者血清α1-酸性糖蛋白(AGP)的水平与CML病情发展、伊马替尼血浆谷浓度和疗效的关系.方法 2008年8月至2010年2月南方医科大学南方医院血液科112例CML患者,其中男72例,女40例,中位年龄39(6~76)岁;慢性期102例,加速期4例,急性变期6例.有99例给予伊马替尼治疗,13例给予羟基脲治疗,20例健康献血者作为对照组,采用免疫比浊法检测AGP.有12例患者分别在伊马替尼治疗前和治疗后3个月同时检测AGP和伊马替尼浓度.84例应用伊马替尼治疗的患者同时采用高效液相色谱-质谱联用法检测伊马替尼血浆谷浓度.按疗效分组评价AGP水平的意义及其与伊马替尼浓度的关系.结果 未缓解(NR)组血清AGP水平[(1.18±0.26)g/L]显著高于完全细胞遗传学缓解(CCR)组、完全血液学缓解(CHR)组及对照组[(0.60±0.21)、( 0.71±0.17)、(0.52±0.15) g/L,均P0.05).NR组与复发组及加速急变期组差异均无统计学意义(均P>0.05).12例患者在伊马替尼治疗后第3个月时AGP水平低于治疗前[(0.54±0.17)g/L 比(0.83±0.31)g/L,P0.05). There were no significant differences between NR, relapse or accelerated/blastic phase group (P>0.05). The serum AGP of 12 patients on a 3-month therapy of imatinib were lower than that of patients at pre-treatment [(0.54±0.17)g/L vs(0.83±0.31)g/L,P<0.01]. The plasma trough concentration of imatinib was (1307± 586) μg/L (range: 109-3400 μg/L) in 84 patients. And it was positively correlated with the serum level of AGP (r=0.443, P<0.01).Conclusion The serum level of AGP can reflect the in vivo loads of leukemic cells for CML patients. There is a positive correlation between the serum level of AGP and the plasma trough concentration of imatinib. Serum AGP can be used as a monitoring index of efficacy for CML patients.

  6. Oridonin Triggers Chaperon-mediated Proteasomal Degradation of BCR-ABL in Leukemia

    Science.gov (United States)

    Huang, Huilin; Weng, Hengyou; Dong, Bowen; Zhao, Panpan; Zhou, Hui; Qu, Lianghu

    2017-01-01

    Inducing degradation of oncoproteins by small molecule compounds has the potential to avoid drug resistance and therefore deserves to be exploited for new therapies. Oridonin is a natural compound with promising antitumor efficacy that can trigger the degradation of oncoproteins; however, the direct cellular targets and underlying mechanisms remain unclear. Here we report that oridonin depletes BCR-ABL through chaperon-mediated proteasomal degradation in leukemia. Mechanistically, oridonin poses oxidative stress in cancer cells and directly binds to cysteines of HSF1, leading to the activation of this master regulator of the chaperone system. The resulting induction of HSP70 and ubiquitin proteins and the enhanced binding to CHIP E3 ligase hence target BCR-ABL for ubiquitin-proteasome degradation. Both wild-type and mutant forms of BCR-ABL can be efficiently degraded by oridonin, supporting its efficacy observed in cultured cells as well as mouse tumor xenograft assays with either imatinib-sensitive or -resistant cells. Collectively, our results identify a novel mechanism by which oridonin induces rapid degradation of BCR-ABL as well as a novel pharmaceutical activator of HSF1 that represents a promising treatment for leukemia. PMID:28128329

  7. Update on the management of Philadelphia chromosome positive chronic myelogenous leukemia: role of nilotinib

    Directory of Open Access Journals (Sweden)

    Emole J

    2016-02-01

    Full Text Available Josephine Emole,1 Taiwo Talabi,2 Javier Pinilla-Ibarz1 1Department of Malignant Hematology, 2Moffitt Program for Outreach Wellness Education and Resources, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Abstract: Chronic myelogenous leukemia (CML is a pluripotent stem cell disease characterized by the presence of the Philadelphia chromosome and the bcr-abl gene. The discovery of tyrosine kinase inhibitors (TKIs revolutionized therapy for CML, such that durable response, increased overall survival, and increased progression-free survival of patients in chronic phase CML is now possible. Due to resistance and intolerance to imatinib, there was need for development of second- and third-generation TKIs for the treatment of CML. This review examines the role of nilotinib, an oral second-generation TKI, in the treatment of Philadelphia positive CML. The pharmacology, efficacy, and safety of nilotinib are critically evaluated. Patient-related issues, including tolerance, drug interactions, and quality of life issues are also examined. Keywords: chronic myelogenous leukemia, nilotinib, tyrosine kinase inhibitor

  8. Antioxidant activity and cytotoxicity of Cyrtosperma johnstonii extracts on drug sensitive and resistant leukemia and small cell lung carcinoma cells.

    Science.gov (United States)

    Okonogi, Siriporn; Khonkarn, Ruttiros; Mankhetkorn, Samlee; Unger, Frank M; Viernstein, Helmut

    2013-03-01

    The number of patients with cancer is increasing. New therapeutic agents to overcome drug-resistant tumors are urgently needed. Cyrtosperma johnstonii N.E. Br. (Araceae) is used for treatment of cancer in Thai traditional medicine. This study aimed to evaluate antioxidant activity and cytotoxicity of C. johnstonii extracts on human cancer cells. Dried powder of C. johnstonii rhizomes was extracted with several solvents. The 0.1 mg/ml extract solution was tested for antioxidant activity by 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and ferric reducing antioxidant power (FRAP) assays. Color formation from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to determine cell viability. Standardization of the extract was performed by high-performance liquid chromatography (HPLC) with photodiode array detector at 254 and 360 nm. Cell cycle arrest was evaluated by flow cytometry after 5 min, 12 h and 24 h treated with 20 µg/ml of the acetone extract. The acetone extract exhibited the highest phenolic content and antioxidant activity (TEAC and EC values = 19.2 ± 0.14 and 19.2 ± 0.31 mM/mg, respectively). The IC₅₀ values for leukemia ranged from 11 ± 1 to 29 ± 3 µg/ml and from 5 ± 2 to 6 ± 0 µg/ml for small cell lung carcinoma cells. Cell cycle arrest occurred at the G2/M phase followed by apoptosis. HPLC analysis revealed that rutin is the major constituents of the extract. The acetone extract of C. johnstoni is a promising source of natural antioxidants and anticancer. The extract inhibits cancer cells effectively with less effect on normal cells.

  9. A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia.

    Science.gov (United States)

    Tong, Wing H; Pieters, Rob; Kaspers, Gertjan J L; te Loo, D Maroeska W M; Bierings, Marc B; van den Bos, Cor; Kollen, Wouter J W; Hop, Wim C J; Lanvers-Kaminsky, Claudia; Relling, Mary V; Tissing, Wim J E; van der Sluis, Inge M

    2014-03-27

    This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m(2) every 2 weeks) in intensification after receiving native E coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m(2) 2-3 times weekly) was given. Eighty-nine patients were enrolled in the PEGasparaginase study. Twenty (22%) of the PEGasparaginase-treated patients developed an allergy; 7 (8%) showed silent inactivation. The PEGasparaginase level was 0 in all allergic patients (grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the Erwinia asparaginase study; 2 (3%) developed an allergy and none silent inactivation. Ninety-six percent had at least 1 trough level ≥100 U/L. The serum asparagine level was not always completely depleted with Erwinia asparaginase in contrast to PEGasparaginase. The presence of asparaginase antibodies was related to allergies and silent inactivation, but with low specificity (64%). Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront in induction, and we suggest that the dose could be lowered. Switching to Erwinia asparaginase leads to effective asparaginase levels in most patients. Therapeutic drug monitoring has been added to our ALL-11 protocol to individualize asparaginase therapy.

  10. Advances in the treatment of chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Morley Kimberly

    2011-08-01

    Full Text Available Abstract Although imatinib is firmly established as an effective therapy for newly diagnosed patients with chronic myeloid leukemia (CML, the field continues to advance on several fronts. In this minireview we cover recent results of second generation tyrosine kinase inhibitors in newly diagnosed patients, investigate the state of strategies to discontinue therapy and report on new small molecule inhibitors to tackle resistant disease, focusing on agents that target the T315I mutant of BCR-ABL. As a result of these advances, standard of care in frontline therapy has started to gravitate toward dasatinib and nilotinib, although more observation is needed to fully support this. Stopping therapy altogether remains a matter of clinical trials, and more must be learned about the mechanisms underlying the persistence of leukemic cells with treatment. However, there is good news for patients with the T315I mutation, as effective drugs such as ponatinib are on their way to regulatory approval. Despite these promising data, accelerated or blastic phase disease remains a challenge, possibly due to BCR-ABL-independent resistance.

  11. Identification of a novel SEPT9-ABL1 fusion gene in a patient with T-cell prolymphocytic leukemia

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    Rikio Suzuki

    2014-01-01

    Full Text Available T-cell prolymphocytic leukemia (T-PLL, a rare type of peripheral T-cell leukemia, is characterized by marked splenomegaly with rapidly progressive lymphocytosis and a poor prognosis. Nine kinds of ABL1 chimeric genes have been identified in various kinds of hematological malignancies, such as chronic myeloid leukemia and B- or T-lymphoblastic leukemia. However, there have been no reports describing T-PLL cases with ABL1 rearrangements. We herein report a case of T-PLL with a novel SEPT9-ABL1 fusion gene which induced strong resistance to tyrosine kinase inhibitors such as imatinib and dasatinib.

  12. Fitness conferred by BCR-ABL kinase domain mutations determines the risk of pre-existing resistance in chronic myeloid leukemia.

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    Kevin Leder

    Full Text Available Chronic myeloid leukemia (CML is the first human malignancy to be successfully treated with a small molecule inhibitor, imatinib, targeting a mutant oncoprotein (BCR-ABL. Despite its successes, acquired resistance to imatinib leads to reduced drug efficacy and frequent progression of disease. Understanding the characteristics of pre-existing resistant cells is important for evaluating the benefits of first-line combination therapy with second generation inhibitors. However, due to limitations of assay sensitivity, determining the existence and characteristics of resistant cell clones at the start of therapy is difficult. Here we combined a mathematical modeling approach using branching processes with experimental data on the fitness changes (i.e., changes in net reproductive rate conferred by BCR-ABL kinase domain mutations to investigate the likelihood, composition, and diversity of pre-existing resistance. Furthermore, we studied the impact of these factors on the response to tyrosine kinase inhibitors. Our approach predicts that in most patients, there is at most one resistant clone present at the time of diagnosis of their disease. Interestingly, patients are no more likely to harbor the most aggressive, pan-resistant T315I mutation than any other resistance mutation; however, T315I cells on average establish larger-sized clones at the time of diagnosis. We established that for patients diagnosed late, the relative benefit of combination therapy over monotherapy with imatinib is significant, while this benefit is modest for patients with a typically early diagnosis time. These findings, after pre-clinical validation, will have implications for the clinical management of CML: we recommend that patients with advanced-phase disease be treated with combination therapy with at least two tyrosine kinase inhibitors.

  13. Response to treatment in women with chronic myeloid leukemia during pregnancy and after delivery.

    Science.gov (United States)

    Klamová, Hana; Marková, Markéta; Moravcová, Jana; Sisková, Magda; Cetkovský, Petr; Machová Poláková, Katerina

    2009-11-01

    Here we report response to treatment of chronic myeloid leukemia (CML) of five pregnant women during and after pregnancy. CML was diagnosed during pregnancy in three patients. Pregnancy was confirmed during CML in two patients: in one in the 21st week of pregnancy while on imatinib, in another in the 12th week during the interferon treatment. Interferon with leukapheresis when needed was applied in the 2nd and 3rd trimester. All patients except one achieved complete hematological response during pregnancy. After delivery four patients achieved partial cytogenetic response on imatinib and two patients achieved major molecular response after crossover to dasatinib.

  14. The biology and targeting of FLT3 in pediatric leukemia

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    Colleen eAnnesley

    2014-09-01

    Full Text Available Despite remarkable improvement in treatment outcomes in pediatric leukemia over the past several decades, the prognosis for high risk groups of acute myeloid leukemia (AML and acute lymphoblastic leukemia (ALL, as well as for relapsed leukemia, remains poor. Intensified chemotherapy regimens have somewhat improved success rates, but at the cost of drastically increased morbidity and long term adverse effects. With the success of imatinib in Philadelphia-chromosome positive leukemia and all-trans retinoic acid in acute promyelocytic leukemia, the quest to find additional molecularly targeted therapies has generated much excitement over the past 15 years. Another such possible target in pediatric acute leukemia is FMS-like tyrosine kinase 3 (FLT3. FLT3 aberrations are among the most frequently identified transforming events in AML, and have significant clinical implications in both high risk pediatric AML and in certain high risk groups of pediatric ALL. Therefore, the successful targeting of FLT3 has tremendous potential to improve outcomes in these subsets of patients. This article will give an overview of the molecular function and signaling of the FLT3 receptor, as well as its pathogenic role in leukemia. We review the discovery of targeting FLT3, discuss currently available FLT3 inhibitors in pediatric leukemia and results of clinical trials to date, and finally, consider the future promise and challenges of FLT3 inhibitor therapy.

  15. Spotlight on nilotinib in the treatment of chronic myelogenous leukemia

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    Harnicar S

    2014-08-01

    Full Text Available Stephen Harnicar, Sherry Mathew Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY, USA Abstract: Nowhere has targeted therapy been more successful in the hematologic malignancy arena than chronic myelogenous leukemia (CML. By targeting the BCR–ABL fusion oncogene, the introduction of tyrosine-kinase inhibitors (TKIs has dramatically improved the outcomes of this disease. Nilotinib is a second-generation TKI that initially gained approval for the treatment of imatinib-resistant or -intolerant disease for patients with chronic or accelerated-phase CML. Investigation in the first-line setting also demonstrated efficacy, and expanded nilotinib’s approval to include therapy for patients with treatment-naïve chronic-phase CML. Data also exist for blast-phase disease, which allows nilotinib to be an option for all phases. Nilotinib’s place in therapy is continuously being expanded by research in novel areas, such as post-hematopoietic stem cell transplants for prevention of relapse and in the pediatric arena. With multiple TKIs now approved for the treatment of CML, delineating the pharmacologic distinctions of nilotinib is an asset when determining therapy. By understanding the pharmacokinetics and dependence on hepatic metabolism of nilotinib, the clinician can manage the potential toxicities, interactions, and unique dosing of this drug. The recognition of mechanisms of resistance, patient adherence, and cost-effectiveness are similarly significant considerations. Actively integrating these various specifics will allow clinicians to optimize nilotinib therapy for the CML patient. Keywords: nilotinib, chronic myelogenous leukemia, CML, tyrosine-kinase inhibitor, TKI 

  16. Chronic myelogenous leukemia (CML)

    Science.gov (United States)

    CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... Chronic myelogenous leukemia is grouped into phases: Chronic Accelerated Blast crisis The chronic phase can last for ...

  17. Childhood Leukemia

    Science.gov (United States)

    ... fast growing type while chronic leukemia grows slowly. Children with leukemia usually have one of the acute types. Symptoms include Infections Fever Loss of appetite Tiredness Easy bruising or bleeding Swollen lymph nodes ...

  18. Fluid retention associated with imatinib treatment in patients with gastroenterol stromal: Quantitative radiologic assessment and implications for management

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung Won; Shinagare, Atul B.; Krajewski, Katherine M.; Tirumani, Sree Harsha; Jagannathan, Jyothi P.; Ramaiya, Nikihil H. [Dept. of Imaging, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Harvard Medical School, Boston (United States); Pyo, Jun Hee [The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston (United States)

    2015-04-15

    We aimed to describe radiologic signs and time-course of imatinib-associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management.

  19. Comparative study of DNA damage, cell cycle and apoptosis in human K562 and CCRF-CEM leukemia cells: role of BCR/ABL in therapeutic resistance.

    Science.gov (United States)

    Pytel, Dariusz; Wysocki, Tomasz; Majsterek, Ireneusz

    2006-09-01

    The Philadelphia translocation t(9;22) resulting in the bcr/abl fusion gene is the pathogenic principle of almost 95% of human chronic myelogenous leukemia (CML). Imatinib mesylate (STI571) is a specific inhibitor of the BCR/ABL fusion tyrosine kinase that exhibits potent antileukemic effects in CML. BCR/ABL-positive K562 and -negative CCRF-CEM human leukemia cells were investigated. MTT survival assay and clonogenic test of the cell proliferation ability were used to estimate resistance against idarubicin. DNA damage after cell treatment with the drug at the concentrations from 0.001 to 3 microM with or without STI571 pre-treatment were examined by the alkaline comet assay. We found that the level of DNA damages was lower in K562 cells after STI571 pre-treatment. It is suggested that BCR/ABL activity may promote genomic instability, moreover K562 cells were found to be resistant to the drug treatment. Further, we provided evidence of apoptosis inhibition in BCR/ABL-positive cells using caspase-3 activity colorimetric assay and DAPI nuclear staining for chromatin condensation. We suggest that these processes associated with cell cycle arrest in G2/M checkpoint detected in K562 BCR/ABL-positive compared to CCRF-CEM cells without BCR/ABL expression might promote clone selection resistance to drug treatment.

  20. Allogeneic Transplantation for Patients With Acute Leukemia or Chronic Myelogenous Leukemia (CML)

    Science.gov (United States)

    2016-06-14

    Leukemia, Lymphocytic, Acute; Leukemia; Leukemia Acute Promyelocytic Leukemia (APL); Leukemia Acute Lymphoid Leukemia (ALL); Leukemia Chronic Myelogenous Leukemia (CML); Leukemia Acute Myeloid Leukemia (AML); Leukemia Chronic Lymphocytic Leukemia (CLL)

  1. Leukemia cutis

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    Varuna Mallya

    2015-01-01

    Full Text Available Patients with leukemia may show involvement of the skin. This skin involvement can be due to infiltration of skin by leukemic cells or it may be a part of nonspecific cutaneous manifestations. Leukemia cutis is the infiltration of neoplastic leucocytes or their precursors into the skin resulting in extensive clinical manifestations. Described mostly in acute myeloid leukemia and acute myelocytic monocytic leukemia, it is rare in chronic myeloid leukemia and is seen mostly during the blast crises. Its presence signals poor prognosis.

