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Sample records for acute promyelocytic leukaemia

  1. Reduced activity of TAFI (thrombin-activatable fibrinolysis inhibitor) in acute promyelocytic leukaemia

    NARCIS (Netherlands)

    Meijers, JCM; Oudijk, EJD; Mosnier, LO; Nieuwenhuis, HK; Fijnheer, R; Bouma, Bonno N.; Bos, R

    Acute promyelocytic leukaemia (APL) is a disease that is distinguished from other leukaemias by the high potential for early haemorrhagic death. Several processes are involved, such as disseminated intravascular coagulation and hyperfibrinolysis. Recently, TAFI (thrombin-activatable fibrinolysis

  2. MicroRNAs as Potential Biomarkers in Acute Promyelocytic Leukaemia

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    Imilia Ismail

    2014-01-01

    Full Text Available Acute promyelocytic leukaemia (APL is an M3 subtype of acute myeloid leukaemia (AML. This classification is based on the morphology of promyelocytic cell. The clinical characteristics of APL can be recognized by haemorrhagic episodes, a differentiation block at the promyelocytic stage, and sensitivity to the differentiation response to all-trans-retinoic acid (ATRA. Cytogenetically, APL is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the production of PML/RARα fusion protein. Recent studies reported that microRNAs (miRNAs have also been proposed to contribute to the pathogenesis of APL. miRNAs have been associated with the pathogenesis of cancer and their involvement as oncogenic and tumour suppressor activities have been identified. They are involved in various biological processes including the cell proliferation, differentiation, growth and development, metabolism, apoptosis, and haematopoiesis. The new discovery of miRNAs as possible therapeutic markers will provide new insight for the diagnosis and therapeutic entries for the treatment of APL. This review highlights the potential of miRNAs as biomarkers in APL.

  3. Pharm GKB: Leukemia, Promyelocytic, Acute [PharmGKB

    Lifescience Database Archive (English)

    Full Text Available Overview Alternate Names: Synonym APL - Acute promyelocytic leukaemia; APL - Acute ...promyelocytic leukemia; APML - Acute promyelocytic leukaemia; APML - Acute promyelocytic leukemia; Acute Promyelocytic Leukemia; Acut...e Promyelocytic Leukemias; Acute myeloid leukaemia, PML/RAR-alpha; Acute myeloid le...ukemia, PML/RAR-alpha; Acute myeloid leukemia, t(15;17)(q22;q11-12); Acute promye...locytic leukaemia (clinical); Acute promyelocytic leukaemia, FAB M3; Acute promyelocytic leukaemia, PML/RAR-alpha; Acute

  4. Acute Myeloid Leukaemia of Donor Cell Origin Developing 17 Years after Allogenic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukaemia

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    Jiménez, Pilar; Alvarez, J. Carlos; Garrido, Pilar; Lorente, J. Antonio; Palacios, Jorge; Ruiz-Cabello, Francisco

    2012-01-01

    Donor cell leukaemia (DCL) is a rare complication of allogenic hematopoietic cell transplantation (HCT). We report the case of a female patient with acute promyelocytic leukaemia (APL), FAB type M3, who developed acute myeloid leukaemia (AML) type M5 of donor origin 17 years after allogenic bone marrow transplantation (BMT) from her HLA-matched sister. Morphology and immunophenotyping showed differences with the initial leukaemia, and short tandem repeat (STR) analysis confirmed donor-type haematopoiesis. Interphase fluorescence in situ hybridisation (FISH) showed an 11q23 deletion. Given that the latency period between transplant and development of leukaemia was the longest reported to date, we discuss the mechanisms underlying delayed leukaemia onset. PMID:23675279

  5. The acute promyelocytic leukaemia success story: curing leukaemia through targeted therapies.

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    Rice, K L; de Thé, H

    2014-07-01

    The recent finding that almost all patients with acute promyelocytic leukaemia (APL) may be cured using a combination of retinoic acid (RA) and arsenic trioxide (As(2)O(3)) (N Engl J Med, 369, 2013 and 111) highlights the progress made in our understanding of APL pathogenesis and therapeutic approaches over the past 25 years. The study of APL has revealed many important lessons related to transcriptional control, nuclear organization, epigenetics and the role of proteolysis in biological control. Even more important has been the clinical demonstration that molecularly targeted therapy can eradicate disease. © 2014 The Association for the Publication of the Journal of Internal Medicine.

  6. Gemtuzumab-induced orchitis in a patient with refractory acute promyelocytic leukaemia.

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    Jalil-ur-Rehman; Kelta, Muhammad; Awad, Khalid; Beirouti, Basim Al; Nasser, Shahzad; Aslam, Muhammad

    2012-09-01

    We report the case of a 22-year-old Saudi male patient who was treated extensively in the past with various regimens for acute promyelocytic leukaemia that was refractory to all standard treatments. He was ultimately administered Gemtuzumab to induce remission and subjected to an allogeneic bone marrow transplant. However, he developed orchitis, which has not been previously reported with this agent.

  7. Tretinoin in pregnancy complicated with acute promyelocytic leukaemia.

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    Leong, K W; Teh, A; Bosco, J J

    2000-06-01

    Acute promyelocytic leukemia (APL) in pregnancy poses serious danger to both the mother and fetus. Cytotoxic chemotherapy may cause teratogenicity to the fetus. APL is unique because it is usually associated with a coagulopathy that markedly increases the risk for the mother and fetus. A 21 year old lady with APL in her third trimester of pregnancy was treated with oral tretinoin. Tretinoin reversed the coagulopathy and normalised her blood counts without causing cytotoxic damage associated with cancer chemotherapy. Fetal distress occurred at 37 weeks of gestation and an emergency caesarean section was performed without complications and no blood transfusion support was needed as her coagulopathy and thrombocytopenia had resolved. A remission was achieved with only tretinoin induction. She subsequently had consolidation and maintenance chemotherapy. The mother and baby remain well at 4 years from completion of chemotherapy. A total of 10 pregnancies associated with APL have been reported in the current literature. Premature delivery and a fetal arrhythmia were the only complications. Although retinoin is considered teratogenic, its use so far in second and third trimester has been safe.

  8. Identification of Arsenic Direct-Binding Proteins in Acute Promyelocytic Leukaemia Cells

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    Tao Zhang

    2015-11-01

    Full Text Available The identification of arsenic direct-binding proteins is essential for determining the mechanism by which arsenic trioxide achieves its chemotherapeutic effects. At least two cysteines close together in the amino acid sequence are crucial to the binding of arsenic and essential to the identification of arsenic-binding proteins. In the present study, arsenic binding proteins were pulled down with streptavidin and identified using a liquid chromatograph-mass spectrometer (LC-MS/MS. More than 40 arsenic-binding proteins were separated, and redox-related proteins, glutathione S-transferase P1 (GSTP1, heat shock 70 kDa protein 9 (HSPA9 and pyruvate kinase M2 (PKM2, were further studied using binding assays in vitro. Notably, PKM2 has a high affinity for arsenic. In contrast to PKM2, GSTP1and HSPA9 did not combine with arsenic directly in vitro. These observations suggest that arsenic-mediated acute promyelocytic leukaemia (APL suppressive effects involve PKM2. In summary, we identified several arsenic binding proteins in APL cells and investigated the therapeutic mechanisms of arsenic trioxide for APL. Further investigation into specific signal pathways by which PKM2 mediates APL developments may lead to a better understanding of arsenic effects on APL.

  9. Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis.

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    Daver, Naval; Kantarjian, Hagop; Marcucci, Guido; Pierce, Sherry; Brandt, Mark; Dinardo, Courtney; Pemmaraju, Naveen; Garcia-Manero, Guillermo; O'Brien, Susan; Ferrajoli, Alessandra; Verstovsek, Srdan; Popat, Uday; Hosing, Chitra; Anderlini, Paolo; Borthakur, Gautam; Kadia, Tapan; Cortes, Jorge; Ravandi, Farhad

    2015-03-01

    The clinical characteristics, treatment options and outcomes in patients with acute promyelocytic leukaemia (APL) and hyperleucocytosis remain poorly defined. This study reviewed 242 consecutive patients with APL; 29 patients (12%) had a white blood cell count (WBC) ≥ 50 × 10(9) /l at presentation (median WBC 85·5 × 10(9) /l). Patients with hyperleucocytosis had inferior complete remission (CR) rates (69% vs. 88%; P = 0·004) and higher 4-week mortality (24% vs. 9%; P = 0·018) compared to patients without hyperleucocytosis. We noted a trend towards inferior 3-year disease-free survival (DFS) (69% vs. 80%; P = 0·057) and inferior 3-year overall survival (OS) (74% vs. 92%; P = 0·2) for patients with hyperleucocytosis. Leukapheresis was performed in 11 (38%) of the 29 patients with hyperleucocytosis. CR rate and 3-year OS were not significantly improved in patients who received leukapheresis. CR rate and 3-year OS for the 15 patients with hyperleucocytosis treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) plus cytotoxic therapy (idarubicin or gemtuzumab ozogamicin) combinations were 100% and 100% vs. 57% and 35% for the 14 patients treated with non-ATRA/ATO combinations (P = 0·004 and P = 0·002). Leukapheresis does not improve the outcomes in patients with APL presenting with hyperleucocytosis. ATRA/ATO-based combinations are superior to other regimens in these patients.

  10. FISH Detection of PML-RARA Fusion in ins(15;17 Acute Promyelocytic Leukaemia Depends on Probe Size

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    Lynda J. Campbell

    2013-01-01

    Full Text Available The diagnosis of acute promyelocytic leukaemia (APL is usually confirmed by cytogenetics showing the characteristic t(15;17, but a minority of patients have a masked PML/RARA fusion. We report ten patients with APL and no evidence of the t(15;17, in whom the insertion of RARA into PML could not be demonstrated by initial FISH studies using a standard dual fusion probe but was readily identified using smaller probes. Given the need for rapid diagnosis of APL, it is important to be aware of the false negative rate for large PML/RARA FISH probes in the setting of masked rearrangements.

  11. Bayesian network meta-analysis comparing five contemporary treatment strategies for newly diagnosed acute promyelocytic leukaemia.

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    Wu, Fenfang; Wu, Di; Ren, Yong; Duan, Chongyang; Chen, Shangwu; Xu, Anlong

    2016-07-26

    Acute promyelocytic leukemia (APL) is a curable subtype of acute myeloid leukemia. The optimum regimen for newly diagnosed APL remains inconclusive. In this Bayesian network meta-analysis, we compared the effectiveness of five regimens-arsenic trioxide (ATO) + all-trans retinoic acid (ATRA), realgar-indigo naturalis formula (RIF) which contains arsenic tetrasulfide + ATRA, ATRA + anthracycline-based chemotherapy (CT), ATO alone and ATRA alone, based on fourteen randomized controlled trials (RCTs), which included 1407 newly diagnosed APL patients. According to the results, the ranking efficacy of the treatment, including early death and complete remission in the induction stage, was the following: 1. ATO/RIF + ATRA; 2. ATRA + CT; 3. ATO, and 4. ATRA. For long-term benefit, ATO/RIF + ATRA significantly improved overall survival (OS) (hazard ratio = 0.35, 95%CI 0.15-0.82, p = 0.02) and event-free survival (EFS) (hazard ratio = 0.32, 95%CI 0.16-0.61, p = 0.001) over ATRA + CT regimen for the low-to-intermediate-risk patients. Thus, ATO + ATRA and RIF + ATRA might be considered the optimum treatments for the newly diagnosed APL and should be recommended as the standard care for frontline therapy.

  12. JNK and NFκB dependence of apoptosis induced by vinblastine in human acute promyelocytic leukaemia cells.

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    Calviño, Eva; Tejedor, M Cristina; Sancho, Pilar; Herráez, Angel; Diez, José C

    2015-06-01

    The relationship between the mitogen-activated protein kinase response, nuclear factor-κB (NFκB) expression and the apoptosis in human acute promyelocytic leukaemia NB4 cells treated with vinblastine was investigated in this work. Cell viability, subdiploid DNA and cell cycle were analysed by propidium iodide permeability and flow cytometry analyses. Apoptosis was determined by annexin V-Fluorescein isothiocyanate assays. Western-blot analysis was used for determination of expression levels of apoptotic factors (p53, Bax and Bcl2), intracellular kinases [serine/threonine-specific protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK)], NFκB factor and caspases. Electrophoretic mobility shift assay was usefully applied to study DNA-NFκB interaction. In NB4 cells, vinblastine produces alteration of p53 and DNA fragmentation. Vinblastine treatment had an antiproliferative effect via the induction of apoptosis producing Bax/Bcl-2 imbalance. Vinblastine treatment suppressed NFκB expression and depressed NFκB-DNA binding activity while maintaining JNK activation that subsequently resulted in apoptotic response through caspase-dependent pathway. Our study provides a possible anti-cancer mechanism of vinblastine action on NB4 cells by deregulation of the intracellular signalling cascade affecting to JNK activation and NFκB expression. Moreover, JNK activation and NFκB depression can be very significant factors in apoptosis induction by vinblastine.

  13. Rapid detection of t(15;17)(q24;q21) in acute promyelocytic leukaemia by microwave-assisted fluorescence in situ hybridization.

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    Soriani, Silvia; Mura, Cinzia; Panico, Anna Rita; Scarpa, Anna Maria; Recchimuzzo, Patrizia; Dadati, Raffaella; Farioli, Renata; De Canal, Gabriella; Mura, Maria Angela; Cesana, Clara

    2017-03-01

    Acute promyelocytic leukaemia (APL) is a hematologic malignancy characterized by the rearrangement of the PML and RARα genes, mostly due to a reciprocal chromosomal translocation t(15;17)(q24;q21). A quick APL diagnosis is essential for starting a prompt suitable therapy. We describe a new rapid diagnostic laboratory approach to detect the PML-RARα rearrangement, which gives clear genetic results within 30 min of hybridization. It combines quick cell harvesting, fluorescence in situ hybridization performed with commercial DNA probe and microwave beams supplied by a domestic microwave oven. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  14. All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia : a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies

    NARCIS (Netherlands)

    Sanz, Miguel A.; Montesinos, Pau; Kim, Haesook T.; Ruiz-Argueelles, Guillermo J.; Undurraga, Maria S.; Uriarte, Maria R.; Martinez, Lem; Jacomo, Rafael H.; Gutierrez-Aguirre, Homero; Melo, Raul A. M.; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Fagundes, Evandro M.; Vellenga, Edo; Holowiecka, Alexandra; Gonzalez-Huerta, Ana J.; Fernandez, Pascual; De la Serna, Javier; Brunet, Salut; De Lisa, Elena; Gonzalez-Campos, Jose; Ribera, Jose M.; Krsnik, Isabel; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C.; Lo-Coco, Francesco; Lowenberg, Bob; Rego, Eduardo M.

    2015-01-01

    Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diag

  15. Acute leukaemia following malignant ependymoma: a case report

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    Pai, M.R.; Advani, S.H.; Gopal, R.; Nair, C.N.; Saikia, T.; Kamat, D.M.

    1985-05-01

    Though an increasing number of chemotherapy- and radiotherapy-related leukaemias are being reported, acute promyelocytic leukaemia developing as a therapy-related second malignancy is still uncommon. Here the authors report a case of acute promyelocytic leukemia, microgranular variant, developing in a case of intracranial malignant ependymoma, 1.5 years following treatment with craniospinal radiotherapy.

  16. Genital Ulcer Development in Patients with Acute Promyelocytic Leukaemia Treated with All-Trans Retinoic Acid: A Case Series

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    Mohammed Al Huneini

    2013-05-01

    Full Text Available We report here four cases of genital ulcers that developed after the administration of all-trans retinoic acid (ATRA for the treatment of acute promyelocytic leukemia (APL. Between October 2007 and March 2010, three males and one female (age range 19-35 years were identified to have genital ulcers after being prescribed all-trans retinoic acid (ATRA as a part of chemotherapy for APL. This is the first series of cases describing genital ulcers, as a unique and rare complication of ATRA used for treatment of APL in these patients, with no other cause identified. Following temporary cessation of ATRA for a few days in these three cases, improvement of the ulcers was noted.

  17. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial.

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    Burnett, A K; Hills, R K; Grimwade, D; Jovanovic, J V; Craig, J; McMullin, M F; Kell, J; Wheatley, K; Yin, J A L; Hunter, A; Milligan, D; Russell, N H

    2013-04-01

    Two hundred eighty-five patients, median age 42, with PML-RARα-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

  18. Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia.

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    Pandolfi, P P; Alcalay, M; Fagioli, M; Zangrilli, D; Mencarelli, A; Diverio, D; Biondi, A; Lo Coco, F; Rambaldi, A; Grignani, F

    1992-01-01

    The acute promyelocytic leukaemia (APL) 15;17 translocation generates a PML/RAR alpha chimeric gene which is transcribed as a fusion PML/RAR alpha mRNA. Molecular studies on a large series of APLs revealed great heterogeneity of the PML/RAR alpha transcripts due to: (i) variable breaking of chromosome 15 within three PML breakpoint cluster regions (bcr1, bcr2 and bcr3), (ii) alternative splicings of the PML portion and (iii) alternative usage of two RAR alpha polyadenylation sites. Nucleotide sequence analysis predicted two types of proteins: multiple PML/RAR alpha and aberrant PML. The PML/RAR alpha proteins varied among bcr1, 2 and 3 APL cases and within single cases. The fusion proteins contained variable portions of the PML N terminus joined to the B-F RAR alpha domains; the only PML region retained was the putative DNA binding domain. The aberrant PML proteins lacked the C terminus, which had been replaced by from two to ten amino acid residues from the RAR alpha sequence. Multiple PML/RAR alpha isoforms and aberrant PML proteins were found to coexist in all APLs. These findings indicate that two potential oncogenic proteins are generated by the t(15;17) and suggest that the PML activation pathway is altered in APLs. Images PMID:1314166

  19. Exceptions in patterns of arsenic compounds in urine of acute promyelocytic leukaemia patients treated with As2O3.

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    Šlejkovec, Zdenka; Podgornik, Helena; Černelč, Peter; Falnoga, Ingrid

    2016-02-01

    Arsenic trioxide (As(III) in solution) has been shown to be the most active single agent in combating acute promyelocytic leukemia (APL). It is metabolized and excreted via urine as monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and As(V), along with excess As(III). In our study eight APL patients were treated (intravenously) with 0.15 mg As2O3/kg/day. During the therapy As(III) and its metabolites were followed in pre- and post-infusion urine using HPLC for separation followed by on-line detection using hydride generation-atomic fluorescence spectrometry. Five patients had a normal excretion pattern of residual arsenic compounds in morning pre-infusion urine, with 15-25% of As(III), 35-55% of DMA, 25-30% of MMA and 1-5% of As(V), while three patients showed unexpected exceptions from typical excretion patterns of arsenic compounds (i) a high DMA/MMA ratio (factor 5.3), (ii) severe As(III) oxidation (10.2% As(III) converted to As(V)) or (iii) the presence of an excessive amount of As(III) (average 30.4% of total arsenic). Intriguing was the occurrence of post-infusion oxidation of As(III) to As(V) observed in almost all patients and being especially high (>40%) in patient with increased residual As(V). Results indicate that arsenic metabolites patterns can be unpredictable. Observed high levels of un-metabolised As(III) are a warning signal for side effects and for routine determination of arsenic metabolites during first days of treatment. High or low percentages of MMA or DMA did not show any observable effect on treatment results, while clear presence of post-infusion As(V) supports theoretical claims of in vivo oxidation (detoxification) of As(III) to As(V) associated with various metabolic processes.

  20. Acute promyelocytic leukaemia with translocation of t(11;17(q23;q21: a case report and review of literature

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    Xiao-li CHANG

    2013-05-01

    Full Text Available Objective  To study the clinical attributes, treatment and prognosis of acute promyelocytic leukaemia (APL with translocation of t(11;17(q23;q21. Methods  A case of APL with t(11;17(q23;q21 was reported, and the cytomorphology, immunology, cytogenetics and molecular genetics of the patient were analyzed. The related literature published in recent 20 years domestically and abroad was reviewed. Results  The case herewith studied was a male patient aged 35 years with leucocyte count (WBC of 38.17×109 in peripheral blood, and 88.5% of promyelocytes in bone marrow. Marrow karyotype analysis showed 46, XY, t(11;17(q23;q21 and PLZF-RARA rearrangement was detected. The patient was definitely diagnosed as APL with t(11;17 (q23;q21. Complete morphological and genetic remission was achieved after a combined chemotherapy of As2O3 and ATRA, then a molecular biological remission was achieved after the treatment of 3 courses of large dose cytarabine. The patient was followed up to February 2013 with disease-free survival of nearly 10 months. Up to date, 20 cases of APL with t(11;17(q23;q21 have been reported domestically and abroad, and their clinical attributes were reviewed. For the 20 cases, the mean age was 48.9±16.3 years and the male/female ratio was 9:1. Among the patients, males aged over 45 years accounted for 55%, implying that the elderly males may be high-risk population. The incidence of DIC was 60%, most of which got poor curative effect of ATRA. Conclusion  APL with t(11;17(q23;q21 is a very rare illness with distinct morphological changes and clinical characteristics. Prolonged combined chemotherapy with As2O3 and ATRA with large dose cytarabine may be beneficial to attain a remission and prolong survival.

  1. Acute promyelocytic leukaemia in patients originating in Latin America is associated with an increased frequency of the bcr1 subtype of the PML/RARalpha fusion gene.

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    Douer, Dan; Santillana, Sergio; Ramezani, Laleh; Samanez, Cesar; Slovak, Marilyn L; Lee, Ming S; Watkins, Kristy; Williams, Tony; Vallejos, Carlos

    2003-08-01

    The PML/RARalpha fusion gene in acute promyelocytic leukaemia (APL) has three subtypes based on the breakpoint site of the PML gene: long (bcr1), short (bcr3) and variable (bcr2) subtypes. The PML/RARalpha fusion protein is involved in the pathogenesis of APL and the breakpoint site of the PML gene might be associated with aetiological factor(s). Because APL is over-represented in patients that originate in Latin America (Latinos), we evaluated whether the distribution of the PML/RARalpha fusion mRNA in this population is different to that reported in non-Latinos. Among 52 APL patients (28 from Mexico and Central America diagnosed in Los Angeles and 24 from Peru, South America), bcr1, bcr2 and bcr3 expression was 75%, 10% and 15% respectively. However, bcr1 breakpoints were significantly higher compared with non-Latino patients (340/654, 52%) reported in four studies. Often bcr1 and bcr2 are reported together; 862 (60%) of 1429 non-Latino APL patients reported in nine studies were either bcr1 or bcr2, compared with 44 (85%) in our 52 Latino patients. This difference was also statistically significant when our patients were compared to each of the individual studies from USA and Europe, but not for a small series from China and Japan. These results suggest that the overrepresentation of APL among Latin American patients can be accounted for by an increase of a single subtype--bcr1, and the breakage sites in the PML gene may not be random but possibly influenced by genetic and/or environmental factor(s).

  2. Establishment of a retinoic acid-resistant human acute promyelocytic leukaemia (APL) model in human granulocyte-macrophage colony-stimulating factor (hGM-CSF) transgenic severe combined immunodeficiency (SCID) mice.

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    Fukuchi, Y; Kizaki, M; Kinjo, K; Awaya, N; Muto, A; Ito, M; Kawai, Y; Umezawa, A; Hata, J; Ueyama, Y; Ikeda, Y

    1998-10-01

    To understand the mechanisms and identify novel approaches to overcoming retinoic acid (RA) resistance in acute promyelocytic leukaemia (APL), we established the first human RA-resistant APL model in severe combined immunodeficiency (SCID) mice. UF-1 cells, an RA-resistant APL cell line established in our laboratory, were transplanted into human granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing SCID (hGMTg SCID) mice and inoculated cells formed subcutaneous tumours in all hGMTg SCID mice, but not in the non-transgenic control SCID mice. Single-cell suspensions (UF-1/GMTg SCID cells) were similar in morphological, immunological, cytogenetic and molecular genetic features to parental UF-1 cells. All-trans RA did not change the morphological features of cells or their expression of CD11b. RA did not alter the growth curve of cells as determined by MTT assay, suggesting that UF-1/GMTg SCID cells are resistant to RA. These results demonstrate that this is the first RA-resistant APL animal model that may be useful for investigating the biology of this myeloid leukaemia in vivo, as well as for evaluating novel therapeutic approaches including patients with RA-resistant APL.

  3. The influence of joint application of arsenic trioxide and daunorubicin on primary acute promyelocytic leukaemia cells and apoptosis and blood coagulation of cell strain.

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    Zhang, Xiaojuan; Qin, Na; Chen, Xinghua; Guo, Shuxia

    2015-05-01

    This test cultivated three groups of acute promyelocytic leukemia (APL) and NB4 cells in liquid in vitro, processed them with arsenic trioxide (ATO), daunorubicin (DNR), ATO+DNR respectively, and then set up blank control group. Apoptosis of cells in each group was observed using flow cytometry, procoagulant activity of APL and NB4 cells in each group was detected with recalcification time, and expressions of tissue factor (TF), thrombomodulin and annexin II of NB4 cells in each group were measured using ELISA method. The results showed that the apoptosis rate increased 4-8 times compared with blank control group after processing APL and NB4 cells with ATO and DNR; procoagulant activity decreased obviously; and expression of TF and annexin II of NB4 cells reduced significantly (P<0.05). We concluded that combination of ATO and DNR could promote APL and NB4 cell apoptosis effectively without aggravating blood coagulation disorders, which might improve coagulation function of APL by inhibiting coagulation and hyperfibrinolysis through reducing expression of TF and annexin II. This drug combination may be a safe and effective method in the treatment of APL of primary high white blood cells type.

  4. Acute promyelocytic leukemia and pregnancy.

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    Giagounidis, A A; Beckmann, M W; Giagounidis, A S; Aivado, M; Emde, T; Germing, U; Riehs, T; Heyll, A; Aul, C

    2000-04-01

    In acute promyelocytic leukemia (APL), the use of all-trans-retinoic acid (ATRA) as a differentiating agent induces complete remission in a high percentage of patients. In pregnancy, however, this drug bears the risk of severe teratogenicity to the child. We report the case of a 23-yr-old woman at 21 weeks' gestation suffering from APL. She was treated with ATRA (45 mg/m2) for 40 d and two courses of standard chemotherapy. The mother achieved complete remission within 22 d of treatment. Fetal development was normal, and a healthy premature girl was born in the 35th week of pregnancy. In a review of the literature we have identified 14 cases of APL in pregnancy treated with ATRA alone or in combination with chemotherapy. ATRA has been used as early as in the 3rd week of gestation and in no case have malformations or other teratogenic effects occurred. Side-effects, however, ranged from fetal cardiac arrhythmias to induction of labour. Although known to exhibit severe teratogenic effects during the first trimester of pregnancy, ATRA seems to be reasonably safe during the second and third trimesters in the treatment of APL. However, careful obstetric follow-up is mandatory regarding fetal cardiac complications.

  5. Oral manifestations of acute leukaemia

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    Ivanović Mirjana

    2011-01-01

    Full Text Available Acute leukaemia is the most common form of chilhood cancer. The aim of this paper was to underline the importance of oral manifestations in children with acute leukaemia. The disease and its treatment can directly or indirectly affect oral health. Oral manifestations are gingival inflammation and enlargement. Leukaemic cells are capable of infiltrating the gingiva and the deeper periodontal tissues which leads to ulceration and infection of oral tissues. Gingival bleeding is a common sign in patients with leukaemia. Symptoms include local lymphadenopathy, mucous membrane Petechiae and ecchymoses. Cytotoxic drugs have direct effects like mucositis, involving atrophy, desquamation and ulceration of the mucosa, with increasing the risk for local and systemic infections. Leukaemia can directly influence dental care and dental treatment, while oral lesions may have life-threatening consequences. Knowledge and skills among dentists may also not be adequate to treat children with acute leukaemia. It is therefore imperative that all stomatologists be aware of dental problems that occur in leukaemia in order to be able to effectively carry out appropriate measures to mitigate these problems.

  6. Genetics Home Reference: acute promyelocytic leukemia

    Science.gov (United States)

    ... a shortage of normal white and red blood cells and platelets in the body, which causes many of the signs and symptoms of the condition. People with acute promyelocytic leukemia are especially susceptible to developing bruises, small red dots under the skin (petechiae), nosebleeds, bleeding ...

  7. Successful pregnancy in acute promyelocytic leukemia.

    Science.gov (United States)

    Alegre, A; Chunchurreta, R; Rodriguez-Alarcon, J; Cruz, E; Prada, M

    1982-01-01

    A successful pregnancy with a normal baby in a woman with acute promyelocytic leukemia treated with daunorubicin from the ninth week of gestation is reported. Daunorubicin is an effective agent against this leukemia during pregnancy. That daunorubicin may be safely used, when required during the early gestation, is suggested.

  8. Acute leukaemia following renal transplantation.

    Science.gov (United States)

    Subar, M; Gucalp, R; Benstein, J; Williams, G; Wiernik, P H

    1996-03-01

    Four renal transplant patients on immunosuppressive therapy who presented with acute myeloid leukaemia are described. In two cases, azathioprine may have played an important role as a cofactor in leukaemogenesis. In a third case, the alkylating agent cyclophosphamide may have contributed. All patients were treated for leukaemia with full doses of cytotoxic chemotherapy and, in each case, a functioning renal allograft was preserved throughout the treatment despite attenuation of immunosuppressive therapy. Three patients achieved complete remission. Of the three, one is surviving at 2 years and two expired during the pancytopenic phase of their treatment with no active leukaemia present, and with intact renal function. As increasing expertise in the field of organ transplantation allows patients to survive longer, such patients' exposure to immunosuppressive and potentially leukaemogenic drugs is prolonged. The risk of secondary neoplasia has been previously documented in this population. Two of the four cases reported here suffered from polycystic kidney disease as their underlying condition. While this report suggests that the leukaemias are related to renal transplantation, we cannot rule out an association with the underlying disease which led to the transplant. This report further suggests that the leukaemia that develops in such patients may respond to standard therapy, and that such treatment does not compromise the transplanted kidney.

  9. Global characteristics of childhood acute promyelocytic leukemia.

    Science.gov (United States)

    Zhang, L; Samad, A; Pombo-de-Oliveira, M S; Scelo, G; Smith, M T; Feusner, J; Wiemels, J L; Metayer, C

    2015-03-01

    Acute promyelocytic leukemia (APL) comprises approximately 5-10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning >60 countries) identified, variation was apparent-de novo APL represented from 2% (Switzerland) to >50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed.

  10. Elastase mediated fibrinolysis in acute promyelocytic leukemia.

    Science.gov (United States)

    Oudijk, E J; Nieuwenhuis, H K; Bos, R; Fijnheer, R

    2000-06-01

    The bleeding syndrome of acute promyelocytic leukemia (APL) is complex and consists of disseminated intravascular coagulation (DIC) and hyperfibrinolysis. Elastase, derived from malignant promyelocytes, is believed to mediate the fibrinogeno- and fibrinolysis by aspecific proteolysis. In this study we measured the role of elastase in fifteen patients with APL by using an assay for elastase degraded fibrin(ogen) and the results were compared with those obtained in patients with sepsis induced DIC. High levels of elastase were observed in sepsis and APL. The levels of fibrinogen and fibrin degradation products were significantly higher in APL patients compared to patients with sepsis induced DIC. Nevertheless, the level of elastase degraded fibrin(ogen) was higher in the sepsis group (635.3 ng/ml, compared to 144.3 ng/ml in APL; p <0.0001). So, the enormous increase in fibrin and fibrinogen degradation products in APL cannot be explained by elastase activity. This study suggests a minor role for elastase mediated proteolysis in the hemorrhagic diathesis in APL patients.

  11. Acute Lymphoblastic Leukaemia presenting as Juvenile Idiopathic ...

    African Journals Online (AJOL)

    Acute Lymphoblastic Leukaemia presenting as Juvenile Idiopathic Arthritis in a Nigerian boy. ... lead to delay in commencing appropriate treatment. ... of two months duration, had an elevated Rheumatoid factor and X-ray findings suggestive of ...

  12. Gene expression profiling in acute myeloid leukaemia

    NARCIS (Netherlands)

    de Jonge, H. J. M.; Huls, G.; de Bont, E. S. J. M.

    Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by clonal malignant haematopoiesis with a differentiation arrest and excessive proliferation of leukaemic blasts. Over the past decades, the heterogeneity of AML has been illustrated by evolving classifications based on

  13. Acute leukemic appendicitis in a patient with acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Hatim Karachiwala

    2012-01-01

    Full Text Available Leukemic and lymphomatous infiltration of the appendix is a rare complication. We present the case of a 31-year-old male with acute promyelocytic leukemia who developed acute abdomen on day 11 of induction chemotherapy with idarubicin and cytarabine. After appropriate work-up, a clinical diagnosis of acute appendicitis was made. Despite severe pancytopenia, he successfully underwent laparoscopic appendectomy. The final pathology revealed leukemic infiltration of the appendix. It is hypothesized that the leukemic infiltration may play a role in the development of acute appendicitis. Further, this case demonstrates the need to maintain a high index of suspicion and prompt surgical intervention for surgical pathologies in neutropenic patients.

  14. Adenovirus protein IX sequesters host-cell promyelocytic leukaemia protein and contributes to efficient viral proliferation.

    Science.gov (United States)

    Rosa-Calatrava, Manuel; Puvion-Dutilleul, Francine; Lutz, Pierre; Dreyer, Dominique; de Thé, Hugues; Chatton, Bruno; Kedinger, Claude

    2003-10-01

    The product of adenovirus type 5 (Ad5) gene IX, protein IX (pIX), is a multifunctional protein that stabilizes the viral capsid and has transcriptional activity. We show that pIX also contributes to the Ad5-induced reorganization of the host-cell nuclear ultrastructure: pIX induces the formation of specific and dynamic nuclear inclusions, and the host promyelocytic leukaemia (PML) protein, which is the main structural organizer of PML bodies, is stably relocated and confined within the pIX-induced inclusions late in infection. Our results suggest that Ad5 has evolved a unique strategy that leads to the sustained neutralization of PML bodies throughout infection, thereby ensuring optimal viral proliferation.

  15. Notch signaling in acute promyelocytic leukemia.

    Science.gov (United States)

    Grieselhuber, N R; Klco, J M; Verdoni, A M; Lamprecht, T; Sarkaria, S M; Wartman, L D; Ley, T J

    2013-07-01

    Acute promyelocytic leukemia (APL) is initiated by the PML-RARA (PR) fusion oncogene and has a characteristic expression profile that includes high levels of the Notch ligand Jagged-1 (JAG1). In this study, we used a series of bioinformatic, in vitro, and in vivo assays to assess the role of Notch signaling in human APL samples, and in a PML-RARA knock-in mouse model of APL (Ctsg-PML-RARA). We identified a Notch expression signature in both human primary APL cells and in Kit+Lin-Sca1+ cells from pre-leukemic Ctsg-PML-RARA mice. Both genetic and pharmacologic inhibition of Notch signaling abrogated the enhanced self-renewal seen in hematopoietic stem/progenitor cells from pre-leukemic Ctsg-PML-RARA mice, but had no influence on cells from age-matched wild-type mice. In addition, six of nine murine APL tumors tested displayed diminished growth in vitro when Notch signaling was inhibited pharmacologically. Finally, we found that genetic inhibition of Notch signaling with a dominant-negative Mastermind-like protein reduced APL growth in vivo in a subset of tumors. These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis.

  16. Treatment of acute promyelocytic leukemia during pregnancy.

    Science.gov (United States)

    Yang, Daisy; Hladnik, Lindsay

    2009-06-01

    Management of the pregnant patient with acute promyelocytic leukemia (APL) is a challenge. Immediate treatment of APL is critical, as it is an oncologic emergency, with a high risk of morbidity and mortality associated with disseminated intravascular coagulation. However, administration of chemotherapy and differentiating agents in pregnancy is controversial because of potential teratogenic effects. In addition, complications associated with APL, including retinoic acid syndrome, add to the complexity of management. To better understand how to manage this complex patient care situation, we searched the PubMed database (January 1972-May 2008) for English-language articles about maternal and fetal outcomes resulting from APL treatment during pregnancy. A total of 42 cases from 35 articles were identified: 12 first-trimester, 21 second-trimester, and 9 third-trimester cases. The most commonly administered agents were all-trans-retinoic acid (ATRA), anthracyclines, and antimetabolites. Complete remission was reported in 35 (83%) of 42 patients. Administration of ATRA or chemotherapy in the first trimester was associated with an increased risk of fetal malformations and spontaneous abortion, whereas administration in the second and third trimesters was associated with relatively favorable fetal outcomes. The overall treatment of the pregnant patient with APL should include a discussion about pregnancy termination, especially if APL is diagnosed in the first trimester. If the pregnancy is to continue, then the appropriate chemotherapy regimen needs to be determined. Frequent fetal monitoring, along with aggressive management of potential APL-related complications, is necessary to allow for optimal maternal and fetal outcomes.

  17. Acute leukaemia: making sense of a complex blood cancer.

    LENUS (Irish Health Repository)

    Meenaghan, Teresa

    2012-01-01

    Acute leukaemia represents a diverse group of blood cancers that affect both children and adults. Treatment schedules for these haematology cancers are often prolonged, with many associated side effects and complications. Nurses caring for patients with acute leukaemia require an anticipatory approach, where care is aimed at minimizing the side effects of treatment and being constantly vigilant for any impending adverse effects. Moreover, patients require support for the psychosocial issues that can arise for patients during their illness. This article provides an overview of acute lymphoblastic leukaemia and acute myeloid leukaemia. Nursing considerations in the care of patients being treated for acute leukaemia are also explored.

  18. Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats

    DEFF Research Database (Denmark)

    Mortensen, B T; Jensen, P O; Helledie, N;

    1998-01-01

    The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats....... Here we have investigated how the development and progression of this leukaemia affect oxygenation, pH and proliferation of normal and leukaemic cells in vivo. Bone marrow pH was measured by a needle electrode. Nitroimidazol-theophylline (NITP) was used to identify hypoxic cells, and we applied...... bromodeoxyuridine (BrdUrd) to identify DNA replicating cells. The leukaemia progressed slowly until day 27 after which a rapid deterioration could be observed leading to severe changes over the following 5 d. In whole blood there was evidence of progressing metabolic acidosis. In bone marrow the fraction...

  19. Acute Lymphoblastic Leukaemia presenting as Juvenile Idiopathic ...

    African Journals Online (AJOL)

    PROF. EZECHUKWU

    2013-04-28

    Apr 28, 2013 ... Acute lymphoblastic leukaemia (ALL) accounts for about 77% of cases ... tosis with a White Blood Cell count (WBC) of greater than 30 x 109/L and ... tarsometatarsal, small interphalangeal joints of the feet and vertebrae.3 Our ...

  20. Childhood acute lymphoblastic leukaemia and birthweight

    DEFF Research Database (Denmark)

    Roman, Eve; Lightfoot, Tracy; Smith, Alexandra G

    2013-01-01

    BACKGROUND: Heavy birthweight is one of the few established risk factors for childhood acute lymphoblastic leukaemia (ALL). To provide new insight into this relationship, particularly at the extremes ( 4500 g), we pooled data from three of the largest childhood cancer case...

  1. Klinefelter syndrome and acute basophilic leukaemia--case report.

    Science.gov (United States)

    Ljubić, Nives; Lang, Nada; Skelin, Ika Kardum; Lasan, Ruzica; Dominis, Mara; Perković, Leila; Zupanić-Krmek, Dubraka; Grgurević-Batinica, Anita

    2010-06-01

    Patients with 47, XXY karyotype (Klinefelter syndrome) appear to have increased risk of developing cancer, especially male breast cancer, germ cell tumours and non Hodgkin lymphomas, but rarely acute myeloid leukaemia. We report a patient with acute basophilic leukaemia with 47, XXY karyotype in both the tumour and constitutional cells. Acute basophilic leukaemia is very rare disease comprising less than 1% of all acute myeloid leukaemias. Morphological characteristic of leukaemic blast cells is moderately basophilic cytoplasm containing a variable number of coarse basophilic granules. The most characteristic cytochemical reaction is metachromatic positivity with toluidine blue. Blast are myeloperoxidase negative. Also leukemic blasts express myeloid and monocyte markers. There is no consistent chromosomal abnormality identified in this leukaemia. This is the first reported case of acute basophilic leukaemia in patient with Klinefelter syndrome. In this article the medical history of the patient is given and the possible connection between Klinefelter syndrome and acute myeloid leukaemia is discussed.

  2. Induction of the pro-myelocytic leukaemia gene by type I and type II interferons

    Directory of Open Access Journals (Sweden)

    M. Heuser

    1998-01-01

    Full Text Available The physiological role of the pro-myelocytic leukaemia (PML gene product is poorly defined. Among other functions, PML is involved in haem atopoietic differentiation and in control of cell growth and tumorigenesis. We investigated the regulation of human PML expression by interferons (IFNs and IL-1 in various human haematopoietic lines (U937, THP1, HL60, NB4, in human diploid fibroblasts and in human peripheral blood leukocytes. Cytokineinduced modulation of PML expression was assessed by Northern blot analyses, flow cytometry studies and in situ immunolabelling. Our data show that IFNs and IL-1 upregulate PML transcript and protein expression in a time and dose-dependent manner. In situ immunolabelling revealed that upregulation of protein expression by IFN-α is a consequence of a marked increase in both the number and the intensity of the staining of so-called PML nuclear bodies. Our data suggest that stimulation of PML expression by interferons and IL-1 may account for upregulation of PMLproteins observed in inflammatory tissues and in proliferative states.

  3. Pneumatosis Intestinalis in a Patient with Acute Promyelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Abhishek Mangaonkar

    2015-01-01

    Full Text Available Pneumatosis Intestinalis is a rare condition characterized by the presence of gas within the intestinal wall. We describe a case of a 33-year-old woman with acute promyelocytic leukemia who developed nausea and nonbloody diarrhea. CT showed intramural air in transverse and descending colon. Patient clinically improved with conservative management.

  4. Gemtuzumab Ozogamicin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Acute Promyelocytic Leukemia

    Science.gov (United States)

    2016-07-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia

  5. Prolonged remission maintenance in acute myeloid leukaemia.

    Science.gov (United States)

    Spiers, A S; Goldman, J M; Catovsky, D; Costello, C; Galton, D A; Pitcher, C S

    1977-08-27

    Twenty-five patients with acute myeloid leukaemia were treated with three quadruple drug combinations in predetermined rotation: TRAP (thioguanine, daunorubicin, cytarabine, prednisolone); COAP (cyclophosphamide, vincristine, cytarabine, prednisolone); and POMP (prednisolone, vincristine, methotrexate, mercaptopurine). Fifteen patients (60%) achieved complete remission and five (20%) partial remission. For maintenance, five-day courses of drugs were administered every 14 to 21 days and doses were increased to tolerance. The median length of complete remission was 66 weeks. In eight patients remission maintenance treatment was discontinued and some remained in complete remission for over two years. In this series the remission induction rate was comparable with that reported for other regimens and complete remission lasted longer with this intensive maintenance regimen than with others. Nevertheless, the TRAP programme must still be regarded as only palliative treatment for acute myeloid leukaemia.

  6. Advances in Management of Acute Promyelocytic Leukemia with Arsenic Trioxide

    Institute of Scientific and Technical Information of China (English)

    MA Jun

    2007-01-01

    @@ Acute promyelocytic leukemia (APL), with specific features in cell morphology, is classified as M3 by French-American-British (FAB).Among M3, 95% of patients show specific chromosome translocation t(15;17)q(22;21) with PML-RAR α fusion gene, and 5% of patients show other subtypes. According to the statistical analysis of 2 540 adult acute myeloid leukemia (AML)cases in Harbin Institute of Hematology & Oncology, APL accounted for 23%.

  7. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure.

    Science.gov (United States)

    Ablain, Julien; Rice, Kim; Soilihi, Hassane; de Reynies, Aurélien; Minucci, Saverio; de Thé, Hugues

    2014-02-01

    Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies.

  8. Acute myeloid leukaemia after treatment for acute lymphoblastic leukaemia in girl with Bloom syndrome.

    Science.gov (United States)

    Adams, Madeleine; Jenney, Meriel; Lazarou, Laz; White, Rhian; Birdsall, Sanda; Staab, Timo; Schindler, Detlev; Meyer, Stefan

    2013-09-18

    Bloom syndrome (BS) is an inherited genomic instability disorder caused by disruption of the BLM helicase and confers an extreme cancer predisposition. Here we report on a girl with BS who developed acute lymphoblastic leukaemia (ALL) at age nine, and treatment-related acute myeloid leukaemia (t-AML) aged 12. She was compound heterozygous for the novel BLM frameshift deletion c.1624delG and the previously described c.3415C>T nonsense mutation. Two haematological malignancies in a child with BS imply a fundamental role for BLM for normal haematopoiesis, in particular in the presence of genotoxic stress.

  9. Tailored therapy of adult acute leukaemia in Jehovah's Witnesses: unjustified reluctance to treat.

    Science.gov (United States)

    Laszlo, Daniele; Agazzi, Alberto; Goldhirsch, Aron; Cinieri, Saverio; Bertolini, Francesco; Rabascio, Cristina; Pruneri, Giancarlo; Calabrese, Liliana; Cocquio, Angela; Martinelli, Giovanni

    2004-04-01

    Treatment of acute leukaemia in adult Jehovah's Witnesses (JW) is challenging because of 'a priori' refusal of most physicians to apply diagnostic and therapeutic procedures to haematological abnormalities resembling acute leukaemia. Rejection of blood transfusions by individuals of this faith is usually blamed to justify this attitude, thus leading to severe personal, medical and psychological distress related to the lack of care. We therefore intended to verify whether a standard (tailored) chemotherapy, without the use of prophylactic blood product transfusions, could be applied during treatment of acute leukaemia under such circumstances. Eleven consecutive JW adult patients with acute leukaemia, all of whom had been denied care in other institutions, were treated at the European Institute of Oncology (EIO) in Milan, Italy. Five had acute lymphoblastic leukaemia (ALL) (one bcr/abl positive), six had acute myeloid leukaemia (AML) with immunophenotype and/or cytogenetic intermediate-high risk features, except one patient with acute promyelocytic leukaemia (APML). Standard induction chemotherapy [cytosine arabinoside (ARA-C) and daunorubicin (DNR) for AML, vincristine (VCR), DNR and prednisone (PDN) for ALL, all-trans retinoic acid (ATRA) and DNR for APML] with the antracycline dose of at least 30 mg/sqm were used. All patients experienced severe anaemia after induction chemotherapy despite erythropoietin. Median haemoglobin nadir for patients with ALL and AML was 4.5 g/dL (range 1.3-6.9) and 5.1 g/dL (range 2.6-6.8), respectively. Median platelet nadir counts for all patients was 14.5 x 10(9))/L (range 1-24). One patient died during induction probably due to haemorrhage. Four of five patients with ALL achieved a complete remission (CR) (including the bcr/abl case) while among patients with AML only the one with APML achieved CR. Three patients (APML = 1 and ALL = 2) are still alive and disease-free. This small series of adult patients with leukaemia illustrates

  10. Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats

    DEFF Research Database (Denmark)

    Mortensen, B T; Jensen, P O; Helledie, N;

    1998-01-01

    cells (from about 45% to 25%), evidently as a result of the severely changed microenvironment. In this study we have demonstrated in vivo the development of an acidic and hypoxic bone marrow hampering normal haemopoiesis during leukaemic growth. Our data support the notion of BNML as a valuable tool......The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats....... Here we have investigated how the development and progression of this leukaemia affect oxygenation, pH and proliferation of normal and leukaemic cells in vivo. Bone marrow pH was measured by a needle electrode. Nitroimidazol-theophylline (NITP) was used to identify hypoxic cells, and we applied...

  11. Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia

    Science.gov (United States)

    2016-07-08

    Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Childhood Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Myeloid Neoplasm

  12. Exploring the acute myeloid leukaemias

    Directory of Open Access Journals (Sweden)

    TB Thapa

    2013-10-01

    Full Text Available The acute myeloid leukemias are genetically a diverse group of neoplasm with varied clinical behavior and response to treatment. Advances in immunophenotyping, cytogenetics and molecular genetics have resulted in better understanding of their genesis. Risk stratification of different variants is now emerging. Therapy strategies are now increasingly being developed considering the inherent biological behavior of the different subtypes. It is anticipated that in the future, deeper secrets of these once fatal diseases will be unraveled by advances in newer genomic techniques. It is hoped that future use of gene specific tailored therapy and strategies will result in longer survival in cases showing poorer prognosis at present. DOI: http://dx.doi.org/10.3126/jpn.v3i6.9001 Journal of Pathology of Nepal (2013 Vol. 3, 497-501

  13. All-trans-retinoic acid-induced pseudotumor cerebri in acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    T. M. Anoop

    2014-01-01

    Full Text Available All-trans-retinoic acid is an integral part in the treatment strategy of acute promyelocytic leukemia (APL. Here we describe a case of pseudotumor cerebri associated with all-trans-retinoic acid (ATRA during the induction therapy in an adult with acute promyelocytic leukemia (APL.

  14. HISTORY OF ACUTE PROMYELOCYTIC LEUKEMIA: A TALE OF ENDLESS REVOLUTION

    Directory of Open Access Journals (Sweden)

    Laura Cicconi

    2011-01-01

    Full Text Available Only few thousand people are diagnosed each year of Acute Promyelocytic Leukemia (APL worldwide. However, for a number of reasons such rare disease is regarded as a paradigm in the entire field of medicine. Once considered the most malignant human leukemia as well as the one associated with the worst prognosis, APL has been transformed in the past few decades into the most frequently curable one. This extraordinary progress has been the result of an unprecedented coincidence of advances in both biological and clinical research.

  15. Massive pulmonary embolism at the onset of acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Federica Sorà

    2016-07-01

    Full Text Available Life-threatening bleeding is a major and early complication of acute promyelocytic leukemia (APL, but in the last years there is a growing evidence of thromboses in  APL. We report the first case of a young woman with dyspnea as the first symptom of APL due to massive pulmonary embolism (PE successfully treated with thrombolysis for PE and heparin. APL has been processed with a combination of all-trans retinoic acid (ATRA and arsenic trioxide (ATO obtaining complete remission.

  16. Aberrant Gene Expression in Acute Myeloid Leukaemia

    DEFF Research Database (Denmark)

    Bagger, Frederik Otzen

    model to investigate the role of telomerase in AML, we were able to translate the observed effect into human AML patients and identify specific genes involved, which also predict survival patterns in AML patients. During these studies we have applied methods for investigating differentially expressed......Summary Acute Myeloid Leukaemia (AML) is an aggressive cancer of the bone marrow, affecting formation of blood cells during haematopoiesis. This thesis presents investigation of AML using mRNA gene expression profiles (GEP) of samples extracted from the bone marrow of healthy and diseased subjects....... Here GEPs from purified healthy haematopoietic populations, with different levels of differentiation, form the basis for comparison with diseased samples. We present a mathematical transformation of mRNA microarray data to make it possible to compare AML samples, carrying expanded aberrant...

  17. Serum & cerebrospinal fluid ferritin levels in children with acute leukaemia.

    Science.gov (United States)

    Srinivasan, A; Rusia, U; Anand, N K; Sood, S K

    1989-06-01

    Serum and CSF ferritin were estimated in 35 consecutive patients of acute leukaemia at the time of admission and on induction of remission. Serum ferritin levels were significantly raised in 94 per cent patients of acute leukaemia. The mean (+/- SD) serum ferritin (314.36 +/- 158.4 micrograms/1) was significantly higher when compared with control values (P less than 0.001). Remission induction resulted in significant fall in serum ferritin values to a mean of 149 (+/- 98.7) micrograms/l (P less than 0.05). Serum ferritin is thus of value in assessing the state of remission and is a sensitive indicator of the leukaemic cell mass and the state of activity of the disease. CSF ferritin levels in acute leukaemia were comparable to normal control values. CSF ferritin did not reflect CNS involvement in acute leukaemia and therefore its value as a tumour marker of CNS infiltration is doubtful.

  18. Adrenal crisis in a patient with acute myeloid leukaemia

    OpenAIRE

    Li, Wang; Okwuwa, Ikemefuna; Toledo-Frazzini, Karla; Alhomosh, Alaaedin

    2013-01-01

    Adrenal crisis is a group of clinical manifestation predominantly with hypotensive shock, electrolyte imbalance in a patient with adrenal insufficiency or in a patient who was abruptly withdrawn from glucocorticoid treatment acute myeloid leukaemia (AML) is one of the most common acute leukaemia in adults. Though the above diseases are commonly seen in individual patients, the coexistence of both conditions in the same patient is rare. We reported a 64-year-old African-American man with a his...

  19. Tretinoin, Cytarabine, and Daunorubicin Hydrochloride With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia

    Science.gov (United States)

    2013-06-04

    Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Promyelocytic Leukemia (M3); Childhood Acute Promyelocytic Leukemia (M3); Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  20. [Biphenotypic acute leukaemia with Burkitt-like cytology].

    Science.gov (United States)

    Coche, D; Bergues, B; Harrivel, V; Guillaume, N

    2009-01-01

    Biphenotypic acute leukaemia (BAL) represents about 5% of adult acute leukaemia. Based on a previously described scoring system, the European Group for Immunologic Classification of Leukaemia (EGIL) proposed a set of diagnostic criteria for BAL. This scoring system is based on the number and degree of the specificity of several markers for myeloid or T/B lymphoid blasts. Here, we report the case of a BAL with Burkitt-like cytology, corresponding to "the acute lymphoblastic leukaemia, Burkitt type" L3 for the FAB classification. By flow cytometry, the blasts showed a positivity for B lymphoid cytoplasmic (CD79a and mu) and membrane (CD19, CD22, CD24, IgM) markers AND a positivity for the myeloid (CD13, CD33, CD65, CD15) markers.

  1. Active acute leukaemia: should transplant be offered to all patients?

    Science.gov (United States)

    Avni, Batia; Shapira, Michael Y; Resnick, Igor B; Stepensky, Polina; Or, Reuven; Grisariu, Sigal

    2016-06-24

    The probability of achieving long term remission for patients with refractory acute leukaemia is very low. Allogeneic stem cell transplantation (SCT) is offered to these patients in order to improve their dismal outcome. We retrospectively analyzed 361 acute leukaemia patients, who underwent allogeneic SCT in the Hadassah's bone marrow transplantation department between the years 2005 and 2012 and identified 84 patients with active leukaemia at transplantation. Median age was 34 years. Sixty four patients were diagnosed with acute myeloid leukaemia (AML), 18 patients with acute lymphoblastic leukaemia and two with biphenotypic leukaemia. The majority of patients were diagnosed with de-novo AML and transplanted at relapse. In the surviving patients, median follow up was 15 months. One year OS was 20%. At time of last follow up, 13 patients were alive (15.5%): ten patients with AML and two patients with acute lymphoblastic leukaemia. In the univariate analysis, factors associated with significantly better overall survival were as follows: matched unrelated donor (p = 0.006), matched donor (p = 0.014) and occurrence of acute graft-versus-host disease (aGVHD) (p = 0.019). Karnofsky performance score at SCT and occurrence of cGVHD were found to be borderline significant. Only matched unrelated donor and aGVHD were found to affect overall survival significantly in the multivariate analysis. Other than performance score at SCT, none of the pretransplant patients' characteristics were found to influence survival. In conclusion, as none of the pretransplant characteristics were found to influence the ability to select the patients that will benefit from HSC transplantation, this work supports offering HSCT to all active leukaemia eligible patients with reasonable performance status. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  2. Successful therapy with ABLC, surgery and posaconazole for Rhizopus microsporus var. rhizopodiformis liver eumycetoma in a child with acute leukaemia.

    Science.gov (United States)

    Sedlacek, Petr; Vavra, Vladimir; Masova, Ivana; Codl, Daniel; Laznickova, Tana; Malaskova, Ludmila; Nyc, Otakar; Stary, Jan

    2009-05-01

    Invasive fungal infection negatively influences the morbidity and mortality in heavily immuno-incompetent patients. Diagnosis of non-Aspergillus mould infections remains challenging despite application of a wide spectrum of non-culture-based microbiological techniques. Invasive diagnostic procedures are often essential. In this article, we present the case of a 15-month-old boy diagnosed with Rhizopus microsporus var. rhizopodiformis liver mycetoma during induction chemotherapy for acute promyelocytic leukaemia. Following surgery, he was effectively treated with a combination of ABLC and posaconazole during ongoing intensive chemotherapy. Posaconazole was also used as long-term secondary prophylaxis.

  3. Cellulitis with Leukocytopenia as an Initial Sign of Acute Promyelocytic Leukemia

    OpenAIRE

    Sachiko Sakamoto; Naoki Oiso; Masakatsu Emoto; Shusuke Uchida; Ayaka Hirao; Yoichi Tatsumi; Itaru Matsumura; Akira Kawada

    2012-01-01

    Patients with hematologic malignancies are immunosuppressive and may develop cutaneous or invasive infections as a primary sign of immune suppression. Acute promyelocytic leukemia (acute myeloid leukemia M3) is caused by translocation of reciprocal chromosomal rearrangement t(15;17), which produces an oncogenic protein. We herein describe a 71-year-old man having cellulitis with leukocytopenia as a first sign of acute promyelocytic leukemia. Dermatologists and hematologists should keep in min...

  4. Acute Promyelocytic Leukemia in Four Year Old Female Child - A Case Report

    Directory of Open Access Journals (Sweden)

    Anirudha V. Kushtagi

    2014-07-01

    Full Text Available Leukemia is the most common malignancy of childhood representing about 30 % of oncohematological diseases diagnosed in children less than 15 years of age. We report the case of a 4 year old girl with acute promyelocytic leukemia whose blasts showed the morphology characteristic of acute promyelocytic leukemia variant. The case is reported because in the paediatric population the acute promyelocytic leukemia is a rare occurrence moreover, it represent a true oncohematology emergency, in this case the laboratory has a significant role since the timing of diagnosis must be very short. It helps in therapeutic protocols compared to conventional therapeutic protocols in Acute Myeloid Leukemia (AML, the introduction of retinoid All-Trans-Retinoic Acid (ATRA, both in children and adults with Acute Promyelocytic Leukemia (APL, has significantly reduced the early mortality.

  5. Survival and treatment response in adults with acute promyelocytic leukemia treated with a modified International Consortium on Acute Promyelocytic Leukemia protocol

    Directory of Open Access Journals (Sweden)

    Erick Crespo-Solis

    Full Text Available ABSTRACT Acute promyelocytic leukemia has good prognosis in view of the high complete remission and survival rates achieved with therapies containing all-trans retinoic acid or arsenic trioxide. However, there is a significant risk of death during induction due to hemorrhage secondary to disseminated intravascular coagulation. This has contributed to a gap in the prognosis of patients between developed and developing countries. The International Consortium on Acute Promyelocytic Leukemia was created in 2005 and proposed a treatment protocol based on daunorubicin and all-trans retinoic acid stratified by risk geared toward developing countries. Herein are presented the results from the first patient cohort treated in a single developing country hospital employing a slightly modified version of the International Consortium protocol in a real life setting. Twenty patients with acute promyelocytic leukemia were enrolled: 27.8% had low-risk, 55.6% intermediate risk and 16.7% high-risk. The complete remission rate was 94.4% after a median of 42 days. Both relapse rates and death rates were one patient (5.5% each. No deaths were observed during consolidation. After a median follow-up of 29 months, the overall survival rate was 89.1%. Efficacy and safety of the International Consortium on Acute Promyelocytic Leukemia protocol has been reproduced in acute promyelocytic leukemia patients from a developing country.

  6. Acute Promyelocytic Leukemia with i(17)(q10)

    Science.gov (United States)

    Inamura, Junki; Ikuta, Katsuya; Tsukada, Nodoka; Hosoki, Takaaki; Shindo, Motohiro; Sato, Kazuya

    2016-01-01

    We herein report a rare chromosomal abnormality observed in an acute promyelocytic leukemia (APL) patient. She had several APL derivative clones including a clone with i(17)(q10) abnormality, which consists of two kinds of structural abnormalities, a cryptic translocation of t(15;17) and an isochromosome of 17q. Although an obvious microscopic t(15;17) change was not observed on either arms of the isochromosome, PML/RARα fusion signals were detected on an interphase fluorescence in situ hybridization analysis. By several cytogenetic analyses of her bone marrow cells, it was confirmed that the i(17)(q10) clone was derived from the classic t(15;17) clone via another intervening clone, cryptic t(15;17). PMID:27853080

  7. Acute promyelocytic leukemia: what is the new standard of care?

    Science.gov (United States)

    Watts, Justin M; Tallman, Martin S

    2014-09-01

    Acute promyelocytic leukemia (APL) is one of the most exciting stories of modern medicine. Once a disease that was highly lethal, the majority of patients are now cured with the advent of molecularly targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In many patients, chemotherapy can be omitted completely, particularly in patients with low- or intermediate-risk disease (white blood cell count ≤ 10,000/μl). Recent data show overall survival exceeding 90% with ATRA and ATO-based induction and consolidation strategies. In the uncommon patient in whom relapse does occur, most can still be cured with ATO and autologous hematopoietic cell transplantation. Remaining challenges in APL management include the rapid identification and treatment of newly diagnosed patients to decrease the early death rate, optimizing treatment strategies in high-risk patients (white blood cell count>10,000/μl), and the role of maintenance therapy in lower risk patients.

  8. Acute Promyelocytic Leukemia Presenting with Severe Marrow Fibrosis

    Directory of Open Access Journals (Sweden)

    Harsh Shah

    2015-01-01

    Full Text Available We report a case of acute promyelocytic leukemia (APL presenting with severely fibrotic marrow. There are four other reports of similar cases in the literature. Our patient was treated with All-Transretinoic Acid- (ATRA- containing induction chemotherapy, followed by consolidation and maintenance therapy. He achieved a complete morphologic remission with adequate count recovery in a timely fashion, and later a molecular remission was documented. The patient remains in molecular remission and demonstrates normal blood counts now more than 4 years after induction. Since the morphological appearance may not be typical and the bone marrow may not yield an aspirate for cytogenetic analysis, awareness of such entity is important to make a correct diagnosis of this potentially curable disease.

  9. Acute promyelocytic leukemia during pregnancy: a systematic analysis of outcome.

    Science.gov (United States)

    Verma, Vivek; Giri, Smith; Manandhar, Samyak; Pathak, Ranjan; Bhatt, Vijaya Raj

    2016-01-01

    The outcomes of acute promyelocytic leukemia (APL) in pregnancy are largely unknown. The MEDLINE database was systematically searched to obtain 43 articles with 71 patients with new-onset APL during pregnancy. Induction therapy included various regimens of all-trans retinoic acid (ATRA), cytarabine, and anthracycline and resulted in a complete remission rate of 93%. Obstetric and fetal complications included pre-term deliveries (46%), spontaneous/therapeutic abortion/intrauterine death (33.3%) and other neonatal complications (25.9%). Mothers diagnosed in the first trimester were more likely to experience obstetric (p pregnancy. The vast majority of APL patients in pregnancy may achieve remission with initial induction therapy. APL or its therapy in pregnancy, however, is associated with a high risk of fetal and obstetrical complications. The results of our study may help in patient counseling and informed decision-making.

  10. Acute promyelocytic leukemia during pregnancy: report of 3 cases.

    Science.gov (United States)

    Consoli, Ugo; Figuera, Amalia; Milone, Giuseppe; Meli, Carmela Rita; Guido, Giulia; Indelicato, Francesco; Moschetti, Gaetano; Leotta, Salvatore; Tornello, Antonella; Poidomani, Massimo; Murgano, Pamela; Pinto, Valeria; Giustolisi, Rosario

    2004-01-01

    Acute promyelocytic leukemia (APL) is characterized by onset at a young age and a life-threatening hemorrhagic diathesis, which is attributed to a disseminated intravascular coagulation (DIC)-like coagulopathy. The discovery of all-trans-retinoic acid has changed the course of APL treatment by reducing the onset of DIC and inducing a complete and durable remission in more than 90% of patients. The occurrence of APL during pregnancy is not a frequent event, but the management of these patients raises many therapeutic and ethical dilemmas and requires a careful clinical case evaluation of fetal and maternal risk, coagulation status, the parents' wishes, and therapeutic options. Here we describe 3 patients with APL diagnosed during pregnancy. Clinical data and the therapeutic approaches are presented. In the discussion, we analyze clinical decisions and therapeutic options and compare our cases with those found in the literature.

  11. Treatment of adult acute lymphoblastic leukaemia.

    Science.gov (United States)

    Jacobs, P; Wood, L; Novitzky, N

    1990-01-01

    Eighty-five consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 24 years (range 10-69 years), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, Adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate and monthly intrathecal therapy, with drug intensification comprising either vincristine, Adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was obtained in 59 patients (69%) and only the French-American-British (FAB) L1 morphology was a significant predictive factor (P = 0.048). Twenty-three patients failed to achieve CR and of these 12 had primary drug resistance. Median follow-up is currently 260 weeks, median predicted survival of all patients is 58 weeks and for those who achieved CR it is 104 weeks. Median duration of CR is 70 weeks. Of the prognostic factors for survival, only FAB L1 subtype was significant. Bone marrow relapses occurred in 29 patients, and of these 9 (31%) achieved CR. There has been CNS relapse in two patients and both have died. Eleven patients continue in CR off therapy, with a median of 152 weeks. This regimen is effective, with acceptable toxicity, and a number of patients are potentially cured. The incidence of resistant and relapsing disease is an argument for further intensifying both induction and postinduction therapy.

  12. Unusual presentations of childhood acute lymphoblastic leukaemia

    African Journals Online (AJOL)

    PROF. EZECHUKWU

    2014-04-06

    Apr 6, 2014 ... leukaemia: A case report. Accepted: ... accumulation of lymphoid blasts in the bone marrow and some ... tion; typically its clinical presentation is related to bone marrow .... haematopoietic stem cell transplantation. Treatment.

  13. Inhibition factors of arsenic trioxide therapeutic effects in patients with acute promyelocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    Sui Meijuan; Zhang Zhuo; Zhou Jin

    2014-01-01

    Objective To summarize limitations involved in arsenic trioxide therapeutic effects in acute promyelocytic leukemia,because current studies show that some individuals of acute promyelocytic leukemia have relatively poor outcomes during treatment with arsenic trioxide.Data sources Most relevant articles were included in the PubMed database between 2000 and 2013 with the keywords "acute promyelocytic leukemia","arsenic trioxide","thiol" or "methylation".In addition,a few older articles were also reviewed.Study selection Data and articles related to arsenic trioxide effect in acute promyelocytic leukemia treatment were selected and reviewed.We developed an overview of limitations associated with arsenic trioxide therapeutic effect.Results This review focuses on the researches about the arsenic trioxide therapeutic effect in acute promyelocytic leukemia and summarizes three mainly limitations which can influence the arsenic trioxide therapeutic effect to different degrees.First,with the combination of arsenic and glutathione the therapeutic effect and cytotoxicity decrease when glutathione concentration increases; second,arsenic methylation,stable arsenic methylation products weaken the apoptosis effect of arsenic trioxide in leukemia cells; third,gene mutations affect the sensitivity of tumor cells to arsenic trioxide and increase the resistance of leukemia cells to arsenic trioxide.Conclusions The chief limitations are listed in the review.If we can exclude all of them,we can obtain a better therapeutic effect of arsenic trioxide in patients with acute promyelocytic leukemia.

  14. Down syndrome with microgranular variant of acute promyelocytic leukemia in a child: a case report

    Directory of Open Access Journals (Sweden)

    Jain Deepali

    2007-11-01

    Full Text Available Abstract Background Acute promyelocytic leukemia (APL accounts for less than 10% of pediatric AML. Cases of APL in Down syndrome (DS have been described in the literature rarely and it is rarer still to find the microgranular variant (M3v of APL in trisomy 21 patients. Case presentation We present a case of a five-year-old female with Down syndrome diagnosed with acute promyelocytic leukemia (APL. She came to our hospital with bleeding manifestations. Blood and bone marrow examination revealed promyelocytes showing a few fine granules and occasional Auer rods. Based on this morphology and cytochemistry, a diagnosis of APL microgranular variant (M3v was made. Conclusion This case report emphasizes the importance of a high index of suspicion in the diagnosis of acute promyelocytic leukemia microgranular variant in Down syndrome.

  15. Treatment of acute lymphoblastic leukaemia (ALL).

    Science.gov (United States)

    Jacobs, P; Wood, L

    1992-08-01

    Forty-six consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 23 years (range 14 to 64), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard central nervous system (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate, and monthly intrathecal chemotherapy, with drug intensification comprising either vincristine, adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was achieved in 36 patients (78%) and only the FAB L1 morphology was a significant predictive factor (Chi-squared = 3.91: p < 0.05). Eight of the 10 non-responders had significant drug resistance and 3 deaths were associated with marrow hypoplasia. Median follow-up is 52 months. Median duration of CR is 28 months, median survival of all patients is 16 months, and for those who achieved CR is 44 months. There was no difference between the two maintenance arms. Significant prognostic factors for survival are French-American-British (FAB) subtype, in which the L1 is better than L2 (p = 0.05), and age (p = 0.035). Nineteen patients have experienced medullary relapse and 7 (37%) achieved subsequent CR; this is durable in a single patient who underwent allogeneic bone marrow transplantation. Eight patients (17%) had CNS disease at diagnosis; 5 achieved CR and 1 is alive and disease-free at 65+ months. There has been 1 CNS relapse. These results demonstrate that prolonged remissions and survival can be achieved with this protocol and many patients possibly cured. The level of toxicity is acceptable and the pattern of induction failure indicates that a margin exists for intensifying chemotherapy and thereby possibly further improving results.

