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Sample records for chronic lymphoid leukemia

  1. Osseous pseudo-myelomatose compromise, in leukemia chronic lymphoid

    International Nuclear Information System (INIS)

    Martinez Betancur, Octavio; Lopez de Goenaga, Maria Ines

    2000-01-01

    It was described a case of chronic lymphocytic leukemia in a 75 year old man, with pseudomyelomatosis osteolytic lesions in the skull, excluding other potential causes of osteolytic lesions in the clinical context of malignant lymphoproliferative neoplasm. The real frequency of osseous compromise in chronic lymphocytic leukemia is 10%. Lesions are defined as generalized osteoporosis and osteolysis with lacunar aspect, similar to myeloma lesions. Because histopathology in lymphoproliferative neoplasms may be similar, it might be difficult to diagnose chronic lymphocytic leukemia certainly, if the clinical manifestations are not considered. Differential diagnosis with other lymphoproliferative neoplasm is based basically in absolute lymphocytosis greater than 10 X 109/L, with lymphocytes with mature appearance

  2. Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia.

    Science.gov (United States)

    Kikushige, Yoshikane; Miyamoto, Toshihiro

    2015-11-01

    Human malignancies progress through a multistep process that includes the development of critical somatic mutations over the clinical course. Recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations in hematological malignancies and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are thought to originate directly from differentiated mature lymphocytes; however, recent compelling data have shown that primitive HSCs and hematopoietic progenitor cells contribute to the pathogenesis of mature lymphoid malignancies. Several representative mutations of hematological malignancies have been identified within the HSCs of CLL and lymphoma patients, indicating that the self-renewing long-lived fraction of HSCs can serve as a reservoir for the development of oncogenic events. Novel mice models have been established as human mature lymphoma models, in which specific oncogenic events target the HSCs and immature progenitor cells. These data collectively suggest that HSCs can be the cellular target involved in the accumulation of oncogenic events in the pathogenesis of mature lymphoid and myeloid malignancies.

  3. [Disappearance of Philadelphia chromosomes after remission induction in lymphoid crisis of chronic myelogenous leukemia].

    Science.gov (United States)

    Nagafuji, K; Iwakiri, R; Miyamoto, T; Okamura, H; Yokota, E; Matsumoto, I

    1992-09-01

    The authors report a rare case of chronic myelogenous leukemia (CML) in which the Ph1 clone disappeared after remission induction of lymphoid crisis. A 58-year-old man was admitted to our hospital because of fever in July 1988. The white cell count was elevated. Bone marrow aspirate showed hypercellularity with myeloid hyperplasia. In the chromosomal analysis, Ph1 chromosomes were detected in 100% of bone marrow cells analysed. Diagnosis of CML was made and treatment was initiated with recombinant interferon-alpha 2a. Hematological remission without cytogenetic improvement was achieved. In March 1990 he developed lymphoid crisis with proliferation of CD10-positive cells. The chromosomal analysis revealed additional abnormalities including, 45, X, -Y, t(9;22) (q34;q11), +1, -8. With vincristine 0.6 mgX4, pirarubicin 15 mgX4, dexamethasone 40 mgX4 therapy complete remission was obtained. In December 1990 the Ph1 positive clone completely disappeared judging from normal karyotypes in the chromosomal analysis and the disappearance of M-bcr gene rearrangement.

  4. Chronic myeloid leukemia may be associated with several bcr-abl transcripts including the acute lymphoid leukemia-type 7 kb transcript

    NARCIS (Netherlands)

    Selleri, L.; von Lindern, M.; Hermans, A.; Meijer, D.; Torelli, G.; Grosveld, G.

    1990-01-01

    In the majority of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) patients, the c-abl gene is fused to the bcr gene, resulting in the transcription of an 8.5 kb chimeric bcr-abl mRNA, which is translated into a p210bcr-abl fusion protein. In about 50% of the Ph-positive acute lymphoid

  5. Chronic myelogenous leukemia (CML)

    Science.gov (United States)

    CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... nuclear disaster. It takes many years to develop leukemia from radiation exposure. Most people treated for cancer ...

  6. Interphase FISH for BCR-ABL1 rearrangement on neutrophils: A decisive tool to discriminate a lymphoid blast crisis of chronic myeloid leukemia from a de novo BCR-ABL1 positive acute lymphoblastic leukemia.

    Science.gov (United States)

    Balducci, Estelle; Loosveld, Marie; Rahal, Ilhem; Boudjarane, John; Alazard, Emilie; Missirian, Chantal; Lafage-Pochitaloff, Marina; Michel, Gérard; Zattara, Hélène

    2018-02-01

    Discrimination between lymphoid blast crisis of chronic myeloid leukemia (CML) and de novo BCR-ABL1 positive acute lymphoblastic leukemia (ALL) represents a diagnostic challenge because this distinction has a major incidence on the management of patients. Here, we report an uncommon pediatric case of ALL with cryptic ins(22;9)(q11;q34q34) and p190-type BCR-ABL1 transcript. We performed interphase fluorescence in situ hybridization (FISH) for BCR-ABL1 rearrangement on blood neutrophils, which was positive consistent with the diagnosis of lymphoid blast crisis of CML. This case illustrates the major interest of interphase FISH for BCR-ABL1 rearrangement on blood neutrophils as a decisive method to discriminate a lymphoid blast crisis of CML from a de novo BCR-ABL1 positive ALL. Copyright © 2017 John Wiley & Sons, Ltd.

  7. Atypical Chronic Myelogenous Leukemia

    Science.gov (United States)

    ... myeloproliferative neoplasms, leukemia , and other conditions . Chronic Myelomonocytic Leukemia Key Points Chronic myelomonocytic leukemia is a disease ... chance of recovery) and treatment options. Chronic myelomonocytic leukemia is a disease in which too many myelocytes ...

  8. Chronic Myelogenous Leukemia

    Science.gov (United States)

    Chronic myelogenous leukemia Overview Chronic myelogenous leukemia (CML) is an uncommon type of cancer of the blood cells. The term "chronic" in chronic myelogenous leukemia indicates that this cancer ...

  9. Normalization of lymphocyte count after high ablative dose of I-131 in a patient with chronic lymphoid leukemia and secondary papillary carcinoma of the thyroid: case report

    International Nuclear Information System (INIS)

    Thom, Anneliese Rosmarie Gertrud Fischer; Hamerschlak, Nelson; Osawa, Akemi; Santos, Fabio Pires de Souza; Pasqualin, Denise da Cunha; Wagner, Jairo; Yamaga, Lilian Yuri Itaya; Cunha, Marcelo Livorsi da; Campos Neto, Guilherme de Carvalho; Funari, Marcelo Buarque de Gusmao; Teles, Veronica Goes

    2014-01-01

    The authors report the case of a 70-year-old male patient with chronic lymphoid leukemia who presented subsequently a papillary carcinoma of the thyroid with metastases to regional lymph nodes. The patient was treated with surgical thyroidectomy with regional and cervical lymph node excision and radioiodine therapy (I-131). The protocolar control scintigraphy 4 days after the radioactive dose showed I-131 uptake in both axillae and even in the inguinal regions. PET/CT showed faint FDG-F-18 uptake in one lymph node of the left axilla. An ultrasound guided fine needle biopsy of this lymph node identified by I-131 SPECT/CT and FDG-F-18 PET/CT revealed lymphoma cells and was negative for thyroid tissue and thyroglobulin content. The sequential blood counts done routinely after radiation treatment showed a marked fall until return to normal values of leucocytes and lymphocytes (absolute and relative), which were still normal in the last control 19 months after the radioiodine administration. Chest computed tomography showed a decrease in size of axillary and paraaortic lymph nodes. By immunohistochemistry, cells of the lymphoid B lineage decreased from 52% before radioiodine therapy to 5% after the procedure. The authors speculate about a possible sodium iodide symporter expression by the cells of this lymphoma, similar to some other non-thyroid tumors, such as breast cancer cells. (author)

  10. Chronic lymphocytic leukemia (CLL)

    Science.gov (United States)

    ... is used for painful and enlarged lymph nodes. Blood transfusions or platelet transfusions may be required if blood ... unexplained fatigue, bruising, excessive sweating, or weight loss. Alternative ... Leukemia - chronic lymphocytic (CLL); Blood cancer - chronic lymphocytic leukemia; Bone marrow cancer - chronic ...

  11. A high number of losses in 13q14 chromosome band is associated with a worse outcome and biological differences in patients with B-cell chronic lymphoid leukemia

    Science.gov (United States)

    Hernández, José Ángel; Rodríguez, Ana Eugenia; González, Marcos; Benito, Rocío; Fontanillo, Celia; Sandoval, Virgilio; Romero, Mercedes; Martín-Núñez, Guillermo; de Coca, Alfonso García; Fisac, Rosa; Galende, Josefina; Recio, Isabel; Ortuño, Francisco; García, Juan Luis; de las Rivas, Javier; Gutiérrez, Norma Carmen; San Miguel, Jesús F.; Hernández, Jesús María

    2009-01-01

    Background Among patients with B-cell chronic lymphoid leukemia, those with 13q14 deletion have a favorable outcome. However, whether the percentage of cells with 13q- influences the prognosis or the biological characteristics of this disease is unknown. We analyzed the clinico-biological characteristics and outcome of patients with B-cell chronic lymphoid leukemia with loss of 13q as the sole cytogenetic aberration. Design and Methods Three hundred and fifty patients with B-cell chronic lymphoid leukemia were studied. Clinical data were collected and fluorescence in situ hybridization and molecular studies were carried out. In addition, a gene expression profile was obtained by microarray-based analysis. Results In 109 out of the 350 cases (31.1%) loss of 13q was the sole cytogenetic aberration at diagnosis. In the subgroup of patients with 80% or more of cells with loss of 13q (18 cases), the overall survival was 56 months compared with not reached in the 91 cases in whom less than 80% of cells had loss of 13q (p< 0.0001). The variables included in the multivariate analysis for overall survival were the percentage of losses of 13q14 (p=0.001) and B symptoms (p=0.007). The time to first therapy in the group with 80% or more vs. less than 80% of losses was 38 months vs. 87 months, respectively (p=0.05). In the multivariate analysis the variables selected were unmutated status of IgVH (p=0.001) and a high level of β2microglobulin (p=0.003). Interestingly, these differences regarding overall survival and time to first therapy were also present when other cut-offs were considered. The gene expression profile of patients with a high number of losses in 13q14 showed a high proliferation rate, downregulation of apoptosis-related genes, and dysregulation of genes related to mitochondrial functions. Conclusions Patients with B-cell chronic lymphoid leukemia with a high number of losses in 13q14 as the sole cytogenetic aberration at diagnosis display different clinical and

  12. Clinical epidemiological aspects of chronic lymphoid leukaemia

    International Nuclear Information System (INIS)

    Rodriguez Brunet, Marisol; Hernandez Galano, Geldris P; Suarez Beyries, Lidia C; Duverger Magdaleon, Ernesto

    2011-01-01

    A descriptive and retrospective study of 71 patients with chronic lymphoid leukemia, attended at the Hematology Service from 'Dr Juan Bruno Zayas Alfonso' Teaching General Hospital in Santiago de Cuba was carried out from January, 2001 to November, 2006, in order to identify some clinical epidemiological variables on them, to show the therapeutical variables more used, as well as to assess survival, mortality, and the main causes of the clinical entity. Elderly, male sex, and high risk category related to advanced stage were predominant in the series. The therapeutical schedule of chlorambucil and prednisone was the most used, achieving good results in the majority of the case material. The survival of patients, in general, ranged among 1-5 years, whereas deaths occurred due to disease progression, infectious respiratory processes, pro-lymphocytic transformation, second neoplasias, and strokes. (author)

  13. Chronic neutrophilic leukemia.

    Science.gov (United States)

    Bredeweg, Arthur; Burch, Micah; Krause, John R

    2018-01-01

    Chronic neutrophilic leukemia is a rare myeloproliferative disorder characterized by a sustained peripheral blood neutrophilia, absence of the BCR/ABL oncoprotein, bone marrow hypercellularity with less than 5% myeloblasts and normal neutrophil maturation, and no dysplasia. This leukemia has been associated with mutations in the colony-stimulating factor 3 receptor (CSF3R) that may activate this receptor, leading to the proliferation of neutrophils that are the hallmark of chronic neutrophilic leukemia. We present a case of chronic neutrophilic leukemia and discuss the criteria for diagnosis and the significance of mutations found in this leukemia.

  14. Stages of Chronic Myelogenous Leukemia

    Science.gov (United States)

    ... ALL Treatment Childhood AML Treatment Research Chronic Myelogenous Leukemia Treatment (PDQ®)–Patient Version General Information About Chronic Myelogenous Leukemia Go to Health Professional Version Key Points Chronic ...

  15. Occurrence of chronic lymphocytic leukemia in patients with chronic myelogenous leukemia

    Directory of Open Access Journals (Sweden)

    Pritish K Bhattacharyya

    2013-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is the most common leukemia of adults in the western world and constitutes about 33% of all leukemia′s. The incidence of CLL increases with age and are more common in older population. Chronic myeloid leukemia (CML on the contrary occurs in both young adults and elderly and is a chronic myeloproliferative disease that originates from abnormal pluripotent stem cells and results in involvement of multiple hematopoietic lineages, but predominantly myeloid and less commonly lymphoid. Association between CLL and myeloid malignancies (CML, acute myeloid leukemia and MDS, myelodysplastic syndrome is rare. In literature documenting CLL and CML in same patients, occur either simultaneously or CML is preceded by CLL.

  16. How Is Chronic Myeloid Leukemia Diagnosed?

    Science.gov (United States)

    ... Myeloid Leukemia? More In Chronic Myeloid Leukemia About Chronic Myeloid Leukemia Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treatment After Treatment Back To Top Imagine a world ...

  17. Chronic Lymphocytic Leukemia

    Science.gov (United States)

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

  18. Chronic Myeloid Leukemia

    Science.gov (United States)

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

  19. Stages of Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... of the lymph system . Having relatives who are Russian Jews or Eastern European Jews. Signs and symptoms ... information about clinical trials is also available. To Learn More About Chronic Lymphocytic Leukemia For more information ...

  20. Treatment Option Overview (Chronic Myelogenous Leukemia)

    Science.gov (United States)

    ... ALL Treatment Childhood AML Treatment Research Chronic Myelogenous Leukemia Treatment (PDQ®)–Patient Version General Information About Chronic Myelogenous Leukemia Go to Health Professional Version Key Points Chronic ...

  1. General Information about Chronic Myelogenous Leukemia

    Science.gov (United States)

    ... ALL Treatment Childhood AML Treatment Research Chronic Myelogenous Leukemia Treatment (PDQ®)–Patient Version General Information About Chronic Myelogenous Leukemia Go to Health Professional Version Key Points Chronic ...

  2. Esterase Isoenzyme Profiles in Acute and Chronic Leukemias.

    Science.gov (United States)

    Drexler, H G; Gignac, S M; Hoffbrand, A V; Minowada, J

    1991-01-01

    Using isoelectric focusing (IEF) a number of carboxylic esterase isoenzymes (EC 3.1.1.1) with isoelectric points between pH 4.5-8.0 can be separated. One particular isoenzyme with an isoelectric point at about pH 6.0, the Mono-band, can be selectively and completely inhibited by sodium fluoride; this isoenzyme comprises a number of closely related subcomponents and may appear in more than one band on the gel. We analyzed the expression of typical esterase isoenzyme patterns in cells from a large panel of leukemias which were tested under identical conditions by IEF on horizontal thin-layer polyacrylamide gels with an ampholyte of pH 2-11. The 442 cases of acute and chronic myeloid and lymphoid leukemia (AML/AMMoL, CML/CMML, ALL, CLL) were classified according to clinical, morpho-cytochemical and immunophenotyping criteria. While bands between pH 4.5-5.5 appeared not to be specific for lineage or stage of differentiation, isoenzymes between pH 6.6-7.7 provided information on the type of leukemia involved. Seven typical isoenzyme patterns termed Mono1/Mono2 (fo monocyte-associated), My1/My2 (myeloid), Lym1/Lym2 (lymphoid) and Und (undifferentiated) could be discerned. Lym and Und patterns are characterized by fewer bands with a weaker staining intensity than Mono and My patterns. Nearly all cases of lymphoid leukemias (acute and chronic) expressed only Lym or Und esterase isoenzyme patterns, but no Mono or My patterns. Cases of acute or chronic myeloid and (myelo)monocytic leukemia showed strong isoenzyme staining displaying predominantly Mono or My isoenzyme patterns. The isoenzyme patterns found in CML in lymphoid or myeloid blast crisis corresponded to those seen in the respective acute leukemias, ALL or AML. The Mono-band was found in most cases of leukemias with monocytic elements (AMMoL 80%, CML 44%, CMML 100%), in the occasional case of CML-myeloid blast crisis or AML, but in none of the cases of ALL or CLL. This isoenzyme is a distinctive, specific marker for

  3. [Occurrence of associated tumours in chronic lymphocytic leukemia].