  2. Berbamine exhibits potent antitumor effects on imatinib-resistant CML cells in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    Yan-lin WEI; Lei XU; Yun LIANG; Xiao-hua XU; Xiao-ying ZHAO

    2009-01-01

    Aim: The aim of this study was to explore the effects and mechanism of berbamine on imatinib-resistant BCR-ABL-positive human leukemia K562 (K562-r) cells in vitro and in vivo. Methods: Cell viability was measured by MTT assay, and apoptotic morphology changes were detected by fluorescence microscopy. The apoptosis rate was measured by flow cytometric assay, mdr-1 mRNA levels were determined by RT-PCR. Bcl-2 family proteins, cytochrome c( cyt C), poly (ADP-ribose) polymerase (PARP), and P-glycoprotein were detected by Western blot. BALB/c nu/nu mice were injected with K562-r ceils subcutaneously. Tumor-bearing mice were treated intravenously with berbamine.Results: MTT tests revealed that berbamine significantly inhibited K562-r cell proliferation and increased the chemo-sensitivity of Kf62-r cells to imatirtib. The apoptosis rate was significantly increased following treatment with 21.2 μmol/L berbamine; formation of typical apoptotic blebs was apparent, as observed by fluorescence microscopy. Expression levels of mdr-1 mRNA and P-gp protein were high in untreated K562-r cells and significantly down-regulated by berbamine treatment. Berbamine-treated K562-r cells also exhibited down-regulated expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, up-regulated expression of the apoptotic proteins Box and cytoplasmic cyt C, and stimulated proteolytic cleavage of PARP. In addition, berbamine also suppressed the growth of K562-r xenotransplanted tumors in vivo. Conclusion: Berbamine inhibited proliferation of K562-r cells both in vitro and in vivo. Berbamine-induced apoptosis in K562-r cells appeared to occur through a mechanism involving Bcl-2 family proteins, as well as mdr-1 mRNA and P-gp pro- tein. 13erbamine in combination with imatirtib restored the chemo-sensitivity of K562-r cells to imatinib. Our findings sug-gest that berbamine may be useful in treating imatinib-resistant CML patients.

  3. Overexpression of Mcl-1 Confers Multidrug Resistance, Whereas Topoisomerase IIβ Downregulation Introduces Mitoxantrone-Specific Drug Resistance in Acute Myeloid Leukemia

    Science.gov (United States)

    Hermanson, David L.; Das, Sonia G.; Li, Yunfang

    2013-01-01

    Drug resistance is a serious challenge in cancer treatment and can be acquired through multiple mechanisms. These molecular changes may introduce varied extents of resistance to different therapies and need to be characterized for optimal therapy choice. A recently discovered small molecule, ethyl-2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) (CXL017), reveals selective cytotoxicity toward drug-resistant leukemia. A drug-resistant acute myeloid leukemia cell line, HL60/MX2, also failed to acquire resistance to CXL017 upon chronic exposure and regained sensitivity toward standard therapies. In this study, we investigated the mechanisms responsible for HL60/MX2 cells’ drug resistance and the molecular basis for its resensitization. Results show that the HL60/MX2 cell line has an elevated level of Mcl-1 protein relative to the parental cell line, HL60, and its resensitized cell line, HL60/MX2/CXL017, whereas it has a reduced level of topoisomerase IIβ. Mcl-1 overexpression in HL60/MX2 cells is mainly regulated through phospho-extracellular signal-regulated protein kinases 1 and 2–mediated Mcl-1 stabilization, whereas the reduction of topoisomerase IIβ in HL60/MX2 cells is controlled through genetic downregulation. Upregulating Mcl-1 introduces multidrug resistance to standard therapies, whereas its downregulation results in significant cell death. Downregulating topoisomerase IIβ confers resistance specifically to mitoxantrone, not to other topoisomerase II inhibitors. Overall, these data suggest that Mcl-1 overexpression is a critical determinant for cross-resistance to standard therapies, whereas topoisomerase IIβ downregulation is specific to mitoxantrone resistance. PMID:23696245

  4. Idiopathic intracranial hypertension: a possible association with ImatinibIdiopathic intracranial hypertension: a possible association with Imatinib

    Directory of Open Access Journals (Sweden)

    Thomas Baumann

    2011-06-01

    Full Text Available Idiopathic intracranial hypertension (IIH is characterized by an increased intracranial pressure in the absence of a tumor and in the absence of a venous thrombosis. Associated risk factors include obesity and several medications such as tetracyclines. We report a 60-year-old patient who developed IIH under treatment with imatinib. To our knowledge such a possible connection has not been reported in the literature, even though intracranial hypertension is now listed as a rare possible side effect of treatment with imatinib in the Swiss List of Medications Arzneimittelkompendium. It remains to be seen, if further case reports will support this observation.

  5. Prospect of Imatinib in the Treatment of Systemic Sclerosis%伊马替尼在系统性硬化症的应用前景

    Institute of Scientific and Technical Information of China (English)

    刘心娟; 李梦涛; 曾小峰

    2011-01-01

    系统性硬化症(systemic sclerosis,SSc)以胶原过度产生和细胞外基质过度沉积导致组织纤维化为主要特征.血小板源性生长因子受体(platelet-derived growth factor receptor,PDGFR)、转化生长因子-β(transforming growth factor-β,TGF-β)以及细胞免疫的异常可能参与了这一过程.甲磺酸伊马替尼(imatinib mesylate,IM)是一种人工合成的酪氨酸蛋白激酶抑制剂,最早被用于治疗慢性粒细胞白血病,近年发现其具有抗纤维化作用.目前认为,IM可以通过抑制PDGFR和TGF-β,并可能通过影响调节性T细胞的增殖和功能达到治疗SSc的目的.但是,IM治疗SSc的临床研究刚刚起步,其疗效及安全性有待已经启动的大规模随机对照临床试验(RCT)的结果来评价.%Systemic sclerosis is a multisystem fibrotic disorder characterized by excessive deposition of collagen and other extracellular matrix components. The disorders of platelet-derived growth factor receptor (PDGFR),transforming growth factor-β (TGF-β) and cell-mediated immunity are hypothesized to be involved in the pathogenesis of systemic sclerosis (SSc). Imatinib mesylate is a small molecule that antagonizes specific tyrosine kinases which has been approved to be the treatment of chronic myeloid leukemia. Recently,imatinib began to be used to treat SSc which is mostly based on the known anti-proliferative properties, as an inhibitor of PDGFR and TGF-β, even anti-regulatory T lymphocytes (Treg). The preliminary clinical data raised the possibility that patients with SSc may benefit clinically from imatinib therapy. Large prospective randomized clinical trials are needed to further investigate the effects of imatinib on SSc.Gratifyingly, several clinical trials using imatinib in SSc are currently in progress.

  6. Field-assisted paper spray mass spectrometry for the quantitative evaluation of imatinib levels in plasma.

    Science.gov (United States)

    D'Aronco, Sara; Calandra, Eleonora; Crotti, Sara; Toffoli, Giuseppe; Marangon, Elena; Posocco, Bianca; Traldi, Pietro; Agostini, Marco

    Drug levels in patients' bloodstreams vary among individuals and consequently therapeutic drug monitoring (TDM) is fundamental to controlling the effective therapeutic range. For TDM purposes, different analytical approaches have been used, mainly based on immunoassay, liquid chromatography- ultraviolet, liquid chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. More recently a matrix-assisted laser desorption/ionisation method has been proposed for the determination of irinotecan levels in the plasma of subjects under therapy and this method has been cross- validated by comparison with data achieved by LC-MS/MS. However, to reach an effective point-of-care monitoring of plasma drug concentrations, a TDM platform technology for fast, accurate, low-cost assays is required. In this frame, recently the use of paper spray mass spectrometry, which is becoming a popular and widely employed MS method, has been proposed. In this paper we report the results obtained by the development of a paper spray-based method for quantitative analysis in plasma samples of imatinib, a new generation of anticancer drug. Preliminary experiments showed that poor sensitivity, reproducibility and linear response were obtained by the "classical" paper spray set-up. In order to achieve better results, it was thought of interest to operate in presence of a higher and more homogeneous electrical field. For this aim, a stainless steel needle connected with the high voltage power supply was mounted below the paper triangle. Furthermore, in order to obtain valid quantitative data, we analysed the role of the different equilibria participating to the phenomena occurring in paper spray experiments, depending either on instrumental parameters or on the chemical nature of analyte and solvents. A calibration curve was obtained by spiking plasma samples containing different amounts of imatinib (1) with known amounts of deuterated imatinib (1d3) as

  7. Complete haematological response to Imatinib in chronic myeloid ...

    African Journals Online (AJOL)

    Dr Erius

    1Catholic University of Health and Allied Sciences, Mwanza Tanzania ... A few studies have defined patient delays and primary ... Imatinib (Glivec), a very selective ... patients attending care at the Ocean Road Cancer Institute (ORCI) in Dar es ... transfusion history prior to treatment, complete blood count indices, spleen size ...

  8. Cross-resistance of an amsacrine-resistant human leukemia line to topoisomerase II reactive DNA intercalating agents. Evidence for two topoisomerase II directed drug actions

    Energy Technology Data Exchange (ETDEWEB)

    Zwelling, L.A.; Mayes, J.; Hinds, M.; Chan, D.; Altschuler, E.; Carroll, B.; Parker, E.; Deisseroth, K.; Radcliffe, A.; Seligman, M.; Li, Li; Farquhar, D. (Univ. of Texas M.D. Anderson Cancer Center, Houston (USA))

    1991-04-23

    HL-60/AMSA is a human leukemia cell line that is 50-100-fold more resistant than its drug-sensitive HL-60 parent line to the cytotoxic actions of the DNA intercalator amsacrine (m-AMSA). HL-60/AMSA topoisomerase II is also resistant to the inhibitory actions of m-AMSA. HL-60/AMSA cells and topoisomerase II are cross-resistant to anthracycline and ellipticine intercalators but relatively sensitive to the nonintercalating topoisomerase II reactive epipodophyllotoxin etoposide. The authors now demonstrate that HL-60/AMSA and its topoisomerase II are cross-resistant to the DNA intercalators mitoxantrone and amonafide, thus strongly indicating that HL-60/AMSA and its topoisomerase II are resistant to topoisomerase II reactive intercalators but not to nonintercalators. At high concentrations, mitoxantrone and amonafide were also found to inhibit their own, m-AMSA's, and etoposide's abilities to stabilize topoisomerase II-DNA complexes. These results suggest that the cytotoxicity of m-AMSA and etoposide is initiated primarily by the stabilization of the topoisomerase II-DNA complex. Other topoisomerase II reactive drugs may inhibit the enzyme at other steps in the topoisomerization cycle, particularly at elevated concentrations. Under these conditions, these latter drugs may not produce protein-associated DNA cleavage while still inhibiting topoisomerase II function as well as the actions of other topoisomerase II reactive drugs.

  9. Antiproliferation effect of imatinib mesylate on MCF7, T-47D tumorigenic and MCF 10A nontumorigenic breast cell lines via PDGFR-β, PDGF-BB, c-Kit and SCF genes

    Science.gov (United States)

    Kadivar, Ali; Kamalidehghan, Behnam; Akbari Javar, Hamid; Karimi, Benyamin; Sedghi, Reihaneh; Noordin, Mohamed Ibrahim

    2017-01-01

    Recent cancer molecular therapies are targeting main functional molecules to control applicable process of cancer cells. Attractive targets are established by receptor tyrosine kinases, such as platelet-derived growth factor receptors (PDGFRs) and c-Kit as mostly irregular signaling, which is due to either over expression or mutation that is associated with tumorigenesis and cell proliferation. Imatinib mesylate is a selective inhibitor of receptor tyrosine kinase, including PDGFR-β and c-Kit. In this research, we studied how imatinib mesylate would exert effect on MCF7 and T-47D breast cancer and MCF 10A epithelial cell lines, the gene and protein expression of PDGFR-β, c-Kit and their relevant ligands platelet-derived growth factor (PDGF)-BB and stem cell factor (SCF). The MTS assay was conducted in therapeutic relevant concentration of 2–10 µM for 96, 120 and 144 h treatment. In addition, apoptosis induction and cytostatic activity of imatinib mesylate were investigated with the terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL and cell cycle assays, respectively, in a time-dependent manner. Comparative real-time PCR and Western blot analysis were conducted to evaluate the expression and regulation of imatinib target genes and proteins. Our finding revealed that imatinib mesylate antiproliferation effect, apoptosis induction and cytostatic activity were significantly higher in breast cancer cell lines compared to MCF 10A. This effect might be due to the expression of PDGFR-β, PDGF-BB, c-Kit and SCF, which was expressed by all examined cell lines, except the T-47D cell line which was not expressed c-Kit. However, examined gene and proteins expressed more in cancer cell lines. Therefore, imatinib mesylate was more effective on them. It is concluded that imatinib has at least two potential targets in both examined breast cancer cell lines and can be a promising drug for targeted therapy to treat breast cancer. PMID:28260860

  10. A prospective, multi-centre clinical trial to evaluate the early clinical efficacy and safety of a generic imatinib in treating patients with chronic phase of chronic myelogenous leukemia%国产甲磺酸伊马替尼治疗慢性髓性白血病慢性期早期疗效和安全性的前瞻性、多中心临床研究

    Institute of Scientific and Technical Information of China (English)

    江倩; 赵东陆; 金洁; 吴德沛; 孟凡义; 胡建达; 刘兵城; 杜欣; 刘霆

    2015-01-01

    目的 评价国产甲磺酸伊马替尼(商品名昕维,江苏豪森药业股份有限公司产品)治疗新诊断慢性髓性白血病慢性期(CML-CP)患者的早期血液学、细胞遗传学、分子学反应和安全性.方法 107例年龄≥18岁、初次确诊、除羟基脲外未接受其他任何抗CML治疗的CML-CP患者,给予国产甲磺酸伊马替尼400 mg每日1次治疗,评价3、6个月时的血液学、细胞遗传学和分子学反应及安全性.结果 107例患者均治疗≥3个月,其中54例患者治疗≥≥6个月.治疗3个月时,完全血液学反应(CHR)率为98.1%(105/107);57例进行了细胞遗传学检测的患者中47例(82.5%)获得主要细胞遗传学反应(MCyR),其中20例(35.1%)获得完全细胞遗传学反应(CCyR);106例进行了分子学检测的患者中77例(72.6%)国际标准化BCR-ABL转录本水平(BCR-ABLIs)≤10%,其中11例(10.4%)BCR-ABLIS≤0.1%.治疗6个月时,CHR率为100%(54/54);CCyR率为71.8%(28/39);37例(68.5%)BCR-ABLIS≤1%,其中18例(33.3%) BCR-ABIS≤0.1%.Ⅲ级白细胞减少、血小板减少和贫血发生率分别为19.5%、23.0%和13.8%,无Ⅳ级血液学不良反应发生.最常见的非血液学不良反应依次为水肿(74.7%)、恶心(48.3%)、骨关节痛(42.5%)、皮疹(36.8%)、腹泻(34.5%)、发热(23.0%)、肌肉痉挛(11.5%)和肝功能损害(3.4%).无一例患者出现Ⅳ级非血液学不良反应.无药物毒性相关性死亡.结论 国产甲磺酸伊马替尼初始治疗新诊断CML-CP的早期血液学、细胞遗传学和分子学反应优异,安全性良好.%Objective To evaluate the early hematologic,cytogenetic and molecular responses in newly diagnosed patients with chronic myelogenous leukemia in chronic phase (CML-CP) and initially treated with a generic imatinib (Xinwei),manufactured by Jiansu Hansoh Pharmaceutical Group Co.,Ltd.Methods 107 newly diagnosed patients of CML-CP,whose ages were above 18-year-old and who had

  11. Appropriate modulation of autophagy sensitizes malignant peripheral nerve sheath tumor cells to treatment with imatinib mesylate.

    Science.gov (United States)

    Okano, Munehiro; Sakata, Naoki; Ueda, Satoshi; Takemura, Tsukasa

    2014-04-01

    Malignant peripheral nerve sheath tumor (MPNST), very rare in childhood, is a highly aggressive soft-tissue tumor. We experienced a case of a 7-year-old boy with MPNST who was treated with imatinib mesylate (imatinib) after the identification of platelet-derived growth factor receptor expression in his tumor. We were unable to observe clinical benefits of imatinib in this patient. Therefore, cellular reactions of imatinib were investigated in vitro using 3 MPNST cell lines. Imatinib induced cytotoxicity in vitro with variable IC50 values (11.7 to >30 μM). Induction of apoptosis was not a pivotal mechanism in the inhibitory effects. We found that the treatment of MPNST cell lines with imatinib induced autophagy. Suppression of the initiation of autophagy by 3-methyladenine or small interfering RNA (siRNA) against beclin-1 attenuated the imatinib-mediated cytotoxicity. In contrast, blocking the formation of autophagosomes or the development of autolysosomes using siRNA against microtubule-associated protein light chain 3B, bafilomycin A1, chloroquine, or an MEK1/2 inhibitor (U0126) enhanced the imatinib-induced cytotoxicity in MPNST cells. Our data showed that the imatinib-mediated autophagy can function as a cytotoxic mechanism and that appropriate modulation of autophagy may sensitize MPNST cells to imatinib, which in turn may be a novel therapeutic strategy for MPNST.

  12. [Multiple organ failure presumably due to alkylating agents used as preconditioning drugs for autologous peripheral blood stem cell transplantation in an acute promyelocytic leukemia].

    Science.gov (United States)

    Ida, Tori; Hashimoto, Shigeo; Suzuki, Nobuaki; Ebe, Yusuke; Yano, Toshio; Sato, Naoko; Koike, Tadashi

    2016-01-01

    A 52-year-old male was diagnosed as having acute promyelocytic leukemia (APL) in 2006. He received induction chemotherapy including all-trans retinoic acid and initially achieved a complete remission (CR). After several courses of consolidation therapy combining anthracyclines and cytarabine, he maintained CR. In 2009, an APL relapse was diagnosed, and he was treated with arsenic trioxide. Since he achieved a second CR, he underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) with a conditioning regimen consisting of busulfan and melphalan. At four months after auto-PBSCT, he developed a pneumothorax and acute respiratory failure. He died despite intensive therapy. Autopsy findings included various atypical and apoptotic cells in his pulmonary tissue. These changes were confirmed in multiple organs throughout the body, suggesting them to be drug-induced. The findings in this case suggested multiple organ failure due to alkylating agents.