  16. Secondary pure erythroid leukaemia in relapsed acute lymphoblastic leukaemia: lineage switch or chemotherapy effect?

    Science.gov (United States)

    Gupta, Sanjeev Kumar; Kumar, Rajive; Chharchhodawala, Taher; Kumar, Lalit

    2014-05-19

    Pure erythroid leukaemia is a rare subtype of acute myeloid leukaemia (AML) and its occurrence at acute lymphoblastic leukaemia (ALL) relapse has not been reported earlier. A 39-year-old man received chemotherapy for Philadelphia-negative B cell ALL. Subsequently, he developed pure erythroid leukaemia with >80% immature erythroid precursors in bone marrow showing block positivity on periodic acid-Schiff stain, expressing CD71, CD34 but lacking CD235a. The interval between exposure to multidrug chemotherapy including cyclophosphamide and AML diagnosis was 2 years and 9 months. No cytogenetic abnormality was detected at the time of relapse. The patient died 2 weeks after starting AML chemotherapy. The relatively narrow time interval (usually 5-10 years) between chemotherapy and AML development and normal karyotype at relapse raises a possibility of lineage switch besides therapy-related AML as the likely pathogenesis. Further exploration of such cases may unravel the pathways responsible for lineage assignment in pluripotent stem cells. 2014 BMJ Publishing Group Ltd.

  17. Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

    NARCIS (Netherlands)

    Cervera, Jose; Montesinos, Pau; Hernandez-Rivas, Jesus M.; Calasanz, Maria J.; Aventin, Anna; Ferro, Maria T.; Luno, Elisa; Sanchez, Javier; Vellenga, Edo; Rayon, Chelo; Milone, Gustavo; de la Serna, Javier; Rivas, Concha; Gonzalez, Jose D.; Tormo, Mar; Amutio, Elena; Gonzalez, Marcos; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A.

    2010-01-01

    Background Acute promyelocytic leukemia is a subtype of acute myeloid leukemia characterized by the t(15;17). The incidence and prognostic significance of additional chromosomal abnormalities in acute promyelocytic leukemia is still a controversial matter. Design and Methods Based on cytogenetic dat

  18. Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

    NARCIS (Netherlands)

    J. Cervera (José); P. Montesinos (Pau); J.M. Hernandez-Rivas (J. M.); M.J. Calasanz (Maria); A. Aventín (Anna); M.T. Ferro (María); E. Luño (Elisa); J. Sánchez (Javier); E. Vellenga (Edo); C. Rayón (Chelo); G. Milone (Gustavo); J. de Serna (Javier); C. Rivas (Concha); J.D. González (José David); M. Tormo (Mar); E. Amutio (Elena); S. Brunet (Salut); B. Löwenberg (Bob); M.A. Sanz (Miguel Angel)

    2010-01-01

    textabstractBackground: Acute promyelocytic leukemia is a subtype of acute myeloid leukemia characterized by the t(15;17). The incidence and prognostic significance of additional chromosomal abnormalities in acute promyelocytic leukemia is still a controversial matter. Design and Methods: Based on c

  19. ETV6-RUNX1 (+) Acute Lymphoblastic Leukaemia in Identical Twins.

    Science.gov (United States)

    Ford, Anthony M; Greaves, Mel

    2017-01-01

    Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes; multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance. The most common chromosome translocation observed is the t(12;21) that results in an in-frame fusion between the first five exons of ETV6 (TEL) and almost the entire coding region of RUNX1 (AML1).The natural history of childhood ALL is almost entirely clinically silent and is well advanced at the point of diagnosis. It has, however, been possible to backtrack this process through molecular analysis of appropriate clinical samples: (i) leukaemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukaemia; and (iii) stored, viable cord blood cells.Here, we outline our studies on the aetiology and pathology of childhood ALL that provide molecular evidence for a monoclonal, prenatal origin of ETV6-RUNX1+ leukaemia in monozygotic identical twins. We provide mechanistic support for the concept that altered patterns of infection during early childhood can deliver the necessary promotional drive for the progression of ETV6-RUNX1+ pre-leukaemic cells into a postnatal overt leukaemia.

  20. Targeted Therapy: The New Lease on Life for Acute Promyelocytic Leukemia, and Beyond%Targeted Therapy: The New Lease on Life for Acute Promyelocytic Leukemia, and Beyond

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    Under a research project funded by NSFC, Prof. Chen Saijuan of Shanghai Jiaotong University Ruijin Hospital and Prof. Zhou Guangbiao of Institute of Zoology of CAS, published a review article entitled "Targeted therapy. The new lease on life for acute promyelocytic leukemia, and beyond" on IUBMB Life, 64(8). 671-675, 2012

  1. Academic career after treatment for acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Kingma, A; Rammeloo, LAJ; van der Does-van den Berg, A; Rekers-Mombarg, L; Postma, A

    2000-01-01

    Aim-To evaluate academic career in long term survivors of childhood acute lymphoblastic leukaemia (ALL), in comparison to their healthy siblings. Patients-Ninety four children treated for ALL with cranial irradiation 18 or 25 Gy and intrathecal methotrexate as CNS prophylaxis. Median age at evaluati

  2. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Wolthers, Benjamin O.; Frandsen, Thomas L.; Baruchel, André

    2017-01-01

    BACKGROUND: Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing pa...

  3. Immunophenotypes and Immune Markers Associated with Acute Promyelocytic Leukemia Prognosis

    Directory of Open Access Journals (Sweden)

    Fang Xu

    2014-01-01

    Full Text Available CD2+, CD34+, and CD56+ immunophenotypes are associated with poor prognoses of acute promyelocytic leukemia (APL. The present study aimed to explore the role of APL immunophenotypes and immune markers as prognostic predictors on clinical outcomes. A total of 132 patients with de novo APL were retrospectively analyzed. Immunophenotypes were determined by flow cytometry. Clinical features, complete remission (CR, relapse, and five-year overall survival (OS rate were assessed and subjected to multivariate analyses. The CD13+CD33+HLA-DR-CD34− immunophenotype was commonly observed in patients with APL. Positive rates for other APL immune markers including cMPO, CD117, CD64, and CD9 were 68.7%, 26%, 78.4%, and 96.6%, respectively. When compared with patients with CD2− APL, patients with CD2+ APL had a significantly higher incidence of early death (50% versus 15.7%; P=0.016, lower CR rate (50% versus 91.1%; P=0.042, and lower five-year OS rate (41.7% versus 74.2%; P=0.018. White blood cell (WBC count before treatment was found to be the only independent risk factor of early death, CR failure, and five-year mortality rate. Flow cytometric immunophenotype analysis can facilitate prompt APL diagnosis. Multivariate analysis has demonstrated that WBC count before treatment is the only known independent risk factor that predicts prognosis for APL in this study population.

  4. Retinoid receptor signaling and autophagy in acute promyelocytic leukemia.

    LENUS (Irish Health Repository)

    Orfali, Nina

    2014-05-15

    Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies.

  5. Retinoid receptor signaling and autophagy in acute promyelocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Orfali, Nina [Cork Cancer Research Center, University College Cork, Cork (Ireland); Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. (United States); McKenna, Sharon L. [Cork Cancer Research Center, University College Cork, Cork (Ireland); Cahill, Mary R. [Department of Hematology, Cork University Hospital, Cork (Ireland); Gudas, Lorraine J., E-mail: ljgudas@med.cornell.edu [Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. (United States); Mongan, Nigel P., E-mail: nigel.mongan@nottingham.ac.uk [Faculty of Medicine and Health Science, School of Veterinary Medicine and Science, University of Nottingham, LE12 5RD (United Kingdom); Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. (United States)

    2014-05-15

    Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies. - Highlights: • Normal and aberrant retinoid signaling in hematopoiesis and leukemia is reviewed. • We suggest a novel role for RARα in the development of X-RARα gene fusions in APL. • ATRA therapy in APL activates transcription and promotes onco-protein degradation. • Autophagy may be involved in both onco-protein degradation and differentiation. • Pharmacologic autophagy induction may potentiate ATRA's therapeutic effects.

  6. Revisiting the differentiation paradigm in acute promyelocytic leukemia.

    Science.gov (United States)

    Ablain, Julien; de The, Hugues

    2011-06-02

    As the result of intense clinical and basic research, acute promyelocytic leukemia (APL) has progressively evolved from a deadly to a curable disease. Historically, efforts aimed at understanding the molecular bases for therapy response have repeatedly illuminated APL pathogenesis. The classic model attributes this therapeutic success to the transcriptional reactivation elicited by retinoic acid and the resulting overcoming of the differentiation block characteristic of APL blasts. However, in clinical practice, retinoic acid by itself only rarely yields prolonged remissions, even though it induces massive differentiation. In contrast, as a single agent, arsenic trioxide neither directly activates transcription nor triggers terminal differentiation ex vivo, but cures many patients. Here we review the evidence from recent ex vivo and in vivo studies that allow a reassessment of the role of differentiation in APL cure. We discuss alternative models in which PML-RARA degradation and the subsequent loss of APL cell self-renewal play central roles. Rather than therapy aimed at inducing differentiation, targeting cancer cell self-renewal may represent a more effective goal, achievable by a broader range of therapeutic agents.

  7. Acute myocardial infarction as a finding of acute promyelocytic leukemia-related coagulation disorder.

    Science.gov (United States)

    Özkurt, Zübeyde N; Aypar, Eda; Sarifakiogullari, Serpil; Taçoy, Gülten; Özdag, Murat; Kahraman, Seda; Çengel, Atiye

    2015-12-01

    Acute promyelocytic leukemia (APL) has one of the most favorable prognoses among other leukemia subtypes. However, the major cause of mortality in APL is disseminated intravascular coagulation at the presentation. We present a case of acute myocardial infarction (MI) at the time of APL diagnosis before treatment. The patient suffered from chest pain, sweating and giddiness. He was hypoxic, hypotensive and bradycardic. ECG showed inferior MI. Unfractioned heparin infusion (850 U/h) was started and 5 min after the previous ECG showed total ST resolution. We suggest that in this case, MI was not related to atherosclerotic plaque rupture but related to DIC manifestation.

  8. Acute myocardial/cerebral infarction as first/relapse manifestation in one acute promyelocytic leukemia patient.

    Science.gov (United States)

    Li, Ying; Suo, Shanshan; Mao, Liping; Wang, Lei; Yang, Chunmei; Xu, Weilai; Lou, Yinjun; Mai, Wenyuan

    2015-01-01

    In the clinical setting, bleeding is a common manifestation of acute promyelocytic leukemia (APL), whereas thrombosis is relatively rare, especially as an initial symptom. Here, we report an unusual case of APL with acute myocardial infarction as the first manifestation and cerebral infarction as the relapse manifestation in a healthy young woman. This unique case emphasizes that a thrombotic event could be the first manifestation of an underlying hematological disorder such as APL and could also be a sign of relapse. Rapid detection of the underlying disorder and the timely use of anticoagulation therapy and ATRA are crucial for preventing further deterioration of the disease and saving the patient's life.

  9. PATHOGENESIS AND TREATMENT OF THROMBOHEMORRHAGIC DIATHESIS IN ACUTE PROMYELOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Anna Falanga

    2011-12-01

    Full Text Available Acute promyelocytic leukemia (APL is a distinct subtype of myeloid leukemia characterized by t(15;17 chromosomal translocation, which involves the retinoic acid receptor-alpha (RAR-alpha. APL typically presents with a life-threatening hemorrhagic diathesis. Before the introduction of all-trans retinoic acid (ATRA for the cure of APL, fatal hemorrhages due, at least in part, to the APL-associated coagulopathy, were a major cause of induction remission failure. The laboratory abnormalities of blood coagulation found in these patients are compatible with a syndrome of disseminated intravascular coagulation (DIC. Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells, including procoagulant factors, fibrinolytic proteins, and non-specific proteolytic enzymes. In addition, these cells have an increased capacity to adhere to the vascular endothelium, and to secrete inflammatory cytokines [i.e. interleukin-1beta (IL-1beta and tumor necrosis factor (TNF-alpha], which in turn stimulate the expression of prothrombotic activities by endothelial cells and leukocytes. ATRA can interfere with each of the principal hemostatic properties of the leukemic cell, thus reducing the APL cell procoagulant potential, in parallel to the induction of cellular differentiation. This effect occurs in vivo, in the bone marrow of APL patients receiving ATRA, and is associated with the improvement of the bleeding symptoms. Therapy with arsenic trioxide (ATO also beneficially affects coagulation in APL. However, early deaths from bleeding still remain a major problem in APL and further research is required in this field. In this review, we will summarize our current knowledge of the pathogenesis of the APL-associated coagulopathy and will overview the therapeutic approaches for the management of this complication.

  10. Measurable residual disease testing in acute myeloid leukaemia.

    Science.gov (United States)

    Hourigan, C S; Gale, R P; Gormley, N J; Ossenkoppele, G J; Walter, R B

    2017-07-01

    There is considerable interest in developing techniques to detect and/or quantify remaining leukaemia cells termed measurable or, less precisely, minimal residual disease (MRD) in persons with acute myeloid leukaemia (AML) in complete remission defined by cytomorphological criteria. An important reason for AML MRD-testing is the possibility of estimating the likelihood (and timing) of leukaemia relapse. A perfect MRD-test would precisely quantify leukaemia cells biologically able and likely to cause leukaemia relapse within a defined interval. AML is genetically diverse and there is currently no uniform approach to detecting such cells. Several technologies focused on immune phenotype or cytogenetic and/or molecular abnormalities have been developed, each with advantages and disadvantages. Many studies report a positive MRD-test at diverse time points during AML therapy identifies persons with a higher risk of leukaemia relapse compared with those with a negative MRD-test even after adjusting for other prognostic and predictive variables. No MRD-test in AML has perfect sensitivity and specificity for relapse prediction at the cohort- or subject levels and there are substantial rates of false-positive and -negative tests. Despite these limitations, correlations between MRD-test results and relapse risk have generated interest in MRD-test result-directed therapy interventions. However, convincing proof that a specific intervention will reduce relapse risk in persons with a positive MRD-test is lacking and needs testing in randomized trials. Routine clinical use of MRD-testing requires further refinements and standardization/harmonization of assay platforms and results reporting. Such data are needed to determine whether results of MRD-testing can be used as a surrogate end point in AML therapy trials. This could make drug-testing more efficient and accelerate regulatory approvals. Although MRD-testing in AML has advanced substantially, much remains to be done.

  11. Microgranular acute promyelocytic leukemia: a distinct clinical, ultrastructural, and cytogenetic entity

    Energy Technology Data Exchange (ETDEWEB)

    Golomb, H.M.; Rowley, J.D.; Vardiman, J.W.; Testa, J.R.; Butler, A.

    1980-02-01

    Three patients with acute leukemia, disseminated intravaslar coagulation, and a specific acquired chromosome abnormality (t(15;17)) were found by transmission electron microscopy to have the typical distribution of granules seen in promyelocytes. However, the average granule sizes were 120, 170 and 180 nm, respectively, for the three patients, significantly less than the 250-nm resolution of light microscopy. We regard the leukemia in these three patients as comprising a distinct clinical, ultrastructural, and cytogenetic entity that we have chosen to all microgranular acute promyelocytic leukemia.

  12. High-flow priapism in acute lymphatic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Mentzel, Hans-Joachim; Vogt, Susanna; Kaiser, Werner A. [Institute of Diagnostic and Interventional Radiology, Department of Pediatric Radiology, Friedrich-Schiller-Universitaet Jena, Bachstrasse 18, 07740, Jena (Germany); Kentouche, Karim; Doerfel, Claus; Zintl, Felix [Department of Paediatrics, University of Jena (Germany)

    2004-07-01

    Priapism is defined as prolonged and persistent erection of the penis without sexual stimulation. It is associated with excessive hyperleukocytosis (e.g. in acute or chronic leukaemia); however, this complication is rarely seen in the pediatric population. We report a 12-year-old boy suffering from acute leukaemia presenting with, at first intermittent, but increasingly persistent erection. Doppler US revealed signs of high-flow priapism. MRI excluded intrapelvic tumour masses, and three-dimensional contrast-enhanced MR angiography could not demonstrate an arteriovenous fistula or thrombosis. Cavernosal blood-gas measurement was in agreement with high-flow priapism. On the basis of the imaging findings, invasive therapeutic management was avoided in our patient with a successful outcome. (orig.)

  13. Label-free imaging and identification of typical cells of acute myeloid leukaemia and myelodysplastic syndrome by Raman microspectroscopy.

    Science.gov (United States)

    Vanna, R; Ronchi, P; Lenferink, A T M; Tresoldi, C; Morasso, C; Mehn, D; Bedoni, M; Picciolini, S; Terstappen, L W M M; Ciceri, F; Otto, C; Gramatica, F

    2015-02-21

    In clinical practice, the diagnosis and classification of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) start from the manual examination of stained smears of bone marrow (BM) and peripheral blood (PB) by using an optical microscope. This step is subjective and scarcely reproducible. Therefore, the development of subjective and potentially automatable methods for the recognition of typical AML/MDS cells is necessary. Here we have used Raman spectroscopy for distinguishing myeloblasts, promyelocytes, abnormal promyelocytes and erhytroblasts, which have to be counted for a correct diagnosis and morphological classification of AML and MDS. BM samples from patients affected by four different AML subtypes, mostly characterized by the presence of the four subpopulations selected for this study, were analyzed. First, each cell was scanned by acquiring 4096 spectra, thus obtaining Raman images which demonstrate an accurate description of morphological features characteristic of each subpopulation. Raman imaging coupled with hierarchical cluster analysis permitted the automatic discrimination and localization of the nucleus, the cytoplasm, myeloperoxidase containing granules and haemoglobin. Second, the averaged Raman fingerprint of each cell was analysed by multivariate analysis (principal component analysis and linear discriminant analysis) in order to study the typical vibrational features of each subpopulation and also for the automatic recognition of cells. The leave-one-out cross validation of a Raman-based classification model demonstrated the correct classification of myeloblasts, promyelocytes (normal/abnormal) and erhytroblasts with an accuracy of 100%. Normal and abnormal promyelocytes were distinguished with 95% accuracy. The overall classification accuracy considering the four subpopulations was 98%. This proof-of-concept study shows that Raman micro-spectroscopy could be a valid approach for developing label-free, objective and automatic

  14. SCENARIO OF ACUTE LYMPHOBLASTIC LEUKAEMIA IN GWALIOR REGION

    Directory of Open Access Journals (Sweden)

    Mangal

    2016-04-01

    Full Text Available BACKGROUND Leukaemia is the most prevalent childhood cancer and Acute Lymphoblastic Leukaemia (ALL constitutes about 75% of all cases. The most frequent presenting symptoms are fever, weight loss and pallor. Early diagnosis of this haematological malignancy can be helpful for prognosis of disease. AIMS AND OBJECTIVES The objectives of the present study were to assess frequency of presenting symptoms, laboratory data and prognostic factors in children with diagnosis of ALL. MATERIALS AND METHODS The present study (2014 was performed in the Department of Pathology of Gajra Raja Medical College, Gwalior, over a period of one year from October 2013 to September 2014. The blood samples were received from patients attending various Departments of Jayarogya Groups of Hospitals, a tertiary care hospital. RESULTS Out of the 37 cases diagnosed as Acute Lymphoblastic Leukaemia, 25 (67.57% were male and 12 (32.43% were female, (male:female ratio: 2.1:1; 43.35% of patients which comprises highest number of cases belonged to 11-20 years of age group. The most frequent presenting symptoms was fever (83.78% followed by weakness (70.27% and loss of appetite (27%, while most frequent presenting sign was pallor (86.48% followed by lymphadenopathy (67.57% and splenomegaly (48.65%. Complete blood cell count was abnormal in all of the patients and pancytopenia was detected in 10.81% of the patients. Of all the patients, 91.89% had abnormal White Blood Cell (WBC count at presentation with about 80% were presented with Leukocytosis. FAB L1 subtype was more common as compared to FAB L2 subtype. CONCLUSION In our study (2014, Acute Lymphoblastic Leukaemia was more prevalent in males than in females and more common in childhood than in adult. FAB L1 subtype was more common as compared to FAB L2 subtype.

  15. REPEATED ARSENIC TRIOXIDE INTRAVENOUS INFUSION CAUSES FOCAL BONE MARROW NECROSIS IN TWO ACUTE PROMYELOCYTIC LEUKEMIA PATIENTS

    Institute of Scientific and Technical Information of China (English)

    Jin Zhou; Ran Meng; Xin-hua Sui; Bao-feng Yang

    2004-01-01

    @@ Arsenic trioxide (As2O3) is an effective agent used in treatment of acute promyelocytic leukemia (APL). However,appearances of side effects using clinical therapeutic dosages of As2O3 occur during the initial or consolidated stage in APL therapy. We report two APL patients suffering focal bone marrow necrosis after discontinuous As2O3 treatment during consolidated stage.

  16. Intestinal stromal tumor coexisted with acute promyelocytic leukemia: a case report

    Institute of Scientific and Technical Information of China (English)

    LI Deng-ju; ZHANG Yi-cheng; ZHOU Jian-feng; TANG Jin-zhi

    2008-01-01

    @@ Lower gastrointestinal hemorrhage is a nonspecific common symptom of both acute promyelocytic leukemia (APL) and gastrointestinal stromal tumors (GIST). The possibility of GISTs is rarely considered in patients with APL when intestinal hemorrhage occurres. We treated a case of GISTs coexisting with APL in July 2006. The diagnosis of GIST was verified through surgery and pathological examination of the resected intestinal mass.

  17. The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia

    DEFF Research Database (Denmark)

    Arteaga, Maria Francisca; Mikesch, Jan-Henrik; Qiu, Jihui

    2013-01-01

    While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We id...

  18. All-trans retinoic acid in acute promyelocytic leukemia in late pregnancy.

    Science.gov (United States)

    Stentoft, J; Nielsen, J L; Hvidman, L E

    1994-09-01

    All-trans retinoic acid (ATRA) was used in a case of acute promyelocytic leukemia (APL) in late pregnancy. A very prompt maternal risk reduction was achieved with subsequent complete remission and spontaneous delivery of two live children in whom no fetal damage seems to have occurred.

  19. Increased cellular hypoxia and reduced proliferation of both normal and leukaemic cells during progression of acute myeloid leukaemia in rats

    DEFF Research Database (Denmark)

    Jensen, P O; Mortensen, B T; Hodgkiss, R J;

    2000-01-01

    The microenvironmental changes in the bone marrow, spleen and liver during progression of the transplantable promyelocytic leukaemia in the Brown Norwegian rat (BNML) have been studied. We used flow cytometry to estimate cellular hypoxia and proliferation based on in vivo pulse-labelling with a m......The microenvironmental changes in the bone marrow, spleen and liver during progression of the transplantable promyelocytic leukaemia in the Brown Norwegian rat (BNML) have been studied. We used flow cytometry to estimate cellular hypoxia and proliferation based on in vivo pulse...

  20. Acute promyelocytic leukemia in a hemophilia A patient:a case report

    Institute of Scientific and Technical Information of China (English)

    张磊; 李洪强; 赵辉; 王婷婷; 季林祥; 杨仁池; 韩忠朝

    2004-01-01

    @@ Acute promyelocytic leukemia (APL) is the M3 subtype of the French-American-British (FAB) classification of acute myeloid leukemia (AML). Hemophilia is a congenital bleeding disorder characterized by a deficiency of coagulation factor VIII or IX. In our center, more than one thousand patients with haemophilia A have been treated since 1980.1 In June 2002, APL was first diagnosed in one person with haemophilia (PWH). The coincidence of these two diseases led to challenges in developing a treatment strategy.

  1. Treatment and long-term results in children with acute myeloid leukaemia treated according to the AIEOP AML protocols.

    Science.gov (United States)

    Pession, A; Rondelli, R; Basso, G; Rizzari, C; Testi, A M; Fagioli, F; De Stefano, P; Locatelli, F

    2005-12-01

    Since 1982, four consecutive studies on childhood acute myeloid leukaemia (AML) (namely LAM-82, -87, -87M and -92) have been conducted in Italy by the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) group. The induction therapy of the first three studies consisted of daunorubicin and cytarabine structured in a 3+7 backbone. In the most recent protocol (LAM92), patients received two induction courses including idarubicin, cytarabine and etoposide. Patients with acute promyelocytic leukaemia (20% of diagnoses) were included in LAM-87 and 87M studies. Postremissional therapy significantly changed over time, with an ever-increasing role given to stem cell transplantation (SCT). The long-term outcome of patients enrolled in the LAM-82, 87 and 87M studies was comparable, whereas that of children treated according to LAM-92 study was significantly better (P<0.005). Either allogeneic or autologous SCT was employed as consolidation therapy in more than 75% of cases enrolled in this latter study. Patients enrolled in the LAM-92 study were stratified in standard and high-risk groups with different outcome (67 vs 47%, respectively, P=0.04). Altogether, the results obtained in these four studies have permitted a progressive refinement of treatment, contributing to the structure of the ongoing LAM-2002 protocol that stratifies patients according to the presence of definite genetic anomalies and response to induction therapy.

  2. Molecular mechanisms involved in chemoresistance in paediatric acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Stanković Tatjana

    2008-01-01

    Full Text Available Acute lymphoblastic leukaemia (ALL is the most common paediatric cancer. Despite cure rates approaching 80%, resistance to treatment and disease relapse remain a significant clinical problem. Identification of the genes and biological pathways responsible for chemoresistance is therefore crucial for the design of novel therapeutic approaches aiming to improve patient survival. Mutations in the membrane transporter P-glycoprotein genes, genetic variations in drug-metabolising enzymes and defects in apoptotic pathways are mechanisms of chemoresistance common to a wide spectrum of cancers and also play a role in paediatric ALL. In addition, several recent microarray studies have identified transcriptional profiles specifically associated with chemoresistance and pointed to a number of potentially novel therapeutic targets. These microarray studies have shown that genes discriminating between clinically responsive and resistant leukaemias tend to be involved in cellular processes such as regulation of cell cycle, proliferation, and DNA repair. Here we review the outcomes of these microarray studies and also present our own investigations into apoptotic resistance to DNA double strand breaks (DSBs in paediatric ALL. We present stratification of paediatric ALL by the profile of DNA damage response following ionising radiation (IR in vitro. This approach allows classification of ALL tumours at presentation into IR-apoptotic sensitive and IR-apoptotic resistant. Furthermore, apoptotic resistant leukaemias exhibit abnormal response of NFkB pathway following irradiation and inhibition of this pathway can sensitise leukaemic cells to IR-induced DSBs.

  3. Leukaemia relapse after allogeneic transplants for acute myeloid leukaemia: predictive role of WT1 expression.

    Science.gov (United States)

    Pozzi, Sarah; Geroldi, Simona; Tedone, Elisabetta; Luchetti, Silvia; Grasso, Raffaella; Colombo, Nicoletta; Di Grazia, Carmen; Lamparelli, Teresa; Gualandi, Francesca; Ibatici, Adalberto; Bregante, Stefania; Van Lint, Maria Teresa; Raiola, Anna Maria; Dominietto, Alida; Varaldo, Riccardo; Signori, Alessio; Bacigalupo, Andrea

    2013-02-01

    We assessed WT1 expression (expressed as messenger copies/10(4) ABL1) from marrow cells of 122 patients with acute myeloid leukaemia (AML), before and after an unmanipulated allogeneic haemopoietic stem cell transplant (HSCT). The median age was 44 years (15-69), 59% were in first remission, 74% received a myeloablative conditioning regimen and the median follow up was 865 d (34-2833). Relapse was higher in 67 patients with WT1 expression, at any time post-HSCT, exceeding 100 copies (54%), as compared to 16%, for 55 patients with post-HSCT WT1 expression <100 copies (P < 0·0001). Similarly, actuarial 5-year survival (OS) was 40% vs. 63%, respectively (P = 0·03). In multivariate Cox analysis, WT1 expression post-HSCT was the strongest predictor of relapse (Hazard Ratio [HR] 4·5, P = 0·0001), independent of disease phase (HR 2·3, P = 0·002). Donor lymphocyte infusions (DLI) were given to 17 patients because of increasing WT1 levels: their OS was 44%, vs. 14% for 21 patients with increasing WT1 expression who did not receive DLI (P = 0·004). In conclusion, WT1 expression post-HSCT is a strong predictor of leukaemia relapse and survival in AML; WT1 may be used as a marker for early interventional therapy.

  4. [2 cases of acute disseminated intravascular coagulation in normal pregnancy and as the first symptom of acute promyelocytic leukemia].

    Science.gov (United States)

    Kardaszewicz, E; Bujak, M; Spychałowicz, W; Siudyka, A; Harbut-Gryłka, A

    Two cases of the acute disseminated intravascular coagulation (DIC) are presented. DIC in the first case was diagnosed in healthy pregnant woman without any obstetric pathology. This patient recovered completely. The acute DIC in another patient preceded the acute promyelocytic leukemia. The patient died despite a control of DIC. DIC therapy included antifibrinolytic agents and additionally corticoids in pregnant patient. Heparin was not administered because of post partum period and foreseen cytostatic therapy in the leukemic patient.

  5. [Disseminated fusariosis in a patient with acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Hermansen, N.E.; Ralfkiaer, E.M.; Kjeldsen, L.

    2008-01-01

    Invasive mould infections are a major cause of infectious mortality in highly immunosuppressed patients. Incidence in this high risk group is 10-20% with a death rate in excess of 50%. Most invasive moulds are Aspergillus spp. We present a case of a 74-year-old woman with acute lymphoblastic...... leukaemia who developed a rare disseminated mould infection with Fusarium solani during induction chemotherapy. We present the case story and discuss the pathogenesis, clinical characteristics and treatment of invasive fusariosis Udgivelsesdato: 2008/9/8...

  6. Tetraploidy acute promyelocytic leuemia with double t(15;17)/PML-RARA, a case report with review of literature.

    Science.gov (United States)

    Dalia, Samir M; Horna, Pedro; Zhang, Ling

    2014-01-01

    Acute promyelocytic leukemia (APL) with tetraploidy chromosome harboring t(15;17)(q23;a21) is extremely rare. To date, there are 14 such cases reports that describe this entity, mostly found in Eastern hemisphere. Herein we described a 51-year-old man with a diagnosis of tetraploid acute promyelocytic leukemia with double (15;17) translocations and compare the prototypically clinicopathologic, genetic and molecular findings with those reported in the literature.

  7. Acute myeloid leukaemia induced by mitoxantrone: case report Leucemia mielóide aguda induzida por mitoxantrone: relato de caso

    Directory of Open Access Journals (Sweden)

    Walter Oleschko Arruda

    2005-06-01

    Full Text Available Mitoxantrone (MX is an immunosupressant drug used in secondarily progressive multiple sclerosis (SPMS and in relapsing-remitting multiple sclerosis (RRMS. It has a leukemogenesis potential induced by cytogenetic abnormalities, though with a low incidence. Promyelocitic leukaemia (type M3 and other forms of acute myeloblastic leukaemias (M4 and M5 have been described in a few MS patients who received MX during their treatment. We describe a white female patient, 47 year-old, with SPMS (EDSS = 4 with 14 years of disease. She received MX during her disease and developed acute promyelocytic leukaemia (M3, with severe thrombocytopenia 30 months later. She ultimately died due to intracerebral hemorrhage. Other cases of treatment related to AML are reviewed and discussed.Mitoxantrone (MX é uma agente imunossupressor utilizado nas formas progressivas secundárias de esclerose múltipla (EM ou formas surto-remissão sem resposta com outras formas de tratamento (p.ex. beta-interferon, acetato de glatirâmer. Com o uso desta medicação, ocorre uma incidência maior, embora pequena, de desenvolvimento de leucemia mielóide aguda induzida por quimioterápicos. Descrevemos o caso de uma paciente com forma progressiva secundária de EM, submetida a uma dose única de MX de 15mg e que 30 meses após desenvolveu quadro fulminante de leucemia promieloblástica aguda (M3, com trombocitopenia grave. A paciente faleceu por hemorragia intracerebral maciça. É feita revisão de outros casos relatados na literatura e os possíveis mecanismos de desenvolvimento desta complicação grave secundária ao uso do MX.

  8. Myeloid Sarcoma: An Unusual Presentation of Acute Promyelocytic Leukemia Causing Spinal Cord Compression

    Directory of Open Access Journals (Sweden)

    Tay Za Kyaw

    2012-09-01

    Full Text Available Acute promyelocytic leukemia with concurrent myeloid sarcoma is a rare clinical event. Herein we describe a patient that presented with back pain and bilateral leg weakness caused by spinal cord compression due to extramedullary deposition of leukemic cells. Acute promyelocytic leukemia was suspected based on immunophenotypic findings of malignant cells in bone marrow aspirate. The diagnosis was confirmed by the presence of PML-RARα fusion copies. MRI showed multiple hyperintense changes on the vertebral bodies, together with intraspinal masses causing spinal cord compression. The patient immediately underwent radiotherapy, and was treated with all-trans retinoic acid and idarubicin. Reassessment MRI showed complete resolution of all intraspinal masses and the disappearance of most of the bony lesions. Post-treatment bone marrow aspirate showed complete hematological and molecular remission. The motor power of his legs fully recovered from 0/5 to 5/5; however, sensory loss below the T4 level persisted.

  9. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.

    Science.gov (United States)

    Ley, Timothy J; Mardis, Elaine R; Ding, Li; Fulton, Bob; McLellan, Michael D; Chen, Ken; Dooling, David; Dunford-Shore, Brian H; McGrath, Sean; Hickenbotham, Matthew; Cook, Lisa; Abbott, Rachel; Larson, David E; Koboldt, Dan C; Pohl, Craig; Smith, Scott; Hawkins, Amy; Abbott, Scott; Locke, Devin; Hillier, Ladeana W; Miner, Tracie; Fulton, Lucinda; Magrini, Vincent; Wylie, Todd; Glasscock, Jarret; Conyers, Joshua; Sander, Nathan; Shi, Xiaoqi; Osborne, John R; Minx, Patrick; Gordon, David; Chinwalla, Asif; Zhao, Yu; Ries, Rhonda E; Payton, Jacqueline E; Westervelt, Peter; Tomasson, Michael H; Watson, Mark; Baty, Jack; Ivanovich, Jennifer; Heath, Sharon; Shannon, William D; Nagarajan, Rakesh; Walter, Matthew J; Link, Daniel C; Graubert, Timothy A; DiPersio, John F; Wilson, Richard K

    2008-11-06

    Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.

  10. Case report: hydroquinone and/or glutaraldehyde induced acute myeloid leukaemia?

    Directory of Open Access Journals (Sweden)

    Alexopoulos Evangelos C

    2006-07-01

    Full Text Available Abstract Background Exposures to high doses of irradiation, to chemotherapy, benzene, petroleum products, paints, embalming fluids, ethylene oxide, herbicides, pesticides, and smoking have been associated with an increased risk of acute myelogenous leukemia (AML. Although there in no epidemiological evidence of relation between X-ray developer, fixer and replenisher liquids and AML, these included glutaraldehyde which has weakly associated with lymphocytic leukemia in rats and hydroquinone has been increasingly implicated in producing leukemia, causing DNA and chromosomal damage, inhibits topo-isomerase II, alter hematopoiesis and inhibit apoptosis of neoplastic cells. Case presentation Two white females (A and B hired in 1985 as medical radiation technologists in a primary care center, in Greece. In July 2001, woman A, 38-years-old, was diagnosed as having acute monocytic leukaemia (FAB M5. The patient did not respond to therapy and died threeweeks later. In August 2001, woman B, 35-year-old, was diagnosed with acute promyelocytic leukaemia (FAB M3. Since discharge, she is in continuous complete remission. Both women were non smokers without any medical history. Shortly after these incidents official inspectors and experts inspected workplace, examined equipment, archives of repairs, notes, interviewed and monitored employees. They concluded that shielding was inadequate for balcony's door but personal monitoring did not show any exceeding of TLV of 20 mSv yearly and cytogenetics analysis did not reveal findings considered to be characteristics of ionizing exposure. Equipment for developing photos had a long list of repairs, mainly leakages of liquids and increases of temperature. On several occasions the floor has been flooded especially during 1987–1993 and 1997–2001. Inspection confirmed a complete lack of ventilation and many spoiled medical x-ray films. Employees reported that an "osmic" level was continuously evident and frequently

  11. Clinical Effects of Arsenic Trioxide by Slowing-intravenous Infusion on Acute Promyelocyte Leukemia

    Institute of Scientific and Technical Information of China (English)

    Jin Zhou; Ran Meng; Bao-feng Yang

    2005-01-01

    @@ Although As2O3 is effective in the treatment of acute promyelocytic leukemia (APL), some side effects, such as leukocytosis which can increase the incidence of cerebral hemorrhage and early death rate, often occur during the early stage of As2O3 treatment. In this paper, the advantages of continuously slow intravenous As2O3 infusion on relieving leukocytosis and decreasing the incidence of cerebral hemorrhage and early death rate were observed clinically.

  12. Parenthood in patients with acute promyelocytic leukemia after treatment with arsenic trioxide: a case series.

    Science.gov (United States)

    Gupta, Shilpa; Bagel, Bhausaheb; Gujral, Sumeet; Subramanian, P G; Khattry, Navin; Menon, Hari; Nair, Reena

    2012-11-01

    Arsenic trioxide, believed to be a carcinogen and a teratogen, has found its niche in the treatment of acute promyelocytic leukemia (APL). APL is a disease affecting young patients. Post-treatment fertility and outcome of pregnancy are always a concern in a disease with high cure rates. We report a case series of six patients who were treated successfully for APL with arsenic trioxide and who parented at least one healthy offspring after completing their treatment.

  13. Molecular subtypes of PMI/RaRa in patients with acute promyelocytic leukemia

    OpenAIRE

    2014-01-01

    The objective was to describe the frequency of molecular subtypes of PML/RARα in patients with acute promyelocytic leukemia (APL) and their distribution according to risk of recurrence and cytomorphology. A case series was carried out, including fifty patients registered at the National Institute of Neoplastic Diseases (INEN) during 2010-2012, with molecular diagnosis of APL PML/RARα and bcr1, bcr2 and bcr3 subtypes by reverse-transcription polymerase chain reaction (RT-PCR). Bcr1 subtype...

  14. Acute myeloid dendritic cell leukaemia with specific cutaneous involvement: a diagnostic challenge.

    Science.gov (United States)

    Ferran, M; Gallardo, F; Ferrer, A M; Salar, A; Pérez-Vila, E; Juanpere, N; Salgado, R; Espinet, B; Orfao, A; Florensa, L; Pujol, R M

    2008-05-01

    Myeloid or type 1 dendritic cell leukaemia is an exceedingly rare haematopoietic neoplasm characterized by a specific immunophenotypic profile close to plasmacytoid dendritic cell and acute myelogenous leukaemia. A 77-year-old man presenting specific cutaneous infiltration by myeloid dendritic cell leukaemia is reported. The clinical features as well as the cutaneous histopathological and immunohistochemical features led to the initial diagnosis of CD4+/CD56+ haematodermic neoplasm. However, extensive immunophenotypic studies performed from peripheral blood blasts disclosed that leukaemic cells expressed myeloid dendritic cell markers, confirming the diagnosis. The diagnostic difficulties of specific cutaneous involvement by myeloid dendritic cell leukaemia on the basis of routine histopathological and immunohistochemical features are highlighted.

  15. Trombose arterial em leucemia promielocítica aguda Arterial thrombosis in acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Sonia Regina Iantas

    2007-12-01

    Full Text Available Acute promyeloclocytic leukemia can present coagulopathies which are frequently very serious due to hemorrhagic conditions. Treatment using anthracyclines and retinoids provide a good response. The development of arterial thrombosis is uncommon. In this work a 56-year-old male patient with acute arterial insufficiency was evaluated. This patient was immediately submitted to thromboembolectomy with the removal of a white thrombus. Postoperative tests showed acute promyelocytic leukemia with transposition (15;17 Treatment with ATRA and Idarubicin chemotherapy was initiated with the patients's response being satisfactory. Currently, the patient is incomplete remission and a recent cytogenetics test does not show the t(15;17.

  16. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era.

    Science.gov (United States)

    Ramadan, Safaa M; Di Veroli, Ambra; Camboni, Agnese; Breccia, Massimo; Iori, Anna Paola; Aversa, Franco; Cupelli, Luca; Papayannidis, Cristina; Bacigalupo, Andrea; Arcese, William; Lo-Coco, Francesco

    2012-11-01

    The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed.

  17. ATRA (all-trans-retinoic acid) syndrome in acute promyelocytic leukemia: clinical and radiologic findings

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Keon Ha; Goo, Jin Mo; Im, Jung Gi; Chung, Myung Jin; Do, Kyung Hyun; Park, Seon Yang [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of); Seo, Joon Beom [Gachon Univ. Medical School, Gil Medical Center, Seoul (Korea, Republic of)

    2001-03-01

    To describe the clinical and radiologic findings of all-trans-retinoic acid (ATRA) syndrome in acute promyelocytic leukemia. Among 21 patients with acute promyelocytic leukemia who were treated with all-trans-retinoic acid between 1995 and 1998, we retrospectively evaluated the cases of four with ATRA syndrome. Two were male and two were female, and their mean age was 58 years. The clinical and radiologic findings of chest radiography (n=4) and HRCT (n=1) were analyzed. Between seven and 13 days after ATRA treatment, dry cough, dyspnea and high fever developed in all patients. The WBC count in peripheral blood was significantly higher [2.9-25.3(mean, 10.8)-fold] than before ATRA treatment, and in all patients, chest radiography revealed ill-defined consolidation and pleural effusion. Kerley's B line (n=3) and hilar enlargement (n=3) were also seen, and in one patient, HRCT demonstrated septal line thickening. Among four patients treated with prednisolone and Ara-C, three recovered and one died. In acute promyelocytic patients treated with all-trans-retinoic acid, radiologic findings of ill-de-fined consolidation, pleural effusion, hilar prominence and Kerley's B line may suggest ATRA syndrome. The early diagnosis of this will improve the patients' prognosis.

  18. CBL mutations do not frequently occur in paediatric acute myeloid leukaemia

    NARCIS (Netherlands)

    Coenen, Eva A.; Driessen, Emma M. C.; Zwaan, C. Michel; Stary, Jan; Baruchel, Andre; de Haas, Valerie; de Bont, Eveline S. J. M.; Reinhardt, Dirk; Kaspers, Gertjan J. L.; Arentsen-Peters, Susan T. C. J. M.; Meyer, Claus; Marschalek, Rolf; Pieters, Rob; Stam, Ronald W.; van den Heuvel-Eibrink, Marry M.

    2012-01-01

    RAS-pathway mutations, causing a proliferative advantage, occur in acute myeloid leukaemia (AML) and MLL-rearranged leukaemia. Recently, mutations in the Casitas B lineage lymphoma (CBL) gene were reported to be involved in RAS-pathway activation in various myeloid malignancies, but their role in pa

  19. Mx1 GTPase accumulates in distinct nuclear domains and inhibits influenza A virus in cells that lack promyelocytic leukaemia protein nuclear bodies.

    Science.gov (United States)

    Engelhardt, Othmar G; Sirma, Hüseyin; Pandolfi, Pier-Paolo; Haller, Otto

    2004-08-01

    The interferon-induced murine Mx1 GTPase is a nuclear protein. It specifically inhibits influenza A viruses at the step of primary transcription, a process known to occur in the nucleus of infected cells. However, the exact mechanism of inhibition is still poorly understood. The Mx1 GTPase has previously been shown to accumulate in distinct nuclear dots that are spatially associated with promyelocytic leukaemia protein (PML) nuclear bodies (NBs), but the significance of this association is not known. Here it is reported that, in cells lacking PML and, as a consequence, PML NBs, Mx1 still formed nuclear dots. These dots were indistinguishable from the dots observed in wild-type cells, indicating that intact PML NBs are not required for Mx1 dot formation. Furthermore, Mx1 retained its antiviral activity against influenza A virus in these PML-deficient cells, which were fully permissive for influenza A virus. Nuclear Mx proteins from other species showed a similar subnuclear distribution. This was also the case for the human MxA GTPase when this otherwise cytoplasmic protein was translocated into the nucleus by virtue of a foreign nuclear localization signal. Human MxA and mouse Mx1 do not interact or form heterooligomers. Yet, they co-localized to a large degree when co-expressed in the nucleus. Taken together, these findings suggest that Mx1 dots represent distinct nuclear domains ('Mx nuclear domains') that are frequently associated with, but functionally independent of, PML NBs.

  20. BETULINIC ACID WAS MORE CYTOTOXIC TOWARDS THE HUMAN BREAST CANCER CELL LINE MDA-MB-231 THAN THE HUMAN PROMYELOCYTIC LEUKAEMIA CELL LINE HL-60

    Directory of Open Access Journals (Sweden)

    LATIFAH SAIFUL YAZAN

    2009-01-01

    Full Text Available Betulinic acid (BA is a pentacyclic triterpene found in several botanical sources that has been shown to cause apoptosis in a number of cell lines. This study was undertaken to determine the in vitro cytotoxic properties of BA towards the human mammary carcinoma cell line MDA-MB-231 and the human promyelocytic leukaemia cell line HL-60 and the mode of the induced cell death. The cytotoxicity and mode of cell death of BA were determined using the MTT assay and DNAfragmentation analysis, respectively. In our study, the compound was found to be cytotoxic to MDA-MB-231 and HL-60 cells with IC50 values of 58 μg/mL and 134 μg/mL, respectively. Cells treated with high concentrations of BA exhibited features characteristic of apoptosis such as blebbing, shrinking and a number of small cytoplasm body masses when viewed under an inverted light microscope after 24 h. The incidence of apoptosis in MDA-MB-231 was further confirmed bythe DNA fragmentation analysis, with the formation of DNA fragments of oligonucleosomal size (180-200 base pairs, giving a ladder-like pattern on agarose gel electrophoresis. BA was more cytotoxic towards MDA-MB-231 than HL-60 cells, and induced apoptosis in MDA-MB-231 cells.

  1. Acute promyelocytic leukemia after renal transplant and filgrastim treatment for neutropenia

    Science.gov (United States)

    Krause, John R.

    2016-01-01

    Prolonged immunosuppression in solid organ transplant recipients has been considered a risk for developing opportunistic infections and malignancies. Acute leukemia is a rare complication. We report a case of acute promyelocytic leukemia (APL) (FAB M3) after cadaveric renal transplant for focal segmental glomerulosclerosis in a 24-year-old woman. Her immunosuppressive therapy included tacrolimus, mycophenolate mofetil, and prednisone. Approximately 2 years after transplant, she became pancytopenic, prompting administration of filgrastim. A few doses caused a markedly increased blast count, resulting in a diagnosis of APL. She was successfully treated with all-trans-retinoic acid and arsenic trioxide. Myeloproliferative neoplasms after organ transplant or due to filgrastim are rare. PMID:27695174

  2. Severe acute axonal neuropathy following treatment with arsenic trioxide for acute promyelocytic leukemia: a case report

    Directory of Open Access Journals (Sweden)

    Marcus Kuhn

    2016-05-01

    Full Text Available Peripheral neuropathy is a common complication of arsenic toxicity. Symptoms are usually mild and reversible following discontinuation of treatment. A more severe chronic sensorimotor polyneuropathy characterized by distal axonal-loss neuropathy can be seen in chronic arsenic exposure. The clinical course of arsenic neurotoxicity in patients with coexistence of thiamine deficiency is only anecdotally known but this association may potentially lead to severe consequences. We describe a case of acute irreversible axonal neuropathy in a patient with hidden thiamine deficiency who was treated with a short course of arsenic trioxide for acute promyelocytic leukemia. Thiamine replacement therapy and arsenic trioxide discontinuation were not followed by neurological recovery and severe polyneuropathy persisted at 12-month follow-up. Thiamine plasma levels should be measured in patients who are candidate to arsenic trioxide therapy. Prophylactic administration of vitamin B1 may be advisable. The appearance of polyneuropathy signs early during the administration of arsenic trioxide should prompt electrodiagnostic testing to rule out a pattern of axonal neuropathy which would need immediate discontinuation of arsenic trioxide.

  3. Relapsed acute promyelocytic leukemia in a hemodialysis-dependent patient treated with arsenic trioxide: a case report

    Directory of Open Access Journals (Sweden)

    Emmons Gregory S

    2012-10-01

    Full Text Available Abstract Introduction In the relapsed setting, arsenic trioxide remains the backbone of treatment. Scant literature exists regarding treatment of relapsed acute promyelocytic leukemia in patients with renal failure. To the best of our knowledge we are the first to report a safe and effective means of treatment for relapsed acute promyelocytic leukemia in the setting of advanced renal failure, employing titration of arsenic trioxide based on clinical parameters rather than arsenic trioxide levels. Case presentation A 33-year-old Caucasian man with a history of acute promyelocytic leukemia in remission for 3 years, as well as dialysis-dependent chronic renal failure secondary to a solitary kidney and focal segmental glomerulosclerosis and human immunodeficiency virus infection, receiving highly active antiretroviral therapy presented to our hospital with bone marrow biopsy-confirmed relapsed acute promyelocytic leukemia. Arsenic trioxide was begun at a low dose with dose escalation based only on side effect profile monitoring and not laboratory testing for induction as well as maintenance without undue toxicity. Our patient achieved and remains in complete hematologic and molecular remission as of this writing. Conclusion Arsenic trioxide can be used safely and effectively to treat acute promyelocytic leukemia in patients with advanced renal failure using careful monitoring of side effects rather than blood levels of arsenic to guide therapeutic dosing.

  4. From conventional therapy toward microRNA-based therapy in acute promyelocytic leukemia

    Science.gov (United States)

    Ehtesham, Naeim; Sharifi, Mohammadreza

    2016-01-01

    Acute promyelocytic leukemia (APL) is a hematopoietic malignancy that is known with its special cytogenetic feature. Several studies have surveyed expression signature of microRNAs (miRNAs) in APL patients, especially patients who are treated with conventional therapy of this disease. Using miRNAs as diagnostic or prognostic biomarkers in various cancers has been widely studied. Currently, most studies are focusing on exploiting miRNAs as therapeutic tools, and promising progress has been achieved in this field. Recently, studies in the field of miRNA-based therapy in APL have been started. PMID:28028527

  5. Scrotal ulceration following all-trans retinoic acid therapy for acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Illias Tazi

    2011-01-01

    Full Text Available All-trans retinoic acid (ATRA induces complete remission in most cases of acute promyelocytic leukemia. Toxicity of ATRA has been shown to be mild, consisting of headache, dry skin, dermatitis, and gastrointestinal disorders. We describe a case of scrotal ulceration with ATRA use in a Moroccan patient, an occurrence that has been rarely reported in the medical literature. The pathogenesis of scrotal ulceration remains unknown. Our experience indicates the importance of recognizing genital ulcers associated with ATRA in order that appropriate countermeasures can be taken.

  6. Further evidence for a non-random chromosomal abnormality in acute promyelocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Rowley, J.D.; Golomb, H.M.; Vardiman, J.; Fukahara, S.; Dougherty, C.; Potter, D.

    1977-01-01

    We have previously reported on two patients with acute promyelocytic leukemia (APL) who had what appeared to be a deletion of chromosome No. 17. We now describe a third patient with APL. All three patients had a structural rearrangement involving No. 15 and No. 17. Our current interpretation of the chromosomal abnormality is that it is a reciprocal translocation, t (15; 17) (q22; q21). Evidence that this is a consistent rearrangement associated with APL comes not only from our three patients, but also from two other published cases of APL, studied with banding, who also had an identical abnormality.

  7. EXTRAMEDULLARY DISEASE IN ACUTE PROMYELOCYTIC LEUKEMIA: TWO-IN-ONE DISEASE

    Directory of Open Access Journals (Sweden)

    Giorgina Specchia

    2011-01-01

    Full Text Available

    In acute promyelocytic leukemia (APL, extramedullary disease (EMD is particularly rare and shows special clinical and biological features. It is estimated that about 3–5% of APL patients will suffer extramedullary relapse. The most common site of EMD in APL is the CNS.  At present, there are still many issues of EMD in APL needing further clarification, including pathogenesis, risk factors, prognosis and treatment. A better understanding of the biological mechanisms underlying EMD is important to be able to devise more effective CNS prophylaxis and induction-consolidation therapeutic strategies

  8. Acute promyelocytic leukemia associated with a paraprotein that reacts with leukemic cells.

    Science.gov (United States)

    Atkins, H; Drouin, J; Izaguirre, C A; Sengar, D S

    1989-05-01

    A 29-year-old woman developed acute promyelocytic leukemia during pregnancy. At diagnosis, immediately postpartum, she was found to have IgG kappa immunoglobulin on the surface of the leukemic cells as well as a monoclonal protein of IgG kappa specificity in her serum. These resolved with chemotherapy which induced a complete remission. Immunoglobulin gene rearrangement was not found in the leukemic cells, thus indicating that the blasts were not secreting the monoclonal protein. The authors believe that the patient had an autoantibody directed at myeloid cells which was amplified by the development of the leukemic process.

  9. The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.

    Science.gov (United States)

    de Thé, Hugues; Le Bras, Morgane; Lallemand-Breitenbach, Valérie

    2012-07-09

    Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation.

  10. EXTRAMEDULLARY DISEASE IN ACUTE PROMYELOCYTIC LEUKEMIA: TWO-IN-ONE DISEASE

    Directory of Open Access Journals (Sweden)

    Francesco Albano

    2011-12-01

    Full Text Available In acute promyelocytic leukemia (APL, extramedullary disease (EMD is particularly rare and shows special clinical and biological features. It is estimated that about 3–5% of APL patients will suffer extramedullary relapse. The most common site of EMD in APL is the CNS.  At present, there are still many issues of EMD in APL needing further clarification, including pathogenesis, risk factors, prognosis and treatment. A better understanding of the biological mechanisms underlying EMD is important to be able to devise more effective CNS prophylaxis and induction-consolidation therapeutic strategies

  11. EPIDEMIOLOGY AND TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA IN LATIN AMERICA

    Directory of Open Access Journals (Sweden)

    Eduardo Magalhães Rego

    2011-10-01

    Full Text Available Distinct epidemiological characteristics have been described in Acute Promielocytic Leukemia (APL. Populations from Latin America have a higher incidence of APL and in some geographic areas a distinct distribution of the PML-RARA isoforms is present. Here, we review the main differences in APL epidemilogy in Latin America as well as treatment outcomes.

  12. Acute promyelocytic leukemia and differentiation therapy: molecular mechanisms of differentiation, retinoic acid resistance and novel treatments

    Directory of Open Access Journals (Sweden)

    Bülent Özpolat

    2009-06-01

    Full Text Available Incorporation of all-trans-retinoic acid (ATRA into the treatment of acute promyelocytic leukemia (APL, a type of acute myeloid leukemia (AML, revolutionized the therapy of cancer in the last decade and introduced the concept of differentiation therapy. ATRA, a physiological metabolite of vitamin A (retinol, induces complete clinical remissions (CRs in about 90% of patients with APL. In contrast to the cytotoxic chemotherapeutics, ATRA can selectively induce terminal differentiation of promyelocytic leukemic cells into normal granulocytes without causing bone marrow hypoplasia or exacerbation of the frequently occurring fatal hemorrhagic syndromes in patients with APL. However, remissions induced by ATRA alone are transient and the patients commonly become resistant to the therapy, leading to relapses in most patients and thus limiting the use of ATRA as a single agent. Therefore, ATRA is currently combined with anthracycline-based chemotherapy, and this regimen dramatically improves patient survival compared to chemotherapy alone, curing about 70% of the patients. However, 30% of APL patients still relapse and die in five years. Recently, arsenic trioxide (As2O3 was proven to be highly effective in inducing CRs not only in APL patients relapsed after ATRA treatment and conventional chemotherapy but also in primary APL patients. Despite the well-documented clinical efficacy of ATRA, molecular mechanisms responsible for development of ATRA resistance are not well understood. Based on in vitro and clinical observations, several mechanisms, including induction of accelerated metabolism of ATRA, decreased bioavailability and plasma drug levels, point mutations in the ATRA-binding domain of promyelocytic leukemia (PML-retinoic acid receptor-alpha (RARα and other molecular events have been proposed to explain ATRA resistance. In this review, the molecular mechanisms of ATRA-induced myeloid cell differentiation and resistance are discussed, together

  13. [Necrotizing tonsillitis and renal vein thrombosis due to acute myeloid leukaemia].

    Science.gov (United States)

    Akram, Javed; Josefsson, Pernilla; Rømeling, Frans

    2012-09-03

    A 37-year-old woman was admitted to hospital with severe tonsillitis with unilateral necrotizing tonsillitis. She suddenly got fever, malaise, difficulties swallowing, pain in the throat and deterioration despite four days of penicillin treatment. During hospitalisation, she experienced abdominal pain, and blood tests showed pancytopenia. She was transferred to a haematological department, where a bone marrow biopsy showed acute myeloid leukaemia. Subsequently, an abdominal computed tomography with intravenous contrast revealed bilateral renal vein thrombosis, probably because of coagulopathy due to leukaemia.

  14. Disseminated Exfoliative Dermatitis Associated with All-Transretinoic Acid in the Treatment of Acute Promyelocytic Leukemia

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    Yonal Ipek

    2012-01-01

    Full Text Available Acute promyelocytic leukemia (APL is a biologically and clinically separate type of acute myeloid leukemia characterized by a translocation involving the retinoic acid receptor-alpha (RARa locus on chromosome 17, the great majority of which is t(15; 17(q24.1; q21.1 (Collins (1998, Melnick and Licht (1999, and Grimwade (1999. Retinoic acid is a critical ligand in the differentiation pathway of multiple tissues, mediated through binding to an RAR. All-trans retinoic acid (ATRA is a subgroup of the retinoid family, which induces complete remission (CR in APL by causing differentiation and apoptosis in immature malignant promyelocytes rather than inducing cell death by cytotoxicity (Warrell et al. (1993, Liu et al. (2000, and Cassinat et al. (2001. ATRA-associated toxicity consisting of headache, fever, weakness, fatigue, dry skin, dermatitis, gastrointestinal disorders, and hypertriglyceridemia has been shown to be mild (Kurzrock et al. (1993. Herein, we describe a patient with APL that developed an erythematous reaction of the whole body followed by desquamation and exfoliation during ATRA therapy.

  15. LG-362B targets PML-RARα and blocks ATRA resistance of acute promyelocytic leukemia.

    Science.gov (United States)

    Wang, X; Lin, Q; Lv, F; Liu, N; Xu, Y; Liu, M; Chen, Y; Yi, Z

    2016-07-01

    Acute promyelocytic leukemia (APL) is a M3 subtype of acute myeloid leukemia (AML). Promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) translocation generally occurs in APL patients and makes APL unique both for diagnosis and treatment. However, some conventional drugs like all-transretinoic acid (ATRA) and arsenic trioxide (ATO), as the preferred ones for APL therapy, induce irreversible resistance and responsible for clinical failure of complete remission. Herein, we screened a library of novel chemical compounds with structural diversity and discovered a novel synthetic small compound, named LG-362B, specifically inhibited the proliferation of APL and induced apoptosis. Notably, the differentiation arrest was also relieved by LG-362B in cultured APL cells and APL mouse models. Moreover, LG-362B overcame the ATRA resistance on cellular differentiation and transplantable APL mice. These positive effects were driven by caspases-mediated degradation of PML-RARα when treated with LG-362B, making it specific to APL and reasonable for ATRA resistance relief. We propose that LG-362B would be a potential candidate agent for the treatment of the relapsed APL with ATRA resistance in the future.

  16. Increased cellular hypoxia and reduced proliferation of both normal and leukaemic cells during progression of acute myeloid leukaemia in rats

    DEFF Research Database (Denmark)

    Jensen, P O; Mortensen, B T; Hodgkiss, R J

    2000-01-01

    The microenvironmental changes in the bone marrow, spleen and liver during progression of the transplantable promyelocytic leukaemia in the Brown Norwegian rat (BNML) have been studied. We used flow cytometry to estimate cellular hypoxia and proliferation based on in vivo pulse-labelling with a m......The microenvironmental changes in the bone marrow, spleen and liver during progression of the transplantable promyelocytic leukaemia in the Brown Norwegian rat (BNML) have been studied. We used flow cytometry to estimate cellular hypoxia and proliferation based on in vivo pulse......-labelling with a mixture of 2-nitroimidazole linked to theophylline (NITP) and bromodeoxyuridine (BrdUrd). The leukaemic cells were identified with the RM124 antibody. In rats inoculated with leukaemic cells the fraction of RM124+ cells was significantly increased from day 20 onwards in the spleen and from day 27...

  17. Clofarabine in the treatment of poor risk acute myeloid leukaemia.

    LENUS (Irish Health Repository)

    Krawczyk, Janusz

    2010-09-01

    Clofarabine is a second generation nucleoside analogue. It inhibits DNA repair and activates the mitochondrial apoptotic pathway leading to cell death. In vitro clofarabine has demonstrated synergy with daunorubicin and Ara-C and in phase II clinical trials has shown promising activity in poor risk Acute myeloid leukaemia (AML) patients. In our institution over a 24 month period 22 AML patients (11 M, 11 F) with poor risk features, deemed unsuitable for standard therapy, were treated with clofarabine, alone (eight patients) or in combination (14 patients) for up to three cycles of treatment. The median age was 67.5 years (24-76) with 16 patients > 60 years. At the time of treatment 18 patients had active AML. Four patients intolerant of standard induction received clofarabine as consolidation. The overall response rate (ORR) for the 18 patients with active AML was 61%, nine patients (50%) achieving a complete response (CR). Induction and consolidation were well tolerated with no unexpected toxicities. Predictably, all patients developed grade 4 neutropenia but the median duration was only 20 days (17-120). Induction mortality was acceptable at 17%. In conclusion, clofarabine (alone or in combination) is active in poor risk AML with an acceptable safety profile and should be considered a potential option in poor risk AML patients.

  18. Is this acute lymphoblastic leukaemia or juvenile rheumatoid arthritis.

    Science.gov (United States)

    Kirubakaran, Chellam; Scott, Julius Xavier; Ebenezer, Sam

    2011-08-01

    Arthritis could be a presenting feature of acute lymphoblastic leukaemia (ALL) and could be wrongly diagnosed as juvenile rheumatoid arthritis (JRA). Clinical and laboratory parameters might differentiate ALL and JRA in children who present with arthritis. Out of a total of 250 children of ALL, 10 were referred to the department of child health and paediatric haemato-oncology of Christian Medical College, Vellore during 1990-2002. They were compared with 10 age-matched children who had systematic onset of JRA. The age groups in ALL and JRA were 6.05 +/- 2.45 years and 5.47 +/- 4.4 years respectively. Severe pain as evidenced by inability to walk was found in children but one child with JRA was unable to walk (p JRA group. ESR was elevated in all cases in both the groups. One case in each group had antinuclear antibody positivity. It can be concluded that ALL can masquerade as systematic onset of JRA. So paediatricians should be careful enough while diagnosing the disease process.

  19. Somatic PTPN11 mutations in childhood acute myeloid leukaemia.

    Science.gov (United States)

    Tartaglia, Marco; Martinelli, Simone; Iavarone, Ivano; Cazzaniga, Giovanni; Spinelli, Monica; Giarin, Emanuela; Petrangeli, Valentina; Carta, Claudio; Masetti, Riccardo; Aricò, Maurizio; Locatelli, Franco; Basso, Giuseppe; Sorcini, Mariella; Pession, Andrea; Biondi, Andrea

    2005-05-01

    Somatic mutations in PTPN11, the gene encoding the transducer SHP-2, have emerged as a novel class of lesions that upregulate RAS signalling and contribute to leukaemogenesis. In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia (AML), we documented a non-random distribution of PTPN11 mutations among French-American-British (FAB) subtypes. Lesions were restricted to FAB-M5 cases, where they were relatively common (four of 12 cases). Here, we report on the results of a molecular screening performed on 181 additional unselected patients, enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica-AML Study Group, to provide a more accurate picture of the prevalence, spectrum and distribution of PTPN11 mutations in childhood AML and to investigate their clinical relevance. We concluded that PTPN11 defects do not represent a frequent event in this heterogeneous group of malignancies (4.4%), although they recur in a considerable percentage of patients with FAB-M5 (18%). PTPN11 lesions rarely occur in other subtypes. Within the FAB-M5 group no clear association of PTPN11 mutations with any clinical variable was evident. Nearly two third of the patients with this subtype were found to harbour an activating mutation in PTPN11, NRAS, KRAS2 or FLT3.

  20. Intussusception: a rare complication in a patient with acute leukaemia after consolidation chemotherapy.

    Science.gov (United States)

    Qasrawi, Ayman; Abu Ghanimeh, Mouhanna; Abughanimeh, Omar; Qasem, Abdulraheem

    2017-02-28

    Intussusception is telescoping of one segment of the gastrointestinal tract into an adjacent one. It is more common in children than adults. When it occurs in adults, it is usually associated with a lead point. Intussusception is very rare in acute leukaemia and has only been reported in few cases. We present a case of an adult woman who presented with intussusception after a cycle of consolidation chemotherapy with high-dose cytarabine for acute myeloid leukaemia. Other causes of acute abdominal pain were excluded, and the diagnosis was established by CT scan of the abdomen and barium enema. No pathological lead points were found intraoperatively. She underwent a right-sided hemicolectomy with complete recovery. To the best of our knowledge, this is only the fourth case of intussusception that has been reported in an adult patient with acute myeloid leukaemia. 2017 BMJ Publishing Group Ltd.

  1. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Attarbaschi, Andishe; Barzilai, Shlomit

    2016-01-01

    Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi...... method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis......, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14...

  2. Addition of Arsenic Trioxide into Induction Regimens Could Not Accelerate Recovery of Abnormality of Coagulation and Fibrinolysis in Patients with Acute Promyelocytic Leukemia.

    Directory of Open Access Journals (Sweden)

    Ye Zhang

    Full Text Available All-trans retinoic acid combined to anthracycline-based chemotherapy is the standard regimen of acute promyelocytic leukemia. The advent of arsenic trioxide has contributed to improve the anti-leukemic efficacy in acute promyelocytic leukemia. The objectives of the current study were to evaluate if dual induction by all-trans retinoic acid and arsenic trioxide could accelerate the recovery of abnormality of coagulation and fibrinolysis in patients with acute promyelocytic leukemia.Retrospective analysis was performed in 103 newly-diagnosed patients with acute promyelocytic leukemia. Hemostatic variables and the consumption of component blood were comparably analyzed among patients treated by different induction regimen with or without arsenic trioxide.Compared to patients with other subtypes of de novo acute myeloid leukemia, patients with acute promyelocytic leukemia had lower platelet counts and fibrinogen levels, significantly prolonged prothrombin time and elevated D-dimers (P<0.001. Acute promyelocytic leukemia patients with high or intermediate risk prognostic stratification presented lower initial fibrinogen level than that of low-risk group (P<0.05. After induction treatment, abnormal coagulation and fibrinolysis of patients with acute promyelocytic leukemia was significantly improved before day 10. The recovery of abnormal hemostatic variables (platelet, prothrombin time, fibrinogen and D-dimer was not significantly accelerated after adding arsenic trioxide in induction regimens; and the consumption of transfused component blood (platelet and plasma did not dramatically change either. Acute promyelocytic leukemia patients with high or intermediate risk prognostic stratification had higher platelet transfusion demands than that of low-risk group (P<0.05.Unexpectedly, adding arsenic trioxide could not accelerate the recovery of abnormality of coagulation and fibrinolysis in acute promyelocytic leukemia patients who received all

  3. Treatment of newly diagnosed acute promyelocytic leukemia (APL) : a comparison of French-Belgian-Swiss and PETHEMA results

    NARCIS (Netherlands)

    Ades, Lionel; Sanz, Miguel A.; Chevret, Sylvie; Montesinos, Pau; Chevallier, Patrice; Raffoux, Emmanuel; Vellenga, Edo; Guerci, Agnbs; Pigneux, Arnaud; Huguet, Francoise; Rayon, Consuelo; Stoppa, Anne Marie; de la Serna, Javier; Cahn, Jean-Yves; Meyer-Monard, Sandrine; Pabst, Thomas; Thomas, Xavier; de Botton, Stephane; Parody, Ricardo; Bergua, Juan; Lamy, Thierry; Vekhoff, Anne; Negri, Silvia; Ifrah, Norbert; Dombret, Herve; Ferrant, Augustin; Bron, Dominique; Degos, Laurent; Fenaux, Pierre

    2008-01-01

    All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para

  4. Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet

    NARCIS (Netherlands)

    M.A. Sanz (Miguel Angel); D. Grimwade (David); M.S. Tallman (Martin); B. Löwenberg (Bob); P. Fenaux (Pierre); E.H. Estey (Elihu); T. Naoe (Tomoki); E. Lengfelder (Eva); T. Büchner (Thomas); H. Döhner (Hartmut); A.K. Burnett (Alan); F. Lo-Coco (Francesco)

    2009-01-01

    textabstractThe introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with

  5. Treatment of newly diagnosed acute promyelocytic leukemia (APL) : a comparison of French-Belgian-Swiss and PETHEMA results

    NARCIS (Netherlands)

    Ades, Lionel; Sanz, Miguel A.; Chevret, Sylvie; Montesinos, Pau; Chevallier, Patrice; Raffoux, Emmanuel; Vellenga, Edo; Guerci, Agnbs; Pigneux, Arnaud; Huguet, Francoise; Rayon, Consuelo; Stoppa, Anne Marie; de la Serna, Javier; Cahn, Jean-Yves; Meyer-Monard, Sandrine; Pabst, Thomas; Thomas, Xavier; de Botton, Stephane; Parody, Ricardo; Bergua, Juan; Lamy, Thierry; Vekhoff, Anne; Negri, Silvia; Ifrah, Norbert; Dombret, Herve; Ferrant, Augustin; Bron, Dominique; Degos, Laurent; Fenaux, Pierre

    2008-01-01

    All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para

  6. Erythema multiforme due to arsenic trioxide in a case of acute promyelocytic leukemia: A diagnostic challenge

    Directory of Open Access Journals (Sweden)

    Girish V Badarkhe

    2016-01-01

    Full Text Available Erythema multiforme (EM is an acute, self-limited, Type IV hypersensitivity reactions associated with infections and drugs. In this case of acute promyelocytic leukemia, EM diagnosed during the induction phase was mistakenly attributed to vancomycin used to treat febrile neutropenia during that period. However, the occurrence of the lesions of EM again during the consolidation phase with arsenic trioxide (ATO lead to a re-evaluation of the patient and both the Naranjo and World Health Organization-Uppsala Monitoring Centre scale showed the causality association as “probable.” The rash responded to topical corticosteroids and antihistamines. This rare event of EM being caused by ATO may be attributed to the genetic variation of methyl conjugation in the individual which had triggered the response, and the altered metabolic byproducts acted as a hapten in the subsequent keratinocyte necrosis.