    Science.gov (United States)

    Szerafin, László; Jakó, János; Varju, Lóránt

    2016-10-01

    Chronic lymphocytic leukemia is one of the most common hematologic malignancy. The aim of the authors was to investigate the characteristics of malignancies associated with chronic lymphocytic leukemia in patients diagnozed between 2000 and 2015. Data of patients with chronic lymphocytic leukemia who had other associated tumours were analysed using the Leukemia/Lymphoma Registry of the Szabolcs-Szatmár-Bereg County, Hungary and patient records. Between January 1, 2000 and December 31, 2015, 526 patients with chronic lymphocytic leukemia were diagnosed. 95 patients of the 526 patients (18.06%) were diagnosed as having associated other tumours. In 48/95 patients (50.5%) the first diagnosed tumour was chronic lymphocytic leukemia, in 23/95 patients (24.2%) the first recognized malignancy was the associated tumour, whereas in 24/95 patients (25.3%) synchron tumours were diagnosed. The number of patients with more than one associated tumour was 10/95 (10.5%). The total number of tumours was 107. The incidence of chronic lymphoid leukemia increased in the period between 2000 and 2015 as compared to the period between 1983 and 1999 (3.19 vs 5.65/100 000 person/year). The occurrence of associated malignancies increased as well (8.06% vs 18.06%). In addition to the most common tumours (colorectal, breast, lung, prostate), skin squamous cell carcinoma (17/95 patients; 17.9%) and melanoma (6/95 patients; 6.3%) also frequently occurred. The second malignancies were most frequently discovered after the diagnosis of chronic lymphocytic leukemia and synchron tumours accounting for 78.5% (84/107) of all associated tumours. The incidence of second malignancies decreased 10 years after the diagnosis of chronic lymphocytic leukemia. The possible reasons for the high frequency of other tumours associated with chronic lymphocytic leukemia are elderly age of patients, immunsuppressed state and, presumably, chemotherapy of patients with chronic lymphocytic leukemia. During the follow up

  4. Differential protective effects of immune lymphoid cells against transplanted line Ib leukemia and immune polioencephalomyelitis

    International Nuclear Information System (INIS)

    Duffey, P.S.; Lukasewycz, O.A.; Olson, D.S.; Murphy, W.H.

    1978-01-01

    The capacity of immune cells obtained from the major lymphoid compartments to protect C58 mice from transplanted line Ib leukemia, and from an age-dependent autoimmune CNS disease (immune polioencephalomyelitis = IPE) elicited by immunizing old C58 mice with inactivated Ib cells was quantified. Cells used for comparative adoptive protection tests were harvested from the major lymphoid compartments 14 to 15 days after young C58 mice were immunized with inactivated Ib cell preparations. Regression curves were plotted from survival data and the log 10 PD 50 values were determined. Immune spleen (ISC) and peritoneal cells (IPEC) were significantly more protective against transplanted Ib cells than immune lymph node (ILNC), thymic (ITC), and marrow cells (IMC). In contrast, IPEC and IMC were not protective against IPE and ITC were only marginally protective. ILNC afforded significant protection to transplantable leukemia but were only marginally protective to IPE. When ISC were treated with anti-thy 1.2 serum and complement, protection against transplanted leukemia and IPE was reduced > 99%. When donors of immune lymphoid cells were treated with 12.5 mg of cortisone acetate daily for 2 days before lymphoid cells were harvested, protection against transplanted Ib cells by ISC was reduced by approximately 90% whereas protection against IPE was totally eliminated. Considered together, these results indicate that the protective mechanisms to transplantable leukemia and IPE differ significantly in the same indicator mouse strain

  5. Myeloblastic and lymphoblastic markers in acute undifferentiated leukemia and chronic myelogenous leukemia in blast crisis.

    Science.gov (United States)

    Shumak, K H; Baker, M A; Taub, R N; Coleman, M S

    1980-11-01

    Blast cells were obtained from 17 patients with acute undifferentiated leukemia and 13 patients with chronic myelogenous leukemia in blast crisis. The blasts were tested with anti-i serum in cytotoxicity tests and with antisera to myeloblastic leukemia-associated antigens in immunofluorescence tests. The terminal deoxynucleotidyl transferase (TDT) content of the blasts was also measured. Lymphoblasts react strongly with anti-i, do not react with anti-myeloblast serum, and have high levels of TDT; myeloblasts react weakly with anti-i, do not react with anti-myeloblast serum, and have very low levels of TDT. Of the 17 patients with acute undifferentiated leukemia, there were six with blasts which reacted like lymphoblasts, six with blasts which reacted like myeloblasts, and five with blasts bearing different combinations of these lymphoblastic and myeloblastic markers. Eight of the 11 patients with lymphoblastic or mixed lymphoblastic-myeloblastic markers, but only one of the six with myeloblastic markers, achieved complete or partial remission in response to therapy. Thus, in acute undifferentiated leukemia, classification of blasts with these markers may be of prognostic value. Of the 13 patients with chronic myelogenous leukemia in blast crises, the markers were concordant (for myeloblasts) in only two cases. Three of the 13 patients had TDT-positive blasts, but the reactions of these cells with anti-i and with anti-myeloblast serum differed from those seen with lymphoblasts from patients with acute lymphoblastic leukemia. Although the cell involved in "lymphoid" blast crisis of chronic myelogenous leukemia is similar in many respects to that involved in acute lymphoblastic leukemia, these cells are not identical.

  6. Osteogenesis imperfecta and acute lymphoid leukemia: case report

    Directory of Open Access Journals (Sweden)

    Gabriel David Tarud

    2017-08-01

    Discussion: It is well described that genetic and chromosomal abnormalities increase the risk of leukemia, however the relationship between osteogenesis imperfecta and acute lymphoblastic leukemia is rare. In the world literature, there are few cases mentioning this association. It is important to continue observing the occurrence of later cases, which allow describing if there is a direct relationship between these two entities.

  7. Normalization of lymphocyte count after high ablative dose of I-131 in a patient with chronic lymphoid leukemia and secondary papillary carcinoma of the thyroid: case report; Normalizacao da contagem de linfocitos apos dose ablativa de I-131 em um paciente com leucemia linfoide cronica e carcinoma papilifero da tireoide: relato de caso

    Energy Technology Data Exchange (ETDEWEB)

    Thom, Anneliese Rosmarie Gertrud Fischer; Hamerschlak, Nelson; Osawa, Akemi; Santos, Fabio Pires de Souza; Pasqualin, Denise da Cunha; Wagner, Jairo; Yamaga, Lilian Yuri Itaya; Cunha, Marcelo Livorsi da; Campos Neto, Guilherme de Carvalho; Funari, Marcelo Buarque de Gusmao, E-mail: afthom@einstein.br [Hospital Israelita Albert Einstein, Sao Paulo, SP (Brazil); Teles, Veronica Goes [Sociedade Brasileira de Diabetes, Sao Paulo, SP (Brazil)

    2014-07-01

    The authors report the case of a 70-year-old male patient with chronic lymphoid leukemia who presented subsequently a papillary carcinoma of the thyroid with metastases to regional lymph nodes. The patient was treated with surgical thyroidectomy with regional and cervical lymph node excision and radioiodine therapy (I-131). The protocolar control scintigraphy 4 days after the radioactive dose showed I-131 uptake in both axillae and even in the inguinal regions. PET/CT showed faint FDG-F-18 uptake in one lymph node of the left axilla. An ultrasound guided fine needle biopsy of this lymph node identified by I-131 SPECT/CT and FDG-F-18 PET/CT revealed lymphoma cells and was negative for thyroid tissue and thyroglobulin content. The sequential blood counts done routinely after radiation treatment showed a marked fall until return to normal values of leucocytes and lymphocytes (absolute and relative), which were still normal in the last control 19 months after the radioiodine administration. Chest computed tomography showed a decrease in size of axillary and paraaortic lymph nodes. By immunohistochemistry, cells of the lymphoid B lineage decreased from 52% before radioiodine therapy to 5% after the procedure. The authors speculate about a possible sodium iodide symporter expression by the cells of this lymphoma, similar to some other non-thyroid tumors, such as breast cancer cells. (author)

  8. Chaetoglobosin A preferentially induces apoptosis in chronic lymphocytic leukemia cells by targeting the cytoskeleton

    DEFF Research Database (Denmark)

    Knudsen, Peter Boldsen; Hanna, B.; Ohl, S.

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is an incurable malignancy of mature B cells. One of the major challenges in treatment of CLL is the achievement of a complete remission to prevent relapse of disease originating from cells within lymphoid tissues and subsequent chemoresistance. In search for no...... with PI3K and BTK inhibitors, suggesting this compound as a novel potential drug for CLL.Leukemia accepted article preview online, 27 November 2013. doi:10.1038/leu.2013.360....

  9. Mature lymphoid malignancies: origin, stem cells, and chronicity

    DEFF Research Database (Denmark)

    Husby, Simon; Grønbæk, Kirsten

    2017-01-01

    after treatment. Lately, the use of next-generation sequencing techniques has revealed essential information on the clonal evolution of lymphoid malignancies. Also, experimental xenograft transplantation point to the possible existence of an ancestral (stem) cell. Such a malignant lymphoid stem cell...... population could potentially evade current therapies and be the cause of chronicity and death in lymphoma patients; however, the evidence is divergent across disease entities and between studies. In this review we present an overview of genetic studies, case reports, and experimental evidence of the source...

  10. Genetics Home Reference: PDGFRB-associated chronic eosinophilic leukemia

    Science.gov (United States)

    ... associated chronic eosinophilic leukemia PDGFRB-associated chronic eosinophilic leukemia Printable PDF Open All Close All Enable Javascript ... expand/collapse boxes. Description PDGFRB -associated chronic eosinophilic leukemia is a type of cancer of blood-forming ...

  11. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S; Smedby, Karin E; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S; Lan, Qing; Teras, Lauren R; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R; Hartge, Patricia; Purdue, Mark P; Birmann, Brenda M; Vajdic, Claire M; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G; Shanafelt, Tait D; Novak, Anne J; Kay, Neil E; Liebow, Mark; Cunningham, Julie M; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A; Diver, W Ryan; Link, Brian K; Weiner, George J; Conde, Lucia; Bracci, Paige M; Riby, Jacques; Arnett, Donna K; Zhi, Degui; Leach, Justin M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G; Achenbach, Sara J; Vachon, Celine M; Goldin, Lynn R; Strom, Sara S; Leis, Jose F; Weinberg, J Brice; Caporaso, Neil E; Norman, Aaron D; De Roos, Anneclaire J; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María-Dolores; Vermeulen, Roel C H|info:eu-repo/dai/nl/216532620; Travis, Ruth C; Southey, Melissa C; Milne, Roger L; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R; Villano, Danylo J; Maria, Ann; Spinelli, John J; Gascoyne, Randy D; Connors, Joseph M; Bertrand, Kimberly A; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E; Snowden, John A; Wright, Josh; Fraumeni, Joseph F; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R; Chanock, Stephen J; Rothman, Nathaniel; Slager, Susan L

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and

  12. Omacetaxine Mepesuccinate for Chronic Myeloid Leukemia.

    Science.gov (United States)

    Rosshandler, Yasmin; Shen, Ann Q; Cortes, Jorge; Khoury, Hanna Jean

    2016-05-01

    Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.

  13. The Danish National Chronic Lymphocytic Leukemia Registry

    DEFF Research Database (Denmark)

    da Cunha-Bang, Caspar; Geisler, Christian Hartmann; Enggaard, Lisbeth

    2016-01-01

    AIM: In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate...

  14. Genetics Home Reference: chronic myeloid leukemia

    Science.gov (United States)

    ... Central Quintás-Cardama A, Cortes JE. Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc. 2006 Jul;81(7):973-88. Review. Citation on PubMed Skorski T. Genetic mechanisms of chronic myeloid leukemia blastic transformation. Curr Hematol Malig Rep. 2012 Jun; ...

  15. Myeloid- and lymphoid-specific breakpoint cluster regions in chromosome band 13q14 in acute leukemia.

    Science.gov (United States)

    Coignet, L J; Lima, C S; Min, T; Streubel, B; Swansbury, J; Telford, N; Swanton, S; Bowen, A; Nagai, M; Catovsky, D; Fonatsch, C; Dyer, M J

    1999-07-01

    Abnormalities of chromosome band 13q14 occur in hematologic malignancies of all lineages and at all stages of differentiation. Unlike other chromosomal translocations, which are usually specific for a given lineage, the chromosomal translocation t(12;13)(p12;q14) has been observed in both B-cell and T-cell precursor acute lymphoblastic leukemia (BCP-, TCP-ALL), in differentiated and undifferentiated acute myeloblastic leukemia (AML), and in chronic myeloid leukemia (CML) at progression to blast crisis. The nature of these translocations and their pathologic consequences remain unknown. To begin to define the gene(s) involved on chromosome 13, we have performed fluorescence in situ hybridization (FISH) using a panel of YACs from the region, on a series of 10 cases of acute leukemia with t(12;13)(p12;q14) and 1 case each with "variant" translocations including t(12;13)(q21;q14), t(10;13)(q24;q14) and t(9;13)(p21;q14). In 8/13 cases/cell lines, the 13q14 break fell within a single 1.4 Mb CEPH MegaYAC. This YAC fell immediately telomeric of the forkhead (FKHR) gene, which is disrupted in the t(2;13)(q35;q14) seen in pediatric alveolar rhabdomyosarcoma. Seven of the 8 cases with breaks in this YAC were AML. In 4/13 cases, the 13q14 break fell within a 1.7-Mb YAC located about 3 Mb telomeric of the retinoblastoma (RB1) gene: all 4 cases were ALL. One case of myelodysplastic syndrome exhibited a break within 13q12, adjacent to the BRCA2 gene. These data indicate the presence of myeloid- and lymphoid-specific breakpoint cluster regions within chromosome band 13q14 in acute leukemia.

  16. Chronic Lymphocytic Leukemia: Current Concepts.

    Science.gov (United States)

    Yu, Eun-Mi; Kittai, Adam; Tabbara, Imad A

    2015-10-01

    Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, and while in early, asymptomatic stages treatment is not indicated, the threat to the quality of life and increased mortality of patients posed by more advanced-stage disease necessitate therapeutic intervention. Guidelines of when and how to treat are not well-established because CLL is a disease of the elderly and it is important to balance preservation of functional status and control of the disease. Advances in molecular and genetic profiling has led to the ability to identify sub-groups of patients with CLL whose disease may respond to selected therapy. This review discusses current standard therapies in the major sub-groups of CLL based on age and functional status, in both the front-line and relapsed/refractory settings. It also provides a concise review of novel agents that have shown considerable efficacy in CLL. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  17. Specific receptors for phorbol diesters on freshly isolated human myeloid and lymphoid leukemia cells: comparable binding characteristics despite different cellular responses.

    Science.gov (United States)

    Goodwin, B J; Moore, J O; Weinberg, J B

    1984-02-01

    Freshly isolated human leukemia cells have been shown in the past to display varying in vitro responses to phorbol diesters, depending on their cell type. Specific receptors for the phorbol diesters have been demonstrated on numerous different cells. This study was designed to characterize the receptors for phorbol diesters on leukemia cells freshly isolated from patients with different kinds of leukemia and to determine if differences in binding characteristics for tritium-labeled phorbol 12,13-dibutyrate (3H-PDBu) accounted for the different cellular responses elicited in vitro by phorbol diesters. Cells from 26 patients with different kinds of leukemia were studied. PDBu or phorbol 12-myristate 13-acetate (PMA) caused cells from patients with acute myeloblastic leukemia (AML), acute promyelocytic (APML), acute myelomonocytic (AMML), acute monocytic (AMoL), acute erythroleukemia (AEL), chronic myelocytic leukemia (CML) in blast crisis (myeloid), acute undifferentiated leukemia (AUL), and hairy cell leukemia (HCL) (n = 15) to adhere to plastic and spread. However, they caused no adherence or spreading and only slight aggregation of cells from patients with acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or CML-blast crisis (lymphoid) (n = 11). All leukemia cells studied, irrespective of cellular type, displayed specific receptors for 3H-PDBu. The time courses for binding by all leukemia types were similar, with peak binding at 5-10 min at 37 degrees C and 120 min at 4 degrees C. The binding affinities were similar for patients with ALL (96 +/- 32 nM, n = 4), CLL (126 +/- 32 nM, n = 6), and acute nonlymphoid leukemia (73 +/- 14 nM, n = 11). Likewise, the numbers of specific binding sites/cell were comparable for the patients with ALL (6.2 +/- 1.3 X 10(5) sites/cell, n = 4), CLL (5.0 +/- 2.0 X 10(5) sites/cell, n = 6), and acute nonlymphoid leukemia (4.4 +/- 1.9 X 10(5) sites/cell, n = 11). Thus, the differing responses to phorbol diesters of

  18. General Information about Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... of the lymph system . Having relatives who are Russian Jews or Eastern European Jews. Signs and symptoms ... information about clinical trials is also available. To Learn More About Chronic Lymphocytic Leukemia For more information ...

  19. Leukemia -- Chronic T-Cell Lymphocytic

    Science.gov (United States)

    ... social workers, and patient advocates. Cancer.Net Guide Leukemia - Chronic T-Cell Lymphocytic Introduction Statistics Risk Factors Symptoms and Signs Diagnosis Stages Treatment Options About Clinical Trials Latest Research ...

  20. Cellular immune therapy for chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Kater, Arnon P.; van Oers, Marinus H. J.; Kipps, Thomas J.

    2007-01-01

    Although chemotherapy can induce complete responses in patients with chronic lymphocytic leukemia (CLL), it is not considered curative. Treated patients generally develop recurrent disease requiring additional therapy, which can cause worsening immune dysfunction, myelosuppression, and selection for

  1. Effect of total lymphoid irradiation in chronic progressive multiple sclerosis

    International Nuclear Information System (INIS)

    Cook, S.D.; Devereux, C.; Troiano, R.; Hafstein, M.P.; Zito, G.; Hernandez, E.; Lavenhar, M.; Vidaver, R.; Dowling, P.C.