  13. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome

    NARCIS (Netherlands)

    Zwaan, CM; Kaspers, GJL; Pieters, R; Hahlen, K; Janka-Schaub, GE; van Zantwijk, CH; Huismans, DR; de Vries, E; Rots, MG; Peters, GJ; Jansen, G; Creutzig, U; Veerman, AJP

    2002-01-01

    Children with Down syndrome (DS) have an increased risk for leukemia. The prognosis for DS acute myeloid leukemia (AML) is better than for non-DS AML, but the clinical outcome of DS acute lymphoblastic leukemia (ALL) is equal to that of non-DS ALL. Differences in prognosis may reflect differences in

  14. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome

    NARCIS (Netherlands)

    Zwaan, CM; Kaspers, GJL; Pieters, R; Hahlen, K; Janka-Schaub, GE; van Zantwijk, CH; Huismans, DR; de Vries, E; Rots, MG; Peters, GJ; Jansen, G; Creutzig, U; Veerman, AJP

    2002-01-01

    Children with Down syndrome (DS) have an increased risk for leukemia. The prognosis for DS acute myeloid leukemia (AML) is better than for non-DS AML, but the clinical outcome of DS acute lymphoblastic leukemia (ALL) is equal to that of non-DS ALL. Differences in prognosis may reflect differences in

  15. Impact of CYP2C8*3 polymorphism on in vitro metabolism of imatinib to N-desmethyl imatinib.

    Science.gov (United States)

    Khan, Muhammad Suleman; Barratt, Daniel T; Somogyi, Andrew A

    2016-01-01

    1. Imatinib is metabolized to N-desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-desmethyl imatinib formation was unknown. 2. We examined imatinib N-demethylation in human liver microsomes (HLMs) genotyped for CYP2C8*3, in CYP2C8*3/*3 pooled HLMs and in recombinant CYP2C8 and CYP3A4 enzymes. Effects of CYP-selective inhibitors on N-demethylation were also determined. 3. A single-enzyme Michaelis-Menten model with autoinhibition best fitted CYP2C8*1/*1 HLM (n = 5) and recombinant CYP2C8 kinetic data (median ± SD Ki = 139 ± 61 µM and 149 µM, respectively). Recombinant CYP3A4 showed two-site enzyme kinetics with no autoinhibition. Three of four CYP2C8*1/*3 HLMs showed single-enzyme kinetics with no autoinhibition. Binding affinity was higher in CYP2C8*1/*3 than CYP2C8*1/*1 HLM (median ± SD Km = 6 ± 2 versus 11 ± 2 µM, P=0.04). CYP2C8*3/*3 (pooled HLM) also showed high binding affinity (Km = 4 µM) and single-enzyme weak autoinhibition (Ki = 449 µM) kinetics. CYP2C8 inhibitors reduced HLM N-demethylation by 47-75%, compared to 0-30% for CYP3A4 inhibitors. 4. In conclusion, CYP2C8*3 is a gain-of-function polymorphism for imatinib N-demethylation, which appears to be mainly mediated by CYP2C8 and not CYP3A4 in vitro in HLM.

  16. Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

    Science.gov (United States)

    Mazza, Elena; Brandes, Alba; Zanon, Silvia; Eoli, Marika; Lombardi, Giuseppe; Faedi, Marina; Franceschi, Enrico; Reni, Michele

    2016-01-01

    Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma. Patients with recurrent or progressive WHO grade I-III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18-75 years, ECOG performance status 0-2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient's refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9). Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (N = 7; Arm A) or HU alone (N = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75%, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75%, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0. The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.

  17. Restoration of energy metabolism in leukemic mice treated by a siddha drug--Semecarpus anacardium Linn. nut milk extract.

    Science.gov (United States)

    Sugapriya, Dhanasekaran; Shanthi, Palanivelu; Sachdanandam, Panchanatham

    2008-05-09

    Chronic myeloid leukemia (CML) is a clonal disorder characterized by proliferation of hematopoietic cells that possess the BCR-ABL fusion gene resulting in the production of a 210 kDa chimeric tyrosine kinase protein. CML, when left untreated, progresses to a blast phase during which the disease turns aggressive and shows poor response to known treatment regimens. We have studied a Siddha herbal agent, Semecarpus anacardium Linn. nut milk extract (SA) for its antileukemic activity and its effect on the changes in energy metabolism in leukemic mice. Leukemia was induced in BALB/c mice by tail vein injection of BCR-ABL(+) 12B1 murine leukemia cell line. This resulted in an aggressive leukemia, similar to CML in blast crisis, myeloid subtype, confirmed by histopathological study and RT-PCR for the p210 mRNA in the peripheral blood, spleen and liver. Leukemia-bearing mice showed a significant increase in lipid peroxides, glycolytic enzymes, a decrease in gluconeogenic enzymes and significant decrease in the activities of TCA cycle and respiratory chain enzymes as compared to control animals. SA treatment was compared with standard drug imatinib mesylate. SA administration to leukemic animals resulted in clearance of the leukemic cells from the bone marrow and internal organs on histopathological examination and this was confirmed by RT-PCR for the p210 mRNA. Treatment with SA significantly reversed the changes seen in the levels of the lipid peroxides, the glycolytic enzymes, the gluconeogenic enzymes and the mitochondrial enzymes. These effects are probably due to the flavonoids, polyphenols and other compounds present in SA which result in total regression of leukemia and correction of the alterations in energy metabolism. Study of animals treated with SA alone did not reveal any adverse effects. On the basis of the observed results, SA can be considered as a readily accessible, promising and novel antileukemic chemotherapeutic agent.

  18. Reversible sarcopenia in patients with gastrointestinal stromal tumor treated with imatinib

    OpenAIRE

    Moryoussef, Frédérick; Dhooge, Marion; Volet, Julien; Barbe, Coralie; Brezault, Catherine; Hoeffel, Christine; Coriat, Romain; Bouché, Olivier

    2015-01-01

    Background Imatinib is a long-term, oral, targeted therapy for high-risk resected and advanced gastrointestinal stromal tumours (GIST). It is known that sarcopenia affects prognosis and treatment tolerance in patients with various solid cancers. We analysed lumbar skeletal muscle index changes in imatinib-treated GIST patients. Imatinib tolerance was also assessed to evaluate the influence of pre-treatment sarcopenia. Methods Thirty-one patients with advanced (n = 16) or high-risk resected (n...

  19. Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies

    OpenAIRE

    Reilley, Matthew J.; Bailey, Ann; Subbiah, Vivek; Janku, Filip; Naing, Aung; Falchook, Gerald; Karp, Daniel; Piha-Paul, Sarina; Tsimberidou, Apostolia; Fu, Siqing; Lim, JoAnn; Bean, Stacie; Bass, Allison; Montez, Sandra; Vence, Luis

    2017-01-01

    Background Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer. Methods Primary objective of the dose-escalation study (3?+?3 design) was to establish the maximu...

  20. Variant Philadelphia translocations in chronic myeloid leukemia: A report of five cases

    Directory of Open Access Journals (Sweden)

    Vijaya V Mysorekar

    2015-01-01

    Full Text Available The t (9;22(q34;q11 translocation is found in about 90% of the chronic myeloid leukemia patients. About 5 - 10% of these patients have complex variant translocations involving a third chromosome in addition to chromosomes 9 and 22. We describe five male patients in the chronic myeloid leukemia-chronic phase, with rare variant Philadelphia translocations. All of them had the BCR-ABL fusion gene and responded well to treatment with imatinib mesylate. All the patients are on regular follow-up.

  1. Myeloprolipherative disorder type chronic myeloid leukemia--eosinophilic form.

    Science.gov (United States)

    Arnautovic-Custovic, Aida; Hasic, Samira; Kopic, Emina; Jahic, Azra; Jovic, Svetlana

    2011-01-01

    Chronic eosinophilic leukemia (CEL) is a very rare form of leucemia in the western world. Adequate response is seldomly achieved after treatment with corticosteroids, interferon-alfa (INF-alfa) and medications containing hydroxi-urea (Litalir). The study presents a patient with CEL with no initial therapeutic response to the use of corticosteroids, INF-alfa and hydroxy-urea, and with neither clinical nor hematological response. After setting a diagnosis of CEL, patient was ordinated Imatinib (Glivec tabbletes) in a daily dose of 200 mg. Two days afterwards there was an evident withdrawal of subjective and clinical symptoms of disease, and the complete blood count showed significant amendment.

  2. A study of intermittent alternating drug program reinduction therapy on the frequency and duration of response in adult acute leukemia.

    Science.gov (United States)

    McCredie, K B; Freireich, E J; Bodey, G P; Burgess, M A; Whitecar, J P; Smith, T L

    1976-01-01

    Of 41 adults with a diagnosis of acute leukemia that were randomized for induction therapy in combination with methotrexate, 6-MP, vincristine and prednisone (POMP) versus a combination of cytosine arabinoside, cytoxan, vincristine and prednisone (COAP), 23 (56%) patients achieved a complete remission. During remission, patients received consolidation therapy with the three courses of remission induction regimen that they had not received initially. They then received daunomycin (three courses) and L-asparaginase and were then maintained for two years with their induction therapy. The median duration of survival for all patients was 40 weeks; the median duration of survival of those patients that responded to chemotherapy was 80 weeks. There was no significant difference between the two induction regimens with regard to complete remission more than four and one half years from diagnosis and two and one half years from discontinuation of all therapy.

  3. Clinical comparison of imatinib alone and it combined with interferon-α in the treatment of chronic myeloid leukemia%单用伊马替尼及其联合干扰素-α治疗慢性髓性白血病的临床比较

    Institute of Scientific and Technical Information of China (English)

    弋莉

    2015-01-01

    目的 探讨单用伊马替尼及其联合干扰素-α(interferon-α,IFN-α)治疗慢性髓性白血病(chronic myelognous leukemia,CML)的效果.方法 选取2011年1月-2013年1月医院收治的CML患者84例作为研究对象,根据治疗方案随机将患者分为两组,口服伊马替尼400 mg/d治疗作为A组,口服400 mg/d+IFN-α 300万U皮下注射治疗作为B组,持续用药9个月,观察两组临床疗效及不良用药反应,对比观察两组患者完全血液学缓解(complete hematologic remission,CHR)、完全细胞遗传学缓解(complete cytogenetic remission,CCgR)、完全分子学缓解(commplete molecular remission,CMR)数量的发生率,随访1年记录生存率和死亡率,计量资料采用行x2检验,P<0.05具有统计学意义.结果 B组CHR、CCgR、CMR的发生率分别为85.71%、69.05%、76.19%,均较A组(64.29%、45.24%、52.38%)高,差异均有统计学意义(均P<0.05);B组发热、脱发的发生率分别为61.90%、45.24%,均较A组(28.57%、4.76%)高,差异均有统计学意义(均P<0.05).结论 伊马替尼联合IFN-α治疗CML可提高临床疗效,但会增加不良用药反应.

  4. U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.

    Science.gov (United States)

    Lee, Hyon-Zu; Miller, Barry W; Kwitkowski, Virginia E; Ricci, Stacey; DelValle, Pedro; Saber, Haleh; Grillo, Joseph; Bullock, Julie; Florian, Jeffry; Mehrotra, Nitin; Ko, Chia-Wen; Nie, Lei; Shapiro, Marjorie; Tolnay, Mate; Kane, Robert C; Kaminskas, Edvardas; Justice, Robert; Farrell, Ann T; Pazdur, Richard

    2014-08-01

    On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy-designated drug to receive FDA approval. ©2014 American Association for Cancer Research.

  5. In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Lönnerholm, Gudmar; Thörn, Ingrid; Sundström, Christer

    2011-01-01

    Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD......Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD...

  6. Leukemia cutis

    Directory of Open Access Journals (Sweden)

    Angoori G Rao

    2012-01-01

    Full Text Available Leukemia cutis is the infiltration of neoplastic leukocytes or their precursors into the epidermis, the dermis, or the subcutis, resulting in clinically identifiable cutaneous lesions. Leukemia cutis may follow, precede or occur concomitantly with the diagnosis of systemic leukemia. A 50-year-old woman presented with asymptomatic multiple cutaneous nodules all over the body of 4 months duration. Cutaneous examination showed multiple hyperpigmented nodules and plaques involving face, trunk, and extremities. Peripheral smear showed abnormally elevated leucocyte count (TLC-70,000 with abnormal cells: myeloblasts 40%, promyelocytes 8% and myelocytes 39%. Auer rods were present in few myeloblasts. Bone marrow aspiration showed increased cellularity, erythroid hyperplasia with megaloblastic change, increased myeloblasts with maturation arrest. Immunohistochemistry showed strongly positive myeloperoxidase infiltrating cells and negative for CD20 and CD3 consistent with the diagnosis of AML-M 2 with leukemia cutis. This case is reported for its rarity.

  7. Understanding Leukemia

    Science.gov (United States)

    ... material presented in this publication Jane Liesveld, MD Professor, Department of Medicine, Hematology/Oncology Clinical Director, Blood ... of leukemia cell. The marrow has two main jobs. The first job is to form myeloid cells. ...

  8. Fluid Retention Associated with Imatinib Treatment in Patients with Gastrointestinal Stromal Tumor: Quantitative Radiologic Assessment and Implications for Management

    Science.gov (United States)

    Shinagare, Atul B.; Krajewski, Katherine M.; Pyo, Junhee; Tirumani, Sree Harsha; Jagannathan, Jyothi P.; Ramaiya, Nikhil H.

    2015-01-01

    Objective We aimed to describe radiologic signs and time-course of imatinib-associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. Materials and Methods In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. Results The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. Conclusion Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management. PMID:25741192

  9. Drug development: portals of discovery.

    Science.gov (United States)

    Bates, Susan E; Amiri-Kordestani, Laleh; Giaccone, Giuseppe

    2012-01-01

    A British humorist said, "There is much to be said for failure. It is much more interesting than success." This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf-mutated melanoma and crizotinib for non-small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer.

  10. In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Lönnerholm, Gudmar; Thörn, Ingrid; Sundström, Christer

    2011-01-01

    Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD...

  11. Reduced intracellular drug accumulation in drug-resistant leukemia cells is not solely due to MDR-mediated efflux but also to decreased uptake

    Directory of Open Access Journals (Sweden)

    Angela Oliveira Pisco

    2014-10-01

    Full Text Available Expression of ABC family transporter proteins that promote drug efflux from cancer cells is a widely observed mechanism of multi-drug resistance of cancer cells. Cell adaptation in long-term culture of HL60 leukemic cells in the presence of chemotherapy leads to induction and maintenance of the ABC transporters expression, preventing further accumulation of drugs. However, we found that decreased accumulation of drugs and fluorescent dyes was also contributed by a reduced uptake by the resistant cells. Confocal time-lapse microscopy and flow cytometry revealed that fluid-phase endocytosis was diminished in drug-resistant cells compared to drug-sensitive cells. Drug uptake was increased by insulin co-treatment when cells were grown in methylcellulose and monitored under the microscope, but not when cultured in suspension. We propose that multi-drug resistance is not solely achieved by enhanced efflux capacity but also by supressed intake of the drug offering an alternative target to overcome drug resistance or potentiate chemotherapy.

  12. Trends in the treatment changes and medication persistence of chronic myeloid leukemia in Taiwan from 1997 to 2007: a longitudinal population database analysis

    Directory of Open Access Journals (Sweden)

    Chang Chao-Sung

    2012-10-01

    Full Text Available Abstract Background Few studies have examined the longitudinal changes in the patterns, selection, and utilization of treatments for chronic myeloid leukemia (CML in routine clinical practice since the introduction of imatinib. Therefore, we investigated the trends in CML therapy, including changes, patterns, and persistence to imatinib therapy among patients with newly diagnosed CML. Methods We conducted a cross-sectional and longitudinal analysis of 11 years of claims data for patients with newly diagnosed CML included in the Taiwan National Health Insurance program. Pharmacy and diagnosis claims for newly diagnosed CML recorded between 1997 and 2007 year were extracted from the database. Annual overall use, new use of CML therapy, and persistence to imatinib therapy were estimated. The Anatomical Therapeutic Chemical codes for CML therapy [i.e., imatinib and conventional therapy: busulfan, hydroxyurea, interferon-α (IFNα, and cytarabine], and the process code for hematopoietic stem cell transplantation were used to categorize treatment patterns. Associations with patients characteristics were analyzed by multivariate logistic regression. Results Overall, the proportion of patients with newly diagnosed CML to all patients with CML increased by approximately 4-fold between 1998 and 2007. There were steady increases in the proportions of all treated patients and those starting therapy from 2003 to 2007. Fewer comorbid conditions and lower severity of CML were associated with treatment initiation. Medication persistence varied according to treatment duration, as 38.7% patients continued imatinib for ≥ 18 months without interruption but only 7.7% continued imatinib for ≥ 5 years. Factors associated with persistence to imatinib therapy were removal of the need for prior authorization for imatinib, and prior use of hydroxyurea and IFNα, whereas having undergone hematopoietic stem cell transplantation led to reduced likelihood

  13. "To patent or not to patent? the case of Novartis' cancer drug Glivec in India".

    Science.gov (United States)

    Gabble, Ravinder; Kohler, Jillian Clare

    2014-01-06

    Glivec (imatinib mesylate), produced by the pharmaceutical company Novartis, is prescribed in the case of chronic myeloid leukemia, one of the most common blood cancers in eastern countries. After more than a decade of legal battles surrounding its patentability, the Supreme Court of India gave its final decision on April 1st of 2013, rejecting the appeal of the Swiss giant drug manufacturer. In 2006, the Indian Patent Office first refused Glivec's patent under Section 3(d) of the Indian Patent Act arguing that it was only a modified version of an existing drug, Imatinib, and therefore that the drug was not innovative. Novartis replied filing legal challenges against the Indian government but the final verdict in April of 2013 ends the battle. Indeed, the Supreme Court stated that even if the bioavailability of the drug was improved, it did not demonstrate enhanced efficacy and that Glivec was not patentable. The research primarily focused on journal, newspaper and magazine articles relevant to the time frame of the lawsuit (from 1994 to 2013) as well as news searches through Google, Factiva, ProQuest, PubMed, and YouTube where press articles from court verdicts were obtained by using the following keywords: "India", "Novartis", "Glivec", "Patent", "Novartis Case", and "Supreme Court of India". The data sources were interpreted and analyzed according to the authors' own prior knowledge and understanding of the exigencies of the TRIPS Agreement. This case illuminates how India is interpreting international law to fit domestic public health needs. The Novartis case arguably sets an important precedent for the global pharmaceutical industry and ideally will help improve access to lifesaving medicines in the developing world by demanding that patient health needs supersede commercial interests. The Supreme Court of India's decision may affect the interpretation of the article of the TRIPS Agreement, which states members shall be free to determine the appropriate method

  14. Management of chronic myelogenous leukemia in pregnancy.

    Science.gov (United States)

    Bhandari, Amit; Rolen, Katrina; Shah, Binay Kumar

    2015-01-01

    Discovery of tyrosine kinase inhibitors has led to improvement in survival of chronic myelogenous leukemia (CML) patients. Many young CML patients encounter pregnancy during their lifetime. Tyrosine kinase inhibitors inhibit several proteins that are known to have important functions in gonadal development, implantation and fetal development, thus increasing the risk of embryo toxicities. Studies have shown imatinib to be embryotoxic in animals with varying effects in fertility. Since pregnancy is rare in CML, there are no randomized controlled trials to address the optimal management of this condition. However, there are several case reports and case series on CML in pregnancy. At the present time, there is no consensus on how to manage different pregnancy situations in CML. In this article, we review current literature on CML in pregnancy, discuss the effects of several tyrosine kinase inhibitors on fertility and pregnancy and suggest an evidence-based treatment of CML in pregnancy.