  7. Transient ischemic attack as an unusual initial manifestation of acute promyelocytic leukemia.

    Science.gov (United States)

    Liu, Lifeng; Yuan, Xiaoling

    2016-07-01

    Patients with acute promyelocytic leukemia (APL) are prone to both bleeding and thrombosis. Both of these have a significant impact on the morbidity and mortality of patients with this disease. Here we report a case of a 41-year-old male, who presented with transient ischemic attack (TIA) and early neurological deterioration (END) as initial manifestations prior to an ultimate diagnosis of APL. This patient had no cerebrovascular risk factors or familial cerebrovascular disease. The patient experienced an acute ischemic stroke, verified by magnetic resonance imaging (MRI), in less than 24 h after his second hospital admission. Some APL patients suffer from cerebral ischemia as an initial manifestation or during induction therapy, and patients presenting this condition may continue to deteriorate until their death during hospitalization. Thus, APL should be considered as a possible underlying disease in patients with TIA without cerebrovascular risk factors. Delayed diagnosis and treatment of APL can be fatal.

  8. Cryptic PML-RARα positive acute promyelocytic leukemia with unusual morphology and cytogenetics

    Directory of Open Access Journals (Sweden)

    Goyal Manu

    2010-10-01

    Full Text Available Acute Promyelocytic Leukemia (APL is different from other forms of acute myeloid leukemia (AML, to the reason being the potential devastating coagulopathy and the sensitivity to all-trans retinoic acid (ATRA and arsenic trioxide (As 2 O 3 . We hereby present a case of APL, morphologically distinct from the hypergranular APL; however, the flow cytometry revealed a characteristic phenotype showing dim CD45, bright CD13, bright CD33 and dim CD117 positivity. These were negative for CD34, HLA-DR, B-lymphoid and T-lymphoid lineage markers. Conventional cytogenetics revealed a distinct karyotype of a male with translocation t(4;15(q34.2:q26.3. However, interphase florescence-in-situ hybridization (FISH revealed PML/RARA fusion signal on chromosome 15 in 90% cells. The cryptic translocations may be missed on conventional cytogenetics, however, need to be picked by other techniques as FISH.

  9. DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding

    DEFF Research Database (Denmark)

    Schoofs, Till; Rohde, Christian; Hebestreit, Katja;

    2013-01-01

    The origin of aberrant DNA methylation in cancer remains largely unknown. In the present study, we elucidated the DNA methylome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic acid receptor α (PML-RARα) in establishing these patterns. Cells from APL...... patients showed increased genome-wide DNA methylation with higher variability than healthy CD34(+) cells, promyelocytes, and remission BM cells. A core set of differentially methylated regions in APL was identified. Age at diagnosis, Sanz score, and Flt3-mutation status characterized methylation subtypes......-trans retinoic acid also did not result in immediate DNA methylation changes. The results of the present study suggest that aberrant DNA methylation is associated with leukemia phenotype but is not required for PML-RARα-mediated initiation of leukemogenesis....

  10. Mechanisms of all-trans retinoic acid-induced differentiation of acute promyelocytic leukemia cells

    Indian Academy of Sciences (India)

    Ji-Wang Zhang; Jian Gu; Zhen-Yi Wang; Sai-Juan Chen; Zhu Chen

    2000-09-01

    Retinoic acids (RA) play a key role in myeloid differentiation through their agonistic nuclear receptors (RAR/RXR) to modulate the expression of target genes. In acute promyelocytic leukemia (APL) cells with rearrangement of retinoic acid receptor (RAR) (including: PML-RAR, PLZF-RAR, NPM-RAR, NuMA-RAR or STAT5b-RAR) as a result of chromosomal translocations, the RA signal pathway is disrupted and myeloid differentiation is arrested at the promyelocytic stage. Pharmacologic dosage of all-trans retinoic acid (ATRA) directly modulates PML-RAR and its interaction with the nuclear receptor co-repressor complex, which restores the wild-type RAR/RXR regulatory pathway and induces the transcriptional expression of downstream genes. Analysing gene expression profiles in APL cells before and after ATRA treatment represents a useful approach to identify genes whose functions are involved in this new cancer treatment. A chronologically well coordinated modulation of ATRA-regulated genes has thus been revealed which seems to constitute a balanced functional network underlying decreased cellular proliferation, initiation and progression of maturation, and maintenance of cell survival before terminal differentiation.

  11. Cell death induction by the acute promyelocytic leukemia-specific PML/RARα fusion protein

    Science.gov (United States)

    Ferrucci, Pier Francesco; Grignani, Francesco; Pearson, Mark; Fagioli, Marta; Nicoletti, Ildo; Pelicci, Pier Giuseppe

    1997-01-01

    PML/RARα is the abnormal protein product generated by the acute promyelocytic leukemia-specific t(15;17). Expression of PML/RARα in hematopoietic precursor cell lines induces block of differentiation and promotes survival. We report here that PML/RARα has a potent growth inhibitory effect on all nonhematopoietic cell lines and on the majority of the hematopoietic cell lines tested. Inducible expression of PML/RARα in fibroblasts demonstrated that the basis for the growth suppression is induction of cell death. Deletion of relevant promyelocytic leukemia (PML) and retinoic acid receptor (RARα) domains within the fusion protein revealed that its growth inhibitory effect depends on the integrity of the PML aminoterminal region (RING, B1, B2, and coiled coil regions) and the RARα DNA binding region. Analysis of the nuclear localization of the same PML/RARα deletion mutants by immunofluorescence and cell fractionation revealed that the biological activity of the fusion protein correlates with its microspeckled localization and its association to the nuclear matrix. The PML aminoterminal region, but not the RARα zinc fingers, is required for the proper nuclear localization of PML/RARα. We propose that the matrix-associated microspeckles are the active sites of PML/RARα and that targeting of RARα sequences to this specific nuclear subdomain through PML sequences is crucial to the activity of the fusion protein on survival regulation. PMID:9380732

  12. Aplastic anaemia preceding acute lymphoblastic leukaemia in an adult with isolated deletion of chromosome 9q.

    LENUS (Irish Health Repository)

    Kelly, Kevin

    2008-12-01

    Aplastic anaemia (AA) can precede acute lymphoblastic leukaemia (ALL) in 2% of children but this is rarely reported to occur in adults. A 21-year-old male presented with bone marrow failure and bone marrow biopsy showed a profoundly hypocellular marrow. He recovered spontaneously but represented 2 months later when he was diagnosed with pre-B acute lymphoblastic leukaemia. Chromosomal examination revealed 46,XY,del(9)(q13q34). To the best of our knowledge this is the first case to be reported of aplasia preceding ALL with 9q minus as the sole chromosomal abnormality.

  13. Granulocytic sarcoma of the femur in a patient with acute megakaryoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Čolović Milica

    2011-01-01

    Full Text Available Introduction. Granulocytic sarcoma, chloroma or myeloblastoma are observed in 3% to7% of acute myeloid leukaemia and represents localized tumour composed of collection of immature leukaemic cells. It appears most frequently in patients with M2, M4 and M5 subtypes of acute myeloid leukaemia Case Outline. A 58-year-old female presented with pain and oedema of the right upper limb in November 2009. After two months the patinet had fracture dislocation and numerous osteolytic lesions of the right femur. Immunohistochemistry of tumour biopsy showed megakaryoblastic granulocytic sarcoma which was CD31++, F-XIII++, CD34-, FVIII+++, S100-, aktin-, EMA++, Bcl2++, CD43++, with positive proliferative marker measured with Ki-67 positivity in more of 50% of cells. Aspirate of bone marrow and immunophenotyping with flowcytometry revealed diagnosis of acute megakaryoblastic leukaemia. The course of the disease was rapid and the patient died before commencing chemotherapy, five months after first complaints. Conclusion. Granulocytic sarcoma is extramedullary localization of collection of leukaemia cells which can proceed, to arise concomitantly with leukaemia, or may be the only manifestation of the disease. The diagnosis can be established only with immunohystochemistry.

  14. Modulation of Gene Expression Networks underlying Realgar-Induced Differentiation of Acute Promyelocytic Leukemia Cells

    Institute of Scientific and Technical Information of China (English)

    王怀宇; 刘陕西

    2002-01-01

    Objective: To elucidate the molecular mechanism of the differentiation of acute promyelocytic leukemia (APL) cell line NB4 induced by realgar. Methods: The response of NB4 cell to realgar was explored with a cDNA microarray representing 1003 different human genes. Results: The analysis of gene expression profiles indicated that 8 genes were up-regulated and 33 genes were down-regulated 48 hrs after realgar treatment. Among the 8 up-regulated genes, 2 genes were involved in ubiquitin proteasome degradation pathway. Some genes related to RNA processing, protein synthesis and signal transduction were down-regulated. Conclusion: The ubiquitin-proteasome degradation pathway may play an important role in the degradation of PML/RAR α fusion protein and the differentiation of NB4 cells.

  15. DETECTION AND ITS CLINICAL VALUE OF MINIMAL RESIDUAL DISEASES IN ACUTE PROMYELOCYTIC LEUKEMIA

    Institute of Scientific and Technical Information of China (English)

    姜国胜; 唐天华; 毕可红; 张玉昆; 任海全; 赵良玉; 郭桂月; 刘秀兰; 任青华; 姜枫勤; 刘传芳; 彭军; 田志刚

    2002-01-01

    Objective: To detect the minimal residual diseases (MRD) in acute promyelocytic leukemia (APL) after complete remission (CR) and to analyze its clinical value in prognosis. Methods: Reverse transcription Polymerase chain reaction (RT/PCR) was used to detect MRD of patients with APL. Results: MRD positive rate in patients with APL was 92.8% (39/42) before treatment and 56.7 (21/37) immediately after the ATRA or chemotherapy- induced CR. Furthermore, MRD positive rate wasrelated to the relapse in APL patients and could be considered as a marker to predict the relapse of patients with APL after CR. The MRD detection could also be applied to direct the consolidation therapy to prevent relapses. Conclusion: RT-PCR is valuable to monitor MRD and can be used as a marker to predict relapses.

  16. Acute promyelocytic leukemia with JAK2 V617F and severe differentiation syndrome

    Directory of Open Access Journals (Sweden)

    Theodore P. Braun

    2015-01-01

    Full Text Available Myeloproliferative neoplasms transformed into AML usually have a poor prognosis. We report a case of essential thrombocythemia with myelofibrosis that transformed into acute promyelocytic leukemia (APL with both the t(15;17 translocation as well as the JAK2 V617F mutation. Clinically, this case was notable for severe differentiation syndrome despite treatment with high-dose dexamethasone. Cytokine production by differentiating APL cells was not directly abrogated by JAK2 inhibitors in vitro, suggesting that JAK2 V617F enhances the hyperinflammatory response downstream of cytokines. JAK1/2 inhibitors may therefore dampen the inflammatory cascade downstream of cytokine production, similar to glucocorticoids, and have a role in treating severe differentiation syndrome.

  17. Pregnancy after treatment of secondary acute promyelocytic leukemia following Hodgkin's disease: a case report.

    Science.gov (United States)

    Elezović, I; Colović, M; Tomin, D; Bosković, D

    2000-08-01

    The authors report a case of therapy-related acute promyelocytic leukemia (t-APL), with typical cytogenetic translocation t(15;17), which appeared following chemotherapy (ABVD), and radiotherapy for Hodgkin's disease (IIB). After treatment with all-trans retinoic acid (Vesanoid(R) 45 mg/m2 daily) complete remission of t-APL was achieved. Then only one course of chemotherapy '3+7' (doxorubicin 45 mg/m2 1-3 d, cytosar 200 mg/m2 1-7d) was applied and the patient interrupted further treatment in July 1994. Four years later she had a normal pregnancy and delivered a healthy female infant in December 1998.

  18. Acute promyelocytic leukemia, hypogranular variant, with uncharacteristic staining with chloroacetate esterase.

    Science.gov (United States)

    Dunphy, C H; Polski, J M; Johns, G; Evans, H L; Gardner, L J

    2001-06-01

    A diagnosis of the hypogranular variant of acute promyelocytic leukemia (APLv) may be difficult to establish based on cytomorphology alone. However, the great majority of cases have a classical immunophenotype by flow cytometric immunophenotyping (FCI) (CD13+, CD33+, dim CD64+, HLA-DR-, and CD34-) and a classical enzyme cytochemical (EC) staining pattern. [intensely staining with myeloperoxidase, Sudan Black B, and chloroacetate esterase (CAE) and negative with alpha'-naphthyl acetate and butyrate esterases]. Although the immunophenotype of APLv by FCI has varied in the literature (HLA-DR +/- and CD34 +/-), the EC staining pattern has remained constant. We report a case of APLv with characteristic cytomorphology, compatible FCI data (CD13+, CD33+, dim CD64+, HLA-DR +/-, and CD34-), chromosomal detection of t(15; 17), and molecular detection of the PML/RAR alpha fusion gene; however, staining of the leukemic cells with CAE was quite uncharacteristic. We describe our findings.

  19. The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia.

    Science.gov (United States)

    Arteaga, Maria Francisca; Mikesch, Jan-Henrik; Qiu, Jihui; Christensen, Jesper; Helin, Kristian; Kogan, Scott C; Dong, Shuo; So, Chi Wai Eric

    2013-03-18

    While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RARα fusions to activate expression of their downstream targets upon ATRA treatment. Forced expression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance. ATRA sensitivity depends on the enzymatic activity and phosphorylation status of PHF8, which can be pharmacologically manipulated to resurrect ATRA sensitivity to resistant cells. These findings provide important molecular insights into ATRA response and a promising avenue for overcoming ATRA resistance.

  20. The antioxidant protein peroxiredoxin 4 is epigenetically down regulated in acute promyelocytic leukemia.

    Science.gov (United States)

    Palande, Karishma K; Beekman, Renee; van der Meeren, Lotte E; Beverloo, H Berna; Valk, Peter J M; Touw, Ivo P

    2011-01-20

    The antioxidant peroxiredoxin (PRDX) protein family comprises 6 members, which are implicated in a variety of cellular responses, including growth factor signal transduction. PRDX4 resides in the endoplasmic reticulum (ER), where it locally controls oxidative stress by reducing H(2)O(2) levels. We recently provided evidence for a regulatory function of PRDX4 in signal transduction from a myeloid growth factor receptor, the granulocyte colony-stimulating factor receptor (G-CSFR). Upon activation, the ligand-induced G-CSFR undergoes endocytosis and routes via the early endosomes where it physically interacts with ER-resident PRDX4. PRDX4 negatively regulates G-CSFR mediated signaling. Here, we investigated whether PRDX4 is affected in acute myeloid leukemia (AML); genomic alterations and expression levels of PRDX4 were investigated. We show that genomic abnormalities involving PRDX4 are rare in AML. However, we find a strong reduction in PRDX4 expression levels in acute promyelocytic leukemia (APL) compared to normal promyelocytes and different molecular subtypes of AML. Subsequently, the possible role of DNA methylation and histone modifications in silencing of PRDX4 in APLs was investigated. We show that the reduced expression is not due to methylation of the CpG island in the promoter region of PRDX4 but correlates with increased trimethylation of histone 3 lysine residue 27 (H3K27me3) and lysine residue 4 (H3K4me3) at the transcriptional start site (TSS) of PRDX4, indicative of a bivalent histone code involved in transcriptional silencing. These findings suggest that the control of G-CSF responses by the antioxidant protein PRDX4 may be perturbed in APL.

  1. The antioxidant protein peroxiredoxin 4 is epigenetically down regulated in acute promyelocytic leukemia.

    Directory of Open Access Journals (Sweden)

    Karishma K Palande

    Full Text Available The antioxidant peroxiredoxin (PRDX protein family comprises 6 members, which are implicated in a variety of cellular responses, including growth factor signal transduction. PRDX4 resides in the endoplasmic reticulum (ER, where it locally controls oxidative stress by reducing H(2O(2 levels. We recently provided evidence for a regulatory function of PRDX4 in signal transduction from a myeloid growth factor receptor, the granulocyte colony-stimulating factor receptor (G-CSFR. Upon activation, the ligand-induced G-CSFR undergoes endocytosis and routes via the early endosomes where it physically interacts with ER-resident PRDX4. PRDX4 negatively regulates G-CSFR mediated signaling. Here, we investigated whether PRDX4 is affected in acute myeloid leukemia (AML; genomic alterations and expression levels of PRDX4 were investigated. We show that genomic abnormalities involving PRDX4 are rare in AML. However, we find a strong reduction in PRDX4 expression levels in acute promyelocytic leukemia (APL compared to normal promyelocytes and different molecular subtypes of AML. Subsequently, the possible role of DNA methylation and histone modifications in silencing of PRDX4 in APLs was investigated. We show that the reduced expression is not due to methylation of the CpG island in the promoter region of PRDX4 but correlates with increased trimethylation of histone 3 lysine residue 27 (H3K27me3 and lysine residue 4 (H3K4me3 at the transcriptional start site (TSS of PRDX4, indicative of a bivalent histone code involved in transcriptional silencing. These findings suggest that the control of G-CSF responses by the antioxidant protein PRDX4 may be perturbed in APL.

  2. Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor

    NARCIS (Netherlands)

    J.H. Jansen (Joop); M.C. de Breems-de Ridder (Marleen); W.M. Geertsma; C.A.J. Erpelinck (Claudia); K. van Lom (Kirsten); R. Slater (Rosalyn); B.A. van der Reijden (Bert); G.E. de Greef (Georgine); P. Sonneveld (Pieter); B. Löwenberg (Bob); E.M.E. Smit (Elisabeth)

    1999-01-01

    textabstractThe combined use of retinoic acid and chemotherapy has led to an important improvement of cure rates in acute promyelocytic leukemia. Retinoic acid forces terminal maturation of the malignant cells and this application represents the first generally accepted

  3. Risk of acute myelogenous leukaemia and myelodysplasia following cancer treatment.

    Science.gov (United States)

    van Leeuwen, F E

    1996-03-01

    Now that a substantial group of cancer patients has such a favourable prognosis, it has become increasingly important to evaluate the long-term complications of treatment. Of all late effects of treatment, secondary leukaemia is one of the most serious. Increased risk of AML has been observed both after RT and after CT; however, several types of CT have much stronger leukaemogenic properties than RT. Limited field radiation in the therapeutic dose range is associated with very little or no increased risk of leukaemia, which has been attributed to cell killing at the higher radiation doses. With respect to CT, two different syndromes of treatment-related AML have been recognized. Risk of alkylating agent-related AML is highest in the 5-10 year follow-up period and seems to decrease afterwards. This type of leukaemia is often preceded by MDS, and is characterized by deletions of chromosomes 5 and 7. Leukaemias related to treatment with the topoisomerase II inhibitors are characterized by a short induction period, presentation as myelomonocytic or monocytic leukaemia (rather than MDS) and balanced chromosomal translocations involving bands 11q23 and 21q22. This review addresses the risk of secondary AML and MDS following treatment of HD, NHL, testicular cancer, ovarian cancer, breast cancer and paediatric malignancies. In patients with HD, the risk of AML is higher with an increasing number of mechlorethamine-procarbazine-containing cycles, a greater number of CT episodes, and after splenectomy. The majority of data shows that RT does not add to the leukaemia risk from CT, but this issue is still surrounded by some controversy. ABV(D)-treated patients have a very low risk of AML. Generally, patients with NHL, testicular cancer and breast cancer experience much lower risk of AML than patients with HD. NHL and breast cancer treatment regimens with cumulative cyclophosphamide doses of 20 g or less do not confer an appreciable increase of AML. Recently, strongly increased

  4. Effect of glutathione S-transferases on the survival of patients with acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Autrup, Judith; Hokland, Peter; Pedersen, Lars

    2002-01-01

    The objective of the study was to investigate the effect of genetic polymorphisms in glutathione S-transferases (GST) on the survival of acute myeloid leukaemia patients receiving adriamycin induction therapy. A total of 89 patients were included in the study. Patients who carried at least one GS...

  5. High white blood cell count at diagnosis of childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Vaitkeviciene, Goda; Forestier, Erik; Hellebostad, Marit;

    2011-01-01

    Prognostic impact of peripheral blood white blood cell count (WBC) at the diagnosis of childhood acute lymphoblastic leukaemia (ALL) was evaluated in a population-based consecutive series of 2666 children aged 1-15 treated for ALL between 1992 and 2008 in the five Nordic countries (Denmark, Finland...

  6. Clinical relevance of molecular aberrations in paediatric acute myeloid leukaemia at first relapse

    NARCIS (Netherlands)

    Bachas, Costa; Schuurhuis, Gerrit Jan; Reinhardt, Dirk; Creutzig, Ursula; Kwidama, Zinia J.; Zwaan, C. Michel; van den Heuvel-Eibrink, Marry M.; De Bont, Evelina S. J. M.; Elitzur, Sarah; Rizzari, Carmelo; de Haas, Valerie; Zimmermann, Martin; Cloos, Jacqueline; Kaspers, Gertjan J. L.

    2014-01-01

    Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n

  7. Clinical relevance of molecular aberrations in paediatric acute myeloid leukaemia at first relapse

    NARCIS (Netherlands)

    Bachas, Costa; Schuurhuis, Gerrit Jan; Reinhardt, Dirk; Creutzig, Ursula; Kwidama, Zinia J.; Zwaan, C. Michel; van den Heuvel-Eibrink, Marry M.; De Bont, Evelina S. J. M.; Elitzur, Sarah; Rizzari, Carmelo; de Haas, Valerie; Zimmermann, Martin; Cloos, Jacqueline; Kaspers, Gertjan J. L.

    2014-01-01

    Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n

  8. Prognosis in childhood and adult acute lymphoblastic leukaemia : a question of maturation?

    NARCIS (Netherlands)

    Plasschaert, SLA; Kamps, WA; Vellenga, E; de Vries, EGE; de Bont, ESJM

    2004-01-01

    Acute lymphoblastic leukaemia (ALL) is a disease diagnosed in children as well as adults. Progress in the treatment of ALL has led to better survival rates, however, children have benefited more from improved treatment modalities than adults. Recent evidence has underscored that the difference in ch

  9. Venous thromboembolism in adults treated for acute lymphoblastic leukaemia: Effect of fresh frozen plasma supplementation

    NARCIS (Netherlands)

    I. Lauw (Ivoune); B. van der Holt (Bronno); S. Middeldorp (Saskia); J.C.M. Meijers; J.J. Cornelissen (Jan); B.J. Biemond (Bart)

    2013-01-01

    textabstractTreatment of acute lymphoblastic leukaemia (ALL) is frequently complicated by venous thromboembolism (VTE). The efficacy and optimal approach of VTE prevention are unclear, particularly in adult patients. We assessed the effect of thromboprophylaxis on symptomatic VTE incidence in cycle

  10. An analysis of prognostic variables in acute lymphocytic leukaemia in a heterogenous South African population

    NARCIS (Netherlands)

    Hesseling, PB; Buurman, M; Oud, C; Nel, ED

    1997-01-01

    The records of all 96 children below the age of 15 years diagnosed with acute lymphoblastic leukaemia at Tygerberg Hospital in the Republic of South African between 1983 and 1995 were reviewed to determine risk factors which may predict poor outcome. Age <2 and > 8 years, and white cell count >20 x

  11. Role of RT-PCR and FISH in diagnosis and monitoring of acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    S Polampalli

    2011-01-01

    Full Text Available Background: Patients with a presence of Promyelocytic Leukemia-Retinoic Acid Receptor Alpha (PML-RARA genes rearrangement predict a favorable response to all-trans retinoic acid (ATRA, and a significant improvement in survival. Therefore, establishing the presence of PML-RARA rearrangement is important for optimal patient management. Aim: The objective of this study is to compare and assess the role of fluorescent in situ hybridization (FISH and reverse transcriptase polymerase chain reaction (RT-PCR in the diagnosis and long-term monitoring of Acute Promyelocytic Leukemia (APL. Materials and Methods: We compared 145 samples received at different interval of times to analyze the sensitivity of RT-PCR and FISH. Results: The failure rate for RT-PCR was 4% at baseline, 13% at induction, and 0% at the end of consolidation. And for FISH it was 8% at baseline, 38% at induction, and 66% at the end of consolidation. The predictive values of relapse in the patients who were positive and negative by RT-PCR, at the end of induction, were 60 % and 3%, respectively, and at end of consolidation it was 67 % and 4%, respectively. On the other hand the predictive values of relapse in patients who were positive and negative by FISH at end of induction were 57 % and 6%, respectively; while at end of consolidation it was 14% who were negative by FISH. Conclusion: Both RT-PCR and FISH are important for the diagnosis of APL cases, as both techniques complement each other in the absence or failure of any one of them. However, RT-PCR is more sensitive than FISH for the detection of minimal residual disease in the long-term monitoring of these patients. The present study shows that the predictive value of relapse is more associated with minimal residual disease (MRD results by RT-PCR than that by FISH.

  12. Characterization of cryptic rearrangements, deletion, complex variants of PML, RARA in acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Pratibha Kadam Amare

    2011-01-01

    Full Text Available Acute promyelocytic leukemia (APL is characterized by a reciprocal translocation t(15;17(q22;q21 leading to the disruption of Promyelocytic leukemia (PML and Retionic Acid Receptor Alpha (RARA followed by reciprocal PML-RARA fusion in 90% of the cases. Fluorescence in situ hybridization (FISH has overcome the hurdles of unavailability of abnormal and/or lack of metaphase cells, and detection of cryptic, submicroscopic rearrangements. In the present study, besides diagnostic approach we sought to analyze these cases for identification and characterization of cryptic rearrangements, deletion variants and unknown RARA translocation variants by application of D-FISH and RARA break-apart probe strategy on interphase and metaphase cells in a large series of 200 cases of APL. Forty cases (20% had atypical PML-RARA and/or RARA variants. D-FISH with PML/RARA probe helped identification of RARA insertion to PML. By application of D-FISH on metaphase cells, we documented that translocation of 15 to 17 leads to 17q deletion which results in loss of reciprocal fusion and/or residual RARA on der(17. Among the complex variants of t(15;17, PML-RARA fusion followed by residual RARA insertion closed to PML-RARA on der(15 was unique and unusual. FISH with break-apart RARA probe on metaphase cells was found to be a very efficient strategy to detect unknown RARA variant translocations like t(11;17(q23;q21, t(11;17(q13;q21 and t(2;17(p21;q21. These findings proved that D-FISH and break-apart probe strategy has potential to detect primary as well as secondary additional aberrations of PML, RARA and other additional loci. The long-term clinical follow-up is essential to evaluate the clinical importance of these findings.

  13. Recent advances in the diagnosis and management of childhood acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Eun Sun Yoo

    2011-03-01

    Full Text Available Since the successful introduction of all-trans-retinoic acid (ATRA and its combination with anthracycline-containing chemotherapy, the prognosis for acute promyelocytic leukemia (APL has markedly improved. With ATRA and anthracycline-based-chemotherapy, the complete remission rate is greater than 90%, and the long-term survival rate is 70&#8210;89%. Moreover, arsenic trioxide (ATO, which was introduced for APL treatment in 1994, resulted in excellent remission rates in relapsed patients with APL, and more recently, several clinical studies have been designed to explore its role in initial therapy either alone or in combination with ATRA. APL is a rare disease in children and is frequently associated with hyperleukocytosis, which is a marker for higher risk of relapse and an increased incidence of microgranular morphology. The frequency of occurrence of the promyelocytic leukemia/ retinoic acid receptor-alpha (PML/RAR?#6752;isoforms bcr 2 and bcr 3 is higher in children than in adults. Although recent clinical studies have reported comparable long-term survival rates in patients with APL, therapy for APL in children is challenging because of the risk of early death and the potential long-term cardiac toxicity resulting from the need to use high doses of anthracyclines. Additional prospective, randomized, large clinical trials are needed to address several issues in pediatric APL and to possibly minimize or eliminate the need for chemotherapy by combining ATRA and ATO. In this review article, we discuss the molecular pathogenesis, diagnostic progress, and most recent therapeutic advances in the treatment of children with APL.

  14. [Peripheral microthrombotic purpura associated with acute promyelocytic leukemia in pregnancy. A light and electron microscopic study].

    Science.gov (United States)

    Beller, F K; Wagner, H; Büchner, T

    1978-06-15

    A case is presented of a pregnant patient in the 28th week of gestation with promyelocytic leukemia and an unusual thrombohemorrhagic skin lesion. Ultrastructural examination revealed a microthrombotic purpura. Reduced coagulation factors increased during heparin treatment. The exacerbation of disseminated intravascular coagulation is explained by a hypercoagulable state in pregnancy in association with the as yet unknown etiology of "promyelocytic fibrinopathic leukemia".

  15. Epidural spinal cord compression as initial clinical presentation of an acute myeloid leukaemia: case report and literature review

    Institute of Scientific and Technical Information of China (English)

    Dominique N'Dri Oka; Alpha Boubacar Bah; André Valentin Tokpa; Louis Derou

    2016-01-01

    Epidural localization of myeloid leukaemia is rarely reported.Spinal cord compression as an initial presentation of acute myeloid leukaemia is extremely rare.This is a report of a 17-year-old black boy who presented to emergency department with neurological symptoms of spinal cord compression.Imaging modalities showed multiple soft tissue masses in the epidural space.After surgical treatment,histopathological examination of the epidural mass showed myeloid leukaemia cells infiltration.Literature review on Medline and "scholar Google" database was done.The characteristics and management of extra-medullary leukaemia are discussed.Granulocytic sarcoma,myeloid sarcoma or chloroma with acute myeloid leukaemia should be considered as part of epidural spinal cord compression.Therefore surgery is indicated on an emergent basis.

  16. NPM and BRG1 Mediate Transcriptional Resistance to Retinoic Acid in Acute Promyelocytic Leukemia.

    Science.gov (United States)

    Nichol, Jessica N; Galbraith, Matthew D; Kleinman, Claudia L; Espinosa, Joaquín M; Miller, Wilson H

    2016-03-29

    Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA)-sensitive acute promyelocytic leukemia (APL) cell line, we derived an RA-resistant clone characterized by a block in transcription initiation, despite maintaining wild-type PML/RARA expression. We uncovered an aberrant interaction among PML/RARA, nucleophosmin (NPM), and topoisomerase II beta (TOP2B). Surprisingly, RA stimulation in these cells results in enhanced chromatin association of the nucleosome remodeler BRG1. Inhibition of NPM or TOP2B abrogated BRG1 recruitment. Furthermore, NPM inhibition and targeting BRG1 restored differentiation when combined with RA. Here, we demonstrate a role for NPM and BRG1 in obstructing RA differentiation and implicate chromatin remodeling in mediating therapeutic resistance in malignancies. NPM mutations are the most common genetic change in patients with acute leukemia (AML); therefore, our model may be applicable to other more common leukemias driven by NPM.

  17. Secondary acute promyelocytic leukemia following chemotherapy for gastric cancer: a case report.

    Science.gov (United States)

    Zhang, Ying-Cheng; Zhou, Yu-Qi; Yan, Bing; Shi, Jun; Xiu, Li-Juan; Sun, Yu-Wei; Liu, Xuan; Qin, Zhi-Feng; Wei, Pin-Kang; Li, Yong-Jin

    2015-04-14

    Therapy-related acute myeloid leukemia (t-AML) refers to a heterogeneous group of myeloid neoplasms that develop in patients following extensive exposure to either cytotoxic agents or radiation. The development of t-AML has been reported following treatment of cancers ranging from hematological malignancies to solid tumors; however, to our knowledge, t-AML has never been reported following treatment of gastric cancer. In this study, we report the development of t-acute promyelocytic leukemia in a cT4N1M0 gastric cancer patient after an approximate 44 mo latency period following treatment with 4 cycles of oxaliplatin (OXP) (85 mg/m(2) on day 1) plus capecitabine (1250 mg/m(2) orally twice daily on days 1-14) in combination with recombinant human granulocyte-colony stimulating factor treatment. Karyotype analysis of the patient revealed 46,XY,t(15;17)(q22;q21)[15]/46,idem,-9,+add(9)(p22)[2]/46,XY[3], which, according to previous studies, includes some "favorable" genetic abnormalities. The patient was then treated with all-trans retinoic acid (ATRA, 25 mg/m(2)/d) plus arsenic trioxide (ATO, 10 mg/d) and attained complete remission. Our case illuminated the role of certain cytotoxic agents in the induction of t-AML following gastric cancer treatment. We recommend instituting a mandatory additional evaluation for patients undergoing these therapies in the future.

  18. Telomere Length Recovery: A Strong Predictor of Overall Survival in Acute Promyelocytic Leukemia.

    Science.gov (United States)

    Baljevic, Muhamed; Dumitriu, Bogdan; Lee, Ju-Whei; Paietta, Elisabeth M; Wiernik, Peter H; Racevskis, Janis; Chen, Christina; Stein, Eytan M; Gallagher, Robert E; Rowe, Jacob M; Appelbaum, Frederick R; Powell, Bayard L; Larson, Richard A; Coutré, Steven E; Lancet, Jeffrey; Litzow, Mark R; Luger, Selina M; Young, Neal S; Tallman, Martin S

    2016-01-01

    Telomeres are the capping ends of chromosomes that protect the loss of genetic material and prevent chromosomal instability. In human tissue-specific stem/progenitor cells, telomere length (TL) is maintained by the telomerase complex, which consists of a reverse transcriptase catalytic subunit (TERT) and an RNA template (TERC). Very short telomeres and loss-of-function mutations in the TERT and TERC genes have been reported in acute myeloid leukemia, but the role of telomeres in acute promyelocytic leukemia (APL) has not been well established. We report the results for a large cohort of 187 PML/RARα-positive APL patients. No germline mutations in the TERT or TERC genes were identified. Codon 279 and 1062 TERT polymorphisms were present at a frequency similar to that in the general population. TL measured in blood or marrow mononuclear cells at diagnosis was significantly shorter in the APL patients than in healthy volunteers, and shorter telomeres at diagnosis were significantly associated with high-risk disease. For patients who achieved complete remission, the median increase in TL from diagnosis to remission (delta TL) was 2.0 kilobase (kb), and we found delta TL to be the most powerful predictor of overall survival when compared with well-established risk factors for poor outcomes in APL.

  19. Targeted therapy: The new lease on life for acute promyelocytic leukemia, and beyond.

    Science.gov (United States)

    Chen, Sai-Juan; Zhou, Guang-Biao

    2012-08-01

    Leukemia, a group of hematological malignancies characterized by abnormal proliferation, decreased apoptosis, and blocked differentiation of hematopoietic stem/progenitor cells, is a disease involving dynamic change in the genome. Chromosomal translocation and point mutation are the major mechanisms in leukemia, which lead to production of oncogenes with dominant gain of function and tumor suppressor genes with recessive loss of function. Targeted therapy refers to treatment strategies perturbing the molecules critical for leukemia pathogenesis. The t(15;17) which generates PML-RARα, t(8;21) that produces AML1-ETO, and t(9;22) which generates BCR-ABL are the three most frequently seen chromosomal translocations in myeloid leukemia. The past two to three decades have witnessed tremendous success in development of targeted therapies for acute and chronic myeloid leukemia caused by the three fusion proteins. Here, we review the therapeutic efficacies and the mechanisms of action of targeted therapies for myeloid leukemia and show how this strategy significantly improve the clinical outcome of patients and even turn acute promyelocytic leukemia from highly fatal to highly curable.

  20. Results of a randomized trial in children with Acute Myeloid Leukaemia : Medical Research Council AML12 trial

    NARCIS (Netherlands)

    Gibson, Brenda E. S.; Webb, David K. H.; Howman, Andrew J.; De Graaf, Siebold S. N.; Harrison, Christine J.; Wheatley, Keith

    2011-01-01

    The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (

  1. Geographical and ecological analyses of childhood acute leukaemias and lymphomas in north-west England.

    Science.gov (United States)

    McNally, Richard J Q; Alston, Robert D; Cairns, Donal P; Eden, Osborn B; Birch, Jillian M

    2003-10-01

    Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.

  2. The new low-toxic histone deacetylase inhibitor S-(2) induces apoptosis in various acute myeloid leukaemia cells.

    Science.gov (United States)

    Cellai, C; Balliu, M; Laurenzana, A; Guandalini, L; Matucci, R; Miniati, D; Torre, E; Nebbioso, A; Carafa, V; Altucci, L; Romanelli, M N; Paoletti, F

    2012-08-01

    Histone deacetylase inhibitors (HDACi) induce tumour cell cycle arrest and/or apoptosis, and some of them are currently used in cancer therapy. Recently, we described a series of powerful HDACi characterized by a 1,4-benzodiazepine (BDZ) ring hybridized with a linear alkyl chain bearing a hydroxamate function as Zn(++)--chelating group. Here, we explored the anti-leukaemic properties of three novel hybrids, namely the chiral compounds (S)-2 and (R)-2, and their non-chiral analogue 4, which were first comparatively tested in promyelocytic NB4 cells. (S)-2 and partially 4--but not (R)-2--caused G0/G1 cell-cycle arrest by up-regulating cyclin G2 and p21 expression and down-regulating cyclin D2 expression, and also apoptosis as assessed by cell morphology and cytofluorimetric assay, histone H2AX phosphorylation and PARP cleavage. Notably, these events were partly prevented by an anti-oxidant. Moreover, novel HDACi prompted p53 and α-tubulin acetylation and, consistently, inhibited HDAC1 and 6 activity. The rank order of potency was (S)-2 > 4 > (R)-2, reflecting that of other biological assays and addressing (S)-2 as the most effective compound capable of triggering apoptosis in various acute myeloid leukaemia (AML) cell lines and blasts from patients with different AML subtypes. Importantly, (S)-2 was safe in mice (up to 150 mg/kg/week) as determined by liver, spleen, kidney and bone marrow histopathology; and displayed negligible affinity for peripheral/central BDZ-receptors. Overall, the BDZ-hydroxamate (S)-2 showed to be a low-toxic HDACi with powerful anti-proliferative and pro-apototic activities towards different cultured and primary AML cells, and therefore of clinical interest to support conventional anti-leukaemic therapy.

  3. Diffusion tensor imaging and neurocognition in survivors of childhood acute lymphoblastic leukaemia.

    Science.gov (United States)

    Edelmann, Michelle N; Krull, Kevin R; Liu, Wei; Glass, John O; Ji, Qing; Ogg, Robert J; Sabin, Noah D; Srivastava, Deo Kumar; Robison, Leslie L; Hudson, Melissa M; Reddick, Wilburn E

    2014-11-01

    Survivors of childhood acute lymphoblastic leukaemia are at risk for neurocognitive impairment, though little information is available on its association with brain integrity, particularly for survivors treated without cranial radiation therapy. This study compares neurocognitive function and brain morphology in long-term adult survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy alone (n = 36) to those treated with cranial radiation therapy (n = 39) and to healthy control subjects (n = 23). Mean (standard deviation) age at evaluation was 24.9 (3.6) years for the chemotherapy group and 26.7 (3.4) years for the cranial radiation therapy group, while time since diagnosis was 15.0 (1.7) and 23.9 (3.1) years, respectively. Brain grey and white matter volume and diffusion tensor imaging was compared between survivor groups and to 23 healthy controls with a mean (standard deviation) age of 23.1 (2.6) years. Survivors treated with chemotherapy alone had higher fractional anisotropy in fibre tracts within the left (P < 0.05), but not in the right, hemisphere when compared to controls. Survivors of acute lymphoblastic leukaemia, regardless of treatment, had a lower ratio of white matter to intracranial volume in frontal and temporal lobes (P < 0.05) compared with control subjects. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone performed worse in processing speed (P < 0.001), verbal selective reminding (P = 0.01), and academics (P < 0.05) compared to population norms and performed better than survivors treated with cranial radiation therapy on verbal selective reminding (P = 0.02), processing speed (P = 0.05) and memory span (P = 0.009). There were significant associations between neurocognitive performance and brain imaging, particularly for frontal and temporal white and grey matter volume. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone demonstrated significant long-term differences in

  4. Acute promyelocytic leukemia after whole brain irradiation of primary brain lymphomainan HIV-infected patient

    Directory of Open Access Journals (Sweden)

    Boban A

    2009-01-01

    Full Text Available Abstract The occurrence of acute promyelocytic leukemia (APL in HIV-infected patients has been reported in only five cases. Due to a very small number of reported HIV/APL patients who have been treated with different therapies with the variable outcome, the prognosis of APL in the setting of the HIV-infection is unclear. Here, we report a case of an HIV-patient who developed APL and upon treatment entered a complete remission. A 25-years old male patient was diagnosed with HIV-infection in 1996, but remained untreated. In 2004, the patient was diagnosed with primary central nervous system lymphoma. We treated the patient with antiretroviral therapy and whole-brain irradiation, resulting in complete remission of the lymphoma. In 2006, prompted by a sudden neutropenia, we carried out a set of diagnostic procedures, revealing APL. Induction therapy consisted of standard treatment with all-trans-retinoic-acid (ATRA and idarubicin. Subsequent cytological and molecular analysis of bone marrow demonstrated complete hematological and molecular remission. Due to the poor general condition, consolidation treatment with ATRA was given in March and April 2007. The last follow-up 14 months later, showed sustained molecular APL remission. In conclusion, we demonstrated that a complete molecular APL remission in an HIV-patient was achieved by using reduced-intensity treatment.

  5. Prognostic importance of expression of the Wilms' tumor 1 gene in newly diagnosed acute promyelocytic leukemia.

    Science.gov (United States)

    Hecht, Anna; Nolte, Florian; Nowak, Daniel; Nowak, Verena; Reinwald, Mark; Hanfstein, Benjamin; Faldum, Andreas; Büchner, Thomas; Spiekermann, Karsten; Sauerland, Cristina; Weiss, Christel; Hofmann, Wolf-Karsten; Lengfelder, Eva

    2015-01-01

    Wilms' tumor 1 gene (WT1) is known to be highly expressed in acute promyelocytic leukemia (APL) but information on its impact on prognosis is lacking. WT1 expression was analyzed in bone marrow samples of 79 patients with APL at initial diagnosis. Patients had a differing outcome according to their level of WT1 expression. In patients who achieved a complete remission (CR), low or high WT1 expression was significantly associated with inferior overall survival (OS) compared to intermediate WT1 expression (49% for WT1high vs. 63% for WT1low vs. 93% for WT1int; p=0.008). Moreover, there were significant differences in relapse-free survival (RFS) between the three expression groups (42% for WT1high vs. 63% for WT1low vs. 83% for WT1int; p=0.047). In multivariable analysis WT1 expression showed an independent prognostic impact on OS of responders to induction therapy. In conclusion, the level of WT1 expression can add prognostic information in APL risk stratification.

  6. Single-nucleotide polymorphism array-based karyotyping of acute promyelocytic leukemia.

    Directory of Open Access Journals (Sweden)

    Inés Gómez-Seguí

    Full Text Available Acute promyelocytic leukemia (APL is characterized by the t(15;17(q22;q21, but additional chromosomal abnormalities (ACA and other rearrangements can contribute in the development of the whole leukemic phenotype. We hypothesized that some ACA not detected by conventional techniques may be informative of the onset of APL. We performed the high-resolution SNP array (SNP-A 6.0 (Affymetrix in 48 patients diagnosed with APL on matched diagnosis and remission sample. Forty-six abnormalities were found as an acquired event in 23 patients (48%: 22 duplications, 23 deletions and 1 Copy-Neutral Loss of Heterozygocity (CN-LOH, being a duplication of 8(q24 (23% and a deletion of 7(q33-qter (6% the most frequent copy-number abnormalities (CNA. Four patients (8% showed CNAs adjacent to the breakpoints of the translocation. We compared our results with other APL series and found that, except for dup(8q24 and del(7q33-qter, ACA were infrequent (≤3% but most of them recurrent (70%. Interestingly, having CNA or FLT3 mutation were mutually exclusive events. Neither the number of CNA, nor any specific CNA was associated significantly with prognosis. This study has delineated recurrent abnormalities in addition to t(15;17 that may act as secondary events and could explain leukemogenesis in up to 40% of APL cases with no ACA by conventional cytogenetics.

  7. Maternal and fetal outcomes in pregnant women with acute promyelocytic leukemia.

    Science.gov (United States)

    Sanz, Miguel A; Montesinos, Pau; Casale, María F; Díaz-Mediavilla, Joaquín; Jiménez, Santiago; Fernández, Isolda; Fernández, Pascual; González-Campos, José; González, José D; Herrera, Pilar; de Lisa, Elena; Olave, Teresa; Rojas, Rafael; Salamero, Olga; Sayas, María J; Pellicer, Antonio; Perales, Alfredo

    2015-08-01

    The management of pregnant women with acute promyelocytic leukemia (APL) is a challenge with limited evidence-based information available. We are reporting a series of 14 consecutive pregnant women with APL who were registered in the PETHEMA Data Centre between 1996 and 2012. APL was diagnosed during early pregnancy in five women, late pregnancy in seven, and two additional patients after delivery in an extremely poor clinical condition (pulmonary and cerebral hemorrhage). Eleven of the 12 patients eligible for induction therapy with all-trans retinoic acid and idarubicin achieved complete remission (CR 92 %) and are still in the first CR. All early pregnancies ended in abortion (four induced and one spontaneous), with four of them achieving CR. Eight of nine women in late pregnancy delivered a healthy infant (six cesarean section and two vaginal delivery). All eight babies developed normally. Our results confirm a high cure rate for pregnant women with APL who received all-trans retinoic acid and idarubicin for induction therapy, and an excellent outcome for babies when the disease is diagnosed during late pregnancy.

  8. [Two cases of acute promyelocytic leukemia in pregnancy and the effect of anthracyclines on fetal development].

    Science.gov (United States)

    Takatsuki, H; Abe, Y; Goto, T; Sadamura, S; Taguchi, F; Muta, K; Miyoshi, T; Katsuno, M; Umemura, T; Nishimura, J

    1992-11-01

    Two patients with acute promyelocytic leukemia (APL) in 2nd and 3rd trimester of pregnancy are reported on. Case 1: 38-year-old female consulted our hospital because of bleeding tendency and pancytopenia in April, 1988. She was diagnosed as having APL with disseminated intravascular coagulopathy (DIC) and was found to be in the 14th week of gestation. Combined chemotherapy (BHAC-DMP) including the total dose (440 mg) of daunorubicin (DNR) resulted in intrauterine fetal death at 19 weeks of gestation. The fetus was severely anemic and the bone marrow was hypoplastic. Case 2: A 27-year-old female was diagnosed as having APL with DIC at 29 weeks of gestation. BHAC-DMP including 440 mg DNR achieved complete remission. At 35 weeks of gestation, she delivered a normal infant by Caesarean section. The child had normal hematological findings and showed normal growth. Both cases developed APL accompanied by DIC during pregnancy and were treated with a similar regimen including high dose of anthracyclines. Case 2 treated in the late period of gestation delivered a normal infant, while fetal death resulted in case 1, treated in the early period of gestation. We reviewed the literature regarding chemotherapy using anthracyclines during pregnancy.

  9. Genital ulcers during treatment with ALL-trans retinoic acid for acute promyelocytic leukemia.

    Science.gov (United States)

    Fukuno, Kenji; Tsurumi, Hisashi; Goto, Hideko; Oyama, Masami; Tanabashi, Shinobu; Moriwaki, Hisataka

    2003-11-01

    Scrotal ulcer is a unique adverse effect of all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). The pathogenesis of scrotal ulceration remains unknown. We describe genital ulcers that developed in four patients with APL who were undergoing ATRA therapy (45 mg/m2 per day p.o.). Two of the patients were female, in whom this condition is quite rare. Genital ulcers with concomitant fever appeared between 17 and 32 days of therapy in all four patients. Genital ulcers healed in three of the patients while another patient developed Fournier's gangrene and underwent left testectomy. Ulcer healing was brought by either local or intravenous corticosteroids. Intravenous dexamethasone actually enabled continued ATRA administration in one patient, while ATRA was discontinued in other two patients. If corticosteroids cannot control progression of genital ulcers nor concomitant fever, ATRA administration should be discontinued so as not to induce Fournier's gangrene nor retionic acid syndrome. Our experience indicates the importance of recognizing genital ulcers associated with ATRA in order that appropriate countermeasures can be taken.

  10. MOLECULAR CHARACTERIZATION OF THE CHROMOSOME TRANSLOCATION T (15; 17) IN ACUTE PROMYELOCYTIC LEUKEMIA (APL)

    Institute of Scientific and Technical Information of China (English)

    陈赛娟; 童建华; 董硕; 耿解萍; 黄薇; 曹琪; 孙关林; 王振义; 陈竺

    1992-01-01

    Acute promyelocytic leukemia (APL) represents the first example o f a human cancer successfully treated with a differentiation reducer, all-trans retinoic acid. APL is also characterized by a specific chromosome translocution t (15; 17). In this work, using techniques of molecular biology, we demonstrated that the gene coding for the retinoic acid receptor alpha (RARA), normally located on chromosome 17, was disrupted by the t (15; 17) and fused with the PML gene on chromosome 15. The chromosome 17 breaks were mapped consistently within the second intron of the RARA gene while the chromosome 15 breaks were clustered in two limited regions within the PML gene. Molecular cloning and sequence analysis of part of the PML gene allowed to establish a specific "nested" reverse transcription/polymerase chain reaction (PCR) procedure to characterize the expression patterns of the PML-RARA fusion gene. Different iso forms of the fusion transcripts were discovered which were produced as a result of distinct PML gene rearrangements. The biological activity of the PML-RARA fusion gene and its iso forms should be further explored.

  11. Expression pattern of the RAR alpha-PML fusion gene in acute promyelocytic leukemia.

    Science.gov (United States)

    Alcalay, M; Zangrilli, D; Fagioli, M; Pandolfi, P P; Mencarelli, A; Lo Coco, F; Biondi, A; Grignani, F; Pelicci, P G

    1992-01-01

    Two chimeric genes, PML-RAR alpha and RAR alpha-PML, are formed as a consequence of the acute promyelocytic leukemia (APL)-specific reciprocal translocation of chromosomes 15 and 17 [t(15;17)]. PML-RAR alpha is expressed as a fusion protein. We investigated the organization and expression pattern of the RAR alpha-PML gene in a series of APL patients representative of the molecular heterogeneity of the t(15;17) and found (i) two types of RAR alpha-PML mRNA junctions (RAR alpha exon 2/PML exon 4 or RAR alpha exon 2/PML exon 7) that maintain the RAR alpha and PML longest open reading frames aligned and are the result of chromosome 15 breaking at two different sites; and (ii) 10 different RAR alpha-PML fusion transcripts that differ for the assembly of their PML coding exons. A RAR alpha-PML transcript was present in most, but not all, APL patients. Images PMID:1317574

  12. Gangrenous cheilitis associated with all-trans retinoic acid therapy for acute promyelocytic leukemia.

    Science.gov (United States)

    Tanaka, Mariko; Fukushima, Noriyasu; Itamura, Hidekazu; Urata, Chisako; Yokoo, Masako; Ide, Masaru; Hisatomi, Takashi; Tomimasu, Rika; Sueoka, Eisaburo; Kimura, Shinya

    2010-01-01

    A 67-year-old Japanese woman who presented with erythema on the abdomen and pancytopenia was found to have acute promyelocytic leukemia (APL). A skin biopsy revealed invasion of APL cells. She was started on induction treatment with all-trans retinoic acid (ATRA) at 45 mg/m(2). On day 4, the leukemic cell number had increased to over 1.0 x 10(9)/L. Consequently, chemotherapy with idarubicin and cytarabine was initiated. On day 10, dryness of the lips appeared. The lower lip swelled and developed painful black eschars. A high fever was also present. Despite discontinuing ATRA on day 20 and administering antibiotics, an anti-fungal agent and valaciclovir, these signs did not improve. Histopathologically, the biopsied lip revealed infiltration of neutrophils and vasculitis. The patient was given ATRA on days 29 and 30 due to an increase in APL cell numbers, after which the gangrenous cheilitis extended over the whole lip. On day 49, the patient was started on re-induction treatment with arsenic trioxide. She achieved complete remission and the gangrenous cheilitis slowly healed over the following 8 weeks. Since the clinical features of the gangrenous cheilitis in this case were similar to those of ATRA-associated scrotal ulcers, it appears that activated neutrophils derived from differentiated APL cells may have caused the gangrenous cheilitis. Physicians should be alert to the development of gangrenous cheilitis during treatment with ATRA.

  13. Rare presentation of pediatric acute promyelocytic leukemia as multiple lytic bone lesions: Case report and review of literature

    Directory of Open Access Journals (Sweden)

    Manjusha Nair

    2014-01-01

    Full Text Available Acute promyelocytic leukemia (APL is an uncommon malignancy in the pediatric population, accounting for only 5-10% of pediatric acute myeloid leukemias, and for this disease to present with bone lesions at diagnosis is extremely unusual. We wish to convey that very rarely, in a pediatric cancer patient presenting with multiple extensive lytic bone lesions, the diagnosis can be APL. The treatment protocol and prognostic implications are vastly different. Histopathology is the gold standard in arriving at a correct diagnosis and delivering proper treatment in such cases. This patient had excellent response to chemotherapy.

  14. Does acute promyelocytic leukemia in Indian patients have biology different from the West?

    Directory of Open Access Journals (Sweden)

    Dutta Pankhi

    2008-07-01

    Full Text Available Acute promyelocytic leukemia (APML is a well-characterized malignancy with typical clinico-hematological and molecular features. However, Indian data on this malignancy are limited. This study was conducted to determine the clinico-hematological profile of APML in India. Thirty-five patients with APML presenting to Hematology Department, AIIMS, New Delhi, between July 2003 and June 2005 were evaluated for presenting clinical features, hemogram, peripheral smear, bone marrow morphology and cytochemistry. Reverse transcriptase PCR (RT-PCR for PML-RARα was done in all cases. Male-to-female ratio was 0.9:1 (males - 17 and females - 18 with median age 25 years (range 11-57 years. Presenting features included anemia, bleeding, fever, gum hypertrophy and scrotal ulceration. All cases showed hypergranular abnormal promyelocytes. Median hemoglobin was 6.3 g/dL (range - 3.0-9.0 g/dL, total leukocyte count (TLC was 33.88 x 10 9 /L (range - 1-170 x 10 9 /L. Platelet count was 28 x 10 9 /L (range - 4-170 x 10 9 /L. All cases were positive for myeloperoxidase and sudan black (SB, whereas 60% cases also showed non specific esterase (NSE positivity with 40% cases being fluoride sensitive. RT-PCR showed PML-RARα in 33/35 cases with the bcr3 isoform being present in 24/33 positive cases (72.7%. The two cases negative for PML-RARα showed typical morphology and responded to ATRA. On statistical analysis, no correlation was found between bcr isoform and TLC, platelet count, age sex and early death. Unusual features included gum hypertrophy and scrotal ulceration at presentation and high median presenting TLC (33.8 x 10 9 /L. There was, however, no microgranular variant. Another interesting feature was a high incidence of NSE positivity (60%, which was fluoride sensitive in 40%. Moreover, the bcr3 isoform was significantly overexpressed (72.7% in comparison to other studies. APML in India has certain unusual features, which may reflect a different biology.

  15. Therapy-induced secondary acute myeloid leukemia with t(11;19)(q23;p13.1) in a pediatric patient with relapsed acute promyelocytic leukemia.

    Science.gov (United States)

    Dang, Daniel N; Morris, Heather D; Feusner, James H; Koduru, Prasad; Wilson, Kathleen; Timmons, Charles F; Cavalier, MaryEllen; Luu, Hung S

    2014-11-01

    Acute myeloid leukemia is classified based upon recurrent cytogenetic abnormalities. The t(15;17)(q24.1;q21.1) abnormality is found in 5% to 8% of de novo acute myeloid leukemia and is diagnostic of acute promyelocytic leukemia (APL). The translocation results in fusion of the retinoic acid receptor-α (RARA) gene at 17q21.1 and the promyelocytic leukemia (PML) gene at 15q24.1. Standard APL therapy is a combination of all-trans retinoic acid and anthracycline-based chemotherapy. Anthracycline treatment is associated with secondary clonal chromosomal aberrations that can lead to therapy-related secondary myeloid neoplasms. We present a pediatric case of relapsed APL coexistent with treatment-associated secondary myeloid neoplasm with t(11;19)(q23;p13.1).

  16. Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    Van Vlierberghe, Pieter; Pieters, Rob; Beverloo, H Berna; Meijerink, Jules P P

    2008-10-01

    Paediatric T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy of thymocytes that accounts for about 15% of ALL cases and for which treatment outcome remains inferior compared to B-lineage acute leukaemias. In T-ALL, leukemic transformation of maturating thymocytes is caused by a multistep pathogenesis involving numerous genetic abnormalities that drive normal T-cells into uncontrolled cell growth and clonal expansion. This review provides an overview of the current knowledge on onco- and tumor suppressor genes in T-ALL and suggests a classification of these genetic defects into type A and type B abnormalities. Type A abnormalities may delineate distinct molecular-cytogenetic T-ALL subgroups, whereas type B abnormalities are found in all major T-ALL subgroups and synergize with these type A mutations during T-cell pathogenesis.

  17. Detailed molecular characterisation of acute myeloid leukaemia with a normal karyotype using targeted DNA capture.

    Science.gov (United States)

    Conte, N; Varela, I; Grove, C; Manes, N; Yusa, K; Moreno, T; Segonds-Pichon, A; Bench, A; Gudgin, E; Herman, B; Bolli, N; Ellis, P; Haddad, D; Costeas, P; Rad, R; Scott, M; Huntly, B; Bradley, A; Vassiliou, G S

    2013-09-01

    Advances in sequencing technologies are giving unprecedented insights into the spectrum of somatic mutations underlying acute myeloid leukaemia with a normal karyotype (AML-NK). It is clear that the prognosis of individual patients is strongly influenced by the combination of mutations in their leukaemia and that many leukaemias are composed of multiple subclones, with differential susceptibilities to treatment. Here, we describe a method, employing targeted capture coupled with next-generation sequencing and tailored bioinformatic analysis, for the simultaneous study of 24 genes recurrently mutated in AML-NK. Mutational analysis was performed using open source software and an in-house script (Mutation Identification and Analysis Software), which identified dominant clone mutations with 100% specificity. In each of seven cases of AML-NK studied, we identified and verified mutations in 2-4 genes in the main leukaemic clone. Additionally, high sequencing depth enabled us to identify putative subclonal mutations and detect leukaemia-specific mutations in DNA from remission marrow. Finally, we used normalised read depths to detect copy number changes and identified and subsequently verified a tandem duplication of exons 2-9 of MLL and at least one deletion involving PTEN. This methodology reliably detects sequence and copy number mutations, and can thus greatly facilitate the classification, clinical research, diagnosis and management of AML-NK.

  18. Fucoidan Suppresses the Growth of Human Acute Promyelocytic Leukemia Cells In Vitro and In Vivo.

    Science.gov (United States)

    Atashrazm, Farzaneh; Lowenthal, Ray M; Woods, Gregory M; Holloway, Adele F; Karpiniec, Samuel S; Dickinson, Joanne L

    2016-03-01

    Fucoidan, a natural component of seaweeds, is reported to have immunomodulatory and anti-tumor effects. The mechanisms underpinning these activities remain poorly understood. In this study, the cytotoxicity and anti-tumor activities of fucoidan were investigated in acute myeloid leukemia (AML) cells. The human AML cell lines NB4, KG1a, HL60, and K562 were treated with fucoidan and cell cycle, cell proliferation, and expression of apoptotic pathways molecules were analyzed. Fucoidan suppressed the proliferation and induced apoptosis through the intrinsic and extrinsic pathways in the acute promyelocytic leukemia (APL) cell lines NB4 and HL60, but not in KG1a and K562 cells. In NB4 cells, apoptosis was caspase-dependent as it was significantly attenuated by pre-treatment with a pan-caspase inhibitor. P21/WAF1/CIP1 was significantly up-regulated leading to cell cycle arrest. Fucoidan decreased the activation of ERK1/2 and down-regulated the activation of AKT through hypo-phosphorylation of Thr(308) residue but not Ser(473). In vivo, a xenograft model using the NB4 cells was employed. Mice were fed with fucoidan and tumor growth was measured following inoculation with NB4 cells. Subsequently, splenic natural killer (NK) cell cytotoxic activity was also examined. Oral doses of fucoidan significantly delayed tumor growth in the xenograft model and increased cytolytic activity of NK cells. Taken together, these data suggest that the selective inhibitory effect of fucoidan on APL cells and its protective effect against APL development in mice warrant further investigation of fucoidan as a useful agent in treatment of certain types of leukemia.

  19. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Huai, Lei; Wang, Cuicui; Zhang, Cuiping; Li, Qihui; Chen, Yirui; Jia, Yujiao; Li, Yan; Xing, Haiyan; Tian, Zheng; Rao, Qing; Wang, Min [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China); Wang, Jianxiang, E-mail: wangjx@ihcams.ac.cn [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China)

    2012-06-08

    Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.

  20. Nucleophosmin mutation analysis in acute myeloid leukaemia: Immunohistochemistry as a surrogate for molecular techniques

    OpenAIRE

    Anita Chopra; Sushant Soni; Haraprasad Pati; Dev Kumar; Rahul Diwedi; Deepak Verma; Garima Vishwakama; Sameer Bakhshi; Suman Kumar; Ajay Gogia; Rajive Kumar

    2016-01-01

    Background & objectives: Mutation of nucleophosmin (NPM1) gene in the absence of FLT3-ITD (FMS related tyrosine kinase 3 - internal tandem duplications) mutation carries a good prognosis in cytogenetically normal acute myeloid leukaemia (AML). NPM1, a multifunctional nucleolar phosphoprotein that shuttles between nucleus and cytoplasm, gets trapped in the cytoplasm when mutated. Immunohistochemical (IHC) demonstration of its aberrant cytoplasmic location (NPMc+) has been suggested as a simple...

  1. Difficult diagnosis of invasive fungal infection predominantly involving the lower gastrointestinal tract in acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Gulhadiye Avcu

    2016-03-01

    Full Text Available Invasive fungal infections are most commonly seen in immunocompromised patients and usually affect the respiratory system. Gastrointestinal system involvement of mucormycosis and invasive aspergillosis is rarely reported in childhood. Here we describe a 5 year old boy with acute lymphoblastic leukaemia who developed invasive fungal infection particularly affecting the lower gastrointestinal system to emphasise the difficulties in diagnosis and management of invasive fungal infections in immunocompromised patients.

  2. A new transcriptional variant and small azurophilic granules in an acute promyelocytic leukemia case with NPM1/RARA fusion gene.

    Science.gov (United States)

    Kikuma, Tomoe; Nakamachi, Yuji; Noguchi, Yoriko; Okazaki, Yoko; Shimomura, Daisuke; Yakushijin, Kimikazu; Yamamoto, Katsuya; Matsuoka, Hiroshi; Minami, Hironobu; Itoh, Tomoo; Kawano, Seiji

    2015-12-01

    We report here the first case of NPM1/RARA-positive acute promyelocytic leukemia (APL) preceded by myeloid sarcoma (MS) in the vertebra. A 52-year-old man was diagnosed with MS, as the tumor cells were positive for myeloperoxidase and CD68 but negative for CD163. After treatment with steroids and radiation, the size of the tumor was markedly reduced and peripheral blood count was normal. Bone marrow examination showed 89.2% consisted of unclassified promyelocytes characterized by round nuclei and abundant small azurophilic granules but no Auer rods. The results of chromosome analysis showed 46,XY,t(5;17)(q35;q12). Reverse-transcription polymerase chain reaction amplified the NPM1/RARA fusion transcripts derived from a combination of NPM1 exon 4 and RARA exon 5, or of NPM1 exon 1 and RARA exon 5; the latter of these has not been reported previously. Electron microscopic examination of the promyelocyte nuclei showed they were oval with mild nuclear chromatin condensation and small- to medium-sized nucleoli. Hematological and molecular complete remission was attained after induction therapy including all-trans retinoic acid. As MS was also diagnosed in two of the seven other reported cases of APL with NPM1/RARA, MS may occur more frequently in APL with NPM1/RARA than APL with PML/RARA.

  3. [Acute promyelocytic leukemia (APL) resulting in broad cerebral infarction during all-trans retinoic acid (ATRA) treatment].

    Science.gov (United States)

    Ikeda, Y; Yoshinaga, K; Iki, S; Ohbayashi, Y; Urabe, A

    1994-02-01

    A 27-year-old woman visited Kanto Teishin Hospital complaining of fever and petechiae in September, 1992. Her fetus had suddenly died in the uterus two weeks before (in the sixth month of pregnancy). Total white blood cell (WBC) count was 3.2 x 10(3)/microliters with 80% promyelocytes. Bone marrow was hypercellular with 90% promyelocytes. Disseminated intravascular coagulation (DIC) was recognized. She was diagnosed as having acute promyelocytic leukemia (APL), and treatment with daily oral administration of all-trans retinoic acid (ATRA) (70 mg/body/day) was begun. On day 4, hemiplegia and aphasia appeared. Broad cerebral infarction was suspected from computed tomography. On day 9, the WBC count increased rapidly, standard chemotherapy was added and she achieved complete remission. ATRA is known to have stimulatory effects on the differentiation of APL cells, but some reports have described thromboembolic events during the administration of ATRA. In this case, ATRA might have affected coagulability resulting in cerebral infarction.

  4. Acute promyelocytic leukemia in early pregnancy with translocation t(15;17) and variant PML/RARA fusion transcripts.

    Science.gov (United States)

    Park, Tae Sung; Lee, Seung Tae; Kim, Jin Seok; Song, Jaewoo; Lee, Kyung-A; Kim, Sue Jung; Seok, Yoon-Mi; Lee, Hyeon-Ji; Han, Jeong-Hyun; Kim, Jong-Kee; Lee, Eun Yup; Choi, Jong Rak

    2009-01-01

    A 32-year-old pregnant woman in the 13th gestational week was brought to Severance Hospital with gum bleeding and easy bruising. Initial laboratory results revealed anemia and thrombocytopenia. In a peripheral blood smear, 81% of leukocytes were large, abnormal promyelocytes. Bone marrow aspiration showed a hypercellular marrow with packed leukemic promyelocytes, and chromosome study revealed a karyotype of 46,XX,t(15;17)(q22;q21)[10]/46,XX[10]. In addition, variant fusion transcripts of PML/RARA were detected in the marrow specimen. The patient was diagnosed with acute promyelocytic leukemia (APL) and was treated with all-trans retinoic acid (ATRA) and idarubicin. One month from the patient's initial diagnosis a follow-up bone marrow examination was performed, revealing complete remission (CR). We know of no previous reports of APL during pregnancy associated with variant PML/RARA fusion transcripts. Here, we describe a novel case of APL in a pregnant woman with a t(15;17) translocation and variant fusion transcripts.