    1986-01-01

    Total lymphoid irradiation (TLI; 1980 cGy) or sham irradiation was given to 40 patients with chronic progressive multiple sclerosis (MS) in a prospective, randomised, double-blind study. During mean follow-up of 21 months, MS patients treated with TLI has less functional decline than sham-irradiated MS patients (p<0.01). A significant relation was noted between absolute blood lymphocyte counts in the first year after TLI and subsequent course, patients with higher lymphocyte counts generally having a worse prognosis (p<0.01). TLI was well tolerated and associated with only mild short-term, and to date, long-term side-effects. (author)

  2. Diagnosis of chronic myeloid leukemia

    International Nuclear Information System (INIS)

    Demitrovicova, L.; Mikuskova, E.; Copakova, L.; Leitnerova, M.

    2012-01-01

    Chronic myeloid leukemia (CML) was the first cancer associated with the specific chromosomal aberration. Philadelphia chromosome due to translocation (9, 22) is present in 95% cases, fusion gene BCR/ABL is present in 100% cases at the time of diagnosis. Disease has its own characteristics detectable by physical examination, by the examination of blood count and differential and by cytomorhologic examination of bone marrow, however the diagnosis of CML is determined by cytogenetics and molecular genetics. If the diagnosis of Ph+ BCR/ABL positive CML is confirmed, the disease is treated by tyrosine kinase inhibitors (TKI). TKI don´t affect formation of leukemic gene BCR/ABL, but they can stop the action of this gene. The target therapy of tyrosine kinase inhibitors markedly improved the survival of patients with CML by inhibition the proliferation of leukemic clone on the clinically safety level of minimal disease, although probably this treatment cannot cure the CML. Cytogenetics and molecular genetics are very important at the monitoring of residual disease with sensitivity 10"-"6. (author)

  3. Transplantability of human lymphoid cell line, lymphoma, and leukemia in splenectomized and/or irradiated nude mice

    International Nuclear Information System (INIS)

    Watanabe, S.; Shimosato, Y.; Kuroki, M.; Sato, Y.; Nakajima, T.

    1980-01-01

    The effects of splenectomy and/or whole-body irradiation of nude mice before xenotransplantation of lymphoid cell lines, lymphoma, and leukemia were studied. Transplantation after whole-body irradiation resulted in the increased ''take'' rate of three cultured cell lines (two of T-cell-derived acute lymphocytic leukemia and one of B-cell derived acute lymphocytic leukemia) and in the tumorous growth of Burkitt-derived Raji and spontaneously transformed lymphoblastoid cell lines. With splenectomy plus irradiation as a pretreatment, tumorous growth occurred in four other cell lines which were not transplantable after irradiation only (two cell lines of Epstein-Barr virus-transformed cord blood cells and one each of null acute lymphocytic leukemia and nodular lymphoma-derived cell lines). Direct transplantation of leukemia and lymphoma cells into the pretreated mice was successful in 7 of 24 cases (29%). B-cell-derived diffuse large lymphoid lymphoma was transplantable in three of seven cases (43%). However, lymphoma and leukemia of peripheral T-cell origin was difficult to transplant even with pretreatment, and only one pleomorphic T-cell lymphoma grew to a significant size (2 cm). One tumor each of B-cell-derived diffuse large lymphoid and T-cell diffuse lymphoblastic lymphoma became transplantable

  4. Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

    Science.gov (United States)

    2014-08-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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); Blastic Phase Chronic Myelogenous Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Secondary Acute Myeloid Leukemia; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma

  5. Innate lymphoid cells in autoimmunity and chronic inflammatory diseases.

    Science.gov (United States)

    Xiong, Tingting; Turner, Jan-Eric

    2018-03-22

    Abnormal activation of the innate immune system is a common feature of autoimmune and chronic inflammatory diseases. Since their identification as a separate family of leukocytes, innate lymphoid cells (ILCs) have emerged as important effector cells of the innate immune system. Alterations in ILC function and subtype distribution have been observed in a variety of immune-mediated diseases in humans and evidence from experimental models suggests a subtype specific role of ILCs in the pathophysiology of autoimmune inflammation. In this review, we discuss recent advances in the understanding of ILC biology in autoimmune and chronic inflammatory disorders, including multiple sclerosis, inflammatory bowel diseases, psoriasis, and rheumatic diseases, with a special focus on the potential of ILCs as therapeutic targets for the development of novel treatment strategies in humans.

  6. State of the art in microRNA as diagnostic and therapeutic biomarkers in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Mirzaei, Hamed; Fathullahzadeh, Sima; Khanmohammadi, Razieh

    2018-01-01

    such as chronic lymphocytic leukemia (CLL). The CLL is the one of main lymphoid malignancies which is specified by aggregation of mature B lymphocytes. Among different biomarkers (e.g., CD38, chromosomes abnormalities, ZAP-70, TP53, and microRNA [miRNA]), miRNAs have appeared as new diagnostic and therapeutic...

  7. Differential protective effects of immune lymphoid cells against transplanted line Ib leukemia and immune polioencephalomyelitis. [X radiation, mice

    Energy Technology Data Exchange (ETDEWEB)

    Duffey, P.S.; Lukasewycz, O.A.; Olson, D.S.; Murphy, W.H.

    1978-12-01

    The capacity of immune cells obtained from the major lymphoid compartments to protect C58 mice from transplanted line Ib leukemia, and from an age-dependent autoimmune CNS disease (immune polioencephalomyelitis = IPE) elicited by immunizing old C58 mice with inactivated Ib cells was quantified. Cells used for comparative adoptive protection tests were harvested from the major lymphoid compartments 14 to 15 days after young C58 mice were immunized with inactivated Ib cell preparations. Regression curves were plotted from survival data and the log/sub 10/PD/sub 50/ values were determined. Immune spleen (ISC) and peritoneal cells (IPEC) were significantly more protective against transplanted Ib cells than immune lymph node (ILNC), thymic (ITC), and marrow cells (IMC). In contrast, IPEC and IMC were not protective against IPE and ITC were only marginally protective. ILNC afforded significant protection to transplantable leukemia but were only marginally protective to IPE. When ISC were treated with anti-thy 1.2 serum and complement, protection against transplanted leukemia and IPE was reduced > 99%. When donors of immune lymphoid cells were treated with 12.5 mg of cortisone acetate daily for 2 days before lymphoid cells were harvested, protection against transplanted Ib cells by ISC was reduced by approximately 90% whereas protection against IPE was totally eliminated. Considered together, these results indicate that the protective mechanisms to transplantable leukemia and IPE differ significantly in the same indicator mouse strain.

  8. SB-715992 in Treating Patients With Acute Leukemia, Chronic Myelogenous Leukemia, or Advanced Myelodysplastic Syndromes

    Science.gov (United States)

    2013-01-10

    Acute Undifferentiated Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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 Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  9. Fungal natural products targeting chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Bladt, Tanja Thorskov; Kildgaard, Sara; Knudsen, Peter Boldsen

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults from the western world. No curative treatments of CLL are presently known so the treatment strategy today is primarily to prolong patient survival,1 why we have initiated new activities towards discovery of novel compounds......,3 This includes analysis of the spectroscopic data generated from LC-DAD-MS to reveal whether the active principles are either structurally known compounds or are likely to be novel compounds. This paper will illustrate our integrated discovery approaches and recent findings of anti-leukemia compounds....

  10. Thymic irradiation and chronic myelogenous leukemia

    International Nuclear Information System (INIS)

    Shimaoka, K.; Sokal, J.E.

    1977-01-01

    Two cases of Ph positive chronic myelogenous leukemia with a history of thymic irradiation are presented. Both patients received radiation therapy from low voltage x-ray equipment at two to three months of age. Leukemia developed 18 and 22 years later. Presentation, response to antileukemic therapy, and clinical course did not differ from that of other patients with this disease treated in our department

  11. Management of chronic lymphocytic leukemia.

    Science.gov (United States)

    Stilgenbauer, Stephan; Furman, Richard R; Zent, Clive S

    2015-01-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is usually diagnosed in asymptomatic patients with early-stage disease. The standard management approach is careful observation, irrespective of risk factors unless patients meet the International Workshop on CLL (IWCLL) criteria for "active disease," which requires treatment. The initial standard therapy for most patients combines an anti-CD20 antibody (such as rituximab, ofatumumab, or obinutuzumab) with chemotherapy (fludarabine/cyclophosphamide [FC], bendamustine, or chlorambucil) depending on multiple factors including the physical fitness of the patient. However, patients with very high-risk CLL because of a 17p13 deletion (17p-) with or without mutation of TP53 (17p-/TP53mut) have poor responses to chemoimmunotherapy and require alternative treatment regimens containing B-cell receptor (BCR) signaling pathway inhibitors. The BCR signaling pathway inhibitors (ibrutinib targeting Bruton's tyrosine kinase [BTK] and idelalisib targeting phosphatidyl-inositol 3-kinase delta [PI3K-delta], respectively) are currently approved for the treatment of relapsed/refractory CLL and all patients with 17p- (ibrutinib), and in combination with rituximab for relapsed/refractory patients (idelalisib). These agents offer great efficacy, even in chemotherapy refractory CLL, with increased tolerability, safety, and survival. Ongoing studies aim to determine the best therapy combinations with the goal of achieving long-term disease control and the possibility of developing a curative regimen for some patients. CLL is associated with a wide range of infectious, autoimmune, and malignant complications. These complications result in considerable morbidity and mortality that can be minimized by early detection and aggressive management. This active monitoring requires ongoing patient education, provider vigilance, and a team approach to patient care.

  12. Do We Know What Causes Chronic Myeloid Leukemia?

    Science.gov (United States)

    ... Be Prevented? More In Chronic Myeloid Leukemia About Chronic Myeloid Leukemia Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treatment After Treatment Back To Top Imagine a world ...

  13. Chronic myeloid leukemia: reminiscences and dreams

    Science.gov (United States)

    Mughal, Tariq I.; Radich, Jerald P.; Deininger, Michael W.; Apperley, Jane F.; Hughes, Timothy P.; Harrison, Christine J.; Gambacorti-Passerini, Carlo; Saglio, Giuseppe; Cortes, Jorge; Daley, George Q.

    2016-01-01

    With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. This work was also of major importance to support the idea that cytogenetic changes were drivers of leukemogenesis. John Goldman originally made seminal contributions to the use of autologous and allogeneic stem cell transplantation from the late 1970s onwards. Then, in collaboration with Brian Druker, he led efforts to develop ABL1 tyrosine kinase inhibitors for the treatment of patients with chronic myeloid leukemia in the late 1990s. He also led the global efforts to develop and harmonize methodology for molecular monitoring, and was an indefatigable organizer of international conferences. These conferences brought together clinicians and scientists, and accelerated the adoption of new therapies. The abundance of praise, tributes and testimonies expressed by many serve to illustrate the indelible impressions these two passionate and affable scholars made on so many people’s lives. This tribute provides an outline of the remarkable story of chronic myeloid leukemia, and in writing it, it is clear that the historical triumph of biomedical science over this leukemia cannot be considered without appreciating the work of both Janet Rowley and John Goldman. PMID:27132280

  14. Septic arthritis as the first sign of Candida tropicalis fungaemia in an acute lymphoid leukemia patient

    Directory of Open Access Journals (Sweden)

    Vicari Perla

    2003-01-01

    Full Text Available Fungal infections caused by Candida species have increased in incidence during the past two decades in England, North America and Europe. Candidal arthritis is rare in patients who are not intravenous drug users or are who not using a prostheses. We report the case of a 24-year-old man with acute lymphoid leukemia, who developed Candida tropicalis arthritis during an aplastic period after chemotherapy. This is the eighth case described in the literature of C. tropicalis causing arthritis without intra-articular inoculation. We call attention to an unusual first sign of fungal infection: septic arthritis without intra-articular inoculation. However, this case differs from the other seven, since despite therapy a fast and lethal evolution was observed. We reviewed reported cases, incidence, risk factors, mortality and treatment of neutropenic patients with fungal infections.

  15. Expresión fenotípica de las moléculas CD5 y CD6 en la leucemia linfoide crónica B-CD5+ The B-CD5+ chronic lymphoid leukemia related to the phenotype expression

    Directory of Open Access Journals (Sweden)

    Bertha Beatriz Socarrás Ferrer

    2009-04-01

    Full Text Available Las moléculas CD5 y CD6 tienen función coestimuladora y muestran homología en su estructura. Se evaluó la expresión de la molécula CD6 mediante el uso del anticuerpo monoclonal anti-CD6 (T1 en el inmunofenotipaje celular de pacientes con leucemia linfoide crónica By se comparó con la expresión de la molécula CD5.Los resultados demuestranuna homología en la expresión fenotípica de ambas moléculas, CD5 y CD6, lo que asociado con que ambos receptores linfocitarios se encuentran físicamente vinculados, permite sugerir que la molécula CD6 constituye un marcador biológico de interés en la evaluación del pronóstico y la posibilidad de nuevas variantes terapéuticas en esta enfermedad.CD5 and CD6 molecules have a co-stimulant function and show homology in structure. We assessed CD6 molecule expression using anti-CD6 (T1 monoclonal antibody in the cellular immunophenotyping from patients presenting B chronic lymphoid leukemia, and it was compared to CD5 molecule expression. Results show a homology in phenotype expression of both molecules (CD5 and CD6, what associated with the fact that both lymphocyte receptors are physically linked, allow to suggest that CD6 molecule is a interesting biological marker in prognosis assessment, and the possibility of new therapeutic variants in this disease.

  16. Secondary acute non lymphoid leukemia in patients treated for non Hodgkin's lymphoma

    International Nuclear Information System (INIS)

    Cimino, G.; Anselma, A.; Cartoni, C.

    1987-01-01

    The present study was undertaken to evaluate the frequency, characteristics and actual risk of secondary acute non lymphoid leukemia (s-ANLL) in 141 patients treated for non Hodgkin's lymphoma with different modalities. One hundred and twenty-four patients received chemotherapy according to PROVECIP protocol (9). Of these, 15 also received as induction treatment a local nodal irradiation and 33 an extended field radiotherapy. Seventeen out of 141 were treated by total body irradiation. Of these, 15 relapsed and received salvage chemotherapy. Sixteen of the 124 patients trated with PROVECIP also underwent different chemotherapeutic programs as salvage treatment. Of the entire population studied, 2 patients significantly affected the occurrence of s-ANLL, since both leukemias occurred in patients treated with total body irradiation, given alone or followed by chemotherapy. The actuarial risk at 8 years was 5.24% in the whole group, whereas it greatly increased in the group of patients treated with total body irradiation (24%). Conversely, no risk was found in the group treated with PROVECIP, alone, with additional chemotherapy, or with associated local or extended field radiotherapy

  17. Appearance and Disappearance of Chronic Myeloid Leukemia (CML) in Patient with Chronic Lymphocytic Leukemia (CLL)

    OpenAIRE

    Payandeh, Mehrdad; Sadeghi, Edris; Khodarahmi, Reza; Sadeghi, Masoud

    2014-01-01

    Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common leukemias of the elderly (>43 year). However, the sequential occurrence of CML followed by CLL in the same patient is extremely rare. In our report, a 52-year-old female was diagnosed with CLL (type of bone marrow (BM) infiltration was nodular and interstitial) and was treated with chlorambucil. 64 months after the diagnosis of CLL, she developed CML. She was treated with imatinib (400mg/day). After a fe...

  18. Appearance and Disappearance of Chronic Myeloid Leukemia (CML) in Patient with Chronic Lymphocytic Leukemia (CLL).

    Science.gov (United States)

    Payandeh, Mehrdad; Sadeghi, Edris; Khodarahmi, Reza; Sadeghi, Masoud

    2014-10-01

    Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common leukemias of the elderly (>43 year). However, the sequential occurrence of CML followed by CLL in the same patient is extremely rare. In our report, a 52-year-old female was diagnosed with CLL (type of bone marrow (BM) infiltration was nodular and interstitial) and was treated with chlorambucil. 64 months after the diagnosis of CLL, she developed CML. She was treated with imatinib (400mg/day). After a few months, signs of CML were disappeared and CLL became dominant. This is first reported case.

  19. Brick mortar exposure and chronic lymphocytic leukemia.

    Science.gov (United States)

    Markovic-Denic, L; Jankovic, S; Marinkovic, J; Radovanovic, Z

    1995-01-01

    A case-control study of 130 patients with chronic lymphocytic leukemia (CLL) and 130 controls matched with respect to sex, age (2 years), type of residence (urban-rural) and area of residence (according to the national per capita income) was carried out. Conditional logistic regression analysis showed that, apart of four risk factors already described in the literature (work in a hazardous industry, hair dye use, family history of leukemia and exposure to electromagnetic radiation), brick mortar exposure was also significantly related to CLL.

  20. Brick mortar exposure and chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Markovic-Denic, Lj.; Jankovic, S.; Marinkovic, J.; Radovanovic, Z.

    1995-01-01

    A case-control study of 130 patients with chronic lymphocytic leukemia (CLL) and 130 controls matched with respect to sex, age (2 years), type of residence, (urban-rural) and area of residence (according to the national per capita income) was carried out. Conditional logistic regression analysis showed that, apart of four risk factors already described in the literature (work in a hazardous industry, hair dye use, family history of leukemia and exposure to electromagnetic radiation), brick mortar exposure was also significantly related to CLL. (author)

  1. Brick mortar exposure and chronic lymphocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Markovic-Denic, Lj; Jankovic, S [Institute of Epidemiology, Faculty of Medicine, Belgrade (Yugoslavia); Marinkovic, J [Institute of Social Medicine, Statistics and Healt Research, Faculty of Medicine, Belgrade (Yugoslavia); Radovanovic, Z [Department of Community Medicine and Behavioural Sciences, Faculty of Medicine, 13110 Safat (Kuwait)

    1996-12-31

    A case-control study of 130 patients with chronic lymphocytic leukemia (CLL) and 130 controls matched with respect to sex, age (2 years), type of residence, (urban-rural) and area of residence (according to the national per capita income) was carried out. Conditional logistic regression analysis showed that, apart of four risk factors already described in the literature (work in a hazardous industry, hair dye use, family history of leukemia and exposure to electromagnetic radiation), brick mortar exposure was also significantly related to CLL. (author) 1 tab., 30 refs.