  15. The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms.

    Science.gov (United States)

    Beranova, Lenka; Pombinho, Antonio R; Spegarova, Jarmila; Koc, Michal; Klanova, Magdalena; Molinsky, Jan; Klener, Pavel; Bartunek, Petr; Andera, Ladislav

    2013-06-01

    TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand from the TNF-alpha family that is under consideration, along with agonistic anti-TRAIL receptor antibodies, as a potential anti-tumor agent. However, most primary human tumors are resistant to monotherapy with TRAIL apoptogens, and thus the potential applicability of TRAIL in anti-tumor therapy ultimately depends on its rational combination with drugs targeting these resistances. In our high-throughput screening for novel agents/drugs that could sensitize TRAIL-resistant colorectal cancer cells to TRAIL-induced apoptosis, we found homoharringtonine (HHT), a cephalotaxus alkaloid and tested anti-leukemia drug, to be a very effective, low nanomolar enhancer of TRAIL-mediated apoptosis/growth suppression of these resistant cells. Co-treatment of TRAIL-resistant RKO or HT-29 cells with HHT and TRAIL led to the effective induction of apoptosis and the complete elimination of the treated cells. HHT suppressed the expression of the anti-apoptotic proteins Mcl-1 and cFLIP and enhanced the TRAIL-triggered activation of JNK and p38 kinases. The shRNA-mediated down-regulation of cFLIP or Mcl-1 in HT-29 or RKO cells variably enhanced their TRAIL-induced apoptosis but it did not markedly sensitize them to TRAIL-mediated growth suppression. However, with the notable exception of RKO/sh cFLIP cells, the downregulation of cFLIP or Mcl-1 significantly lowered the effective concentration of HHT in HHT + TRAIL co-treatment. Combined HHT + TRAIL therapy also led to the strong suppression of HT-29 tumors implanted into immunodeficient mice. Thus, HHT represents a very efficient enhancer of TRAIL-induced apoptosis with potential application in TRAIL-based, anti-cancer combination therapy.

  16. [Reversal effect of LBH589 alone or in combination with bortezomib on drug-resistance in myeloid leukemia and its mechanism].

    Science.gov (United States)

    Jiang, Xue-Jie; Meng, Fan-Yi; Zhou, Hong-Sheng; Wang, Qiang; Wu, Fu-Qun; Huang, Kai-Kai; Huang, Ming; Wang, Zhi-Xiang; Chen, Wei-Wei

    2011-08-01

    To investigate reversal effect of histone deacetylase inhibitor LBH589 alone or in combination with proteasome inhibitor bortezomib on drug resistance in acute myeloid leukemia (AML) and its mechanism. Ex vivo cultures of HL-60/ADM cells and fresh refractory AML cells were treated with LBH589, bortezomib or their combination at varying concentrations. Proliferation capacity, apoptosis rate and reversal of drug resistance were evaluated by MTT assay, dual staining of Hoechst 33342 and Annexin VFITC/PI by flow cytometry, and adriamycin uptake rate with proliferation inhibition, respectively. The change of signal pathway at protein level was analyzed by Western blot. Synergistic cytotoxicity was observed in the combination treatment with LBH589 and bortezomib against HL-60/ADM cells, as well as the fresh AML cells, the most powerful synergy being observed at 21 nmol/L LBH589 plus 12 nmol/L bortezomib, with CI values of 0.531 and 0.498, respectively by Calcusyn software analysis. Moreover, the accumulation of adriamycin in HL-60/ADM cells was increased more in combination treatment [(64.81 +/- 3.69)%] than in either LBH589 [(28.96 +/- 2.52)%] or bortezomib [(37.29 +/- 3.71)%] alone (P kinase (PI3K)/Akt/nuclear factor-kappaB (NF-kappaB) signaling pathway. Combination treatment of drug resistant AML cells with LBH589 and bortezomib produces a synergistic effect of in creating sensitivity to chemotherapy. The mechanism may be mainly resulted from inhibition of PI3K/ Akt/NF-kappaB signaling pathway.

  17. Chemokines and relapses in childhood acute lymphoblastic leukemia: A role in migration and in resistance to antileukemic drugs.

    Science.gov (United States)

    Gómez, Ana M; Martínez, Carolina; González, Miguel; Luque, Alfonso; Melen, Gustavo J; Martínez, Jesús; Hortelano, Sonsoles; Lassaletta, Álvaro; Madero, Luís; Ramírez, Manuel

    2015-10-01

    We studied whether chemokines may have a role in relapses in childhood acute lymphoblastic leukemia (ALL). We compared the levels of chemokine receptors in marrow samples from 82 children with ALL at diagnosis versus 15 at relapses, and quantified the levels of chemokines in central system fluid (CSF) samples. The functional role of specific chemokines was studied in vitro and in vivo. The expression of some chemokine receptors was upregulated upon leukemic relapse, both in B- and in T-ALL, and in cases of medullary and extramedullary involvement. CXCL10 induced chemotaxis in leukemic cell lines and in primary leukemic cells, depending upon the levels of CXCR3 expression. CXCL10 specifically diminished chemotherapy-induced apoptosis on ALL cells expressing CXCR3, partially inhibiting caspase activation and maintaining the levels of the antiapoptotic protein Bcl-2. Finally, immunodeficient mice engrafted with CXCR3-expressing human leukemic cells showed decreased infiltration of marrow, spleen, and CNS after receiving a CXCR3-antagonist molecule. CXCR3 signaling in ALL may have a dual function: chemotactic for the localisation of leukemic blasts in specific niches, and it may also confer resistance to chemotherapy, enhancing the chances for relapses.

  18. Therapeutic effect of low-dose imatinib on pulmonary arterial hypertension in dogs.

    Science.gov (United States)

    Arita, Shinji; Arita, Noboru; Hikasa, Yoshiaki

    2013-03-01

    This was a pilot study to determine the effectiveness of low-dose imatinib therapy for hemodynamic disturbances, including pulmonary arterial hypertension (PAH), and clinical manifestations caused by chronic heart failure in dogs. Six client-owned dogs with PAH were administered imatinib mesylate orally, 3 mg/kg body weight q24h, for 30 d. Physical examination, blood biochemical tests, radiography, and Doppler echocardiography were performed prior to imatinib administration and again 30 days after administration. Clinical scores were significantly reduced after imatinib treatment. Systolic pulmonary arterial pressure, heart rate, maximum tricuspid regurgitation velocity, left atrium/aorta ratio, right and left ventricular Tei indexes, early diastolic transmitral flow wave/mitral annulus velocity ratio, and plasma atrial natriuretic peptide concentration decreased significantly after therapy. Diastolic blood pressure, stroke volume, cardiac output, and left ventricular fractional shortening increased significantly after therapy. These results indicate that low-dose imatinib therapy was effective for heart failure in dogs with PAH.

  19. From dissection of disease pathogenesis to elucidation of mechanisms of targeted therapies: leukemia research in the genomic era

    Institute of Scientific and Technical Information of China (English)

    Guang-biao ZHOU; Guo LI; Sai-juan CHEW; Zhu CHEN

    2007-01-01

    Leukemia is a group of heterozygous diseases of hematopoietic stem/progenitor cells that involves dynamic change in the genome. Dissection of genetic abnor-malities critical to leukemia initiation provides insights into the elusive leukemogenesis, identifies distinct subsets of leukemia and predicts prognosisindividually, and can also provide rational therapeutic targets for curative approaches. The past three decades have seen tremendous advances in the analysis of genotype-phenotype connection of leukemia, and in the identifica-tion of molecular biomarkers for leukemia subtypes. Intriguingly, differentiation therapy, targeted therapy and chemotherapy have turned several subtypes of leukemia from highly fatal to highly curable. The use of all-trans retinoic acid and arsenic trioxide, which trigger degradation of PML-RARα, the causative fusion protein generated by t (15;17) translocation in acute promyelocytic leukemia (APL),has led to a dramatic improvement of APL clinical outcome. Imatinib mesylate/Gleevec/STI571, which inhibits the tyrosine kinase activity of BCR-ABL oncoprotein, has now become the new gold standard for the treatmtent of chronic myeloid leukemia. Optimal use of chemotherapeutic agents together with a strin-gent application of prognostic factors for risk-directed therapy in clinical trials has resulted in a steady improvement in the treatment outcome of acute lympho-blastic leukemia. Hence, the pace of progress extrapolates to a prediction of leukemia control in the twenty-first century.

  20. Oridonin effectively reverses the drug resistance of cisplatin involving induction of cell apoptosis and inhibition of MMP expression in human acute myeloid leukemia cells

    Directory of Open Access Journals (Sweden)

    Yuan Zhang

    2017-03-01

    Full Text Available Cisplatin is the first generation platinum-based chemotherapy agent. However, the extensive application of cisplatin inevitably causes drug resistance, which is a major obstacle to cancer chemotherapy. Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activity. The aim of our study is to investigate the role of oridonin to reverse the cisplatin-resistance in human acute myeloid leukemia (AML cells. The effect of oridonin on human AML cell proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays in cisplatin-resistant human AML cells. Furthermore, cell apoptosis was examined by flow cytometry. The inhibitive effect of oridonin in vivo was determined using xenografted nude mice. In addition, the expressions of MMP2 and MMP9 were detected by Western blot. There was a synergistic antitumor effect between cisplatin and oridonin on cisplatin-resistant human AML cells in vitro and in vivo. In addition, the combination of cisplatin and oridonin synergistically induced cell apoptosis. Furthermore, the combination treatment not only inhibited AML cell migration and invasion, but more significantly, decreased the expressions of MMP2 and MMP9 proteins. Our results suggest that the synergistic effect between both agents is likely to be driven by the inhibition of MMP expression and the resulting increased apoptosis.

  1. Clinical effects of nilotinib on chronic myelogenous leukemia%尼洛替尼治疗慢性粒细胞白血病的临床观察

    Institute of Scientific and Technical Information of China (English)

    江慧敏; 曾庆曙; 倪婧; 鲍静; 阮敏

    2012-01-01

    To observe the efficacy and adverse reactions of a second -generation tyrosine kinase inhibitor( TKI) nilotinib on 14 chronic myelogenous leukemia ( CML) cases who were resistance or intolerance of imatinib therapy . 10 cases(71. 4% ) achieved complete hematologic remission ( CHR) ,2 cases (20% ) relapsed after remission. 2 cases ( 14. 3% ) were complete cytogenetic remission ( CCyR) , 4 cases (28. 6% ) were partial cytogenetic remission (PCyR) ,of which 1 case(16. 7% ) relapsed in 3 months after remission. Nilotinib is a effective drug for the resistance or intolerance of imatinib in patients with CML , which has a higher remission rate of hematology and genetics .%观察二代酪氨酸激酶抑制剂(TKI)尼洛替尼对14例伊马替尼耐药或不耐受的慢性粒细胞白血病(CML)患者的疗效及不良反应.14例患者有10例(71.4%)获得血液学完全缓解(CHR),其中2例(20%)缓解后复发.14例患者中2例(14.3%)获得完全遗传学缓解(CCyR),4例(28.6%)获部分遗传学缓解(PCyR),其中1例(16.7%)缓解后3个月复发.提示尼洛替尼对伊马替尼治疗耐药或不耐受的CML患者有较高的血液学及遗传学缓解率.

  2. Resultados maternos e perinatais em gestantes portadoras de leucemia Maternal and perinatal outcomes in pregnant women with leukemia

    Directory of Open Access Journals (Sweden)

    Roseli Mieko Yamamoto Nomura

    2011-08-01

    trimester opted for therapeutic abortion. Four patients with acute leukemia received chemotherapy during pregnancy, with a diagnosis established after the 20th week. In one case of ALL with a late diagnosis (30 weeks, chemotherapy was started after delivery. All pregnant women with acute leukemia developed anemia and thrombocytopenia, and four (57.1% developed febrile neutropenia. Of nine pregnant women with CML, four were treated with imatinib mesylate when they became pregnant, with treatment being interrupted in the first trimester in three of them and in the second trimester in one. During pregnancy, three patients (33.3% required no chemotherapy after discontinuation of imatinib, and six (66.7% were treated with the following drugs: interferon (n=5 and/or hydroxyurea (n=3 . In the group of pregnant women with CML, anemia occurred in four (44.4% cases and thrombocytopenia in one (11.1%. The perinatal outcomes of pregnancies complicated by acute leukemia were as follows: mean gestational age at delivery was 32 weeks (standard deviation - SD=4.4 and the mean birth weight was 1476 g (SD=657 g, there were 2 (40.0% perinatal deaths (a fetal one and a neonatal one. In pregnancies complicated by CML, the mean gestational age at delivery was 37.6 weeks (SD=1.1 and the mean birth weight was 2870 g (SD=516 g. There was no perinatal death and no fetal abnormality was detected. CONCLUSIONS: Maternal and fetal morbidity is high in pregnancies complicated by acute leukemia. Whereas, in pregnancies complicated by CML, the maternal and fetal prognosis appears to be more favorable, with greater ease in management of complications.

  3. Supportive Care for Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... low red blood cell counts, it is called autoimmune hemolytic anemia (AIHA). This also can be treated with drugs ... Leukemia Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treatment After Treatment Back To Top ...

  4. Uso neoadjuvante do mesilato de imatinibe no tratamento de GIST retal volumoso: relato de caso Neoadjuvant use of imatinib mesylate for treatment of large rectal GIST: case report

    Directory of Open Access Journals (Sweden)

    Paulo Rocha França Neto

    2011-03-01

    Full Text Available Tem sido relevante o papel das drogas que interferem na atividade tirosina-quinase dos receptores c-kit, no tratamento dos tumores derivados do estroma gastrintestinal (GISTs, sobretudo em tumores volumosos. Relata-se o caso de um paciente do sexo masculino, 56 anos, obeso, com quadro de peso retoanal associado a tenesmo e à sensação de evacuação incompleta. Foi diagnosticado volumoso GIST de reto inferior de localização posterior, visualizado por ressonância magnética e confirmado por estudo imunoistoquímico em punção-biópsia parassacral, guiada por tomografia. A impressão inicial foi de necessidade de amputação abdômino-perineal do reto, pois havia importante compressão do canal anal e do aparelho esfincteriano. Optou-se, então, por indicação de neoadjuvância com mesilato de imatinibe (Glivec® na tentativa de preservação esfincteriana. Após quatro meses de tratamento, apresentava, ao toque retal, redução significativa (cerca de 50% do volume da massa e em menor grau à ressonância magnética. Paciente foi submetido à excisão total do mesorreto e anastomose colo-anal manual, com ileostomia protetora. Evoluiu com necrose do cólon abaixado, tendo sido realizada ressecção do mesmo e colostomia terminal ilíaca. O paciente recusou a se submeter a uma nova tentativa de abaixamento colo-anal, tendo sido fechada a ileostomia e restabelecido trânsito pela colostomia ilíaca. No tratamento dos GISTs de reto muito volumosos ou irressecáveis, deve-se avaliar a indicação pré-operatória do imatinibe, uma vez que a cirurgia radical deve ser sempre indicada, a fim de minimizar a possibilidade de recorrência local.The role of drugs that intervene with the tirosine kinase activity on the c-kit receptors in the treatment of gastrointestinal stromal tumors (GISTs has been considered very important, mainly in large tumors. We report a case of a male patient, 56 years-old, obese, presenting with feeling of rectal pressure

  5. In vitro inhibitory effects of imatinib mesylate on stromal cells and hematopoietic progenitors from bone marrow

    Directory of Open Access Journals (Sweden)

    P.B. Soares

    2013-01-01

    Full Text Available Imatinib mesylate (IM is used to treat chronic myeloid leukemia (CML because it selectively inhibits tyrosine kinase, which is a hallmark of CML oncogenesis. Recent studies have shown that IM inhibits the growth of several non-malignant hematopoietic and fibroblast cells from bone marrow (BM. The aim of the present study was to evaluate the effects of IM on stromal and hematopoietic progenitor cells, specifically in the colony-forming units of granulocyte/macrophage (CFU-GM, using BM cultures from 108 1.5- to 2-month-old healthy Swiss mice. The results showed that low concentrations of IM (1.25 µM reduced the growth of CFU-GM in clonogenic assays. In culture assays with stromal cells, fibroblast proliferation and α-SMA expression by immunocytochemistry analysis were also reduced in a concentration-dependent manner, with a survival rate of approximately 50% with a dose of 2.5 µM. Cell viability and morphology were analyzed using MTT and staining with acrydine orange/ethidium bromide. Most cells were found to be viable after treatment with 5 µM IM, although there was gradual growth inhibition of fibroblastic cells while the number of round cells (macrophage-like cells increased. At higher concentrations (15 µM, the majority of cells were apoptotic and cell growth ceased completely. Oil red staining revealed the presence of adipocytes only in untreated cells (control. Cell cycle analysis of stromal cells by flow cytometry showed a blockade at the G0/G1 phases in groups treated with 5-15 µM. These results suggest that IM differentially inhibits the survival of different types of BM cells since toxic effects were achieved.

  6. What Is Chronic Myeloid Leukemia?

    Science.gov (United States)

    ... Chronic Myeloid Leukemia (CML) About Chronic Myeloid Leukemia What Is Chronic Myeloid Leukemia? Cancer starts when cells ... their treatment is the same as for adults. What is leukemia? Leukemia is a cancer that starts ...

  7. What Is Chronic Lymphocytic Leukemia?

    Science.gov (United States)

    ... Chronic Lymphocytic Leukemia (CLL) About Chronic Lymphocytic Leukemia What Is Chronic Lymphocytic Leukemia? Cancer starts when cells ... body, including the lymph nodes, liver, and spleen. What is leukemia? Leukemia is a cancer that starts ...

  8. Control of proliferating potential of myeloid leukemia cells during long-term treatment with vitamin D3 analogues and other differentiation inducers in combination with antileukemic drugs: in vitro and in vivo studies.

    Science.gov (United States)

    Kasukabe, T; Honma, Y; Hozumi, M; Suda, T; Nishii, Y

    1987-01-15

    Growth inhibition of murine and human myeloid leukemia cells by differentiation inducers during long-term culture was examined to improve the strategy for therapy of myeloid leukemia by differentiation inducers. When the effect of 1 alpha,25-dihydroxyvitamin D3, a typical differentiation inducer, on proliferation of mouse myeloid leukemia M1 cells was examined at a constant product of time and concentration (480 nM in 20 days), the continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3 was the most effective for inhibition of cell proliferation. After 20 days, the cumulative cell number was reduced about 3 X 10(5) times by continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3. Similar results were obtained when M1 cells were treated continuously with dexamethasone. M1 cells resistant to 1 alpha,25-dihydroxyvitamin D3 appeared about 25 days after the start of continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3. On the other hand, when M1 cells were treated continuously with 1 alpha,25-dihydroxyvitamin D3 and noncytotoxic doses of antileukemic drugs such as 1-beta-D-arabinofuranosylcytosine and daunomycin, resistant cells did not appear for at least 35 days. A similar effect of 1 alpha,25-dihydroxyvitamin D3 and antileukemic drugs on cell proliferation was observed with the human monoblast-like cell line U937. The survival of syngeneic SL mice inoculated with M1 cells was prolonged more by treatment with both 1 alpha-hydroxyvitamin D3 and daunomycin than by treatment with either drug alone. These results suggest that continuous treatment with both differentiation inducers and certain antileukemic drugs may be more effective therapeutically than treatment with a differentiation inducer alone.