  5. Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme

    NARCIS (Netherlands)

    van der Helm, Lieke H.; Alhan, Canan; Wijermans, Pierre W.; Kooy, Marinus van Marwijk; Schaafsma, Ron; Biemond, Bart J.; Beeker, Aart; Hoogendoorn, Mels; van Rees, Bastiaan P.; de Weerdt, Okke; Wegman, Jurgen; Libourel, Ward J.; Luykx-de Bakker, Sylvia A.; Minnema, Monique C.; Brouwer, Rolf E.; Boer, Fransien Croon-de; Eefting, Matthijs; Jie, Kon-Siong G.; de Loosdrecht, Arjan A. van; Koedam, Jan; Veeger, Nic J. G. M.; Vellenga, Edo; Huls, Gerwin

    2011-01-01

    The efficacy of azacitidine in the treatment of high-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) (20-30% blasts) has been demonstrated. To investigate the efficacy of azacitidine in daily clinical practice and to identify predictors

  6. Effect of arsenic trioxide on cytokine expression by acute promyelocytic leukemia cells

    Institute of Scientific and Technical Information of China (English)

    姜国胜; 毕可红; 唐天华; 张玉昆; 任海全; 姜枫勤; 任青华; 真刚; 刘传芳; 彭军; 郭桂月; 刘秀兰; 田志刚

    2003-01-01

    Objective To detect the expression of cytokines by acute promyelocytic leukemia (APL) cells before and after exposure to arsenic trioxide. Methods Diagnoses were performed according to the FAB cytological classification criteria and cytogenetic criteria. Bone marrow or blood samples from APL patients were collected in heparinized tubes,then primary APL cells were separated by traditional Ficoll-Hypaque density centrifugation and purified after adherence to plastic surfaces. IL-1β, IL-6, IL-8, TNFα and G-CSF levels in the leukemia cell culture supernatants were detected by ELISA. At the same time, nitro blue tetrazolium (NBT) reduction test was used to detect the differentiation of APL cells. Results After 96 hours exposure to arsenic trioxide, 10-6 mol/L in vitro or 10 mg/d in vivo, APL cells showed a significant increase of IL-1β(P<0.05) and G-CSF(P<0.05) production, and a significant decrease of IL-6 (P<0.05) and IL-8 (P<0.05). However, there was no obvious variation of TNFα when compared with APL cells without exposure to arsenic trioxide. On the other hand, the proliferation ratio of APL cells in vitro was statistically correlated to the IL-1β secretion ratio or G-CSF secretion ratio. The cell number ratio in patients with detectable IL-1β or G-CSF was higher than that without detectable IL-1β or G-CSF.Conclusion IL-1β and G-CSF secretion may play an important role in the proliferation of APL cells after exposure to arsenic trioxide.

  7. Berbamine selectively induces apoptosis of human acute promyelocytic leukemia cells via survivin-mediated pathway

    Institute of Scientific and Technical Information of China (English)

    ZHAO Xiao-ying; HE Zhi-wen; WU Dong; XU Rong-zhen

    2007-01-01

    Background Currently, resistance and relapse are still major problems in acute promyelocytic leukemia (APL) cases.Thus, new agents that override the resistance are crucial to the development of curative therapies for APL. In this study,we investigated the effects of berbamine on the proliferation of APL cell line NB4 and its possible mechanisms.Methods NB4 cells were treated with berbamine at different concentrations (0-64 μg/ml) for 72 hours. MTT assay was used to determine proliferation inhibition of NB4 cells. Cell apoptosis was evaluated by both flow cytometry (FCM) and morphological examination. PML/RAR-α and survivin mRNAs were measured by nested-RT-PCR and RT-PCR,respectively. Activated-caspase 3 was determined by FCM.Results Berbamine greatly inhibited the proliferation of NB4 cells in dose- and time-dependent manners, and its IC50 value was 3.86 μg/ml at 48 hours. Both morphological observations and FCM results showed that berbamine induced apoptosis of NB4 cells with concomitant increase of activated caspase-3 and decrease of survivin mRNA. After treatment with berbamine at 8 μg/ml for 48 hours, the percentage of apoptotic cells increased from 2.83% to 58.44% (P<0.01), and the percentage of cells with activated-caspase 3 elevated from 2.06% to 70.89% (P<0.01), whereas, level of survivin mRNA was reduced to 38.24% of control (P<0.01). However, no significant change was observed in PML/RAR-α mRNA.Conclusions Berbamine induces caspase-3-dependent apoptosis of leukemia NB4 cells via survivin-mediated pathway, suggesting that berbamine may be a novel potential agent against APL with a mechanism distinct from that of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

  8. PML-RARa modulates the vascular signature of extracellular vesicles released by acute promyelocytic leukemia cells.

    Science.gov (United States)

    Fang, Yi; Garnier, Delphine; Lee, Tae Hoon; D'Asti, Esterina; Montermini, Laura; Meehan, Brian; Rak, Janusz

    2016-01-01

    Oncogenic transformation is believed to impact the vascular phenotype and microenvironment in cancer, at least in part, through mechanisms involving extracellular vesicles (EVs). We explored these questions in the context of acute promyelocytic leukemia cells (NB4) expressing oncogenic fusion protein, PML-RARa and exquisitely sensitive to its clinically used antagonist, the all-trans retinoic acid (ATRA). We report that NB4 cells produce considerable numbers of EVs, which are readily taken up by cultured endothelial cells triggering their increased survival. NB4 EVs contain PML-RARa transcript, but no detectable protein, which is also absent in endothelial cells upon the vesicle uptake, thereby precluding an active intercellular trafficking of this oncogene in this setting. ATRA treatment changes the emission profile of NB4-related EVs resulting in preponderance of smaller vesicles, an effect that occurs in parallel with the onset of cellular differentiation. ATRA also increases IL-8 mRNA and protein content in NB4 cells and their EVs, while decreasing the levels of VEGF and tissue factor (TF). Endothelial cell uptake of NB4-derived EVs renders these cells more TF-positive and procoagulant, and this effect is diminished by pre-treatment of EV donor cells with ATRA. Profiling angiogenesis-related transcripts in intact and ATRA-treated APL cells and their EVs reveals multiple differences attributable to cellular responses and EV molecular packaging. These observations point to the potential significance of changes in the angiogenic signature and activity associated with EVs released from tumor cells subjected to targeted therapy.

  9. LEUKOCYTOSIS AND RETINOIC ACID SYNDROME IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA TREATED WITH ARSENIC TRIOXIDE

    Institute of Scientific and Technical Information of China (English)

    Bo Jin; Ke-zuo Hou; Yun-peng Liu; Ping Yu

    2006-01-01

    Objective To study the incidence of leukocytosis and retinoic acid (RA) syndrome in newly diagnosed and relapsed acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO).Methods Thirty patients with newly diagnosed or relapsed APL received ATO for remission induction at the dose of 10 mg/d. RA syndrome was defined when patient was with one or more of the following signs or symptoms: fever,dyspnea, serous cavity effusion, muscular pain, pulmonary infiltration, weight gain, or pulmonary infiltration on chest X-ray.Results Twenty-three (77%) patients achieved complete remission, mean time to remission was 37.1 days. Leukocytosis was observed in 14 (47%) patients, mean time to leukocytosis was 12.7 days, median baseline leukocyte count for patients with leukocytosis was 3.1 × 109/L, which was higher than that for patients who did not develop leukocytosis (2.6×109/L, z=-2.635, P=0.008). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in 9(30%) patients, mean time to diagnose of RA syndrome was 13.9 days, median baseline leukocyte count for patients with RA syndrome was 3.6×109/L, which was higher than that for patients who did not develop RA syndrome (2.6 × 109/L, z=-1.909, P=0.046). No patient died of RA syndrome.Conclusion Leukocytosis and RA syndrome are associated with ATO and baseline leukocyte count respectively,and there is distinct link between leukocytosis and RA syndrome.

  10. Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients.

    Science.gov (United States)

    Testa, Ugo; Lo-Coco, Francesco

    2016-04-01

    All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 10(9)/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease.

  11. Simple, rapid and accurate molecular diagnosis of acute promyelocytic leukemia by loop mediated amplification technology.

    Science.gov (United States)

    Spinelli, Orietta; Rambaldi, Alessandro; Rigo, Francesca; Zanghì, Pamela; D'Agostini, Elena; Amicarelli, Giulia; Colotta, Francesco; Divona, Mariadomenica; Ciardi, Claudia; Coco, Francesco Lo; Minnucci, Giulia

    2015-01-01

    The diagnostic work-up of acute promyelocytic leukemia (APL) includes the cytogenetic demonstration of the t(15;17) translocation and/or the PML-RARA chimeric transcript by RQ-PCR or RT-PCR. This latter assays provide suitable results in 3-6 hours. We describe here two new, rapid and specific assays that detect PML-RARA transcripts, based on the RT-QLAMP (Reverse Transcription-Quenching Loop-mediated Isothermal Amplification) technology in which RNA retrotranscription and cDNA amplification are carried out in a single tube with one enzyme at one temperature, in fluorescence and real time format. A single tube triplex assay detects bcr1 and bcr3 PML-RARA transcripts along with GUS housekeeping gene. A single tube duplex assay detects bcr2 and GUSB. In 73 APL cases, these assays detected in 16 minutes bcr1, bcr2 and bcr3 transcripts. All 81 non-APL samples were negative by RT-QLAMP for chimeric transcripts whereas GUSB was detectable. In 11 APL patients in which RT-PCR yielded equivocal breakpoint type results, RT-QLAMP assays unequivocally and accurately defined the breakpoint type (as confirmed by sequencing). Furthermore, RT-QLAMP could amplify two bcr2 transcripts with particularly extended PML exon 6 deletions not amplified by RQ-PCR. RT-QLAMP reproducible sensitivity is 10(-3) for bcr1 and bcr3 and 10(-)2 for bcr2 thus making this assay particularly attractive at diagnosis and leaving RQ-PCR for the molecular monitoring of minimal residual disease during the follow up. In conclusion, PML-RARA RT-QLAMP compared to RT-PCR or RQ-PCR is a valid improvement to perform rapid, simple and accurate molecular diagnosis of APL.

  12. Therapy-related acute promyelocytic leukemia following etoposide-based chemotherapy in non-seminomatous germ cell tumor

    Directory of Open Access Journals (Sweden)

    T N Kumar

    2014-01-01

    Full Text Available Therapy related AML (t- AML accounts for 10-20% of all cases of AML. Cytotoxic agents implicated are alkylating agents, topoisomerase II inhibitors and rarely anti metabolites and anti tubulin agents. A growing incidence of therapy related acute promyelocytic leukemia (t-APL has been reported over the last few decades in malignant and non malignant conditions. To the best of our knowledge this is the first t-APL case report to be reported in NSGCT post etoposide based therapy.

  13. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.

    Science.gov (United States)

    Zhang, Jinghui; Ding, Li; Holmfeldt, Linda; Wu, Gang; Heatley, Sue L; Payne-Turner, Debbie; Easton, John; Chen, Xiang; Wang, Jianmin; Rusch, Michael; Lu, Charles; Chen, Shann-Ching; Wei, Lei; Collins-Underwood, J Racquel; Ma, Jing; Roberts, Kathryn G; Pounds, Stanley B; Ulyanov, Anatoly; Becksfort, Jared; Gupta, Pankaj; Huether, Robert; Kriwacki, Richard W; Parker, Matthew; McGoldrick, Daniel J; Zhao, David; Alford, Daniel; Espy, Stephen; Bobba, Kiran Chand; Song, Guangchun; Pei, Deqing; Cheng, Cheng; Roberts, Stefan; Barbato, Michael I; Campana, Dario; Coustan-Smith, Elaine; Shurtleff, Sheila A; Raimondi, Susana C; Kleppe, Maria; Cools, Jan; Shimano, Kristin A; Hermiston, Michelle L; Doulatov, Sergei; Eppert, Kolja; Laurenti, Elisa; Notta, Faiyaz; Dick, John E; Basso, Giuseppe; Hunger, Stephen P; Loh, Mignon L; Devidas, Meenakshi; Wood, Brent; Winter, Stuart; Dunsmore, Kimberley P; Fulton, Robert S; Fulton, Lucinda L; Hong, Xin; Harris, Christopher C; Dooling, David J; Ochoa, Kerri; Johnson, Kimberly J; Obenauer, John C; Evans, William E; Pui, Ching-Hon; Naeve, Clayton W; Ley, Timothy J; Mardis, Elaine R; Wilson, Richard K; Downing, James R; Mullighan, Charles G

    2012-01-11

    Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

  14. Incidence and predictors of treatment-related mortality in paediatric acute leukaemia in El Salvador

    Science.gov (United States)

    Gupta, S; Bonilla, M; Fuentes, S L; Caniza, M; Howard, S C; Barr, R; Greenberg, M L; Ribeiro, R; Sung, L

    2009-01-01

    Survival rates among children with leukaemia in low-income countries are lower than those in high-income countries. This has been attributed in part to higher treatment-related mortality (TRM). We examined the demographics, treatment, and outcomes of paediatric patients in El Salvador with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) to determine the incidence, causes, and risk factors for TRM. Two trained data managers collected data prospectively; no patients were excluded. Biological, socioeconomic and nutritional predictors were examined. A total of 469 patients with ALL and 78 patients with AML were included. The 2-year cumulative incidence of TRM was significantly higher among children with AML (35.4±6.4%) than those with ALL (12.5±1.7%; P<0.0001). However, the proportion of deaths attributable to the toxicity of treatment did not differ significantly between AML (25/47, 53.2%) and ALL (55/107, 51.4%; P=0.98). Among children with ALL, low monthly income (P=0.04) and low parental education (P=0.02) significantly increased the risk of TRM. Among children with AML, biological, socioeconomic, and nutritional variables were not associated with TRM. In this low-income country, toxic death significantly contributes to mortality in both ALL and AML. A better understanding of the effect of socioeconomic status on TRM may suggest specific strategies for patients with ALL. PMID:19293804

  15. Application of genomics for risk stratification of childhood acute lymphoblastic leukaemia: from bench to bedside?

    Science.gov (United States)

    Izraeli, Shai

    2010-10-01

    The remarkable progress in the treatment of childhood acute lymphoblastic leukaemia (ALL) has been based on the adjustment of therapy to subgroups of leukaemia stratified by their prognostic implications. Here, the contribution of the last decade of advanced genomic research on the clinical management of childhood ALL is examined. The application of genomics for routine diagnosis of ALL is feasible but depends on commercial development of appropriate certified platforms. The discovery of several novel high-risk markers, such as deletions in IKZF1 might be integrated into clinical protocols in the near future. Several novel targets for therapy have been identified and have led to phase I/II therapeutic trials. This and any future progress depends on the maintenance of high quality bio-banks including biological material and clinical data of each patient enrolled on a prospective clinical protocol. © 2010 Blackwell Publishing Ltd.

  16. Combination chemotherapy for marrow relapse in children and adolescents with acute lymphocytic leukaemia.

    Science.gov (United States)

    Amadori, S; Spiriti, M A; Meloni, G; Pacilli, L; Papa, G; Mandelli, F

    1981-04-01

    38 children with acute lymphocytic leukaemia (ALL) in haematologic relapse were retreated with vincristine, daunomycin and prednisone (VPD) together with intrathecal methotrexate and prednisone, followed by asparaginase in those patients not in complete remission after 4 weeks. The overall complete remission (CR) rate was 79%; asparaginase was needed to achieve CR in 7 of the 30 responding patients. The median duration of second remission was only 36 weeks, but 6 out of 15 children receiving the COAP-POMP-CART consolidation regimen remain in continuous second remission after 37-260 weeks; 3 of them are currently off all therapy. It is concluded that a prolonged second remission can be achieved in children with ALL in bone marrow relapse by combining intensive chemotherapy with the prevention of meningeal leukaemia.

  17. Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes

    DEFF Research Database (Denmark)

    Schmiegelow, K.

    2016-01-01

    Although most children with acute lymphoblastic leukaemia (ALL) do not harbor germline mutations that strongly predispose them to development of this malignancy, large syndrome registries and detailed mapping of exomes or whole genomes of familial leukaemia kindreds have revealed that 3-5% of all...... patients is important in order to adjust therapy and offer genetic counseling and cancer surveillance to mutation carriers in the family. In the coming years large genomic screening projects are expected to reveal further hitherto unrecognised familial ALL syndromes. The treatment of ALL cases harboring...... cancer predisposing mutations can be challenging for both the physician and the patient due to their preexisting symptoms, their reduced tolerance to radio- and/or chemotherapy with enhanced risk of life-threatening organ toxicities, and the paucity of data from ALL patients with the same or similar...

  18. Acute sinusitis and blindness as the first presentation of chronic lymphocytic leukaemia.

    Science.gov (United States)

    Lim, K H; Thomas, G; van Beers, E J; Hosman, A E; Mourits, M P; van Noesel, C J M; Kater, A P; Reinartz, S M

    2014-12-01

    Chronic lymphocytic leukaemia (CLL) is the most frequent form of leukaemia among adults in the Western world, presenting at a median age of 65 years. The diagnosis is usually made incidentally during routine blood examination while the disease is still in its early phase. We report a case of blindness of 24 hours due to acute sinusitis based on CLL localisation in a patient with undiagnosed CLL. Emergency endoscopic sinus surgery and intra- and extra-ocular orbital decompression were performed. The sinusitis resolved after surgery and intravenous antibiotics. Her vision improved within 24 hours and eventually recovered completely after six months. Her CLL remained in an indolent state, needing no active treatment. This case illustrates that blindness from a lymphoproliferative disorder may be treated with emergency endoscopic sinus surgery instead of conventional chemotherapy in order to salvage the vision first, even if the vision is lost for more than 24 hours.

  19. Acute myelomonocytic leukaemia with short-term spontaneous remission in a cat.

    Science.gov (United States)

    Mylonakis, M E; Petanides, T A; Valli, V E; Vernau, W; Koytinas, A F; Michael, R S

    2008-06-01

    A 2-year-old, spayed female domestic shorthair cat was referred with a history of anorexia and depression of 1 week duration. On physical examination, the cat was lethargic and febrile, with splenomegaly, anisocoria and ulcerative stomatitis. A complete blood count (CBC) and a biochemistry profile showed leukocytosis, numerous blast cells in the peripheral blood, thrombocytopenia, hyperglobulinaemia and a positive test for feline leukaemia virus antigen. A diagnosis of acute myelomonocytic leukaemia was made on the basis of the results of bone marrow cytology, histopathology, and immunochemistry (CD3, CD79a, lysozyme, and myeloperoxidase) tests. Following an unexpected 1-month period of clinical and clinicopathological remission without chemotherapy, the cat relapsed and died 1 week later.

  20. THE DIFFERENTIATION SYNDROME IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA: EXPERIENCE OF THE PETHEMA GROUP AND REVIEW OF THE LITERATURE.

    Directory of Open Access Journals (Sweden)

    Pau Montesinos

    2011-12-01

    Full Text Available Differentiation syndrome (DS, formerly known as retinoic acid syndrome, is the main life-threatening complication of therapy with differentiating agents (all-trans retinoic acid [ATRA] or arsenic trioxide [ATO] in patients with acute promyelocytic leukemia (APL. The differentiation of leukemic blasts and promyelocytes induced by ATRA and/or ATO may lead to cellular migration, endothelial activation, and release of interleukins and vascular factors responsible of tissue damage. Roughly one quarter of patients with APL undergoing induction therapy will develop the DS, characterized by unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, and/or a vascular capillary leak syndrome leading to acute renal failure. Although the development of the DS, particularly of the severe form, is still associated with a significant increase in morbidity and mortality during induction, the early administration of high-dose dexamethasone at the onset of the first symptoms seems likely to have dramatically reduced the mortality rate of this complication. In this article, we will review the clinical features, incidence, prognostic factors, management, and outcome of the DS reported in the scientific literature. We will make focus in the experience of the three consecutive Programa Español de Tratamientos en Hematología trials (PETHEMA LPA96, LPA99, and LPA2005, in which more than one thousand patients were treated with ATRA plus idarubicin for induction.

  1. THE DIFFERENTIATION SYNDROME IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA: EXPERIENCE OF THE PETHEMA GROUP AND REVIEW OF THE LITERATURE.

    Directory of Open Access Journals (Sweden)

    Pau Montesinos

    2011-01-01

    Full Text Available

    Differentiation syndrome (DS, formerly known as retinoic acid syndrome, is the main life-threatening complication of therapy with differentiating agents (all-trans retinoic acid [ATRA] or arsenic trioxide [ATO] in patients with acute promyelocytic leukemia (APL. The differentiation of leukemic blasts and promyelocytes induced by ATRA and/or ATO may lead to cellular migration, endothelial activation, and release of interleukins and vascular factors responsible of tissue damage. Roughly one quarter of patients with APL undergoing induction therapy will develop the DS, characterized by unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, and/or a vascular capillary leak syndrome leading to acute renal failure. Although the development of the DS, particularly of the severe form, is still associated with a significant increase in morbidity and mortality during induction, the early administration of high-dose dexamethasone at the onset of the first symptoms seems likely to have dramatically reduced the mortality rate of this complication. In this article, we will review the clinical features, incidence, prognostic factors, management, and outcome of the DS reported in the scientific literature. We will make focus in the experience of the three consecutive Programa Español de Tratamientos en Hematología trials (PETHEMA LPA96, LPA99, and LPA2005, in which more than one thousand patients were treated with ATRA plus idarubicin for induction.

  2. KEGG DISEASE / Acute myeloid leukemia (AML) [KEGG DISEASE

    Lifescience Database Archive (English)

    Full Text Available DISEASE: H00003 Entry H00003Disease Name Acute myeloid leukemia (AML) Description Acute.... Category Cancer Brite Human diseases [BR:br08402] Cancers Cancers of haematopoietic and lymphoid tissues H00003Acute...atopoietic and related tissue C92Myeloid leukaemia H00003Acute myeloid leukemia (AML) Cancer-accociated carb...ohydrates [br08441.html] H00003 Pathway hsa05221Acute myeloid leukemiahsa05202Transcriptional misregulation ... or t(16; 16)(p13, q22), (CBF-beta/MYH11) ICD-O: 9866/3, Tumor type: Acute promyelocytic leukaemia (AML with

  3. Prevention of infection in children with acute leukaemia - No major difference between total and selective bowel decontamination

    NARCIS (Netherlands)

    Muis, N; Kamps, WA

    1996-01-01

    To evaluate the effect of total bowel decontamination (TD) and selective bowel decontamination (SD) in a non-protective environment clinical and laboratory data of children treated for acute leukaemia between 1983 and 1991 were analysed retrospectively. From 1983 until 1989 34 patients [18 acute non

  4. Stepwise discriminant function analysis for rapid identification of acute promyelocytic leukemia from acute myeloid leukemia with multiparameter flow cytometry.

    Science.gov (United States)

    Chen, Zhanguo; Li, Yan; Tong, Yongqing; Gao, Qingping; Mao, Xiaolu; Zhang, Wenjing; Xia, Zunen; Fu, Chaohong

    2016-03-01

    Diagnosis of acute promyelocytic leukemia (APL) has been accelerated by multiparameter flow cytometry (MFC). However, diagnostic interpretation of MFC readouts for APL depends on individual experience and knowledge, which inevitably increases the risk of arbitrariness. We appraised the feasibility of using stepwise discriminant function analysis (SDFA) based on MFC to optimize the minimal variables needed to distinguish APL from other acute myeloid leukemia (AML) without complicated data interpretation. Samples from 327 patients with APL (n = 51) and non-APL AML (n = 276) were randomly allocated into training (243 AML) and test sets (84 AML) for SDFA. The discriminant functions from SDFA were examined by correct classification, and the final variables were validated by differential expression. Finally, additional 20 samples from patients with atypical APL and AML confusable with APL were also identified by SDFA method and morphological analysis. The weighed discriminant function reveals seven differentially expressed variables (CD2/CD9/CD11b/CD13/CD34/HLA-DR/CD117), which predict a molecular result for APL characterization with an accuracy that approaches 99% (99.6 and 98.8% for AML samples in training and test sets, respectively). Furthermore, the SDFA outperformed either single variable analysis or the more limited 3-component analysis (CD34/CD117/HLA-DR) via separate SDFA, and was also superior to morphological analysis in terms of diagnostic efficacy. The established SDFA based on MFC with seven variables can precisely and rapidly differentiate APL and non-APL AML, which may contribute to the urgent initiation of all-trans-retinoic acid-based APL therapy.

  5. High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia.

    Science.gov (United States)

    Lucena-Araujo, Antonio R; Kim, Haesook T; Thomé, Carolina; Jacomo, Rafael H; Melo, Raul A; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Glória, Ana Beatriz F; Chauffaille, Maria de Lourdes; Athayde, Melina; Chiattone, Carlos S; Mito, Ingrid; Bendlin, Rodrigo; Souza, Carmino; Bortolheiro, Cristina; Coelho-Silva, Juan L; Schrier, Stanley L; Tallman, Martin S; Grimwade, David; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C; Lo-Coco, Francesco; Löwenberg, Bob; Sanz, Miguel A; Rego, Eduardo M

    2015-11-12

    The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.

  6. Cytoplasmic nucleophosmin (cNPM) in acute myeloid leukaemia ...

    African Journals Online (AJOL)

    Amani H. Kazem

    2011-08-26

    Aug 26, 2011 ... novo) patients with Acute Myeloid Leukemia with normal karyotype of all ... AML secondary to MDS, AML therapy related ... A second line of mAb were used to further ... ing techniques to detect visually accessible aberrations.

  7. Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia.

    Science.gov (United States)

    Park, Jung Eun; Yuen, Hiu Fung; Zhou, Jian Biao; Al-Aidaroos, Abdul Qader O; Guo, Ke; Valk, Peter J; Zhang, Shu Dong; Chng, Wee Joo; Hong, Cheng William; Mills, Ken; Zeng, Qi

    2013-09-01

    FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan-Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients.

  8. Effect of arsenic sulfide on tissue factor expression in acute promyelocytic leukemia cell lines

    Institute of Scientific and Technical Information of China (English)

    赵晓艾; 刘陕西

    2003-01-01

    Objective: To investigate the effect of arsenic sulfide (tetra-arsenic tetra-sulfide As4S4; diarsenic trisulfide As2S3) on tissue factor (TF) expression and procoagulant activity (PCA) of acute promyelocytic leukemia(APL) cell lines (NB4 and MR2) and the basic mechanism of their role. Methods: NB4 and MR2 cells were respectively treated with As4S4, As2S3, As4S4 and Cyclohexamide(CHX). PCA of the cells was detected using one-stage clotting assay. TF antigen was detected by ELISA. TF and PML/RARα fusion gene mRNA by semi-quantitive RT-PCR. The PCA and TF antigen of HL-60 and K562 cells were also examined. Results: The PCA and TF antigen level in NB4 and MR2 cells were significantly higher than that in HL-60 and K562 cells. Both As4S4 and As2S3 can down-regulate the TF antigen, TF mRNA transcription and membrane PCA of NB4 and MR2 cells in vitro in a time-dependent manner. The role of As4S4 was stronger than that of As2S3. Both As4S4 and As2S3 had no effect on PML/RARαfusion gene transcription. CHX treatment completely suppressed the down-regulate effect of As4S4 on the TF mRNA expression. Conclusion: As4S4 and As2S3 may down regulate tissue factor expression and PCA of NB4 and MR2 cells. By down-regulating TF expression, As4S4 and As2S3 might be used to improve the DIC-related hemorrhage in APL patients. Elevated TF antigen level of NB4 and MR2 cells may be related to the fusion gene PML/RARα. The modulation of the TF mRNA expression in NB4 and MR2 cells by As4S4 and As2S3 might be indirect and might not involve PML/RARα fusion gene.

  9. Nutritional status and dietary intake of children with acute leukaemia during induction or consolidation chemotherapy.

    Science.gov (United States)

    Tan, S Y; Poh, B K; Nadrah, M H; Jannah, N A; Rahman, J; Ismail, M N

    2013-07-01

    The assessment of nutritional status among paediatric patients is important for the planning and execution of nutritional strategies that strive to optimise the quality of life and growth among sick children. The present study aimed to evaluate the nutritional status and dietary intake among children with acute leukaemia. This cross-sectional study included 53 paediatric patients aged 3-12 years old, who were diagnosed with either acute lymphoblastic leukaemia or acute myelogenous leukaemia and were undergoing chemotherapy treatments (induction or consolidation phase). Patients were matched for sex, age (±6 months) and ethnicity with healthy children as controls. Weight, height, body mass index, waist circumference, mid-upper arm circumference, triceps skinfold thickness, mid-upper arm muscle area and fat area were determined. Dietary intake was assessed using 3-day food records. Anthropometric variables were generally higher among patients compared to controls, although the differences were not statistically significant (P > 0.05). The prevalence of overnutrition among patients according to body mass index-for-age, waist circumference-for-age, mid-upper arm circumference-for-age and triceps skinfold-for-age were 24.5%, 29.1%, 17.0% and 30.2%, respectively. Mean energy [5732 ± 1958 kJ (1370 ± 468 kcal) versus 6945 ± 1970 kJ (1660 ± 471 kcal), P Nutrition and Dietetics © 2013 The British Dietetic Association Ltd.

  10. Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy

    NARCIS (Netherlands)

    Barragan, Eva; Montesinos, Pau; Camos, Mireia; Gonzalez, Marcos; Calasanz, Maria J.; Roman-Gomez, Jose; Gomez-Casares, Maria T.; Ayala, Rosa; Lopez, Javier; Fuster, Oscar; Colomer, Dolors; Chillon, Carmen; Larrayoz, Maria J.; Sanchez-Godoy, Pedro; Gonzalez-Campos, Jose; Manso, Felix; Amador, Maria L.; Vellenga, Edo; Lowenberg, Bob; Sanz, Miguel A.

    2011-01-01

    Background Fms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established. Design and Methods We evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoic acid and a

  11. Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy

    NARCIS (Netherlands)

    P. Montesinos (Pau); M. González (Marcos); F. Manso (Félix); E. Vellenga (Edo); B. Löwenberg (Bob); M.A. Sanz (Miguel Angel)

    2011-01-01

    textabstractBackground Fms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established. Design and Methods We evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoi

  12. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all- trans retinoic acid and anthracycline chemotherapy: Characteristics, outcome, and prognostic factors

    NARCIS (Netherlands)

    P. Montesinos (Pau); J.M. Bergua (Juan Miguel); E. Vellenga (Edo); C. Rayón (Chelo); R. Parody (Ricardo); J. de Serna (Javier); A. León (Angel); J. Esteve (Jordi); G. Milone (Gustavo); G. Debén (Guillermo); C. Rivas (Concha); M. González (Marcos); M. Tormo (Mar); D.M. Joaquín; J.D. González (José David); S. Negri (Silvia); E. Amutio (Elena); S. Brunet (Salut); B. Löwenberg (Bob); M.A. Sanz (Miguel Angel)

    2009-01-01

    textabstractDifferentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all- trans retinoic acid (ATRA). Detailed knowl- edge about DS has remained limited. We present an analysis of the incidence, char- a

  13. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin

    NARCIS (Netherlands)

    de la Serna, Javier; Montesinos, Pau; Vellenga, Edo; Rayon, Chelo; Parody, Ricardo; Leon, Angel; Esteve, Jordi; Bergua, Juan M.; Milone, Gustavo; Deben, Guillermo; Rivas, Concha; Gonzalez, Marcos; Tormo, Mar; Diaz-Mediavilla, Joaquin; Gonzalez, Jose D.; Negri, Silvia; Amutio, Elena; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A.

    2008-01-01

    An understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of induction

  14. Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy

    NARCIS (Netherlands)

    Barragan, Eva; Montesinos, Pau; Camos, Mireia; Gonzalez, Marcos; Calasanz, Maria J.; Roman-Gomez, Jose; Gomez-Casares, Maria T.; Ayala, Rosa; Lopez, Javier; Fuster, Oscar; Colomer, Dolors; Chillon, Carmen; Larrayoz, Maria J.; Sanchez-Godoy, Pedro; Gonzalez-Campos, Jose; Manso, Felix; Amador, Maria L.; Vellenga, Edo; Lowenberg, Bob; Sanz, Miguel A.

    2011-01-01

    Background Fms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established. Design and Methods We evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoic acid and

  15. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all- trans retinoic acid and anthracycline chemotherapy: Characteristics, outcome, and prognostic factors

    NARCIS (Netherlands)

    P. Montesinos (Pau); J.M. Bergua (Juan Miguel); E. Vellenga (Edo); C. Rayón (Chelo); R. Parody (Ricardo); J. de Serna (Javier); A. León (Angel); J. Esteve (Jordi); G. Milone (Gustavo); G. Debén (Guillermo); C. Rivas (Concha); M. González (Marcos); M. Tormo (Mar); D.M. Joaquín; J.D. González (José David); S. Negri (Silvia); E. Amutio (Elena); S. Brunet (Salut); B. Löwenberg (Bob); M.A. Sanz (Miguel Angel)

    2009-01-01

    textabstractDifferentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all- trans retinoic acid (ATRA). Detailed knowl- edge about DS has remained limited. We present an analysis of the incidence, char-

  16. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin

    NARCIS (Netherlands)

    J. de Serna (Javier); P. Montesinos (Pau); E. Vellenga (Edo); C. Rayón (Chelo); R. Parody (Ricardo); A. León (Angel); J. Esteve (Jordi); J.M. Bergua (Juan Miguel); G. Milone (Gustavo); G. Debén (Guillermo); C. Rivas (Concha); M. González (Marcos); M. Tormo (Mar); J. Díaz-Mediavilla (Joaquín); J.D. González (Jose); S. Negri (Silvia); E. Amutio (Elena); S. Brunet (Salut); B. Löwenberg (Bob); M.A. Sanz (Miguel Angel)

    2008-01-01

    textabstractAn understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of

  17. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens

    NARCIS (Netherlands)

    Montesinos, Pau; Rayon, Chelo; Vellenga, Edo; Brunet, Salut; Gonzalez, Jose; Gonzalez, Marcos; Holowiecka, Aleksandra; Esteve, Jordi; Bergua, Juan; Gonzalez, Jose D.; Rivas, Concha; Tormo, Mar; Rubio, Vicente; Bueno, Javier; Manso, Felix; Milone, Gustavo; de la Serna, Javier; Perez, Inmaculada; Perez-Encinas, Manuel; Krsnik, Isabel; Ribera, Josep M.; Escoda, Lourdes; Lowenberg, Bob; Sanz, Miguel A.

    2011-01-01

    The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthr

  18. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin

    NARCIS (Netherlands)

    de la Serna, Javier; Montesinos, Pau; Vellenga, Edo; Rayon, Chelo; Parody, Ricardo; Leon, Angel; Esteve, Jordi; Bergua, Juan M.; Milone, Gustavo; Deben, Guillermo; Rivas, Concha; Gonzalez, Marcos; Tormo, Mar; Diaz-Mediavilla, Joaquin; Gonzalez, Jose D.; Negri, Silvia; Amutio, Elena; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A.

    2008-01-01

    An understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of induction f

  19. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens

    NARCIS (Netherlands)

    Montesinos, Pau; Rayon, Chelo; Vellenga, Edo; Brunet, Salut; Gonzalez, Jose; Gonzalez, Marcos; Holowiecka, Aleksandra; Esteve, Jordi; Bergua, Juan; Gonzalez, Jose D.; Rivas, Concha; Tormo, Mar; Rubio, Vicente; Bueno, Javier; Manso, Felix; Milone, Gustavo; de la Serna, Javier; Perez, Inmaculada; Perez-Encinas, Manuel; Krsnik, Isabel; Ribera, Josep M.; Escoda, Lourdes; Lowenberg, Bob; Sanz, Miguel A.

    2011-01-01

    The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and

  20. Embryo cryopreservation in a case of acute promyelocytic leukemia, incidentally diagnosed during ovarian stimulation for in-vitro fertilization

    Directory of Open Access Journals (Sweden)

    Manish Banker

    2014-01-01

    Full Text Available 31-year-old woman presented with secondary infertility, a history of previous miscarriage and two ectopic pregnancies. Salpingectomy had been performed for the left ruptured tubal pregnancy whereas the right unruptured tubal pregnancy was managed medically. In-vitro fertilization (IVF was advised to treat tubal factor infertility of 2 years duration. The patient developed fever and cough on day-10 of ovarian stimulation. Complete blood count and peripheral smear with marked leukocytosis were suggestive of acute leukemia. After obtaining the patient′s informed consent, 18 oocytes were retrieved. Following intra cytoplasmic sperm injection, 14 eggs were fertilized, and the resulting embryos were cryopreserved. On a referral to a hemato-oncologist, a bone marrow biopsy was performed, which confirmed acute promyelocytic leukemia (APL. Literature review suggests this to be the first case of APL reported during the course of ovulation stimulation for IVF.

  1. Embryo cryopreservation in a case of acute promyelocytic leukemia, incidentally diagnosed during ovarian stimulation for in-vitro fertilization.

    Science.gov (United States)

    Banker, Manish; Joshi, Bharat; Shah, Preeti; Patel, Deven

    2014-07-01

    A 31-year-old woman presented with secondary infertility, a history of previous miscarriage and two ectopic pregnancies. Salpingectomy had been performed for the left ruptured tubal pregnancy whereas the right unruptured tubal pregnancy was managed medically. In-vitro fertilization (IVF) was advised to treat tubal factor infertility of 2 years duration. The patient developed fever and cough on day-10 of ovarian stimulation. Complete blood count and peripheral smear with marked leukocytosis were suggestive of acute leukemia. After obtaining the patient's informed consent, 18 oocytes were retrieved. Following intra cytoplasmic sperm injection, 14 eggs were fertilized, and the resulting embryos were cryopreserved. On a referral to a hemato-oncologist, a bone marrow biopsy was performed, which confirmed acute promyelocytic leukemia (APL). Literature review suggests this to be the first case of APL reported during the course of ovulation stimulation for IVF.

  2. Competitive PCR for quantification of minimal residual disease in acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Nyvold, C; Madsen, H O; Ryder, L P;

    2000-01-01

    A very precise and reproducible polymerase chain reaction (PCR) method was developed in order to quantify minimal residual disease (MRD) in children with acute lymphoblastic leukaemia (ALL). A clone-specific competitor was constructed by introducing a restriction site in a PCR product identical...... under identical conditions. After restriction enzyme cleavage, the PCR products originating from the competitor and the malignant clone can be distinguished by size in a gel electrophoresis step and the amount of residual disease can be determined. The method is very sensitive with a detection limit...

  3. Acute myeloid leukaemia presenting as bilateral proptosis in a young child

    Directory of Open Access Journals (Sweden)

    Charudutt Kalamkar

    2016-06-01

    Full Text Available Myeloid sarcoma is an extramedullary manifestation of acute myeloid leukaemia (AML. Aims We are reporting a paediatric case presenting with bilateral proptosis, which we were able to diagnose with peripheral blood smear (PBS examination. Methods Case Report Results This case highlights the utility of simple routinely available PBS test in diagnosing this rare disease. Conclusion Our case highlights the importance of haemogram and peripheral blood smear in the initial evaluation of proptosis. Correct diagnosis of this rare entity is vital especially in cases where (myeloid sarcoma MS is the presenting feature of AML.

  4. Acute Coronary Syndrome Manifesting as an Adverse Effect of All-trans-Retinoic Acid in Acute Promyelocytic Leukemia: A Case Report with Review of the Literature and a Spotlight on Management

    Directory of Open Access Journals (Sweden)

    K. Govind Babu

    2016-01-01

    Full Text Available Background. Acute promyelocytic leukemia is characterized by t(15;17. This leads to the formation of PML/RARα which blocks the differentiation of blasts at the stage of promyelocytes. This is reversed by all-trans-retinoic acid (ATRA, a vitamin A derivative. Acute myocardial ischemia is a rare side effect of ATRA. Case Report. We report a case of acute coronary syndrome manifesting as an adverse effect of ATRA in a lady with APL who had no other risk factors for cardiovascular disease. Conclusions. We emphasize the need for high index of suspicion for the diagnosis of this entity. In the light of this case, the rare instances of ATRA associated acute myocardial ischemia recorded in the literature and the options available for treatment of acute promyelocytic leukemia sans ATRA have been reviewed.

  5. A rare case of acute lymphoblastic leukaemia with hemophilia A

    Directory of Open Access Journals (Sweden)

    John Biju

    2009-12-01

    Full Text Available Abstract A rare case of Acute lymphoblastic leukemia with hemophillia in a 12 year old boy is presented in the article. Patient was known case of hemophillia (factor VIII deficiency. He was diagnosed as a case of ALL based on bone marrow examination and immunophenotypic study. Patient was treated as per Children Cancer group guidelines. The main aim of reporting this rare association lies in developing treatment strategies in preventing life threatening bleeding due to this rare association which though may be accidental but need further research.

  6. Detecting PML-RARα transcript in acute promyelocytic leukemia using real-time quantitative RT-PCR

    Institute of Scientific and Technical Information of China (English)

    ZHU Hong-hu; LIU Yan-rong; QIN Ya-zhen; JIANG Bin; SHAN Fu-xiang; WU Shu-lan; YANG Ping-di; ZHAO Jie; LU Dao-pei

    2007-01-01

    Background Real-time quantitative RT-PCR (RQ-PCR) assay has become a vital tool to monitor residual disease of leukemia. However, the complexity and standardization of RQ-PCR should never be overlooked and the results should be interpreted cautiously in clinical conditions. We aimed to assess the methodology of RQ-PCR and its clinical applications in monitoring molecular kinetics of 36 newly diagnosed cases of acute promyelocytic leukemia patients with t (15; 17) from October 2004 to December 2005.Methods All the TaqMan probe-based RQ-PCR reactions and analysis were performed on an ABI-PRISM 7500platform. The quantitation of PML-RARα transcripts was represented by the normalized quotient, that is, PML-RARα transcript copies divided by ABL transcript copies. According to induction therapy, the patients were classed into two groups: group 1 (n=23), three-drug combination including arsenics, all-trans retinoic acid and mitoxantrone; and group 2 (n=13), two-drug combination from all-trans retinoic acid, arsenics and mitoxantrone.Results The sensitivity of RQ-PCR was 1 per 105 cells and 5 copies of the PML-RARα transcript could be reproducibly detected. No false positive results occurred in 40 non-acute promyelocytic leukemia samples. Optimal amplification efficiency could be attained, which was determined by the slope of the standard curves (slope: -3.2 - -3.7). The inter-assay and intra-assay variation coefficients of the method were 1.01% and 0.56% respectively. Although the time to attain hematological complete remission was similar in both groups, the time to achieve molecular remission of group 1 was significantly shorter than that of group 2 (61 days vs 75 days, P=0.034). The rate of molecular remission within 70days was higher in group 1 than in group 2 (75.00% vs 38.46%, P=0.036). Compared with pretreatment, median reduction of the PML-RARα transcript before first consolidation therapy differed significantly between group 1 and group 2 (log scale, 3.15 vs 2

  7. Increased cellular hypoxia and reduced proliferation of both normal and leukaemic cells during progression of acute myeloid leukaemia in rats

    DEFF Research Database (Denmark)

    Jensen, P O; Mortensen, B T; Hodgkiss, R J;

    2000-01-01

    The microenvironmental changes in the bone marrow, spleen and liver during progression of the transplantable promyelocytic leukaemia in the Brown Norwegian rat (BNML) have been studied. We used flow cytometry to estimate cellular hypoxia and proliferation based on in vivo pulse...... in the bone marrow and liver, reaching a level of 65-87% in these organs at day 32. At day 32, the NITP+ fraction of RM124+ cells had increased significantly in the bone marrow and spleen to 88% and 90%, respectively. The corresponding fractions of NITP+ normal cells reached 63% and 65%, respectively. From......-labelling with a mixture of 2-nitroimidazole linked to theophylline (NITP) and bromodeoxyuridine (BrdUrd). The leukaemic cells were identified with the RM124 antibody. In rats inoculated with leukaemic cells the fraction of RM124+ cells was significantly increased from day 20 onwards in the spleen and from day 27...

  8. Study of clinical, haematological and cytogenetic profile of patients with acute erythroid leukaemia

    Science.gov (United States)

    Linu, Jacob Abraham; Udupa, MS Namratha; Madhumathi, DS; Lakshmaiah, KC; Babu, K Govind; Lokanatha, D; Babu, MC Suresh; Lokesh, KN; Rajeev, LK; Rudresha, AH

    2017-01-01

    Background Acute erythroid leukaemia (AEL) is a rare subtype of acute myeloid leukaemia (AML), constituting cytogenetic profile of this disease, considering the rarity of its occurrence and poor prognosis. Materials and methods This study was done by retrospective analysis of data from 32 case files of patients diagnosed with AEL. Clinical details noted down were the demographic profile, peripheral blood smear details and bone marrow examination details: (1) blasts-erythroblasts and myeloblasts, (2) dysplasia in the cell lineages and (3) cytogenetic abnormalities. Results The most common presenting symptom was fever. Pancytopenia at presentation was seen in 81.25% of patients. Dysplasia was observed in bone marrow in 100% of erythroblasts and in 40% of myeloblasts in erythroid/myeloid subtype. In pure myeloid subtype, myeloid and megakaryocytic dysplasias were not obvious. Complex karyotype was noticed only in patients of pEL. Conclusion AEL is a rare group of heterogeneous diseases with many neoplastic and non-neoplastic conditions mimicking the diagnosis. The clinical presentation and cytogenetics are also non-specific, presenting additional challenges to the diagnosis. PMID:28144286

  9. Medical neglect death due to acute lymphoblastic leukaemia: an autopsy case report.

    Science.gov (United States)

    Usumoto, Yosuke; Sameshima, Naomi; Tsuji, Akiko; Kudo, Keiko; Nishida, Naoki; Ikeda, Noriaki

    2014-12-01

    We report the case of 2-year-old girl who died of precursor B-cell acute lymphoblastic leukaemia (ALL), the most common cancer in children. She had no remarkable medical history. She was transferred to a hospital because of respiratory distress and died 4 hours after arrival. Two weeks before death, she had a fever of 39 degrees C, which subsided after the administration of a naturopathic herbal remedy. She developed jaundice 1 week before death, and her condition worsened on the day of death. Laboratory test results on admission showed a markedly elevated white blood cell count. Accordingly, the cause of death was suspected to be acute leukaemia. Forensic autopsy revealed the cause of death to be precursor B-cell ALL. With advancements in medical technology, the 5-year survival rate of children with ALL is nearly 90%. However, in this case, the deceased's parents preferred complementary and alternative medicine (i.e., naturopathy) to evidence-based medicine and had not taken her to a hospital for a medical check-up or immunisation since she was an infant. Thus, if she had received routine medical care, she would have a more than 60% chance of being alive 5 years after diagnosis. Therefore, we conclude that the parents should be accused of medical neglect regardless of their motives.

  10. TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA WITH SINGLE-AGENT ARSENIC TRIOXIDE

    Directory of Open Access Journals (Sweden)

    Biju George

    2011-01-01

    Full Text Available

    It is well recognized that arsenic trioxide (ATO is an efficacious agent for the treatment of acute promyelocytic leukemia (APL. Use of single agent ATO in the treatment of APL leads to remissions which are durable in the majority. ATO is probably the most effective single agent in the treatment of APL and there have been very few reports of primary resistance. It has been used both as a single agent and in combination with other conventional drugs to treat APL. Use of ATO is the accepted standard of care in the management of relapsed APL, where it is often used effectively as a bridge to a stem cell transplant. However, its role in newly diagnosed APL remains controversial. ATO probably has multiple mechanisms of action. Better understanding of its mechanisms of action/s is likely to lead to more rationale use of this agent or its derivatives either alone or in combination with other drugs. There is limited data on the kinetics of leukemia clearance and normal haematopoietic recovery after the administration of single agent ATO for the treatment of APL, preliminary data suggests that it is likely to be different from conventional therapy. There have been a number of concerns of the potential short and long term toxicity of this agent. Most such concerns arise from the toxicity profile noted in people exposed to long term arsenic exposure in the environment. With the therapeutic doses and schedules of administration of ATO in the treatment of malignancies the overall toxicity profile has been favorable. In a resource constrained environments the use of a single agent ATO based regimen is a realistic and acceptable option to treat almost all patients. In the developed world it has the potential in combination with other

  11. COMPARISON OF CLINICAL OBSERVATIONS BETWEEN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA TREATED WITH ALL-TRANS RETINOIC ACID AND CHEMOTHERAPY

    Institute of Scientific and Technical Information of China (English)

    张芬琴; 吴立德; 李秀松; 孙关林; 蔡敬仁; 王振义

    1992-01-01

    Clinical observations were retrospectively compared between 2 matched groups of patients with acute promyelocytic leukemia (APL) each 20. The first group were treated with chemotherapy, the other with all-tram retinoic acid (ATRA) alone at a dose of 45-60mg/M~2/d. The complete remission (CR) rate of ATRA group was significantly higher than that of chemotherapy (90% vs 55%). The time for obtaining CR as well as the duration of fever and hospitalization were shorter and the amount of blood transfused was less in the former than in the latter group. Seven cases were complicated by DIC and 4 died in the group of chemotherapy, while no case was by of DIC or death in the ATRA group. The mechanism was discussed. ATRA is an alternative effective drug for remission induction therapy in APL with high rate of CR.

  12. Identification of target genes of transcription factor CEBPB in acute promyelocytic leukemia cells induced by all-trans retinoic acid

    Institute of Scientific and Technical Information of China (English)

    Lei Yu; Yang-De Zhang; Jun Zhou; De-Ming Yao; Xiang Li

    2013-01-01

    Objective: To indentify target genes of transcription factor CCAAT enhancer-binding proteinβ (CEBPB) in acute promyelocytic leukemia cells induced by all-trans retinoic acid. Methods:A new strategy for high-throughput identification of direct target genes was established by combining chromatin immunoprecipitation (ChIP) with in vitro selection. Then, 106 potential CEBPB binding fragments from the genome of the all-trans retinoic acid (ATRA)-treated NB4 cells were identified. Results: Of them, 82 were mapped in proximity to known or previously predicted genes; 7 were randomly picked up for further confirmation by ChIP-PCR and 3 genes (GALM, ITPR2 and ORM2) were found to be specifically up-regulated in the ATRA-treated NB4 cells, indicating that they might be the down-stream target genes of ATRA. Conclusions: Our results provided new insight into the mechanisms of ATRA-induced granulocytic differentiation.

  13. [Successful treatment of acute promyelocytic leukemia in a pregnant woman by using all-trans retinoic acid].

    Science.gov (United States)

    Tsuda, H; Doi, H; Inada, T; Shirono, K

    1994-07-01

    A 34-year-old woman was admitted because of pancytopenia with DIC in the 28th week of pregnancy. Bone marrow aspirate demonstrated 81.2% abnormal cells which showed Auer bodies and faggot formation. Chromosomal analysis demonstrated an abnormality, t (15; 17). The patient was diagnosed as having acute promyelocytic leukemia (APL) and started to receive treatment with all-trans retinoic acid (ATRA) 70 mg/body/day per os. She had a cesarean section and gave birth to a female infant in the 29th week of pregnancy. An increase of WBC counts was observed on the 9th hospital day, then chemotherapy with anti-cancer agents was performed additionally. Complete remission was achieved on the 27th hospital day. Management of pregnant patients with APL could be improved by using ATRA instead of conventional combinations of cytotoxic agents.

  14. [A neonate born to a mother with acute promyelocytic leukemia treated by all-trans retinoic acid].

    Science.gov (United States)

    Maeda, M; Tyugu, H; Okubo, T; Yamamoto, M; Nakamura, K; Dan, K

    1997-09-01

    We report a female neonate delivered in week 32 of gestation by a mother who had acute promyelocytic leukemia (APL) treated by all-trans retinoic acid (ATRA). APL was diagnosed in week 29 of gestation and was treated with ATRA from week 30. Physical examination and laboratory tests showed no abnormalities at birth. The girl has since shown normal development, with no peripheral blood abnormalities at 2 years old. Hypersegmented neutrophils, which often appear during ATRA treatment, were seen in the peripheral blood of the mother and cord blood but not peripheral blood of the neonate on the day of birth. ATRA is known to cross the placenta, and has been revealed to be teratogenic in animal studies. There have been eight neonates born to the mothers with APL who were treated with ATRA during pregnancy. All infants, including this one, have shown normal growth without any complications.

  15. Genital ulcers after treatment with all-trans-retinoic acid in a child with acute promyelocytic leukemia.

    Science.gov (United States)

    Unal, Selma; Gümrük, Fatma; Cetin, Mualla; Hiçsönmez, Gönül

    2005-01-01

    All-trans-retinoic acid (ATRA) has been shown to improve the outcome of patients with acute promyelocytic leukemia (APL). However, various adverse effects of ATRA treatment have been noted, such as scrotal and genital ulcers in adult patients. The authors report genital ulcers that developed in a child with APL after ATRA treatment. An 8-year-old girl with APL was treated with ATRA for 21 days and after discontinuation of ATRA treatment she developed genital ulcers. Systemic and local antibiotic pomades were applied and the lesions improved within 15 days. In conclusion, genital ulcers may develop in children with APL as a complication of ATRA treatment and physicians should be alert to this possibility.

  16. Refractory acute promyelocytic leukemia successfully treated with combination therapy of arsenic trioxide and tamibarotene: A case report

    Directory of Open Access Journals (Sweden)

    Minoru Kojima

    2016-01-01

    Full Text Available A 40-year-old male developed refractory acute promyelocytic leukemia (APL after various treatments including all-trans retinoic acid, tamibarotene, arsenic trioxide (As2O3, conventional chemotherapy, and autologous peripheral blood stem cell transplantation. We attempted to use both tamibarotene and As2O3 as a combination therapy, and he achieved molecular complete remission. Grade 2 prolongation of the QTc interval on the electrocardiogram was observed during the therapy. The combination therapy of As2O3 and tamibarotene may be effective and tolerable for treating refractory APL cases who have no treatment options, even when they have previously been treated with tamibarotene and As2O3 as a single agent.

  17. Successful Control of Disseminated Intravascular Coagulation by Recombinant Thrombomodulin during Arsenic Trioxide Treatment in Relapsed Patient with Acute Promyelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Motohiro Shindo

    2012-01-01

    Full Text Available Disseminated intravascular coagulation (DIC frequently occurs in patients with acute promyelocytic leukemia (APL. With the induction of therapy in APL using all-trans retinoic acid (ATRA, DIC can be controlled in most cases as ATRA usually shows immediate improvement of the APL. However, arsenic trioxide (ATO which has been used for the treatment of relapse in APL patients has shown to take time to suppress APL cells, therefore the control of DIC in APL with ATO treatment is a major problem. Recently, the recombinant soluble thrombomodulin fragment has received a lot of attention as the novel drug for the treatment of DIC with high efficacy. Here, we present a relapsed patient with APL in whom DIC was successfully and safely controlled by rTM during treatment with ATO.

  18. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy

    DEFF Research Database (Denmark)

    Grövdal, Michael; Karimi, Mohsen; Khan, Rasheed

    2010-01-01

    This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction...

  19. Low frequency of MLL-partial tandem duplications in paediatric acute myeloid leukaemia using MLPA as a novel DNA screenings technique.

    NARCIS (Netherlands)

    Balgobind, B.V.; Hollink, I.H.; Reinhardt, D.; Wering, E.R. van; Graaf, S.S.N. de; Baruchel, A.; Stary, J.; Beverloo, H.B.; Greef, G.E. de; Pieters, R.; Zwaan, C.M.; Heuvel-Eibrink, M.M. van den

    2010-01-01

    Mixed-lineage leukaemia (MLL)-partial tandem duplications (PTDs) are found in 3-5% of adult acute myeloid leukaemia (AML), and are associated with poor prognosis. In adult AML, MLL-PTD is only detected in patients with trisomy 11 or internal tandem duplications of FLT3 (FLT3-ITD). To date, studies i

  20. Label-free imaging and identification of typical cells of acute myeloid leukaemia and myelodysplastic syndrome by Raman microspectroscopy

    NARCIS (Netherlands)

    Vanna, R.; Ronchi, P.; Lenferink, A.T.M.; Terstappen, L.W.M.M.; Tresoldi, C.; Morasso, C.; Mehn, D.; Bedoni, M.; Ciceri, F.; Otto, C.; Gramatica, F.

    2015-01-01

    In clinical practice, the diagnosis and classification of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) start from the manual examination of stained smears of bone marrow (BM) and peripheral blood (PB) by using an optical microscope. This step is subjective and scarcely reproducib

  1. Central line-related bacteraemia due to Roseomonas mucosa in a neutropenic patient with acute myeloid leukaemia in Piraeus, Greece.

    Science.gov (United States)

    Christakis, G B; Perlorentzou, S; Alexaki, P; Megalakaki, A; Zarkadis, I K

    2006-08-01

    A case of central venous catheter-related bacteraemia due to Roseomonas mucosa in a neutropenic patient with acute myelogenous leukaemia is reported. The patient was successfully treated with amikacin and piperacillin-tazobactam. The clinical isolate was identified as R. mucosa by 16S rRNA gene sequencing.

  2. Prolonged bone marrow T1-relaxation in acute leukaemia. In vivo tissue characterization by magnetic resonance imaging

    DEFF Research Database (Denmark)

    Thomsen, C; Sørensen, P G; Karle, H

    1987-01-01

    osseous tissue. Nine patients with acute leukaemia, one patient with myelodysplastic syndrome, and ten normal volunteers were included in the study. The T1- and T2-relaxation processes were measured in the lumbar spine bone marrow using a wholebody superconductive MR-scanner operating at 1.5 Tesla...

  3. Variation in survival of European children with acute lymphoblastic leukaemia, diagnosed in 1978-1992 : the EUROCARE study

    NARCIS (Netherlands)

    Coebergh, JW; Pastore, G; Gatta, G; Corazziari, [No Value; Kamps, W

    2001-01-01

    The aim of this study was to provide a comparative description of geographical variations and time trends in the population-based survival of European children with acute lymphoblastic leukaemia (ALL). Data on 13 344 newly diagnosed children (0-14 years) with ALL were included in the EUROCARE study

  4. Splenic artery pseudoaneurysm due to acute pancreatitis in a 6-year-old boy with acute lymphoblastic leukaemia treated with L-aspariginase

    DEFF Research Database (Denmark)

    Larsen, Cæcilie Crawley; Laursen, Christian B; Dalby, Kasper;

    2014-01-01

    Acute pancreatitis is a rare phenomenon in children but its incidence seems to be increasing. In children, it is generally caused due to systemic illness, biliary disease, trauma, idiopathy and side effects of medicines like L-aspariginase. Acute pancreatitis is difficult to diagnose in children...... pseudoaneurysm due to acute pancreatitis in a 6-year-old boy with acute lymphoblastic leukaemia treated with L-aspariginase. He presented with fever, irritability and pain in his left groin region....

  5. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

    Science.gov (United States)

    Gu, Zhaohui; Churchman, Michelle; Roberts, Kathryn; Li, Yongjin; Liu, Yu; Harvey, Richard C.; McCastlain, Kelly; Reshmi, Shalini C.; Payne-Turner, Debbie; Iacobucci, Ilaria; Shao, Ying; Chen, I-Ming; Valentine, Marcus; Pei, Deqing; Mungall, Karen L.; Mungall, Andrew J.; Ma, Yussanne; Moore, Richard; Marra, Marco; Stonerock, Eileen; Gastier-Foster, Julie M.; Devidas, Meenakshi; Dai, Yunfeng; Wood, Brent; Borowitz, Michael; Larsen, Eric E.; Maloney, Kelly; Mattano Jr, Leonard A.; Angiolillo, Anne; Salzer, Wanda L.; Burke, Michael J.; Gianni, Francesca; Spinelli, Orietta; Radich, Jerald P.; Minden, Mark D.; Moorman, Anthony V.; Patel, Bella; Fielding, Adele K.; Rowe, Jacob M.; Luger, Selina M.; Bhatia, Ravi; Aldoss, Ibrahim; Forman, Stephen J.; Kohlschmidt, Jessica; Mrózek, Krzysztof; Marcucci, Guido; Bloomfield, Clara D.; Stock, Wendy; Kornblau, Steven; Kantarjian, Hagop M.; Konopleva, Marina; Paietta, Elisabeth; Willman, Cheryl L.; L. Loh, Mignon; P. Hunger, Stephen; Mullighan, Charles G.

    2016-01-01

    Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered. PMID:27824051

  6. Adult acute lymphoblastic leukaemia in Denmark. A national population-based retrospective study on acute lymphoblastic leukaemia in Denmark 1998-2008

    DEFF Research Database (Denmark)

    Toft, Nina; Schmiegelow, Kjeld; Klausen, Tobias W

    2012-01-01

    with historical controls, we performed a retrospective national population-based study of adult ALL between 1998 and 2008. Patients were identified through the Danish Patobank and the Danish Cancer Registry; data was collected from patient files, and included 277 patients (median age, 47 years, range 15-91 years......Since July 2008, children and adults 1-45 years, diagnosed with acute lymphoblastic leukaemia (ALL) in Denmark have been treated according to the common Nordic Society for Paediatric Haematology and Oncology ALL2008 protocol. To explore whether this strategy will improve survival compared......). The 5-year projected event-free survival (pEFS(5y) ) and overall survival (pOS(5y) ) for the whole cohort was 27·5% [95% confidence interval (CI) 22·4-33·6] and 34·1% (95% CI 28·7-40·4), respectively. No patient above 65 years survived beyond 5 years from diagnosis. For patients receiving curatively...

  7. Treatment of newly diagnosed and relapsed acute promyelocytic leukemia with intravenous liposomal all-trans retinoic acid.

    Science.gov (United States)

    Douer, D; Estey, E; Santillana, S; Bennett, J M; Lopez-Bernstein, G; Boehm, K; Williams, T

    2001-01-01

    A novel intravenous liposomal formulation of all-trans retinoic acid (ATRA) was evaluated in 69 patients with acute promyelocytic leukemia (APL): 32 new diagnoses, 35 relapses, and 2 oral ATRA failures. Liposomal ATRA (90 mg/m(2)) was administered every other day until complete remission (CR) or a maximum of 56 days. Treatment following CR was liposomal ATRA with or without chemotherapy. In an intent-to-treat (ITT) analysis of all patients, CR rates were 62%, 70%, and 20% in newly diagnosed, group 1 first relapses (ATRA naive or off oral ATRA more than or equal to 1 year), or group 2 relapses (second or subsequent relapse or first relapses off oral ATRA less than 1 year), respectively. In 56 evaluable patients (receiving 4 or more doses), CR rates for the same groups were 87% (20 of 23), 78% (14 of 18), and 23% (3 of 13). Remission failure in newly diagnosed patients was not from resistant disease. Several patients in CR became polymerase chain reaction (PCR) negative for promyelocytic leukemia/retinoic acid receptor-alpha (PML/RARalpha) after liposomal ATRA alone. Toxicity was generally mild, most commonly headaches (67. 5%). Eighteen patients (26%) had ATRA syndrome develop during induction. One-year survival of ITT patients was 62%, 56%, and 20% for newly diagnosed, group 1, and group 2, respectively. The medium duration of CR has not yet been reached and was 18 and 5.5 months in the same groups. These results demonstrate that liposomal ATRA is effective in inducing CR in newly diagnosed or group 1 APL patients. It provides a reliable dosage of ATRA for patients with APL unable to swallow or absorb medications and can induce molecular remissions without chemotherapy.

  8. Hospitalisation for infection prior to diagnosis of acute lymphoblastic leukaemia in children

    DEFF Research Database (Denmark)

    Vestergaard, Therese Risom; Rostgaard, Klaus; Grau, Katrine

    2013-01-01

    . PROCEDURE: A nation-wide cohort encompassing all Danish children aged 0-14 years and born between 1977 and 2008 (N = 1,778,129) was established and followed for hospitalisations for infectious diseases and risk of childhood ALL. The exposure was lagged 1 year to limit reverse causality. In the statistical......BACKGROUND: It has been proposed that infections in infancy and early childhood are associated with a reduced risk of childhood acute lymphoblastic leukaemia (ALL). We tested this hypothesis in a register-based study of hospitalisations for infectious diseases prior to diagnosis of childhood ALL...... analyses exposure was defined as (time dependent) number of early or late (before 2 or at/after 2 years of age) hospitalisations to further explore possible age-dependent associations. RESULTS: A total of 815 children were diagnosed with ALL during follow-up. Risk of ALL was associated neither...

  9. Arthroplasties of hips and knees ankylosis in an adolescent with acute lymphoblastic leukaemia.

    Directory of Open Access Journals (Sweden)

    Dipo Samuel OLABUMUYI

    2011-10-01

    Full Text Available Acute lymphoblastic leukaemia (ALL is the most common malignancy in children, representing one third of all paediatric malignancies. Patients are often at high risk for complications due aggressive chemotherapy regimes required for treatment. Musculoskeletal complications include septic arthritis, osteonecrosis, osteoporosis, avascular necrosis and bony ankylosis. We report the case of a 16-year-old boy with ALL who developed osteonecrosis of multiple bones on a background of septicaemia, resulting in bony ankylosis of both hips and knees. He was treated with bilateral conversion of ankylosed hips (one hip to total hip replacement, the second hip to Girdlestone arthroplasty and bilateral ankylosed knees to total knee replacements. He remained well in remission five years after the last surgery. Our case highlights he possible musculoskeletal complications of ALL. 

  10. Diagnostic & prognostic role of microRNAs in paediatric acute myeloid leukaemia

    Directory of Open Access Journals (Sweden)

    Sachin Kumar

    2016-01-01

    Full Text Available Dysregulation in microRNAs (miRNAs expression has been observed in distinct acute myeloid leukaemia (AML subtypes, and their potential as an effective diagnostic and prognostic biomarker is slowly being realized. Certain miRNAs have been found to be associated with various cytogenetic and molecular abnormalities of prognostic significance in AML. Experimental evidences have indicated the potential of modulating miRNA expression as an effective antileukaemic strategy. This has opened a new window for miRNAs-based targeted therapies. In this review, we present results of some studies analyzing the dysregulation in miRNAs expression pattern in paediatric AML and also discuss their use as diagnostic and prognostic markers.

  11. Competitive PCR for quantification of minimal residual disease in acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Nyvold, C; Madsen, H O; Ryder, L P

    2000-01-01

    A very precise and reproducible polymerase chain reaction (PCR) method was developed in order to quantify minimal residual disease (MRD) in children with acute lymphoblastic leukaemia (ALL). A clone-specific competitor was constructed by introducing a restriction site in a PCR product identical...... to parts of the highly specific rearranged T-cell receptor delta (TCR-delta), T-cell receptor gamma (TCR-gamma), or immunoglobulin heavy chain (IgH) genes of the malignant clone. Using primers located externally to the restriction site the competitor and the DNA from the malignant clone will be amplified...... under identical conditions. After restriction enzyme cleavage, the PCR products originating from the competitor and the malignant clone can be distinguished by size in a gel electrophoresis step and the amount of residual disease can be determined. The method is very sensitive with a detection limit...

  12. Fetal liver transplantation in 2 patients with acute leukaemia after total body irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Lucarelli, G.; Izzi, T.; Porcellini, A.; Delfini, C.; Galimberti, M.; Moretti, L.; Polchi, P.; Agostinelli, F.; Andreani, M.; Manna, M. (Haematological Department, Pesaro Hospital, Pesaro, Italy)

    1982-01-01

    2 patients with acute leukaemia in relapse were transplanted with fetal liver cells following a conditioning regimen of cyclophosphamide (120 mg/kg) and total body irradiation (1000 r). Each patient achieved a remission with haematopoietic recovery that was rapid in one case and delayed in the other. In one case there was evidence of chimerism as demonstrated by the presence of the XYY karyotype of the donor fetus in 20 % of marrow metaphases, by the presence of double Y bodies in the peripheral blood, by the appearance of new HLA-antigens, and by red cell isoenzyme phenotypes of donor origin. In the second case there was prompt haemotopoietic recovery and the appearance of red cell isoenzyme phenotypes of donor origin. Survival was 153 and 30 d, respectively, and both patients died of interstitial pneumonia without evidence of graft versus host disease.

  13. Auricular Oedema and Dyshidrotic Eczema in a Patient with Acute Myeloid Leukaemia Treated with Cytarabine

    Directory of Open Access Journals (Sweden)

    K. Brandt

    2010-10-01

    Full Text Available Cytarabine is an effective drug in the treatment of haematological malignancies. The therapy is associated with various complications. Frequencies of dermatological side-effects range from 2–72% and occur most commonly after high-dose regimens. Although most cutaneous reactions are mild and resolve spontaneously within several days, they may result in an increased risk of infection and alterations in comfort. In some cases, severe life-threatening reactions have been reported. Here we describe the case of a patient with acute myeloid leukaemia, who developed severe exceptional skin toxicity in terms of auricular oedema and palmar dyshidrotic eczema after the application of low-dose cytarabine. Re-administration of the drug resulted in reduced skin toxicity during further cycles of chemotherapy. Negative epicutaneous patch-testing supported the existence of cytarabine-provoked toxicity.

  14. Organ irradiation and combination chemotherapy in treatment of acute lymphocytic leukaemia in children.

    Science.gov (United States)

    Lanzkowsky, P; Shende, A; Aral, I; Saluja, G

    1975-01-01

    Lanzkowsky, P., Shende, A., Aral, I., Saluja, G. (1975). Archives of Disease in Childhood, 50, 685. Organ irradiation and combination chemotherapy in treatment of acute lymphocytic leukaemia in children. A total of 30 consecutive children with acute lymphocytic leukaemia (ALL) were treated from June 1971 until December 1974. Remission was induced with the use of vincristine and prednisone. After induction of remission, cranial irradiation and intrathecal methotrexate were given. Then the liver, spleen, and kidney were irradiated and 6-mercaptopurine, cyclophosphamide, and methotrexate were administered during the maintenance phase. Pulsed doses of vincristine and prednisone were administered at 10- to 12-week intervals. The patients were subdivided into two groups based on their initial white blood cell (WBC) counts: a standard risk group with an initial WBC count of less than 25 000/mm3 (25 X 10(9)/1) and a high risk group with an initial WBC count greater than 25 000/mm3 (25 X 10(9)/1). Of the 30 children entered in this study one standard risk patient died in the induction phase before attaining remission. Analysis of the results is therefore based on the remaining 29 patients, 22 standard risk and 7 high risk patients, who attained complete remission. Survival rates in continuous remission were found to be 43% of the high risk group, 88% for the standard risk group, and 77% for the combined group. Analysis of the data indicates that this therapy is unsatisfactory in high risk ALL. The results to date of this therapy for standard risk are sufficiently encouraging to continue its use in this subgroup of patients. PMID:1059384

  15. 6-C-methyl flavonoids isolated from Pinus densata inhibit the proliferation and promote the apoptosis of the HL-60 human promyelocytic leukaemia cell line.