  2. Biological Prognostic Markers in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Vladimíra Vroblová

    2009-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is the most frequent leukemic disease of adults in the Western world. It is remarkable by an extraordinary heterogeneity of clinical course with overall survival ranging from several months to more than 15 years. Classical staging sytems by Rai and Binet, while readily available and useful for initial assessment of prognosis, are not able to determine individual patient’s ongoing clinical course of CLL at the time of diagnosis, especially in early stages. Therefore, newer biological prognostic parameters are currently being clinically evaluated. Mutational status of variable region of immunoglobulin heavy chain genes (IgVH, cytogenetic aberrations, and both intracellular ZAP- 70 and surface CD38 expression are recognized as parameters with established prognostic value. Molecules regulating the process of angiogenesis are also considered as promising markers. The purpose of this review is to summarize in detail the specific role of these prognostic factors in chronic lymphocytic leukemia.

  3. Two-dimensional analysis of metabolically and cell surface radiolabeled proteins of some human lymphoid and myeloid leukemia cell lines. II. Glycosylated and phosphorylated proteins

    Energy Technology Data Exchange (ETDEWEB)

    Chorvath, B; Duraj, J; Sedlak, J; Pleskova, I

    1986-01-01

    Cell surface glycoproteins, radiolabelled by the sodium metaperiodate/tritiated borohydride technique, and cell phosphoproteins, metabolically radiolabelled with /sup 32/P-orthophosphate were analyzed by two-dimensional electrophoretic analysis in some myeloid and lymphoid leukemia cell lines. Some markedly expressed major glycoproteins were predominant in some of the cell lines (such as 95k and 100k glycoproteins with marked charge heterogeneity in non-T, non-B acute lymphoblastic leukemia cell lines NALM 6 and NALM 16), but markedly quantitatively reduced in other examined cell lines, such as lymphoblastoid cell line UHKT 34/2. /sup 32/P-orthophosphate radiolabelled phosphoprotein two-dimensional patterns of the examined lymphoid leukemia cell lines were essentially similar, with some minor differences, in examined lymphoid and myeloid leukemia cell lines, such as marked expression of a series of large phosphoproteins in the molecular weight range 80-100k in lymphoid cell lines and almost complete absence of these phosphoproteins on the examined myeloid leukemia cell lines. Another configuration of acidic phosphoproteins (30-35k) exhibited individual cell line variability and differences between both individual myeloid leukemia cell lines and between the lymphoid and myeloid cell lines examined. (author) 2 figs., 15 refs.

  4. Splenic irradiation in chronic myeloid leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Hukku, S.; Baboo, H.A.; Venkataratnam, S.; Vidyasagar, M.S.; Patel, N.L. (Department of Radiation Therapy, Gujarat Cancer Research Institute, Ahmedabad, India)

    1983-01-01

    Results of splenic irradiation as the initial and only method of treatment are reported in 25 patients with chronic myeloid leukemia. Peripheral remission was induced in all the patients. Induction was achieved after a short period of 11 to 30 days in the majority of the patients, the longest period being 40 days. Several patients were in remission 9 months after treatment. The results are compared with those obtained by chemotherapy. Some advantages of splenic irradiation over chemotherapy are emphasized.

  5. Imatinib mesylate in chronic myelogenous leukemia: a Congolese ...

    African Journals Online (AJOL)

    Major cytogenetic response was noticed in 87.18%. After a median follow up of 12 months, chronic myeloid leukemia had not progressed to the accelerated or blastic phase in an estimated 91.8% of patients and 86.6% were alive. Conclusion: Imatinib is effective in newly chronic phase chronic myeloid leukemia patient ...

  6. Chronic Lymphocytic Leukemia as an Unusual Cause of Rapid Airway Compromise

    Directory of Open Access Journals (Sweden)

    Adrian R. Bersabe

    2017-01-01

    Full Text Available Chronic Lymphocytic Leukemia (CLL is the most prevalent form of non-Hodgkin’s lymphoma (NHL in Western countries predominantly affecting adults over the age of 65. CLL is commonly indolent in nature but can present locally and aggressively at extranodal sites. Although CLL may commonly present with cervical lymphadenopathy, manifestation in nonlymphoid regions of the head and neck is not well described. CLL causing upper airway obstruction is even more uncommon. We describe a case of a patient with known history of CLL and stable lymphocytosis that developed an enlarging lymphoid base of tongue (BOT mass resulting in rapid airway compromise.

  7. Ibrutinib (PCI-32765) in chronic lymphocytic leukemia.

    Science.gov (United States)

    Jain, Nitin; O'Brien, Susan

    2013-08-01

    B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Radiation treatment of acute lymphoid leukemia in children at the National Institute of Oncology, Budapest, Hungary, from 1975 to 1980

    International Nuclear Information System (INIS)

    Kocsis, Bela; Horvath, Akos; Varjas, Geza; Kardos, Gabriella; Csete, Ferencne

    1987-01-01

    Between 1975 and 1980 the authors performed prophylactic irradiation of the central nervous system of patients younger than 16 years with acute lymphoid leukemia. The theoretic and practical basis of prophylactic irradiation is overviewed. For mean and high level of malignity 24 Gy/g, for low level 18 Gy/g total dose is indicated. Irradiation technique involves the use of cobalt or 3-10 MV bremmstrahlung. The data of 178 patients including the duration of remission, the site of first occurrence and their frequency are presented. The 5-year survival of their patients was found to be 51,7%. (author)

  9. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.

    Science.gov (United States)

    Grupp, Stephan A; Kalos, Michael; Barrett, David; Aplenc, Richard; Porter, David L; Rheingold, Susan R; Teachey, David T; Chew, Anne; Hauck, Bernd; Wright, J Fraser; Milone, Michael C; Levine, Bruce L; June, Carl H

    2013-04-18

    Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.

  10. Leukemia

    International Nuclear Information System (INIS)

    Mabuchi, Kiyohiko; Kusumi, Shizuyo

    1992-01-01

    Leukemia is the first malignant disease found among A-bomb survivors. Leukemia registration has greatly contributed to epidemiological and hematological studies on A-bomb radiation-related leukemia and other hematopoietic diseases, consisting of community population and the RERF Life Span Study (LSS) sample (approximately 120,000 persons containing A-bomb survivors). Using the fixed LSS cohort, the prevalence rate of leukemia reached the peak during the years 1950-1954, and thereafter, it has been gradually decreased. However, risk patterns for leukemia are still unsolved: has leukemia risk increased in recent years?; are serial changes in leukemia risk influenced by age at the time of exposure (ATE)?; is there variation between Hiroshima and Nagasaki?; and others. To solve these questions, leukemia data are now under analysis using the revised DS86. Relative risk for leukemia, especially chronic myelogenous leukemia and acute lymphocytic leukemia (ALL), is found to be linearly increased with increasing bone marrow doses. Serial patterns of both excess risk and excess relative risk have revealed that leukemia risk is high at 5-10 years after A-bombing in younger A-bomb survivors ATE. The influence of age ATE on serial changes is noticeable in ALL. Another factor involved in the prevalence of leukemia is background (spontaneously developed leukemia), which is the recent interest because young A-bomb survivors ATE reach the cancer-prone age. (N.K.)

  11. ALLOGENEIC TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Luca Laurenti

    2010-08-01

    Full Text Available Even if Chronic lymphocytic leukemia (CLL often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment. Allogeneic transplant has potential curative role in CLL, however burden with very  high transplant related mortality (TRM rates of 38-50%: A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT has been the introduction of non-myeloablative or reduced intensity conditioning (RIC regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL activity. The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD affecting quality of life, high graft rejection and infection rates rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients. Sensitive minimal residual disease (MRD quantification has strong prognostic impact after transplant.

  12. Soluble HLA-G Molecules Are Increased during Acute Leukemia, Especially in Subtypes Affecting Monocytic and Lymphoid Lineages'

    Directory of Open Access Journals (Sweden)

    Frédéric Gros

    2006-03-01

    Full Text Available Human leukocyte antigen G (HLA-G molecules corresponding to nonclassic class I genes of the major histocompatibility complex exhibit immunomodulatory properties. They are either membrane-bound or solubly expressed during certain tumoral malignancies. Soluble human leukocyte antigen G (sHLA-G molecules seem more frequently expressed than membranebound isoforms during hematologic malignancies, such as lymphoproliferative disorders. Assay of these molecules by enzyme-linked immunosorbent assay in patients suffering from another hematologic disorder (acute leukemia highlights increased sHLA-G secretion. This increased secretion seems more marked in acute leukemia subtypes affecting monocytic and lymphoid lineages such as FABM4 and FABM5, as well as both B and T acute lymphoblastic leukemia (ALL. Moreover, this study uses in vitro cytokine stimulations and reveals the respective potential roles of granulocyte-macrophage colony-stimulating factor and interferon-γ in increasing this secretion in FABM4 and ALL. Correlations between sHLA-G plasma level and clinical biologic features suggest a link between elevated sHLA-G level and 1 the absence of anterior myelodysplasia and 2 high-level leukocytosis. All these findings suggest that sHLA-G molecules could be a factor in tumoral escape from immune survey during acute leukemia.

  13. [Molecular characterization of atypical chronic myeloid leukemia and chronic neutrophilic leukemia].

    Science.gov (United States)

    Senín, Alicia; Arenillas, Leonor; Martínez-Avilés, Luz; Fernández-Rodríguez, Concepción; Bellosillo, Beatriz; Florensa, Lourdes; Besses, Carles; Álvarez-Larrán, Alberto

    2015-06-08

    Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) display similar clinical and hematological characteristics. The objective of the present study was to determine the mutational status of SETBP1 and CSF3R in these diseases. The mutational status of SETBP1 and CSF3R was studied in 7 patients with aCML (n = 3), CNL (n = 1) and unclassifiable myeloproliferative neoplasms (MPN-u) (n = 3). Additionally, mutations in ASXL1, SRSF2, IDH1/2, DNMT3A, and RUNX1 were also analyzed. SETBP1 mutations (G870S and G872R) were detected in 2 patients with MPN-u, and one of them also presented mutations in SRSF2 (P95H) and ASXL1 (E635fs). The CNL case showed mutations in CSFR3 (T618I), SETBP1 (G870S) and SRSF2 (P95H). No patient classified as aCML had mutations in SETBP1 or CSF3R. One of the patients with mutations evolved to acute myeloid leukemia, while the other 2 had disease progression without transformation to overt leukemia. The knowledge of the molecular alterations involved in these rare diseases is useful in the diagnosis and may have an impact on both prognosis and therapy. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  14. Additional chromosome abnormalities in chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Hui-Hua Hsiao

    2011-02-01

    Full Text Available The Philadelphia (Ph chromosome and/or Breakpoint cluster region-Abelson leukemia virus oncogene transcript are unique markers for chronic myeloid leukemia (CML. However, CML demonstrates heterogeneous presentations and outcomes. We analyzed the cytogenetic and molecular results of CML patients to evaluate their correlation with clinical presentations and outcome. A total of 84 newly diagnosed CML patients were enrolled in the study. Patients were treated according to disease status. Bone marrow samples were obtained to perform cytogenetic and molecular studies. Clinical presentations, treatment courses, and survival were reviewed retrospectively. Among 84 patients, 72 had chronic phase and 12 had accelerated phase CML. Cytogenetic study showed 69 (82.1% with the classic Ph chromosome, 6 (7.2% with a variant Ph chromosome, and 9 (10.7% with additional chromosome abnormalities. Fifty-four (64.3% cases harbored b3a2 transcripts, 29 (34.5% had b2a2 transcript, and 1 had e19a2 transcript. There was no difference in clinical presentations between different cytogenetic and molecular groups; however, additional chromosome abnormalities were significantly associated with the accelerated phase. Imatinib therapy was an effective treatment, as measured by cytogenetic response, when administered as first- and second-line therapy in chronic phase patients. Survival analysis showed that old age, additional chromosome abnormalities, high Sokal score, and no cytogenetic response in second-line therapy had a significant poor impact (p<0.05. In conclusion, we presented the cytogenetic and molecular pattern of CML patients and demonstrated that the additional chromosome abnormality was associated with poor outcome.

  15. Disseminated Cryptococcosis With Brain Involvement in Patients With Chronic Lymphoid Malignancies on Ibrutinib.

    Science.gov (United States)

    Messina, Julia A; Maziarz, Eileen K; Spec, Andrej; Kontoyiannis, Dimitrios P; Perfect, John R

    2017-01-01

    We report 2 cases of disseminated cryptococcosis with central nervous system involvement in patients with chronic lymphoid malignancies occurring within 1 month of starting on ibrutinib. Characteristically, in both cases, no inflammation was seen in the cerebrospinal fluid. Central nervous system mycoses should be considered as a potential complication of ibrutinib.

  16. Disseminated Cryptococcosis With Brain Involvement in Patients With Chronic Lymphoid Malignancies on Ibrutinib

    OpenAIRE

    Messina, Julia A.; Maziarz, Eileen K.; Spec, Andrej; Kontoyiannis, Dimitrios P.; Perfect, John R.

    2017-01-01

    Abstract We report 2 cases of disseminated cryptococcosis with central nervous system involvement in patients with chronic lymphoid malignancies occurring within 1 month of starting on ibrutinib. Characteristically, in both cases, no inflammation was seen in the cerebrospinal fluid. Central nervous system mycoses should be considered as a potential complication of ibrutinib.

  17. Chronic Subdural Hematoma Associated with Acute Biphenotypic Leukemia: Case Report

    OpenAIRE

    Besime Utku; Uygar Utku

    2015-01-01

    Spontaneous chronic subdural hematoma associated with neoplasm is a rare disorder. A rare case of chronic subdural hematoma associated with acute biphenotypic leukemia presented here. A 78-year-old woman who diagnosed as acute biphenotypic leukemia by hematology was complicated with a large chronic subdural hematoma. She presented to our emergency medicine service of hospital with left-sided weakness. Her non-contrast brain computerized tomography scan showed a non-traumatic right-sided, larg...

  18. Pembrolizumab Alone or With Idelalisib or Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Other Low-Grade B-Cell Non-Hodgkin Lymphomas

    Science.gov (United States)

    2017-06-30

    Recurrent Chronic Lymphocytic Leukemia; Recurrent Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Nodal Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Splenic Marginal Zone Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Nodal Marginal Zone Lymphoma; Refractory Small Lymphocytic Lymphoma; Refractory Splenic Marginal Zone Lymphoma; Richter Syndrome; Waldenstrom Macroglobulinemia

  19. Chronic lymphocytic leukemia: concepts and observations

    Energy Technology Data Exchange (ETDEWEB)

    Chandra, P.; Chanana, A.D.; Chikkappa, G.; Cronkite, E.P.

    1977-01-01

    Thirty-five patients with chronic lymphocytic leukemia (CLL) were studied for assessment of total body leukemic mass and abnormality in T-lymphocyte function associated with clinical stages of CLL. Total body potassium (TBK), an indicator of lean body mass, was found to correlate well with increase in the clinical stage of the disease. Use of TBK for monitoring the regression and relapse of leukemic load is suggested. No correlation was found between whole cell and nuclear volumes of lymphocytes in CLL patients and clinical stages of the disease. Blast transformation and proliferation under phytohemagglutinin (PHA) stimulation appeared to be normal in purified T cells of early stages and abnormal in the late stages of disease.

  20. Lymphoid Progenitor Cells from Childhood Acute Lymphoblastic Leukemia Are Functionally Deficient and Express High Levels of the Transcriptional Repressor Gfi-1

    Directory of Open Access Journals (Sweden)

    Jessica Purizaca

    2013-01-01

    Full Text Available Acute lymphoblastic leukemia (ALL is the most frequent malignancy of childhood. Substantial progress on understanding the cell hierarchy within ALL bone marrow (BM has been recorded in the last few years, suggesting that both primitive cell fractions and committed lymphoid blasts with immature stem cell-like properties contain leukemia-initiating cells. Nevertheless, the biology of the early progenitors that initiate the lymphoid program remains elusive. The aim of the present study was to investigate the ability of lymphoid progenitors from B-cell precursor ALL BM to proliferate and undergo multilineage differentiation. By phenotype analyses, in vitro proliferation assays, and controlled culture systems, the lymphoid differentiation potentials were evaluated in BM primitive populations from B-cell precursor ALL pediatric patients. When compared to their normal counterparts, functional stem and progenitor cell contents were substantially reduced in ALL BM. Moreover, neither B nor NK or dendritic lymphoid-cell populations developed recurrently from highly purified ALL-lymphoid progenitors, and their proliferation and cell cycle status revealed limited proliferative capacity. Interestingly, a number of quiescence-associated transcription factors were elevated, including the transcriptional repressor Gfi-1, which was highly expressed in primitive CD34+ cells. Together, our findings reveal major functional defects in the primitive hematopoietic component of ALL BM. A possible contribution of high levels of Gfi-1 expression in the regulation of the stem/progenitor cell biology is suggested.

  1. ALLOGENEIC TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Patrizia Chiusolo

    2010-05-01

    Full Text Available

    Even if Chronic lymphocytic leukemia (CLL often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment.

    Allogeneic transplant has potential curative role in CLL, however burden with very  high transplant related mortality (TRM rates of 38-50%:

    A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT has been the introduction of non-myeloablative or reduced intensity conditioning (RIC regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL activity.