  9. Assessment of genotoxicity and acute toxic effect of the imatinib mesylate in plant bioassays.

    Science.gov (United States)

    Pichler, Clemens; Filipič, Metka; Kundi, Michael; Rainer, Bernhard; Knasmueller, Siegfried; Mišík, Miroslav

    2014-11-01

    Imatinib mesylate (IM) is at present one of the most widely used cytostatic drugs in developed countries but information on its ecotoxicological activities is scarce. This article describes the results of the first investigation in which genotoxic and acute toxic properties of the drug were studied in higher plants. IM was tested in two widely used plant bioassays namely in micronucleus (MN) assays with meiotic tetrad cells of Tradescantia (clone #4430) and in mitotic root tip cells of Allium cepa. Additionally, acute toxic effects (inhibition of cell division and growth of roots) were monitored in the onions. Furthermore, we studied the impact of the drug on the fertility of higher plants in pollen abortion experiments with three wildlife species (Chelidonium majus, Tradescantia palludosa and Arabidopsis thaliana). In MN assays with Tradesacantia a significant effect was seen with doses ⩾10μM; the Allium MN assay was even more sensitive (LOEL⩾1.0μM). A significant decrease of the mitotic indices was detected at levels ⩾10μM in the onions and reduction of root growth with ⩾100μM. In the pollen fertility assays clear effects were observed at doses ⩾147.3mgkg(-1). Data concerning the annual use of the drug in European countries (France, Germany, Slovenia) enable the calculation of the predicted environmental concentration (PEC) values which are in the range between 3.3 and 5.0ngL(-1). Although comparisons with the genotoxic potencies of other commonly used cytostatic drugs and with highly active heavy metal compounds show that IM is an extremely potent genotoxin in higher plants, it is evident that the environmental concentrations are ⩾5 orders of magnitude lower as the levels which are required to cause adverse effects. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Inhibition of c-Kit is not required for reversal of hyperglycemia by imatinib in NOD mice.

    Directory of Open Access Journals (Sweden)

    Janet Lau

    Full Text Available AIM/HYPOTHESIS: Recent studies indicate that tyrosine kinase inhibitors, including imatinib, can reverse hyperglycemia in non-obese diabetic (NOD mice, a model of type 1 diabetes (T1D. Imatinib inhibits c-Abl, c-Kit, and PDGFRs. Next-generation tyrosine kinase inhibitors for T1D treatment should maintain activities required for efficacy while sparing inhibition of targets that might otherwise lead to adverse events. In this study, we investigated the contribution of c-Kit inhibition by imatinib in reversal of hyperglycemia in NOD mice. METHODS: The T670I mutation in c-Kit, which confers imatinib resistance, was engineered into the mouse genome and bred onto the NOD background. Hematopoietic stem cells (HSCs from NOD.c-Kit(T670I mice and NOD.c-Kit(wt littermates were expanded in the presence or absence of imatinib to verify imatinib resistance of the c-Kit(T670I allele. Diabetic mice were treated with imatinib at the onset of hyperglycemia for three weeks, and blood glucose was monitored. RESULTS: In vitro expansion of HSCs from NOD.c-Kit(wt mice was sensitive to imatinib, while expansion of HSCs from NOD.c-Kit(T670I mice was insensitive to imatinib. However, in vivo treatment with imatinib lowered blood glucose levels in both strains of mice. CONCLUSIONS/INTERPRETATION: The HSC experiment confirmed that, in NOD.c-Kit(T670I mice, c-Kit is resistant to imatinib. As both NOD.c-Kit(T670I and NOD.c-Kit(wt mice responded comparably to imatinib, c-Kit inhibition does not substantially contribute to the efficacy of imatinib in T1D. Thus, we conclude that inhibition of c-Kit is not required in next-generation tyrosine kinase inhibitors for T1D treatment, and may be selected against to improve the safety profile.

  11. Adult Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Faderl, Stefan; O’Brien, Susan; Pui, Ching-Hon; Stock, Wendy; Wetzler, Meir; Hoelzer, Dieter; Kantarjian, Hagop M.

    2016-01-01

    Acute lymphoblastic leukemia (ALL), a clonal expansion of hematopoietic blasts, is a highly heterogeneous disease comprising many entities for which distinct treatment strategies are pursued. Although ALL is a success story in pediatric oncology, results in adults lag behind those in children. An expansion of new drugs, more reliable immunologic and molecular techniques for the assessment of minimal residual disease, and efforts at more precise risk stratification are generating new aspects of adult ALL therapy. For this review, the authors summarized pertinent and recent literature on ALL biology and therapy, and they discuss current strategies and potential implications of novel approaches to the management of adult ALL. PMID:20101737

  12. Complete genome sequence, lifestyle, and multi-drug resistance of the human pathogen Corynebacterium resistens DSM 45100 isolated from blood samples of a leukemia patient

    Science.gov (United States)

    2012-01-01

    Background Corynebacterium resistens was initially recovered from human infections and recognized as a new coryneform species that is highly resistant to antimicrobial agents. Bacteremia associated with this organism in immunocompromised patients was rapidly fatal as standard minocycline therapies failed. C. resistens DSM 45100 was isolated from a blood culture of samples taken from a patient with acute myelocytic leukemia. The complete genome sequence of C. resistens DSM 45100 was determined by pyrosequencing to identify genes contributing to multi-drug resistance, virulence, and the lipophilic lifestyle of this newly described human pathogen. Results The genome of C. resistens DSM 45100 consists of a circular chromosome of 2,601,311 bp in size and the 28,312-bp plasmid pJA144188. Metabolic analysis showed that the genome of C. resistens DSM 45100 lacks genes for typical sugar uptake systems, anaplerotic functions, and a fatty acid synthase, explaining the strict lipophilic lifestyle of this species. The genome encodes a broad spectrum of enzymes ensuring the availability of exogenous fatty acids for growth, including predicted virulence factors that probably contribute to fatty acid metabolism by damaging host tissue. C. resistens DSM 45100 is able to use external L-histidine as a combined carbon and nitrogen source, presumably as a result of adaptation to the hitherto unknown habitat on the human skin. Plasmid pJA144188 harbors several genes contributing to antibiotic resistance of C. resistens DSM 45100, including a tetracycline resistance region of the Tet W type known from Lactobacillus reuteri and Streptococcus suis. The tet(W) gene of pJA144188 was cloned in Corynebacterium glutamicum and was shown to confer high levels of resistance to tetracycline, doxycycline, and minocycline in vitro. Conclusions The detected gene repertoire of C. resistens DSM 45100 provides insights into the lipophilic lifestyle and virulence functions of this newly recognized

  13. A case of chronic myelogenous leukemia in pregnancy characterized by a complex translocation t(9;22;11(q34;q11.2;q13

    Directory of Open Access Journals (Sweden)

    Surachit Kumar

    2011-11-01

    Full Text Available The management of chronic myelogenous leukemia during pregnancy requires balancing the well-being of the mother with that of the fetus. We report a case of a 26-year-old lady who was diagnosed with chronic myelogenous leukemia (CML at 15 weeks gestation and who had an atypical chromosome t(9;22;11 (q34;q11.2;q13 translocation. She was observed through the remainder of the pregnancy and the disease remained stable; she delivered a normal boy. Treatment with imatinib mesylate was initiated shortly after delivery and she went into molecular complete remission. We discuss the course of the disease and suggest guidelines for managing pregnancy with respect to the currently available agents imatinib, dasatinib and nilotinib.

  14. Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers.

    Science.gov (United States)

    Jung, J A; Kim, N; Yang, J-S; Kim, T-e; Kim, J-R; Song, G-S; Kim, H; Ko, J W; Huh, W

    2014-12-01

    Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea.An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods.A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 μg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 μg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · μg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively.A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.

  15. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Michio [Minamata City Hospital and Medical Center, Minamata City, Kumamoto 867 (Japan); Kortylewicz, Zbigniew P.; Enke, Charles A.; Mack, Elizabeth; Baranowska-Kortylewicz, Janina, E-mail: jbaranow@unmc.edu [Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, NE 68198 (United States)

    2011-05-25

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy.

  16. Imatinib mesylate inhibits osteoclastogenesis and joint destruction in rats with collagen-induced arthritis (CIA).

    Science.gov (United States)

    Ando, Wataru; Hashimoto, Jun; Nampei, Akihide; Tsuboi, Hideki; Tateishi, Kosuke; Ono, Takeshi; Nakamura, Norimasa; Ochi, Takahiro; Yoshikawa, Hideki

    2006-01-01

    Macrophage colony-stimulating factor (M-CSF) is a key factor for osteoclastogenesis at the bone-pannus interface in patients with rheumatoid arthritis as well as a receptor activator of NF-kappaB ligand (RANKL). Imatinib mesylate inhibits the phosphorylation of c-fms, a receptor for M-CSF. The present study investigates the effect of imatinib mesylate on joint destruction in rats with collagen-induced arthritis (CIA) and on osteoclastogenesis in vitro. Imatinib mesylate (50 or 150 mg/kg), dexamethasone, or vehicle was administered daily to CIA rats for 4 weeks from the onset of arthritis. Hind-paw swelling and body weight were measured weekly. At weeks 2 and 4, the metatarsophalangeal (MTP) joints and the ankle and subtalar joints were radiographically and histologically assessed. The effect of imatinib mesylate on osteoclast formation from rat bone marrow cells with M-CSF and soluble RANKL (sRANKL) in vitro was also examined. Radiographic assessment showed that 150 mg/kg imatinib mesylate suppressed the destruction of the MTP and the ankle and subtalar joints at week 2, and MTP joint destruction at week 4 in CIA rats, although hind-paw swelling was not suppressed. The number of TRAP-positive cells at the bone-pannus interface was significantly reduced in the group administered with 150 mg/kg imatinib mesylate compared with that given vehicle at week 4. Imatinib mesylate dose-dependently inhibited the proliferation of M-CSF-dependent osteoclast precursor cells in vitro as well as osteoclast formation induced by M-CSF and sRANKL. These findings suggest that imatinib mesylate could prevent joint destruction in patients with rheumatoid arthritis.

  17. Partial response to imatinib treatment in a patient with unresectable gastrointestinal stromal tumor: A case report and mini literature review

    Science.gov (United States)

    Wu, Xiaolong; Feng, Libo; Liu, Qing; Xia, Dong; Xu, Liang

    2016-01-01

    The aim of the present study was to evaluate the efficacy and safety of imatinib mesylate in unresectable gastrointestinal stromal tumor (GIST) and to discuss its therapeutic regimen. A patient with unresectable GIST is described, and several key clinical studies are reviewed, including the clinical trials B2222 and S0033, which contain recently reported results of the long-term clinical outcome of imatinib in patients with unresectable or metastatic GIST. The recent results of the two studies demonstrate the long-term efficacy and safety of imatinib for unresectable or metastatic GIST. A positive response to imatinib treatment was observed in the present patient, which is consistent with the data of the B2222 and S0033 trials. However, further long-term, large-scale, multicenter and controlled trials are required to determine the relative efficacy of combining imatinib agents with surgical procedures or administering imatinib alone. PMID:27698727

  18. Tuberculous and Non-Tuberculous Granulomatous Lymphadenitis in Patients Receiving ImatinibMesylate (Glivec for Metastatic Gastrointestinal Stromal Tumor

    Directory of Open Access Journals (Sweden)

    Abbas Agaimy

    2013-03-01

    Full Text Available Background: Imatinib mesylate (IM is the standard treatment for BCR-ABL-positive chronic myelogenous leukemia (CML and is the first-line adjuvant and palliative treatment for metastatic and inoperable gastrointestinal stromal tumor (GIST. IM is not known to be associated with an increased risk for development of granulomatous diseases. Methods: We describe our experience with 2 patients (42 and 62 years of age who developed granulomatous disease during IM treatment for metastatic GIST. Results: Mean duration of IM treatment was 12 (range 8-16 months. Enlarged lymph nodes with increased metabolism on FDG-PET-CT examination were detected and resected. Affected sites were supraclavicular (1 and subcarinal/mediastinal (1 lymph nodes. Histological examination revealed caseating and non-caseating granulomas suggestive of tuberculosis and sarcoidosis, respectively. Mycobacterium tuberculosis was detected by PCR in lymph nodes of 1 patient who was then successfully treated by anti-tuberculous agents. The other patient had negative sputum test for acid-fast bacilli and PCR-DNA-analysis was negative for M. tuberculosis and other mycobacteria. He received no anti-tuberculous therapy and had no evidence of progressive lymphadenopathy or new lung lesions during follow-up. Conclusion: Our observations underline the necessity to obtain biopsy material from enlarged or metabolically active lymph nodes developing during IM treatment for timely diagnosis and appropriate treatment of these rare complications. Follow-up without treatment is safe for patients without detectable microorganisms by sputum examination and PCR.

  19. Efficacy of imatinib dose escalation in Chinese gastrointestinal stromal tumor patients

    Institute of Scientific and Technical Information of China (English)

    Jian Li; Ji-Fang Gong; Jie Li; Jing Gao; Nai-Ping Sun; Lin Shen

    2012-01-01

    AIM:To investigate the efficacy and safety of imatinib dose escalation in Chinese patients with advanced gastrointestinal stromal tumor (GIST).METHODS:Advanced GIST patients previously failing 400 mg imatinib treatment were enrolled in this study.Patients received imatinib with dose escalation to 600mg/d,and further dose escalation to 800 mg/d if imatinib 600 mg/d failed.Progression-free survival,overall survival,clinical efficacy,c-kit/PDGFRA genotype and safety were evaluated.RESULTS:52 patients were enrolled in this study.For the 47 evaluable patients receiving imatinib (600 mg/d),the disease control rate was 40.4%,and the median progression-free survival for all patients was 17 wk (95% CI:3.9-30.1).The median overall survival after dose escalation was 81 wk (95% CI:36.2-125.8).Adverse events,mainly edema,fatigue,granulocytopenia and skin rash were tolerable.However,further dose escalation (800 mg/d) in 14 cases was ineffective,with disease progression and severe adverse events.Among 30 cases examined for gene mutations,patients with exon 9 mutations experienced a better progression-free survival of 47 wk.CONCLUSION:Imatinib dose escalation to 600 mg/d is more appropriate for Chinese patients and may achieve further survival benefit.

  20. Positron emission tomography in patients with aggressive fibromatosis/desmoid tumours undergoing therapy with imatinib

    Energy Technology Data Exchange (ETDEWEB)

    Kasper, Bernd; Hohenberger, Peter [University of Heidelberg, Sarcoma Unit, ITM - Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Mannheim (Germany); Dimitrakopoulou-Strauss, Antonia; Strauss, Ludwig G. [German Cancer Research Center, Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany)

    2010-10-15

    We used {sup 18}F-FDG PET to evaluate the FDG uptake in patients with aggressive fibromatosis (AF, also known as desmoid tumours) undergoing therapy with imatinib (imatinib mesylate, Glivec). The pilot study included nine patients with progressive AF receiving oral treatment with imatinib at a daily dose of 800 mg. Patients were examined using PET prior to the start of therapy and during imatinib treatment. Restaging according to the Response Evaluation Criteria in Solid Tumors (RECIST) was performed in parallel using CT and/or MRI and served as reference. The clinical outcomes in nine evaluable patients were as follows: seven patients with stable disease, and two patients with progressive disease. A 27% decrease in the median average standardized uptake value (SUV) of the sequential PET examinations was demonstrated in all evaluable patients with three patients (33%) showing a decrease in SUV of more than 40% (48%, 52% and 54%, respectively); no patient showed a substantial increase in SUV. To our knowledge, this is the first series of AF patients undergoing treatment with imatinib and monitored using sequential PET imaging, that allows detection of SUV changes after imatinib induction, thus helping to decide whether treatment should be continued or not. (orig.)

  1. Effects and Mechanism of Imatinib in Inhibiting Colon Cancer Cell Proliferation.

    Science.gov (United States)

    Samei, Lv; Yaling, Pang; Lihua, Yang; Yan, Zhang; Shuyan, Jiang

    2016-11-01

    BACKGROUND This study investigated the effects and mechanism of imatinib in inhibiting colon cancer cell proliferation. MATERIAL AND METHODS The SW480 cells were divided into 4 imatinib-treated groups: 0 μM, 1.25 μM, 2.5 μM, and 5μM. We analyzed the apoptosis and cell cycle of the 4 groups. The gene and protein expressions of p21, p27, HGF, and GAPDH were measured by RT-PCR and Western blot. RESULTS Compared with the 0-μM imatinib-treated group, the apoptosis of 1.25-μM, 2.5-μM, and 5.0-μM treated groups was significantly induced (P<0.05, all). The G1 phase was significantly up-regulated in the 1.25-μM, 2.5-μM, and 5.0-μM treated groups compared with the 0-μM imatinib-treated group (P<0.05, respectively), but the S and G2 phase of 3 imatinib-treated groups were significantly down-regulated (P<0.05, all). The gene and protein expressions of p27 and HGF were significantly different among the 4 groups (P<0.05, all). CONCLUSIONS Imatinib inhibits proliferation of colon cancer cells by reducing HGF and increasing p27 in a dose-dependent manner.

  2. Integrative computational in-depth analysis of dysregulated miRNA-mRNA interactions in drug-resistant pediatric acute lymphoblastic leukemia cells: an attempt to obtain new potential gene-miRNA pathways involved in response to treatment.

    Science.gov (United States)

    Mesrian Tanha, Hamzeh; Mojtabavi Naeini, Marjan; Rahgozar, Soheila; Moafi, Alireza; Honardoost, Mohammad Amin

    2016-06-01

    Acute lymphoblastic leukemia (ALL) is the major neoplasia type among children. Despite the tremendous success of current treatment strategies, drug resistance still remains a major cause of chemotherapy failure and relapse in pediatric patients. Overwhelming evidence illustrates that microRNAs (miRNAs) act as post-transcriptional regulators of drug-resistance-related genes. The current study was aimed at how dysregulated miRNA-mRNA-signaling pathway interaction networks mediate resistance to four commonly used chemotherapy agents in pediatric ALL, including asparaginase, daunorubicin, prednisolone, and vincristine. Using public expression microarray datasets, a holistic in silico approach was utilized to investigate candidate drug resistance miRNA-mRNA-signaling pathway interaction networks in pediatric ALL. Our systems biology approach nominated significant drug resistance and cross-resistance miRNAs, mRNAs, and cell signaling pathways based on anti-correlative relationship between miRNA and mRNA expression pattern. To sum up, our systemic analysis disclosed either a new potential role of miRNAs, or a possible mechanism of cellular drug resistance, in chemotherapy resistance of pediatric ALL. The current study may shed light on predicting drug response and overcoming drug resistance in childhood ALL for subsequent generations of chemotherapies.

  3. Leukemia revisited

    Energy Technology Data Exchange (ETDEWEB)

    Cronkite, E P

    1980-01-01

    Selected features of the historical development of our knowledge of leukemia are discussed. The use of different methodologies for study of the nature of leukemic cell proliferation are analyzed. The differences between older cell kinetic data using tritiated thymidine and autoradiography and the newer cell culture methods are more apparent than real. It is suggested that tritiated thymidine and extracorporeal irradiation of the blood may be useful for therapeutic agents that have not been given an adequate trial. Radiation leukemogenesis presents an opportunity for study of the nature of leukemogenesis that has not been exploited adequately.