    Science.gov (United States)

    Yue, Rongcai; Li, Bo; Shen, Yunheng; Zeng, Huawu; Li, Bo; Yuan, Hu; He, Yiren; Shan, Lei; Zhang, Weidong

    2013-08-01

    Three structurally related 6-C-methyl flavonoids isolated from Pinus densata, including 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone (PD1), 5,7,4'-trihydroxy-3,8-dimethoxy-6-C-methylflavone (PD2), and 5,7,4'-trihydroxy-3-methoxy-6-C-methylflavone (PD3), were tested for their ability to inhibit the proliferation and promote the apoptosis of the HL-60 human leukaemia cell line. Cytotoxicity assays in the HL-60 human cancer cell line demonstrated that 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone exhibited the most potent cytotoxicity of the three structurally related 6-C-methyl flavonoids. 5,4'-Dihydroxy-3,7,8-trimethoxy-6-C-methylflavone inhibited the proliferation of HL-60 cells in a dose-dependent manner with an IC₅₀ of 7.91 µM (48 h treatment). Furthermore, 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone-induced apoptosis was associated with mitochondrial membrane disruption and cytochome c release. Flow cytometry analyses revealed an increase in the hypodiploid population in 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone-treated HL-60 cells. Treatment with a concentration of 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone that induced apoptosis activated caspase-3 but did not activate caspase-1. A caspase-3 inhibitor (Ac-DEVD-CHO), but not a caspase-1 inhibitor (Ac-YVAD-CHO), reversed the cytotoxic effects of 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone in HL-60 cells. These data demonstrated that 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone effectively induced the apoptosis of HL-60 cells and exhibited significant anticancer activity via the mitochondrial caspase-3-dependent apoptosis pathway.

  16. Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin.

    Science.gov (United States)

    Ikezoe, Takayuki

    2014-07-01

    Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia characterized by the proliferation of blasts with distinct morphology, a specific balanced reciprocal translocation t(15;17), and life-threatening hemorrhage caused mainly by enhanced fibrinolytic-type disseminated intravascular coagulation (DIC). The introduction of all-trans retinoic acid (ATRA) into anthracycline-based induction chemotherapy regimens has dramatically improved overall survival of individuals with APL, although hemorrhage-related death during the early phase of therapy remains a serious problem. Moreover, population-based studies have shown that the incidence of early death during induction chemotherapy is nearly 30 %, and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required. Recombinant human soluble thrombomodulin (rTM) comprises the active extracellular domain of TM, and has been used for treatment of DIC since 2008 in Japan. Use of rTM in combination with remission induction chemotherapy, including ATRA, produces potent resolution of DIC without exacerbation of bleeding tendency in individuals with APL. This review article discusses the pathogenesis and features of DIC caused by APL, as well as the possible anticoagulant and anti-leukemic action of rTM in APL patients.

  17. [PML-RARα and p21 are key factors for maintaining acute promyelocytic leukemia stem cells survival].

    Science.gov (United States)

    Ding, Fei; Li, Jun-Min

    2011-10-01

    Tumor stem/progenitor cells are the cells with the characteristics of self-renewal, differentiating to all the other cell populations within tumor, which are also regarded as the source of tumor relapse, drug-resistance and metastasis. As a subtype of acute myeloid leukemia, acute promyelocytic leukemia (APL) represents the target of therapy due to the good response of the oncogenic protein PML-RARα to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). This review summarizes the latest research results of APL as follows: (1) there probably are two APL stem/progenitor cell populations within APL, and self-renewal and survival of APL stem/progenitor cells highly depend on PML-RARα expression, cell cycle inhibitor p21, self-renewal associated molecules and chemokines; and (2) ATRA and ATO eradicate APL stem/progenitor cells mainly by PML-RARα degradation, FOXO3A activation and the inhibition of self-renewal-associated signaling pathway of sonic hedgehog. These findings are helpful to improve other tumor therapy.

  18. High-Risk Microgranular Acute Promyelocytic Leukemia with a Five-Way Complex Translocation Involving PML-RARA

    Directory of Open Access Journals (Sweden)

    Benjamin Powers

    2015-01-01

    Full Text Available Acute promyelocytic leukemia (APL is classically characterized by chromosomal translocation (15;17, resulting in the PML-RARA fusion protein leading to disease. Here, we present a case of a 50-year-old man who presented with signs and symptoms of acute leukemia with concern for APL. Therapy was immediately initiated with all-trans retinoic acid. The morphology of his leukemic blasts was consistent with the hypogranular variant of APL. Subsequent FISH and cytogenetic analysis revealed a unique translocation involving five chromosomal regions: 9q34, 17q21, 15q24, 12q13, and 15q26.1. Molecular testing demonstrated PML/RARA fusion transcripts. Treatment with conventional chemotherapy was added and he went into a complete remission. Given his elevated white blood cell count at presentation, intrathecal chemotherapy for central nervous system prophylaxis was also given. The patient remains on maintenance therapy and remains in remission. This is the first such report of a 5-way chromosomal translocation leading to APL. Similar to APL with chromosomal translocations other than classical t(15;17 which result in the typical PML-RARA fusion, our patient responded promptly to an ATRA-containing regimen and remains in complete remission.

  19. High-Risk Microgranular Acute Promyelocytic Leukemia with a Five-Way Complex Translocation Involving PML-RARA.

    Science.gov (United States)

    Powers, Benjamin; Persons, Diane; Rao, Deepthi; Woodroof, Janet; Lin, Tara L

    2015-01-01

    Acute promyelocytic leukemia (APL) is classically characterized by chromosomal translocation (15;17), resulting in the PML-RARA fusion protein leading to disease. Here, we present a case of a 50-year-old man who presented with signs and symptoms of acute leukemia with concern for APL. Therapy was immediately initiated with all-trans retinoic acid. The morphology of his leukemic blasts was consistent with the hypogranular variant of APL. Subsequent FISH and cytogenetic analysis revealed a unique translocation involving five chromosomal regions: 9q34, 17q21, 15q24, 12q13, and 15q26.1. Molecular testing demonstrated PML/RARA fusion transcripts. Treatment with conventional chemotherapy was added and he went into a complete remission. Given his elevated white blood cell count at presentation, intrathecal chemotherapy for central nervous system prophylaxis was also given. The patient remains on maintenance therapy and remains in remission. This is the first such report of a 5-way chromosomal translocation leading to APL. Similar to APL with chromosomal translocations other than classical t(15;17) which result in the typical PML-RARA fusion, our patient responded promptly to an ATRA-containing regimen and remains in complete remission.

  20. Development of real-time quantitative polymerase chain reaction assays to track treatment response in retinoid resistant acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    Jelena V Jovanovic

    2011-10-01

    Full Text Available Molecular detection of minimal residual disease (MRD has become established to assess remission status and guide therapy in patients with PML-RARA+ acute promyelocytic leukemia (APL. However, there are few data on tracking disease response in patients with rarer retinoid resistant subtypes of APL, characterized by PLZF-RARA and STAT5b-RARA. Despite their relative rarity (<1% of APL we identified 6 cases (PLZF-RARA, n=5; STAT5b-RARA, n=1, established the respective breakpoint junction regions and designed real-time quantitative polymerase chain reaction (RQ-PCR assays to detect leukemic transcripts. The relative level of fusion gene expression in diagnostic samples was comparable to that observed in t(15;17-associated APL, affording assay sensitivities of ~1 in 104-105. Serial samples were available from 2 PLZF-RARA APL patients. One showed persistent PCR positivity, predicting subsequent relapse, and remains in CR2, ~11 years post-autograft. The other, achieved molecular remission (CRm with combination chemotherapy, remaining in CR1 at 6 years. The STAT5b-RARA patient failed to achieve CRm following frontline combination chemotherapy and ultimately proceeded to allogeneic transplant on the basis of a steadily rising fusion transcript level. These data highlight the potential of RQ-PCR detection of MRD to facilitate development of more individualized approaches to the management of rarer molecularly-defined subsets of acute leukemia.

  1. Heterogeneity in the therapeutic approach to relapsed elderly patients with acute myeloid leukaemia: a survey from the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Acute Leukaemia Working Party.

    Science.gov (United States)

    Ferrara, Felicetto; Fazi, Paola; Venditti, Adriano; Pagano, Livio; Amadori, Sergio; Mandelli, Franco

    2008-06-01

    The percentage of long-term survivors in acute myeloid leukaemia (AML) in the elderly does not exceed 10-15% of patients enrolled into clinical trials because of lower complete remission (CR) rates and higher incidence of relapse. However, few data are available as the treatment of elderly patients with relapsed disease is concerned. The aim of this study was of collecting data on criteria adopted for the treatment of these patients. A questionnaire was e-mailed to 32 haematologic institutions involved in the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) group. Questions to be addressed regarded: (1) per cent of relapsed elderly patients treated with aggressive salvage chemotherapy; (2) the selection criteria adopted for inclusion into intensive reinduction; (3) the specific treatment adopted; (4) the treatment given to patients not eligible for intensive salvage. Per cent of patients enrolled into aggressive salvage regimens varied from 10 to 80% (median 50%). The most frequent factor influencing the therapeutic choice was performance status (97%). Additional factors were age >70 years (44%) and duration of first CR (53%). Fludarabine including regimens were most frequently used as aggressive salvage therapy (59%), while gemtuzumab ozogamicin was adopted in various combinations at 11 out of 32 institutions (34%). For patients not eligible to aggressive therapy, the most frequent approach included hydroxyurea (59%). Low dose ARA-C (LDARA-C) was adopted at five centres: as single agent (n = 1), with 6-thioguanine (n = 1), with vitamin D3 and all-trans retinoic acid (ATRA) (n = 2), or with ATRA alone (n = 1). The FLT3 inhibitor CEP-701 was used at one centre. We conclude that the treatment of AML in elderly relapsed patients is extremely heterogeneous. A marked selection is operated as to inclusion into aggressive salvage regimens and only a small minority of patients are offered experimental approaches.

  2. Whole-Exome Sequencing of ETV6/RUNX1 in Four Childhood Acute Lymphoblastic Leukaemia Cases

    Science.gov (United States)

    Zakaria, Zubaidah; Othman, Norodiyah; Ismail, Azli; Kamaluddin, Nor Rizan; Esa, Ezalia; Abdul Rahman, Eni Juraida; Mat Yusoff, Yuslina; Mohd Fauzi, Fazlin; Sew Keoh, Ten

    2017-04-01

    Background: ETV6/RUNX1 gene fusion is the most frequently seen chromosomal abnormality in childhood acute lymphobastic leukamia (ALL). However, additional genetic changes are known to be required for the development of this type of leukaemia. Therefore, we here aimed to assess the somatic mutational profile of four ALL cases carrying the ETV6/RUNX1 fusion gene using whole-exome sequencing. Methods: DNA was isolated from bone marrow samples using a QIAmp DNA Blood Mini kit and subsequently sequenced using the Illumina MiSeq system. Results: We identified 12,960 to17,601 mutations in each sample, with a total of 16,466 somatic mutations in total. Some 15,533 variants were single nucleotide polymorphisms (SNPs), 129 were substitutions, 415 were insertions and 389 were deletions. When taking into account the coding region and protein impact, 1,875 variants were synonymous and 1,956 were non-synonymous SNPs. Among non-synonymous SNPs, 1,862 were missense, 13 nonsense, 35 frameshifts, 11 nonstop, 3 misstart, 15 splices disrupt and 17 in-frame indels. A total of 86 variants were located in leukaemia-related genes of which 32 variants were located in the coding regions of GLI2, SP140, GATA2, SMAD5, KMT2C, CDH17, CDX2, FLT3, PML and MOV10L1. Conclusions: Detection and identification of secondary genetic alterations are important in identifying new therapeutic targets and developing rationally designed treatment regimens with less toxicity in ALL patients. Creative Commons Attribution License

  3. A 17-gene stemness score for rapid determination of risk in acute leukaemia.

    Science.gov (United States)

    Ng, Stanley W K; Mitchell, Amanda; Kennedy, James A; Chen, Weihsu C; McLeod, Jessica; Ibrahimova, Narmin; Arruda, Andrea; Popescu, Andreea; Gupta, Vikas; Schimmer, Aaron D; Schuh, Andre C; Yee, Karen W; Bullinger, Lars; Herold, Tobias; Görlich, Dennis; Büchner, Thomas; Hiddemann, Wolfgang; Berdel, Wolfgang E; Wörmann, Bernhard; Cheok, Meyling; Preudhomme, Claude; Dombret, Herve; Metzeler, Klaus; Buske, Christian; Löwenberg, Bob; Valk, Peter J M; Zandstra, Peter W; Minden, Mark D; Dick, John E; Wang, Jean C Y

    2016-12-15

    Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors. There is an urgent need for better biomarkers to identify these high-risk patients before starting induction chemotherapy, to enable testing of alternative induction strategies in clinical trials. The high rate of relapse in AML has been attributed to the persistence of leukaemia stem cells (LSCs), which possess a number of stem cell properties, including quiescence, that are linked to therapy resistance. Here, to develop predictive and/or prognostic biomarkers related to stemness, we generated a list of genes that are differentially expressed between 138 LSC(+) and 89 LSC(-) cell fractions from 78 AML patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, we performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score (LSC17). The LSC17 score was highly prognostic in five independent cohorts comprising patients of diverse AML subtypes (n = 908) and contributed greatly to accurate prediction of initial therapy resistance. Patients with high LSC17 scores had poor outcomes with current treatments including allogeneic stem cell transplantation. The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.

  4. TESTIN Induces Rapid Death and Suppresses Proliferation in Childhood B Acute Lymphoblastic Leukaemia Cells.

    Directory of Open Access Journals (Sweden)

    Robert J Weeks

    Full Text Available Childhood acute lymphoblastic leukaemia (ALL is the most common malignancy in children. Despite high cure rates, side effects and late consequences of the intensive treatments are common. Unquestionably, the identification of new therapeutic targets will lead to safer, more effective treatments. We identified TES promoter methylation and transcriptional silencing as a very common molecular abnormality in childhood ALL, irrespective of molecular subtype. The aims of the present study were to demonstrate that TES promoter methylation is aberrant, to determine the effects of TES re-expression in ALL, and to determine if those effects are mediated via TP53 activity.Normal fetal and adult tissue DNA was isolated and TES promoter methylation determined by Sequenom MassARRAY. Quantitative RT-PCR and immunoblot were used to confirm re-expression of TES in ALL cell lines after 5'-aza-2'-deoxycytidine (decitabine exposure or transfection with TES expression plasmids. The effects of TES re-expression on ALL cells were investigated using standard cell proliferation, cell death and cell cycle assays.In this study, we confirm that the TES promoter is unmethylated in normal adult and fetal tissues. We report that decitabine treatment of ALL cell lines results in demethylation of the TES promoter and attendant expression of TES mRNA. Re-expression of TESTIN protein in ALL cells using expression plasmid transfection results in rapid cell death or cell cycle arrest independent of TP53 activity.These results suggest that TES is aberrantly methylated in ALL and that re-expression of TESTIN has anti-leukaemia effects which point to novel therapeutic opportunities for childhood ALL.

  5. A new three-way variant t(15;22;17)(q22;q11.2;q21) in acute promyelocytic leukemia.

    Science.gov (United States)

    Kato, Takayasu; Hangaishi, Akira; Ichikawa, Motoshi; Motokura, Toru; Takahashi, Tsuyoshi; Kurokawa, Mineo

    2009-03-01

    Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q21), which results in the fusion of the promyelocytic leukemia (PML) gene at 15q22 with the retinoic acid alpha-receptor (RARA) at 17q21. We report the case of a 44-year-old man with APL carrying a new complex variant translocation (15;22;17). Karyotypic analysis with G-banding of bone marrow cells revealed t(15;22;17) (q22;q11.2;q21). Fluorescence in situ hybridization with a PML/RARA dual-color DNA probe showed the fusion signals. RT-PCR analysis showed long-form PML/RARA fusion transcripts. A complete remission was attained with a course of conventional chemotherapy with all-trans retinoic acid (ATRA). This is the first report of a new three-way translocation of 22q11 involvement with APL.

  6. Activity of Bruton's tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells.

    Science.gov (United States)

    Rushworth, Stuart A; Pillinger, Genevra; Abdul-Aziz, Amina; Piddock, Rachel; Shafat, Manar S; Murray, Megan Y; Zaitseva, Lyubov; Lawes, Matthew J; MacEwan, David J; Bowles, Kristian M

    2015-05-01

    Roughly 80% of patients with acute myeloid leukaemia have high activity of Bruton's tyrosine-kinase (BTK) in their blast cells compared with normal haemopoietic cells, rendering the cells sensitive to the oral BTK inhibitor ibrutinib in vitro. We aimed to develop the biological understanding of the BTK pathway in acute myeloid leukaemia to identify clinically relevant diagnostic information that might define a subset of patients that should respond to ibrutinib treatment. We obtained acute myeloid leukaemia blast cells from unselected patients attending our UK hospital between Feb 19, 2010, and Jan 20, 2014. We isolated primary acute myeloid leukaemia blast cells from heparinised blood and human peripheral blood mononuclear cells to establish the activity of BTK in response to CD117 activation. Furthermore, we investigated the effects of ibrutinib on CD117-induced BTK activation, downstream signalling, adhesion to primary bone-marrow mesenchymal stromal cells, and proliferation of primary acute myeloid leukaemia blast cells. We used the Mann-Whitney U test to compare results between groups. We obtained acute myeloid leukaemia blast cells from 29 patients. Ibrutinib significantly inhibited CD117-mediated proliferation of primary acute myeloid leukaemia blast cells (p=0·028). CD117 activation increased BTK activity by inducing phosphorylated BTK in patients with CD117-positive acute myeloid leukaemia. Furthermore, ibrutinib inhibited CD117-induced activity of BTK and downstream kinases at a concentration of 100 nM or more. CD117-mediated adhesion of CD117-expressing blast cells to bone-marrow stromal cells was significantly inhibited by Ibrutinib at 500 nM (p=0·028) INTERPRETATION: As first-in-man clinical trials of ibrutinib in patients with acute myeloid leukaemia commence, the data suggest not all patients will respond. Our findings show that BTK has specific pro-tumoural biological actions downstream of surface CD117 activation, which are inhibited by ibrutinib

  7. The effect of dietary intake changes on nutritional status in acute leukaemia patients after first induction chemotherapy.

    Science.gov (United States)

    Malihi, Z; Kandiah, M; Chan, Y M; Esfandbod, M; Vakili, M; Hosseinzadeh, M; Zarif Yeganeh, M

    2015-07-01

    This study aimed to evaluate how changes in dietary intake among acute lymphoblastic and acute myeloid leukaemia (ALL and AML) patients affect nutritional status after the first induction chemotherapy. Dietary intake was assessed using 24-h recall and a 136-item food frequency questionnaire. Nutritional status was assessed by Patients Subjective Global Assessment questionnaire before starting induction therapy and again after 1 month. All newly diagnosed acute leukaemia patients aged 15 years old and older who attended three referral hospitals for initiation of their induction chemotherapy were included in the sample selection provided that they gave informed consent. A total of 30 AML and 33 ALL patients participated in the study. Dietary intake and nutritional status worsened after the chemotherapy treatment. Dietary intake in terms of macronutrients, micronutrients, food variety and diet diversity score changed significantly after the induction chemotherapy. No significant relationship was found between the changes in dietary indices and nutritional status. Chemotherapy-related side effects as an additional factor to cancer itself could affect dietary intake of leukaemia patients. The effectiveness of an early assessment of nutritional status and dietary intake should be further investigated in order to deter further deterioration. © 2014 The Authors. European Journal of Cancer Care Published by John Wiley & Sons Ltd.

  8. Radioimmunotherapy for treatment of acute myeloid leukaemia and myelodysplastic syndrome. Conceptual chances

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    Buchmann, I.; Helisch, A.; Bartenstein, P. [Klinik und Poliklinik fuer Nuklearmedizin, Universitaetsklinikum Mainz (Germany); Meyer, R.G.; Herr, W. [III. Medizinische Klinik und Poliklinik (Haematologie), Universitaetsklinikum Mainz (Germany)

    2005-07-01

    The prognosis of patients with acute myeloid leukaemia (AML) has improved considerably by introduction of aggressive consolidation chemotherapy and haematopoietic stem cell transplantation (SCT). Nevertheless, only 20-30% of patients with AML achieve long-term disease-free survival after SCT. The most common cause of treatment failure is relapse. Additionally, mortality rates are significantly increased by therapy-related causes such as toxicity of chemotherapy and complications of SCT. Including radioimmunotherapies in the treatment of AML and myelodyplastic syndrome (MDS) allows for the achievement of a pronounced antileukaemic effect for the reduction of relapse rates on the one hand. On the other hand, no increase of acute toxicity and later complications should be induced. These effects are important for the primary reduction of tumour cells as well as for the myelblative conditioning before SCT. This paper provides a systematic and critical review of the currently used radionuclides and immunoconjugates for the treatment of AML and MDS and summarizes the literature on primary tumour cell reductive radioimmunotherapies on the one hand and conditioning radioimmunotherapies before SCT on the other hand. (orig.)

  9. Rationale and efficacy of proteasome inhibitor combined with arsenic trioxide in the treatment of acute promyelocytic leukemia

    Science.gov (United States)

    Ganesan, S; Alex, A A; Chendamarai, E; Balasundaram, N; Palani, H K; David, S; Kulkarni, U; Aiyaz, M; Mugasimangalam, R; Korula, A; Abraham, A; Srivastava, A; Padua, R A; Chomienne, C; George, B; Balasubramanian, P; Mathews, V

    2016-01-01

    Arsenic trioxide (ATO) mediates PML-RARA (promyelocytic leukemia–retinoic acid receptor-α) oncoprotein degradation via the proteasome pathway and this degradation appears to be critical for achieving cure in acute promyeloytic leukemia (APL). We have previously demonstrated significant micro-environment-mediated drug resistance (EMDR) to ATO in APL. Here we demonstrate that this EMDR could be effectively overcome by combining a proteasome inhibitor (bortezomib) with ATO. A synergistic effect on combining these two agents in vitro was noted in both ATO-sensitive and ATO-resistant APL cell lines. The mechanism of this synergy involved downregulation of the nuclear factor-κB pathway, increase in unfolded protein response (UPR) and an increase in reactive oxygen species generation in the malignant cell. We also noted that PML-RARA oncoprotein is effectively cleared with this combination in spite of proteasome inhibition by bortezomib, and that this clearance is mediated through a p62-dependent autophagy pathway. We further demonstrated that proteasome inhibition along with ATO had an additive effect in inducing autophagy. The beneficial effect of this combination was further validated in an animal model and in an on-going clinical trial. This study raises the potential of a non-myelotoxic proteasome inhibitor replacing anthracyclines in the management of high-risk and relapsed APL. PMID:27560113

  10. Acute promyelocytic leukemia with cryptic t(15;17) on isochromosome 17: a case report and review of literature.

    Science.gov (United States)

    Tang, Yuting; Wang, Ying; Hu, Liang; Meng, Fankai; Xu, Danmei; Wan, Kai; Huang, Lifang; Li, Chunrui; Zhou, Jianfeng

    2015-01-01

    Acute Promyelocytic Leukemia (APL) is one of the most curable leukemia which shows great sensitivity to all-trans retinoic acid (ATRA) although a small number of the patients present poor prognosis and short survival. Isochromosome 17 in APL which usually bears an additional copy of RARA/PML fusion gene is considered to be a negative factor on its prognosis. Cryptic t(15;17) on i(17q) leads to an extra copy of PML/RARA rather than RARA/PML which may confer a worse prognosis. We describe here a rare APL case with complex chromosomal abnormality including isochromosome 17 bearing cryptic t(15;17) showing poor outcome. The patient lacks a classic t(15;17) and fluorescence in situ hybridization (FISH) presents 2 PML/RARA fusion signals on both long arms of the isochromosome. The patient also acquired a secondary mutation at relapse when the initial karyotype was already a complex karyotype involving chromosome 13, 17 and 22 at the same time. The poor response of this patient to traditional chemotherapy like ATRA and novel therapy like arsenic trioxide (ATO) suggests that early auto-hematological stem cell transplantation may be the choice of APL with isochromosome 17 especially with cryptic t(15;17) on i(17q). We are the first to show a clear history and evidence of FISH of these kind of cases. A small summary of cases with cryptic t(15;17) on isochromosome 17 is also made.

  11. The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.

    Directory of Open Access Journals (Sweden)

    Mariam Ibáñez

    Full Text Available Preliminary Acute Promyelocytic Leukemia (APL whole exome sequencing (WES studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11 with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

  12. Metabolomics profiles delineate uridine deficiency contributes to mitochondria-mediated apoptosis induced by celastrol in human acute promyelocytic leukemia cells

    Science.gov (United States)

    Li, Lei; Huan, Fei; Li, Aiping; Liu, Yanqing; Xia, Yankai; Duan, Jin-ao; Ma, Shiping

    2016-01-01

    Celastrol, extracted from “Thunder of God Vine”, is a promising anti-cancer natural product. However, its effect on acute promyelocytic leukemia (APL) and underlying molecular mechanism are poorly understood. The purpose of this study was to explore its effect on APL and underlying mechanism based on metabolomics. Firstly, multiple assays indicated that celastrol could induce apoptosis of APL cells via p53-activated mitochondrial pathway. Secondly, unbiased metabolomics revealed that uridine was the most notable changed metabolite. Further study verified that uridine could reverse the apoptosis induced by celastrol. The decreased uridine was caused by suppressing the expression of gene encoding Dihydroorotate dehydrogenase, whose inhibitor could also induce apoptosis of APL cells. At last, mouse model confirmed that celastrol inhibited tumor growth through enhanced apoptosis. Celastrol could also decrease uridine and DHODH protein level in tumor tissues. Our in vivo study also indicated that celastrol had no systemic toxicity at pharmacological dose (2 mg/kg, i.p., 21 days). Altogether, our metabolomics study firstly reveals that uridine deficiency contributes to mitochondrial apoptosis induced by celastrol in APL cells. Celastrol shows great potential for the treatment of APL. PMID:27374097

  13. Prognostic factors of patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide-based frontline therapy.

    Science.gov (United States)

    Lou, Yinjun; Ma, Yafang; Suo, Shanshan; Ni, Wanmao; Wang, Yungui; Pan, Hanzhang; Tong, Hongyan; Qian, Wenbin; Meng, Haitao; Mai, Wenyuan; Huang, Jian; Yu, Wenjuan; Wei, Juyin; Mao, Liping; Jin, Jie

    2015-09-01

    Prognostic factors for patients with acute promyelocytic leukemia (APL) treated in the context of arsenic trioxide (ATO)-based frontline regimes have not been established clearly. We retrospectively analyzed the clinical features, immunophenotypes, Fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD), and outcomes of 184 consecutive newly diagnosed APL patients treated by intravenous ATO-based therapy. The median age was 40 years (14-77 years). The early death rate was 4.9% (9/184 patients). With a median follow-up time of 36 months (9-74 months), the 3-year relapse-free survival (RFS) and overall survival (OS) were 93.3% and 92.2%, respectively. Interestingly, there was no meaningful association between 3-year RFS and initial white blood cell count, FLT3-ITD status, or type of PML-RARA isoforms. In multivariable analysis, the CD56 expression was the only independent risk factor in terms of RFS (hazard ratio, 4.70; P=0.005). These results suggested that ATO-based therapy may ameliorate the unfavorable influence of previously known high-risk features; moreover, CD56 expression remains to be a potentially unfavorable prognostic factor in APL patients.

  14. Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases.

    Science.gov (United States)

    Gianni, M; Ponzanelli, I; Mologni, L; Reichert, U; Rambaldi, A; Terao, M; Garattini, E

    2000-05-01

    In the NB4 model of acute promyelocytic leukemia (APL), ATRA, 9-cis retinoic acid (9-cis RA), the pan-RAR and RARalpha-selective agonists, TTNPB and AM580, induce growth inhibition, granulocytic differentiation and apoptosis. By contrast, two RXR agonists, a RARbeta agonist and an anti-AP1 retinoid have very limited activity, ATRA- and AM580-dependent effects are completely inhibited by RAR antagonistic blockade, while 9-cis RA-induced cell-growth-inhibition and apoptosis are equally inhibited by RAR and RXR antagonists. ATRA, 9-cis RA and AM580 cause upregulation of the mRNAs coding for pro-caspase-1, -7, -8, and -9, which, however, results in increased synthesis of only pro-caspase-1 and -7 proteins. These phenomena are associated with activation of pro-caspase-6, -7 and -8, cytochrome c release from the mitochondria, inversion of Bcl-2/Bax ratio and degradation of PML-RARalpha. Caspase activation is fundamental for retinoid-induced apoptosis, which is suppressed by the caspase-inhibitor z-VAD.

  15. The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.

    Science.gov (United States)

    Ibáñez, Mariam; Carbonell-Caballero, José; García-Alonso, Luz; Such, Esperanza; Jiménez-Almazán, Jorge; Vidal, Enrique; Barragán, Eva; López-Pavía, María; LLop, Marta; Martín, Iván; Gómez-Seguí, Inés; Montesinos, Pau; Sanz, Miguel A; Dopazo, Joaquín; Cervera, José

    2016-01-01

    Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

  16. New strategies in acute promyelocytic leukemia: moving to an entirely oral, chemotherapy-free upfront management approach.

    Science.gov (United States)

    Zeidan, Amer M; Gore, Steven D

    2014-10-01

    Incorporation of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) into the management paradigms of acute promyelocytic leukemia (APL) has markedly improved outcomes. Significant progress occurred in understanding the molecular pathogenesis of APL. ATO, in contrast with ATRA, is capable of eradicating the APL-initiating cells and can result in cure. Preclinical and clinical data confirmed the synergy of ATO and ATRA, and the ATRA-ATO combination was proved noninferior to a standard ATRA-chemotherapy regimen in patients with non-high-risk APL. Oral formulations of arsenic exhibited excellent activity in advanced clinical testing and their combinations with ATRA offer an opportunity for a completely oral, chemotherapy-free regimen for curing APL. Nonetheless, significant challenges remain. Reducing early death due to bleeding complications is an important area of unmet need. Data suggest that delays in initiation of ATRA upon suspecting APL continue to occur in the community and contribute to early mortality. Questions remain about the optimal place and schedule of arsenic in the therapeutic sequence and the role of the oral formulations. Refining the role of minimal residual disease in directing treatment decisions is important. Development of novel targeted agents to treat relapsed disease requires deeper understanding of the secondary resistance mechanisms to ATRA and ATO. ©2014 American Association for Cancer Research.

  17. Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study.

    Science.gov (United States)

    Lucena-Araujo, Antonio R; Kim, Haesook T; Jacomo, Rafael H; Melo, Raul A; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Fagundes, Evandro M; Chauffaille, Maria de Lourdes; Chiattone, Carlos S; Lima, Ana Silvia; Ruiz-Argüelles, Guillermo; Undurraga, Maria Soledad; Martinez, Lem; Kwaan, Hau C; Gallagher, Robert; Niemeyer, Charlotte M; Schrier, Stanley L; Tallman, Martin S; Grimwade, David; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C; Lo-Coco, Francesco; Löwenberg, Bob; Sanz, Miguel A; Rego, Eduardo M

    2014-12-01

    Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITD(positive) patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD(negative) patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.

  18. Acute lymphoblastic leukaemia after treatment of nephrotic syndrome with immunosuppressive drugs.

    Science.gov (United States)

    Kuis, W; de Kraker, J; Kuijten, R H; Donckerwolcke, R A; Voûte, P A

    1976-06-01

    The authors present a 4-year-old girl with nephrotic syndrome who developed actue lymphoblastic leukaemia 5 months after the start of a combined treatment of alternate day prednisone and daily cyclophosphamide during 3 months. The nephrotic syndrome was due to focal segmental glomerulosclerosis. The occurrence of leukaemia might be related to the preceeding treatment with cyclophosphamide.

  19. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry.

    Science.gov (United States)

    Lehmann, S; Ravn, A; Carlsson, L; Antunovic, P; Deneberg, S; Möllgård, L; Derolf, A Rangert; Stockelberg, D; Tidefelt, U; Wahlin, A; Wennström, L; Höglund, M; Juliusson, G

    2011-07-01

    Our knowledge about acute promyelocytic leukemia (APL) patients is mainly based on data from clinical trials, whereas population-based information is scarce. We studied APL patients diagnosed between 1997 and 2006 in the population-based Swedish Adult Acute Leukemia Registry. Of a total of 3897 acute leukemia cases, 3205 (82%) had non-APL acute myeloid leukemia (AML) and 105 (2.7%) had APL. The incidence of APL was 0.145 per 100,000 inhabitants per year. The median age at the time of diagnosis was 54 years; 62% were female and 38% male. Among younger APL patients, female sex predominated (89% of patients <40 years). Of the 105 APL patients, 30 (29%) died within 30 days (that is, early death (ED)) (median 4 days) and 28 (26%) within 14 days from diagnosis. In all, 41% of the EDs were due to hemorrhage; 35% of ED patients never received all-trans-retinoic acid treatment. ED rates increased with age but more clearly with poor performance status. ED was also associated with high white blood cells, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count. Of non-ED patients, 97% achieved complete remission of which 16% subsequently relapsed. In total, 62% are still alive at 6.4 years median follow-up. We conclude that ED rates remain very high in an unselected APL population.

  20. Pharm GKB: Leukemia, Myeloid, Acute [PharmGKB

    Lifescience Database Archive (English)

    Full Text Available Amino Acid Translations are all sourced from dbSNP 144 Overview Alternate Names: Synonym AML - Acute... myeloblastic leukaemia; Acute Myeloblastic Leukemia; Acute Myeloblastic Leukemias; Acute... Myelocytic Leukemia; Acute Myelocytic Leukemias; Acute Myelogenous Leukemia; Acute Myelogenous Leukemias; Acute... granulocytic leukaemia; Acute myeloblastic leukemia; Acute myeloid leukaemia; Acute myeloid leukaemia - category; Acute... myeloid leukaemia, disease; Acute myeloid leukemia; Acute myelo

  1. PERCENTAGE OF CIPROFLOXACIN-RESISTANT STRAINS OF CITROBACTER FREUNDII IN ACUTE LEUKAEMIA PATIENTS WITH CIPROFLOXACIN PROPHYLAXIS

    Directory of Open Access Journals (Sweden)

    Rika Strauch

    2004-12-01

    Full Text Available Background. Authors tried to determine an efficiency of ciprofloxacin as infection prophylaxis in patients with acute leukaemia treated at the Department of Haematology in Clinical Center of Ljubljana. Due to cytotoxic chemotherapy, aplasia of bone marrow is inevitable. Therefore, these patients are at high risk for bacterial and fungal infection. The authors have noticed a rise in the number of ciprofloxacin-resistant strains of Citrobacter freundii and decided to find out if ciprofloxacin is still usable in this setting.Patients and methods. 45 patients with acute leukaemia were admitted to the Department of Haematology in the Clinical Center of Ljubljana during the year 2001 and 2002. All the patients received ciprofloxacin 2 × 500 mg on a daily basis. Citrobacter freundii was isolated in 11 patients, to whom we determined the proportion of ciprofloxacin-resistant strains of Citrobacter freundii and other Enterobacteriaceae. Susceptibility testing was done by the NCCCLS standards by the disc diffusion method and minimal inhibitory concentration.Results. C. freundii was isolated in 11 patients with AL. Extended-spectrum beta-lactamases (ESBL C. freundii was isolated in 6 patients (54.5%. Ciprofloxacin-resistant C. freundii was isolated in 6 patients (54.5%. Six patients (54.5% had ciprofloxacin-resistant C. freundii which was ESBL positive at the same time. In AL patients with C. freundii (n = 11 almost half of isolated bacteria were Gram negative bacilli (45.2%, n = 292, mostly from the family of Enterobacteriaceae. More than half of enterobacteria were ciprofloxacin-resistant, one third of them were also ESBL positive. Out of 131 enterobacteria, C. freundii was isolated 37 times. (28.2%.Conclusions. C. freundii was isolated in one fourth of AL patients. Half of the isolates were ciprofloxacin-resistant. The same was true for isolated enterobacteria. Almost all of ciprofloxacin-resistant bacteria were ESBL positive. There is a question

  2. The detection and classification of blast cell in Leukaemia Acute Promyelocytic Leukaemia (AML M3) blood using simulated annealing and neural networks

    OpenAIRE

    W. Ismail; Hassan, R.; PAYNE, A.; Swift, S

    2011-01-01

    This paper was delivered at AIME 2011: 13th Conference on Artifical Intelligence in Medicine. This paper presents a method for the detection and classification of blast cells in M3 with others sub-types using simulated annealing and neural networks. In this paper, we increased our test result from 10 images to 20 images. We performed Hill Climbing, Simulated Annealing and Genetic Algorithms for detecting the blast cells. As a result, simulated annealing is the “best” heuristic search for d...

  3. Anti-leukemic effects of HDACi Belinostat and HMTi 3-Deazaneplanocin A on human acute promyelocytic leukemia cells.

    Science.gov (United States)

    Valiulienė, Giedrė; Stirblytė, Ieva; Jasnauskaitė, Monika; Borutinskaitė, Veronika; Navakauskienė, Rūta

    2017-03-15

    Development of acute myeloid leukemia is usually sustained by deregulated epigenome. Alterations in DNA methylation and histone modifications are common manifestations of the disease. Acute promyelocytic leukemia (APL) is not an exception. Therefore, drugs that target epigenetic processes suggest an appealing strategy for APL treatment. In this study we tested the anti-leukemic activity of histone deacetylase inhibitor (HDACi) Belinostat (PXD101, (2E)-N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide), and histone methyltransferase inhibitor (HMTi) 3-Deazaneplanocin A (DZNep, 5R-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)-3-cyclopentene-1S,2R-diol) combined with retinoic acid (RA) in APL cells NB4 and HL-60. We demonstrated that APL cell treatment with combinations of differentiation inductor RA, HDACi Belinostat and HMTi DZNep caused a depletion of leukemia cell growth and viability, initiated apoptosis and exaggerated RA induced granulocytic differentiation. Also an increased expression of transcription factors C/EBPε and PPARγ was demonstrated, while no significant reduction in C/EBPα gene level was detected. Furthermore, combined treatment depleted gene expression levels of EZH2 and SUZ12, especially in HL-60 cells, and diminished protein levels of Polycomb Repressive Complex 2 (PRC2) components EZH2, SUZ12 and EED. In addition, our study has shown that Belinostat and DZNep together with RA caused a depletion in HDAC1 and HDAC2 protein levels, HDAC2 gene expression and increased hyperacetylation of histone H4 in both leukemia cell lines. Using ChIP method we also demonstrated the increased association of hyperacetylated histone H4 with the C/EBPα and C/EBPε promoter regions in HL-60 cells. Summarizing, these findings indicate that combined treatment with RA, Belinostat and 3-Deazaneplanocin A is an effective epigenetic inducer for leukemia cell differentiation.

  4. Management of adult and paediatric acute lymphoblastic leukaemia in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013.

    Science.gov (United States)

    Yeoh, Allen E J; Tan, Daryl; Li, Chi-Kong; Hori, Hiroki; Tse, Eric; Pui, Ching-Hon

    2013-11-01

    Survival for adults and children with acute lymphoblastic leukaemia has risen substantially in recent years because use of improved risk-directed treatments and supportive care has widened. In nearly all developed countries, multidisciplinary panels of leukaemia experts have formulated clinical practice guidelines in which standard treatment approaches are recommended on the basis of current evidence. However, those guidelines do not take into account resource limitations in low-income countries, including financial and technical challenges. In Asia, huge disparities in economy and infrastructure exist between countries, and even among different regions in some large countries. At a consensus session held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand, a panel of experts summarised recommendations for management of adult and paediatric acute lymphoblastic leukaemia. Strategies were developed for Asian countries on the basis of available financial, skill, and logistical resources and were stratified in a four-tier system according to the resources available in a particular country or region (basic, limited, enhanced, and maximum).

  5. Flow cytometric immunobead assay for fast and easy detection of PML-RARA fusion proteins for the diagnosis of acute promyelocytic leukemia.

    Science.gov (United States)

    Dekking, E H A; van der Velden, V H J; Varro, R; Wai, H; Böttcher, S; Kneba, M; Sonneveld, E; Koning, A; Boeckx, N; Van Poecke, N; Lucio, P; Mendonça, A; Sedek, L; Szczepański, T; Kalina, T; Kanderová, V; Hoogeveen, P; Flores-Montero, J; Chillón, M C; Orfao, A; Almeida, J; Evans, P; Cullen, M; Noordijk, A L; Vermeulen, P M; de Man, M T; Dixon, E P; Comans-Bitter, W M; van Dongen, J J M

    2012-09-01

    The PML-RARA fusion protein is found in approximately 97% of patients with acute promyelocytic leukemia (APL). APL can be associated with life-threatening bleeding complications when undiagnosed and not treated expeditiously. The PML-RARA fusion protein arrests maturation of myeloid cells at the promyelocytic stage, leading to the accumulation of neoplastic promyelocytes. Complete remission can be obtained by treatment with all-trans-retinoic acid (ATRA) in combination with chemotherapy. Diagnosis of APL is based on the detection of t(15;17) by karyotyping, fluorescence in situ hybridization or PCR. These techniques are laborious and demand specialized laboratories. We developed a fast (performed within 4-5 h) and sensitive (detection of at least 10% malignant cells in normal background) flow cytometric immunobead assay for the detection of PML-RARA fusion proteins in cell lysates using a bead-bound anti-RARA capture antibody and a phycoerythrin-conjugated anti-PML detection antibody. Testing of 163 newly diagnosed patients (including 46 APL cases) with the PML-RARA immunobead assay showed full concordance with the PML-RARA PCR results. As the applied antibodies recognize outer domains of the fusion protein, the assay appeared to work independently of the PML gene break point region. Importantly, the assay can be used in parallel with routine immunophenotyping for fast and easy diagnosis of APL.

  6. Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): A case report and review of the literature

    Science.gov (United States)

    GUAN, HONGZAI; LIU, JING; GUO, XIAOFANG; WU, CHUNMEI; YU, HUAWEI

    2015-01-01

    Acute promyelocytic leukemia (APL) with variant translocations is rare. The patient of the present case report, a 2-year-old male with a microgranular variant of APL carrying der(17) ins(17;15) translocation, exhibited fever and epistaxis. The complete blood count showed marked leukocytosis with 72% atypical promyelocytes, anemia and thrombocytopenia. Conventional cytogenetic analysis of the bone marrow cells revealed a karyotype of 47, XY, add(3)(q29), −7, ins(17;15)(q12;q14q22),+21,+mar. The promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement and insertion were confirmed by fluorescence in situ hybridization. The PML/RARα transcripts were not detected by the reverse transcription polymerase chain reaction, and the patient was diagnosed with microgranular variant M3 APL. The patient achieved remission after a 30-day treatment and was still in remission during a recent follow-up. The present findings suggest that the ins(17;15) variant in APL may not be associated with an unfavorable prognosis. In summary, we reported an extremely rare case of APL with der(17) ins(17;15) abnormality in a pediatric patient and reviewed the literature. PMID:26622430

  7. A Fatal Case of Acute Myeloid Leukaemia-Methotrexate Related or Primary Autoimmune Disease Related: A Rare Case Report.

    Science.gov (United States)

    Agarwal, Saurabh; Kaeley, Nidhi; Gupta, Priyanka; Gupta, Vibha; Bhatia, Rohan

    2016-03-01

    Methotrexate is being used for many years in the treatment of chronic medical disorders e.g. rheumatoid arthritis since 1951. It has been associated with various systemic toxicities and complications including bone marrow suppression and lymphomas. The development of leukaemia in a patient of chronic rheumatoid arthritis is either related with the primary disease or due to the drugs which are used in the treatment like cyclophosphamide. In our present case, a 70-year-old female who was a known case of Rheumatoid Arthritis (RA) and was on methotrexate once a week orally for the past 20 years presented with complaints of loss of appetite, loss of weight and anaemia since 2 months. After thorough examination and investigation, she was diagnosed with acute myeloid leukaemia (AML-M4) with bilateral chest consolidation.

  8. Serum posaconazole levels during acute myeloid leukaemia induction therapy: correlations with breakthrough invasive fungal infections.

    Science.gov (United States)

    Cattaneo, Chiara; Panzali, Annafranca; Passi, Angela; Borlenghi, Erika; Lamorgese, Cinzia; Petullà, Marta; Re, Alessandro; Caimi, Luigi; Rossi, Giuseppe

    2015-06-01

    The usefulness of posaconazole therapeutic drug monitoring (TDM) is still a matter of debate. A correlation between posaconazole serum levels and breakthrough invasive fungal infections (IFI) has not been clearly demonstrated so far. We analysed posaconazole serum levels in patients with acute myeloid leukaemia (AML) during induction therapy and correlated them with the incidence of breakthrough IFI and the need of systemic antifungal therapy. Overall, 77 AML patients receiving posaconazole were evaluated for serum levels; breakthrough IFI were observed in five with at least one posaconazole TDM (6.5%). Median serum level was 534 ng ml(-1) (IQ range: 298.5-750.5 ng ml(-1) ) and did not change significantly over time. Four of the 40 patients with median posaconazole levels posaconazole levels on day 7 were 384.5 ng ml(-1) (IQ range: 207-659 ng ml(-1) ) and 560.5 ng ml(-1) (IQ range: 395-756 ng ml(-1) ) in patients requiring or not systemic antifungal treatment respectively (P = 0.067). These results seem to confirm that higher median serum levels of posaconazole correlate with higher prophylactic efficacy against proven/probable IFI and with lesser need of systemic antifungal therapy.

  9. Modelling the mechanism of GR/c-Jun/Erg crosstalk in apoptosis of acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Daphne eChen

    2012-11-01

    Full Text Available Acute lymphoblastic leukaemia (ALL is one of the most common forms of malignancy that occurs in lymphoid progenitor cells, particularly in children. Synthetic steroid hormones glucocorticoids (GCs are widely used as part of the ALL treatment regimens due to their apoptotic function, but their use also brings about various side effects and drug resistance. The identification of the molecular differences between the GCs responsive and resistant cells therefore are essential to decipher such complexity and can be used to improve therapy. However, the emerging picture is complicated as the activities of genes and proteins involved are controlled by multiple factors. By adapting the systems biology framework to address this issue, we here integrated the available knowledge together with experimental data via the building of a series of mathematical models. This rationale enabled us to unravel molecular interactions involving c-Jun in GC induced apoptosis and identify Erg as determinant for GC resistance. The results revealed an alternative potential mechanism where c-Jun may be an indirect GR target that is controlled via an upstream repressor protein. The models also highlight the importance of Erg for GR function, particularly in GC sensitive C7 cells where Erg directly regulates GR in agreement with our previous experimental results. Our models describe potential GR-controlled molecular mechanisms of c-Jun/Bim and Erg regulation. We also demonstrate the importance of using a systematic approach to translate human disease processes into computational models in order to derive information-driven new hypotheses.

  10. Immunoglobulin genes and T-cell receptors as molecular markers in children with acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Lazić Jelena

    2009-01-01

    Full Text Available Introduction. Acute lymphoblastic leukaemia (ALL is a malignant clonal disease, one of the most common malignancies in childhood. Contemporary protocols ensure high remission rate and long term free survival. The ability of molecular genetic methods help to establish submicroscopic classification and minimal residual disease (MRD follow up, in major percent responsible for relapse. Objective. The aim of the study was to detect the frequency of IgH and TCR gene rearrangements and their correlation with clinical parameters. Methods. Forty-one children with ALL were enrolled in the study group, with initial diagnosis of IgH and TCR gene rearrangements by polimerase chain reaction ( PCR. MRD follow-up was performed in induction phase when morphological remission was expected, and after intensive chemiotherapy. Results. In the study group IgH rearrangement was detected in 82.9% of children at the diagnosis, while TCR rearrangement was seen in 56.1%. On induction day 33, clonal IgH rearrangements persisted in 39% and TCR rearrangements in 36.5% of children. Conclusion. Molecular analysis of genetic alterations and their correlation with standard prognostic parameters show the importance of risk stratification revision which leads to new therapy intensification approach. MRD stands out as a precise predictive factor for the relapse of disease.

  11. First-line treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia in adults.

    Science.gov (United States)

    Ottmann, Oliver G; Pfeifer, Heike

    2009-06-01

    The tyrosine kinase inhibitor (TKI) imatinib has become an integral part of front-line therapy for Philadelphia chromosome-positive acute lymphoblastic leukaemia, with remission rates exceeding 90% irrespective of whether imatinib is given alone or combined with chemotherapy. Treatment outcome with imatinib-based regimens has improved compared with historic controls, but most patients who do not undergo allogeneic stem cell transplantation (SCT) eventually relapse. Second-generation TKI, e.g. dasatinib and nilotinib, show activity against most of the bcr-abl tyrosine kinase domain mutations involved in acquired imatinib resistance, but clinical benefit is generally short lived. Accordingly, SCT in first complete response is considered to be the best curative option. Strategies to improve outcome in patients ineligible for transplantation as well as after SCT include front-line treatment with more effective TKI to increase molecular response rates. Following SCT, the pre-emptive use of imatinib appears to reduce the relapse rate. Novel immunotherapeutic interventions and combinations of TKI are also being explored.

  12. Impact of NOD2 polymorphisms on infectious complications following chemotherapy in patients with acute myeloid leukaemia.

    Science.gov (United States)

    Yomade, Olaposi; Spies-Weisshart, Bärbel; Glaser, Anita; Schnetzke, Ulf; Hochhaus, Andreas; Scholl, Sebastian

    2013-08-01

    We sought to investigate the relationship between polymorphisms of the NOD2 gene and infectious complications following intensive induction chemotherapy in patients with acute myeloid leukaemia (AML). We hypothesised that single nucleotide polymorphisms (SNPs) of the NOD2 gene are associated with a higher rate of infections during the phase of severe neutropenia. In 131 AML patients receiving induction therapy, the presence of the three most frequent polymorphisms of NOD2 (Arg702Trp, Gly908Arg, Leu1007fsinsC) was analysed. SNP analyses by means of genomic PCR incorporating fluorescence-labelled probes with characteristic melting curves were performed using the LightCycler platform. Our data suggest a significantly lower probability of mucositis or enteritis in AML patients lacking any of the three evaluated NOD2 polymorphisms. Furthermore, bloodstream cultures of AML patients carrying either a missense or a frameshift mutation of NOD2 were significantly more frequently tested positive concerning Streptococcus spp. In contrast, the presence of NOD2 polymorphisms had no impact on such important infectious complications as systemic inflammatory response syndrome or sepsis, the rate of central venous catheter infections or the incidence of pneumonia including fungal infections. Our data represent one of the first reports investigating the impact of polymorphisms of the innate immune system on infectious complications in patients with neutropenia following chemotherapy. A correlation between NOD2 polymorphisms and infectious events in AML patients is demonstrated.

  13. Constitutional abnormalities of chromosome 21 predispose to iAMP21-acute lymphoblastic leukaemia.

    Science.gov (United States)

    Harrison, Christine J; Schwab, Claire

    2016-03-01

    In addition to Down syndrome, individuals with other constitutional abnormalities of chromosome 21 have an increased risk of developing childhood acute lymphoblastic leukaemia (ALL). Specifically, carriers of the Robertsonian translocation between chromosomes 15 and 21, rob(15;21) (q10; q10)c, have ∼2,700 increased risk of developing ALL with iAMP21 (intrachromosomal amplification of chromosome 21). In these patients, chromosome 15 as well as chromosome 21 is involved in the formation of iAMP21, referred to here as der(21)(15;21). Individuals with constitutional ring chromosomes involving chromosome 21, r(21)c, are also predisposed to iAMP21-ALL, involving the same series of mutational processes as seen in sporadic- and der(21)(15;21)-iAMP21 ALL. Evidence is accumulating that the dicentric nature of the Robertsonian and ring chromosome is the initiating factor in the formation of the complex iAMP21 structure. Unravelling these intriguing predispositions to iAMP21-ALL may provide insight into how other complex rearrangements arise in cancer.

  14. Mitochondrial cytochrome c oxidase subunit II variations predict adverse prognosis in cytogenetically normal acute myeloid leukaemia.

    Science.gov (United States)

    Silkjaer, Trine; Nyvold, Charlotte Guldborg; Juhl-Christensen, Caroline; Hokland, Peter; Nørgaard, Jan Maxwell

    2013-10-01

    Alterations in the two catalytic genes cytochrome c oxidase subunits I and II (COI and COII) have recently been suggested to have an adverse impact on prognosis in patients with acute myeloid leukaemia (AML). In order to explore this in further detail, we sequenced these two mitochondrial genes in diagnostic bone marrow or blood samples in 235 patients with AML. In 37 (16%) patients, a non-synonymous variation in either COI or COII could be demonstrated. No patients harboured both COI and COII non-synonymous variations. Twenty-four (10%) patients had non-synonymous variations in COI, whereas 13 (6%) patients had non-synonymous variations in COII. The COI and COII are essential subunits of cytochrome c oxidase that is the terminal enzyme in the oxidative phosphorylation complexes. In terms of disease course, we observed that in patients with a normal cytogenetic analysis at disease presentation (CN-AML) treated with curative intent, the presence of a non-synonymous variation in the COII was an adverse prognostic marker for both overall survival and disease-free survival (DFS) in both univariate (DFS; hazard ratio (HR) 4.4, P = 0.006) and multivariate analyses (DFS; HR 7.2, P = 0.001). This is the first demonstration of a mitochondrial aberration playing an adverse prognostic role in adult AML, and we argue that its role as a potentially novel adverse prognostic marker in the subset of CN-AML should be explored further.

  15. Longitudinal assessment of nutritional status in children treated for acute lymphoblastic leukaemia in Cuba.

    Science.gov (United States)

    González, A; Cortina, L; González, P; González, C; García, T; de Svarch, E G

    2004-05-01

    Malnutrition has a deleterious effect on the results of therapy for malignant diseases in childhood. The impact of radiotherapy on growth is well known but the impact of cytotoxic drugs on nutritional status is more controversial. The purpose of this study was to determine the nutritional status of a cohort of children treated for acute lymphoblastic leukaemia (ALL) in Cuba. The study involved 49 children admitted to a single center and treated with a Berlin-Frankfurt-Munster-based protocol. Nutritional assessment included measurements of height, weight, body mass index and skin-fold thickness, made at diagnosis, after the intensive phase of treatment and at the end of therapy. Z-scores were used for height and comparison of percentiles for the rest of the variables. All the patients were above the third percentile in all the measurements. There were no statistically significant differences between the results at diagnosis, after intensive therapy and at the end of treatment. Although the sample was small, there was no demonstrable effect of chemotherapy on nutritional status in this Cuban paediatric population, in contrast to that reported in children with ALL in other developing countries.

  16. Acute lymphoblastic leukaemia: cyclical chemotherapy with three combinations of four drugs (COAP-POMP-CART regimen).

    Science.gov (United States)

    Spiers, A S; Roberts, P D; Marsh, G W; Parekh, S J; Franklin, A J; Galton, D A; Szur, Z L; Paul, E A; Husband, P; Wiltshaw, E

    1975-12-13

    Forty-two adults and children with previously untreated acute lymphoblastic leukaemia (ALL) were entered into a programme of chemotherapy in which three combinations, each of four drugs were administered in a predetermined cyclical rotation together with cranial irradiation and intrathecal injections of methotrexate. Forty-one patients (98%) entered remission and no patient developed neuroleukaemia. Relapse of ALL occurred in 10 patients, and three patients died during remission, while eight patients stopped treatment after two and a half years and have remained in remission for two to 26 months. Comparison of remission and survival experience in this mixed group of children and adults with the experience of children treated at Memphis and in the Medical Research Council's UKALL-I trial showed no significant differences. On the other hand, analysis by prognostic factors showed that neither age nor blast cell count at presentation had any adverse effect in patients treated in this study. No relapses occurred in nine patients with blast cell counts greater than 20 x 109/1 at presentation. This regimen is effective treatment for ALL and may be of special value in patients with poor prognoses. The regiment has not as yet proved superior for the treatment of children with ALL who do not have adverse prognostic features.

  17. New Quantitative Method to Identify NPM1 Mutations in Acute Myeloid Leukaemia

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    Sarah Huet

    2013-01-01

    Full Text Available Somatic mutations in the NPM1 gene, which encodes for nucleophosmin, have been reported to be the most frequent genetic abnormalities found in acute myeloid leukaemia (AML. Their identification and quantification remain crucial for the patients’ residual disease monitoring. We investigated a new method that could represent a novel reliable alternative to sequencing for its identification. This method was based on high-resolution melting analysis in order to detect mutated patients and on an allele-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR for the identification and quantification of the transcripts carrying NPM1 mutations (NPM1m. Few patients carrying known NPM1m enabled us to set up a table with the different primers’ ΔCT values, identifying a profile for each mutation type. We then analysed a series of 337 AML patients' samples for NPM1 mutational status characterization and confirmed the ASO-RQ-PCR results by direct sequencing. We identified some mutations in 86 samples, and the results were fully correlated in 100% of the 36 sequenced samples. We also detected other rare NPM1m in two samples, that we confirmed by direct sequencing. This highly specific method provides a novel quick, useful, and costless tool, easy to use in routine practice.

  18. Symptom experience and management among people with acute myeloid leukaemia in Thailand.

    Science.gov (United States)

    Temtap, Suthisa; Nilmanat, Kittikorn

    2011-08-01

    In Thailand, haematological malignancy is one of the most common types of cancer. This cross-sectional study, conducted in Southern Thailand, aimed to describe the symptom experiences of and symptom management strategies among patients with acute myeloid leukaemia (AML). Sixty hospitalized patients with AML were recruited. The Symptom Experience Scale and two open-ended questions regarding symptom-management strategies were used to collect data via face-to-face interviews 2 weeks after the induction phase of the AML protocol. The data was analysed using descriptive statistics and content analysis. High fever, weakness, nausea, and anorexia were the four most prevalent symptoms reported. Other prevalent symptoms included weight loss, bleeding, nausea and vomiting, dysphagia, and a cluster of psycho-emotional symptoms: worrying, fear, feeling discouraged, and feeling bored. Patients used various approaches and strategies to alleviate their symptoms, which could be categorized into five groups: preventive, direct, distraction, complementary, and restorative approaches. This study has provided important information for the development of symptom-management nursing programmes for patients with AML, particularly in Thailand.

  19. Noma in a child with acute leukaemia: when the 'face of poverty' finds an ally.

    Science.gov (United States)

    Singh, Amitabh; Mandal, Anirban; Seth, Rachna; Kabra, Sushil Kumar

    2016-01-06

    A 2-year-6-month old, appropriately immunised, well-thriving boy, symptomatic for the past 6 months, presented with recurrent fever, progressive pallor, lymphadenopathy and a raw area on the right cheek, with discharging sinus. The necrotising infection of the face developed after one and half months of febrile illness. This febrile illness with bicytopaenia was diagnosed as enteric fever and treated with antibiotics. Skin grafting was performed for the full-thickness defect of the face. The patient continued to have a non-healing oral ulcer with progressive pallor and was finally diagnosed as having acute lymphoblastic leukaemia. Immunodeficiency was ruled out by appropriate investigations. Noma is an indirect measure of extreme poverty, but malignancy is known to predispose to this debilitating condition. The worldwide incidence of Noma is reported to be 30,000-140,000, with a preponderance in sub-Saharan Africa. This case emphasises the need for a thorough search for the underlying illness predisposing to a rare opportunistic infection such as Noma in a well-thriving child.

  20. Early adolescent language development following intrathecal chemotherapy for acute lymphoblastic leukaemia.

    Science.gov (United States)

    Lewis, Fiona M; Bohan, Jaycie K

    2017-04-10

    Central nervous system (CNS) prophylaxis in the treatment of childhood acute lymphoblastic leukaemia (ALL) is routinely achieved through intrathecal chemotherapy (ITC). The presence of high level language deficits in older children who received CNS-directed ITC for ALL in early childhood is yet to be elucidated, with previous research suggesting that high level language deficits may appear later in ALL survivors' development at an age when these skills typically emerge. A test battery covering foundational language skills and higher-order language skills was administered to five participants (aged 10-15 years) with a history of ITC for ALL. Conversion of each child's language performance scores to z scores allowed for clinical interpretation of data across the language areas tested. Foundational language skills were, in general, of no clinical concern. Three of the five children presented with clinically impaired language skills in areas including resolving ambiguity, making inferences and composing novel sentences. Performance variation between the participants and within the individual participants was noted. Given the importance of early adolescent language abilities to academic and social development in late primary and secondary schooling, these preliminary findings suggest further research into emerging adolescent language abilities following ITC for ALL is warranted.

  1. Childhood T-cell acute lymphoblastic leukaemia expressing "Ia-like" antigen:" a case report.

    Science.gov (United States)

    Kupa, A; Beckman, I G; Bradley, J; Moore, H; Thomas, M; Zola, H; Cheney, K; Rice, M; Toogood, I

    1982-01-01

    A 4-year-old girl presenting with vomiting, abdominal pain, and renal failure was found to have gross hepatosplenomegaly, a renal mass, and bilateral pleural effusions. A diagnosis of acute lymphoblastic leukaemia (ALL) was suggested by a peripheral white cell count (WCC) of 119,000 x 10(6)mm3, 57% blasts, 22% lymphocytes, and confirmed by bone marrow examination. Lymphocyte surface marker studies at diagnosis enabled classification as a T-ALL, with a significant proportion of the T cells also bearing receptors for the third component of complement (C3). Seventy-two percent of the peripheral blood mononuclear cells reacted with anti-Ia monoclonal antibody (FMC44), and a smaller proportion (25%) carried receptors for the Fc portion of IgG. The T-classification of this ALL was verified at central nervous system (CNS) relapse and at a subsequent nodal relapse. Double-marker studies on cells from the infiltrated lymph node prepared in suspension confirmed the presence of Ia-positive T cells. The Ia marker is usually a useful discriminant between T and non-T cells in normal and ALL cell populations. The case described here highlights the need for a panel of markers to be used in classification of childhood ALL and supports the suggestion that there is a distinct subtype of Ia-positive T-ALL.

  2. Developing "Care Assistant": A smartphone application to support caregivers of children with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Wang, Jingting; Yao, Nengliang; Wang, Yuanyuan; Zhou, Fen; Liu, Yanyan; Geng, Zhaohui; Yuan, Changrong

    2016-04-01

    Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy. Caring for children with ALL is an uncommon experience for parents without medical training. They urgently need professional assistance when their children are recovering at home. This paper documents the process of developing an Android application (app) "Care Assistant" for family caregivers of children with ALL. Key informant interviews and focus group studies were used before programming the app. The key informants and focus group members included: caregivers of children with ALL, cancer care physicians and nurses, and software engineers. We found several major challenges faced by caregivers: limited access to evidence-based clinic information, lack of financial and social assistance, deficient communications with doctors or nurses, lack of disease-related knowledge, and inconvenience of tracking treatments and testing results. This feedback was used to develop "Care Assistant". This app has eight modules: personal information, treatment tracking, family care, financial and social assistance, knowledge centre, self-assessment questionnaires, interactive platform, and reminders. We have also developed a web-based administration portal to manage the app. The usability and effectiveness of "Care Assistant" will be evaluated in future studies. © The Author(s) 2015.

  3. Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.

    Directory of Open Access Journals (Sweden)

    Ezhilarasi Chendamarai

    Full Text Available There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL in comparison with newly diagnosed cases (NAPL. We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022. The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38% of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92, cell survival (n=50, immune regulation (n=74 and stem cell regulation (n=51. Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001 in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.

  4. Effect of all-trans retinoic acid on newly diagnosed acute promyelocytic leukemia patients: results of a Brazilian center

    Directory of Open Access Journals (Sweden)

    B.C. de-Medeiros

    1998-12-01

    Full Text Available Thirty-seven patients with acute promyelocytic leukemia (APL were treated with all-trans retinoic acid (ATRA. Patients received 45 mg m-2 day-1 po of ATRA until complete remission (CR was achieved, defined as: a presence of less than 5% blasts in the bone marrow, with b white blood cells >103/mm3, c platelets >105/mm3 and d hemoglobin concentration >8 g/dl, with no blood or platelet transfusions. Thirty-one (83.7% patients achieved CR by day 50, and 75% of these before day 30. Correction of the coagulopathy, achieved between days 2 and 10 (mean, 3 days, was the first evidence of response to treatment. Only one patient had been previously treated with chemotherapy and three had the microgranular variant M3 form. Dryness of skin and mucosae was the most common side effect observed in 82% of the patients. Thrombosis, hepatotoxicity and retinoid acid syndrome (RAS were observed in 7 (19%, 6 (16% and 4 (11% patients, respectively. Thirteen (35% patients had to be submitted to chemotherapy due to hyperleukocytosis (above 40 x 103/mm3 and six of these presented with new signs of coagulopathy after chemotherapy. Four (11% patients died secondarily to intracerebral hemorrhage (IH and two (5.4% dropped out of the protocol due to severe ATRA side effects (one RAS and one hepatotoxicity. RAS and IH were related strictly to hyperleukocytosis. The reduced use of platelets and fresh frozen plasma probably lowered the total cost of treatment. We conclude that ATRA is an effective agent for inducing complete remission in APL patients.

  5. CLINICAL FEATURES AND CLINICAL OUTCOME OF ACUTE PROMYELOCYTIC LEUKEMIA PATIENTS TREATED AT CAIRO NATIONAL CANCER INSTITUTE IN EGYPT

    Directory of Open Access Journals (Sweden)

    Tamer M Fouad

    2011-01-01

    Full Text Available

    The current study reports the clinical features and treatment outcome of 67 patients with acute promyelocytic leukemia (APL presented to National Cancer Institute (NCI-Cairo, in Egypt from January 2007 to January 2011. The median follow-up time was 36 months. All patients were treated with the simultaneous administration of all-trans retinoic acid (ATRA and anthracyclin. The treatment protocol was modified due to resource limitations at the NCI-Cairo by replacing of idarubicin with doxorubicin in most of the cases and the inclusion of cytarbine during the consolidation phase only in pediatric patients. All patients who achieved molecular complete remission (CRm after consolidation received two-year maintenance treatment with low dose chemotherapy composed of 6 mercaptopurine, methotrexate and intermittent ATRA courses. The median age at presentation was 29 years. There was a slight male predominance (53%.  Bleeding was the most common presenting symptom (79%. Most patients had an intermediate risk Sanz score (49% and 34% had a high risk score.  All patients achieved molecular CR at end of consolidation therapy with a median duration of 100 days. The main therapeutic complications during the induction phase were febrile neutropenia (42%, bleeding (18% and differentiation syndrome (11%. Five patients died at diagnosis due to bleeding, three died during induction chemotherapy due to febrile neutropenia (n=2 and bleeding (n=1 and one patient died during consolidation therapy due to febrile neutropenia.  The 3-year OS was 89% and relapse rate was 3%. Adapting standard AIDA treatment protocols to limited resources by reducing dose-intensity during treatment consolidation, using ATRA in the consolidation phase and alternative anthracyclin (doxorubicin may be a valid treatment option in developing countries. In spite of the increased incidence of high and intermediate risk score APL in our sample, we reported an acceptable CR rate

  6. Expression of CD56 is an unfavorable prognostic factor for acute promyelocytic leukemia with higher initial white blood cell counts.

    Science.gov (United States)

    Ono, Takaaki; Takeshita, Akihiro; Kishimoto, Yuji; Kiyoi, Hitoshi; Okada, Masaya; Yamauchi, Takahiro; Emi, Nobuhiko; Horikawa, Kentaro; Matsuda, Mitsuhiro; Shinagawa, Katsuji; Monma, Fumihiko; Ohtake, Shigeki; Nakaseko, Chiaki; Takahashi, Masatomo; Kimura, Yukihiko; Iwanaga, Masako; Asou, Norio; Naoe, Tomoki

    2014-01-01

    Expression of CD56 has recently been introduced as one of the adverse prognostic factors in acute promyelocytic leukemia (APL). However, the clinical significance of CD56 antigen in APL has not been well elucidated. We assessed the clinical significance of CD56 antigen in 239 APL patients prospectively treated with all-trans retinoic acid and chemotherapy according to the Japan Adult Leukemia Study Group APL97 protocol. All patients were prospectively treated by the Japan Adult Leukemia Study Group APL97 protocol. The median follow-up period was 8.5 years. Positive CD56 expression was found in 23 APL patients (9.6%). Expression of CD56 was significantly associated with lower platelet count (P = 0.04), severe disseminated intravascular coagulation (P = 0.04), and coexpression of CD2 (P = 0.03), CD7 (P = 0.04), CD34 (P < 0.01) and/or human leukocyte antigen-DR (P < 0.01). Complete remission rate and overall survival were not different between the two groups. However, cumulative incidence of relapse and event-free survival (EFS) showed an inferior trend in CD56(+) APL (P = 0.08 and P = 0.08, respectively). Among patients with initial white blood cell counts of 3.0 × 10(9)/L or more, EFS and cumulative incidence of relapse in CD56(+) APL were significantly worse (30.8% vs 63.6%, P = 0.008, and 53.8% vs 28.9%, P = 0.03, respectively), and in multivariate analysis, CD56 expression was an unfavorable prognostic factor for EFS (P = 0.04). In conclusion, for APL with higher initial white blood cell counts, CD56 expression should be regarded as an unfavorable prognostic factor.