    The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD affecting quality of life, high graft rejection and infection rates rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients.

    Sensitive minimal residual disease (MRD quantification has strong prognostic impact after transplant.

     

  2. Gut-associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation.

    Science.gov (United States)

    Koboziev, Iurii; Karlsson, Fridrik; Grisham, Matthew B

    2010-10-01

    The etiologies of the inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis) have not been fully elucidated. However, there is very good evidence implicating T cell and T cell trafficking to the gut and its associated lymphoid tissue as important components in disease pathogenesis. The objective of this review is to provide an overview of the mechanisms involved in naive and effector T cell trafficking to the gut-associated lymphoid tissue (GALT; Peyer's patches, isolated lymphoid follicles), mesenteric lymph nodes and intestine in response to commensal enteric antigens under physiological conditions as well as during the induction of chronic gut inflammation. In addition, recent data suggests that the GALT may not be required for enteric antigen-driven intestinal inflammation in certain mouse models of IBD. These new data suggest a possible paradigm shift in our understanding of how and where naive T cells become activated to yield disease-producing effector cells. © 2010 New York Academy of Sciences.

  3. The Conjunctiva-Associated Lymphoid Tissue in Chronic Ocular Surface Diseases.

    Science.gov (United States)

    Mastropasqua, Rodolfo; Agnifili, Luca; Fasanella, Vincenzo; Nubile, Mario; Gnama, Agbeanda A; Falconio, Gennaro; Perri, Paolo; Di Staso, Silvio; Mariotti, Cesare

    2017-08-01

    Ocular surface diseases (OSDs) represent a widely investigated field of research given their growing incidence and the negative impact on quality of life. During OSDs, cytokines generated by damaged epithelia trigger and deregulate the lymphoid cells composing the eye-associated lymphoid tissues, inducing an immune-mediated chronic inflammation that amplifies and propagates the disease during time. The conjunctiva-associated lymphoid tissue (CALT), given its particular position that permits immune cells covering the cornea, might play a crucial role in the development of OSDs. Despite the recognized inflammatory role of mucosa-associated lymphoid tissues in other stations taking contact with the external environment (gut or bronchus), CALT did not gain the deserved consideration. In the last years, the diffusion of the in vivo confocal microscopy (IVCM) stimulated the interest to CALT, especially in dry eye, ocular allergy, and glaucoma. Though the initial stimuli were different, IVCM documented similar changes, represented by increased lymphoid cells within the diffuse layer, follicles and interfollicular spaces. These findings, which need to be validated by immunohistology, support the CALT stimulation during OSDs. However, while an involvement of the CALT in OSDs is hypothesizable, the exact role of this structure in their pathogenesis remains unclear and warrants further investigations.

  4. Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

    Science.gov (United States)

    2017-03-27

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; 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); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  5. Chronic Lymphocytic Leukemia Treatment (PDQ®)—Health Professional Version

    Science.gov (United States)

    Chronic lymphocytic leukemia (CLL) treatment options can include observation, steroids, chemotherapy, targeted therapy, and/or stem cell transplant. Get detailed information about newly diagnosed and recurrent CLL and available treatment modalities in this summary for clinicians.

  6. Allogeneic cellular immunotherapy for chronic B-cell leukemia

    NARCIS (Netherlands)

    Hoogendoorn, Mels

    2007-01-01

    Allogeneic stem cell transplantation (SCT) following reduced-intensity conditioning (RIC) as treatment modality has curative potential in patients suffering from chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL), illustrating susceptibility of these leukemic cells for the

  7. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    AnnaMaria Nosari

    2012-11-01

    Full Text Available Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles. Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

  8. Tyrosine Kinase Inhibitor Treatment for Newly Diagnosed Chronic Myeloid Leukemia.

    Science.gov (United States)

    Radich, Jerald P; Mauro, Michael J

    2017-08-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder that accounts for approximately 10% of new cases of leukemia. The introduction of tyrosine kinase inhibitors has led to a reduction in mortalities. Thus, the estimated prevalence of CML is increasing. The National Comprehensive Cancer Network and the European Leukemia Net guidelines incorporate frequent molecular monitoring of the fusion BCR-ABL transcript to ensure that patients reach and keep treatment milestones. Most patients with CML are diagnosed in the chronic phase, and approximately 10% to 30% of these patients will at some time in their course meet definition criteria of resistance to imatinib. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Derangements of lacrimal drainage-associated lymphoid tissue (LDALT) in human chronic dacryocystitis.

    Science.gov (United States)

    Ali, Mohammad Javed; Mulay, Kaustubh; Pujari, Aditi; Naik, Milind N

    2013-12-01

    To study the changes in the lacrimal drainage-associated lymphoid tissue of the lacrimal sac in human chronic dacryocystitis and its possible implications in understanding the immune defense mechanisms and etiopathogenesis of primary acquired nasolacrimal duct obstruction. Retrospective interventional study involving 200 lacrimal sacs of 164 consecutive patients seen between July 2009 and July 2012. Data collected include demographics, clinical presentation, laterality, age at presentation, duration of symptoms, diagnostic irrigation, indications for a dacyrocystectomy, pattern and severity of lymphoid infiltrate, types of lymphoid follicles and their locations, plasma cells, and other cellular infiltrates. The associated epithelial, stromal, and luminal changes with an emphasis on acini, mucosal glands, blood vessels, lymphatics, and goblet cells were also noted. Immunohistochemistry using CD3, CD20, CD138, and immunoglobulin A were used to substantiate the lymphoid tissues of the lacrimal sac. A total of 200 lacrimal sacs were obtained from dacryocystectomy of 164 patients. The patients included 60.5% (99/164) females and 39.6% (65/164) males, with a mean age of 58.4 years at presentation. Laterality showed a predominance of left lacrimal sacs (55%, 110/200) as compared to the right lacrimal sacs (45%, 90/200). Symptoms of epiphora and discharge of more than 6 months duration were considered to be chronic. Lymphoid infiltrate pattern was diffuse in majority of the sacs (81%, 162/200), with subepithelial and intraepithelial together being the commonest location (46.5%, 93/200). Distinct lymphoid follicles were seen in 28% (56/200). Most of the sacs showed mild plasma cell infiltration (66.5%, 133/200). IgA-rich secretions were noted in the lumen and the lining epithelium in 34.5% (69/200). Other common changes noted include increase in the goblet cells (82%, 164/200), dilated lymphatics (94%, 188/200), proliferating blood vessels (99%, 198/200), thickened

  10. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  11. Cytogenetic investigations of chronic lymphocytic leukemia.

    Science.gov (United States)

    Wren, Catherine; Moriarty, Helen; Marsden, Katherine; Tegg, Elizabeth

    2010-04-15

    This study aimed to determine which culture method would yield the highest culture success rate, mitotic index, banding resolution, and abnormality rate in investigation of patients with chronic lymphocytic leukemia (CLL). A range of culture techniques for conventional cytogenetic (CC) analyses was compared: 24-hour unstimulated, 72 hours incubation with additional fetal calf serum, 72 hours stimulation with interleukin 4, 72 hours stimulation with lipopolysaccharide (LPS), 72 hours stimulation with TPA (12-O-tetradecanoylphorbol 13-acetate), and 72 hours stimulation with CpG-oligonucleotide DSP30 + Interleukin-2 (IL-2). CC abnormality rates were also compared to fluorescence in situ hybridization (FISH) results using probes for CLL (LSI D13S319/13q34/CEP 12: LSI ATM/p53). Forty-five samples from 24 patients (consisting of 11 newly diagnosed and 13 previously diagnosed patients) were included. For CC, a 100.0% culture success rate was achieved (n = 45) by means of an EDTA (ethylenediaminetetraacetic acid) peripheral blood sample with an associated 62.5% CC abnormality rate (n = 24). FISH detected an abnormality rate of 75.0% (n = 24). The combined CC and FISH abnormality rate was 87.5% (n = 24). This study demonstrates that CC that uses TPA and DSP30 + IL-2 on EDTA peripheral blood is effective in the investigation of CLL and may be used as a supplement to FISH studies. Copyright 2010 Elsevier Inc. All rights reserved.

  12. Therapeutic advancement of chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Lu Kang

    2012-09-01

    Full Text Available Abstract Despite the combinations of chemotherapy with monoclonal antibodies have further improved response rates, chronic lymphocytic leukemia (CLL remains an incurable disease with an extremely variable course. This article reviews the ongoing clinical advances in the treatment of CLL in both previously untreated and relapsed disease and focuses on the benefit of different therapeutic strategies, the most effective therapy combinations and the potential activity of novel agents. Novel agents and combination therapies have been investigated by several studies in both the upfront and relapsed setting, particularly for patients with 17p deletion, TP53 mutation and fludarabine-refractory CLL. While these agents and combination therapies have improved initial response rates, ongoing studies are continued to determine and improve the efficacy and safety. Despite advancements in the treatment of CLL have led to high response rates, allogeneic hematopoietic stem cell transplantation (allo-HSCT remains the only curative option and reduced-intensity conditioning (RIC allo-HSCT must be strongly considered whenever feasible. As such, ongoing studies of these agents and other novel approaches in clinical development are needed to expand and improve treatment options for CLL patients.

  13. Splenic function in chronic myelogenous leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Covas, D.T.; Zago, M.A.

    1987-01-01

    Spleen function was evaluated by measurement of the clearance of autologous heat-damaged /sup 99m/Tc-labelled erythrocytes from the circulation and into the spleen and the enumeration of pitted erythrocytes by interference contrast microscopy, and the spleen area was determined by scintillation scanning. All measurements were performed on 12 patients with chronic myelogenous leukemia and compared with 10 controls with apparently normal spleens, 6 splenectomized subjects and 9 patients with a reactive splenomegaly. Patients with CML had spleen function test results similar to normal controls in spite of having enlarged spleens whose projection area did not differ from that of the patients with reactive splenomegaly. Thus, patients with CML have a decreased spleen function per unit volume and signs of splenic hypofunction in the peripheral blood. The reduction of spleen function per unit volume in CML is the result of a severe decrease of the splenic blood perfusion which could result from the combined effects of the myeloid metaplasia and the increased whole-blood viscosity due to high white-cell counts.

  14. Splenic function in chronic myelogenous leukemia

    International Nuclear Information System (INIS)

    Covas, D.T.; Zago, M.A.

    1987-01-01

    Spleen function was evaluated by measurement of the clearance of autologous heat-damaged 99m Tc-labelled erythrocytes from the circulation and into the spleen and the enumeration of pitted erythrocytes by interference contrast microscopy, and the spleen area was determined by scintillation scanning. All measurements were performed on 12 patients with chronic myelogenous leukemia and compared with 10 controls with apparently normal spleens, 6 splenectomized subjects and 9 patients with a reactive splenomegaly. Patients with CML had spleen function test results similar to normal controls in spite of having enlarged spleens whose projection area did not differ from that of the patients with reactive splenomegaly. Thus, patients with CML have a decreased spleen function per unit volume and signs of splenic hypofunction in the peripheral blood. The reduction of spleen function per unit volume in CML is the result of a severe decrease of the splenic blood perfusion which could result from the combined effects of the myeloid metaplasia and the increased whole-blood viscosity due to high white-cell counts. (author)

  15. Optimized Treatment Schedules for Chronic Myeloid Leukemia.

    Directory of Open Access Journals (Sweden)

    Qie He

    2016-10-01

    Full Text Available Over the past decade, several targeted therapies (e.g. imatinib, dasatinib, nilotinib have been developed to treat Chronic Myeloid Leukemia (CML. Despite an initial response to therapy, drug resistance remains a problem for some CML patients. Recent studies have shown that resistance mutations that preexist treatment can be detected in a substantial number of patients, and that this may be associated with eventual treatment failure. One proposed method to extend treatment efficacy is to use a combination of multiple targeted therapies. However, the design of such combination therapies (timing, sequence, etc. remains an open challenge. In this work we mathematically model the dynamics of CML response to combination therapy and analyze the impact of combination treatment schedules on treatment efficacy in patients with preexisting resistance. We then propose an optimization problem to find the best schedule of multiple therapies based on the evolution of CML according to our ordinary differential equation model. This resulting optimization problem is nontrivial due to the presence of ordinary different equation constraints and integer variables. Our model also incorporates drug toxicity constraints by tracking the dynamics of patient neutrophil counts in response to therapy. We determine optimal combination strategies that maximize time until treatment failure on hypothetical patients, using parameters estimated from clinical data in the literature.

  16. Curcumin and Cholecalciferol in Treating Patients With Previously Untreated Stage 0-II Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2018-01-26

    Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia

  17. Chronic Myelogenous Leukemia (CML) (For Parents)

    Science.gov (United States)

    ... studying the leukemia cells collected from the blood, bone marrow, and/or spinal fluid, doctors can determine the type of leukemia a child has. This is important because treatment varies among different types ... blood or bone marrow, doctors can tell whether the Philadelphia chromosome is ...

  18. Apparent feline leukemia virus-induced chronic lymphocytic leukemia and response to treatment.

    Science.gov (United States)

    Kyle, Kristy N; Wright, Zachary

    2010-04-01

    Chylothorax secondary to chronic lymphocytic leukemia (CLL) was diagnosed in a feline leukemia virus (FeLV)-positive 8-year-old castrated male domestic shorthair feline. The leukemia resolved following therapy with chlorambucil, prednisone, cyclophosphamide, doxorubicin, and lomustine. To our knowledge, this is the first reported case of CLL in an FeLV-positive cat. Although a causative relationship cannot be proven, patients diagnosed with either disease may benefit from diagnostics to rule out the presence of the other concurrent condition. Copyright 2009 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

  19. Ibrutinib for treatment of chronic lymphocytic leukemia.

    Science.gov (United States)

    Vela, Cory M; McBride, Ali; Jaglowski, Samantha M; Andritsos, Leslie A

    2016-03-15

    The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ibrutinib are described. Ibrutinib is a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK) approved for treatment of relapsed chronic lymphocytic leukemia (CLL). Ibrutinib blocks downstream signaling of the B-cell receptor, disrupting stromal microenvironment interactions and B-cell cytokine signaling. BTK inhibition has been shown to be effective in relapsed or refractory CLL. A recent Phase III study evaluated ibrutinib (420 mg daily) versus ofatumumab (consistent with labeling) in relapsed or refractory CLL with a primary endpoint of progression free survival (PFS, n = 391). After a median follow-up period of 9.4 months, a PFS was not attained in ibrutinib-treated individuals with and without deletion 17p. In contrast, ofatumumab-treated individuals experienced a PFS of 8.1 months and those with deletion 17p experienced a PFS of 5.8 months. Major hemorrhage was reported in 2 (1%) patients treated with ibrutinib, and a total of 8 (4%) patients discontinued treatment due to toxicity or adverse reactions. Partial response or partial response with lymphocytosis was achieved in 63% of ibrutinib-treated individuals as determined by independent assessments. Overall, ibrutinib reduced the rate of mortality by 57%. Ibrutinib is a first-in-class, orally active, irreversible BTK inhibitor with a novel mechanism of action. This unique mechanism of action and high overall response rates observed in clinical trials make ibrutinib an attractive second-line option in patients who have disease progression while receiving monoclonal antibody therapy or chemoimmunotherapy. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  20. Current Treatment of Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Jamroziak, Krzysztof; Puła, Bartosz; Walewski, Jan

    2017-01-01

    A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions. Ibrutinib was proven as a primary choice for patients with the TP53 gene deletion/mutation, who otherwise have no active treatment available. Idelalisib with rituximab is also an active therapy, but due to increased risk of serious infections, its use in first-line treatment is limited to patients for whom ibrutinib is not an option. A new indication for ibrutinib was recently approved for older patients with comorbidities, as an alternative to the already existing indication for chlorambucil with obinutuzumab. The use of kinase inhibitors is already well established in recurrent/refractory disease. Immunochemotherapy with fludarabine, cyclophosphamide, rituximab (FCR) remains a major first-line option for many CLL patients without the TP53 gene deletion/mutation, and who have no significant comorbidities or history of infections, and is particularly effective in patients with favorable features including mutated IGHV status. There are a number of issues regarding novel therapies for CLL that need further investigation such as optimum duration of treatment with kinase inhibitors, appropriate sequencing of novel agents, mechanisms of resistance to inhibitors and response to class switching after treatment failure, along with the potential role of combinations of targeted agents.

  1. Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk

    NARCIS (Netherlands)

    van Attekum, Martijn H. A.; Eldering, Eric; Kater, Arnon P.

    2017-01-01

    The importance of the tumor microenvironment in chronic lymphocytic leukemia is widely accepted. Nevertheless, the understanding of the complex interplay between the various types of bystander cells and chronic lymphocytic leukemia cells is incomplete. Numerous studies have indicated that bystander

  2. Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk

    OpenAIRE

    van Attekum, Martijn HA; Eldering, Eric; Kater, Arnon P

    2017-01-01

    The importance of the tumor microenvironment in chronic lymphocytic leukemia is widely accepted. Nevertheless, the understanding of the complex interplay between the various types of bystander cells and chronic lymphocytic leukemia cells is incomplete. Numerous studies have indicated that bystander cells provide chronic lymphocytic leukemia-supportive functions, but it has also become clear that chronic lymphocytic leukemia cells actively engage in the formation of a supportive tumor microenv...

  3. Prolonged T1 relaxation of the hemopoietic bone marrow in patients with chronic leukemia

    DEFF Research Database (Denmark)

    Jensen, K E; Sørensen, P G; Thomsen, C

    1990-01-01

    Eleven patients with chronic leukemia (7 with chronic lymphocytic leukemia and 4 with chronic myeloid leukemia) were evaluated with magnetic resonance (MR) imaging and T1 relaxation time measurements by use of a 1.5 tesla whole body MR scanner. Bone marrow biopsies were obtained from the posterior...