  4. Imatinib alters cell viability but not growth factors levels in TM4 Sertoli cells

    Science.gov (United States)

    Hashemnia, Seyyed Mohammad Reza; Atari-Hajipirloo, Somayeh; Roshan-Milani, Shiva; Valizadeh, Nasim; Mahabadi, Sonya; Kheradmand, Fatemeh

    2016-01-01

    Background: The anticancer agent imatinib (IM) is a small molecular analog of ATP that inhibits tyrosine kinase activity of platelet derived growth factors (PDGFs) and stem cell factor (SCF) receptor in cancer cells. However these factors have a key role in regulating growth and development of normal Sertoli, Leydig and germ cells. Objective: The aim of this study was to determine cell viability, PDGF and SCF levels in mouse normal Sertoli cells exposed to IM. Materials and Methods: In this experimental study, the mouse TM4 Sertoli cells were treated with 0, 2.5, 5, 10 and 20 μM IM for 2, 4 or 6 days. The cell viability and growth factors levels were assessed by MTT and ELISA methods, respectively. For statistical analysis, One-Way ANOVA was performed. Results: IM showed significant decrease in Sertoli cell viability compared to control group (p=0.001). However, IM increased PDGF and SCF level insignificantly (p>0.05). Conclusion: Results suggested that IM treatment induced a dose dependent reduction of cell viability in Sertoli cells. It seems that treatment with this anticancer drug is involved in the fertility process. Further studies are needed to evaluate the role of PDGF and SCF in this cell. PMID:27738659

  5. Is imatinib still the best choice as first-line oral TKI

    Directory of Open Access Journals (Sweden)

    Shweta Bansal

    2014-01-01

    Full Text Available Targeted therapy is the buzz word these days. A decade back the emergence of tyrosine kinase inhibitor Imatinib on the horizon, as the targeted therapy, had captured the imagination of everyone in the field of cancer. It is encouraging to see a large number of patients getting relief from deadly CML disease and leading a good quality of life with the help of this drug. However, sky is not the limit and now we have second and third generation tyrosine kinase inhibitors. I still remember the sagacious smile on the face of late Dr. John Goldman, when I asked him about his preferred choice and he replied and I quote "this is going to be the debate of the decade." Here I take the opportunity to contribute to this debate. I have scrutinized various aspects of the three TKIs, now recommended, for the treatment of CML. I`m still convinced it is too early to shift our practice completely towards 2G TKI as more time is required to make a clear recommendation.

  6. Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

    Science.gov (United States)

    2013-01-22

    Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  7. Bcl-2 family members in childhood acute lymphoblastic leukemia : relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome

    NARCIS (Netherlands)

    Salomons, GS; Smets, LA; Verwijs-Janssen, M; Hart, AAM; Haarman, EG; Kaspers, GJL; Van Wering, ER; Van Der Does-Van Den Berg, A; Kamps, WA

    1999-01-01

    We have found that, in addition to Bcl-2 and Bar, the expression levels of apoptosis inducers (Bad, Bak) and inhibitors (Bcl-x(L), Mcl-1) were highly variable in blasts from 78 children with newly diagnosed acute lymphoblastic leukemia (ALL). The patients were enrolled in the national study ALL-7 of

  8. Leukemia, an effective model for chemical biology and target therapy1

    Institute of Scientific and Technical Information of China (English)

    Guo-qiang CHEN; Li-shun WANG; Ying-li WU; Yun YU

    2007-01-01

    The rapid rise of chemical biology aimed at studying signaling networks for basic cellular activities using specific, active small molecules as probes has greatly accelerated research on pathological mechanisms and target therapy of diseases.This research is especially important for malignant tumors such as leukemia, a heterogeneous group of hematopoietic malignancies that occurs worldwide. With the use of a chemical approach combined with genetic manipulation, great progresshas been achieved over the past few decades on the biological, molecular and cytogenetic aspects of leukemia, and in its diagnosis and therapy. In particular,discoveries of the clinical effectiveness of all-trans rctinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia and the kinase inhibitorsImatinib and Dasatinib in the treatment of chronic myelogenous leukemia not only make target therapy of leukemia a reality, but also push mechanisms of leukemo-genesis and leukemic cell activities forward. This review will outline advances in chemical biology that help our understanding of the molecular mechanisms of cell differentiation and apoptosis induction and target therapy of leukemia.

  9. Successful Pregnancy and Delivery in a Patient with Chronic Myeloid Leukemia while on Dasatinib Therapy

    OpenAIRE

    2010-01-01

    Here we report the case of an 18-year-old woman with chronic myeloid leukemia (CML) who became pregnant while undergoing treatment with dasatinib. Before pregnancy, she received imatinib mesylate therapy but could not tolerate the treatment. The regimen was then changed to dasatinib at a dose of 70 mg b.i.d. While she was in hematological remission and on dasatinib therapy, she became pregnant. The unplanned pregnancy was identified after the patient had experienced four weeks of amenorrhea. ...

  10. Successful pregnancy involving a man with chronic myeloid leukemia on dasatinib.

    Science.gov (United States)

    Oweini, Houssam; Otrock, Zaher K; Mahfouz, Rami A R; Bazarbachi, Ali

    2011-01-01

    Dasatinib is a highly potent Bcr-Abl inhibitor that is approved for the treatment of imatinib-resistant or -intolerant chronic myeloid leukemia (CML). The potential effects of dasatinib on sperm counts, sperm function, and fertility have not been studied yet. There is only one report in the medical literature of successful pregnancies while patients were taking dasatinib, thus making our case the second report. Here, we present the case of a 38-year-old man who conceived a healthy baby while on dasatinib therapy.

  11. Imatinib treatment of poor prognosis mesenchymal-type primary colon cancer: a proof-of-concept study in the preoperative window period (ImPACCT).

    Science.gov (United States)

    Ubink, I; Bloemendal, H J; Elias, S G; Brink, M A; Schwartz, M P; Holierhoek, Y C W; Verheijen, P M; Boerman, A W; Mathijssen, R H J; de Leng, W W J; de Weger, R A; van Grevenstein, W M U; Koopman, M; Lolkema, M P; Kranenburg, O; Borel Rinkes, I H M

    2017-04-19

    The identification of four Consensus Molecular Subtypes (CMS1-4) of colorectal cancer forms a new paradigm for the design and evaluation of subtype-directed therapeutic strategies. The most aggressive subtype - CMS4 - has the highest chance of disease recurrence. Novel adjuvant therapies for patients with CMS4 tumours are therefore urgently needed. CMS4 tumours are characterized by expression of mesenchymal and stem-like genes. Previous pre-clinical work has shown that targeting Platelet-Derived Growth Factor Receptors (PDGFRs) and the related KIT receptor with imatinib is potentially effective against mesenchymal-type colon cancer. In the present study we aim to provide proof for the concept that imatinib can reduce the aggressive phenotype of primary CMS4 colon cancer. Tumour biopsies from patients with newly diagnosed stage I-III colon cancer will be analysed with a novel RT-qPCR test to pre-select patients with CMS4 tumours. Selected patients (n = 27) will receive treatment with imatinib (400 mg per day) starting two weeks prior to planned tumour resection. To assess treatment-induced changes in the aggressive CMS4 phenotype, RNA sequencing will be performed on pre- and post-treatment tissue samples. The development of effective adjuvant therapy for primary colon cancer is hindered by multiple factors. First, new drugs that may have value in the prevention of (early) distant recurrence are almost always first tested in patients with heavily pre-treated metastatic disease. Second, measuring on-target drug effects and biological consequences in tumour tissue is not commonly a part of the study design. Third, due to the lack of patient selection tools, clinical trials in the adjuvant setting require large patient populations. Finally, the evaluation of recurrence-prevention requires a long-term follow-up. In the ImPACCT trial these issues are addressed by including newly diagnosed pre-selected patients with CMS4 tumours prior to primary tumour resection, rather

  12. The prevalence and cost of unapproved uses of top-selling orphan drugs.

    Directory of Open Access Journals (Sweden)

    Aaron S Kesselheim

    Full Text Available INTRODUCTION: The Orphan Drug Act encourages drug development for rare conditions. However, some orphan drugs become top sellers for unclear reasons. We sought to evaluate the extent and cost of approved and unapproved uses of orphan drugs with the highest unit sales. METHODS: We assessed prescription patterns for four top-selling orphan drugs: lidocaine patch (Lidoderm approved for post-herpetic neuralgia, modafinil (Provigil approved for narcolepsy, cinacalcet (Sensipar approved for hypercalcemia of parathyroid carcinoma, and imatinib (Gleevec approved for chronic myelogenous leukemia and gastrointestinal stromal tumor. We pooled patient-specific diagnosis and prescription data from two large US state pharmaceutical benefit programs for the elderly. We analyzed the number of new and total patients using each drug and patterns of reimbursement for approved and unapproved uses. For lidocaine patch, we subcategorized approved prescriptions into two subtypes of unapproved uses: neuropathic pain, for which some evidence of efficacy exists, and non-neuropathic pain. RESULTS: We found that prescriptions for lidocaine patch, modafinil, and cinacalcet associated with non-orphan diagnoses rose at substantially higher rates (average monthly increases in number of patients of 14.6, 1.45, and 1.58 than prescriptions associated with their orphan diagnoses (3.12, 0.24, and 0.03, respectively (p75%. Increases in lidocaine patch use for non-neuropathic pain far exceeded neuropathic pain (10.2 vs. 3.6 patients, p<0.001. DISCUSSION: In our sample, three of four top-selling orphan drugs were used more commonly for non-orphan indications. These orphan drugs treated common clinical symptoms (pain and fatigue or laboratory abnormalities. We should continue to monitor orphan drug use after approval to identify products that come to be widely used for non-FDA approved indications, particularly those without adequate evidence of efficacy.

  13. The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia.

    Science.gov (United States)

    Rauzan, Muhammad; Chuah, Charles T H; Ko, Tun Kiat; Ong, S Tiong

    2017-01-01

    Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance.

  14. Safranal, a Crocus sativus L constituent suppresses the growth of K-562 cells of chronic myelogenous leukemia. In silico and in vitro study.

    Science.gov (United States)

    Geromichalos, George D; Papadopoulos, Theophanis; Sahpazidou, Despina; Sinakos, Zacharias

    2014-12-01

    Crocin, a main constituent of Crocus sativus L (saffron), has been found to inhibit the growth of K-562 human chronic myelogenous leukemia (CML) cells expressing Bcr-Abl protein tyrosine kinase activity. The aim of our study is to investigate the ability of the bioactive saffron's constituents, crocin (CRC) and safranal (SFR), to inhibit the Bcr-Abl protein activity employing an in silico approach, as well as the in vitro effect of these compounds on K-562 growth and gene expression of Bcr-Abl. In silico molecular docking studies revealed that mostly SFR can be attached to Bcr-Abl protein, positioned inside the protein's binding cavity at the same place with the drug used in the treatment of CML, imatinib mesylate (IM). The predicted polar interactions and hydrophobic contacts constructing a hydrophobic cavity inside the active site, explain the observed inhibitory activity. Cytotoxicity experiments showed that SFR and CRC mediate cytotoxic response to K562 cells. In vitro studies on the expression of Bcr-Abl gene revealed that SFR and in a lesser degree IM inhibited the expression of the gene, while in contrast CRC induced an increase. The ultimate goal was to evaluate the existence of a potential antitumor activity of saffron's constituents SFR and CRC.

  15. The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia

    Science.gov (United States)

    Rauzan, Muhammad; Chuah, Charles T. H.; Ko, Tun Kiat; Ong, S. Tiong

    2017-01-01

    Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance. PMID:28301600

  16. Sensitivity of acute myeloid leukemia Kasumi-1 cells to binase toxic action depends on the expression of KIT and АML1-ETO oncogenes.

    Science.gov (United States)

    Mitkevich, Vladimir A; Petrushanko, Irina Y; Spirin, Pavel V; Fedorova, Tatiana V; Kretova, Olga V; Tchurikov, Nickolai A; Prassolov, Vladimir S; Ilinskaya, Olga N; Makarov, Alexander A

    2011-12-01

    Some RNases selectively attack malignant cells, triggering an apoptotic response, and therefore are considered as alternative chemotherapeutic drugs. Here we studied the effects of Bacillus intermedius RNase (binase) on murine myeloid progenitor cells FDC-P1; transduced FDC-P1 cells ectopically expressing mutated human KIT N822K oncogene and/or human AML1-ETO oncogene; and human leukemia Kasumi-1 cells expressing both of these oncogenes. Expression of both KIT and AML1-ETO oncogenes makes FDC-P1 cells sensitive to the toxic effects of binase. Kasumi-1 cells were the most responsive to the toxic actions of binase among the cell lines used in this work with an IC50 value of 0.56 µM. Either blocking the functional activity of the KIT protein with imatinib or knocking-down oncogene expression using lentiviral vectors producing shRNA against AML1-ETO or KIT eliminated the sensitivity of Kasumi-1 cells to binase toxic action and promoted their survival, even in the absence of KIT-dependent proliferation and antiapoptotic pathways. Here we provide evidence that the cooperative effect of the expression of mutated KIT and AML1-ETO oncogenes is crucial for selective toxic action of binase on malignant cells. These findings can facilitate clinical applications of binase providing a useful screen based on the presence of the corresponding target oncogenes in malignant cells.

  17. Kelainan Hemostasis pada Leukemia

    Directory of Open Access Journals (Sweden)

    Zelly Dia Rofinda

    2012-09-01

    Full Text Available AbstrakLatar belakang: Leukemia adalah penyakit keganasan pada jaringan hematopoietik yang ditandai denganpenggantian elemen sumsum tulang normal oleh sel darah abnormal atau sel leukemik. Salah satu manifestasi klinisdari leukemia adalah perdarahan yang disebabkan oleh berbagai kelainan hemostasis.Kelainan hemostasis yang dapat terjadi pada leukemia berupa trombositopenia, disfungsi trombosit,koagulasi intravaskuler diseminata, defek protein koagulasi, fibrinolisis primer dan trombosis. Patogenesis danpatofosiologi kelainan hemostasis pada leukemia tersebut terjadi dengan berbagai mekanisme.Kata kunci: leukemia, kelainan hemostasisAbstractBackground: AbstractLeukemia is a malignancy of hematopoietic tissue which is characterized bysubstituted of bone marrow element with abnormal blood cell or leukemic cell. One of clinical manifestation ofleukemia is bleeding that is caused by several hemostasis disorders.Hemostasis disorders in leukemia such asthrombocytopenia, platelet dysfunction, disseminated intravascular coagulation, coagulation protein defect, primaryfibrinolysis and thrombosis. Pathogenesis and pathophysiology of thus hemostasis disorders in leukemia occur withdifferent mechanism.Keywords: leukemia, hemostasis disorder

  18. Management of patients with newly diagnosed chronic myeloid leukemia: opportunities and challenges.

    Science.gov (United States)

    Jabbour, Elias; Cortes, Jorge; O'Brien, Susan; Rios, Mary Beth; Giles, Francis; Kantarjian, Hagop

    2007-03-01

    Chronic myelogenous leukemia (CML) is a progressive and often fatal hematopoietic neoplasm characterized by the presence of the Philadelphia chromosome. This arises from a balanced translocation between chromosomes 9 and 22, creating the bcr-abl fusion gene. It is often stated that the only proven curative option is allogeneic stem cell transplantation, which is indicated for only a limited subset of patients. The Bcr-Abl tyrosine kinase inhibitor imatinib represented a major advance over conventional CML therapy. After imatinib treatment, > 90% of patients had a complete hematologic response, and 70%-80% had a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging and exhibit a major change in the natural history of the disease. The understanding of some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that might overcome this resistance. The outlook today for patients with CML is much brighter than that of a few years ago.

  19. Dramatic regression and bleeding of a duodenal GIST during preoperative imatinib therapy: case report and review

    Directory of Open Access Journals (Sweden)

    Schwandner Thilo

    2010-06-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GISTs are the most common mesenchymal tumors of the digestive tract. The majority of GISTs is located in the stomach. Only 3-5% of GISTs are located in the duodenum associated with an increased risk of gastrointestinal bleeding as primary manifestation. With response rates of up to 90%, but complications like bleeding due to tumor necrosis in 3%, imatinib mesylate dramatically altered the pre- and postoperative therapy for GIST patients. Case presentation A 58-year-old female patient presented with acute upper gastrointestinal bleeding 2 weeks after a giant GIST of the duodenum had been diagnosed. Neoadjuvant imatinib therapy had been initiated to achieve a tumor downsizing prior to surgery. During emergency laparotomy a partial duodenopancreatectomy was performed to achieve a complete resection of the mass. Histology revealed a high-malignancy GIST infiltrating the duodenal wall. Adjuvant imatinib therapy was initiated. At follow-up (19 months the patient is still alive and healthy. Conclusion Giant GISTs of the duodenum are rare and - in contrast to other localizations - harbour a higher risk of serious bleeding as primary manifestation. Tumor necrosis and tumor bleeding are rare but typical adverse effects of imatinib therapy especially during treatment of high-malignancy GIST. In GIST patients with increased risk of tumor bleeding neoadjuvant imatinib therapy should thoroughly be performed during hospitalization. In cases of duodenal GIST primary surgery should be considered as treatment alternative.

  20. Researchers Identify Genomic Alterations Associated with Drug-Targetable Kinase Activation in Ph-like Acute Lymphoblastic Leukemia | Office of Cancer Genomics

    Science.gov (United States)

    Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children and young adults, and standard treatments within this population generally result in favorable outcomes. By contrast, one particular subtype of this disease, Philadelphia chromosome-like ALL (Ph-like ALL), is associated with inferior outcomes. Ph-like ALL exhibits a gene expression profile similar to chromosome 9:22 translocation positive ALL, yet it lacks the characteristic BCR-ABL fusion protein.

  1. Imatinib dose escalation versus sunitinib as a second line treatment in KIT exon 11 mutated GIST: a retrospective analysis.

    Science.gov (United States)

    Vincenzi, Bruno; Nannini, Margherita; Fumagalli, Elena; Bronte, Giuseppe; Frezza, Anna Maria; De Lisi, Delia; Spalato Ceruso, Mariella; Santini, Daniele; Badalamenti, Giuseppe; Pantaleo, Maria Abbondanza; Russo, Antonio; Dei Tos, Angelo Paolo; Casali, Paolo; Tonini, Giuseppe

    2016-10-25

    We retrospectively reviewed data from 123 patients (KIT exon 11 mutated) who received sunitinib or dose-escalated imatinib as second line.All patients progressed on imatinib (400 mg/die) and received a second line treatment with imatinib (800 mg/die) or sunitinib (50 mg/die 4 weeks on/2 off or 37.5 mg/day). Deletion versus other KIT 11 mutation was recorded, correlated with clinical benefits.64% received imatinib, 36% sunitinib. KIT exon 11 mutation was available in 94 patients. With a median follow-up of 61 months, median time to progression (TTP) in patients receiving sunitinib and imatinib was 10 (95% CI 9.7-10.9) and 5 months (95% CI 3.6-6.7) respectively (P = 0.012). No difference was found in overall survival (OS) (P = 0.883). In imatinib arm, KIT exon 11 deletions was associated with a shorter TTP (7 vs 17 months; P = 0.02), with a trend in OS (54 vs 71 months P = 0.063). No difference was found in patients treated with sunitinib (P = 0.370).A second line with sunitinib was associated with an improved TTP in KIT exon 11 mutated patients progressing on imatinib 400 mg/die. Deletions in exon 11 seemed to be correlated with worse outcome in patients receiving imatinib-based second line.