  7. Histone modifications patterns in tissues and tumours from acute promyelocytic leukemia xenograft model in response to combined epigenetic therapy.

    Science.gov (United States)

    Valiulienė, Giedrė; Treigytė, Gražina; Savickienė, Jūratė; Matuzevičius, Dalius; Alksnė, Milda; Jarašienė-Burinskaja, Rasa; Bukelskienė, Virginija; Navakauskas, Dalius; Navakauskienė, Rūta

    2016-04-01

    Xenograft models are suitable for in vivo study of leukemia's pathogenesis and the preclinical development of anti-leukemia agents but understanding of epigenetic regulatory mechanisms linking to adult cell functions in pathological conditions during different in vivo treatments is yet unknown. In this study, for the first time epigenetic chromatin modifications were characterized in tissues and tumours from murine xenograft model generated using the human acute promyelocytic leukemia (APL) NB4 cells engrafted in immunodeficient NOG mice. Xenografts were subjected to combined epigenetic treatment by histone deacetylase inhibitor Belinostat, histone methyltransferase inhibitor 3-DZNeaplanocin A and all-trans-retinoic acid based on in vitro model, where such combination inhibited NB4 cell growth and enhanced retinoic acid-induced differentiation to granulocytes. Xenotransplantation was assessed by peripheral blood cells counts, the analysis of cell surface markers (CD15, CD33, CD45) and the expression of certain genes (PML-RAR alpha, CSF3, G-CSFR, WT1). The combined treatment prolonged APL xenograft mice survival and prevented tumour formation. The analysis of the expression of histone marks such as acetylation of H4, trimethylation of H3K4, H3K9 and H3K27 in APL xenograft mice tumours and tissues demonstrated tissue-specific changes in the level of histone modifications and the APL prognostic mark, WT1 protein. In summary, the effects of epigenetic agents used in this study were positive for leukemia prevention and linked to a modulation of the chromatin epigenetic environment in adult tissues of malignant organism.

  8. CLINICAL FEATURES AND CLINICAL OUTCOME OF ACUTE PROMYELOCYTIC LEUKEMIA PATIENTS TREATED AT CAIRO NATIONAL CANCER INSTITUTE IN EGYPT

    Directory of Open Access Journals (Sweden)

    Ola Khorshid

    2011-12-01

    Full Text Available The current study reports the clinical features and treatment outcome of 67 patients with acute promyelocytic leukemia (APL presented to National Cancer Institute (NCI-Cairo, in Egypt from January 2007 to January 2011. The median follow-up time was 36 months. All patients were treated with the simultaneous administration of all-trans retinoic acid (ATRA and anthracyclin. The treatment protocol was modified due to resource limitations at the NCI-Cairo by replacing of idarubicin with doxorubicin in most of the cases and the inclusion of cytarbine during the consolidation phase only in pediatric patients. All patients who achieved molecular complete remission (CRm after consolidation received two-year maintenance treatment with low dose chemotherapy composed of 6 mercaptopurine, methotrexate and intermittent ATRA courses. The median age at presentation was 29 years. There was a slight male predominance (53%.  Bleeding was the most common presenting symptom (79%. Most patients had an intermediate risk Sanz score (49% and 34% had a high risk score.  All patients achieved molecular CR at end of consolidation therapy with a median duration of 100 days. The main therapeutic complications during the induction phase were febrile neutropenia (42%, bleeding (18% and differentiation syndrome (11%. Five patients died at diagnosis due to bleeding, three died during induction chemotherapy due to febrile neutropenia (n=2 and bleeding (n=1 and one patient died during consolidation therapy due to febrile neutropenia.  The 3-year OS was 89% and relapse rate was 3%. Adapting standard AIDA treatment protocols to limited resources by reducing dose-intensity during treatment consolidation, using ATRA in the consolidation phase and alternative anthracyclin (doxorubicin may be a valid treatment option in developing countries. In spite of the increased incidence of high and intermediate risk score APL in our sample, we reported an acceptable CR rate, toxicity and OS.

  9. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab.

    Science.gov (United States)

    Abaza, Yasmin; Kantarjian, Hagop; Garcia-Manero, Guillermo; Estey, Elihu; Borthakur, Gautam; Jabbour, Elias; Faderl, Stefan; O'Brien, Susan; Wierda, William; Pierce, Sherry; Brandt, Mark; McCue, Deborah; Luthra, Rajyalakshmi; Patel, Keyur; Kornblau, Steven; Kadia, Tapan; Daver, Naval; DiNardo, Courtney; Jain, Nitin; Verstovsek, Srdan; Ferrajoli, Alessandra; Andreeff, Michael; Konopleva, Marina; Estrov, Zeev; Foudray, Maria; McCue, David; Cortes, Jorge; Ravandi, Farhad

    2017-03-09

    The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m(2) daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m(2) on day 1) added to high-risk patients (white blood cell count, >10 × 10(9)/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen.

  10. The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy.

    Science.gov (United States)

    Falchi, Lorenzo; Verstovsek, Srdan; Ravandi-Kashani, Farhad; Kantarjian, Hagop M

    2016-04-15

    The therapeutic potential of arsenic derivatives has long been recognized and was recently rediscovered in modern literature. Early studies demonstrated impressive activity of this compound in patients with relapsed acute promyelocytic leukemia (APL). Over the last 2 decades, intravenous arsenic trioxide has been used successfully, both alone and in combination with other agents, for the treatment of APL and, with some success, of other myeloid neoplasms. Arsenic trioxide is currently part the standard of care for patients with APL. More recently, oral formulations of this compound have been developed and are entering clinical practice. In this review, the authors discuss the evolution of arsenic in the treatment of APL and other myeloid neoplasms.

  11. 儿童急性早幼粒细胞白血病治疗进展%Progress in the treatment of children with acute promyelocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    朱嘉莳; 蒋慧

    2013-01-01

    儿童急性早幼粒细胞白血病(APL)发病率低,且可能治愈.儿童APL的一线治疗药物包括全反式维甲酸和亚砷酸,与成人相似.本文综述儿童APL的治疗情况及研究进展.%Acute promyelocytic leukemia (APL) is a lower morbidity and curable disease in children. Like adults, the first-line medications of children with APL are all-trans-retinoic acid and arsenic trioxide. This review summarizes the progress in the treatment of children with APL.

  12. A Complicated Case of Acute Promyelocytic Leukemia in the Second Trimester of Pregnancy Successfully Treated with All-trans-Retinoic Acid.

    Science.gov (United States)

    Agarwal, Kanika; Patel, Megha; Agarwal, Vandana

    2015-01-01

    A 40-year-old female at 26-week gestation was diagnosed with acute promyelocytic leukemia (APL) after an abnormal prenatal lab workup showed pancytopenia. She was treated with all-trans-retinoic acid (ATRA), idarubicin, and dexamethasone. After day one of treatment, she developed differentiation syndrome, which was treated with dexamethasone. At 30-week gestation, she had preterm premature rupture of membranes and delivered by cesarean section because of the fetus' breech presentation. Despite ATRA's potential for teratogenicity, a viable infant was born without apparent anomalies. Postpartum, she underwent consolidation treatment with ATRA and arsenic trioxide (ATO). The patient continued ATRA therapy after delivery and is currently in remission.

  13. [Successful treatment of acute promyelocytic leukemia in a pregnant patient with all-trans retinoic acid and chemotherapy resulting in a safe delivery].

    Science.gov (United States)

    Itoh, Mitsuru; Takao, Sumiko; Yago, Kazuhiro; Shimada, Hideto

    2003-06-01

    A 32-year-old woman at 21 gestational weeks was admitted because of leukocytosis with DIC. She was diagnosed as having acute promyelocytic leukemia and treated with all-trans retinoic acid (70 mg/body) in combination with daunorubicin and cytosine arabinoside. She achieved complete remission, and continuously received a second treatment with daunorubicin and cytosine arabinoside. Cesarean section was performed, and a live male infant was born in the 30th week of pregnancy. The mother and baby have progressed excellently to date. In a such case, the choice of treatment and time of birth should be considered depending on the individual situation.

  14. Management of adult and paediatric acute lymphoblastic leukaemia in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013

    Science.gov (United States)

    Yeoh, Allen EJ; Tan, Daryl; Li, Chi-Kong; Hori, Hiroki; Tse, Eric; Pui, Ching-Hon

    2014-01-01

    The survival rates for both adult and children with acute lymphoblastic leukaemia have improved substantially in recent years with wider use of improved risk-directed therapy and supportive care. In nearly all developed countries, clinical practice guidelines have been formulated by multidisciplinary panels of leukaemia experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. However, those guidelines do not take into account resource limitations in low-income countries, including financial and technical challenges. In Asia, there are huge disparities in economy and infrastructure among the countries, and even among different regions in some large countries. This review summarizes the recommendations developed for Asian countries by a panel of adult and paediatric leukaemia therapists, based on the availability of financial, skill and logistical resources, at a consensus session held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand. The management strategies described here are stratified by a four-tier system (basic, limited, enhanced and maximum) based on the resources available to a particular country or region. PMID:24176570

  15. The development of a three-dimensional scaffold for ex vivo biomimicry of human acute myeloid leukaemia.

    Science.gov (United States)

    Blanco, Teresa Mortera; Mantalaris, Athanasios; Bismarck, Alexander; Panoskaltsis, Nicki

    2010-03-01

    Acute myeloid leukaemia (AML) is a cancer of haematopoietic cells that develops in three-dimensional (3-D) bone marrow niches in vivo. The study of AML has been hampered by lack of appropriate ex vivo models that mimic this microenvironment. We hypothesised that fabrication and optimisation of suitable biomimetic scaffolds for culturing leukaemic cells ex vivo might facilitate the study of AML in its native 3-D niche. We evaluated the growth of three leukaemia subtype-specific cell lines, K-562, HL60 and Kasumi-6, on highly porous scaffolds fabricated from biodegradable and non-biodegradable polymeric materials, such as poly (L-lactic-co-glycolic acid) (PLGA), polyurethane (PU), poly (methyl-methacrylate), poly (D, L-lactade), poly (caprolactone), and polystyrene. Our results show that PLGA and PU supported the best seeding efficiency and leukaemic growth. Furthermore, the PLGA and PU scaffolds were coated with extracellular matrix (ECM) proteins, collagen type I (62.5 or 125 microg/ml) and fibronectin (25 or 50 microg/ml) to provide biorecognition signals. The 3 leukaemia subtype-specific lines grew best on PU scaffolds coated with 62.5 microg/ml collagen type I over 6 weeks in the absence of exogenous growth factors. In conclusion, PU-collagen scaffolds may provide a practical model to study the biology and treatment of primary AML in an ex vivo mimicry. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

  16. Misfolded N-CoR is linked to the ectopic reactivation of CD34/Flt3-based stem-cell phenotype in promyelocytic and monocytic acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Dawn Sijin Nin

    2015-10-01

    Full Text Available Nuclear receptor co-repressor (N-CoR is the key component of generic co-repressor complex essential for the transcriptional control of genes involved in cellular hemostasis. We have recently reported that N-CoR actively represses Flt3, a key factor of hematopoietic stem cells (HSC self-renewal and growth; and that de-repression of Flt3 by the misfolded N-CoR plays important role in the pathogenesis of promyelocytic and monocytic acute myeloid leukemia (AML. The leukemic cells derived from the promyelocytic and monocytic AML are distinctly characterized by the ectopic reactivation of stem cell phenotypes in relatively committed myeloid compartment. However, the molecular mechanism underlying this phenomenon is not known. Here, we report that N-CoR function is essential for the commitment of primitive hematopoietic cells to the cells of myeloid lineage, and that loss of N-CoR function due to misfolding is linked to the ectopic reactivation of generic stem cell phenotypes in promyelocytic and monocytic AML. Analysis of N-CoR and Flt3 transcripts in mouse hematopoietic cells revealed a positive correlation between N-CoR level and the commitment of myeloid cells and an inverse correlation between N-CoR and Flt3 levels in primitive as well as committed myeloid cells. Enforced N-CoR expression in mouse HSCs inhibited their growth and self-renewal potentials and promoted maturation towards cells of myeloid lineage, suggesting a role of N-CoR in the commitment of cells of myeloid lineage. In contrast to AML cells with natively folded N-CoR, primary and secondary promyelocytic and monocytic AML cells harboring the misfolded N-CoR were highly positive for Flt3 and myeloid antigen based HSC marker CD34. Genetic and therapeutic restoration of N-CoR conformation significantly down-regulated the CD34 levels in monocytic AML cells, suggesting an important role of N-CoR in the suppression of CD34 based hematopoietic stem cell phenotypes. These finding

  17. Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia.

    Directory of Open Access Journals (Sweden)

    Farhat L Khanim

    Full Text Available BACKGROUND: The majority of acute myeloid leukaemia (AML patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis. PRINCIPAL FINDINGS: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ and the sex hormone medroxyprogesterone acetate (MPA against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M converged upon the increased synthesis and reduced metabolism of prostaglandin D(2 (PGD(2 resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Delta(12,14 PGJ(2 (15d-PGJ(2. BEZ increased PGD(2 synthesis via the generation of reactive oxygen species (ROS and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ(2 by inhibiting the PGD(2 11beta -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD(2 to 9alpha11beta-PGF(2alpha. B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ(2. Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors. SIGNIFICANCE: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ(2. These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML.

  18. Predictors of outcome and methodological issues in children with acute lymphoblastic leukaemia in El Salvador.

    Science.gov (United States)

    Bonilla, Miguel; Gupta, Sumit; Vasquez, Roberto; Fuentes, Soad L; deReyes, Gladis; Ribeiro, Raul; Sung, Lillian

    2010-12-01

    Most children with cancer live in low-income countries (LICs) where risk factors in paediatric acute lymphoblastic leukaemia (ALL) developed in high-income countries may not apply. We describe predictors of survival for children in El Salvador with ALL. We included patients El Salvador-Guatemala-Honduras II protocol. Demographic, disease-related, socioeconomic and nutritional variables were examined as potential predictors of event-free survival (EFS) and overall survival (OS). 260/443 patients (58.7%) were classified as standard risk. Standard- and high-risk 5-year EFS were 56.3 ± 4.5% and 48.6 ± 5.5%; 5-year OS were 77.7 ± 3.8% and 61.9 ± 5.8%, respectively. Among standard-risk children, socioeconomic variables such as higher monthly income (hazard ratio [HR] per $100 = 0.84 [95% confidence interval (CI) 0.70-0.99; P=0.04]) and parental secondary education (HR = 0.49, 95% CI 0.29-0.84; P = 0.01) were associated with better EFS. Among high-risk children, higher initial white blood cell (HR per 10×10(9)/L = 1.03, 95% CI 1.02-1.05; P<0.001) predicted worse EFS; socioeconomic variables were not predictive. The difference in EFS and OS appeared related to overestimating OS secondary to poor follow-up after abandonment/relapse. Socioeconomic variables predicted worse EFS in standard-risk children while disease-related variables were predictive in high-risk patients. Further studies should delineate pathways through which socioeconomic status affects EFS in order to design effective interventions. EFS should be the primary outcome in LIC studies. Copyright © 2010 Elsevier Ltd. All rights reserved.

  19. Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Francis Richard W

    2010-04-01

    Full Text Available Abstract Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL. However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.

  20. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.

    Science.gov (United States)

    Li, Yilong; Schwab, Claire; Ryan, Sarra L; Papaemmanuil, Elli; Robinson, Hazel M; Jacobs, Patricia; Moorman, Anthony V; Dyer, Sara; Borrow, Julian; Griffiths, Mike; Heerema, Nyla A; Carroll, Andrew J; Talley, Polly; Bown, Nick; Telford, Nick; Ross, Fiona M; Gaunt, Lorraine; McNally, Richard J Q; Young, Bryan D; Sinclair, Paul; Rand, Vikki; Teixeira, Manuel R; Joseph, Olivia; Robinson, Ben; Maddison, Mark; Dastugue, Nicole; Vandenberghe, Peter; Haferlach, Claudia; Stephens, Philip J; Cheng, Jiqiu; Van Loo, Peter; Stratton, Michael R; Campbell, Peter J; Harrison, Christine J

    2014-04-03

    Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

  1. Principal results of the Medical Research Council's 8th acute myeloid leukaemia trial.

    Science.gov (United States)

    Rees, J K; Gray, R G; Swirsky, D; Hayhoe, F G

    1986-11-29

    Between 1978 and 1983, 1127 patients with de-novo acute myeloid leukaemia (AML) were entered into the Medical Research Council (MRC)'s 8th AML trial. All received the same induction therapy consisting of daunorubicin, cytarabine, and 6-thioguanine--DAT (1 + 5). The 67% who entered complete remission were randomised to consolidation with two or six further courses of DAT. Adults under the age of 55 were randomised for central nervous system (CNS) prophylaxis with intrathecal cytarabine and methotrexate. Finally, those still in remission after 1 year of cytarabine and 6-thioguanine (AT) maintenance were randomised to receive either late intensification with cyclophosphamide, vincristine, cytarabine, and prednisolone (COAP) or continued AT. The median survival for the whole group was 12 months; the median duration of first remission was 15 months, with relapse-free survival at 5 years estimated at 18%. The factors most strongly associated with poor survival were performance status and age at presentation, but even among those over 60 years of age, half went into remission. Six courses of DAT consolidation gave a small advantage over two courses in reducing the number of late relapses but no significant survival advantage. Late intensification showed a marginally significant advantage over continued AT maintenance. The incidence of CNS relapse was low and unaffected by prophylaxis. The second remission rate varied from 10% when the first remission was shorter than 6 months to 61% when it had continued for more than 2 years. 40 patients received histocompatible allogeneic bone-marrow transplants in first remission. There was a high procedure-related death rate, particularly among patients over 30 years of age. Thus, initially at least, the transplanted group had shorter survival than a comparable group of chemotherapy-treated patients. Treatment specifications remained unchanged throughout the trial but those enrolled in the later half of the trial had a better (p = 0

  2. Targeting etoposide to acute myelogenous leukaemia cells using nanostructured lipid carriers coated with transferrin

    Science.gov (United States)

    Khajavinia, Amir; Varshosaz, Jaleh; Jafarian Dehkordi, Abbas

    2012-10-01

    The aim of the present study was to evaluate the diverse properties of transferrin (Tf)-conjugated nanostructured lipid carriers (NLCs) prepared using three different fatty amines, including stearylamine (SA), dodecylamine (DA) and spermine (SP), and two different methods for Tf coupling. Etoposide-loaded NLCs were prepared by an emulsion-solvent evaporation method followed by probe sonication. Chemical coupling of NLCs with Tf was mediated by an amide linkage between the surface-exposed amino group of the fatty amine and the carboxyl group of the protein. The physical coating was performed in a Ringer-Hepes buffer medium. NLCs were characterized by their particle size, zeta potential, polydispersity index, drug entrapment percentage, drug release profiles and Tf-coupling efficiency. The cytotoxicity of NLCs on K562 acute myelogenous leukaemia cells was studied by MTT assay, and their cellular uptake was studied by a flow cytometry method. SA-containing NLCs showed the lowest particle size, the highest zeta potential and the largest coupling efficiency values. The drug entrapment percentage and the zeta potential decreased after Tf coupling, but the average particle size increased. SP-containing formulations released their drug contents comparatively slower than SA- or DA-containing NLCs. Unconjugated NLCs released moderately more drug than Tf-NLCs. Flow cytometry studies revealed enhanced cellular uptake of Tf-NLCs compared to unconjugated ones. Blocking Tf receptors resulted in a significantly higher cell survival rate for Tf-NLCs. The highest cytotoxic activity was observed in the chemically coupled SA-containing nanoparticles, with an IC50 value of 15-fold lower than free etoposide.

  3. A role for paclitaxel in the combination chemotherapy of acute myeloblastic leukaemia: preclinical cell culture studies.

    Science.gov (United States)

    Curtis, J E; Minkin, S; Minden, M D; McCulloch, E A

    1996-11-01

    Paclitaxel dose responses in culture have been investigated alone and in association with cytosine arabinoside (ARA-C) and all-trans retinoic acid (ATRA), with the objective of identifying a role for paclitaxel in the treatment of acute myeloblastic leukaemia (AML). Initial studies were done to determine if paclitaxel dose responses of AML blast cell precursors were altered by regulatory compounds known to modify the dose responses of ARA-C. In contrast to ARA-C, paclitaxel dose responses were independent of cell culture method, the growth factors G-CSF and GM-CSF, and the ligands all-trans retinoic acid (ATRA) and hydrocortisone. Most blast cell populations were sensitive to paclitaxel; compared with normal marrow progenitors the dose responses were markedly heterogenous with some more, and others less, sensitive. Remission marrow progenitor paclitaxel responses resembled those of AML blasts in heterogeneity. The cell culture model tested the effect of pacliataxel and ATRA on the ARA-C dose responses of OCI/ AML-5; paclitaxel exposure was either before or after ARA-C to test for an effect of schedule; ATRA was added to the MEC cultures after paclitaxel and ARA-C. Repeat experiments were done to test three dose levels each of paclitaxel and ATRA. When paclitaxel was given after ARA-C, synergism was found for all but one of the dose combinations tested; only three examples of synergy were seen when paclitaxel preceded ARA-C. The studies justify trials combining ARA-C, paclitaxel and ATRA using a schedule suggested by the cell culture findings.

  4. Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children

    DEFF Research Database (Denmark)

    Xu, Heng; Zhang, Hui; Yang, Wenjian;

    2015-01-01

    There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant...... of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation...

  5. Genome‐wide analysis of cytogenetic aberrations in ETV6/RUNX1‐positive childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Borst, Louise; Wesolowska, Agata; Joshi, Tejal

    2012-01-01

    The chromosomal translocation t(12;21) resulting in the ETV6/RUNX1 fusion gene is the most frequent structural cytogenetic abnormality among patients with childhood acute lymphoblastic leukaemia (ALL). We investigated 62 ETV6/RUNX1‐positive childhood ALL patients by single nucleotide polymorphism......, and gains of 10 and 21) seemed independent of each other. Finally, we identified the most common regions with recurrent gains and losses, which comprise microRNA clusters with known oncogenic or tumour‐suppressive roles. The present study sheds further light on the genetic diversity of ETV6/RUNX1‐positive...

  6. Alternating hemiparesis and orolingual apraxia as manifestations of methotrexate neurotoxicity in a paediatric case of acute lymphoblastic leukaemia.

    Science.gov (United States)

    Yap, Siew Mei; MacEneaney, Peter; Ryan, Clodagh; O'Toole, Orna

    2016-04-25

    A 15-year-old girl with a recent diagnosis of acute lymphoblastic leukaemia was admitted to hospital with pancytopaenia after having received high-dose intrathecal methotrexate 1 day prior. During the next week she had intermittent episodes of alternating hemiparesis associated with speech arrest lasting minutes to hours at a time. The episodes were not associated with altered level of consciousness or headache. MRI of the brain showed features consistent with methotrexate encephalopathy. This report discusses the typical clinical and radiological features of methotrexate neurotoxicity in addition to differential diagnoses and the proposed pathophysiological mechanisms.

  7. Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy

    Directory of Open Access Journals (Sweden)

    Denise Niewerth

    2016-09-01

    Full Text Available Abstract Background Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML and acute lymphocytic leukaemia (ALL. Methods We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children’s Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1 and AML (COG-AAML07P1. Expression of proteasome subunits was examined in 72 patient samples (ALL n = 60, AML n = 12 obtained before start of therapy. Statistical significance between groups was determined by Mann-Whitney U test. Results Ratios of immunoproteasome to constitutive proteasome subunit expression were significantly higher in pre-B ALL cells than in AML cells for both β5i/β5 and β1i/β1 subunits (p = 0.004 and p < 0.001. These ratios correlated with therapy response in AML patients; β1i/β1 ratios were significantly higher (p = 0.028 between patients who did (n = 4 and did not reach complete remission (CR (n = 8, although for β5i/β5 ratios, this did not reach significance. For ALL patients, the subunit ratios were also higher for patients who showed a good early response to therapy but this relation was not statistically significant. Overall, for this study, the patients were treated with combination therapy, so response was not only attributed to proteasome inhibition. Moreover, the leukaemic blast cells were not purified for these samples. Conclusions These first ex vivo results encourage further studies into relative proteasome subunit expression to improve proteasome inhibition-containing therapy and as a potential indicator of bortezomib response in acute leukaemia.

  8. In vitro study on arsenic sulfide (realgar)-induced apoptosis of retinoic acid susceptible or resistant acute promyelocytic leukemia cell lines

    Institute of Scientific and Technical Information of China (English)

    CHEN Si-yu; LIU Shan-xi; LI Xin-min

    2002-01-01

    Objective: To further understand the possible mechanisms of arsenic sulfide (realgar) in the treatment of acute promyelocytic leukemia (APL). Methods: All-trans retinoic acid (ATRA)-susceptible APL cell line (NB4 cells) and ATRA-resistant APL cell line (MR2 subclone) were used as models in vitro. At various times after incubated with various concentrations of realgar, NB4 and MR2 cells were observed by cell viability, cell proliferation and cell morphology; cell cycle and the expression of Annexin V were assayed by flow cytometry. Results: Cell viability and proliferation of NB4 and MR2 cells were inhibited after the treatment,to some extent, in a dose and time dependent manner. 177-711 μg/L of realgar treated NB4 and MR2 cell presented morphologically some features of apoptotic cells such as intact cell membrane, chromatin condensation and nuclear fragmentation, apoptosis body could be found by electron microscopy as well. Sub-G1 ceils andcell cycle arrest were observed by flow cytometry. The proportion of Annexin V -FITC+/PI cells, which represent apoptotic cells, was up-regulated. Conclusion: Realgar could induce apoptosis of acute promyelocytic leukemia cell despite its susceptibility to retinoic acid in the way that may be different from retinoic acid.

  9. Acute myeloid leukaemia as a cause of acute ischaemic heart disease

    NARCIS (Netherlands)

    van Haelst, P.L.; Schot, Bart; Hoendermis, E.S.; van den Berg, M.P.

    2006-01-01

    Ischaemic heart disease is almost invariably the result of atherosclerotic degeneration of the coronary arteries. However, other causes of ischaemic heart disease should always be considered. Here we describe two patients with a classic presentation of ischaemic heart disease resulting from acute le

  10. Acute myeloid leukaemia as a cause of acute ischaemic heart disease

    NARCIS (Netherlands)

    van Haelst, P.L.; Schot, Bart; Hoendermis, E.S.; van den Berg, M.P.

    2006-01-01

    Ischaemic heart disease is almost invariably the result of atherosclerotic degeneration of the coronary arteries. However, other causes of ischaemic heart disease should always be considered. Here we describe two patients with a classic presentation of ischaemic heart disease resulting from acute

  11. Acute myeloid leukaemia as a cause of acute ischaemic heart disease

    NARCIS (Netherlands)

    van Haelst, P.L.; Schot, Bart; Hoendermis, E.S.; van den Berg, M.P.

    2006-01-01

    Ischaemic heart disease is almost invariably the result of atherosclerotic degeneration of the coronary arteries. However, other causes of ischaemic heart disease should always be considered. Here we describe two patients with a classic presentation of ischaemic heart disease resulting from acute le

  12. Acute Myeloid Leukemia with Translocation t(8;16) Presents with Features Which Mimic Acute Promyelocytic Leukemia and is Associated With Poor Prognosis

    Science.gov (United States)

    Diab, Adi; Zickl, Lynette; Abdel-Wahab, Omar; Jhanwar, Suresh; Gulam, Manjit A; Panageas, Katherine S.; Patel, Jay P.; Jurcic, Joseph; Maslak, Peter; Paietta, Elisabeth; Mangan, James K.; Carroll, Martin; Fernandez, Hugo F.; Teruya-Feldstein, Julie; Luger, Selina M.; Douer, Dan; Litzow, Mark R.; Lazarus, Hillard M.; Rowe, Jacob M.; Levine, Ross L.; Tallman, Martin S.

    2017-01-01

    Previous small series have suggested that acute myeloid leukemia with t(8;16) is a distinct morphologic and clinical entity associated with poor prognosis. We describe 18 patients with t(8;16) AML, including their clinical, cytomorphologic, immunophenotypic and cytogenetic features. Half of the patients had extramedullary disease, most commonly leukemia cutis, which often preceded bone marrow involvement and six had therapy-related AML. Patients with t(8;16) AML commonly present with clinical and pathological features that mimic APL, with promyelocytes and promyeloblast-like cells and coagulopathy in most patients. Several patients also presented with marrow histiocytes with hemophagocytosis and erythrophagocytosis. Comprehensive molecular analysis for co-occurring genetic alterations revealed a somatic mutation in RUNX1 in 1 of 6 t(8;16) patients with no known AML mutation in the remaining five t(8;16) patients. This suggests that the t(8;16) translocation could be sufficient to induce hematopoietic cell transformation to AML without acquiring other genetic alteration. These data further support classifying t(8;16) AML as a clinically and molecularly defined subtype of AML marked by characteristic clinical and cytomorphologic features that mimic APL, and is associated with very poor survival. PMID:23102703

  13. Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARalpha-mediated increase of type II transglutaminase.

    Science.gov (United States)

    Benedetti, L; Grignani, F; Scicchitano, B M; Jetten, A M; Diverio, D; Lo Coco, F; Avvisati, G; Gambacorti-Passerini, C; Adamo, S; Levin, A A; Pelicci, P G; Nervi, C

    1996-03-01

    All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t-RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15;17) translocation and expressing the PML-RARalpha product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor beta subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t-RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARalpha-selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RAR alpha-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARalpha-dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARalpha gene in myeloid U937 precursor cells resulted in the ability of these cells to

  14. Combination of arsenicum trioxide and all trans retinoic acid in the treatment of relapsed acute promyelocytic leukemia

    Directory of Open Access Journals (Sweden)

    A. N. Sokolov

    2015-01-01

    Full Text Available From 2001 to 2013 eleven patients with relapsed acute promyelocytic leukemia (APL (median age – 30 years received arsenicum trioxide (ATO. ATO was administered as a 2nd line relapse therapy in 9 patients, as 1st line relapse therapy in 2 patients. ATO was administered in a dose of 0.1 mg/kg in 7 patients, 0.15 mg/kg – in 4 patients. The induction duration was 14 days in 3 patients, 24–35 days in 2 patients, 60 days in 6 patients. From the 1st day of ATO patients received 45 mg/m2 all trans retinoic acid (ATRA (1 patient – from day 29 of ATO therapy. Maintenance therapy ATO + ATRA (10–14 days courses, every four weeks patients were receiving during 10–15 months. 2 from 3 patients with molecular relapses achieved remission lasting 57 and 89 months after the 14-day ATO courses. 1 from 2 patients with bone marrow relapse achieved remission lasting 27 months after the 24–35-day ATO courses. 60-day courses were effective in 5 of 6 patients: in 4 of which remission are retained during 16, 19, 27, 57 months; 1 patient was relapsed after 12 months; 1 patient did not achieve molecular remission. 3 patients received allogeneic hematopoietic stem cell transplantation (alloHSCT, 2 of which alive in remission. 1 patient received autologous hematopoietic stem cell transplantation in the 2nd molecular remission (alive in remission. 4 patients died: 1 – in the 3rd relapse (duration of 2nd remission – 9 months, 1 – in remission from complications after alloHSCT, 1 – from APL progression, 1 – sudden death in 2nd remission lasting 72 months. ATO + ATRA for 60 days with supportive therapy are more effective than chemotherapy in the treatment of APL relapse. Interferon α + ATRA are inappropriate treatment of APL molecular and cytogenetic relapse. Using autologous HSCT in 2nd molecular remission will improve the results of APL relapse treatment.

  15. Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican inter-institutional group for the identification of the causes of childhood leukaemia

    Science.gov (United States)

    Núñez-Enríquez, J C; Fajardo-Gutiérrez, A; Buchán-Durán, E P; Bernáldez-Ríos, R; Medina-Sansón, A; Jiménez-Hernández, E; Amador-Sanchez, R; Peñaloza-Gonzalez, J G; Paredes-Aguilera, R; Alvarez-Rodriguez, F J; Bolea-Murga, V; de Diego Flores-Chapa, J; Flores-Lujano, J; Bekker-Mendez, V C; Rivera-Luna, R; del Carmen Rodriguez-Zepeda, M; Rangel-López, A; Dorantes-Acosta, E M; Núñez-Villegas, N; Velazquez-Aviña, M M; Torres-Nava, J R; Reyes-Zepeda, N C; Cárdenas-Cardos, R; Flores-Villegas, L V; Martinez-Avalos, A; Salamanca-Gómez, F; Gorodezky, C; Arellano-Galindo, J; Mejía-Aranguré, J M

    2013-01-01

    Background: Allergies have been described as protective factors against the development of childhood acute leukaemia (AL). Our objective was to investigate the associations between allergy history and the development of AL and acute lymphoblastic leukaemia (ALL) in children with Down syndrome (DS). Methods: A case–control study was performed in Mexico City. The cases (n=97) were diagnosed at nine public hospitals, and the controls (n=222) were recruited at institutions for children with DS. Odds ratios (OR) were calculated. Results: Asthma was positively associated with AL development (OR=4.18; 95% confidence interval (CI): 1.47–11.87), whereas skin allergies were negatively associated (OR=0.42; 95% CI: 0.20–0.91). Conclusion: Our findings suggest that allergies and AL in children with DS share biological and immune mechanisms. To our knowledge, this is the first study reporting associations between allergies and AL in children with DS. PMID:23695017

  16. MR features of isolated uterine relapse in an adolescent with acute lymphoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Novellas, Sebastien; Fournol, Maude; Geoffray, Anne; Chevallier, Patrick [Regional Hospital Centre and University of Nice, Medical Imaging Service, Archet 2 Hospital, 151 route de Saint Antoine de Ginestiere, B.P. 3079, Nice Cedex 3 (France); Deville, Anne [Regional Hospital Centre and University of Nice, Paediatric Service, Archet 2 Hospital, Nice (France); Kurzenne, Jean-Yves [Regional Hospital Centre and University of Nice, Paediatric Surgery Service, Archet 2 Hospital, Nice (France)

    2008-03-15

    Relapses of lymphoblastic leukaemia traditionally involve the central nervous system and testes in boys. Involvement of the female pelvic organs is frequently found at autopsy; however, involvement of the cervical uterus is rare and even less commonly symptomatic. A 13-cm uterine mass was discovered in a 15-year-old adolescent with a history of lymphoblastic leukaemia during childhood. Pelvic MRI was the best tool to assess the size, characteristics and invasive nature of this lesion of the uterine cervix. To our knowledge, this is a unique case in that we describe the MRI appearance of a relapsing lymphoblastic leukaemic mass both before and after treatment. (orig.)

  17. Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group

    NARCIS (Netherlands)

    Tallman, Martin S.; Kim, Haesook T.; Montesinos, Pau; Appelbaum, Frederick R.; de la Serna, Javier; Bennett, John M.; Deben, Guillermo; Bloomfield, Clara D.; Gonzalez, Jose; Feusner, James H.; Gonzalez, Marcos; Gallagher, Robert; Gonzalez-San Miguel, Jose D.; Larson, Richard A.; Milone, Gustavo; Paietta, Elisabeth; Rayon, Chelo; Rowe, Jacob M.; Rivas, Concha; Schiffer, Charles A.; Vellenga, Edo; Shepherd, Lois; Slack, James L.; Wiernik, Peter H.; Willman, Cheryl L.; Sanz, Miguel A.

    2010-01-01

    Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-transretinoic acid-based therapy on 3 clinical trials, North American I

  18. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy : long-term outcome of the LPA 99 multicenter study by the PETHEMA Group

    NARCIS (Netherlands)

    Sanz, Miguel A.; Montesinos, Pau; Vellenga, Edo; Rayon, Consuelo; de la Serna, Javier; Parody, Ricardo; Bergua, Juan M.; Leon, Angel; Negri, Silvia; Gonzalez, Marcos; Rivas, Concha; Esteve, Jordi; Milone, Gustavo; Gonzalez, Jose D.; Amutio, Elena; Brunet, Salut; Garcia-Larana, J.; Colomer, Dolors; Calasanz, Maria J.; Chillon, Carmen; Barragan, Eva; Bolufer, Pascual; Lowenberg, Bob

    2008-01-01

    A previous report of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leukemia

  19. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: Long-term outcome of the LPA 99 multicenter study by the PETHEMA Group

    NARCIS (Netherlands)

    M.A. Sanz (Miguel Angel); P. Montesinos (Pau); E. Vellenga (Edo); C. Rayón (Consuelo); J. de Serna (Javier); R. Parody (Ricardo); J.M. Bergua (Juan Miguel); A. León (Angel); S. Negri (Silvia); M. González (Marcos); C. Rivas (Concha); J. Esteve (Jordi); G. Milone (Gustavo); E. Amutio (Elena); S. Brunet (Salut); J. García-Laraña; D. Colomer (Dolors); M.J. Calasanz (Maria); C. Chillón (Carmen); E. Barragán (Eva); P. Bolufer (Pascual); B. Löwenberg (Bob)

    2008-01-01

    textabstractA previous report of the Programa de Estudio y Tratamiento de las Hemopatfas Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic

  20. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: Further improvements in treatment outcome

    NARCIS (Netherlands)

    M.A. Sanz (Miguel Angel); P. Montesinos (Pau); C. Rayón (Chelo); A. Holowiecka (Aleksandra); J. De La Serna (Javier); G. Milone (Gustavo); E. de Lisa (Elena); S. Brunet (Salut); V. Rybio (Vicente); J.M. Ribera (Josep Maria); C. Rivas (Concha); I. Krsnik (Isabel); J.M. Bergua (Juan Miguel); J.D. González (José David); J. Díaz-Mediavilla (Joaquín); R. Rojas (Rafael); F. Manso (Félix); G.J. Ossenkoppele (Gert); B. Löwenberg (Bob)

    2010-01-01

    textabstractA risk-adapted strategy based on all-trans retinoic acid (ATRA) and anthracycline monochemotherapy (PETHEMALPA99 trial) has demonstrated a high antileukemic efficacy in acute promyelocytic leukemia. We designed a new trial (LPA2005) with the objective of achieving stepwise improvements i

  1. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: Long-term outcome of the LPA 99 multicenter study by the PETHEMA Group

    NARCIS (Netherlands)

    M.A. Sanz (Miguel Angel); P. Montesinos (Pau); E. Vellenga (Edo); C. Rayón (Consuelo); J. de Serna (Javier); R. Parody (Ricardo); J.M. Bergua (Juan Miguel); A. León (Angel); S. Negri (Silvia); M. González (Marcos); C. Rivas (Concha); J. Esteve (Jordi); G. Milone (Gustavo); E. Amutio (Elena); S. Brunet (Salut); J. García-Laraña; D. Colomer (Dolors); M.J. Calasanz (Maria); C. Chillón (Carmen); E. Barragán (Eva); P. Bolufer (Pascual); B. Löwenberg (Bob)

    2008-01-01

    textabstractA previous report of the Programa de Estudio y Tratamiento de las Hemopatfas Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leu

  2. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy : long-term outcome of the LPA 99 multicenter study by the PETHEMA Group

    NARCIS (Netherlands)

    Sanz, Miguel A.; Montesinos, Pau; Vellenga, Edo; Rayon, Consuelo; de la Serna, Javier; Parody, Ricardo; Bergua, Juan M.; Leon, Angel; Negri, Silvia; Gonzalez, Marcos; Rivas, Concha; Esteve, Jordi; Milone, Gustavo; Gonzalez, Jose D.; Amutio, Elena; Brunet, Salut; Garcia-Larana, J.; Colomer, Dolors; Calasanz, Maria J.; Chillon, Carmen; Barragan, Eva; Bolufer, Pascual; Lowenberg, Bob

    2008-01-01

    A previous report of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leukemia result

  3. [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.

  4. Survival of Mexican Children with Acute Myeloid Leukaemia Who Received Early Intensification Chemotherapy and an Autologous Transplant

    Science.gov (United States)

    Jiménez-Hernández, Elva; Dueñas-González, María Teresa; Arellano-Galindo, José; Medrano-Ortíz-De-Zárate, María Elena; Bekker-Méndez, Vilma Carolina; Berges-García, Adolfina; Solís-Labastida, Karina; Sánchez-Jara, Berenice; Tiznado-García, Héctor Manuel; Jaimes-Reyes, Ethel Zulie; García-Jiménez, Xochiketzalli; Espinoza-Hernández, Laura; Núñez-Villegas, Nora Nancy; Franco-Ornelas, Sergio; Pérez-Casillas, Ruy Xavier; Martínez Villegas, Octavio; Palomares, Teresa Marin; Mejía-Aranguré, Juan Manuel

    2015-01-01

    Background. In Mexico and other developing countries, few reports of the survival of children with acute leukaemia exist. Objective. We aimed at comparing the disease-free survival of children with acute myeloid leukaemia who, in addition to being treated with the Latin American protocol of chemotherapy and an autologous transplant, either underwent early intensified chemotherapy or did not undergo such treatment. Procedure. This was a cohort study with a historical control group, forty patients, less than 16 years old. Group A (20 patients), diagnosed in the period 2005–2007, was treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy: high doses of cytarabine and mitoxantrone. Group B (20 patients), diagnosed in the period 1999–2004, was treated as Group A, but without the early intensified chemotherapy. Results. Relapse-free survival for Group A was 90% whereas that for Group B it was 60% (P = 0.041). Overall survival for Group A (18, 90%) was higher than that for Group B (60%). Complete remission continued for two years of follow-up. Conclusions. Relapse-free survival for paediatric patients treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy was higher than that for those who did not receive early intensified chemotherapy. PMID:25821830

  5. Survival of Mexican Children with Acute Myeloid Leukaemia Who Received Early Intensification Chemotherapy and an Autologous Transplant

    Directory of Open Access Journals (Sweden)

    Elva Jiménez-Hernández

    2015-01-01

    Full Text Available Background. In Mexico and other developing countries, few reports of the survival of children with acute leukaemia exist. Objective. We aimed at comparing the disease-free survival of children with acute myeloid leukaemia who, in addition to being treated with the Latin American protocol of chemotherapy and an autologous transplant, either underwent early intensified chemotherapy or did not undergo such treatment. Procedure. This was a cohort study with a historical control group, forty patients, less than 16 years old. Group A (20 patients, diagnosed in the period 2005–2007, was treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy: high doses of cytarabine and mitoxantrone. Group B (20 patients, diagnosed in the period 1999–2004, was treated as Group A, but without the early intensified chemotherapy. Results. Relapse-free survival for Group A was 90% whereas that for Group B it was 60% (P=0.041. Overall survival for Group A (18, 90% was higher than that for Group B (60%. Complete remission continued for two years of follow-up. Conclusions. Relapse-free survival for paediatric patients treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy was higher than that for those who did not receive early intensified chemotherapy.

  6. Analysis of Promyelocyte Counts of Bone Marrow from the Patients with Acute Promyelocytic Leukemia by Chemotherapeuty%APL化疗前后患者骨髓早幼粒细胞计数结果分析

    Institute of Scientific and Technical Information of China (English)

    莫建坤; 黎永新

    2003-01-01

    目的了解急性早幼粒细胞白血病(Acute Promyelocytic Leukemia APL)患者化疗前后骨髓早幼粒细胞计数结果的变化.方法采用三尖杉酯碱、柔红霉素、阿糖胞苷化疗药物治疗17例APL患者,其中男11例,女6例,年龄4~49岁,采集APL患者治疗前、后骨髓,并对骨髓进行细胞分类计数.结果APL化疗前、后骨髓细胞分类计数早幼粒细胞分别是:(80.68±10.66)%,(3.11±1.48)%,其结果表明治疗后骨髓早幼粒细胞显著减少(t=20.243,p<0.001).结论采用三尖杉酯碱、柔红霉素、阿糖胞苷、维甲酸化疗药物治疗APL能促使病人骨髓早幼粒细胞显著减少.

  7. Results of a Prospective Multicentre Myeloablative Double-Unit Cord Blood Transplantation Trial in Adult Patients with Acute Leukaemia and Myelodysplasia

    Science.gov (United States)

    Barker, Juliet N.; Fei, Mingwei; Karanes, Chatchada; Horwitz, Mitchell; Devine, Steven; Kindwall-Keller, Tamila L.; Holter, Jennifer; Adams, Alexia; Logan, Brent; Navarro, Willis H.; Riches, Marcie

    2017-01-01

    Summary Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the one-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2.62 (larger unit) and 2.02 (smaller unit) × 107/kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80–96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51–76) and 36% (95%CI: 24–49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26–52), and the 3-year relapse incidence was 11% (95%CI: 4–21). With a median 37-month (range 23–71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37–63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed. PMID:25272241

  8. Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia : a time-dependent analysis

    NARCIS (Netherlands)

    Versluis, Jurjen; Hazenberg, Carin L. E.; Passweg, Jakob R.; van Putten, Wim L. J.; Maertens, Johan; Biemond, Bart J.; Theobald, Matthias; Graux, Carlos; Kuball, Jurgen; Schouten, Harry C.; Pabst, Thomas; Lowenberg, Bob; Ossenkoppele, Gert; Vellenga, Edo; Cornelissen, Jan J.

    2015-01-01

    Background Acute myeloid leukaemia mainly affects elderly people, with a median age at diagnosis of around 70 years. Although about 50-60% of patients enter first complete remission upon intensive induction chemotherapy, relapse remains high and overall outcomes are disappointing. Therefore, effecti

  9. Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype

    Directory of Open Access Journals (Sweden)

    Virijevic Marijana

    2016-12-01

    Full Text Available Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2 genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK. The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up.

  10. High white blood cell count at diagnosis of childhood acute lymphoblastic leukaemia: biological background and prognostic impact. Results from the NOPHO ALL-92 and ALL-2000 studies

    DEFF Research Database (Denmark)

    Vaitkeviciene, G; Forestier, E; Hellebostad, M;

    2011-01-01

    Prognostic impact of peripheral blood white blood cell count (WBC) at the diagnosis of childhood acute lymphoblastic leukaemia (ALL) was evaluated in a population-based consecutive series of 2666 children aged 1–15 treated for ALL between 1992 and 2008 in the five Nordic countries (Denmark, Finland...

  11. Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study

    DEFF Research Database (Denmark)

    Tierens, Anne; Bjørklund, Elizabeth; Siitonen, Sanna;

    2016-01-01

    Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society...

  12. Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology

    DEFF Research Database (Denmark)

    Ranta, Susanna; Tuckuviene, Ruta; Mäkipernaa, Anne

    2014-01-01

    We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO...

  13. A 4-gene expression score associated with high levels of Wilms Tumor-1 (WT1) expression is an adverse prognostic factor in acute myeloid leukaemia

    NARCIS (Netherlands)

    Niavarani, A. (Ahmadreza); Herold, T. (Tobias); Y. Reyal (Yasmin); M.C. Sauerland (Maria); T. Büchner (Thomas); W. Hiddemann (Wolfgang); S.K. Bohlander (Stefan); P.J.M. Valk (Peter); Bonnet, D. (Dominique)

    2016-01-01

    textabstractWilms Tumor-1 (WT1) expression level is implicated in the prognosis of acute myeloid leukaemia (AML). We hypothesized that a gene expression profile associated with WT1 expression levels might be a good surrogate marker. We identified high WT1 gene sets by comparing the gene expression p

  14. In vitro drug resistance and prognostic impact of p16(INK4A)/p15(INK4B) deletions in childhood T-cell acute lymphoblastic leukaemia

    NARCIS (Netherlands)

    Ramakers-van Woerden, NL; Pieters, R; Slater, RM; Loonen, A.H.; Beverloo, HB; van Drunen, E; Heyman, M; Moreno, TC; Rots, MG; van Wering, ER; Kamps, WA; Janka-Schaub, GE; Veerman, AJP

    2001-01-01

    p16 gene deletions are present in about 70% of primary paediatric T-cell acute lymphoblastic leukaemia (T-ALL) and 20% of common/precursor B-cell ALL cases. It is not clear what the impact of the frequent p16 deletions is within the subgroup of T-lineage ALL. We studied the relationship between p16/

  15. Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study

    NARCIS (Netherlands)

    Mavinkurve-Groothuis, A.M.C.; Marcus, K.A.; Pourier, M.; Loonen, J.; Feuth, T.; Hoogerbrugge, P.M.; Korte, C.L. de; Kapusta, L.

    2013-01-01

    AIMS: The aim of this study was to investigate myocardial 2D strain echocardiography and cardiac biomarkers in the assessment of cardiac function in children with acute lymphoblastic leukaemia (ALL) during and shortly after treatment with anthracyclines. METHODS AND RESULTS: Cardiac function of 60 c

  16. Dose intensification in acute myeloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's AML9 study. MRC Leukaemia in Adults Working Party.

    Science.gov (United States)

    Rees, J K; Gray, R G; Wheatley, K

    1996-07-01

    Between 1984 and 1990, 972 patients aged 1-79 years with acute myeloid leukaemia (AML), from 85 British hospitals, were entered into the MRC's 9th AML trial. Patients were randomized between DAT 1 + 5 (daunorubicin for 1 d, with cytarabine and 6-thioguanine for 5 d) and DAT 3 + 10 (same dose drugs for 3 and 10 d respectively) as induction therapy. The 63% who achieved complete remission (CR) were randomized to receive two courses of DAT 2 + 7 alternating with two courses of either MAZE (m-AMSA, 5-azacytidine, etoposide) or COAP (cyclophosphamide, vincristine, cytarabine, prednisone). Finally, those still in CR were randomized to receive either 1 year of maintenance treatment with eight courses of cytarabine and thioguanine followed by four courses of COAP, or no further cytotoxic therapy. Resistance to induction therapy was less common with the DAT 3 + 10 regimen than with DAT 1 + 5 (13% v 23%; P = 0.0001) and hence, despite a 5% increase in the risk of induction death, the CR rate was higher (66% v 61%; P = 0.15). Moreover, CR was achieved more rapidly with DAT 3 + 10 (median 34 v 46 d; P COAP. 5-year survival was not significantly higher with MAZE (37% v 31%). Finally, although 1 year of outpatient maintenance treatment appeared to delay, but not prevent, recurrence it did not improve 5-year survival which was non-significantly worse for those allocated maintenance treatment (41% v 44%). We conclude that the more intensive induction regimen, DAT 3 + 10, is not only more effective than DAT 1 + 5, even for older patients, but is also less expensive; intensive post-remission therapy with MAZE achieves better leukaemic control but at the cost of substantial toxicity; whereas low-level maintenance therapy confers no apparent advantage in survival as well as being inconvenient and costly.

  17. CD33 monoclonal antibody conjugated Au cluster nano-bioprobe for targeted flow-cytometric detection of acute myeloid leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Retnakumari, Archana; Jayasimhan, Jasusri; Chandran, Parwathy; Menon, Deepthy; Nair, Shantikumar; Mony, Ullas; Koyakutty, Manzoor, E-mail: manzoork@aims.amrita.edu, E-mail: ullasmony@aims.amrita.edu [Amrita Centre for Nanoscience and Molecular Medicine, Amrita Institute of Medical Science, Cochin 682 041 (India)

    2011-07-15

    Protein stabilized gold nanoclusters (Au-NCs) are biocompatible, near-infrared (NIR) emitting nanosystems having a wide range of biomedical applications. Here, we report the development of a Au-NC based targeted fluorescent nano-bioprobe for the flow-cytometric detection of acute myeloid leukaemia (AML) cells. Au-NCs with {approx} 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of {approx} 0.8 nm were prepared by bovine serum albumin assisted reduction-cum-stabilization in aqueous phase. The protein protected clusters were conjugated with monoclonal antibody against CD33 myeloid antigen, which is overexpressed in {approx} 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of {approx} 12 nm retained bright fluorescence over an extended duration of {approx} a year, as the albumin protein protects Au-NCs against degradation. Nanotoxicity studies revealed excellent biocompatibility of Au-NC conjugates, as they showed no adverse effect on the cell viability and inflammatory response. Target specificity of the conjugates for detecting CD33 expressing AML cells (KG1a) in flow cytometry showed specific staining of {approx} 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of {approx} 8.2% in human peripheral blood cells (PBMCs) which are CD33{sup low}. The confocal imaging also demonstrated the targeted uptake of CD33 conjugated Au-NCs by leukaemia cells, thus confirming the flow cytometry results. This study demonstrates that novel nano-bioprobes can be developed using protein protected fluorescent nanoclusters of Au for the molecular receptor targeted flow cytometry based detection and imaging of cancer cells.

  18. Sinonasal Lymphoma Presenting as a Probable Sanctuary Site for Relapsed B Acute Lymphoblastic Leukaemia: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    W. Y. Lim

    2015-01-01

    Full Text Available Sinonasal lymphoma is a non-Hodgkin lymphoma (NHL representing 1.5% of all lymphomas. It presents as an unremitting ulceration with progressive destruction of midline sinonasal and surrounding structures. Poor prognosis warrants early treatment although diagnosis is challenging and frequently delayed. It is usually primary in origin and to our knowledge the sinonasal region has never been reported as a sanctuary site in leukaemia/lymphoma relapse. We present a unique case of B-cell ALL (acute lymphoblastic leukaemia with late relapse to the nasal septum as a sinonasal lymphoblastic lymphoma and with genetic support for this as a sanctuary site.

  19. Genome-scale definition of the transcriptional programme associated with compromised PU.1 activity in acute myeloid leukaemia.

    Science.gov (United States)

    Sive, J I; Basilico, S; Hannah, R; Kinston, S J; Calero-Nieto, F J; Göttgens, B

    2016-01-01

    Transcriptional dysregulation is associated with haematological malignancy. Although mutations of the key haematopoietic transcription factor PU.1 are rare in human acute myeloid leukaemia (AML), they are common in murine models of radiation-induced AML, and PU.1 downregulation and/or dysfunction has been described in human AML patients carrying the fusion oncogenes RUNX1-ETO and PML-RARA. To study the transcriptional programmes associated with compromised PU.1 activity, we adapted a Pu.1-mutated murine AML cell line with an inducible wild-type PU.1. PU.1 induction caused transition from leukaemia phenotype to monocytic differentiation. Global binding maps for PU.1, CEBPA and the histone mark H3K27Ac with and without PU.1 induction showed that mutant PU.1 retains DNA-binding ability, but the induction of wild-type protein dramatically increases both the number and the height of PU.1-binding peaks. Correlating chromatin immunoprecipitation (ChIP) Seq with gene expression data, we found that PU.1 recruitment coupled with increased histone acetylation induces gene expression and activates a monocyte/macrophage transcriptional programme. PU.1 induction also caused the reorganisation of a subgroup of CEBPA binding peaks. Finally, we show that the PU.1 target gene set defined in our model allows the stratification of primary human AML samples, shedding light on both known and novel AML subtypes that may be driven by PU.1 dysfunction.

  20. Azole-based chemoprophylaxis of invasive fungal infections in paediatric patients with acute leukaemia: an internal audit.

    Science.gov (United States)

    Yunus, Sara; Pieper, Stephanie; Kolve, Hedwig; Goletz, Grazyna; Jürgens, Heribert; Groll, Andreas H

    2014-03-01

    Children and adolescents with acute myeloid leukaemia (AML) and recurrent acute leukaemias (RALs) are at high risk of life-threatening invasive fungal infections (IFIs). We analysed implementation, safety and efficacy of a standard operating procedure for oral, azole-based, mould-active antifungal prophylaxis. Patients with AML and RALs aged ≥13 years received 200 mg of posaconazole three times daily and patients aged 2-12 years received 200 mg of voriconazole two times daily from the completion of chemotherapy until haematopoietic recovery. Algorithms for fever or focal findings in all patients with haematological malignancies included blood cultures, high-resolution CT and other appropriate imaging, serial serum galactomannan, invasive diagnostics and pre-emptive therapy with change in class if on antifungal medication. From 2006 to 2010, 40 patients (0.8-17 years; 21 males) with newly diagnosed AML (n = 31) or RAL (n = 9) were admitted, of whom 36 received a total of 149 courses of chemotherapy (reasons for exclusion: contraindications and early death ≤3 days). Azole prophylaxis was given in 87.2% (n = 130/149) of episodes. Pre-emptive antifungal therapy for pulmonary infiltrates was initiated in 5/36 (13.9%) patients or 6/130 (4.6%) episodes for a duration of 3-22 days. No proven or probable IFIs occurred. Adverse events (AEs) were common but mostly low grade and reversible. Three courses (2.3%) were discontinued due to AEs. In simultaneously admitted new patients with acute lymphatic leukaemia (ALL; n = 101) and paediatric lymphomas (n = 29) not receiving standard antifungal prophylaxis, proven/probable IFIs occurred in 4 patients with ALL (4.0%) and 7/130 patients (5.4%) received pre-emptive therapy. Azole-based, mould-active antifungal prophylaxis in high-risk paediatric patients with AML and RALs was satisfactorily implemented, well tolerated and effective. The low rate of IFIs in patients with ALL/lymphoma supports the lack of a general indication for

  1. International Society of Thrombosis and Hemostasis Scoring System for disseminated intravascular coagulation ≥ 6: a new predictor of hemorrhagic early death in acute promyelocytic leukemia.

    Science.gov (United States)

    Mitrovic, Mirjana; Suvajdzic, Nada; Bogdanovic, Andrija; Kurtovic, Nada Kraguljac; Sretenovic, Aleksandra; Elezovic, Ivo; Tomin, Dragica

    2013-03-01

    High-hemorrhagic early death (ED) rate is a major impediment in the managing of acute promyelocytic leukemia (APL). In our group of 56 newly diagnosed APL patients, ED occurred in 12 subjects, due to endocranial bleeding (8/12), differentiation syndrome (2/12), or infection (2/12). Predictors of hemorrhagic ED were as follows: white blood cells count ≥ 20 × 10(9)/L (P = 0.002337), Eastern cooperative oncology group performance status ≥ 3 (P = 0.00173), fibrinogen level disseminated intravascular coagulation (ISTH DIC score) ≥ 6 (P = 0.00741). Multivariate analysis indicated ISTH DIC score ≥ 6 to be the most significant predictor for hemorrhagic ED (P = 0.008). The main finding of this study is that simple coagulation-related tests, performed on hospital admission and combined in the ISTH DIC score, might help to identify patients at high risk for fatal bleeding needing more aggressive supportive measures.

  2. A Complicated Case of Acute Promyelocytic Leukemia in the Second Trimester of Pregnancy Successfully Treated with All-trans-Retinoic Acid

    Directory of Open Access Journals (Sweden)

    Kanika Agarwal

    2015-01-01

    Full Text Available A 40-year-old female at 26-week gestation was diagnosed with acute promyelocytic leukemia (APL after an abnormal prenatal lab workup showed pancytopenia. She was treated with all-trans-retinoic acid (ATRA, idarubicin, and dexamethasone. After day one of treatment, she developed differentiation syndrome, which was treated with dexamethasone. At 30-week gestation, she had preterm premature rupture of membranes and delivered by cesarean section because of the fetus’ breech presentation. Despite ATRA’s potential for teratogenicity, a viable infant was born without apparent anomalies. Postpartum, she underwent consolidation treatment with ATRA and arsenic trioxide (ATO. The patient continued ATRA therapy after delivery and is currently in remission.

  3. NPM-RAR, not the RAR-NPM reciprocal t(5;17)(q35;q21) acute promyelocytic leukemia fusion protein, inhibits myeloid differentiation.

    Science.gov (United States)

    Pollock, Sheri L; Rush, Elizabeth A; Redner, Robert L

    2014-06-01

    The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the nucleophosmin (NPM) gene at 5q35 with the retinoic acid receptor alpha (RARA) at 17q12-22. We have previously shown that leukemic cells express both NPM-RAR and RAR- NPM reciprocal translocation products. In this study we investigated the potential role of both proteins in modulating myeloid differentiation. Expression of NPM-RAR inhibited vitamin D3/transforming growth factor β (TGFβ)-mediated differentiation of U937 cells by more than 50%. In contrast, RAR-NPM expression did not alter vitamin D3/TGFβ-induced differentiation of U937 clones. These results indicate that NPM-RAR, not RAR-NPM, is the prime mediator of myeloid differentiation arrest in t(5;17) APL.

  4. Early Death in Two Patients with Acute Promyelocytic Leukemia Presenting the bcr3 Isoform, FLT3-ITD Mutation, and Elevated WT1 Level

    Directory of Open Access Journals (Sweden)

    Marianna Greco

    2013-01-01

    Full Text Available Despite major advances in the treatment of acute promyelocytic leukemia (APL, the problem of early death (ED remains unsolved. Alongside the currently known clinical and hematological risk factors, prognostic significance has been attributed to internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD, hypogranular variant morphology, and the bcr-3 isoform of PML-RARα. We describe premature death of two patients with the hypogranular variant of APL who presented remarkably high expression levels of Wilms' tumor gene (WT1. Our results point to WT1 as an important prognostic factor of ED that needs to be promptly evaluated in all newly diagnosed cases of APL.

  5. Y-chromosome loss as the sole karyotypic anomaly with 3'RARalpha submicroscopic deletion in a case of M3r subtype of acute promyelocytic leukemia.

    Science.gov (United States)

    Han, Yongsheng; Xue, Yongquan; Zhang, Jun; Pan, Jinlan; Wu, Yafang; Bai, Shuxiao

    2009-10-01

    Acute promyelocytic leukemia (APL) is characterized by the presence of a chromosomal rearrangement involving retinoic acid receptor alpha (RARalpha) gene generating the X-RARalpha fusion. We describe here a unique RARalpha gene rearrangement in a patient with M3r subtype of APL. Conventional cytogenetic analysis revealed Y-chromosome loss as the sole karyotypic anomaly. No X-RARalpha fusion was detected by fluorescence in situ hybridization (FISH) using PML/RARalpha dual-color dual-fusion translocation probe set, or RARalpha dual-color break apart rearrangement probe or reverse-transcription polymerase chain reaction (RT-PCR). However, FISH using RARalpha dual-color break apart rearrangement probe showed a deletion of the entire 3'-end of one allele of RARalpha gene. To our knowledge, this is the first documented APL with 3'RARalpha submicroscopic deletion which is not associated with X-RARalpha fusion. The molecular consequences of this anomaly remain to be elucidated.

  6. Research Progress in Pathogenesis of Acute Promyelocytic Leukemia%急性早幼粒细胞白血病发病机制研究新进展

    Institute of Scientific and Technical Information of China (English)

    鞠满凯; 张磊

    2016-01-01

    There has been deep research about the pathogenesis of acute promyelocytic leukemia .The classical pathogenesis is due to the translocation of chromosome t (15;17),the formation of promyelocyti-cleukemia (PML)/retinoic acid receptor α(RARα) fusion gene and then the generation of PML/RARαfusion protein which leads to the occurrence of the disease.In recent years,with the development of the re-search,more fusion genes are discovered,with relatively different natures.Although the classic PML/RARαaccounts for the majority of acute promyelocytic leukemia,other types have lots of differences in drug sensitiv-ity,so the pathogenesis should be made clear so as to instruct the treatment.%急性早幼粒细胞白血病的发病机制已有较深入研究,经典的发病机制是由于染色体 t (15;17)易位形成PML/维甲酸受体α(RARα)融合基因,进而产生PML/RARα融合蛋白导致疾病的发生。近年来随着研究的进展,更多的融合基因被发现,且有相对各异的性质。虽然经典的 PML/RARα占急性早幼粒细胞白血病的大多数,但其他类型基因对药物敏感性却各有不同,应明确其发病机制,指导治疗。

  7. Clinicopathological features of acute promyelocytic leukemia: an experience in one institute emphasizing the morphological and immunophenotypic changes at the time of relapse.

    Science.gov (United States)

    Yoshii, Miyuki; Ishida, Mitsuaki; Yoshida, Takashi; Okuno, Hiroko; Nakanishi, Ryota; Horinouchi, Akiko; Hodohara, Keiko; Okabe, Hidetoshi

    2013-01-01

    Acute promyelocytic leukemia (APL) has two morphological variants, namely macrogranular (M3) and microgranular (M3v). M3v, characterized by the presence of neoplastic promyelocytes with only sparse fine azurophilic granules, accounts for 10-25% of all APL and has unique biological characteristics. Relapse occurs in approximately 20% of patients with APL. The morphological type of the leukemic cells at relapse is usually identical with the primary disease, and only one case of morphological change at relapse has been reported. Here, we analyzed the clinicopathological features of APL, including 4 relapsed cases emphasizing morphological changes at the time of relapse. The unique finding of the present study is that 2 of 4 relapsed cases changed from M3 to M3v at relapse. The morphological features of these were different in each case (one had blastic features and the other resembled monocytoid leukemic cells). Cytogenetic analyses revealed the continued presence of t(15;17)(q22;q12) at the time of relapse and morphological change. Moreover, the immune phenotype of the leukemic cells changed from CD2(-)/CD34(-) to CD2(+)/CD34(+) at that time. These findings suggest that morphological change at relapse in APL may not be a rare event, and that the leukemic cells can show variable morphological features at the time of relapse, which could result in misdiagnosis as a different type of acute myeloid leukemia. Therefore, a comprehensive approach with emphasis on combined morphological, immunophenotypic, and cytogenetic analyses is important for diagnosis and appropriate treatment of relapsed APL.

  8. Nursing of acute promyelocytic leukemia with DIC%急性早幼粒细胞白血病合并DIC患者的护理

    Institute of Scientific and Technical Information of China (English)

    黎成霞

    2014-01-01

    目的:探讨急性早幼粒细胞白血病( APL)治疗期间合并DIC护理方法。方法:对2010年1月~2012年11月我科收治的16例APL患者进行密切观察,采取及时有效的护理措施。结果:实施相关护理后,16例患者中眼底出血致双眼失明1例,单眼失明1例,无死亡病例发生。结论:密切观察及早发现APL治疗期间DIC的发生,及时提供临床资料非常重要;采取正确护理,能够提高患者生活质量,降低死亡率。%Objective:To discuss the nursing measures of DIC occurred during acute promyelocytic leukemia treatment. Methods:From Jan. 2010-Nov. 2012 in our hospital treated 16 cases of acute promyelocytic leukemia patients received close observation and effective nursing. Results:1 case of bilateral blindness induced retinal hemorrhage,and 1 case of monocular blindness,no death case. Conclusion:Close observation and early detection of APL treatment during DIC,and provide clinical data timely is very important,it could improve the quality of life of patients and reduce the mortality rate.

  9. The pleiotropic effects of fisetin and hesperetin on human acute promyelocytic leukemia cells are mediated through apoptosis, cell cycle arrest, and alterations in signaling networks.

    Science.gov (United States)

    Adan, Aysun; Baran, Yusuf

    2015-11-01

    Fisetin and hesperetin, flavonoids from various plants, have several pharmaceutical activities including antioxidative, anti-inflammatory, and anticancer effects. However, studies elucidating the role and the mechanism(s) of action of fisetin and hesperetin in acute promyelocytic leukemia are absent. In this study, we investigated the mechanism of the antiproliferative and apoptotic actions exerted by fisetin and hesperetin on human HL60 acute promyelocytic leukemia cells. The viability of HL60 cells was evaluated using the MTT assay, apoptosis by annexin V/propidium iodide (PI) staining and cell cycle distribution using flow cytometry, and changes in caspase-3 enzyme activity and mitochondrial transmembrane potential. Moreover, we performed whole-genome microarray gene expression analysis to reveal genes affected by fisetin and hesperetin that can be important for developing of future targeted therapy. Based on data obtained from microarray analysis, we also described biological networks modulated after fisetin and hesperetin treatment by KEGG and IPA analysis. Fisetin and hesperetin treatment showed a concentration- and time-dependent inhibition of proliferation and induced G2/M arrest for both agents and G0/G1 arrest for hesperetin at only the highest concentrations. There was a disruption of mitochondrial membrane potential together with increased caspase-3 activity. Furthermore, fisetin- and hesperetin-triggered apoptosis was confirmed by annexin V/PI analysis. The microarray gene profiling analysis revealed some important biological pathways including mitogen-activated protein kinases (MAPK) and inhibitor of DNA binding (ID) signaling pathways altered by fisetin and hesperetin treatment as well as gave a list of genes modulated ≥2-fold involved in cell proliferation, cell division, and apoptosis. Altogether, data suggested that fisetin and hesperetin have anticancer properties and deserve further investigation.