  4. Efficacy of total lymphoid irradiation for chronic allograft rejection following double lung transplantation

    International Nuclear Information System (INIS)

    Diamond, David A.; Michalski, Jeff M.; Trulock, Elbert M.; Lynch, John P.

    1997-01-01

    Purpose: The purpose of this study was to assess the safety and efficacy of total lymphoid irradiation in a series of patients experiencing chronic rejection following bilateral lung transplantation. Patients and Materials: Eleven patients (10 males, 1 female) received total lymphoid irradiation for chronic allograft rejection (bronchiolitis obliterans syndrome) refractory to conventional treatment modalities. Treatment was delivered between March, 1995, and September, 1996. Mean patient age was 33 years (range 15-51). Indications for transplantation included cystic fibrosis (7 patients), alpha 1 anti-trypsin deficiency (2 patients), primary pulmonary hypertension (1 patient), and emphysema (1 patient). Radiation therapy was prescribed as 800 cGy delivered in ten 80 cGy fractions, 2 fractions per week, via AP/PA mantle and inverted-Y fields. Radiation was withheld for total wbc count 3 , absolute neutrophil count 3 , or platelets 3 . Serial pre- and post-radiation therapy pulmonary function values, complete blood counts, and immunosuppressive augmentation requirements (use of methylprednisolone, azathioprine, mycophenolate mofetil, OKT3, and FK506) were monitored. Results: In the 3 months preceding total lymphoid irradiation, the average decrease in FEV 1 was 34% (range 0-75%) and the median number of immunosuppression augmentations was 3 (range 0-5). At initiation of radiation therapy, the average FEV 1 was 1.4 liters (range 0.77-2.28). Only (4(11)) patients completed all 10 treatment fractions. Reasons for discontinuation included unabated rejection (4 patients), worsening pulmonary infection (2 patients), and persistent thrombocytopenia (1 patient). No treatment course was discontinued because of persistent neutropenia or leukopenia. Seven of the 11 patients failed within 8 weeks of treatment cessation. One patient had unabated rejection and received bilateral living related donor transplants. He is alive and well. Six patients died. Two of these deaths were due

  5. Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alfa therapy.

    Science.gov (United States)

    Schmidt, M; Hochhaus, A; König-Merediz, S A; Brendel, C; Proba, J; Hoppe, G J; Wittig, B; Ehninger, G; Hehlmann, R; Neubauer, A

    2000-10-01

    Mice experiments have established an important role for interferon regulatory factor (IRF) family members in hematopoiesis. We wanted to study the expression of interferon regulatory factor 4 (IRF4) in various hematologic disorders, especially chronic myeloid leukemia (CML), and its association with response to interferon alfa (IFN-alpha) treatment in CML. Blood samples from various hematopoietic cell lines, different leukemia patients (70 CML, 29 acute myeloid leukemia [AML], 10 chronic myelomonocytic leukemia [CMMoL], 10 acute lymphoblastic leukemia, and 10 chronic lymphoid leukemia patients), and 33 healthy volunteers were monitored for IRF4 expression by reverse transcriptase polymerase chain reaction. Then, with a focus on CML, the IRF4 level was determined in sorted cell subpopulations from CML patients and healthy volunteers and in in vitro-stimulated CML cells. Furthermore, IRF4 expression was compared in the CML samples taken before IFN-alpha therapy and in 47 additional CML samples taken during IFN-alpha therapy. IRF4 expression was then correlated with cytogenetic response to IFN-alpha. IRF4 expression was significantly impaired in CML, AML, and CMMoL samples. The downregulation of IRF4 in CML samples was predominantly found in T cells. In CML patients during IFN-alpha therapy, a significant increase in IRF4 levels was detected, and this was also observed in sorted T cells from CML patients. The increase seen during IFN-alpha therapy was not due to different blood counts. In regard to the cytogenetic response with IFN-alpha, a good response was associated with high IRF4 expression. IRF4 expression is downregulated in T cells of CML patients, and its increase is associated with a good response to IFN-alpha therapy. These data suggest IRF4 expression as a useful marker to monitor, if not predict, response to IFN-alpha in CML.

  6. Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors

    DEFF Research Database (Denmark)

    Xochelli, Aliki; Baliakas, Panagiotis; Kavakiotis, Ioannis

    2017-01-01

    Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether...

  7. Interferon alpha for treatment of chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Hjorth-Hansen, Henrik; Bjerrum, Ole Weis

    2011-01-01

    Treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-a) was introduced in the early 1980s. Several clinical trials showed a survival advantage for patients treated with IFN-a compared to conventional chemotherapy. Some patients achieved longstanding complete cytogenetic remissions...

  8. Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia

    OpenAIRE

    Benjamin Arthurs, MD; Kathy Wunderle, MD; Maylee Hsu, MD; Suil Kim, MD, PhD

    2017-01-01

    We report a case of invasive pulmonary aspergillosis in a patient taking ibrutinib, a Bruton's tyrosine kinase inhibitor used to treat refractory chronic lymphocytic leukemia. We hypothesize that ibrutinib promoted this infection by suppressing innate immune responses against Aspergillus. Clinicians should be aware of potential Aspergillus infections in patients treated with this drug.

  9. Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Benjamin Arthurs, MD

    2017-01-01

    Full Text Available We report a case of invasive pulmonary aspergillosis in a patient taking ibrutinib, a Bruton's tyrosine kinase inhibitor used to treat refractory chronic lymphocytic leukemia. We hypothesize that ibrutinib promoted this infection by suppressing innate immune responses against Aspergillus. Clinicians should be aware of potential Aspergillus infections in patients treated with this drug.

  10. Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia.

    Science.gov (United States)

    Arthurs, Benjamin; Wunderle, Kathy; Hsu, Maylee; Kim, Suil

    2017-01-01

    We report a case of invasive pulmonary aspergillosis in a patient taking ibrutinib, a Bruton's tyrosine kinase inhibitor used to treat refractory chronic lymphocytic leukemia. We hypothesize that ibrutinib promoted this infection by suppressing innate immune responses against Aspergillus . Clinicians should be aware of potential Aspergillus infections in patients treated with this drug.

  11. Paraneoplastic pemphigus as the initial presentation of chronic lymphocytic leukemia

    NARCIS (Netherlands)

    van Mook, WNKA; Fickers, MMF; Theunissen, PHMH; vander Kley, JAMJ; Duijvestijn, JA; Pas, HH; Flikweert, DC

    The case history of a 61-year-old male patient is described, who presented with severe stomatitis, conjunctivitis and leukocytosis. The diagnosis chronic lymphocytic leukemia (CLL) stage A (0) was made, for which no treatment was necessary. Progression of stomatitis and conjunctivitis and

  12. Peripheral retinal nonperfusion associated with chronic myeloid leukemia.

    NARCIS (Netherlands)

    Nobacht, S.; Vandoninck, K.F.; Deutman, A.F.; Klevering, B.J.

    2003-01-01

    PURPOSE: To report a case of peripheral retinal nonperfusion and chronic myeloid leukemia in a 23-year-old woman. DESIGN: Observational case report. METHODS: A complete ophthalmic and systemic evaluation was performed. RESULTS: Ophthalmic examination revealed peripheral retinal nonperfusion with

  13. Diagnosis and treatment of acute and chronic leukemia

    International Nuclear Information System (INIS)

    1978-01-01

    The Cancergram covers both acute and chronic leukemia in all of its forms (acute lymphocytic, acute monocytic, acute or sub-acute granulocytic, chronic granulocytic, chronic lymphocytic, chronic monocytic, plasma cell, stem cell, and hairy cell). Other neoplastic conditions of the reticuloendothelial system, lymphatic system, spleen, multiple myeloma, macroglobulinemia and other monoclonal gammopathies are excluded, and will be coveted by other Cancergrams now under development. This Cancergram includes abstracts concerning all clinical aspects of the disease, such as diagnosis and staging, supportive care, evaluation, and therapy. Animal models, tissue culture experiments, carcinogenesis and other pre-clinical studies are generally excluded, except for those considered to have direct clinical relevance

  14. Retroviral insertions in the VISION database identify molecular pathways in mouse lymphoid leukemia and lymphoma.

    Science.gov (United States)

    Weiser, Keith C; Liu, Bin; Hansen, Gwenn M; Skapura, Darlene; Hentges, Kathryn E; Yarlagadda, Sujatha; Morse Iii, Herbert C; Justice, Monica J

    2007-10-01

    AKXD recombinant inbred (RI) strains develop a variety of leukemias and lymphomas due to somatically acquired insertions of retroviral DNA into the genome of hematopoetic cells that can mutate cellular proto-oncogenes and tumor suppressor genes. We generated a new set of tumors from nine AKXD RI strains selected for their propensity to develop B-cell tumors, the most common type of human hematopoietic cancers. We employed a PCR technique called viral insertion site amplification (VISA) to rapidly isolate genomic sequence at the site of provirus insertion. Here we describe 550 VISA sequence tags (VSTs) that identify 74 common insertion sites (CISs), of which 21 have not been identified previously. Several suspected proto-oncogenes and tumor suppressor genes lie near CISs, providing supportive evidence for their roles in cancer. Furthermore, numerous previously uncharacterized genes lie near CISs, providing a pool of candidate disease genes for future research. Pathway analysis of candidate genes identified several signaling pathways as common and powerful routes to blood cancer, including Notch, E-protein, NFkappaB, and Ras signaling. Misregulation of several Notch signaling genes was confirmed by quantitative RT-PCR. Our data suggest that analyses of insertional mutagenesis on a single genetic background are biased toward the identification of cooperating mutations. This tumor collection represents the most comprehensive study of the genetics of B-cell leukemia and lymphoma development in mice. We have deposited the VST sequences, CISs in a genome viewer, histopathology, and molecular tumor typing data in a public web database called VISION (Viral Insertion Sites Identifying Oncogenes), which is located at http://www.mouse-genome.bcm.tmc.edu/vision .

  15. Role of the gut-associated and secondary lymphoid tissue in the induction of chronic colitis.

    Science.gov (United States)

    Takebayashi, Koichi; Koboziev, Iurii; Ostanin, Dmitry V; Gray, Laura; Karlsson, Fridrik; Robinson-Jackson, Sherry A; Kosloski-Davidson, Melissa; Dooley, Angela Burrows; Zhang, Songlin; Grisham, Matthew B

    2011-01-01

    It is well known that enteric bacterial antigens drive the development of chronic colitis in a variety of different mouse models of the inflammatory bowel diseases (IBD). The objective of this study was to evaluate the role of gut-associated lymphoid tissue (GALT; Peyer's patches, isolated lymphoid follicles), mesenteric lymph nodes (MLNs) and spleen in the pathogenesis of chronic colitis in mice. Surgical as well as genetic approaches were used to generate lymphopenic mice devoid of one or more of these lymphoid tissues. For the first series of studies, we subjected recombinase activating gene-1-deficient mice (RAG(-/-) ) to sham surgery (Sham), mesenteric lymphadenectomy (MLNx), splenectomy (Splx) or both (MLNx/Splx). In a second series of studies we intercrossed lymphotoxinβ-deficient (LTβ(-/-) ) mice with RAG(-/-) animals to generate LTβ(-/-) x RAG(-/-) offspring that were anticipated to contain functional MLNs but be devoid of GALT and most peripheral lymph nodes. Flow purified naïve (CD4(+) CD45RB(high) ) T-cells were adoptively transferred into the different groups of RAG(-/-) recipients to induce chronic colitis. We found that at 3-5 wks following T-cell transfer, all four of the surgically-manipulated RAG(-/-) groups (Sham, MLNx, Splx and MLNx/Splx) developed chronic colitis that was similar in onset and severity. Flow cytometric analysis revealed no differences among the different groups with respect to surface expression of different gut-homing markers nor were there any differences noted in IFN-γ and IL-17 generation by mononuclear cells isolated among these surgically-manipulated mice. Although we anticipated that LTβ(-/-) x RAG(-/-) mice would contain functional MLNs but be devoid of GALT and peripheral lymph nodes (PLNs), we found that LTβ(-/-) x RAG(-/-) mice were in fact devoid of MLNs as well as GALT and PLNs. Adoptive transfer of CD45RB(high) T-cells into LTβ(-/-) x RAG(-/-) mice or their littermate controls (LTβ(+/+) x RAG

  16. JAK2V617F mutation in a patient with B-cell chronic lymphocytic leukemia and prefibrotic primary myelofibrosis

    Directory of Open Access Journals (Sweden)

    Ristić Slobodan

    2015-01-01

    Full Text Available Introduction. Secondary malignancies, particularly solid tumors, are common in patients with chronic lymphocytic leukemia (CLL, but association of myeloproliferative neoplasms and chronic lymphocytic leukemia in the same patient is very rare. Case Outline. We report of a 67-year-old man with B-cell chronic lymphoid leukemia (B-CLL who developed primary myelofibrosis (PMF nine years after initial diagnosis. Patient received alkylation agents and purine analogue, which can be a predisposing factor for the development of myeloproliferative neoplasms. JAK2V617F mutation was not present initially at the time of CLL diagnosis, but was found after nine years when PMF occurred, which indicates that B-CLL and PMF represent two separate clonal origin neoplasms. Conclusion. Pathogenic mechanisms for the development of myeloproliferative and lymphoproliferative neoplasms in the same patient are unknown. Further research is needed to determine whether these malignancies originate from two different cell clones or arise from the same pluripotent hematopoietic stem cell. [Projekat Ministarstva nauke Republike Srbije, br. III 41004

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

    Science.gov (United States)

    2018-04-20

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

  18. Bosutinib in the management of chronic myelogenous leukemia

    Directory of Open Access Journals (Sweden)

    Keller-von Amsberg G

    2013-05-01

    Full Text Available Gunhild Keller-von Amsberg, Philippe SchafhausenDepartment of Hematology and Oncology and, Stem Cell Transplantation and Pulmonology Division, Oncological Center, University Hospital Hamburg-Eppendorf, Hamburg, GermanyAbstract: Bosutinib (SKI-606 is an orally available, once-daily dual Src and Abl kinase inhibitor, approved by the US Food and Drug Administration for the treatment of adults with chronic, accelerated, or blast-phase Philadelphia chromosome-positive chronic myelogenous leukemia who are intolerant of or resistant to first- or second-generation tyrosine kinase inhibitors. Bosutinib effectively overcomes the majority of imatinib-resistance-conferring BCR-ABL mutations except V299L and T315I. In the Bosutinib Efficacy and Safety in chronic myeloid LeukemiA (BELA trial, bosutinib attained a faster and deeper molecular response than imatinib in newly diagnosed chronic-phase chronic myelogenous leukemia patients. Treatment-emergent adverse events are usually very manageable. Low grade, mostly self-limiting diarrhea represents the most frequently observed toxicity of bosutinib. Anti-diarrheal drugs, antiemetic agents, and/or fluid replacement should be used to treat these patients. The improved hematological toxicity of bosutinib compared with other tyrosine kinase inhibitors has been ascribed to its minimal activity against platelet-derived growth factor receptor and KIT. In this review, we give an overview on the profile of bosutinib, the clinical potential and treatment-emergent adverse events.Keywords: CML, BCR-ABL, SRC/ABL kinase inhibitor, resistance-conferring mutation

  19. IL-33-responsive innate lymphoid cells are an important source of IL-13 in chronic rhinosinusitis with nasal polyps.

    Science.gov (United States)

    Shaw, Joanne L; Fakhri, Samer; Citardi, Martin J; Porter, Paul C; Corry, David B; Kheradmand, Farrah; Liu, Yong-Jun; Luong, Amber

    2013-08-15

    Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) are associated with Th1 and Th2 cytokine polarization, respectively; however, the pathophysiology of CRS remains unclear. The importance of innate lymphoid cells in Th2-mediated inflammatory disease has not been clearly defined. The objective of this study was to investigate the role of the epithelial cell-derived cytokine IL-33 and IL-33-responsive innate lymphoid cells in the pathophysiology of CRS. Relative gene expression was evaluated using quantitative real-time polymerase chain reaction. Innate lymphoid cells in inflamed ethmoid sinus mucosa from patients with CRSsNP and CRSwNP were characterized using flow cytometry. Cytokine production from lymphoid cells isolated from inflamed mucosa of patients with CRS was examined using ELISA and intracellular cytokine staining. Elevated expression of ST2, the ligand-binding chain of the IL-33 receptor, was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP and healthy control subjects. An increased percentage of innate lymphoid cells was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP. ST2(+) innate lymphoid cells are a consistent source of IL-13 in response to IL-33 stimulation. Significant induction of IL-33 was observed in epithelial cells derived from patients with CRSwNP compared with patients with CRSsNP in response to stimulation with Aspergillus fumigatus extract. These data suggest a role for sinonasal epithelial cell-derived IL-33 and an IL-33-responsive innate lymphoid cell population in the pathophysiology of CRSwNP demonstrating the functional importance of innate lymphoid cells in Th2-mediated inflammatory disease.

  20. Ambiguous roles of innate lymphoid cells in chronic development of liver diseases.

    Science.gov (United States)

    Shen, Yue; Li, Jing; Wang, Si-Qi; Jiang, Wei

    2018-05-14

    Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T-bet and can produce interferon-γ; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORγt and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets.