  2. Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia?

    Directory of Open Access Journals (Sweden)

    Avital F. Barak

    2011-12-01

    Full Text Available The outcome and quality of life of chronic myeloid leukemia (CML patients has remarkably changed with the treatment of tyrosine kinase inhibitors (TKIs. Currently, hematopoietic stem cell transplantation (HSCT is considered mainly as a third line salvage therapy in cases of TKIs resistance or intolerance. Here we describe a patient with chronic phase CML who developed both resistance and late occurrence of s severe thrombocytopenia on first and second generation TKIs and eventually underwent HSCT. Although the mechanism of the myelosuppression is not fully understood, we showed for the first time the development of dose dependent platelet antibodies in the presence of TKIs, suggesting the possibility of TKIs induced thrombocytopenia. Our case emphasizes that late development of severe myelosuppression during imatinib treatment is probably an important indication for consideration of early HSCT.

  3. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug 'Chlorambucil' As A Potential Treatment for Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Marie-Christine R. Shakib

    2015-06-01

    Full Text Available Chronic lymphocytic leukemia (CLL is one of the chronic lymphoproliferative disorders (lymphoid neoplasms. It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL. Beetroot-carrot juice is used as a complementary and or/ alternative therapy used in conjunction with conventional leukemic treatment (chlorambucil that has been a standard first-line chemotherapeutic agent for patients with CLL and known to have serious and undesirable side-effects. After one month and 15 days of administration of beetroot-carrot juice therapy, the patient had improved appetite, a sense of general well-being and increased vigor daily activities. Furthermore, beetroot-carrot juice was used as an adjuvant to chlorambucil resulted in a substantial reduction in leukocytes and lymphocytes count in peripheral blood and improvement in the relevant biochemical parameters.  Beetroot-carrot juice can be used as an effective treatment for CLL alone or in combination with chlorambucil when taken orally with regular diet on daily basis.

  4. Pharm GKB: Leukemia, Nonlymphocytic, Acute [PharmGKB

    Lifescience Database Archive (English)

    Full Text Available Overview Alternate Names: Synonym ANLL; Acute Nonlymphoblastic Leukemia; Acute Nonl...ymphoblastic Leukemias; Acute Nonlymphocytic Leukemia; Acute Nonlymphocytic Leukemias; Leukemia, Acute Nonly...mphoblastic; Leukemia, Acute Nonlymphocytic; Leukemia, Nonlymphoblastic, Acute; Leukemias, Acute Nonlymphoblastic; Leukemias, Acute... Nonlymphocytic; Nonlymphoblastic Leukemia, Acute; Nonlymphoblastic Leukemias, Acut...e; Nonlymphocytic Leukemia, Acute; Nonlymphocytic Leukemias, Acute PharmGKB Accessi

  5. Acute Myeloid Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, however, the bone marrow produces abnormal white blood ...

  6. Chronic Myeloid Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  7. Acute Lymphocytic Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, however, the bone marrow produces abnormal white blood ...

  8. Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  9. Nonaqueous capillary electrophoresis of imatinib mesylate and related substances.

    Science.gov (United States)

    Ye, Lei; Huang, Yifei; Li, Jian; Xiang, Guangya; Xu, Li

    2012-08-01

    In the present study, nonaqueous capillary electrophoretic separation of imatinib mesylate (IM) and related substances, N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (PYA), N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((piperazin-1-yl)methyl) benzamide (NDI) and 4-chloromethyl-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (CPB) was developed. The influential factors affecting separation, including type and concentration of the electrolyte, applied voltage, and buffer modifier were investigated. Baseline separation of the studied analytes was obtained using a buffer of 50 mM Tris and 50 mM methanesulfonic acid in methanol at a apparent pH (pH*) of 1.65. To enhance the sensitivity, large-volume sample stacking was employed for online concentration. The strongest analytical signal with a suitable separation was achieved when the injection time was 100 s. The linearity ranges of PYA and NDI were 0.100-2.50 μg mL(-1), and that of CPB was 0.125-2.50 μg mL(-1), with good coefficients (r(2) > 0.9948). The relative standard deviations of intra- and interday were satisfactory. Under the optimized conditions, seven batches of the synthesized samples were analyzed and CPB was detected in two batches. Owing to its simplicity, effectiveness, and low price, the developed method is promising for quality control of IM.

  10. [Clinical study of 32 patients with adult Philadelphia chromosome-positive acute lymphoblastic leukemia].

    Science.gov (United States)

    Chen, Xiao-Yun; Zheng, Yong-Liang; Chen, Yi-Jian

    2014-12-01

    This study was aimed to evaluate the efficacy and safety of imatinib in the treatment of patients with adult Ph chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL). A total of 32 diagnosed adult Ph(+)ALL patients from July 2007 to February 2014 in our hospital were retrospectively analyzed and were divided into two groups: imatinib plus chemotherapy group and traditional chemotherapy group. The differences between two groups were analysed in disease-free survival time (DFS), overall survival time (OS) and toxicity. The G banding technigue was used to analyse the karyotype, and the flow cytometry was applyed to detect the immune markers on surface of cells. The results showed that all patients expressed B cell and hematopietic stem/progenitor cell immune markers, out of them 21 patients (65.6%) were with myeloid antigens, 27 patients with simple Ph (+) phenotype and 5 patients with additional chromosome abnormality. The DFS and OS of the imatinib group were statistically longer than those of the traditional chemotherapy group (14.3 ± 4.7 months vs 10.7 ± 3.8 months) (P 0.05)). It is concluded that the all cases of adult Ph(+)ALL are with B cell phenotype and express hematopietic stem/progenitor cell antigen. They often accompanied by expression of myeloid antigens and additonal chromosome abnormality in genetics. The combination of imatinib with chemotherapy can prolong remission time and survival time for patients of non-hematopietic stem cell transplantation on the basis of no notably increasing the toxic effects.

  11. Leucemia eosinofílica crônica com expressão do rearranjo FIP1L1-PDGFRα: relato de caso e revisão da literatura Chronic eosinophilic leukemia with a FIP1L1-PDGFRα fusion: case report and literature review

    Directory of Open Access Journals (Sweden)

    Martha M. A. S. Arruda

    2010-01-01

    myeloproliferation or lymphoproliferation, alterations in peripheral blood and bone marrow and diffuse tissue injury due to the release of cytokines and humoral factors from eosinophilic granules. The presence of the PDGFR-α rearrangement is commonly related to chronic eosinophilic leukemia, with alterations in peripheral mastocytes and neutrophils, and rarely to acute myeloid leukemia or T lymphoblastic lymphoma with eosinophilia. The most prevalent PDGFR-α rearrangement is one resulting from an interstitial deletion in the long arm of chromosome 4, that allows the formation of a neogene from the fusion of the FIP1L1 and PDGFRα genes. This codes a constitutively active tyrosine kinase, which can be inhibited by imatinib mesylate. In 2002, the successful treatment of a patient using imatinib to treat hypereosinophilic syndrome was reported. Since then, this drug has been utilized with fast, complete and lasting clinical responses. Here we describe a case of chronic eosinophilic syndrome with expression of the FIP1L1-PDGFR-α rearrangement.

  12. Leukemia in pregnancy.

    Science.gov (United States)

    Firas, Al Sabty; Demeckova, E; Mistrik, M

    2008-01-01

    Pregnancy complicated with leukemia is rare. Validated data, out of which conclusions may be drawn regarding the management of pregnancy with leukemia are sparse. We report 5 cases of leukemia diagnosed during pregnancy with an overview of published literature (Ref. 19). Full Text (Free, PDF) www.bmj.sk.

  13. [Resection of a Huge Gastrointestinal Stromal Tumor of the Stomach Following Neoadjuvant Chemotherapy with Imatinib].

    Science.gov (United States)

    Sato, Yoshihiro; Karasawa, Hideaki; Aoki, Takeshi; Imoto, Hirofumi; Tanaka, Naoki; Watanabe, Kazuhiro; Abe, Tomoya; Nagao, Munenori; Ohnuma, Shinobu; Musha, Hiroaki; Takahashi, Masanobu; Motoi, Fuyuhiko; Naitoh, Takeshi; Ishioka, Chikashi; Unno, Michiaki

    2016-11-01

    We report a case of a huge gastric gastrointestinal stromal tumor(GIST)that was safely resected followingpreoperative imatinib therapy. A 72-year-old woman was hospitalized with severe abdominal distension. Computed tomography revealed a 27×17 cm tumor in the left upper abdominal cavity. The patient was diagnosed with high risk GIST by EUS-FNA. We initiated preoperative adjuvant chemotherapy with imatinib to achieve a reduction of operative risks and functional preservation. After 6 months of chemotherapy, CT showed a reduction in the tumor size and the patient underwent partial gastrectomy and partial resection of the diaphragm. Histologically, most of the tumor cells were replaced by hyalinized collagen and viable cells were scattered only around the blood vessels. Neoadjuvant chemotherapy with imatinib has the potential to become an important therapeutic option for the treatment of huge GISTs.

  14. Analysis of imatinib in bone marrow and plasma samples of chronic myeloid leukaemia patients using solid phase extraction LC-ESI-MS

    OpenAIRE

    Iqbal, Z; Elliott, M; Watson, D.G.; Holyoake, T. L.; Jorgensen, H G

    2011-01-01

    The LC-ESI-MS was developed and validated for the analysis of imatinib in plasma and bone marrow samples using deuterated imatinib (D(8)-IM) as an internal standard. The biological samples were extracted using Strata-X-C SPE cartridges and separated on C8 column (50 x 3 mm, 3 µm), and methanol: 0.1% formic acid (70:30) was delivered at the rate of 0.7 ml/min as a mobile phase. Imatinib was quantified in samples by monitoring the ions m/z 494.3 for imatinib and 502.3 for D8-imatinib on ma...

  15. Analysis of distribution and drug resistance of fungal infections in patients with leukemia%白血病患者真菌感染分布及药敏分析

    Institute of Scientific and Technical Information of China (English)

    刘慧; 张虹丽; 孙润月; 田姗

    2015-01-01

    OBJECTIVE To study the distribution and drug resistance of fungal infections in patients with leukemia in order to reduce the infection rate .METHODS The retrospective analysis was conducted on 56 cases of patients with leukemia in Apr .2008 to Apr .2014 in our hospital .Clinical data of the leukemia patients who had invasive fungal infections were investigated to analyze the pathogenic bacterial distribution and drug resistance .RESULTS Totally 7 of 56 cases of patients with leukemia had invasive fungal infections ,the infection rate was 12 .5% ,the specimen sources of sputum ,urine and secretion accounted for 28 .6% ,42 .8% and 14 .3% ,respectively .A total of 13 strains of fungi were cultured ,mainly including Candida ,accounting for 84 .6% .The main bacteria of fungal infection were Candida albicans ,accounting for 46 .1% .The five kinds of fungi were most sensitive to amphotericin B and voriconazole with the sensitive rate up to 100 .0% .CONCLUSION C .albicans is the main pathogen of fungal infections in patients with leukemia .Amphotericin B and voriconazole have good antibacterial properties .%目的:研究白血病患者感染真菌分布以及敏感性,以降低感染率。方法采用回顾性分析的研究方法,选取2008年4月-2014年4月收治的白血病患者56例,调查白血病患者合并侵袭性真菌感染相关资料,分析其病原菌分布及敏感性。结果56例白血病患者中发生侵袭性真菌感染7例,感染率为12.5%,其中痰液、尿液以及分泌物分别占28.6%、42.8%和14.3%;共培养出真菌13株,主要为假丝酵母菌属,占84.6%,感染的主要真菌是白色假丝酵母菌,占46.1%;5种真菌对两性霉素B、伏立康唑敏感率最高,均为100.0%。结论白色假丝酵母菌是白血病患者真菌感染主要病原菌,其中两性霉素B和伏立康唑具有较好的抗菌性。

  16. 全反式维甲酸治疗急性早幼粒细胞白血病耐药机制的研究进展%Advancement about the drug resistance of ATRA in curing acute promyelocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    唐善浩; 裴仁治

    2009-01-01

    全反式维甲酸(ATRA)治疗急性早幼粒细胞白血病(APL)的耐药机制至今还未完全清楚,它涉及到很多方面的学说,其中基因、蛋白质以及细胞信号传导途径等方面的研究目前越来越成为科学家们研究的热点.%The mechanism of drug resistance about ATRA curing acute promyelocytic leukemia involves many aspects and was not understood completely now. Among them, gene, protein and cell signal conduction way have become hot points that scientists are focusing on recently.

  17. Myeloid neoplasm with prominent eosinophilia and PDGFRA rearrangement treated with imatinib mesylate

    DEFF Research Database (Denmark)

    Rathe, Mathias; Kielsgaard Kristensen, Thomas; Møller, Michael Boe

    2010-01-01

    The FIP1L1-PDGFRA fusion gene is the most frequent genetic aberration in myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1. Affected patients in adult populations are very sensitive to imatinib therapy. Pediatric cases are rare and so far only one case...... of FIP1L1-PDGFRA positive disease has been reported. We report a 2-year-old female with a myeloid neoplasm associated with eosinophilia and rearrangement of PDGFRA. Treatment with imatinib resulted in complete and durable clinical, hematological, and molecular remission within 3 months after starting...

  18. Rationally designed aberrant kinase-targeted endogenous protein nanomedicine against oncogene mutated/amplified refractory chronic myeloid leukemia.

    Science.gov (United States)

    Retnakumari, Archana P; Hanumanthu, Prasanna Lakshmi; Malarvizhi, Giridharan L; Prabhu, Raghuveer; Sidharthan, Neeraj; Thampi, Madhavan V; Menon, Deepthy; Mony, Ullas; Menon, Krishnakumar; Keechilat, Pavithran; Nair, Shantikumar; Koyakutty, Manzoor

    2012-11-05

    Deregulated protein kinases play a very critical role in tumorigenesis, metastasis, and drug resistance of cancer. Although molecularly targeted small molecule kinase inhibitors (SMI) are effective against many types of cancer, point mutations in the kinase domain impart drug resistance, a major challenge in the clinic. A classic example is chronic myeloid leukemia (CML) caused by BCR-ABL fusion protein, wherein a BCR-ABL kinase inhibitor, imatinib (IM), was highly successful in the early chronic phase of the disease, but failed in the advanced stages due to amplification of oncogene or point mutations in the drug-binding site of kinase domain. Here, by identifying critical molecular pathways responsible for the drug-resistance in refractory CML patient samples and a model cell line, we have rationally designed an endogenous protein nanomedicine targeted to both cell surface receptors and aberrantly activated secondary kinase in the oncogenic network. Molecular diagnosis revealed that, in addition to point mutations and amplification of oncogenic BCR-ABL kinase, relapsed/refractory patients exhibited significant activation of STAT5 signaling with correlative overexpression of transferrin receptors (TfR) on the cell membrane. Accordingly, we have developed a human serum albumin (HSA) based nanomedicine, loaded with STAT5 inhibitor (sorafenib), and surface conjugated the same with holo-transferrin (Tf) ligands for TfR specific delivery. This dual-targeted "transferrin conjugated albumin bound sorafenib" nanomedicine (Tf-nAlb-Soraf), prepared using aqueous nanoprecipitation method, displayed uniform spherical morphology with average size of ∼150 nm and drug encapsulation efficiency of ∼74%. TfR specific uptake and enhanced antileukemic activity of the nanomedicine was found maximum in the most drug resistant patient sample having the highest level of STAT5 and TfR expression, thereby confirming the accuracy of our rational design and potential of dual

  19. Myeloid Leukemia while on Dasatinib Therapy

    Directory of Open Access Journals (Sweden)

    Monika Conchon

    2010-01-01

    Full Text Available Here we report the case of an 18-year-old woman with chronic myeloid leukemia (CML who became pregnant while undergoing treatment with dasatinib. Before pregnancy, she received imatinib mesylate therapy but could not tolerate the treatment. The regimen was then changed to dasatinib at a dose of 70 mg b.i.d. While she was in hematological remission and on dasatinib therapy, she became pregnant. The unplanned pregnancy was identified after the patient had experienced four weeks of amenorrhea. Because the patient elected to continue the pregnancy to term, dasatinib was stopped immediately. Meanwhile, CML hematological relapse occurred and then she was treated with interferon- (IFN- (9 million IU/day throughout the pregnancy without a complete hematological response. She successfully gave birth to a male baby at 33 weeks by cesarean section delivery with no sequelae or malformations. Although this experience is limited to a single patient, it provides a useful contribution for counselling patients inadvertently exposed to dasatinib during pregnancy.

  20. Which TKI? An embarrassment of riches for chronic myeloid leukemia patients.

    Science.gov (United States)

    Hughes, Timothy; White, Deborah

    2013-01-01

    With the approval in many countries of nilotinib and dasatinib for frontline therapy in chronic myeloid leukemia, clinicians now have to make a difficult choice. Because none of the 3 available tyrosine kinase inhibitors (TKIs) have shown a clear survival advantage, they all represent reasonable choices. However, in individual patients, the case may be stronger for a particular TKI. In the younger patient, in whom the prospect of eventually achieving treatment-free remission is likely to be of great importance, dasatinib or nilotinib may be preferred, although their advantage over imatinib in this setting remains to be proven. In patients with a higher risk of transformation (which is currently based on prognostic scoring), the more potent TKIs may be preferred because they appear to be more effective at reducing the risk of transformation to BC. However, imatinib still represents an excellent choice for many chronic myeloid leukemia patients. All of these considerations need to be made in the context of the patient's comorbidities, which may lead to one or more TKIs being ruled out of contention. Whatever first choice of TKI is made, treatment failure or intolerance must be recognized early because a prompt switch to another TKI likely provides the best chance of achieving optimal response.

  1. Segumiento de la carga tumoral en pacientes con leucemia mielode crónica de novo y en remisión citogenética completa tratados con imatinib en Colombia

    Directory of Open Access Journals (Sweden)

    Gonzalo Guevara

    2012-12-01

    Full Text Available Normal 0 21 false false false ES X-NONE X-NONE Objective: To evaluate the hematological, cytogenetic, and molecular responses in Colombian patients with CML chronic myeloid leukemia (CML treated with imatinib. Methods: Two groups of patients, one with the novo diagnostic and another in state of complete cytogenetic remission were followed for 12 months with quantitative PCR evaluations every three months and with chromosomal analysis every 6 months. Results: The group with the novo diagnosis showed 50% of complete cytogenetic remission at 12 months while the other 50% were considered to have primary resistance. Respect the molecular analysis, 10.5% of the patients reached undetectable BCR-ABL transcripts at 12 months. In the complete cytogenetic remission group, 10.6% lost the state of complete cytogene­tic remission at 12 months, 50% reached undetectable BCR-ABL transcripts but 10% showed levels higher than 10%, which in our standardization was equal to no molecular response. Conclusions: Despite having received the conventional dosages of 400 mg/day of imatinib, the cytogenetic and molecular responses obtained in our group of Colombian patients with CML, were lower than those in other international studies.