  10. Haemostatic function and biomarkers of endothelial damage before and after platelet transfusion in patients with acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Larsen, A M; Leinøe, E B; Johansson, P I

    2015-01-01

    and after platelet transfusion in patients with acute myeloid leukaemia. MATERIALS AND METHODS: Blood was sampled before, 1 and 24 h after platelet transfusion. Primary and secondary haemostasis was evaluated by whole blood aggregometry (Multiplate) and thromboelastography (TEG). Endothelial biomarkers (s......OBJECTIVES: The beneficial effect of platelet transfusion on haemostasis is well established, but there is emerging evidence that platelet transfusion induces an inflammatory response in vascular endothelial cells. BACKGROUND: We investigated haemostatic function and endothelial biomarkers before......ICAM-1, syndecan-1, sThrombomodulin, sVE-Cadherin) and platelet activation biomarkers (sCD40L, TGF-beta) were investigated along with haematology/biochemistry analyses. RESULTS: Twenty-two patients were included. Despite continued low platelet counts, platelet transfusion normalised the median values...

  11. Incidence and significance of FLT3-ITD and NPM1 mutations in patients with normal karyotype acute myeloid leukaemia.

    LENUS (Irish Health Repository)

    Haslam, K

    2012-02-01

    BACKGROUND: Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells. Approximately half of all adult AML patients have a normal karyotype (NK-AML) and an intermediate risk prognosis. AIMS: To determine the incidence and prognostic significance of NPM1 and FLT3-ITD mutations in a population of patients with NK-AML. METHODS: FLT3-ITD and NPM1 mutation status was retrospectively sought in presentation samples from 44 NK-AML patients. RESULTS: FLT3-ITD and NPM1 mutations were detected in 45.5 and 54.5% of patients, respectively, allowing stratification according to genotype. CONCLUSIONS: FLT3-ITD and NPM1 mutation status can be defined in NK-AML. Prospective screening for these mutations is advocated in all NK-AML patients, as the genotype is of clinical importance when considering treatment options including stem cell transplantation.

  12. Discontinuation of empirical antibiotic therapy in neutropenic acute myeloid leukaemia patients with fever of unknown origin: is it ethical?

    Science.gov (United States)

    Micol, J-B; Chahine, C; Woerther, P-L; Ghez, D; Netzer, F; Dufour, C; Merad, M; Blot, F; Chachaty, E; de Botton, S; Gachot, B

    2014-07-01

    Based on recommendations of the ECIL-4, we prospectively evaluated discontinuation of empirical antibiotic therapy in high-risk neutropenic acute myeloid leukaemia patients with fever of unknown origin. Seven patients (median neutropenia duration 30 days) were included. Four of them remained afebrile but quickly recovered from neutropenia. The other three had rapid recurrent fever. Two of these three patients had bacteraemia with susceptible strains and one of them was transferred to the ICU for septic shock. Median duration of sparing of antibiotics for the seven patients was 3 days (2-4). Because of these limited results the study was stopped. © 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

  13. Successful management of hepatic mucormycosis in an acute lymphoblastic leukaemia patient: a case report and review of the literature.

    Science.gov (United States)

    Tuysuz, Gulen; Ozdemir, Nihal; Senyuz, Osman Faruk; Emre, Senol; Kantarcioglu, Serda; Adaletli, Ibrahim; Kepil, Nuray; Tutuncu, Cigdem; Celkan, Tiraje

    2014-08-01

    We present a case of hepatic mucormycosis in a 9-year-old boy with acute lymphoblastic leukaemia. Despite long-term use of combined liposomal amphotericin B and posaconazole therapy, the lesion persisted and could only be treated by surgical excision. After surgery, antifungal treatment was continued with posaconazole. On follow-up, the patient had two episodes of ascending cholangitis which were responsive to intravenous antibiotics. He is doing well at the moment in remission for 2.5 years. Mucormycosis was long regarded as a fatal infection with poor prognosis. With early medical and surgical management, survival rates increase. Isolated hepatic mucormycosis is rare and only seven cases were reported in the literature up to now. We wanted to emphasise the role of early surgery in patients with hepatic mucormycosis in view of the literature.

  14. Outcome after cessation of therapy in childhood acute lymphoblastic leukaemia. The Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP).

    Science.gov (United States)

    Jankovic, M; Fraschini, D; Amici, A; Aricò, M; Arrighini, A; Basso, G; Colella, R; DiTullio, M T; Haupt, R; Macchia, P

    1993-01-01

    A total of 2192 children with acute lymphoblastic leukaemia who had reached cessation of therapy in complete remission were followed for a median time of 52 months after treatment suspension. Of the 485 relapses observed, 62.3% occurred in the first year off therapy and 68.9% involved the bone marrow. Eight relapses were reported more than 5 years (62-143 months) after treatment withdrawal. Males fared worse than females consistently, experiencing 1.5 times more relapses (P 20 years) were married and 16 have had 21 healthy children. Twenty-four per cent of patients experienced an unfavourable event. Relapses accounted for 93% of failures. Central nervous system late effects and second malignancies were the major causes of non-leukaemic morbidity and mortality.

  15. A new Leukemia Prognostic Scoring System for refractory/relapsed adult acute myelogeneous leukaemia patients: a GOELAMS study.

    Science.gov (United States)

    Chevallier, P; Labopin, M; Turlure, P; Prebet, T; Pigneux, A; Hunault, M; Filanovsky, K; Cornillet-Lefebvre, P; Luquet, I; Lode, L; Richebourg, S; Blanchet, O; Gachard, N; Vey, N; Ifrah, N; Milpied, N; Harousseau, J-L; Bene, M-C; Mohty, M; Delaunay, J

    2011-06-01

    A simplified prognostic score is presented based on the multivariate analysis of 138 refractory/relapsed acute myeloid leukaemia (AML) patients (median age 55 years, range: 19-70) receiving a combination of intensive chemotherapy+Gemtuzumab as salvage regimen. Overall, 2-year event-free survival (EFS) and overall survival (OS) were 29±4% and 36±4%, respectively. Disease status (relapse Leukemia Prognostic Scoring System was then validated on an independent cohort of 111 refractory/relapsed AML patients. This new simplified prognostic score, using three clinical and biological parameters routinely applied, allow to discriminate around two third of the patients who should benefit from a salvage intensive regimen in the setting of refractory/relapsed AML patients. The other one third of the patients should receive investigational therapy.

  16. Outcome of hyperleukocytic adult acute myeloid leukaemia: a single-center retrospective study and review of literature.

    Science.gov (United States)

    Marbello, Laura; Ricci, Francesca; Nosari, Anna Maria; Turrini, Mauro; Nador, Guido; Nichelatti, Michele; Tedeschi, Alessandra; Vismara, Eleonora; Morra, Enrica

    2008-08-01

    Hyperleukocytic acute myeloid leukaemia is considered to have a poor prognosis due to high early death rate secondary to leukostasis. Supportive treatments do not seem to have reduced early exitus in this subset of patients. Prognostic impact of hyperleukocytosis on outcome has been the object of few studies. Clinical characteristics and outcome of 45 consecutive adult patients with newly diagnosed acute myeloid leukaemia presenting to our institution with a white cell count (WBC) above 100 x 10(9)L(-1) were reviewed. The outcome of this subset of patients was compared with 200 patients with a leukocyte count lower than 100 x 10(9)L(-1) similarly treated in the same period. Eight hyperleukocytic patients (17%) died of intracranial haemorrhage or pulmonary failure due to leukostasis within the first 7 days of treatment. A significant association was found between complete response (CR) and absence of hyperleukocytosis, but if early deaths were removed from analysis the difference was no longer significant. Hyperleukocytosis also significantly reduces the overall survival (OS) but does not significantly influence the disease-free survival (DFS). We reviewed in literature studies in which the outcome of series of at least 10 patients with hyperleukocytosis were compared with that of patients with a leukocyte count lower than 100 x 10(9)L(-1). Our data were consistent with those of the literature regarding the rate of early mortality and causes of death. In most of the reviewed series hyperleukocytosis does not seem to influence the outcome of patients. Avoiding early death seems to be an important step in this subset of patients. New data about pathophysiology of leukostasis are needed.

  17. Environmental factors and leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Brandt, L.

    1985-01-01

    Investigations on the association between environmental hazards and the development of various types of leukaemia are reviewed. Regarding acute non-lymphocytic leukaemia (ANLL) exposure to ionizing radiation is a well-documented risk factor. According to several recent studies exposure to strong electromagnetic fields may be suspected to be of etiologic importance for ANLL. There is evidence that occupational handling of benzene is a risk factor and other organic solvents may also be leukaemogenic. Occupational exposure to petrol products has been proposed to be a risk factor although the hazardous substances have not yet been defined. Results of cytogenetic studies in ANLL suggest that exposure to certain environmental agents may be associated with relatively specific clonal chromosome aberrations. Exposure in utero to ionizing radiation has been proposed to be a risk factor for acute lymphocytic leukaemia (ALL) in children. Unlike ANLL there seems at present to be little evidence that ALL is related to exposure to some chemicals. Chronic myeloid leukaemia (CML) may follow exposure to high doses of ionizing radiation whereas such exposure seems to be of insignificant importance for the development of chronic lymphocytic leukaemia (CLL). According to some studies an abnormally high incidence of CLL may be found among farmers in the USA. These results have not been confirmed in Scandinavian studies. There seems to be little evidence that CML or CLL are related to occupational handling of some chemicals. 35 references.

  18. Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients.

    Science.gov (United States)

    Lou, Yinjun; Ma, Yafang; Sun, Jianai; Ye, Xiujin; Pan, Hanzhang; Wang, Yungui; Qian, Wenbin; Meng, Haitao; Mai, Wenyuan; He, JingSong; Tong, Hongyan; Jin, Jie

    2015-11-01

    The aim of the study is to better understand the mechanism of relapse and acquired clinical resistance to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Thirty relapsed acute promyelocytic leukemia (APL) patients were followed. Fifteen patients experienced two or more relapses; nine patients had clinical resistance to ATO-based therapy. The frequency and clinical significance of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) mutational status using Sanger sequencing were evaluated. Overall, eight different types of mutations in the RARA region (V218D, R272Q, T278A, T291I, N299D, R294W, A300G, and L220_F228delinsP) were identified in 11 patients. Eight missense mutations (L211P, C213R, S214L, A216V, L217F, D219H, S221G, and D241G) were found in the PML portion of PML-RARA in 14 patients, with A216V as the predominant mutation. Eight patients were found to harbor both PML and RARA mutations over the course of the disease. The PML-region mutations were associated with response to ATO-based therapy (P < 0.0001), number of relapses (P = 0.001), and early relapse (P = 0.013). Notably, one case sampled at nine different time points showed alternating clonal dominance over the course of treatment. This study demonstrated frequent mutations of PML-RARA and supported a clonal selection model in relation to APL relapse and ATO resistance.

  19. Arsenic sulfide promotes apoptosis in retinoid acid resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein.

    Directory of Open Access Journals (Sweden)

    Yuwang Tian

    Full Text Available Tetra-arsenic tetra-sulfide (As4S4 is an arsenic compound with anti-tumor activity, especially in acute promyelocytic leukemia (APL that are resistant to retinoic acid (RA. Although recent studies revealed that the therapeutic action of As4S4 is closely associated with the induction of cellular apoptosis, the exact molecular mechanism of action of As4S4 in RA-resistant APL remains to be clarified. In this study, we found that As4S4-induced apoptosis was accompanied by reduced mRNA and protein expression of SET gene in RA-resistant NB4-R1 cells. Moreover, RNAi knockdown of SET gene further promoted As4S4-induced apoptosis, while SET over-expression inhibited it, suggesting that As4S4 induces apoptosis through the reduction of SET protein in NB4-R1 cells. We also demonstrated that the knockdown of SET gene resulted in the upregulation of protein phosphatase 2 (PP2A expression and the downregulation of promyelocytic leukemia and retinoic acid receptor α fusion gene (PML-RARα expression, which were enhanced by As4S4 treatments. By contrast, over-expression of SET gene resulted in PP2A downregulation and PML-RARα upregulation, which were abolished by As4S4 pretreatment. Since PP2A is a pro-apoptotic factor and PMLRARα is an anti-apoptotic factor, our results suggest that As4S4-induced apoptosis in NB4-R1 cells is through the downregulation of SET protein expression, which in turn increases PP2A and reduces PML-RARα expressions to lead to cell apoptosis.

  20. Clonal diversity of Ig and T-cell receptor gene rearrangements in childhood B-precursor acute lymphoblastic leukaemia.

    Science.gov (United States)

    Stankovic, T; Weston, V; McConville, C M; Green, E; Powell, J E; Mann, J R; Darbyshire, P J; Taylor, A M

    2000-01-01

    The majority of paediatric B precursor acute lymphoblastic leukaemias in children are derived from a single transformed haematopoietic cell with complete or partial VDJ recombination within the immunoglobulin heavy chain gene. A high frequency of patients also show rearrangements within TCRdelta and TCRgamma loci and in up to 40% of children there is an excess of immune system gene rearrangements compared with the number of identified alleles of immune system genes, suggesting the presence of multiple leukaemic subclones -clonal diversity. It has been observed by us and other investigators that in individual patients the pattern of immune system gene rearrangements often changes between presentation and relapse. In order to explore the possibility that clonal diversity plays a biological role during disease progression we optimised methods for subclone detection and analysed the prognostic significance of clonal diversity among 75 children with B precursor-ALL. Our results suggest that clonal diversity plays a role in disease progression as patients with oligoclonal disease showed a significantly shorter disease free survival than patients with monoclonal disease. This trend was of particular importance in the 'standard risk' group of ALL where aggressive disease could not be recognised by other means. In addition, generation of independent subclones from an early, non-rearranged tumour progenitor appears to be a common feature among leukaemias with aggressive clinical behaviour. We speculate on the type of genetic factors which may participate both in the generation of subclones and also in wider genomic instability and which are likely to be required for the aggressive clinical phenotype in children with ALL.

  1. True histiocytic lymphoma following B-acute lymphoblastic leukaemia: case report with evidence for a common clonal origin in both neoplasms.

    Science.gov (United States)

    Bouabdallah, R; Abéna, P; Chetaille, B; Aurran-Schleinitz, T; Sainty, D; Dubus, P; Arnoulet, C; Coso, D; Xerri, L; Gastaut, J A

    2001-06-01

    True histiocytic lymphoma (THL) is a very rare type of non-Hodgkin's lymphoma (NHL) in which neoplastic cells exhibit markers of histiocytic differentiation. Some cases of THL have been reported in patients with previous acute lymphoblastic leukaemia (ALL), especially in children and young adults, in whom the acute leukaemia was of T-cell origin. The relationship between the initial lymphoid tumour and the secondary THL remains unclear, as a common monoclonal origin shared by both neoplasms has never been definitively demonstrated. We report a patient with B-ALL who developed a nodal and extranodal tumour with histological and immunohistochemical features of THL 4 years after the initial diagnosis. Genotypic study showed that both neoplasms contained the same immunoglobulin heavy gene rearrangement, which has not been reported previously.

  2. Persistence of DNMT3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia

    Science.gov (United States)

    Bhatnagar, Bhavana; Eisfeld, Ann-Kathrin; Nicolet, Deedra; Mrózek, Krzysztof; Blachly, James S.; Orwick, Shelley; Lucas, David M.; Kohlschmidt, Jessica; Blum, William; Kolitz, Jonathan E.; Stone, Richard M.; Bloomfield, Clara D.; Byrd, John C.

    2016-01-01

    Summary Somatic mutation of the DNMT3A gene at the arginine R882 site is common in acute myeloid leukaemia (AML). The prognostic significance of DNMT3A R882 mutation clearance, using traditional diagnostic next generation sequencing (NGS) methods, during complete remission (CR) in AML patients is controversial. We examined the impact of clearing DNMT3A R882 mutations at diagnosis to the detectable threshold of NGS methods, persist in the majority of AML patients in CR. PMID:27476855

  3. 治疗急性早幼粒细胞白血病的几个问题%Problems in the treatment of acute promyelocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    林凤茹; 郭晓楠; 任金海

    2011-01-01

    Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia, is characterized by rapid progress, prone to developing DIC, and high mortality. Typical chromosome translocation with PMLRARα fusion gene occurs in more than 95% of APL cases. Since 1986, the outcome of APL has been significantly improved in our country by firstly using ATRA and ATO for treating APL, making APL of AML curable by chemotherapy only. Based on our limited experiences, we discussed the related problems in the treatment of APL.%急性早幼粒细胞白血病(APL)为急性髓系白血病的一个亚型,以进展快,易发生弥散性血管内凝血(DIC)和死亡率高为特征.95%以上APL患者有典型染色体易位t(15;17)形成PMLRARα融合基因.1986年以来,中国首创以全反式维甲酸(ATRA)和亚砷酸(ATO)治疗APL,使APL的转归大大改观,成为仅用药物可治愈的AML.结合作者经验讨论治疗APL中的有关问题.

  4. Acute WT1-positive promyelocytic leukemia with hypogranular variant morphology, bcr-3 isoform of PML-RARα and Flt3-ITD mutation: a rare case report

    Directory of Open Access Journals (Sweden)

    Xi Zhang

    Full Text Available ABSTRACT CONTEXT: Acute promyelocytic leukemia (APL accounts for 8% to 10% of cases of acute myeloid leukemia (AML. Remission in cases of high-risk APL is still difficult to achieve, and relapses occur readily. CASE REPORT: Here, we describe a case of APL with high white blood cell counts in blood tests and hypogranular variant morphology in bone marrow, together with fms-like tyrosine kinase-3 with internal tandem duplication mutations (FLT3-ITD, and bcr-3 isoform of PML-RARα. Most importantly, we detected high level of Wilms’ tumor gene (WT1 in marrow blasts, through the reverse transcription polymerase chain reaction (RT-PCR. To date, no clear conclusions about an association between WT1 expression levels and APL have been reached. This patient successively received a combined treatment regimen consisting of hydroxycarbamide, arsenic trioxide and idarubicin plus cytarabine, which ultimately enabled complete remission. Unfortunately, he subsequently died of sudden massive hemoptysis because of pulmonary infection. CONCLUSION: Based on our findings and a review of the literature, abnormal functioning of WT1 may be a high-risk factor in cases of APL. Further studies aimed towards evaluating the impact of WT1 expression on the prognosis for APL patients are of interest.

  5. Implication of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukin-3 (IL-3) in Children with Acute Myeloid Leukaemia (AML).

    Science.gov (United States)

    Elbaz, O; Shaltout, A

    2000-01-01

    Granulocyte-macrophage colony stimulating factor (GM-CSF) and Interleukin-3 (IL-3) are increasingly used to stimulate granulopoiesis in neutropenic patients but these are rarely used in the lights of knowledge of the endogenous CSF-levels. In this study we measured serum levels of GM-CSF and IL-3 at diagnosis and after remission in children with acute leukaemia, using an enzyme linked immuno-sorbent assay (ELISA) techniques in 14 patients with acute myeloid leukaemia (AML) and 27 patients with acute lymphoblastic leukaemia (ALL). Twelve healthy age-matched children were used as a reference group. AML patients showed a highly significant increase in serum levels of GM-CSF and IL-3 before induction of therapy (p 0.5), with no significant difference between preinduction and postinduction serum levels of either (p > 0.5). Since these cytokines are known to be fundamental for the growth of AML cells, we postulate that the pretreatment levels of both GM-CSF and IL-3 could play a role in the pathogenesis of AML.

  6. Implication of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukin-3 (IL-3) in Children with Acute Myeloid Leukaemia (AML); Malignancy.

    Science.gov (United States)

    Elbaz, Osama; Shaltout, Ali

    2001-01-01

    Granulocyte-macrophage colony stimulating factor (GM-CSF) and Interleukin-3 (IL-3) are increasingly used to stimulate granulopoiesis in neutropenic patients but these are rarely used in the lights of knowledge of the endogenous CSF-levels. In this study we measured serum levels of GM-CSF and IL-3 at diagnosis and after remission in children with acute leukaemia, using an enzyme linked immuno-sorbent assay (ELISA) techniques in 14 patients with acute myeloid leukaemia (AML) and 27 patients with acute lymphoblastic leukaemia (ALL). Twelve healthy age-matched children were used as a reference group. AML patients showed a highly significant increase in serum levels of GM-CSF and IL-3 before induction of therapy (p 0.5), with no significant difference between preinduction and postinduction serum levels of either (p > 0.5). Since these cytokines are known to be fundamental for the growth of AML cells, we postulate that the pretreatment levels of both GM-CSF and IL-3 could play a role in the pathogenesis of AML.

  7. PROGNOSIS AND THERAPY WHEN ACUTE PROMYELOCYTIC LEUKEMIA AND OTHER “GOOD RISK” ACUTE MYELOID LEUKEMIAS OCCUR AS A THERAPY-RELATED MYELOID NEOPLASM

    Directory of Open Access Journals (Sweden)

    Richard A. Larson

    2011-07-01

    Full Text Available Treatment for a pre-existing condition using chemotherapy, radiation therapy, immunosuppressive therapy, or a combination of these modalities may lead to the devastating complication of therapy-related myelodysplastic syndrome or acute myeloid leukemia (t-MDS/t-AML, collectively known as therapy-related myeloid neoplasm (t-MN. This disorder arises as a direct consequence of mutational events induced by the primary treatment.  The outcomes for these patients have been historically poor compared to people who develop AML de novo.  Currently comprising 10-20% of all cases of AML, t-MN is relatively resistant to conventional leukemia therapies, and is associated with short survival times. Median life expectancy from diagnosis is about 8-10 months in most series. Although the spectrum of cytogenetic abnormalities in t-AML is similar to AML de novo, the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-MN.  Two distinct groups of patients with t-MN have been described. The more common subtype, seen in about 75% of patients, typically occurs 5-7 years after first exposure to alkylating agents or radiation, is often preceded by a myelodysplastic syndrome, and is frequently accompanied by clonal cytogenetic abnormalities such as the loss of all or part of chromosomes 5 or 7. Mutations of the P53 tumor suppressor gene are also common.  The risk is related to total cumulative exposure over time to alkylating agents. In contrast, among individuals who develop t-AML after treatment with topoisomerase II inhibitors, the latency period to the development of t-AML is often only 1-3 years, antecedent MDS is rare, and gene rearrangements involving MLL at 11q23 or RUNX1/AML1 at 21q22 are common. It is now well recognized that acute promyelocytic leukemia (APL and other subtypes of AML with balanced translocations sometimes occur as a t-MN in patients who have previously

  8. 急性早幼粒细胞白血病的发病机制及治疗进展%Advance in the pathogenesis and treatment of acute promyelocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    谢琴芬; 金洁; 黄健

    2009-01-01

    急性早幼粒细胞白血病(APL)是目前发病机制了解最清楚的血液系统恶性肿瘤.维甲酸和三氧化二砷直接针对PML-RARα融合蛋白的治疗使得该疾病成为肿瘤靶向治疗的第一个模型,各种新型治疗方案也得到了广泛的关注.现对APL的发病机制及最新的临床治疗进展进行总结和讨论.%Pathogenesis of acute promyelocytic leukemia is one of the best understood disease among human hematological malignancies. Becasue of retinoic acid (RA) and arsenic trioxide which directly target the oncogenic promyelocytic leukemia-retinoic receptor A (PML-RARα) fusion protein, this disease became the first model for oncogene-targeted therapies.And other new therapy methods also gain great concern. The complexity of recent views of acute promyelocytic leukemia pathogenesis, as well as latest progress in clinical treatment were summarized and discussed in this review.

  9. Co-expression of t(15;17 and t(8;21 in a Case of Acute Promyelocytic Leukemia: Review of the Literature

    Directory of Open Access Journals (Sweden)

    Burak Uz

    2013-12-01

    Full Text Available Additional chromosomal abnormalities in acute myelogenous leukemia have been identified as one of the most important prognostic factors. Favorable chromosomal changes such as t(8;21, inv(16, and t(15;17 are associated with higher rates of complete remission and event-free survival. Translocation (15;17 characterizes acute promyelocytic leukemia (APL (French- American-British class M3 in almost all patients. Secondary chromosomal abnormalities are also present in approximately 23%-29% of patients with newly diagnosed APL. The prognostic implications of t(8;21 and other secondary cytogenetic aberrations in APL are reviewed here. We present a 47-year-old woman diagnosed with APL whose initial cytogenetic analysis included both t(8;21 and t(15;17. The initial induction chemotherapy included 3 days of idarubicin (12 mg/m2/day and daily all-trans retinoic acid (ATRA; 45 mg/m2/day. At the sixth week of treatment, a control bone marrow biopsy was found to be normocellular, t(15;17 bcr3 and t(8;21 were negative, and t(15;17 bcr1 fusion transcripts were reduced from 5007 (1.78525699% copies per 1 μg RNA to 40 (0.00062020% with real-time quantitative polymerase chain reaction. Consolidation with 4 days of idarubicin (5 mg/m2/day, ATRA (45 mg/m2/day for 15 days, and cytarabine (1 g/m2/day for 4 days was then started. However, the patient became pancytopenic and had neutropenic fever after consolidation treatment. Unfortunately, she died 3 months after the time of APL diagnosis, due to acute respiratory distress syndrome-like respiratory problems and multiorgan dysfunction requiring respiratory support and hemodialysis.

  10. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy

    DEFF Research Database (Denmark)

    Grövdal, Michael; Karimi, Mohsen; Khan, Rasheed

    2010-01-01

    This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction...... and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated......-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients....

  11. Clinical effectiveness of palifermin in prevention and treatment of oral mucositis in children with acute lymphoblastic leukaemia:a case-control study

    Institute of Scientific and Technical Information of China (English)

    Dorina Lauritano; Massimo Petruzzi; Dario Di Stasio; Alberta Lucchese

    2014-01-01

    The aim of this study was to evaluate the efficacy of palifermin, an N-terminal truncated version of endogenous keratinocyte growth factor, in the control of oral mucositis during antiblastic therapy. Twenty patients undergoing allogeneic stem-cell transplantation for acute lymphoblastic leukaemia were treated with palifermin, and compared to a control group with the same number of subjects and similar inclusion criteria. Statistical analysis were performed to compare the outcomes in the treatment vs. control groups. In the treatment group, we found a statistically significant reduction in the duration of parenteral nutrition (P50.002), duration of mucositis (P50.003) and the average grade of mucositis (P50.03). The statistical analysis showed that the drug was able to decrease the severity of mucositis. These data, although preliminary, suggest that palifermin could be a valid therapeutic adjuvant to improve the quality of life of patients suffering from leukaemia.

  12. Clinical Study on Prospective Efficacy of All-Trans Acid, Realgar-Indigo Naturalis Formula Combined with Chemotherapy as Maintenance Treatment of Acute Promyelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Li Xiang-Xin

    2014-01-01

    Full Text Available Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA, Realgar-Indigo naturalis formula (RIF and chemotherapy (CT were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL. Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen, while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX plus 6-mercaptopurine (6-MP alternately (ATRA/CTlow regimen. The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity.

  13. Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype.

    Science.gov (United States)

    Poiré, Xavier; Moser, Barry K; Gallagher, Robert E; Laumann, Kristina; Bloomfield, Clara D; Powell, Bayard L; Koval, Gregory; Gulati, Kabir; Holowka, Nicholas; Larson, Richard A; Tallman, Martin S; Appelbaum, Frederick R; Sher, Dorie; Willman, Cheryl; Paietta, Elisabeth; Stock, Wendy

    2014-07-01

    The addition of arsenic trioxide (ATO) to frontline therapy of acute promyelocytic leukemia (APL) has been shown to result in significant improvements in disease-free survival (DFS). FLT3 mutations are frequently observed in APL, but its prognostic significance remains unclear. We analyzed 245 newly diagnosed adult patients with APL treated on intergroup trial C9710 and evaluated previously defined biological and prognostic factors and their relationship to FLT3 mutations and to additional karyotypic abnormalities. FLT3 mutations were found in 48% of patients, including 31% with an internal tandem duplication (FLT3-ITD), 14% with a point mutation (FLT3-D835) and 2% with both mutations. The FLT3-ITD mutant level was uniformly low, < 0.5. Neither FLT3 mutation had an impact on remission rate, induction death rate, DFS or overall survival (OS). The addition of ATO consolidation improved outcomes regardless of FLT3 mutation type or level, initial white blood cell count, PML-RARA isoform type or transcript level. The presence of a complex karyotype was strongly associated with an inferior OS independently of post-remission treatment. In conclusion, the addition of ATO to frontline therapy overcomes the impact of previously described adverse prognostic factors including FLT3 mutations. However, complex karyotype is strongly associated with an inferior OS despite ATO therapy.

  14. 急性早幼粒细胞白血病21例临床分析%Clinic Study about 21 Cases of Acute Promyelocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    张建瑜; 唐加明

    2007-01-01

    目的 探讨急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)合并出血的临床特点和防治方法.方法 回顾性分析21例APL患者的临床特点及疗效.结果 初诊时合并出血症状20例(95.2%),合并弥漫性血管内凝血(DIC)10例(47.6%),早期死亡5例(23.8%),经全反式维A酸等治疗及血小板及凝血因子输注后完全缓解13例(61.9%).结论 APL出血发生率高,全反式维A酸(ATRA)的应用、血小板及凝血因子输注等治疗可以减少早期出血病死率.

  15. Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo

    Science.gov (United States)

    Atashrazm, Farzaneh; Lowenthal, Ray M.; Dickinson, Joanne L.; Holloway, Adele F.; Woods, Gregory M.

    2016-01-01

    The morbidity and mortality associated with current therapies for acute promyelocytic leukemia (APL) remain a significant clinical concern, despite improvements in patient survival. Consequently, the development of adjuvant therapies that increase efficacy while reducing morbidities is important. Reducing the concentration of the toxic drugs in adjuvant therapy has the potential to reduce unwanted side effects. Therefore, this study aimed to determine the synergistic effects of fucoidan, an anti-tumor agent, with current APL therapies. When the human APL cell line, NB4, was treated in vitro with fucoidan plus ATO and ATRA at therapeutic and sub-therapeutic doses, there was an increase in sub-G0/G1 cells, annexin V/PI-positive-apoptotic cells and DNA fragmentation. This reduction in proliferation and increase in apoptosis was accompanied by enhanced myeloid differentiation as indicated by an increased expression of CD11b. This was not observed with the AML cell line Kasumi-1, suggesting specificity for APL. In vivo treatment of APL-bearing mice with fucoidan+ATRA or fucoidan+ATO delayed tumor growth, induced differentiation and increased tumor volume doubling time. The differentiated APL cells derived from the excised tumor mass exhibited decreased CD44 expression in fucoidan+ATRA treated mice. This could translate to decreased cell migration in APL patients. Our findings provide evidence supporting the use of fucoidan as an adjuvant therapeutic agent in the treatment of APL. PMID:27329592

  16. Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo.

    Science.gov (United States)

    Atashrazm, Farzaneh; Lowenthal, Ray M; Dickinson, Joanne L; Holloway, Adele F; Woods, Gregory M

    2016-07-19

    The morbidity and mortality associated with current therapies for acute promyelocytic leukemia (APL) remain a significant clinical concern, despite improvements in patient survival. Consequently, the development of adjuvant therapies that increase efficacy while reducing morbidities is important. Reducing the concentration of the toxic drugs in adjuvant therapy has the potential to reduce unwanted side effects. Therefore, this study aimed to determine the synergistic effects of fucoidan, an anti-tumor agent, with current APL therapies.When the human APL cell line, NB4, was treated in vitro with fucoidan plus ATO and ATRA at therapeutic and sub-therapeutic doses, there was an increase in sub-G0/G1 cells, annexin V/PI-positive-apoptotic cells and DNA fragmentation. This reduction in proliferation and increase in apoptosis was accompanied by enhanced myeloid differentiation as indicated by an increased expression of CD11b. This was not observed with the AML cell line Kasumi-1, suggesting specificity for APL.In vivo treatment of APL-bearing mice with fucoidan+ATRA or fucoidan+ATO delayed tumor growth, induced differentiation and increased tumor volume doubling time. The differentiated APL cells derived from the excised tumor mass exhibited decreased CD44 expression in fucoidan+ATRA treated mice. This could translate to decreased cell migration in APL patients.Our findings provide evidence supporting the use of fucoidan as an adjuvant therapeutic agent in the treatment of APL.

  17. Targeting PML-RARα and Oncogenic Signaling Pathways by Chinese Herbal Mixture Tien-Hsien Liquid in Acute Promyelocytic Leukemia NB4 Cells

    Directory of Open Access Journals (Sweden)

    Chih-Jung Yao

    2011-01-01

    Full Text Available Tien-Hsien Liquid (THL is a Chinese herbal mixture that has been used worldwide as complementary treatment for cancer patients in the past decade. Recently, THL has been shown to induce apoptosis in various types of solid tumor cells in vitro. However, the underlying molecular mechanisms have not yet been well elucidated. In this study, we explored the effects of THL on acute promyelocytic leukemia (APL NB4 cells, which could be effectively treated by some traditional Chinese remedies containing arsenic trioxide. The results showed THL could induce G2/M arrest and apoptosis in NB4 cells. Accordingly, the decrease of cyclin A and B1 were observed in THL-treated cells. The THL-induced apoptosis was accompanied with caspase-3 activation and decrease of PML-RARα fusion protein. Moreover, DNA methyltransferase 1 and oncogenic signaling pathways such as Akt/mTOR, Stat3 and ERK were also down-regulated by THL. By using ethyl acetate extraction and silica gel chromatography, an active fraction of THL named as EAS5 was isolated. At about 0.5–1% of the dose of THL, EAS5 appeared to have most of THL-induced multiple molecular targeting effects in NB4 cells. Based on the findings of these multi-targeting effects, THL might be regarding as a complementary and alternative therapeutic agent for refractory APL.

  18. Severe stomatitis and ileocecal perforation developed after all-trans retinoic acid monotherapy in an HLA-B51-positive patient with acute promyelocytic leukemia.

    Science.gov (United States)

    Kimura, Kenji; Takeuchi, Masahiro; Hasegawa, Nagisa; Togasaki, Emi; Shimizu, Ryoh; Kawajiri, Chika; Muto, Tomoya; Tsukamoto, Shokichi; Takeda, Yusuke; Ohwada, Chikako; Sakaida, Emiko; Sakai, Shio; Mimura, Naoya; Ota, Satoshi; Iseki, Tohru; Nakaseko, Chiaki

    2016-06-01

    A 34-year-old man who had been referred to our hospital was diagnosed with acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA), oral administration, was initiated. On day 25, he developed fever and respiratory distress with bilateral pulmonary infiltrates, suggesting differentiation syndrome (DS) caused by ATRA. These symptoms showed amelioration after discontinuing ATRA and initiating methylprednisolone. ATRA was re-started on day 29 at half the original dose because of residual APL blasts. The patient subsequently developed fever, severe stomatitis, and oropharyngeal ulcers, which persisted even after discontinuing ATRA. On day 48, he suddenly developed severe abdominal pain with free air, observable on an abdominal X-ray, and underwent emergency ileocecal resection. Pathological examination of the resected ileocecal intestines revealed multiple ulcers and perforations. No leukemic cell infiltration was observed. In this case, only ATRA was administered for APL treatment. These findings suggest that ileocecal ulcerations and perforations, as well as oropharyngeal ulcers, might have been caused by DS or ATRA. Furthermore, DNA typing of the HLA-B locus revealed that the patient had HLA-B51 associated with Behçet's disease. Therefore, hypercytokinemia with DS might have induced Behçet's disease-like symptoms, including stomatitis and ileocecal perforation, complications that are particularly observed in patients with HLA-B51.

  19. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity.

    Science.gov (United States)

    Jacoby, Elad; Nguyen, Sang M; Fountaine, Thomas J; Welp, Kathryn; Gryder, Berkley; Qin, Haiying; Yang, Yinmeng; Chien, Christopher D; Seif, Alix E; Lei, Haiyan; Song, Young K; Khan, Javed; Lee, Daniel W; Mackall, Crystal L; Gardner, Rebecca A; Jensen, Michael C; Shern, Jack F; Fry, Terry J

    2016-07-27

    Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.

  20. Empirical caspofungin therapy in clinical practice for suspected invasive fungal disease in adults with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Kiehl, Michael G; Egerer, Gerlinde; Engelhardt, Monika; Gross, Barbara

    2015-02-01

    Patients with acute lymphoblastic leukaemia (ALL) after cytotoxic chemotherapy or haematopoietic stem cell transplantation (HSCT) are at risk for life-threatening invasive fungal disease (IFD). The aim was to evaluate the characteristics, antifungal therapy and outcome of adult patients with ALL after chemotherapy or HSCT receiving caspofungin empirically in a clinical setting. Retrospective chart reviews were conducted at nine large tertiary care centres in Germany. Adult patients with ALL treated empirically with caspofungin according to the product label between 2006 and 2012 were eligible. Data were extracted as case reports. In total, 25 patients (12 males, 13 females; median age 37 years; 19 with B-ALL, 6 with T-ALL) with 28 treatment episodes because of suspected IFD (18 episodes after chemotherapy, 10 episodes after allogeneic HSCT) were included in the analysis. Empirical caspofungin therapy (median duration: 19 days, range 1-105 days) was given as first-line monotherapy in 20 (71.4%), second-line monotherapy in five (17.9%) and combination therapy in three (10.7%) episodes respectively. Therapy rated successful according to the physician's overall assessment (inflammatory parameters, clinical symptoms): 20 (95%) of 21 evaluable episodes with therapy duration of at least 8 days. Empirical caspofungin appears to be an effective therapeutic option in critically ill adult ALL patients with suspected IFD in clinical practice.

  1. Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia.

    Science.gov (United States)

    Vidriales, María-Belén; Pérez-López, Estefanía; Pegenaute, Carlota; Castellanos, Marta; Pérez, José-Juan; Chandía, Mauricio; Díaz-Mediavilla, Joaquín; Rayón, Consuelo; de Las Heras, Natalia; Fernández-Abellán, Pascual; Cabezudo, Miguel; de Coca, Alfonso García; Alonso, Jose M; Olivier, Carmen; Hernández-Rivas, Jesús M; Montesinos, Pau; Fernández, Rosa; García-Suárez, Julio; García, Magdalena; Sayas, María-José; Paiva, Bruno; González, Marcos; Orfao, Alberto; San Miguel, Jesús F

    2016-01-01

    The clinical utility of minimal residual disease (MRD) analysis in acute myeloid leukaemia (AML) is not yet defined. We analysed the prognostic impact of MRD level at complete remision after induction therapy using multiparameter flow cytometry in 306 non-APL AML patients. First, we validated the prognostic value of MRD-thresholds we have previously proposed (≥ 0.1%; ≥ 0.01-0.1%; and Cytogenetics is the most relevant prognosis factor in AML, however intermediate risk cytogenetics represent a grey zone that require other biomarkers for risk stratification, and we show that MRD evaluation discriminate three prognostic subgroups (p=0.03). Also, MRD assessments yielded relevant information on favourable and adverse cytogenetics, since patients with favourable cytogenetics and high MRD levels have poor prognosis and patients with adverse cytogenetics but undetectable MRD overcomes the adverse prognosis. Interestingly, in patients with intermediate or high MRD levels, intensification with transplant improved the outcome as compared with chemotherapy, while the type of intensification therapy did not influenced the outcome of patients with low MRD levels. Multivariate analysis revealed age, MRD and cytogenetics as independent variables. Moreover, a scoring system, easy in clinical practice, was generated based on MRD level and cytogenetics.

  2. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.

    Science.gov (United States)

    Middeke, Jan M; Herold, Sylvia; Rücker-Braun, Elke; Berdel, Wolfgang E; Stelljes, Matthias; Kaufmann, Martin; Schäfer-Eckart, Kerstin; Baldus, Claudia D; Stuhlmann, Reingard; Ho, Anthony D; Einsele, Hermann; Rösler, Wolf; Serve, Hubert; Hänel, Mathias; Sohlbach, Kristina; Klesse, Christian; Mohr, Brigitte; Heidenreich, Falk; Stölzel, Friedrich; Röllig, Christoph; Platzbecker, Uwe; Ehninger, Gerhard; Bornhäuser, Martin; Thiede, Christian; Schetelig, Johannes

    2016-03-01

    Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.

  3. Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    Akahane, Koshi; Li, Zhaodong; Etchin, Julia; Berezovskaya, Alla; Gjini, Evisa; Masse, Craig E; Miao, Wenyan; Rocnik, Jennifer; Kapeller, Rosana; Greenwood, Jeremy R; Tiv, Hong; Sanda, Takaomi; Weinstock, David M; Look, A Thomas

    2017-04-01

    Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI-031301 treatment and was responsible for NDI-031301-induced T-ALL cell death, as pharmacological inhibition of p38 MAPK partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI-031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT-K1 T-ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T-ALL.

  4. Vitamin and mineral supplements in pregnancy and the risk of childhood acute lymphoblastic leukaemia: a case-control study

    Directory of Open Access Journals (Sweden)

    Skegg David CG

    2007-07-01

    Full Text Available Abstract Background An earlier case-control study from Western Australia reported a protective effect of maternal folic acid supplementation during pregnancy on the risk of childhood acute lymphoblastic leukaemia (ALL. The present study tested that association. Methods A national case-control study was conducted in New Zealand. The mothers of 97 children with ALL and of 303 controls were asked about vitamin and mineral supplements taken during pregnancy. Results There was no association between reported folate intake during pregnancy and childhood ALL (adjusted odds ratio (OR 1.1, 95% confidence interval (CI 0.5–2.7. Combining our results with the study from Western Australia and another study from Québec in a meta-analysis gave a summary OR of 0.9 (95% CI 0.8–1.1. Conclusion Our own study, of similar size to the Australian study, does not support the hypothesis of a protective effect of folate on childhood ALL. Neither do the findings of the meta-analysis.

  5. Vitamin and mineral supplements in pregnancy and the risk of childhood acute lymphoblastic leukaemia: a case-control study.

    Science.gov (United States)

    Dockerty, John D; Herbison, Peter; Skegg, David C G; Elwood, Mark

    2007-07-03

    An earlier case-control study from Western Australia reported a protective effect of maternal folic acid supplementation during pregnancy on the risk of childhood acute lymphoblastic leukaemia (ALL). The present study tested that association. A national case-control study was conducted in New Zealand. The mothers of 97 children with ALL and of 303 controls were asked about vitamin and mineral supplements taken during pregnancy. There was no association between reported folate intake during pregnancy and childhood ALL (adjusted odds ratio (OR) 1.1, 95% confidence interval (CI) 0.5-2.7). Combining our results with the study from Western Australia and another study from Québec in a meta-analysis gave a summary OR of 0.9 (95% CI 0.8-1.1). Our own study, of similar size to the Australian study, does not support the hypothesis of a protective effect of folate on childhood ALL. Neither do the findings of the meta-analysis.

  6. Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial.

    Science.gov (United States)

    Patel, B; Kirkwood, A A; Dey, A; Marks, D I; McMillan, A K; Menne, T F; Micklewright, L; Patrick, P; Purnell, S; Rowntree, C J; Smith, P; Fielding, A K

    2017-01-01

    Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/m(2) PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25-65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death >40 versus ⩽40 years, odds ratio (OR) 18.5 (2.02-169.0), P=0.01; Ph- versus Ph+ disease, OR 13.60 (3.52-52.36), P40 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib.

  7. Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute Myeloid Leukaemia and Clonal Haematopoiesis

    Science.gov (United States)

    Chaudry, Sabah F.

    2017-01-01

    Acute myeloid leukaemia (AML) is a haematological malignancy characterized by clonal stem cell proliferation and aberrant block in differentiation. Dysfunction of epigenetic modifiers contributes significantly to the pathogenesis of AML. One frequently mutated gene involved in epigenetic modification is DNMT3A (DNA methyltransferase-3-alpha), a DNA methyltransferase that alters gene expression by de novo methylation of cytosine bases at CpG dinucleotides. Approximately 22% of AML and 36% of cytogenetically normal AML cases carry DNMT3A mutations and around 60% of these mutations affect the R882 codon. These mutations have been associated with poor prognosis and adverse survival outcomes for AML patients. Advances in whole-exome sequencing techniques have recently identified a large number of DNMT3A mutations present in clonal cells in normal elderly individuals with no features of haematological malignancy. Categorically distinct from other preleukaemic conditions, this disorder has been termed clonal haematopoiesis of indeterminate potential (CHIP). Further insight into the mutational landscape of CHIP may illustrate the consequence of particular mutations found in DNMT3A and identify specific “founder” mutations responsible for clonal expansion that may contribute to leukaemogenesis. This review will focus on current research and understanding of DNMT3A mutations in both AML and CHIP. PMID:28286768

  8. Clinical effectiveness and cost-effectiveness of stem cell transplantation in the management of acute leukaemia: a systematic review.

    Science.gov (United States)

    Ashfaq, K; Yahaya, I; Hyde, C; Andronis, L; Barton, P; Bayliss, S; Chen, Y-F

    2010-12-01

    Acute leukaemia is a group of rapidly progressing cancers of bone marrow and blood classified as either acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL). Haemopoietic stem cell transplantation (SCT) has developed as an adjunct to or replacement for conventional chemotherapy with the aim of improving survival and quality of life. A systematic overview of the best available evidence on the clinical effectiveness and cost-effectiveness of SCT in the treatment of acute leukaemia. Clinical effectiveness: electronic databases, including MEDLINE, EMBASE and the Cochrane Library, were searched from inception to December 2008 to identify published systematic reviews and meta-analyses. Cochrane CENTRAL, MEDLINE, EMBASE and Science Citation Index (SCI) were searched from 1997 to March 2009 to identify primary studies. Cost-effectiveness: MEDLINE, EMBASE, Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evaluation Database (NHS EED) were searched from inception to January 2009. Potentially relevant papers were retrieved and independently checked against predefined criteria by two reviewers (one in the case of the cost-effectiveness review). Included reviews and meta-analyses were critically appraised and data extracted and narratively presented. Included randomised controlled trials (RCTs) and donor versus no donor (DvND) studies were mapped to the evidence covered in existing systematic reviews and meta-analyses according to a framework of 12 decision problems (DPs): DP1 related to SCT in adults with AML in first complete remission (CR1); DP2 to adults with AML in second or subsequent remission or with refractory disease (CR2+); DP3 to children with AML in CR1; DP4 to children with AML in CR2+; DP5 to adults with ALL in CR1; DP6 to adults with ALL in CR2+; DP7 to children with ALL in CR1; DP8 to children with ALL in CR2+; DP9 to comparison of different sources of stem cells in transplantation; DP10 to different conditioning regimens; DP

  9. Acute Myeloid Leukaemia | EU Clinical Trials Register [EU Clinical Trials Register

    Lifescience Database Archive (English)

    Full Text Available inical trial with GRASPA, Red Blood cells encapsulating L-Asparaginase, in patients affected by Acute Myeloi...ndition or disease under investigation E.1.1Medical condition(s) being investigated Acute...ion E.1.2Version 14.1 E.1.2Level LLT E.1.2Classification code 10000886 E.1.2Term Acute...old and less than 85 years old- Newly diagnosed Acute Myeloid Leukemia (AML) or post myelodysplastic syndrom

  10. Cancer procoagulant and tissue factor are differently modulated by all-trans-retinoic acid in acute promyelocytic leukemia cells.

    Science.gov (United States)

    Falanga, A; Consonni, R; Marchetti, M; Locatelli, G; Garattini, E; Passerini, C G; Gordon, S G; Barbui, T

    1998-07-01

    All-trans-retinoic acid (ATRA) downregulates the expression of two cellular procoagulants, tissue factor (TF) and cancer procoagulant (CP), in human promyelocytic leukemia cells. To evaluate whether or not changes of the procoagulant activities (PCAs) may share mechanisms with the ATRA-induced cyto-differentiation process, we have characterized the effect of ATRA on the TF and CP expression by NB4 cells, an ATRA maturation-inducible cell line, and two NB4-derived cell lines resistant to ATRA-induced maturation, the NB4. 306 and NB4.007/6 cells. Next, we evaluated the effect on the PCAs of the NB4 parental cells of three synthetic retinoid analogues, ie: AM580 (selective for the retinoic acid receptor [RAR] alpha), capable to induce the granulocytic differentiation of NB4 cells; and CD2019 (selective for RARbeta) and CD437 (selective for RARgamma), both lacking this capability. Cells were treated with either ATRA or the analogues (10(-6) to 10(-8) mol/L) for 96 hours. The effect on cell differentiation was evaluated by morphologic changes, cell proliferation, nitro blue tetrazolium reduction assay, and flow cytometry analysis of the CD33 and CD11b surface-antigen expression. PCA was first measured in 20 mmol/L Veronal Buffer cell extracts by the one-stage clotting assay of normal and FVII-deficient plasmas. Further TF and CP have been characterized and quantified in cell-sample preparations by chromogenic and immunological assays. In the first series of experiments, ATRA downregulates both TF and CP in NB4 parental cells, as expected. However, in the differentiation-resistant cell lines, it induced a significant loss of TF but had little or no effect on CP. In a second series of experiments, in the NB4 parental cells, the RARalpha agonist (AM580) induced cell maturation and reduced 91% CP expression, whereas CD437 and CD2019 had no cyto-differentiating effects and did not affect CP levels. On the other hand, in the same cells the TF expression was reduced by ATRA

  11. Live cell detection of chromosome 2 deletion and Sfpi1/PU1 loss in radiation-induced mouse acute myeloid leukaemia.

    Science.gov (United States)

    Olme, C-H; Finnon, R; Brown, N; Kabacik, S; Bouffler, S D; Badie, C

    2013-10-01

    The CBA/H mouse model of radiation-induced acute myeloid leukaemia (rAML) has been studied for decades to bring to light the molecular mechanisms associated with multistage carcinogenesis. A specific interstitial deletion of chromosome 2 found in a high proportion of rAML is recognised as the initiating event. The deletion leads to the loss of Sfpi, a gene essential for haematopoietic development. Its product, the transcription factor PU.1 acts as a tumour suppressor in this model. Although the deletion can be detected early following ionising radiation exposure by cytogenetic techniques, precise characterisation of the haematopoietic cells carrying the deletion and the study of their fate in vivo cannot be achieved. Here, using a genetically engineered C57BL/6 mouse model expressing the GFP fluorescent molecule under the control of the Sfpi1 promoter, which we have bred onto the rAML-susceptible CBA/H strain, we demonstrate that GFP expression did not interfere with X-ray induced leukaemia incidence and that GFP fluorescence in live leukaemic cells is a surrogate marker of radiation-induced chromosome 2 deletions with or without point mutations on the remaining allele of the Sfpi1 gene. This study presents the first experimental evidence for the detection of this leukaemia initiating event in live leukemic cells.

  12. Outcomes of patients with acute leukaemia who relapsed after reduced-intensity stem cell transplantation from HLA-identical or one antigen-mismatched related donors.

    Science.gov (United States)

    Kobayashi, Kazuhiko; Kami, Masahiro; Murashige, Naoko; Kusumi, Eiji; Kishi, Yukiko; Hamaki, Tamae; Hori, Akiko; Matsumura, Tomoko; Yuji, Koichiro; Masuo, Shigeru; Mori, Shinichiro; Miyakoshi, Shigesaburo; Tanosaki, Ryuji; Mitamura, Tadayuki; Takaue, Yoichi; Taniguchi, Shuichi

    2005-06-01

    The characteristics of relapse following reduced-intensity stem-cell transplantation (RIST) remain to be clarified. We reviewed the medical records of 19 patients with acute leukaemia [acute myeloid leukaemia (AML), 16; acute lymphoblastic leukaemia (ALL), 3] who relapsed after RIST from related donors using purine-analogue-based regimens. Their median age was 55 years (range, 29-65 years). Median interval between RIST and relapse was 4.9 months (range, 1.8-24.9 months). Three chose not to receive interventions. The remaining 16 patients received withdrawal of immunosuppression (n = 3), chemotherapy (n = 2), donor lymphocyte infusion (n = 10) and second transplantation (n = 7), alone (n = 9) or in combination (n = 7). Four are alive with a median follow-up of 27.6 months (range, 16.0-28.9 months); three in remission and one in relapse. The 2-year overall survival after relapse was 28.9%. Causes of death in 15 patients included progressive disease (n = 7), graft-versus-host disease (n = 5) and infections (n = 3). Cumulative incidences of relapse-related and non-relapse-related deaths at 2 years after relapse were 37% and 32% respectively. Two prognostic factors were identified on univariate analysis: age [P = 0.017; hazard ratio (HR), 1.16; 95% confidence interval (CI), 1.03-1.32], and ALL as underlying disease (P = 0.011; HR, 10.4; 95% CI, 1.73-62.4). Some AML patients who relapse after RIST achieve durable remission with allogeneic immunotherapy-based interventions; however they carry a significant risk of non-relapse mortality.

  13. Detection of dicentric chromosome (9;20) in paediatric B-cell acute lymphoblastic leukaemia: prognostic significance.

    Science.gov (United States)

    Letouzey, Mathilde; Penther, Dominique; Roche-Lestienne, Catherine; Nelken, Brigitte; Devoldère, Catherine; Vannier, Jean-Pierre; Schneider, Pascale

    2015-02-01

    The dicentric chromosome (9;20) (dic(9;20)) is described in 2 % of childhood B-acute lymphoblastic leukaemia. Fluorescence in situ hybridization (FISH) is the most reliable method to identify dic(9;20) when compared with conventional cytogenetics. To define the prognostic importance of dic(9;20), we evaluated treatment response and patient survival. This was a retrospective study in three French university centres. Patients' clinical and laboratory characteristics and treatment response are described. Nine children with dic(9;20) have been identified since 1995. All patients had at least one poor prognostic feature either among the clinical features, the initial laboratory results or in the initial treatment response: central nervous system involvement (2/9), high median leucocyte count (≥50 G/L) (8/9) and poor response to prednisone (2/9). All patients were in complete cytological remission after induction therapy but only three had a good molecular response with minimal residual disease (MRD) <10(-3). Five out of nine patients relapsed and two died, 4 and 12 months after diagnosis, respectively. The event-free survival rate in this population was 44 % (95 % confidence interval (CI) = 0.09-0.79) and overall survival 78 % (95 % CI = 0.51-1.05). In this population, dic(9;20) is associated with a relatively poor prognosis. Patients showing dic(9;20), whether this cytogenetic abnormality is associated with other poor prognostic factors or not, should be identified at the outset in order to be offered a more intensive treatment protocol.

  14. Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Ravandi, Farhad; Jorgensen, Jeffrey L; O'Brien, Susan M; Jabbour, Elias; Thomas, Deborah A; Borthakur, Gautam; Garris, Rebecca; Huang, Xuelin; Garcia-Manero, Guillermo; Burger, Jan A; Ferrajoli, Alessandra; Wierda, William; Kadia, Tapan; Jain, Nitin; Wang, Sa A; Konoplev, Sergei; Kebriaei, Partow; Champlin, Richard E; McCue, Deborah; Estrov, Zeev; Cortes, Jorge E; Kantarjian, Hagop M

    2016-02-01

    The prognostic value of minimal residual disease (MRD) assessed by multi-parameter flow cytometry (MFC) was investigated among 340 adult patients with B-cell acute lymphoblastic leukaemia (B-ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15-84). Median white blood cell count (WBC) was 9·35 × 10(9) /l (range, 0·4-658·1 ×1 0(9) /l). MRD by MFC was initially assessed with a sensitivity of 0·01%, using a 15-marker, 4-colour panel and subsequently a 6-colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease-free survival (DFS) and overall survival (OS) (P = 0·004 and P = 0·03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0·004 and P < 0·0001, respectively) and OS (P = 0·004 and P < 0·0001, respectively). Multivariate analysis including age, WBC at presentation, cytogenetics (standard versus high risk) and MRD status at CR, 3 and 6 months, indicated that MRD negative status at CR was an independent predictor of DFS (P < 0·05). Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in adult patients with ALL.

  15. Outcome of Childhood Acute Lymphoblastic Leukaemia after Induction Therapy --- Three-Year Experience in a Tertiary Care Hospital in Bangladesh

    Directory of Open Access Journals (Sweden)

    M Belayet Hossain

    2017-01-01

    Full Text Available Background: The incidence of different malignancies is increasing among the world populations. Acute lymphoblastic leukaemia (ALL is the most common of all the paediatric malignancies. Response to induction therapy is one of the most important predictors of long term outcome of ALL. Objective: To see the immediate outcome of paediatric ALL patients following induction therapy. Materials and Methods: This retrospective study was conducted from January 2013 to December 2015. Total 221 paediatric ALL patients were included in this study. Diagnosis was based on history, examination, blast cells count on peripheral blood film and bone marrow study, CSF study and immunophenotyping of peripheral blood/bone marrow aspirate in patients who were financially capable. Among them, parents of 40 (18% patients did not agree to start chemotherapy. According to Modified UK ALL 2003 protocol (Regimen A & B 181 patients were given induction therapy (vincristine, prednisolone, L-asparaginase, and daunomycin in high risk patients. Among them 14 patients discontinued, 10 patients died during chemotherapy and rest 157 patients completed induction phase. Bone marrow study was repeated after completion of induction therapy and remission pattern was seen. Results: Out of 157 chemotherapy completed patients, 137 (87% went into complete remission (25% blast cells in the bone marrow. Ten (5.5% patients died due to bleeding, febrile neutropenia and sepsis during the course of induction therapy. Conclusion: ALL in children is curable with effective chemotherapy. Poverty, ignorance and misconception regarding outcome are responsible for refusal and discontinuation of chemotherapy in third world countries like Bangladesh. Mortality and treatment cost can be reduced with the improvement of the facilities for isolation, barrier nursing and supportive treatment, and by creating awareness.

  16. Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response.

    Science.gov (United States)

    Cazzaniga, Giovanni; Lanciotti, Marina; Rossi, Vincenzo; Di Martino, Daniela; Aricò, Maurizio; Valsecchi, Maria Grazia; Basso, Giuseppe; Masera, Giuseppe; Micalizzi, Concetta; Biondi, Andrea

    2002-11-01

    Children with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) represent a subgroup at very high risk for treatment failure, despite intensive chemotherapy. However, recent retrospective studies showed that Ph+ childhood ALL is a heterogeneous disease with regard to treatment response. We have prospectively monitored, by reverse transcription polymerase chain reaction (RT-PCR) during follow-up, the presence of the BCR/ABL fusion transcript in Ph+ ALL children diagnosed in the Italian multicentre Associazione Italiana Ematologia Oncologia Pediatrica ALL-AIEOP-95 therapy protocol. To our knowledge, this is the first report on the evaluation of minimal residual disease (MRD) in childhood Ph+ ALL prospectively enrolled in an intensive, Berlin-Frankfurt-Munster (BFM)-type treatment protocol. Twenty-seven of 36 (75.0%) Ph+ patients consecutively enrolled into the high-risk group of the AIEOP-ALL protocol between May 1995 and October 1999 were successfully analysed. Twenty were good responders to the pre-phase of prednisone/intrathecal methotrexate treatment (PGR) and seven were poor responders (PPR). Within the PPR group, the RT-PCR monitoring constantly showed positivity for the BCR/ABL fusion transcript and all the patients died of disease progression. In contrast, highly sensitive qualitative RT-PCR monitoring revealed heterogeneity within the PGR group of Ph+ childhood ALL patients. Three different subgroups could be defined, according to the clearance of Ph+ cells within the first 5 months of treatment. This provides useful information on the capability of chemotherapy to reduce the leukaemic clone, with prognostic implications.

  17. 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

  18. Adult patients with relapsed and/or refractory B-precursor Acute lymphoblastic leukaemia | EU Clinical Trials Register [EU Clinical Trials Register

    Lifescience Database Archive (English)

    Full Text Available alutare l’efficacia dell’anticorpo BiTE® blinatumomab rispetto alla chemioterapia standard in soggetti adulti affetti da leucemia...rispetto alla chemioterapia standard, in soggetti adulti con leucemia linfoblastica acuta che non hanno risp... with relapsed and/or refractory B-precursor Acute lymphoblastic leukaemia Soggetti adulti affetti da leucemia...esponding to therapy Pazienti adulti con leucemia linfoblastica acuta - un tumore del sangue e midollo - che...alattia- Neoplasia prostatica intraepiteliale senza evidenza di tumore alla prostata .2 . diagnosi di leucemia

  19. Survival of Mexican Children with Acute Lymphoblastic Leukaemia under Treatment with the Protocol from the Dana-Farber Cancer Institute 00-01

    Science.gov (United States)

    Jiménez-Hernández, Elva; Jaimes-Reyes, Ethel Zulie; Arellano-Galindo, José; García-Jiménez, Xochiketzalli; Tiznado-García, Héctor Manuel; Sánchez-Jara, Berenice; Bekker-Méndez, Vilma Carolina; Ortíz-Torres, María Guadalupe; Ortíz-Fernández, Antonio; Marín-Palomares, Teresa; Mejía-Aranguré, Juan Manuel

    2015-01-01

    Our aim in this paper is to describe the results of treatment of acute lymphoblastic leukaemia (ALL) in Mexican children treated from 2006 to 2010 under the protocol from the Dana-Farber Cancer Institute (DFCI) 00-01. The children were younger than 16 years of age and had a diagnosis of ALL de novo. The patients were classified as standard risk if they were 1–9.9 years old and had a leucocyte count 100 × 109/L. The poor outcomes were associated with toxic death during induction, complete remission, and relapse. These factors remain the main obstacles to the success of this treatment in our population. PMID:25922837

  20. Aquaporin 9, a promising predictor for the cytocidal effects of arsenic trioxide in acute promyelocytic leukemia cell lines and primary blasts.

    Science.gov (United States)

    Iriyama, Noriyoshi; Yuan, Bo; Yoshino, Yuta; Hatta, Yoshihiro; Horikoshi, Akira; Aizawa, Shin; Takeuchi, Jin; Toyoda, Hiroo

    2013-06-01

    A close correlation between the cytocidal effects of arsenic trioxide (ATO) and aquaporin-9 (AQP9) expression levels has been proposed, yet detailed studies are still needed to confirm this association. Thus, in the present study, the correlation between the expression levels of AQP9 and sensitivity to ATO was investigated using two acute promyelocytic leukemia (APL) cell lines, NB4 and HT93A, as well as primary APL cells from newly diagnosed and relapsed APL patients. A substantially higher sensitivity to ATO-mediated induction of apoptosis was observed in the NB4 cells when compared to that in the HT93A cells. In addition, markedly higher expression levels of AQP9, as assessed using flow cytometry, along with more intracellular arsenic accumulation, were observed in the NB4 cells. More importantly, similar to APL cell lines, the trend of expression levels of AQP9 correlated closely with the differential sensitivity to ATO-mediated induction of apoptosis in primary APL cells. In contrast, no correlation was observed between ATO sensitivity associated with AQP9 expression levels and the expression profiles of cell surface markers as well as chromosomal alterations. These results provide direct evidence that the expression levels of AQP9, rather than other biomarkers such as cell surface markers and chromosomal alterations, correlate closely with the sensitivity to ATO in both APL cell lines and primary blasts. These findings suggest that the AQP9 expression status of APL patients is a predictive marker for the successful outcome of ATO treatment, since AQP9 plays a pivotal role in various arsenite-mediated biological effects on normal and cancer cells. Moreover, flow cytometry may be a new convenient and valuable tool for analyzing the AQP9 status of APL patients compared to current methods such as western blotting.

  1. Role of JWA in acute promyelocytic leukemia cell differentiation and apoptosis triggered by retinoic acid, 12-tetradecanoylphorbol-13-acetate and arsenic trioxide

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    JWA, a cytoskeleton associated gene, was primarily found to be regulated by all trans-retinoic acid (ATRA), 13 cis-retinoic acid (13 cis-RA) and 12-tetradecano- ylphorbol-13-acetate (TPA). Our previous data showed that JWA might be involved in both cellular differentiation and apoptosis induced by several chemicals. In this study, we addressed the possible mechanism of JWA in the regulation of cell differentiation and apoptosis in NB4, a human acute promyelocytic leukemia cell line. CD11b/CD33 expression and cell cycle were analyzed for detecting of cell differentiation and apoptosis. Both reverse-transcription polymerase chain reaction (RT-PCR) and Western blot assays were used for understanding the expressions of JWA. The results showed that under the indicated concentrations ATRA (10?6 mol/L) and As2O3 (10?6 mol/L) induced cell differentiation and apoptosis separately; while both 4HPR (10?6 mol/L) and TPA (10?7 mol/L) showed dual-directional effects on NB4 cells, they not only trigger cells' differentiation but also induce cells apoptosis at the same time. All chemicals up-regulated JWA expression whatever they trigger cells either differentiation or apoptosis; however, it seems that the chemicals have no effect on PML/RAR? in the treated NB4 cells. Anti-sense JWA oligonucleotide could partially block the ability of TPA in inducing cell differentiation and apoptosis via direct signal pathway. Interestingly, a high molecular weight JWA protein (JWAF) was identified only in de novo primary APL cells and it was also responsible for ATRA treatment. It raises questions of whether the JWAF is a novel APL specific marker and, how it was involved in the known mechanism of APL.

  2. PML/RARα-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia.

    Science.gov (United States)

    Bräuer-Hartmann, Daniela; Hartmann, Jens-Uwe; Wurm, Alexander Arthur; Gerloff, Dennis; Katzerke, Christiane; Verga Falzacappa, Maria Vittoria; Pelicci, Pier Giuseppe; Müller-Tidow, Carsten; Tenen, Daniel G; Niederwieser, Dietger; Behre, Gerhard

    2015-08-15

    In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. microRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as a key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARα oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNA interference (RNAi)-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony-forming capacity, proliferation, and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3'-untranslated region. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell-cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Finally, RASSF1A levels were reduced in PML/RARα knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARα-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL.

  3. [Association of CD34 cell surface antigen expression with cytomorphological characteristics of acute promyelocytic leukemia blasts and clinical characteristics of patients: one center experience].

    Science.gov (United States)

    Ostojić, Alen; Pazur, Marina; Siftar, Zoran; Paro, Mirjana Mariana Kardum; Jelić-Puskarić, Biljana; Gredelj-Simec, Njetocka; Radić-Kristo, Delfa; Kardum-Skelin, Ika; Vrhovac, Radovan; Jaksić, Branimir

    2011-09-01

    The aims of the study were to investigate the association between cytomorphology and immunophenotypic expression of CD34 cell surface antigen of blasts and their relationship with clinical and laboratory characteristics of patients with acute promyelocytic leukemia (APL). Sixteen consecutive patients (male 69% and female 31%) diagnosed with APL at Department of Hematology, Merkur University Hospital between August 1998 and December 2010 were included in the study. The mean age of patients was 43.9 (range: 18-78, SD 14.9). The patients' clinical and laboratory features, cytomorphological characteristics of APL-blasts and their immunophenotype determined by flow cytometry were analyzed. Patients were divided into two groups, CD34- and CD34+, and were then compared according to clinical and laboratory characteristics. There was no difference according to age, sex or white blood cell count between two groups. The mean value of hypogranular/agranular APL-blasts was markedly higher in CD34+ group than CD34- group (34%, range 9-60, SD 24.4 vs. 11.5%, range 0-38, SD 13.7), with borderline statistical significance (P=0.055). CD34- patients had significantly better overall survival than CD34+ ones (P=0.02). Patients without Auer rods detected in APL-blasts had higher CD34 expression (69.4% +/- 33.8) compared to patients with detected Auer rods (7.3% +/- 24.8), but statistical significance was not reached (p=0.053). Our results are consistent with the results of other published studies and point to the fact that higher CD34 expression and lower cytoplasmic granularity of APL-blasts are factors that seem to define a specific subgroup of APL patients. Together with other diagnostic tools currently available, they could be of value in planning treatment of APL patients.

  4. MIR125B1 represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia.

    Science.gov (United States)

    Zeng, Cheng-Wu; Chen, Zhen-Hua; Zhang, Xing-Ju; Han, Bo-Wei; Lin, Kang-Yu; Li, Xiao-Juan; Wei, Pan-Pan; Zhang, Hua; Li, Yangqiu; Chen, Yue-Qin

    2014-10-01

    Acute promyelocytic leukemia (APL) is characterized by the t(15;17)-associated PML-RARA fusion gene. We have previously found that MIR125B1 is highly expressed in patients with APL and may be associated with disease pathogenesis; however, the mechanism by which MIR125B1 exerts its oncogenic potential has not been fully elucidated. Here, we demonstrated that MIR125B1 abundance correlates with the PML-RARA status. MIR125B1 overexpression enhanced PML-RARA expression and inhibited the ATRA-induced degradation of the PML-RARA oncoprotein. RNA-seq analysis revealed a direct link between the PML-RARA degradation pathway and MIR125B1-arrested differentiation. We further demonstrated that the MIR125B1-mediated blockade of PML-RARA proteolysis was regulated via an autophagy-lysosomal pathway, contributing to the inhibition of APL differentiation. Furthermore, we identified DRAM2 (DNA-damage regulated autophagy modulator 2), a critical regulator of autophagy, as a novel target that was at least partly responsible for the function of MIR125B1 involved in autophagy. Importantly, the knockdown phenotypes for DRAM2 are similar to the effects of overexpressing MIR125B1 as impairment of PML-RARA degradation, inhibition of autophagy, and myeloid cell differentiation arrest. These effects of MIR125B1 and its target DRAM2 were further confirmed in an APL mouse model. Thus, MIR125B1 dysregulation may interfere with the effectiveness of ATRA-mediated differentiation through an autophagy-dependent pathway, representing a novel potential APL therapeutic target.