  1. Firstline treatment for chronic phase chronic myeloid leukemia patients should be based on a holistic approach.

    Science.gov (United States)

    Breccia, Massimo; Alimena, Giuliana

    2015-02-01

    New selective and more potent drugs for the cure of chronic phase chronic myeloid leukemia patients are now available: physicians in some countries must decide the best option, selecting one of the drugs available. What the main prognostic factors are in order to make this selection remains a matter of discussion. Introducing a 'holistic approach' for the first time in chronic myeloid leukemia, as practiced in other diseases, and looking at the patient in a complete picture, considering several variables, such as comorbidities, age, concomitant drugs, lifestyle and patient expectations, may be of help to understand, patient by patient, the best therapeutic strategy.

  2. Chronic Myeloid Leukemia In a Pregnant Woman: A Case Report

    Directory of Open Access Journals (Sweden)

    Aytekin Tokmak

    2015-12-01

    Full Text Available Chronic myeloid leukemia (CML is a rare disease in pregnancy. Our aim is to present a 37 weeks of pregnant woman with chronic myelogenous leukemia. A 27 Years in multigravi (gravida 5, parity: 4, at 37 weeks gestation was admitted with the diagnosis of painful pregnancy and CML. Physical examination findings were normal, complete blood count and peripheral blood smear results were consistent with CML. The patient was diagnosed CML in the 30th week of pregnancy and were treated with hydroxyurea and interferon. Treatment depends on the mother and the fetus did not develop any side effects. Our patient with CML is interesting due to lack of perinatal effects and take the diagnosis at an early age. CML diagnosed during pregnancy requires a multidisciplinary approach and hydroxyurea and interferon treatment on the mother and fetus are at low risk of inducing adverse effects. [Cukurova Med J 2015; 40(4.000: 811-813

  3. Chromosomal study for prognostic grouping in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Junaid, A.; Rao, P.N.

    2010-01-01

    To determine the frequency of various cytogenetic aberrations in newly diagnosed chronic lymphocytic leukemia (CLL) patients, and their detection rate by cytogenetic and fluorescent In situ hybridization (FISH) technique separately. Analysis was made on 100 diagnosed chronic lymphocytic leukemia patients. Cytogenetics and FISH technique were performed on blood or bone marrow samples. Nineteen out of 100 cases (19%) showed karyotype abnormalities; whereas 55 showed abnormalities using the CLL - specific FISH probes. The most frequent abnormality detected by standard cytogenetics was trisomy 12. The most common abnormality detected by FISH was a deletion of 13q14 (40 out of 55 cases; 72% of the abnormal). For prognostic grouping of CLL patients, FISH must always be requested which may even replace standard karyotyping. These chromosomal markers help in choosing the therapeutic options. (author)

  4. Pulmonary Mucormycosis in Chronic Lymphocytic Leukemia and Neutropenia

    Directory of Open Access Journals (Sweden)

    Izza Mir

    2018-01-01

    Full Text Available Pulmonary mucormycosis is a rare life-threatening fungal infection associated with high mortality. We present the case of a 61-year-old man with history of chronic lymphocytic leukemia who presented with fever and cough, eventually diagnosed with pulmonary mucormycosis after right lung video-assisted thoracoscopic surgery. The patient was successfully treated with amphotericin B and right lung pneumonectomy; however, he later died from left lung pneumonia.

  5. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia

    OpenAIRE

    Guièze, Romain; Wu, Catherine J.

    2015-01-01

    Defining features of chronic lymphocytic leukemia (CLL) are not only its immunophenotype of CD19+CD5+CD23+sIgdim expressing clonal mature B cells but also its highly variable clinical course. In recent years, advances in massively parallel sequencing technologies have led to rapid progress in our understanding of the CLL genome and epigenome. Overall, these studies have clearly demarcated not only the vast degree of genetic and epigenetic heterogeneity among individuals with CLL but also even...

  6. Recombinant EphB4-HSA Fusion Protein and Azacitidine or Decitabine for Relapsed or Refractory Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia Patients Previously Treated With a Hypomethylating Agent

    Science.gov (United States)

    2017-08-18

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes; Recurrent Adult Acute Myeloid Leukemia

  7. Coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma with antecedent chronic lymphocytic leukemia: a case report and review of the literature.

    Science.gov (United States)

    Abuelgasim, Khadega A; Rehan, Hinna; Alsubaie, Maha; Al Atwi, Nasser; Al Balwi, Mohammed; Alshieban, Saeed; Almughairi, Areej

    2018-03-11

    Chronic lymphocytic leukemia and chronic myeloid leukemia are the most common types of adult leukemia. However, it is rare for the same patient to suffer from both. Richter's transformation to diffuse large B-cell lymphoma is frequently observed in chronic lymphocytic leukemia. Purine analog therapy and the presence of trisomy 12, and CCND1 gene rearrangement have been linked to increased risk of Richter's transformation. The coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma in the same patient is extremely rare, with only nine reported cases. Here, we describe the first reported case of concurrent chronic myeloid leukemia and diffuse large B-cell lymphoma in a background of chronic lymphocytic leukemia. A 60-year-old Saudi man known to have diabetes, hypertension, and chronic active hepatitis B was diagnosed as having Rai stage II chronic lymphocytic leukemia, with trisomy 12 and rearrangement of the CCND1 gene in December 2012. He required no therapy until January 2016 when he developed significant anemia, thrombocytopenia, and constitutional symptoms. He received six cycles of fludarabine, cyclophosphamide, and rituximab, after which he achieved complete remission. One month later, he presented with progressive leukocytosis (mostly neutrophilia) and splenomegaly. Fluorescence in situ hybridization from bone marrow aspirate was positive for translocation (9;22) and reverse transcription polymerase chain reaction detected BCR-ABL fusion gene consistent with chronic myeloid leukemia. He had no morphologic or immunophenotypic evidence of chronic lymphocytic leukemia at the time. Imatinib, a first-line tyrosine kinase inhibitor, was started. Eight months later, a screening imaging revealed new liver lesions, which were confirmed to be diffuse large B-cell lymphoma. In chronic lymphocytic leukemia, progressive leukocytosis and splenomegaly caused by emerging chronic myeloid leukemia can be easily overlooked. It is unlikely that chronic myeloid

  8. Watch and Wait – Actualities in the Treatment of Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Bíró Szilárd

    2017-12-01

    Full Text Available In Western countries, chronic lymphocytic leukemia (CLL is one of the most diagnosed leukemia types among elderly patients. CLL is described as an indolent lymphoproliferative disorder, characterized by the presence of a high number of small, mature B-cells in the peripheral blood smear, with a particular immunophenotype (CD5, CD19, CD23 positive and CD20 dim positive and accumulation in the bone marrow and lymphoid tissue (e.g., lymph nodes, spleen. The experience of the past decades showed that CLL is clinically very heterogeneous; while some patients present a chronic clinical evolution, with a prolonged survival, in which the treatment can be delayed, others suffer from a more aggressive form, which must be treated early and is associated with many relapses. This observation led to several genomic studies that have mapped the genetic modifications involved in the disease conformations, including del(13q14, del(11q, or trisomy 12. On the other hand, certain genetic mutations such as del(17p13–p53, NOTCH1 mutation, or ZAP70/CD38 increased expression are associated with worse clinical outcome. In order to apply the right treatment strategy, the RAI and BINET staging systems should be considered, which are based on clinical and laboratory assessment, on genetic mutations that may influence the resistance to chemotherapy, as well as the patient’s age and comorbidities. The aim of this manuscript was to present the therapeutic approaches of CLL, in order to attempt to answer the following question: to treat, or not to treat? This clinical update focuses on the managements of CLL patients in the 21st century.

  9. Bone marrow transplantation for patients with chronic myeloid leukemia

    International Nuclear Information System (INIS)

    Goldman, J.M.; Apperley, J.F.; Jones, L.

    1986-01-01

    Between February 1981 and December 1984 we treated 52 patients with chronic myeloid leukemia in the chronic phase and 18 patients with more advanced disease by high-dose chemoradiotherapy followed by allogeneic bone marrow transplantation using marrow cells from HLA-identical sibling donors. In addition, the 40 patients who had not previously undergone splenectomy received radiotherapy to the spleen. To prevent graft versus host disease, cyclosporine was given either alone or in conjunction with donor marrow depleted of T cells. Of the 52 patients treated in the chronic phase, 38 are alive after a median follow-up of 25 months (range, 7 to 50); the actuarial survival at two years was 72%, and the actuarial risk of relapse was 7%. Of the 18 patients with more advanced disease, 4 have survived; the actuarial two-year survival was 18%, and the actuarial risk of relapse was 42%. We conclude that the probability of cure is highest if transplantation is performed while the patient remains in the chronic phase of chronic myeloid leukemia. T-cell depletion may have reduced the incidence and severity of graft versus host disease. The value of irradiation to the spleen before transplantation has not been established

  10. Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation

    International Nuclear Information System (INIS)

    Diamond, David A.; Michalski, Jeff M.; Lynch, John P.; Trulock, Elbert P.

    1998-01-01

    Purpose: To assess the safety and efficacy of total lymphoid irradiation (TLI) in patients experiencing chronic rejection following bilateral lung transplantation (BLT). Patients and Materials: Eleven patients received TLI for chronic allograft rejection (bronchiolitis obliterans syndrome) refractory to conventional treatment modalities. Radiation therapy (RT) was prescribed as 8 Gy delivered in 10 0.8-Gy fractions, 2 fractions/week, via mantle, paraaortic, and inverted-Y fields. Serial pre- and post-RT pulmonary function values, complete blood counts, and immunosuppressive augmentation requirements [use of methylprednisolone, murine anti-human mature T-cell monoclonal antibody (OKT3), polyclonal antithymocyte globulin (ATG), and tacrolimus] were monitored. Results: In the 3 months preceding TLI, the average decrease in forced expiratory volume in 1 s (FEV 1 ) was 34% (range 0-75%) and the median number of immunosuppression augmentations was 3 (range 0-5). Only 4 of 11 patients completed all 10 TLI treatment fractions. Reasons for discontinuation included progressive pulmonary decline (four patients), worsening pulmonary infection (two patients), and persistent thrombocytopenia (one patient). Seven of the 11 patients failed within 8 weeks of treatment cessation. One patient had unabated rejection and received bilateral living related-donor transplants; he is alive and well. Six patients died. Two of these deaths were due to pulmonary infection from organisms isolated prior to the start of RT; the other four deaths were from progressive pulmonary decline. The four remaining patients had durable positive responses to TLI (mean follow-up of 47 weeks; range 24-72). Comparing the 3 months preceding RT to the 3 months following treatment, these four patients had improvements in average FEV 1 (40% decline vs. 1% improvement) and fewer median number of immunosuppressive augmentations (3.5 vs. 0). None of these patients has developed lymphoproliferative disease or has died

  11. Prolonged T1 relaxation of the hemopoietic bone marrow in patients with chronic leukemia

    International Nuclear Information System (INIS)

    Jensen, K.E.; Soerensen, P.G.; Thomsen, C.; Christoffersen, P.; Henriksen, O.; Karle, H.; Hvidovre Hospital; Hvidovre Hospital; Gentofte Hospital

    1990-01-01

    Eleven patients with chronic leukemia (7 with chronic lymphocytic leukemia and 4 with chronic myeloid leukemia) were evaluated with magnetic resonance (MR) imaging and T1 relaxation time measurements by use of a 1.5 tesla whole body MR scanner. Bone marrow biopsies were obtained from the posterior iliac crest (within 72 hours of the MR examination) in order to provide data on bone marrow cellularity and differential counts. The patients with chronic leukemia all showed a significant prolongation of the T1 relaxation times compared with the normal range for hemopoietic bone marrow. (orig.)

  12. Lymphoid follicle cells in chronic obstructive pulmonary disease overexpress the chemokine receptor CXCR3.

    Science.gov (United States)

    Kelsen, Steven G; Aksoy, Mark O; Georgy, Mary; Hershman, Richard; Ji, Rong; Li, Xiuxia; Hurford, Matthew; Solomides, Charalambos; Chatila, Wissam; Kim, Victor

    2009-05-01

    The mechanisms underlying formation of lung lymphoid follicles (LF) in chronic obstructive pulmonary disease (COPD) are unknown. The chemokine receptor CXCR3 regulates immune responses in secondary lymphoid structures elsewhere in the body and is highly expressed by Th1 lymphocytes in the airway in COPD. Because chemokine receptors control inflammatory cell homing to inflamed tissue, we reasoned that CXCR3 may contribute to LF formation in COPD. We assessed the expression of CXCR3 and its ligands (IP-10/CXCL10, Mig/CXCL9, and ITAC/CXCL11) by LF cells in never-smokers, smokers without COPD, and subjects with COPD. CXCR3, IP-10, Mig, and ITAC expression were assessed in lung sections from 46 subjects (never-smokers, smokers without COPD [S], and subjects with COPD in GOLD stages 1-4) by immunohistochemistry. CXCR3-expressing T cells (CD8+ or CD4+) and B cells (CD20+) were topographically distributed at the follicle periphery and center, respectively. The percentage of immunohistochemically identified CXCR3+ cells increased progressively while proceeding from S through GOLD 3-4 (P < 0.01 for GOLD 3-4 vs. S). Moreover, the number of CXCR3+ follicular cells correlated inversely with FEV(1) (r = 0.60). The CXCR3 ligands IP-10 and Mig were expressed by several cell types in and around the follicle, including CD68+ dendritic cells/ macrophages, airway epithelial cells, endothelial cells, and T and B cells. These results suggest that LF form in the COPD lung by recruitment and/or retention of CXCR3-expressing T and B lymphocytes, which are attracted to the region through production of CXCR3 ligands IP-10 and Mig by lung structural and follicular cells.

  13. Mechanisms of Disease Persistence in Chronic Myelogenous Leukemia (CML)

    Science.gov (United States)

    2006-10-01

    9.2 1.4 0.03 K-Ras* 6.7 1.3 0.04 RALA 5.4 1.1 0.13 Opioid receptor mu1 4.4 1.1 0.36 Jak2 4.3 1.2 0.14 TRF1 4.3 1.5 0.06 WT-1* n/a 1.3 0.008 c...2002 American Society of Hematology, Scientific Committee on Neoplasia 2000-2004 American Medical Informatics Association: Global Trial Bank...kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038-1042

  14. Treatment of Chronic Myelomonocytic Leukemia with 5-Azacytidine: Case Reports

    Directory of Open Access Journals (Sweden)

    Peter Rohon

    2012-01-01

    Full Text Available Epigenetic therapy with hypomethylating agent (5-azacytidine; AZA is common in the management of specific subtypes of myelodysplastic syndrome (MDS, but there are only few studies in chronic myelomonocytic leukemia (CMML patients. In this paper our experience with 3 CMML patients treated with AZA is described. In one patient transfusion independency was observed after 4 treatment cycles; in one case a partial response was recorded, but a progression to acute myeloid leukemia (AML after 13 AZA cycles has appeared. In one patient, AZA in reduced dosage was administered as a bridging treatment before allogeneic stem cell transplantation (ASCT, but in the control bone marrow aspirate (before ASCT a progression to AML was recorded. Future studies are mandatory for evaluation of new molecular and clinical features which could predict the efficiency of hypomethylating agents in CMML therapy with respect to overall survival, event-free survival, quality-adjusted life year, and pharmacoeconomy.

  15. Mast cell leukemia associated with undefined morphology and chronic basophilic leukemia.

    Science.gov (United States)

    Cehreli, Cavit; Alacacioglu, Inci; Piskin, Ozden; Ates, Halil; Cehreli, Ruksan; Calibasi, Gizem; Yuksel, Erdinc; Ozkal, Sermin; Ozsan, Guner H

    2014-01-01

    Mast cell leukemia (MCL) is rare type of neoplasia with an incidence of 1% in a large series of 342 adult patients with systemic mastocytosis (SM). Chronic basophilic leukemia (CBL) is an extremely rare type of leukemia with appearance of 7 cases in the literature. A 73 year-old female patient who presented with weaknes, had a prolonged duration of hematologic remission after treatment of her CBL by hydroxyurea (HU). Evolution of SM occurring as a second neoplasia concurrently with relapse of de novo CBL was demonstrated by mast cells (MCs) infiltration in the bone marrow (BM) biopsy and smear and increase in tryptase level. Transformation to MCL with simultaneous occurrance of accelerated phase of CBL were documented by the appearance of MCs in both BM and peripheral blood (PB) smears, antigen expressions detected by flow cytometry and spesific stains. Sequence analysis of c-kit gene revealed c-kit exon 11 K550N mutation. Undefined associations of MCL with different mast cell morphology, increase in IL-6 level and accelerated phase of de novo CBL was described. Elevations in CRP and IL-6 levels occurring with increases in basophil counts to high levels revealed that febrile episodes with abdominal pain seen in our patient were induced by increase in IL-6 levels released from neoplastic basophils. Neoplastic basophils with diffuse and coarse basophilic granules possibly mimic neutrophils with toxic granules and cause wrong characterization of neoplastic basophils as neutrophils by the automated blood cell counters and misleaded physicians.

  16. Ectopic lymphoid tissues support local immunoglobulin production in patients with chronic rhinosinusitis with nasal polyps.