  2. Rapid recognition of drug-resistance/sensitivity in leukemic cells by Fourier transform infrared microspectroscopy and unsupervised hierarchical cluster analysis.

    Science.gov (United States)

    Bellisola, Giuseppe; Cinque, Gianfelice; Vezzalini, Marzia; Moratti, Elisabetta; Silvestri, Giovannino; Redaelli, Sara; Gambacorti Passerini, Carlo; Wehbe, Katia; Sorio, Claudio

    2013-07-21

    We tested the ability of Fourier Transform (FT) InfraRed (IR) microspectroscopy (microFTIR) in combination with unsupervised Hierarchical Cluster Analysis (HCA) in identifying drug-resistance/sensitivity in leukemic cells exposed to tyrosine kinase inhibitors (TKIs). Experiments were carried out in a well-established mouse model of human Chronic Myelogenous Leukemia (CML). Mouse-derived pro-B Ba/F3 cells transfected with and stably expressing the human p210(BCR-ABL) drug-sensitive wild-type BCR-ABL or the V299L or T315I p210(BCR-ABL) drug-resistant BCR-ABL mutants were exposed to imatinib-mesylate (IMA) or dasatinib (DAS). MicroFTIR was carried out at the Diamond IR beamline MIRIAM where the mid-IR absorbance spectra of individual Ba/F3 cells were acquired using the high brilliance IR synchrotron radiation (SR) via aperture of 15 × 15 μm(2) in sizes. A conventional IR source (globar) was used to compare average spectra over 15 cells or more. IR signatures of drug actions were identified by supervised analyses in the spectra of TKI-sensitive cells. Unsupervised HCA applied to selected intervals of wavenumber allowed us to classify the IR patterns of viable (drug-resistant) and apoptotic (drug-sensitive) cells with an accuracy of >95%. The results from microFTIR + HCA analysis were cross-validated with those obtained via immunochemical methods, i.e. immunoblotting and flow cytometry (FC) that resulted directly and significantly correlated. We conclude that this combined microFTIR + HCA method potentially represents a rapid, convenient and robust screening approach to study the impact of drugs in leukemic cells as well as in peripheral blasts from patients in clinical trials with new anti-leukemic drugs.

  3. [Therapeutic effect of focal adhesion kinase gene silence on leukemia].

    Science.gov (United States)

    Xu, Lü-Hong; Fang, Jian-Pei; Weng, Wen-Jun; Xu, Hong-Gui; Zhang, Ya-Ting

    2011-06-01

    This study was aimed to investigate the effects of focal adhesion kinase (FAK) gene silence on leukemia cell growth, leukemogenesis and efficacy of chemotherapy drug. Vector containing lentiviral-FAK-shRNA was constructed and transfected into BCR/ABL-BaF3 leukemic cells, the cell growth and apoptosis were detected in vitro. The effect of FAK shRNA on leukemogenesis was studied in a murine model with leukemia. The apoptosis of leukemia cells and survival of leukemic mice treated by FAK shRNA combined with drug STI571 were monitored. The results showed that FAK gene expression was knocked down by lentiviral-FAK-shRNA. FAK gene silencing inhibited leukemia cell growth in vitro. The apoptosis test results showed that the percentages of Annexin V(+) cells in vector control group and FAK shRNA group were (3.46 ± 0.56)% and (7.3 ± 0.79)%, respectively, and the difference was statistically significant (p silence combined with drug STI571 could enhance the apoptosis of leukemia cells and prolong survival time of leukemic mice. It is concluded that FAK gene silence inhibits leukemogenesis and promotes efficacy of chemotherapy drug on leukemia cells, indicating FAK gene silence may be considered as a new therapeutic strategy for leukemia.

  4. Mixed phenotype acute leukemia

    Institute of Scientific and Technical Information of China (English)

    Ye Zixing; Wang Shujie

    2014-01-01

    Objective To highlight the current understanding of mixed phenotype acute leukemia (MPAL).Data sources We collected the relevant articles in PubMed (from 1985 to present),using the terms "mixed phenotype acute leukemia","hybrid acute leukemia","biphenotypic acute leukemia",and "mixed lineage leukemia".We also collected the relevant studies in WanFang Data base (from 2000 to present),using the terms "mixed phenotype acute leukemia" and "hybrid acute leukemia".Study selection We included all relevant studies concerning mixed phenotype acute leukemia in English and Chinese version,with no limitation of research design.The duplicated articles are excluded.Results MPAL is a rare subgroup of acute leukemia which expresses the myeloid and lymphoid markers simultaneously.The clinical manifestations of MPAL are similar to other acute leukemias.The World Health Organization classification and the European Group for Immunological classification of Leukaemias 1998 cdteria are most widely used.MPAL does not have a standard therapy regimen.Its treatment depends mostly on the patient's unique immunophenotypic and cytogenetic features,and also the experience of individual physician.The lack of effective treatment contributes to an undesirable prognosis.Conclusion Our understanding about MPAL is still limited.The diagnostic criteria have not been unified.The treatment of MPAL remains to be investigated.The prognostic factor is largely unclear yet.A better diagnostic cdteria and targeted therapeutics will improve the therapy effect and a subsequently better prognosis.

  5. Acute pediatric leg compartment syndrome in chronic myeloid leukemia.

    Science.gov (United States)

    Cohen, Eric; Truntzer, Jeremy; Trunzter, Jeremy; Klinge, Steve; Schwartz, Kevin; Schiller, Jonathan

    2014-11-01

    Acute compartment syndrome is an orthopedic surgical emergency and may result in devastating complications in the setting of delayed or missed diagnosis. Compartment syndrome has a variety of causes, including posttraumatic or postoperative swelling, external compression, burns, bleeding disorders, and ischemia-reperfusion injury. Rare cases of pediatric acute compartment syndrome in the setting of acute myeloid leukemia and, even less commonly, chronic myeloid leukemia have been reported. The authors report the first known case of pediatric acute compartment syndrome in a patient without a previously known diagnosis of chronic myeloid leukemia. On initial examination, an 11-year-old boy presented with a 2-week history of progressive left calf pain and swelling after playing soccer. Magnetic resonance imaging scan showed a hematoma in the left superficial posterior compartment. The patient had unrelenting pain, intermittent lateral foot parethesias, and inability to bear weight. Subsequently, he was diagnosed with acute compartment syndrome and underwent fasciotomy and evacuation of a hematoma. Laboratory results showed an abnormal white blood cell count of 440×10(9)/L (normal, 4.4-11×10(9)) and international normalized ratio of 1.3 (normal, 0.8-1.2). Further testing included the BCR-ABL1 fusion gene located on the Philadelphia chromosome, leading to a diagnosis of chronic myeloid leukemia. Monotherapy with imatinib mesylate (Gleevec) was initiated. This report adds another unique case to the growing literature on compartment syndrome in the pediatric population and reinforces the need to consider compartment syndrome, even in unlikely clinical scenarios. Copyright 2014, SLACK Incorporated.

  6. Neoadjuvant Imatinib in Locally Advanced Gastrointestinal Stromal Tumors (GIST): The EORTC STBSG Experience

    NARCIS (Netherlands)

    Rutkowski, P.; Gronchi, A.; Hohenberger, P.; Bonvalot, S.; Schoffski, P.; Bauer, S.; Fumagalli, E.; Nyckowski, P.; Nguyen, B.P.; Kerst, J.M.; Fiore, M.; Bylina, E.; Hoiczyk, M.; Cats, A.; Casali, P.G.; Cesne, A. le; Treckmann, J.; Stoeckle, E.; Wilt, J.H.W. de; Sleijfer, S.; Tielen, R.; Graaf, W.T. van der; Verhoef, C.; Coevorden, F. van

    2013-01-01

    BACKGROUND: Preoperative imatinib therapy of locally advanced GIST may facilitate resection and decrease morbidity of the procedure. METHODS: We have pooled databases from 10 EORTC STBSG sarcoma centers and analyzed disease-free survival (DFS) and disease-specific survival (DSS) in 161 patients with

  7. Neoadjuvant Imatinib in Locally Advanced Gastrointestinal Stromal Tumors (GIST): The EORTC STBSG Experience.

    NARCIS (Netherlands)

    Rutkowski, P.; Gronchi, A.; Hohenberger, P.; Bonvalot, S.; Schoffski, P.; Bauer, S.; Fumagalli, E.; Nyckowski, P.; Nguyen, B.P.; Kerst, J.M.; Fiore, M.; Bylina, E.; Hoiczyk, M.; Cats, A.; Casali, P.G.; Cesne, A. le; Treckmann, J.; Stoeckle, E.; Wilt, J.H.W. de; Sleijfer, S.; Tielen, R.; Graaf, W.T.A. van der; Verhoef, C.; Coevorden, F. van

    2013-01-01

    BACKGROUND: Preoperative imatinib therapy of locally advanced GIST may facilitate resection and decrease morbidity of the procedure. METHODS: We have pooled databases from 10 EORTC STBSG sarcoma centers and analyzed disease-free survival (DFS) and disease-specific survival (DSS) in 161 patients with

  8. Bioequivalence study of 400 and 100 mg imatinib film-coated tablets in healthy volunteers.

    Science.gov (United States)

    Ostrowicz, Andrzej; Mikołajczak, Przemysław L; Wierzbicka, Marzena; Boguradzki, Piotr

    2014-01-01

    The aim of the study was to investigate the bioavailability of a generic product of 100 mg and 400 mg imatinib film-coated tablets (test) as compared to that of a branded product (reference) at the same strength to determine bioequivalence. The secondary objective of the study was to evaluate tolerability of both products. An open-label, randomized, crossover, two-period, single-dose, comparative study was conducted in 43 (Imatynib-Biofarm 100 mg film-coated tablet) and in 42 (Imatynib-Biofarm 400 mg film-coated tablet), brand name Imatenil, Caucasian healthy volunteers in fed conditions. A single oral dose administration of the test or reference product was separated by 14-day washout period. The imatinib and its metabolite N-desmethyl imatinib concentrations were determined using a validated LC MS/MS method. The results of the single-dose study in healthy volunteers indicated that the film-coated tablets of Imatynib-Biofarm 100 mg and 400 mg film-coated tablets manufactured by Biofarm Sp. z o.o. (test products) are bioequivalent to those of Glivec 100 mg and 400 mg film-coated tablets manufactured by Novartis Pharma GmbH (reference products). Both products in the two doses of imatinib were well tolerated.

  9. [Chronic lymphatic leukemia].

    Science.gov (United States)

    Bergmann, Manuela; Wendtner, Clemens-Martin

    2015-04-01

    Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. Median age at diagnosis is around 70 years. To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, CD20 and CD23 has to be confirmed by flow cytometry. A bone marrow biopsy is not mandatory for the diagnosis. Before start of treatment the assessment of 17 p deletion and/or TP53-mutational status is recommended. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts (Lymphocyte doubling time less than 6 months). The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit patients. An alternative regimen is the combination of bendamustine and rituximab (BR) or ofatumumab. Physically compromised patients can be treated with the oral drug chlorambucil in combination with an anti-CD20 antibody. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17 p deletion and/or TP53-mutation, lack of response to standard therapy or early relapse. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab, obinutuzumab, in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Novel agents have been designed to block aberrant signaling from the B

  10. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia

    Science.gov (United States)

    Steegmann, J L; Baccarani, M; Breccia, M; Casado, L F; García-Gutiérrez, V; Hochhaus, A; Kim, D-W; Kim, T D; Khoury, H J; Le Coutre, P; Mayer, J; Milojkovic, D; Porkka, K; Rea, D; Rosti, G; Saussele, S; Hehlmann, R; Clark, R E

    2016-01-01

    Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better

  11. Cytarabine dose for acute myeloid leukemia

    NARCIS (Netherlands)

    B. Löwenberg (Bob); T. Pabst (Thomas); E. Vellenga (Edo); W. van Putten; H.C. Schouten (Harry); C. Graux (Carlos); A. Ferrant (Augustin); P. Sonneveld (Pieter); B.J. Biemond (Bart); A. Gratwohl (Alois); G.E. de Greef (Georgine); L.F. Verdonck (Leo); M.R. Schaafsma (Martijn); M. Gregor (Michael); M. Theobald; U. Schanz (Urs); J. Maertens (Johan); G.J. Ossenkoppele (Gert)

    2011-01-01

    textabstractBACKGROUND: Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 m

  12. Cytarabine Dose for Acute Myeloid Leukemia

    NARCIS (Netherlands)

    Lowenberg, Bob; Pabst, Thomas; Vellenga, Edo; van Putten, Wim; Schouten, Harry C.; Graux, Carlos; Ferrant, Augustin; Sonneveld, Pieter; Biemond, Bart J.; Gratwohl, Alois; de Greef, Georgine E.; Verdonck, Leo F.; Schaafsma, Martijn R.; Gregor, Michael; Theobald, Matthias; Schanz, Urs; Maertens, Johan; Ossenkoppele, Gert J.

    2011-01-01

    BACKGROUND Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square

  13. Molecular Insights in MLL Rearranged Acute Leukemia

    NARCIS (Netherlands)

    R.W. Stam (Ronald)

    2006-01-01

    textabstractAcute lymphoblastic leukemia (ALL) in infants (<1 year of age) is characterized by a high incidence (~80%) of rearrangements of the MLL gene, resistance to several important chemotherapeutic drugs, and a poor treatment outcome. With overall survival rates for infant ALL not exceeding 50%

  14. Nanoporous capsules of block co-polymers of [(MeO-PEG-NH)-b-(L-GluA)]-PCL for the controlled release of anticancer drugs for therapeutic applications.

    Science.gov (United States)

    Amgoth, Chander; Dharmapuri, Gangappa; Kalle, Arunasree M; Paik, Pradip

    2016-03-29

    Herein, new nanoporous capsules of the block co-polymers of MeO-PEG-NH-(L-GluA)10 and polycaprolactone (PCL) have been synthesized through a surfactant-free cost-effective self-assembled soft-templating approach for the controlled release of drugs and for therapeutic applications. The nanoporous polymer capsules are designed to be biocompatible and are capable of encapsulating anticancer drugs (e.g., doxorubicin hydrochloride (DOX) and imatinib mesylate (ITM)) with a high extent (∼279 and ∼480 ng μg(-1), respectively). We have developed a nanoformulation of porous MeO-PEG-NH-(L-GluA)10-PCL capsules with DOX and ITM. The porous polymer nanoformulations have been programmed in terms of the release of anticancer drugs with a desired dose to treat the leukemia (K562) and human carcinoma cells (HepG2) in vitro and show promising IC50 values with a very high mortality of cancer cells (up to ∼96.6%). Our nanoformulation arrests the cell divisions due to 'cellular scenescence' and kills the cancer cells specifically. The present findings could enrich the effectiveness of idiosyncratic nanoporous polymer capsules for use in various other nanomedicinal and biomedical applications, such as for killing cancer cells, immune therapy, and gene delivery.

  15. Nanoporous capsules of block co-polymers of [(MeO-PEG-NH)-b-(L-GluA)]-PCL for the controlled release of anticancer drugs for therapeutic applications

    Science.gov (United States)

    Amgoth, Chander; Dharmapuri, Gangappa; Kalle, Arunasree M.; Paik, Pradip

    2016-03-01

    Herein, new nanoporous capsules of the block co-polymers of MeO-PEG-NH-(L-GluA)10 and polycaprolactone (PCL) have been synthesized through a surfactant-free cost-effective self-assembled soft-templating approach for the controlled release of drugs and for therapeutic applications. The nanoporous polymer capsules are designed to be biocompatible and are capable of encapsulating anticancer drugs (e.g., doxorubicin hydrochloride (DOX) and imatinib mesylate (ITM)) with a high extent (˜279 and ˜480 ng μg-1, respectively). We have developed a nanoformulation of porous MeO-PEG-NH-(L-GluA)10-PCL capsules with DOX and ITM. The porous polymer nanoformulations have been programmed in terms of the release of anticancer drugs with a desired dose to treat the leukemia (K562) and human carcinoma cells (HepG2) in vitro and show promising IC50 values with a very high mortality of cancer cells (up to ˜96.6%). Our nanoformulation arrests the cell divisions due to ‘cellular scenescence’ and kills the cancer cells specifically. The present findings could enrich the effectiveness of idiosyncratic nanoporous polymer capsules for use in various other nanomedicinal and biomedical applications, such as for killing cancer cells, immune therapy, and gene delivery.

  16. Successful completion of pregnancy in a patient with chronic myeloid leukemia without active intervention: a case report and review of the literature.

    Science.gov (United States)

    Cole, Suzanne; Kantarjian, Hagop; Ault, Patricia; Cortés, Jorge E

    2009-08-01

    The management of patients with chronic myeloid leukemia (CML) during pregnancy is a matter of continued debate. We present a 21-year-old woman in whom CML was diagnosed during early pregnancy. Because the patient was asymptomatic and desired to carry the pregnancy to term while minimizing fetal exposure to medication, she was observed with no therapy for the duration of her pregnancy. The white blood cell count showed a slow downward trend throughout her pregnancy. She delivered a healthy baby and breast fed for a time before initiating therapy for CML. We reviewed the published case reports of women who had a pregnancy occur in the setting of treatment with imatinib. Given the adverse effects of fetal exposure to imatinib as treatment for the mother with CML, close observation might be an option for selected patients who are diagnosed with CML while pregnant and who have minimal clinical manifestations of CML.

  17. ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells.

    Science.gov (United States)

    Cai, Jianye; Wang, Jiancheng; Huang, Yinong; Wu, Haoxiang; Xia, Ting; Xiao, Jiaqi; Chen, Xiaoyong; Li, Hongyu; Qiu, Yuan; Wang, Yingnan; Wang, Tao; Xia, Huimin; Zhang, Qi; Xiang, Andy Peng

    2016-11-10

    The bone marrow microenvironment facilitates the proliferation and survival of leukemia cells, contributing to disease relapse. Bone marrow-derived mesenchymal stem cells (MSCs) are well known to promote cancer chemoresistance via soluble factors and cell adhesion. However, little is known about the effects of MSCs on the mitochondrial dynamics of T-cell acute lymphoblastic leukemia (T-ALL) cells, or how this may influence the chemoresistance of these cells. Here, we tested both indirect (Transwell) and direct coculture strategies, and found that MSCs protected T-ALL cells from chemotherapeutic cell death and cytotoxicity under both culture conditions. In addition, cell viability was higher in the direct contact system compared with the Transwell system. We further showed that exposure of T-ALL cells to MSCs decreased mitochondrial reactive oxygen species (ROS) levels and promoted a pro-glycolytic shift that was characterized by increased glucose uptake and lactate production with concomitant reductions in adenosine triphosphate production and mitochondrial membrane potential. In T-ALL cells cocultured wi