  5. All-Trans Retinoic Acid plus Arsenic Trioxide versus All-Trans Retinoic Acid plus Chemotherapy for Newly Diagnosed Acute Promyelocytic Leukemia: A Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Yafang Ma

    Full Text Available Recently, the all-trans retinoic acid (ATRA plus arsenic trioxide (ATO protocol has become a promising first-line therapeutic approach in patients with newly diagnosed acute promyelocytic leukemia (APL, but its benefits compared with standard ATRA plus chemotherapy regimen needs to be proven. Herein, we conducted a meta-analysis comparing the efficacy of ATRA plus ATO with ATRA plus chemotherapy for adult patients with newly diagnosed APL.We systematically searched biomedical electronic databases and conference proceedings through February 2016. Two reviewers independently assessed all studies for relevance and validity.Overall, three studies were eligible for inclusion in this meta-analysis, which included a total of 585 patients, with 317 in ATRA plus ATO group and 268 in ATRA plus chemotherapy group. Compared with patients who received ATRA and chemotherapy, patients who received ATRA plus ATO had a significantly better event-free survival (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.22-0.67, p = 0.009, overall survival (HR = 0.44, 95% CI: 0.24-0.82, p = 0.009, complete remission rate (relative risk [RR] = 1.05; 95% CI: 1.01-1.10; p = 0.03. There were no significant differences in early mortality (RR = 0.48; 95% CI: 0.22-1.05; p = 0.07.Thus, this analysis indicated that ATRA plus ATO protocol may be preferred to standard ATRA plus chemotherapy protocol, particularly in low-to-intermediate risk APL patients. Further larger trials were needed to provide more evidence in high-risk APL patients.

  6. Inhibition of mitotic kinase Aurora suppresses Akt-1 activation and induces apoptotic cell death in all-trans retinoid acid-resistant acute promyelocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Long Zi-Jie

    2011-05-01

    Full Text Available Abstract Background Aurora kinase ensures accurate chromosome segregation during cell cycle, maintaining genetic integrity in cell division. VX-680, a small-molecule Aurora kinase inhibitor, interferes with mitotic entry and formation of bipolar spindles. Here, we evaluated VX-680 as a potential agent for treatment of all-trans retinoid acid (ATRA-resistant acute promyelocytic leukemia (APL in vitro. Methods CD11b expression was utilized to assess cell differentiation by flow cytometry. Immunofluorescence staining was conducted to analyze formation of cell monopolar spindle. Cell proliferation was evaluated by MTT assay. Sub-G1 population and Annexin V/PI staining were used to measure cell apoptosis. Hoechst 33342 staining was applied for identifying morphological changes in nucleus of apoptotic cell. Aurora-A (Aur-A activation and the signaling pathways involved in apoptosis were detected by Western blot. JC-1 probe was employed to measure mitochondrial depolarization. Results VX-680 inhibited Aur-A by reducing autophosphorylation at the activation site, Thr288, accompanied by producing monopolar mitotic spindles in APL cell line NB4-R2 that was resistant to ATRA. In addition, we found that VX-680 inhibited cell proliferation as assessed by MTT assay. Flow cytometry showed that VX-680 led to apoptotic cell death in both dose- and time-dependent manners by either Sub-G1 or Annexin V/PI analysis. Hoechst 33342 staining represented typical apoptotic cells with nuclear fragmentation in VX-680 treated cells. Importantly, VX-680 inhibition of Aurora kinase suppressed Akt-1 activation and induced mitochondrial depolarization, which eventually resulted in apoptosis by activation of caspase pathway, as indicated by increasing proteolytic cleavage of procaspase-3 and poly ADP ribose polymerase (PARP in NB4-R2 cells. Conclusions Our study suggested potential clinical use of mitotic Aurora kinase inhibitor in targeting ATRA-resistant leukemic cells.

  7. Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19).

    NARCIS (Netherlands)

    Amadori, S.; Suciu, S.; Selleslag, D.; Stasi, R.; Alimena, G.; Baila, L.; Rizzoli, V.; Borlenghi, E.; Gaidano, G.; Magro, D.; Torelli, G.; Muus, P.; Venditti, A.; Cacciola, E.; Lauria, F.; Vignetti, M.; Witte, T.J.M. de

    2010-01-01

    This study compared two schedules of low-dose gemtuzumab ozogamicin (GO) as induction monotherapy for untreated acute myeloid leukaemia in older patients unfit for intensive chemotherapy, to identify the more promising regimen for further study. Patients were randomized to receive either best

  8. Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19).

    NARCIS (Netherlands)

    Amadori, S.; Suciu, S.; Selleslag, D.; Stasi, R.; Alimena, G.; Baila, L.; Rizzoli, V.; Borlenghi, E.; Gaidano, G.; Magro, D.; Torelli, G.; Muus, P.; Venditti, A.; Cacciola, E.; Lauria, F.; Vignetti, M.; Witte, T.J.M. de

    2010-01-01

    This study compared two schedules of low-dose gemtuzumab ozogamicin (GO) as induction monotherapy for untreated acute myeloid leukaemia in older patients unfit for intensive chemotherapy, to identify the more promising regimen for further study. Patients were randomized to receive either best suppor

  9. Suppressed spontaneous secretion of growth hormone in girls after treatment for acute lymphoblastic leukaemia.

    OpenAIRE

    Moëll, C; Garwicz, S; Westgren, U; Wiebe, T; Albertsson-Wikland, K.

    1989-01-01

    The spontaneous secretion of growth hormone during a 24 hour period and the response of growth hormone to growth hormone releasing hormone was studied in 13 girls who had received treatment for acute lymphoblastic leukemia that included cranial irradiation with 20-24 Gy in 12-14 fractions. At the time of investigation the girls were at varying stages of puberty and had normal concentrations of thyroid hormones. The mean interval between the end of treatment and investigation was 4.6 years. Th...

  10. Clinical treatment of acute promyelocytic leukemia during pregnancy: a report of two cases%妊娠期急性早幼粒细胞白血病的治疗:2例报道

    Institute of Scientific and Technical Information of China (English)

    李晓青; 黄仁魏; 林东军; 肖若芝

    2012-01-01

    Leukemia, promyelocytic, acute; Pregnancy; Antineoplastic combined chemotherapy protocols%妊娠期急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)非常少见,主要表现为粒细胞的分化和成熟障碍,致使大量早幼粒细胞聚集在骨髓组织和外周血中.肿瘤性的早幼粒细胞发生t (15;17)染色体易位,继而产生早幼粒细胞白血病-维甲酸受体α(promyelocytic leukemia/retinoic acid receptor alpha,PML-RARα)融合基因及其相关蛋白,从而抑制早幼粒细胞分化成熟.目前还不清楚APL的具体发病率是多少[1-4],该病的平均发病年龄约为40岁,年轻女性和育龄期女性均可罹患此病.近年来,妊娠期APL的发病率似乎略有增加[5].通常认为妊娠期APL是一种肿瘤急症,会对母亲和胎儿的生命安全造成威胁[5].APL伴出血的发生率很高,发生弥散性血管内凝血(disseminated intravascular coagulation,DIC)导致死亡的发生率也很高,因此在确诊后需立即进行治疗[1].

  11. Clinical management of primary non-acute promyelocytic leukemia acute myeloid leukemia: Practice Guidelines by the Italian Society of Hematology, the Italian Society of Experimental Hematology, and the Italian Group for Bone Marrow Transplantation.

    Science.gov (United States)

    Morra, Enrica; Barosi, Giovanni; Bosi, Alberto; Ferrara, Felicetto; Locatelli, Franco; Marchetti, Monia; Martinelli, Giovanni; Mecucci, Cristina; Vignetti, Marco; Tura, Sante

    2009-01-01

    As many options are now available to treat patients with de novo acute myeloid leukemia, the Italian Society of Hematology and two affiliated societies (SIES and GITMO) commissioned project to an Expert Panel aimed at developing clinical practice guidelines for acute myeloid leukemia treatment. After systematic comprehensive literature review, the Expert Panel formulated recommendations for the management of primary acute myeloid leukemia (with the exception of acute promyelocytic leukemia) and graded them according to the supporting evidence. When evidence was lacking, consensus-based statements have been added. First-line therapy for all newly diagnosed patients eligible for intensive treatment should include one cycle of induction with standard dose cytarabine and an anthracycline. After achieving complete remission, patients aged less than 60 years should receive consolidation therapy including high-dose cytarabine. Myeloablative allogeneic stem cell transplantation from an HLA-compatible sibling should be performed in first complete remission: 1) in children with intermediate-high risk cytogenetics or who achieved first complete remission after the second course of therapy; 2) in adults less than 40 years with an intermediate-risk; in those aged less than 55 years with either high-risk cytogenetics or who achieved first complete remission after the second course of therapy. Stem cell transplantation from an unrelated donor is recommended to be performed in first complete remission in adults 30 years old or younger, and in children with very high-risk disease lacking a sibling donor. Alternative donor stem cell transplantation is an option in high-risk patients without a matched donor who urgently need transplantation. Patients aged less than 60 years, who either are not candidate for allogeneic stem cell transplantation or lack a donor, are candidates for autologous stem cell transplantation. We describe the results of a systematic literature review and an

  12. Oxindole alkaloids from Uncaria tomentosa induce apoptosis in proliferating, G0/G1-arrested and bcl-2-expressing acute lymphoblastic leukaemia cells.

    Science.gov (United States)

    Bacher, Nicole; Tiefenthaler, Martin; Sturm, Sonja; Stuppner, Hermann; Ausserlechner, Michael J; Kofler, Reinhard; Konwalinka, Günther

    2006-03-01

    Natural products are still an untapped source of promising lead compounds for the generation of antineoplastic drugs. Here, we investigated for the first time the antiproliferative and apoptotic effects of highly purified oxindole alkaloids, namely isopteropodine (A1), pteropodine (A2), isomitraphylline (A3), uncarine F (A4) and mitraphylline (A5) obtained from Uncaria tomentosa, a South American Rubiaceae, on human lymphoblastic leukaemia T cells (CCRF-CEM-C7H2). Four of the five tested alkaloids inhibited proliferation of acute lymphoblastic leukaemia cells. Furthermore, the antiproliferative effect of the most potent alkaloids pteropodine (A2) and uncarine F (A4) correlated with induction of apoptosis. After 48 h, 100 micromol/l A2 or A4 increased apoptotic cells by 57%. CEM-C7H2 sublines with tetracycline-regulated expression of bcl-2, p16ink4A or constitutively expressing the cowpox virus protein crm-A were used for further studies of the apoptosis-inducing properties of these alkaloids. Neither overexpression of bcl-2 or crm-A nor cell-cycle arrest in G0/G1 phase by tetracycline-regulated expression of p16INK4A could prevent alkaloid-induced apoptosis. Our results show the strong apoptotic effects of pteropodine and uncarine F on acute leukaemic lymphoblasts and recommend the alkaloids for further studies in xenograft models.

  13. A novel RT-qPCR assay for quantification of the MLL-MLLT3 fusion transcript in acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Abildgaard, Lotte; Ommen, Hans Beier; Lausen, Birgitte Frederiksen

    2013-01-01

    OBJECTIVES: Patients with acute myeloid leukaemia (AML) of the monocytic lineage often lack molecular markers for minimal residual disease (MRD) monitoring. The MLL-MLLT3 fusion transcript found in patients with AML harbouring t(9;11) is amenable to RT-qPCR quantification but because of the heter......OBJECTIVES: Patients with acute myeloid leukaemia (AML) of the monocytic lineage often lack molecular markers for minimal residual disease (MRD) monitoring. The MLL-MLLT3 fusion transcript found in patients with AML harbouring t(9;11) is amenable to RT-qPCR quantification but because...... of the heterogeneity of translocation break points, the MLL-MLLT3 fusion gene is a challenging target. We hypothesised that MRD monitoring using MLL-MLLT3 as a RT-qPCR marker is feasible in the majority of patients with t(9;11)-positive AML. METHODS: Using a locked nucleic acid probe, we developed a sensitive RT-qPCR...... follow-up. Two patients relapsed, and both were MRD positive in BM after first induction course. A total of three relapses occurred, and they were detected by RT-qPCR 3 wks before haematological relapse was diagnosed. CONCLUSION: This MLL-MLLT3 RT-qPCR assay could be useful in MRD monitoring of a group...

  14. Population pharmacokinetics of cytarabine, etoposide and daunorubicin in the treatment of acute myeloid leukaemia

    DEFF Research Database (Denmark)

    Krogh-Madsen, Mikkel; Bender, B.; Jensen, M. K.

    2012-01-01

    (®); for daunorubicin, PK information from a prior study was utilized. RESULTS: Baseline white blood cell count (bWBC) influenced the PK for all drugs. A small, statistically insignificant improvement in model fit was achieved when a relationship between bWBC and daunorubicin central volume of distribution was included...... insights into the PK of this combination treatment. METHODS: A prospective population PK study of twenty-three patients with acute myeloid leukemia was undertaken. Plasma concentrations of patients were determined by high-pressure liquid chromatography. PK models were developed with NONMEM....... The volume increased 1.9% for each increase in bWBC by 1 × 10(6) cells/mL. The clearances of etoposide and cytarabine were significantly increased and decreased, respectively, by increased bWBC. Tenfold changes in bWBC were needed for these relationships to have potential clinical relevance. A decrease...

  15. Bloodstream infection caused by Acinetobacter junii in a patient with acute lymphoblastic leukaemia after allogenic haematopoietic cell transplantation.

    Science.gov (United States)

    Cayô, Rodrigo; Yañez San Segundo, Lucrecia; Pérez del Molino Bernal, Inmaculada Concepción; García de la Fuente, Celia; Bermúdez Rodríguez, Maria Aranzazu; Calvo, Jorge; Martínez-Martínez, Luis

    2011-03-01

    Acinetobacter junii is a rare human pathogen associated with bacteraemia in neonates and paediatric oncology patients. We present a case of A. junii causing bacteraemia in an adult transplant patient with leukaemia. The correct identification of Acinetobacter species can highlight the clinical significance of the different species of this genus.

  16. Malignancy: Case Report: Acute Promyelocytic Leukemia in Late Pregnancy. Successful Treatment with All-Trans-Retinoic Acid (ATRA) and Chemotherapy.

    Science.gov (United States)

    Delgado-Lamas, JOSÉ LUIS; Garcés-Ruiz, OSCAR MIGUEL

    2000-01-01

    The use of all-transretinoic acid (ATRA) in APL is a great advance in the treatment of acute leukemia, driving the maturation steps until adult form. The effect of this medication in pregnant women with APL is being a safe and effective treatment only after the first trimester of pregnancy. If used in the first three months, it can cause fetus malformations due to its potent teratogenicity. The two patients we reported here, gave birth to normal children, yet they received ATRA. After a week with ATRA treatment, fibrinogen level improved and "D" dimers decreased, so as observed slowly maturation of leukemic leucocytes. ATRA used at the same time with chemotherapy; such as Cytarabine and Idarrubicine seems highly useful for induction and long term control of disease. One short discussion about the findings and compare with those found in the literature are presented.

  17. Acute Promyelocytic Leukemia in Late Pregnancy. Successful Treatment with All-Trans-Retinoic Acid (ATRA) and Chemotherapy.

    Science.gov (United States)

    Delgado-Lamas, J L; GarcéS-Ruiz, O M

    1999-01-01

    The use of all-transretinoic acid (ATRA) in APL is a great advance in the treatment of acute leukemia, driving the maturation steps until adult form. The effect of this medication in pregnant women with APL is being a safe and effective treatment only after the first trimester of pregnancy. If used in the first three months, it can cause fetus malformations due to its potent teratogenicity. The two patients we reported here, gave birth to normal children, yet they received ATRA. After a week with ATRA treatment, fibrinogen level improved and "D" dimers decreased, so as observed slowly maturation of leukemic leucocytes. ATRA used at the same time with chemotherapy; such as Cytarabine and Idarrubicine seems highly useful for induction and long term control of disease. One short discussion about the findings and compare with those found in the literature are presented.

  18. Thymoquinone Induces Mitochondria-Mediated Apoptosis in Acute Lymphoblastic Leukaemia in Vitro

    Directory of Open Access Journals (Sweden)

    Bassem Y. Sheikh

    2013-09-01

    Full Text Available There has been a growing interest in naturally occurring compounds from traditional medicine with anti-cancer potential. Nigella sativa (black seed is one of the most widely studied plants. This annual herb grows in countries bordering the Mediterranean Sea and India. Thymoquinone (TQ is an active ingredient isolated from Nigella sativa. The anti-cancer effect of TQ, via the induction of apoptosis resulting from mitochondrial dysfunction, was assessed in an acute lymphocyte leukemic cell line (CEMss with an IC50 of 1.5 µg/mL. A significant increase in chromatin condensation in the cell nucleus was observed using fluorescence analysis. The apoptosis was then confirmed by Annexin V and an increased number of cellular DNA breaks in treated cells were observed as a DNA ladder. Treatment of CEMss cells with TQ encouraged apoptosis with cell death-transducing signals by a down-regulation of Bcl-2 and up-regulation of Bax. Moreover, the significant generation of cellular ROS, HSP70 and activation of caspases 3 and 8 were also observed in the treated cells. The mitochondrial apoptosis was clearly associated with the S phase cell cycle arrest. In conclusion, the results from the current study indicated that TQ could be a promising agent for the treatment of leukemia.

  19. AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells.

    Science.gov (United States)

    Gianní, M; Li Calzi, M; Terao, M; Guiso, G; Caccia, S; Barbui, T; Rambaldi, A; Garattini, E

    1996-02-15

    All-trans retinoic acid (ATRA) is successfully used in the cyto-differentiating treatment of acute promyelocytic leukemia (APL). Paradoxically, APL cells express PML-RAR, an aberrant form of the retinoic acid receptor type alpha (RAR alpha) derived from the leukemia-specific t(15;17) chromosomal translocation. We show here that AM580, a stable retinobenzoic derivative originally synthesized as a RAR alpha agonist, is a powerful inducer of granulocytic maturation in NB4, an APL-derived cell line, and in freshly isolated APL blasts. After treatment of APL cells with AM580 either alone or in combination with granulocyte colony-stimulating factor (G-CSF), the compound induces granulocytic maturation, as assessed by determination of the levels of leukocyte alkaline phosphatase, CD11b, CD33, and G-CSF receptor mRNA, at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects. By contrast, AM580 is not effective as ATRA in modulating the expression of these differentiation markers in the HL-60 cell line and in freshly isolated granulocytes obtained from the peripheral blood of chronic myelogenous leukemia patients during the stable phase of the disease. In NB4 cells, two other synthetic nonselective RAR ligands are capable of inducing LAP as much as AM580, whereas RAR beta- or RAR gamma-specific ligands are totally ineffective. These results show that AM580 is more powerful than ATRA in modulating the expression of differentiation antigens only in cells in which PML-RAR is present. Binding experiments, using COS-7 cells transiently transfected with PML-RAR and the normal RAR alpha, show that AM580 has a lower affinity than ATRA for both receptors. However, in the presence of PML-RAR, the synthetic retinoid is a much better transactivator of retinoic acid-responsive element-containing promoters than the natural retinoid, whereas, in the presence of RAR alpha, AM580 and ATRA have similar activity. This may explain the strong cyto

  20. PIC-1/SUMO-1-Modified PML-Retinoic Acid Receptor α Mediates Arsenic Trioxide-Induced Apoptosis in Acute Promyelocytic Leukemia

    Science.gov (United States)

    Sternsdorf, Thomas; Puccetti, Elena; Jensen, Kirsten; Hoelzer, Dieter; Will, Hans; Ottmann, Oliver Gerhard; Ruthardt, Martin

    1999-01-01

    Fusion proteins involving the retinoic acid receptor α (RARα) and PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemia (APL). APLs with PML-RARα or PLZF-RARα fusion protein differ only in their response to retinoic acid (RA) treatment: the t(15;17) (PML-RARα-positive) APL blasts are sensitive to RA in vitro, and patients enter disease remission after RA treatment, while those with t(11;17) (PLZF-RARα-positive) APLs do not. Recently it has been shown that complete remission can be achieved upon treatment with arsenic trioxide (As2O3) in PML-RARα-positive APL, even when the patient has relapsed and the disease is RA resistant. This appears to be due to apoptosis induced by As2O3 in the APL blasts by poorly defined mechanisms. Here we report that (i) As2O3 induces apoptosis only in cells expressing the PML-RARα, not the PLZF-RARα, fusion protein; (ii) PML-RARα is partially modified by covalent linkage with a PIC-1/SUMO-1-like protein prior to As2O3 treatment, whereas PLZF-RARα is not; (iii) As2O3 treatment induces a change in the modification pattern of PML-RARα toward highly modified forms; (iv) redistribution of PML nuclear bodies (PML-NBs) upon As2O3 treatment is accompanied by recruitment of PIC-1/SUMO-1 into PML-NBs, probably due to hypermodification of both PML and PML-RARα; (v) As2O3-induced apoptosis is independent of the DNA binding activity located in the RARα portion of the PML-RARα fusion protein; and (vi) the apoptotic process is bcl-2 and caspase 3 independent and is blocked only partially by a global caspase inhibitor. Taken together, these data provide novel insights into the mechanisms involved in As2O3-induced apoptosis in APL and predict that treatment of t(11;17) (PLZF-RARα-positive) APLs with As2O3 will not be successful. PMID:10373566

  1. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

    Science.gov (United States)

    Perl, Alexander E; Altman, Jessica K; Cortes, Jorge; Smith, Catherine; Litzow, Mark; Baer, Maria R; Claxton, David; Erba, Harry P; Gill, Stan; Goldberg, Stuart; Jurcic, Joseph G; Larson, Richard A; Liu, Chaofeng; Ritchie, Ellen; Schiller, Gary; Spira, Alexander I; Strickland, Stephen A; Tibes, Raoul; Ustun, Celalettin; Wang, Eunice S; Stuart, Robert; Röllig, Christoph; Neubauer, Andreas; Martinelli, Giovanni; Bahceci, Erkut; Levis, Mark

    2017-08-01

    Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3(mut+)) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3(mut+) patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number

  2. Magnetic fields and leukaemia risks in UK electricity supply workers.

    Science.gov (United States)

    Sorahan, T

    2014-04-01

    To investigate whether leukaemia risks are related to occupational exposure to low-frequency magnetic fields. Leukaemia risks experienced by 73 051 employees of the former Central Electricity Generating Board of England and Wales were investigated for the period 1973-2010. All employees were hired in the period 1952-82 and were employed for at least 6 months with some employment in the period 1973-82. Detailed calculations had been performed by others to enable an assessment to be made of exposures to magnetic fields. Poisson regression was used to calculate relative risks (rate ratios) of developing leukaemia or leukaemia subtypes for categories of lifetime, distant (lagged) and recent (lugged) exposure. Findings for all leukaemias combined were unexceptional; risks were close to unity for all exposure categories and there was no suggestion of risks increasing with cumulative (or recent or distant) magnetic field exposures. There were no statistically significant dose-response effects shown for acute myeloid leukaemia, chronic myeloid leukaemia or chronic lymphocytic leukaemia. There was a significant positive trend for acute lymphocytic leukaemia (ALL), but this was based, in the main, on unusually low risks in the lowest exposure category. This study found no convincing evidence to support the hypothesis that exposure to magnetic fields is a risk factor for leukaemia, and the findings are consistent with the hypotheses that both distant and recent magnetic field exposures are not causally related to the generality of leukaemia. The limited positive findings for ALL may well be chance findings.

  3. Incidence of secondary neoplasms in patients with acute promyelocytic leukemia treated with all-trans retinoic acid plus chemotherapy or with all-trans retinoic acid plus arsenic trioxide.

    Science.gov (United States)

    Eghtedar, Alireza; Rodriguez, Ildefonso; Kantarjian, Hagop; O'Brien, Susan; Daver, Naval; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Kadia, Tapan; Pierce, Sherry; Cortes, Jorge; Ravandi, Farhad

    2015-05-01

    The incidence and pattern of secondary neoplasms in patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA)-containing regimens is not well described. We compared 160 patients with APL treated with ATRA plus idarubicin (n = 54) or ATRA plus arsenic trioxide (ATO) (n = 106) for the incidence of secondary cancers per unit time of follow-up. Median follow-up times for the two cohorts were 136 and 29 months, respectively. Nine patients developed secondary cancers in the chemotherapy group. These included two breast cancers, three myelodysplastic syndromes/acute myeloid leukemia, one vulvar cancer, one prostate cancer, one colon cancer and one soft tissue sarcoma. A melanoma and one pancreatic cancer developed in the ATO group. We conclude that treatment of patients with APL using the non-chemotherapy regimen of ATRA plus ATO is not associated with a higher incidence of secondary cancers (p = 0.29) adjusted for unit time of exposure.

  4. The Polo-Like Kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia.

    Science.gov (United States)

    Casolaro, Alessia; Golay, Josee; Albanese, Clara; Ceruti, Roberta; Patton, Veronica; Cribioli, Sabrina; Pezzoni, Alice; Losa, Marco; Texido, Gemma; Giussani, Ursula; Marchesi, Francesco; Amboldi, Nadia; Valsasina, Barbara; Bungaro, Silvia; Cazzaniga, Gianni; Rambaldi, Alessandro; Introna, Martino; Pesenti, Enrico; Alzani, Rachele

    2013-01-01

    CD56 is expressed in 15-20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56(+) monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56(+) AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML.

  5. Treatment of childhood T-cell lymphoblastic lymphoma according to the strategy for acute lymphoblastic leukaemia, without radiotherapy: long term results of the EORTC CLG 58881 trial.

    Science.gov (United States)

    Uyttebroeck, Anne; Suciu, Stefan; Laureys, Geneviève; Robert, Alain; Pacquement, Hélène; Ferster, Alina; Marguerite, Geneviève; Mazingue, Françoise; Renard, Marleen; Lutz, Patrick; Rialland, Xavier; Mechinaud, Françoise; Cavé, Hélène; Baila, Liliana; Bertrand, Yves

    2008-04-01

    From June 1989 through to November 1998, 121 children with newly diagnosed T-cell lymphoblastic lymphoma (T-LBL) were included in the EORTC 58881 trial conducted by the Children's Leukaemia Group. The therapy regimen was based on a Berlin-Frankfurt-Munster protocol, for a total duration of 24 months. Cranial irradiation, prophylactic cranial and local, was omitted, even for patients with central nervous involvement at diagnosis. In total, 119 patients were evaluable. The median follow-up was 6.7 years. The overall event-free survival (EFS) rate at 6 years was 77.5% (standard error (SE)=4%). Median time of relapse was 1 year after complete remission (range 0.2-5.9 years). Only two (1.8%) patients had an isolated central nervous system relapse. For patients with complete response (n=16) to the 7-day prephase, the EFS rate at 6 years was 100% versus 14% (P<0.001) for patients with no response (n=7). Overall survival rate at 6 years was 86% (SE=3%). An intensive acute lymphoblastic leukaemia type chemotherapy regimen without irradiation leads to a high cure and survival rate in childhood T-LBL without an increased CNS recurrence. This suggests that prophylactic cranial irradiation can safely be omitted. Response to the prephase appeared to be a strong prognostic factor for EFS.

  6. Mixed phenotype acute leukemia: A study of 61 cases using World Health Organization and European Group for the Immunological Classification of Leukaemias criteria.

    Science.gov (United States)

    Weinberg, Olga K; Seetharam, Mahesh; Ren, Li; Alizadeh, Ash; Arber, Daniel A

    2014-12-01

    The 2008 World Health Organization (WHO) classification system grouped bilineal and biphenotypic acute leukemias together under a new heading of mixed phenotype acute leukemia (MPAL). The lineage-specific marker criteria have also changed for a diagnosis of MPAL. The goal of this study was to characterize clinical significance of this new group. Sixty-one patients diagnosed with MPAL using either European Group for the Immunological Classification of Leukaemias (EGIL) criteria or 2008 WHO criteria were included in this study. Sixteen patients (26%) diagnosed with acute biphenotypic leukemia using EGIL criteria did not fulfill 2008 WHO criteria for MPAL. Cytogenetic data were available for 32 patients, and the most common abnormality was t(9;22) (five of 32 cases). Clinical outcome data suggested that younger patients with MPAL (≤21 years) had better overall survival (OS) in both the EGIL and WHO groups (EGIL, P = .0403; WHO, P = .0601). Compared with 177 patients with acute myeloid leukemia (AML), MPAL patients had better OS (P = .0003) and progression-free survival (P = .0001). However, no difference in OS between MPAL and 387 patients with acute lymphoblastic leukemia was present (P = .599). As defined by the 2008 WHO classification, fewer patients are now classified as having MPAL than with the EGIL criteria. In this study, patients with MPAL have a better clinical outcome compared with patients with AML. Copyright© by the American Society for Clinical Pathology.

  7. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study.

    Science.gov (United States)

    Avvisati, G; Lo Coco, F; Diverio, D; Falda, M; Ferrara, F; Lazzarino, M; Russo, D; Petti, M C; Mandelli, F

    1996-08-15

    From March 1993 to October 1993, 20 consecutive, newly diagnosed acute promyelocytic leukemia (APL) patients from 13 Italian institutions entered in a pilot study named AIDA, combining all-trans retinoic acid (ATRA) with idarubicin (IDA). ATRA was administered orally beginning on the first day of induction at the dosage of 45 mg/m2/d until complete remission (CR), whereas IDA was administered intravenously at the dosage of 12 mg/m2/d on days 2, 4, 6, and 8 of the induction. Patients who achieved CR were consolidated with 3 courses of chemotherapy without ATRA; thereafter, they were followed up for molecular and hematologic CR. The median age was 35.3 years (range, 6.5 to 67.6 years); 8 patients were males and 12 females; 4 had the hypogranular variant of APL (M3v), and 4 (2 with M3v) presented with leukocyte counts > or = 10,000/microL. Molecular analysis for the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) hybrid gene at diagnosis was performed in 16 patients by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were RT-PCR+ for the hybrid gene. In the remaining 4 patients, the cytogenetic study showed the presence of the t(15;17). After a median time of 36 days (range, 28 to 52 days) 18 (90%) patients achieved CR; the remaining 2 patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive hemoptysis, respectively. ATRA syndrome was observed in only 2 patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered from the syndrome. However, after recovering, 1 patient achieved CR, whereas the other died at day 34 because of massive hemoptysis; other side effects were very limited. At recovery from the third consolidation course, only 3 of 14 (21.4%) tested patients were RT-PCR+ for the PML-RAR alpha hybrid gene. Of these, 2 relapsed shortly afterwards; however, in the last patient, the PML-RAR alpha disappeared

  8. Outcome of ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall survival

    DEFF Research Database (Denmark)

    Forestier, E.; Heyman, M.; Andersen, Mette Klarskov

    2008-01-01

    The prognostic impact of t(12;21)(p13;q22) [ETV6/RUNX1 fusion] in paediatric acute lymphoblastic leukaemia (ALL) has been extensively debated, particularly with regard to the frequency of late relapses and appropriate treatment regimens. We have retrospectively collected 679 ALLs with known ETV6....../RUNX1 status, as ascertained by fluorescence in situ hybridization or reverse-transcription polymerase chain reaction, treated according to the Nordic Society of Paediatric Haematology and Oncology -ALL-1992 protocol. The assigned risk groups/treatment modalities for the 171 (25%) patients with t(12......, there is no reliable plateau in the EFS curve, a fact that raises the question as to when the prognostic ramifications of ALLs harbouring ETV6/RUNX1 should be evaluated Udgivelsesdato: 2008/3...

  9. Survival of Mexican Children with Acute Lymphoblastic Leukaemia under Treatment with the Protocol from the Dana-Farber Cancer Institute 00-01

    Directory of Open Access Journals (Sweden)

    Elva Jiménez-Hernández

    2015-01-01

    Full Text Available Our aim in this paper is to describe the results of treatment of acute lymphoblastic leukaemia (ALL in Mexican children treated from 2006 to 2010 under the protocol from the Dana-Farber Cancer Institute (DFCI 00-01. The children were younger than 16 years of age and had a diagnosis of ALL de novo. The patients were classified as standard risk if they were 1–9.9 years old and had a leucocyte count 100 × 109/L. The poor outcomes were associated with toxic death during induction, complete remission, and relapse. These factors remain the main obstacles to the success of this treatment in our population.

  10. NPM1 mutation is a stable marker for minimal residual disease monitoring in acute myeloid leukaemia patients with increased sensitivity compared to WT1 expression*

    DEFF Research Database (Denmark)

    Kristensen, Thomas; Møller, Michael B; Friis, Lone;

    2011-01-01

    Mutation in the NPM1 gene occurs in 60% of acute myeloid leukaemia (AML) patients with normal karyotype. NPM1 mutation is potentially a superior minimal residual disease (MRD) marker compared to WT1 gene overexpression by being specific to the malignant clone, although experimental evidence...... published so far includes very limited numbers of relapsed cases. Also, the stability of the NPM1 mutation has been questioned by reports of the mutation being lost at relapse. In the present study we compared NPM1 mutation and WT1 overexpression as MRD markers in 20 cases of relapsed AML. The 20 patients...... experienced a total of 28 morphological relapses. Karyotypic evolution was detected in 56% of relapses. All relapses were accompanied by high levels of NPM1 mutation, along with high WT1 mRNA levels, thus demonstrating complete stability of both markers during relapse. Detectable NPM1 mutation following...

  11. Differential cytogenomics and miRNA signature of the Acute Myeloid Leukaemia Kasumi-1 cell line CD34+38- compartment.

    Science.gov (United States)

    Pedranzini, Laura; Mottadelli, Federica; Ronzoni, Simona; Rossella, Franca; Ferracin, Manuela; Magnani, Ivana; Roversi, Gaia; Colapietro, Patrizia; Negrini, Massimo; Pelicci, Pier Giuseppe; Larizza, Lidia

    2010-10-01

    The t(8;21) Acute Myeloid Leukaemia (AML) Kasumi-1 cell line with N822K KIT mutation, is a model system for leukemogenesis. As AML initiating cells reside in the CD34(+)CD38(-) fraction, we addressed the refined cytogenomic characterization and miRNA expression of Kasumi-1 cell line and its FACS-sorted subpopulations focussing on this compartment. By conventional cytogenetics, Spectral-Karyotyping and array-CGH the cytogenomic profile of Kasumi-1 cells evidenced only subtle regions differentially represented in CD34(+)CD38(-) cells. Expression profiling by a miRNA platform showed a set of miRNA differentially expressed in paired subpopulations and the signature of miR-584 and miR-182 upregulation in the CD34(+)CD38(-) fraction. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  12. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

    Science.gov (United States)

    Kantarjian, Hagop M; Roboz, Gail J; Kropf, Patricia L; Yee, Karen W L; O'Connell, Casey L; Tibes, Raoul; Walsh, Katherine J; Podoltsev, Nikolai A; Griffiths, Elizabeth A; Jabbour, Elias; Garcia-Manero, Guillermo; Rizzieri, David; Stock, Wendy; Savona, Michael R; Rosenblat, Todd L; Berdeja, Jesus G; Ravandi, Farhad; Rock, Edwin P; Hao, Yong; Azab, Mohammad; Issa, Jean-Pierre J

    2017-08-24

    The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m(2) guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m(2) on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m(2) in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock

  13. 急性早幼粒细胞白血病发生机制及治疗研究进展%The progress of acute promyelocytic leukemia in pathogenesis and therapy

    Institute of Scientific and Technical Information of China (English)

    梁雪; 孔佩艳

    2005-01-01

    急性早幼粒细胞白血病是一种预后凶险的白血病,约占成人急性髓系白血病的10%。该型白血病出血倾向严重,易并发弥漫性血管内凝血(diffuse intravascular eoagulation,DIC),尤其在化疗时易发生,常导致患者早期死亡,急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)是临床上第一个应用诱导分化和针对肿瘤特异性标志分子进行治疗并取得显著疗效的人类恶性肿瘤。

  14. 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.

  15. A thoracic-epidural granulocytic sarcoma case that was diagnosed preceding the onset of and that recurred co-incidental to acute promyelocytic leukemia, which developed after surgical treatment.

    Directory of Open Access Journals (Sweden)

    Savranlar A

    2004-10-01

    Full Text Available Granulocytic sarcoma or chloroma is a tumor seen in myelocytic leukemia. Spinal epidural onset is rare and is generally seen before or together with the onset of myelocytic leukemia. An epidural mass located at the 2nd-5th thoracic levels in an 18-year-old male patient was pathologically diagnosed as granulocytic sarcoma. Radiotherapy was performed after surgical intervention. Ten months later, he was re-admitted with abdominal pain. At this time, an epidural mass at the 6th-9th thoracic levels was detected on magnetic resonance imaging, and acute promyelocytic leukemia was diagnosed. After systemic chemotherapy, partial remission was achieved. We aimed to present this rare case with its remarkable follow-up findings.

  16. Pharm GKB: Leukemia, Monocytic, Acute [PharmGKB

    Lifescience Database Archive (English)

    Full Text Available Overview Alternate Names: Synonym Acute Monoblastic Leukemia; Acute Monoblastic Leukemias; Acute... Monocytic Leukemia; Acute Monocytic Leukemias; Acute monoblastic leukaemia; Acute monoblastic leukemia; Acute... monocytic leukaemia; Acute monocytic leukemia, morphology; Acute monocytoid leukemia; Leukemia, Acute... Monoblastic; Leukemia, Acute Monocytic; Leukemia, Monoblastic, Acute; Leukemia, Myeloid, Acute... Schilling-Type Myeloid; Leukemias, Acute Monoblastic; Leukemias, Acute Monocytic; M5a - Acute monoblastic leukaemia; M5a - Acute

  17. Fournier's gangrene as first presentation of promyelocytic leukemia

    NARCIS (Netherlands)

    Faber, HJ; Girbes, ARJ; Daenen, S

    A 50-year-old male is described who presented with Fournier's gangrene as what is probably the first manifestation of a newly diagnosed acute myelogenous leukemia (AML), promyelocytic type or variant type M-3, according to the FAB classification. Despite aggressive fluid resuscitation, tuned

  18. C-kit mutation screening in patients with acute myeloid leukaemia: adaptation of a Giemsa-stained bone-marrow smear DNA extraction technique.

    Science.gov (United States)

    Court, E L; Davidson, K; Smith, M A; Inman, L; Marriott, S A; Smith, J G; Pallister, C J

    2001-01-01

    The scarcity of viable tissue samples for leukaemia research is widely recognised and currently restrictive. Archival bone-marrow smears present a valuable resource that can be exploited easily for mutational analysis. Here, a modified technique to extract DNA is described, and used subsequently for mutation/polymorphism screening of the stem-cell factor receptor proto-oncogene c-kit in 23 patients with acute myeloid leukaemia (AML). The selected method was straightforward and used bone-marrow material scraped from periodic acid-Schiff, sudan black B and May-Grünwald/Giemsa-stained preparations, and treated initially with proteinase K prepared in digestion buffer to digest all proteinaceous matter. Following incubation, saturated sodium chloride was added and DNA extracted from the supernatant by phenol/chloroform/isoamyl alcohol treatment. Retrieved DNA was precipitated with ethanol at -20 degrees C overnight, washed with 95% ethanol, air-dried, resuspended using purite water and stored at -20 degrees C prior to use in mutational analysis. The extraction method described was compared with a commercial reagent for combined DNA, RNA and protein isolation using cryopreserved cells from 20 patients with AML. The quality of extracted DNA isolated by the two methods was comparable by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) techniques. Bone-marrow biopsies are performed regularly on each AML patient to monitor the disease; therefore, an extraction method using this resource could liberate a valuable source of DNA for study (e.g. molecular investigations, including mutation/polymorphism screening etc.). This would allow fresh and programme-frozen cells to be reserved for those investigations requiring intact, viable cells. The use of archived bone-marrow smears would permit vast increase in the scope for retrospective testing and large-scale analyses.

  19. Low frequency of MLL-partial tandem duplications in paediatric acute myeloid leukaemia using MLPA as a novel DNA screenings technique.

    Science.gov (United States)

    Balgobind, Brian V; Hollink, Iris H I M; Reinhardt, Dirk; van Wering, Elisabeth R; de Graaf, Siebold S N; Baruchel, Andre; Stary, Jan; Beverloo, H Berna; de Greef, Georgine E; Pieters, Rob; Zwaan, C Michel; van den Heuvel-Eibrink, Marry M

    2010-07-01

    Mixed-lineage leukaemia (MLL)-partial tandem duplications (PTDs) are found in 3-5% of adult acute myeloid leukaemia (AML), and are associated with poor prognosis. In adult AML, MLL-PTD is only detected in patients with trisomy 11 or internal tandem duplications of FLT3 (FLT3-ITD). To date, studies in paediatric AML are scarce, and reported large differences in the frequency of MLL-PTD, frequently utilising mRNA RT-PCR only to detect MLL-PTDs. We studied the frequency of MLL-PTD in a large cohort of paediatric AML (n=276) and the results from two different methods, i.e. mRNA RT-PCR, and multiplex ligation-dependent probe amplification (MLPA), a method designed to detect copy number differences of specific DNA sequences. In some patients with an MLL-rearrangement, MLL-PTD transcripts were detected, but were not confirmed by DNA-MLPA, indicating that DNA-MLPA can more accurately detect MLL-PTD compared to mRNA RT-PCR. In paediatric AML, MLL-PTD was detected in 7/276 patients (2.5%). One case had a trisomy 11, while the others had normal cytogenetics. Furthermore 4 of the 7 patients revealed a FLT3-ITD, which was significantly higher compared with the other AML cases (p=0.016). In conclusion, using DNA-MLPA as a novel screenings technique in combination with mRNA RT-PCR a low frequency of MLL-PTD in paediatric AML was found. Larger prospective studies are needed to further define the prognostic relevance of MLL-PTD in paediatric AML.

  20. miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Hong; Miao, Mei-hua; Ji, Xue-qiang; Xue, Jun; Shao, Xue-jun, E-mail: xuejunshao@hotmail.com

    2015-04-03

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in leukaemia, particularly T-cell acute lymphoblastic leukaemia (T-ALL), has remained elusive. Here, we identified miR-664 and its predicted target gene PLP2 were differentially expressed in T-ALL using bioinformatics methods. In T-ALL cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-664, while miR-664 inhibitor could significantly inhibited the proliferation. Moreover, migration and invasion assay showed that overexpression of miR-664 could significantly promoted the migration and invasion of T-ALL cells, whereas miR-664 inhibitor could reduce cell migration and invasion. luciferase assays confirmed that miR-664 directly bound to the 3'untranslated region of PLP2, and western blotting showed that miR-664 suppressed the expression of PLP2 at the protein levels. This study indicated that miR-664 negatively regulates PLP2 and promotes proliferation and invasion of T-ALL cell lines. Thus, miR-664 may represent a potential therapeutic target for T-ALL intervention. - Highlights: • miR-664 mimics promote the proliferation and invasion of T-ALL cells. • miR-664 inhibitors inhibit the proliferation and invasion of T-ALL cells. • miR-664 targets 3′ UTR of PLP2 in T-ALL cells. • miR-664 negatively regulates PLP2 in T-ALL cells.

  1. Myeloid Sarcoma of the Uterine Cervix as Presentation of Acute Myeloid Leukaemia after Treatment with Low-Dose Radioiodine for Thyroid Cancer: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Anne Sophie Weingertner

    2009-01-01

    Full Text Available The development of acute myeloid leukaemia after low-dose radioiodine therapy and its presentation as a myeloid sarcoma of the uterine cervix are both rare events. We report a case of acute myeloid leukaemia revealed by a myeloid sarcoma of the uterine cervix in a 48-year-old woman, 17 months after receiving a total dose of 100 mCi 131I for papillary thyroid cancer. A strict hematological follow-up of patients treated with any dose of 131I is recommended to accurately detect any hematological complications which might have been underestimated. Unusual presentations, such as chloroma of the uterine cervix, may reveal myeloid malignancy and should be kept in mind.

  2. Thinking in Diagnosis and Treatment of Acute Promyelocytic Leukemia with Philadelphia Chromosome Positivity%伴Ph染色体阳性的急性早幼粒细胞白血病诊治反思

    Institute of Scientific and Technical Information of China (English)

    蓝海峰; 杨文忠; 姜虹; 贾新颜; 高勇

    2014-01-01

    Objective To explore the clinical features, diagnosis and treatment of acute promyelocytic leukemia ( APL) with philadelphia chromosome ( Ph) positivity in order to avoid misdiagnosis and mistreatment. Methods Clinical data of a patient with Ph-positive acute promyelocytic leukemia manifesting as acute myelomonocytic leukemia was retrospec-tively analyzed, and related literature was reviewed. Results The patient was admitted for fever over three weeks. Primary diagnosis was acute myelomonocytic leukemia after examinations of morphologic, immunophenotypic and histochemistry. But the standard IDA regimen was ineffective, which used idarubicin and cytarabine. APL with positive Ph was confirmed by cyto-genetics and morphologic studies. Complete remission was obtained after treatment with all-trans-retinoic acid ( ATRA) and arsenic trioxide ( ATO) . There was no evidence of recurrence for 8 months after 4 cycles of consolidation therapy. PML-RARA fusion gene was changed to be negative, but BCR-ABL fusion gene was still positive. Conclusion Cytogenetic examination for suspected acute leukemia patients is necessary to reduce misdiagnosis and improve the therapeutic effect.%目的:探讨伴Ph染色体阳性急性早幼粒细胞白血病( acute promyelocytic leukemia, APL)的临床特征及诊治措施,以减少误诊误治。方法回顾性分析我院收治的1例骨髓形态、免疫组织化学及免疫表型极似急性粒单核细胞白血病且Ph染色体阳性APL的临床资料。结果本例因发热3周余就诊,根据骨髓形态学、免疫组织化学及免疫分型结果,初诊为急性粒单核细胞白血病,给予标准IDA方案(伊达比星加阿糖胞苷)化学治疗效果不佳。复查骨髓形态学并结合细胞遗传学检查,确诊为伴Ph染色体阳性APL,经维A酸( ATRA)联合三氧化二砷( ATO)治疗达完全缓解( CR),巩固治疗4个疗程。随访8个月仍处于CR,PML-RARA融合基因转阴,但BCR-ABL融合基因仍阳性。结论细

  3. The role of hematopoietic stem cell transplantation in the elderly patient with acute myeloid leukaemia O papel do transplante de célula-tronco hematopoiética em pacientes idosos com leucemia mielóide aguda

    OpenAIRE

    2008-01-01

    Older adults with Acute Myeloid Leukaemia (AML), when compared to younger patients with the same disease, have a poor prognosis and represent a discrete population in terms of disease biology, treatment-related complications, and overall outcome. As a result, older patients require distinctive management approaches. For 85%-95% of older AML patients, any therapy ultimately will be purely palliative. No randomized trial has ever demonstrated that any amount of post-remission therapy in older A...

  4. Birth weight in offspring and leukaemia risk in parents-A nation-wide register-based cohort study from Denmark

    DEFF Research Database (Denmark)

    Marklund, Maria; Rostgaard, Klaus; Hjalgrim, Lisa

    2013-01-01

    with parental risk of leukaemia overall or of leukaemia subtypes except for a twofold increased acute lymphatic leukaemia risk in fathers of high birth weight offspring and an increasing paternal risk of chronic myeloid leukaemia with increasing offspring birth weight. These may both be chance findings. Our...

  5. Morbility mechanism of acute promyelocytic leukemia%急性早幼粒细胞白血病的发病机制

    Institute of Scientific and Technical Information of China (English)

    许现辉

    2007-01-01

    急性早幼粒细胞白血病(actue promyelocytic leukemia,APL)是临床上第一个应用诱导分化治疗取得显著疗效的人类恶性肿瘤,是人类从分子水平上认识白血病的一个成功例子。在APL中,染色体易位使得17号染色体的RARa基因上,即导致维甲酸受体与位于其他染色体上的配偶基因发生融合,并表达相应的融合蛋白。

  6. Meeting Report: Institute for Social Security and Services for State Workers (ISSSTE on Acute Lymphoblastic Leukaemia, Mexico City, Mexico, 3rd to 4th October 2016

    Directory of Open Access Journals (Sweden)

    Alvarado Ibarra Martha

    2017-06-01

    Full Text Available From October 3 to 4, 2016, the fourth meeting of haematologists who belonged to the institute for social security and services for state workers (ISSSTE was held, the meeting was held in Mexico City, Mexico. Attending this working meeting, medical fellows of the specialty of Haematology and Paediatric Haematology, as well as attached doctors of both specialties that work in different hospitals in Mexico City and the rest of the country, the purpose of the attendees to this consensus was discuss, update, and homogenize the protocols of diagnostic and therapeutic approach in patients with acute lymphoblastic leukaemia of all ages. All participants appreciated the opportunity to participate in one of the most important cooperation projects of the ISSSTE and to be able to offer updated treatment protocols to this population or, failing that, to send them a Medical Center that can provide hospital care as soon as possible. Physicians took advantage of this meeting for the scientific exchange, the discussion on projects in course and were planned the development of other consensuses being the closest the one of lymphomas. As in the previous consensuses that were published in a National magazine. The coordinator of this project raised to the attendees the possibility of a publication in magazines of greater prestige international since in countries like Mexico the cooperative work is not frequent and the group of haematologists belonging to ISSSTE are working towards this goal. This consensus was considered as a very well-organized platform to support the research of young fellows in the specialty to stimulate the team work in protocols of the different haematological pathologies and to inform the world the results achieved in a population of patients attended by the ISSSTE. In agreement with the main objective of this consensus on acute lymphoblastic leukaemia once finished and discussed throughout the haematological group, the coordinator for the

  7. Comparing doctors' and nurses' accounts of how they provide emotional care for parents of children with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Forsey, Mary; Salmon, Peter; Eden, Tim; Young, Bridget

    2013-02-01

    Despite the emphasis that communication skills training (CST) programmes place on attending to the emotional care of patients, evidence suggests that practitioners neglect this aspect of patient care. We describe and compare doctors' and nurses' accounts of managing the emotional care of parents of children with leukaemia, with the overall objective of examining how their accounts might inform training and policy. Audio-recorded qualitative interviews with 30 doctors and nurses working in six UK paediatric oncology and haematology treatment centres were analysed interpretatively, drawing on the constant comparative method. Doctors' and nurses' descriptions of managing emotional care differed markedly. Doctors described reassuring parents through their ongoing clinical care of the child and by explaining the potentially curative nature of treatment. Doctors did not think they could reassure parents by eliciting and explicitly discussing parents' fears. In contrast, nurses relied on psychological skills and explicit discussion of parents' emotions to provide reassurance. Both doctors and nurses relied on each other to ensure that parents' emotional needs were met by the multidisciplinary team rather than by individual practitioners. Nurses' accounts of providing emotional care resembled the emphasis on explicit emotional talk in CST. However, doctors' accounts indicated that they provided emotional care in ways that diverged markedly from expectations in CST but that were more consistent with their biomedical and authoritative role in patient care. These findings may have implications for CST in future revisions of guidelines, but work is first needed to explore parents' perspectives on emotional care. Copyright © 2011 John Wiley & Sons, Ltd.

  8. Predictors of early death and survival among children, adolescents and young adults with acute myeloid leukaemia in California, 1988-2011: a population-based study.

    Science.gov (United States)

    Abrahão, Renata; Keogh, Ruth H; Lichtensztajn, Daphne Y; Marcos-Gragera, Rafael; Medeiros, Bruno C; Coleman, Michel P; Ribeiro, Raul C; Keegan, Theresa H M

    2016-04-01

    A better understanding of factors associated with early death and survival among children, adolescents and young adults with acute myeloid leukaemia (AML) may guide health policy aimed at improving outcomes in these patients. We examined trends in early death and survival among 3935 patients aged 0-39 years with de novo AML in California during 1988-2011 and investigated the associations between sociodemographic and selected clinical factors and outcomes. Early death declined from 9·7% in 1988-1995 to 7·1% in 2004-2011 (P = 0·062), and survival improved substantially over time. However, 5-year survival was still only 50% (95% confidence interval 47-53%) even in the most recent treatment period (2004-2011). Overall, the main factors associated with poor outcomes were older age at diagnosis, treatment at hospitals not affiliated with National Cancer Institute-designated cancer centres, and black race/ethnicity. For patients diagnosed during 1996-2011, survival was lower among those who lacked health insurance compared to those with public or private insurance. We conclude that mortality after AML remained strikingly high in California and increased with age. Possible strategies to improve outcomes include wider insurance coverage and treatment at specialized cancer centres.

  9. A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia.

    Science.gov (United States)

    Kennedy, Glen A; Morris, Kirk L; Subramonpillai, Elango; Curley, Cameron; Butler, Jason; Durrant, Simon

    2013-06-01

    This prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre-, mid- and post- each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 μg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19-130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment-related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.

  10. [Surviving the initial phase: subjective theories of illness in patients suffering from acute leukaemia at the end of initial inpatient treatment].

    Science.gov (United States)

    Koehler, Katharina; Dogan, Elif; Koehler, Michael; Heine, Viktoria; Frommer, Jörg

    2011-01-01

    Studies concentrating on the temporal dependence of subjective concepts during oncological treatment are underrepresented. Subjective interpretation contexts develop in the course of illness. The study focuses on the ideal-typical gestalt of these contents. In a follow-up study on coping, 12 patients with acute leukaemia (AL) were interviewed using a semistructured interview at the end of initial inpatient treatment. Using qualitative methodology, we inductively developed categories and assigned them to formal main categories. The following categories were developed: causal uncertainty as burden; discrepancy between subjective and objective assessment of degree of threat; knowledge of disease: conflict between information-seeking and information-avoiding behavior; dominance of medical approach to treatment; pursuit of normality; defense of emotions; orientation to workflows on the ward; adjustment as a coping strategy; positive attitude as a resource; life between hope and fear; limited future; latent fear of death. Themes of coping with the disease become visible. Some of these contents are tacit and latent, although of high subjective relevance to the patient. Their consideration could improve the patient-physician relationship.

  11. Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical design.

    Science.gov (United States)

    Lionberger, Jack M; Pagel, John M; Sandhu, Vicky K; Xie, Hu; Shadman, Mazyar; Mawad, Raya; Boehm, Alexandra; Dean, Carol; Shannon-Dorcy, Kathleen; Scott, Bart L; Deeg, Hans Joachim; Becker, Pamela S; Hendrie, Paul C; Walter, Roland B; Ostronoff, Fabiana; Appelbaum, Frederick R; Estey, Elihu H

    2014-08-01

    Combinations of agents may improve outcomes among elderly acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) patients. We performed an adaptive phase I/II trial for newly-diagnosed AML or high-risk MDS patients aged ≥50 years using a Bayesian approach to determine whether 1 of 3 doses of bendamustine (45, 60, 75 mg/m(2) days 1-3), together with idarubicin (12 mg/m(2) days 1-2), might provide a complete response (CR) rate ≥40% with 10% marrow blasts; median age 73 years). None of the three bendamustine doses in combination with idarubicin met the required CR and toxicity rates; the 75 mg/m(2) dose because of excess toxicity (two of three patients) and the 60 mg/m(2) dose because of low efficacy (CR rate 10/33), although no grade 3-4 non-haematological toxicity was seen at this dose. Median survival was 7·2 months. All patients began treatment as outpatients but hospitalization was required in 90% (35/39). Although we did not find a dose of bendamustine combined with idarubicin that would provide a CR rate of >40% with acceptable toxicity, bendamustine may have activity in AML/MDS patients, suggesting its addition to other regimens may be warranted.

  12. Implications of delayed bone marrow aspirations at the end of treatment induction for risk stratification and outcome in children with acute lymphoblastic leukaemia.

    Science.gov (United States)

    Zuna, Jan; Moericke, Anja; Arens, Mari; Koehler, Rolf; Panzer-Grümayer, Renate; Bartram, Claus R; Fischer, Susanna; Fronkova, Eva; Zaliova, Marketa; Schrauder, André; Stanulla, Martin; Zimmermann, Martin; Trka, Jan; Stary, Jan; Attarbaschi, Andishe; Mann, Georg; Schrappe, Martin; Cario, Gunnar

    2016-06-01

    Minimal residual disease (MRD) at the end of induction therapy is important for risk stratification of acute lymphoblastic leukaemia (ALL), but bone marrow (BM) aspiration is often postponed or must be repeated to fulfil qualitative and quantitative criteria for morphological assessment of haematological remission and/or MRD analysis. The impact of BM aspiration delay on measured MRD levels and resulting risk stratification is currently unknown. We analysed paired MRD data of 289 paediatric ALL patients requiring a repeat BM aspiration. MRD levels differed in 108 patients (37%) with a decrease in the majority (85/108). This would have resulted in different risk group allocation in 64 of 289 patients (23%) when applying the ALL-Berlin-Frankfurt-Münster 2000 criteria. MRD change was associated with the duration of delay; 40% of patients with delay ≥7 days had a shift to lower MRD levels compared to only 18% after a shorter delay. Patients MRD-positive at the original but MRD-negative at the repeat BM aspiration (n = 50) had a worse 5-year event-free survival than those already negative at first aspiration (n = 115) (86 ± 5% vs. 94 ± 2%; P = 0·024). We conclude that BM aspirations should be pursued as scheduled in the protocol because delayed MRD sampling at end of induction may result in false-low MRD load and distort MRD-based risk assessment.

  13. A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology

    Science.gov (United States)

    Hungate, Eric A.; Vora, Sapana R.; Gamazon, Eric R.; Moriyama, Takaya; Best, Timothy; Hulur, Imge; Lee, Younghee; Evans, Tiffany-Jane; Ellinghaus, Eva; Stanulla, Martin; Rudant, Jéremie; Orsi, Laurent; Clavel, Jacqueline; Milne, Elizabeth; Scott, Rodney J.; Pui, Ching-Hon; Cox, Nancy J.; Loh, Mignon L.; Yang, Jun J.; Skol, Andrew D.; Onel, Kenan

    2016-01-01

    Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (Pcombined=3.32 × 10−15, OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology. PMID:26868379

  14. Wilms' Tumour 1 (WT1) peptide vaccination in patients with acute myeloid leukaemia induces short-lived WT1-specific immune responses.

    Science.gov (United States)

    Uttenthal, Benjamin; Martinez-Davila, Irma; Ivey, Adam; Craddock, Charles; Chen, Frederick; Virchis, Andras; Kottaridis, Panagiotis; Grimwade, David; Khwaja, Asim; Stauss, Hans; Morris, Emma C

    2014-02-01

    Wilms' Tumour 1 (WT1) is a zinc finger transcription factor that is over-expressed in acute myeloid leukaemia (AML). Its restricted expression in normal tissues makes it a promising target for novel immunotherapies aiming to accentuate the cytotoxic T lymphocyte (CTL) response against AML. Here we report a phase I/II clinical trial of subcutaneous peptide vaccination with two separate HLA-A2-binding peptide epitopes derived from WT1, together with a pan-DR binding peptide epitope (PADRE), in Montanide adjuvant. Eight HLA-A2-positive patients with poor risk AML received five vaccination cycles at 3-weekly intervals. The three cohorts received 0·3, 0·6 and 1 mg of each peptide, respectively. In six patients, WT1-specific CTL responses were detected using enzyme-linked immunosorbent spot assays and pWT126/HLA-A*0201 tetramer staining, after ex vivo stimulation with the relevant WT1 peptides. However, re-stimulation of these WT1-specific T cells failed to elicit secondary expansion in all four patients tested, suggesting that the WT1-specific CD8(+) T cells generated following vaccination may be functionally impaired. No correlation was observed between peptide dose, cellular immune response, reduction in WT1 mRNA expression and clinical response. Larger studies are indicated to confirm these findings. © 2013 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

  15. Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns.

    Science.gov (United States)

    Moore, A S; Faisal, A; Gonzalez de Castro, D; Bavetsias, V; Sun, C; Atrash, B; Valenti, M; de Haven Brandon, A; Avery, S; Mair, D; Mirabella, F; Swansbury, J; Pearson, A D J; Workman, P; Blagg, J; Raynaud, F I; Eccles, S A; Linardopoulos, S

    2012-07-01

    Acquired resistance to selective FLT3 inhibitors is an emerging clinical problem in the treatment of FLT3-ITD(+) acute myeloid leukaemia (AML). The paucity of valid pre-clinical models has restricted investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. We generated selective FLT3 inhibitor-resistant cells by treating the FLT3-ITD(+) human AML cell line MOLM-13 in vitro with the FLT3-selective inhibitor MLN518, and validated the resistant phenotype in vivo and in vitro. The resistant cells, MOLM-13-RES, harboured a new D835Y tyrosine kinase domain (TKD) mutation on the FLT3-ITD(+) allele. Acquired TKD mutations, including D835Y, have recently been identified in FLT3-ITD(+) patients relapsing after treatment with the novel FLT3 inhibitor, AC220. Consistent with this clinical pattern of resistance, MOLM-13-RES cells displayed high relative resistance to AC220 and Sorafenib. Furthermore, treatment of MOLM-13-RES cells with AC220 lead to loss of the FLT3 wild-type allele and the duplication of the FLT3-ITD-D835Y allele. Our FLT3-Aurora kinase inhibitor, CCT137690, successfully inhibited growth of FLT3-ITD-D835Y cells in vitro and in vivo, suggesting that dual FLT3-Aurora inhibition may overcome selective FLT3 inhibitor resistance, in part due to inhibition of Aurora kinase, and may benefit patients with FLT3-mutated AML.

  16. Characterisation and Clinical Significance of FLT3-ITD and non-ITD in Acute Myeloid Leukaemia Patients in Kelantan, Northeast Peninsular Malaysia.

    Science.gov (United States)

    Yunus, Noraini Mat; Johan, Muhammad Farid; Ali Nagi Al-Jamal, Hamid; Husin, Azlan; Hussein, Abdul Rahim; Hassan, Rosline

    2015-01-01

    Mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor gene may promote proliferation via activation of multiple signaling pathways. FLT3-internal tandem duplication (FLT3-ITD) is the most common gene alteration found in patients diagnosed with acute myeloid leukaemia (AML) and has been associated with poor prognosis. We performed mutational analysis of exons 14-15 and 20 of the FLT3 gene in 54 AML patients using PCR-CSGE (conformational sensitive gel electrophoresis) followed by sequencing analysis to characterise FLT3 mutations in adult patients diagnosed with AML at Hospital USM, Kelantan, Northeast Peninsular Malaysia. FLT3 exon 14-15 mutations were identified in 7 of 54 patients (13%) whereas no mutation was found in FLT3 exon 20. Six ITDs and one non-ITD mutation were found in exon 14 of the juxtamembrane (JM) domain of FLT3. FLT3-ITD mutations were associated with a significantly higher blast percentage (p-value=0.008) and white blood cell count (p-value=0.023) but there was no significant difference in median overall survival time for FLT3-ITD+/FLT3-ITD- within 2 years (p-value=0.374). The incidence of FLT3-ITD in AML patients in this particular region of Malaysia is low compared to the Western world and has a significant association with WBC and blast percentage.

  17. Lower-limb MRI in the staging and re-staging of osteonecrosis in paediatric patients affected by acute lymphoblastic leukaemia after therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ippolito, D.; Masetto, A.; Franzesi, C.T.; Bonaffini, P.A.; Sironi, S. [University of Milano-Bicocca Milan, School of Medicine, Monza (Italy); Department of Diagnostic Radiology, H. San Gerardo, Monza (Italy); Sala, A.; Biondi, A. [University of Milano-Bicocca Milan, School of Medicine, Monza (Italy); H. San Gerardo, Department of Paediatric Haematology, Monza (Italy)

    2016-04-15

    To assess the diagnostic value of MRI examination in detecting and monitoring osteonecrotic lesions (ON) in childhood acute lymphoblastic leukaemia (ALL) after chemotherapy (CHT) and/or bone marrow transplantation (BMT). Seventy-three patients (37 males, mean age 12.4 years old) with ALL after treatment underwent a lower-limb MR examination between November 2006 and March 2012. In 47 there was clinical suspicion of ON, 26 were asymptomatic. Studies were performed with a 1 T and a 1.5 T scanner, acquiring short tau inversion recovery (STIR) and T1-weighted sequences in coronal plane from the hips to the ankles. The average acquisition time was 18 min. Considering baseline and follow-up examinations, the overall number of MRI studies was 195. Fifty-four of 73 patients showed ON at MRI study, with an overall number of 323 ON (89 involving articular surface, 24 with joint deformity, JD). Twenty-five of 47 symptomatic patients showed subchondral ON lesions, 11 developed JD. Three of 26 asymptomatic patients showed subchondral bone ON at baseline examination but no JD at follow-up. Twenty-two of 28 BMT, 32/45 CHT patients developed ON. Our MRI protocol proved to be feasible in evaluating ON in paediatric patients. Studies should be addressed only to symptomatic patients. (orig.)

  18. Direct X-ray radiogrammetry versus dual-energy X-ray absorptiometry: assessment of bone density in children treated for acute lymphoblastic leukaemia and growth hormone deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Rijn, Rick R. van; Wittenberg, Rianne [Academic Medical Centre Amsterdam, Department of Radiology, Amsterdam Zuid-Oost (Netherlands); Boot, Annemieke; Sluis, Inge M. van der; MuinckKeizer-Schrama, Sabine M.P.F. de [Erasmus MC-Sophia Children' s Hospital, Department of Paediatric Endocrinology, Rotterdam (Netherlands); Heuvel-Eibrink, Marry M. van den [Erasmus MC-Sophia Children' s Hospital, Department of Paediatric Haematology/Oncology, Rotterdam (Netherlands); Lequin, Maarten H. [Erasmus MC-Sophia Children' s Hospital, Department of Paediatric Radiology, Rotterdam (Netherlands); Kuijk, Cornelis Van [University Medical Centre ' Radboud' , Department of Radiology, Nijmegen (Netherlands)

    2006-03-15

    In recent years interest in bone densitometry in children has increased. To evaluate the clinical application of digital X-ray radiogrammetry (DXR) and compare the results with those of dual-energy X-ray absorptiometry (DXA). A total of 41 children with acute lymphoblastic leukaemia (ALL) and 26 children with growth hormone deficiency (GHD) were included in this longitudinal study. Radiographs of the left hand were obtained and used for DXR. DXA of the total body and of the lumbar spine was performed. In both study populations significant correlations between DXR and DXA were found, and, with the exception of the correlation between DXR bone mineral density (DXR-BMD) and bone mineral apparent density in the GHD population, all correlations had a P-value of <0.001. During treatment a change in DXR-BMD was found in children with GHD. Our study showed that DXR in a paediatric population shows a strong correlation with DXA of the lumbar spine and total body and that it is able to detect a change in BMD during treatment. (orig.)

  19. Massive myeloid sarcoma affecting the central nervous system, mediastinum, retroperitoneum, liver, and rectum associated with acute myeloblastic leukaemia: a case report

    Science.gov (United States)

    Best-Aguilera, C R; Vazquez-Del Mercado, M; Muñoz-Valle, J F; Herrera-Zarate, L; Navarro-Hernandez, R E; Martin-Marquez, B T; Oregon-Romero, E; Ruiz-Quezada, S; Bonilla, G M; Lomeli-Guerrero, A

    2005-01-01

    Myeloid sarcomas are extramedullary tumours with granulocytic precursors. When associated with acute myelogenous leukaemia (AML), these tumours usually affect no more than two different extramedullary regions. This report describes a myeloid sarcoma associated with AML with tumour formation at five anatomical sites. The patient was a 37 year old man admitted in September 1999 with a two month history of weight loss, symptoms of anaemia, rectal bleeding, and left facial nerve palsy. The anatomical sites affected were: the rectum, the right lobe of the liver, the mediastinum, the retroperitoneum, and the central nervous system. A bone marrow smear was compatible with AML M2. Flow cytometry showed that the peripheral blood was positive for CD4, CD11, CD13, CD14, CD33, CD45, and HLA-DR. A karyotypic study of the bone marrow revealed an 8;21 translocation. The presence of multiple solid tumours in AML is a rare event. Enhanced expression of cell adhesion molecules may be the reason why some patients develop myeloid sarcomas. PMID:15735171

  20. The Efficacy of Arsenite Combined with Rretinoic Acid and Chemotherapy on Acute Promyelocytic Leukemia%亚砷酸联合维甲酸化疗治疗急性早幼粒细胞白血病疗效观察

    Institute of Scientific and Technical Information of China (English)

    闻艳

    2016-01-01

    Objective: To observe the effect of arsenite combined retinoic acid and chemotherapy on treatment of acute promyelocytic leukemia. Methods:90 cases of acute early promyelocytic leukemia patients admitted in our hospital from April 2008 to April 2015 were selected to retrospective analyse, and according to the treatment plan was divided into two groups. The control group was treated with retinoic acid combined with chemotherapy, and the observation group was treated jointly arsenite. The curative effects of the two groups were compared. Results: The promyelocytic ratio and total number of white blood cells in the observation group improved than that in the control group ( P < 0.05) . Conclusion:For patients with acute promyelocytic leukemia,the treatment method of chemotherapy combined with arsenite and retinoic acid has a satisfactory effect.%目的::研究急性早幼粒细胞白血病行亚砷酸和维甲酸、化疗联合治疗效果。方法:资料取本院2008年4月至2015年4月急性早幼粒细胞白血病90例患者予回顾分析,按治疗方案分成两组,对照组行维甲酸与化疗,观察组联合亚砷酸,对比两组疗效。结果:观察组早幼粒细胞比例与总白细胞数改善效果比对照组优( P<0.05)。结论:急性早幼粒细胞白血病患者行亚砷酸和维甲酸、化疗联合治疗效果满意。