    Science.gov (United States)

    Song, Jia; Wang, Hai; Zhang, Ya-Na; Cao, Ping-Ping; Liao, Bo; Wang, Zhe-Zheng; Shi, Li-Li; Yao, Yin; Zhai, Guan-Ting; Wang, Zhi-Chao; Liu, Li-Meng; Zeng, Ming; Lu, Xiang; Wang, Heng; Yang, Xiang-Ping; Yu, Di; Bachert, Claus; Liu, Zheng

    2018-03-01

    The contribution of ectopic lymphoid tissues (eLTs) to local immunoglobulin hyperproduction in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear. We sought to explore the cellular basis, formation mechanisms, and function of eLTs in patients with CRSwNP. We graded lymphoid aggregations in sinonasal mucosa and histologically studied their structures. The expression of lymphorganogenic factors and molecules required for immunoglobulin production was measured by using real-time PCR, and their localization was analyzed by means of immunohistochemistry and immunofluorescence. The phenotype of follicular helper T cells was analyzed by performing flow cytometry. Immunoglobulin levels were quantified by using the Bio-Plex assay or ImmunoCAP system. Nasal tissue explants were challenged ex vivo with Dermatophagoides pteronyssinus group 1 (Der p 1), and the expression of Iε-Cμ and Iε-Cγ circle transcripts was detected by using seminested PCR. Increased formation of eLTs with germinal center-like structures was discovered in patients with eosinophilic (20.69%) and noneosinophilic (17.31%) CRSwNP compared with that in patients with chronic rhinosinusitis without nasal polyps (5.66%) and control subjects (3.70%). The presence of eLTs was associated with increased expression of lymphorganogenic and inflammatory chemokines and cytokines, as well as their receptors. The expression of molecules required for immunoglobulin production, generation of follicular helper T cells, and production of IgE in eosinophilic polyps and IgG and IgA in both eosinophilic and noneosinophilic polyps were predominantly upregulated in patients with eLTs. After Der p 1 challenge ex vivo, Iε-Cμ transcript was detected only in eosinophilic polyps with eLTs but not in polyps without eLTs and noneosinophilic polyps. eLTs might support local immunoglobulin production and therefore significantly contribute to the development of CRSwNP. Copyright © 2017 American Academy of

  17. Clinical features in accelerated phase of chronic myeloid leukemia

    International Nuclear Information System (INIS)

    Naqi, N.; Ayub, M.

    2001-01-01

    Objective: To identify the clinical indicators of accelerated phase in chronic myeloid leukemia (CML) diagnosed on hematological findings. Design: An observational and prospective study. Place and Duration of Study: The study was conducted at Oncology department of Combined Military Hospital, Rawalpindi and Armed Forces Institute of Pathology from April 1998 to April 1999. Subjects and Methods: The study on 51 patients of Philadelphia positive CML in chronic phase and on hydroxyurea therapy were carried out. Clinical features and hematological parameters in the peripheral blood examination were recorded and statistical analysis carried out to document reliable clinically indicators of accelerated phase of CML in reference to those reported in the literature. Results: Clinical, presence of unexplained fever, re-enlargement of spleen after successful regression with hydroxyurea therapy, and bleeding diathesis were found to be statistically significant pointers of progression into accelerated phase of CML. In the hematological features, with the exception of peripheral basophilia, the findings in the peripheral blood were consistent with those reported in the literature. Conclusion: It is concluded that the occurrences of the clinical features in the follow-up of chronic myeloid leukemia patients herald the accelerated phase of the disease. (author)

  18. Obinutuzumab is Effective in Chronic Lymphocytic Leukemia and Rheumatoid Arthritis After Rituximab Failure: A Case Report

    OpenAIRE

    Lachowiez, Curtis; Deodhar, Atul; Kozin, Eliana; Spurgeon, Stephen

    2017-01-01

    Patient: Male, 68 Final Diagnosis: Chronic lymphocytic leukemia Symptoms: Arthritis Medication: ? Clinical Procedure: ? Specialty: Oncology Objective: Rare co-existance of disease or pathology Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia affecting older adults. As such, many of these patients suffer from co-existing disease states, and the provider must take these comorbidities into account when determining a treatment regimen. The widespread use of monoclonal an...

  19. Activated allogeneic NK cells preferentially kill poor prognosis B-cell chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Diego Sanchez-Martinez

    2016-10-01

    Full Text Available Mutational status of TP53 together with expression of wild type (wt IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL patients. Adoptive cell therapy using allogeneic HLA mismatched Natural Killer (NK cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs the most effective stimulus to activate NK cells. Here we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell activating receptors (NKG2D and NCRs and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.□

  20. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells.

    Science.gov (United States)

    Sánchez-Martínez, Diego; Lanuza, Pilar M; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV ) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.

  1. Aureobasidium pullulans infection in a patient with chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Leonardo Rodrigues de Oliveira

    2013-09-01

    Full Text Available Saprophytic fungi are being increasingly recognized as etiologic agents of mycoses in immunosuppressed patients. We report a case of subcutaneous infiltration by Aureobasidium pullulans, likely due to traumatic inoculation, in a neutropenic patient during chemotherapy for chronic lymphocytic leukemia. The patient was treated with amphotericin B deoxycholate but was subsequently switched to itraconazole, which improved the lesion. This case highlights the importance of considering unusual fungal infections in critically ill patients such as those who are immunosuppressed due to chemotherapy. Diagnostic techniques and effective antifungal therapy have improved the prognosis of these cases.

  2. Current trends in molecular diagnostics of chronic myeloid leukemia.

    Science.gov (United States)

    Vinhas, Raquel; Cordeiro, Milton; Pedrosa, Pedro; Fernandes, Alexandra R; Baptista, Pedro V

    2017-08-01

    Nearly 1.5 million people worldwide suffer from chronic myeloid leukemia (CML), characterized by the genetic translocation t(9;22)(q34;q11.2), involving the fusion of the Abelson oncogene (ABL1) with the breakpoint cluster region (BCR) gene. Early onset diagnosis coupled to current therapeutics allow for a treatment success rate of 90, which has focused research on the development of novel diagnostics approaches. In this review, we present a critical perspective on current strategies for CML diagnostics, comparing to gold standard methodologies and with an eye on the future trends on nanotheranostics.

  3. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Herman, S E M; Niemann, C U; Farooqui, M

    2014-01-01

    Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further...... investigation. Here we report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes (LNs), spleen and bone marrow, assessed phenotypic changes of circulating cells and measured whole-blood viscosity. With just one dose of ibrutinib, the average...

  4. Chronic myelogenous leukemia: molecular monitoring in clinical practice

    Directory of Open Access Journals (Sweden)

    N. R. Ryabchikova

    2013-01-01

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

  5. T-lineage blast crisis of chronic myelogenous leukemia: simple record of 4 cases

    Directory of Open Access Journals (Sweden)

    Kartika W. Taroeno-Hariadi

    2005-09-01

    Full Text Available Blast crisis (BC transformation in chronic myelogenous leukemia (CML can involve each differentiation lineage of the hematopoietic system, i.e. granulocyte, monocyte, erythrocyte, megakaryocyte, and lymphocyte lineage. The lymphoid blast crisis (BC leukemia cells usually belong to B-lineage, commonly having the phenotype of Pre-B stage of the B-lineage, in which cell-surface immunoglobulin (sIg is not yet expressed. In contrast, T-lineage BC of CML is extremely rare. The objective of this study is to describe the fenotype, fusion transcript of bcr-abl, TdT, and cytoplasmic CD3 in T-lineage BC CML cases. Case report study. This report shows a simple summary of 4 cases of T-lineage BC of CML which have been collected in the phenotypic and genotypic analysis study for 17 years (1987-2004. In all cases, the chromosomal analysis revealed the presence of t(9;22(q34;q11 at presentation. Cell surface analysis were done at diagnosis. Cases’ mononuclear cells stored as 10% DMSO were retrieved to be performed reverse transcription (RT PCR BCR-ABL multiplex to demonstrate the presence of the fusion transcript of bcr-abl. RT-PCR was also performed for detecting the expression of cytoplasmic CD3ε and terminal deoxynucleotydil transferase (TdT. The results of cell surface antigen (CSA at presentation showed that 1 case was CD7+, CD5-, and CD2-; 1 case CD7+, CD5+, and CD2-; and 2 cases CD7+, CD5+ and CD2+ indicating that all these T-lineage BC of CML cells show the phenotype of pre-(pro- thymic stage phenotype. In the present study, two cases showed b2a2, one e1a2, and one negative bcr-abl transcript. The RT-PCR revealed the presence of CD3ε mRNA in all cases, and TdT mRNA in only one case. These results can constitute a basis for the future analysis of T-lineage BC of CML from now on. (Med J Indones 2005; 14: 184-9Keywords: chronic myelogenous leukemia (CML, blastic crisis (BC, T-lineage, bcr-abl fusion gene, CDε, TdT

  6. Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia.

    Science.gov (United States)

    Fiorcari, Stefania; Maffei, Rossana; Audrito, Valentina; Martinelli, Silvia; Ten Hacken, Elisa; Zucchini, Patrizia; Grisendi, Giulia; Potenza, Leonardo; Luppi, Mario; Burger, Jan A; Deaglio, Silvia; Marasca, Roberto

    2016-10-04

    In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of ibrutinib on monocyte/macrophage population in CLL.

  7. Ibrutinib: a new frontier in the treatment of chronic lymphocytic leukemia by Bruton's tyrosine kinase inhibition.

    Science.gov (United States)

    Dias, Ajoy Lawrence; Jain, Dharamvir

    2013-12-01

    Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of nonfunctional mature B cells in blood, bone marrow and lymphoid tissues. In the last decade, our understanding of CLL and consequently our diagnostic and therapeutic approaches have changed dramatically. Conventional fludarabine based chemotherapy has led to improved disease response and longer survival in young patients with CLL. However its application in elderly patients has been restricted by substantial myelosuppression and infection. Treatment of CLL is now moving towards targeted therapy. The success of new class of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further search for treatment agents with novel targets to inhibit. The B cell receptor activating pathway involving the Bruton's tyrosine kinase (BTK) is crucial in B cell production and maintenance and is an attractive therapeutic target. Ibrutinib is an oral covalent inhibitor of the BTK pathway that induces apoptosis of B cells. Early phase studies with Ibrutinib either as a single agent or in combination regimens have shown promising results with an excellent safety profile in patients with high-risk, refractory or relapsed CLL and elderly treatment-naïve patients. This review summarizes the current knowledge of Ibrutinib in the treatment of CLL.

  8. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

    Science.gov (United States)

    Berndt, Sonja I.; Camp, Nicola J.; Skibola, Christine F.; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S.; Smedby, Karin E.; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S.; Lan, Qing; Teras, Lauren R.; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R.; Hartge, Patricia; Purdue, Mark P.; Birmann, Brenda M.; Vajdic, Claire M.; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G.; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G.; Shanafelt, Tait D.; Novak, Anne J.; Kay, Neil E.; Liebow, Mark; Cunningham, Julie M.; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T.; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A.; Diver, W Ryan; Link, Brian K.; Weiner, George J.; Conde, Lucia; Bracci, Paige M.; Riby, Jacques; Arnett, Donna K.; Zhi, Degui; Leach, Justin M.; Holly, Elizabeth A.; Jackson, Rebecca D.; Tinker, Lesley F.; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G.; Achenbach, Sara J.; Vachon, Celine M.; Goldin, Lynn R.; Strom, Sara S.; Leis, Jose F.; Weinberg, J. Brice; Caporaso, Neil E.; Norman, Aaron D.; De Roos, Anneclaire J.; Morton, Lindsay M.; Severson, Richard K.; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María- Dolores; Vermeulen, Roel C. H.; Travis, Ruth C.; Southey, Melissa C.; Milne, Roger L.; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R.; Villano, Danylo J.; Maria, Ann; Spinelli, John J.; Gascoyne, Randy D.; Connors, Joseph M.; Bertrand, Kimberly A.; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M.; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E.; Snowden, John A.; Wright, Josh; Fraumeni, Joseph F.; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R.; Chanock, Stephen J.; Rothman, Nathaniel; Slager, Susan L.

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility. PMID:26956414

  9. Prevention of Resistance in Chronic Myeloid Leukemia: the role of combination therapy

    NARCIS (Netherlands)

    W. Deenik (Wendy)

    2010-01-01

    textabstractChronic myeloid leukemia (CML) is a rare disease with a worldwide incidence of approximately 1-2 cases per 100,000 individuals. Chronic myeloid leukemia occurs slightly more frequently in men than in women. The median age at diagnosis is approximately 60 years, and although the incidence

  10. Acute myeloid and chronic lymphoid leukaemias and exposure to low-level benzene among petroleum workers

    Science.gov (United States)

    Rushton, L; Schnatter, A R; Tang, G; Glass, D C

    2014-01-01

    Background: High benzene exposure causes acute myeloid leukaemia (AML). Three petroleum case–control studies identified 60 cases (241 matched controls) for AML and 80 cases (345 matched controls) for chronic lymphoid leukaemia (CLL). Methods: Cases were classified and scored regarding uncertainty by two haematologists using available diagnostic information. Blinded quantitative benzene exposure assessment used work histories and exposure measurements adjusted for era-specific circumstances. Statistical analyses included conditional logistic regression and penalised smoothing splines. Results: Benzene exposures were much lower than previous studies. Categorical analyses showed increased ORs for AML with several exposure metrics, although patterns were unclear; neither continuous exposure metrics nor spline analyses gave increased risks. ORs were highest in terminal workers, particularly for Tanker Drivers. No relationship was found between benzene exposure and risk of CLL, although the Australian study showed increased risks in refinery workers. Conclusion: Overall, this study does not persuasively demonstrate a risk between benzene and AML. A previously reported strong relationship between myelodysplastic syndrome (MDS) (potentially previously reported as AML) at our study's low benzene levels suggests that MDS may be the more relevant health risk for lower exposure. Higher CLL risks in refinery workers may be due to more diverse exposures than benzene alone. PMID:24357793

  11. Total lymphoid irradiation preceding bone marrow transplantation for chronic myeloid leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    James, N D; Apperley, J F; Kam, K C; Mackinnon, S; Goldman, J M; Goolden, A W.G.; Sikora, K [Royal Postgraduate Medical School, London (UK)

    1989-03-01

    Between August 1985 and October 1987 35 patients with chronic myeloid leukaemia (CML) were treated by high dose chemotherapy, total body irradiation (TBI) (1000 or 1200 cGy, n=31) and total lymphoid irradiation (TLI) (800 or 600 cGy, n=35) preceding allogeneic bone marrow transplantation (BMT). Both TBI and TLI were given at 200 cGy/fraction. Twenty-three patients had HLA-identical sibling donors, nine patients had HLA-matched but unrelated donors, and three partially HLA-mismatched donors. Twenty-two patients received T-cell depleted marrow. TLI did not add greatly to the toxicity. Four patients had recurrent leukaemia before engraftment was evaluable. The other 31 patients engrafted and no graft failed. Twenty-two patients survive at a median time from transplant of 305 days (range 81-586 days). Fourteen have no evidence of disease; eight have or had only cytogenetic evidence of leukaemia. It is concluded that addition of TLI to pretransplant immunosuppression increases the probability of reliable engraftment in patients receiving T-cell depleted marrow. This is not associated with significantly increased toxicity. (author).

  12. Total lymphoid irradiation preceding bone marrow transplantation for chronic myeloid leukaemia

    International Nuclear Information System (INIS)

    James, N.D.; Apperley, J.F.; Kam, K.C.; Mackinnon, S.; Goldman, J.M.; Goolden, A.W.G.; Sikora, K.

    1989-01-01

    Between August 1985 and October 1987 35 patients with chronic myeloid leukaemia (CML) were treated by high dose chemotherapy, total body irradiation (TBI) (1000 or 1200 cGy, n=31) and total lymphoid irradiation (TLI) (800 or 600 cGy, n=35) preceding allogeneic bone marrow transplantation (BMT). Both TBI and TLI were given at 200 cGy/fraction. Twenty-three patients had HLA-identical sibling donors, nine patients had HLA-matched but unrelated donors, and three partially HLA-mismatched donors. Twenty-two patients received T-cell depleted marrow. TLI did not add greatly to the toxicity. Four patients had recurrent leukaemia before engraftment was evaluable. The other 31 patients engrafted and no graft failed. Twenty-two patients survive at a median time from transplant of 305 days (range 81-586 days). Fourteen have no evidence of disease; eight have or had only cytogenetic evidence of leukaemia. It is concluded that addition of TLI to pretransplant immunosuppression increases the probability of reliable engraftment in patients receiving T-cell depleted marrow. This is not associated with significantly increased toxicity. (author)

  13. Prevalence and characteristics of central nervous system involvement by chronic lymphocytic leukemia.

    Science.gov (United States)

    Strati, Paolo; Uhm, Joon H; Kaufmann, Timothy J; Nabhan, Chadi; Parikh, Sameer A; Hanson, Curtis A; Chaffee, Kari G; Call, Timothy G; Shanafelt, Tait D

    2016-04-01

    Abroad array of conditions can lead to neurological symptoms in chronic lymphocytic leukemia patients and distinguishing between clinically significant involvement of the central nervous system by chronic lymphocytic leukemia and symptoms due to other etiologies can be challenging. Between January 1999 and November 2014, 172 (4%) of the 4174 patients with chronic lymphocytic leukemia followed at our center had a magnetic resonance imaging of the central nervous system and/or a lumbar puncture to evaluate neurological symptoms. After comprehensive evaluation, the etiology of neurological symptoms was: central nervous system chronic lymphocytic leukemia in 18 patients (10% evaluated by imaging and/or lumbar puncture, 0.4% overall cohort); central nervous system Richter Syndrome in 15 (9% evaluated, 0.3% overall); infection in 40 (23% evaluated, 1% overall); autoimmune/inflammatory conditions in 28 (16% evaluated, 0.7% overall); other cancer in 8 (5% evaluated, 0.2% overall); and another etiology in 63 (37% evaluated, 1.5% overall). Although the sensitivity of cerebrospinal fluid analysis to detect central nervous system disease was 89%, the specificity was only 42% due to the frequent presence of leukemic cells in the cerebrospinal fluid in other conditions. No parameter on cerebrospinal fluid analysis (e.g. total nucleated cells, total lymphocyte count, chronic lymphocytic leukemia cell percentage) were able to offer a reliable discrimination between patients whose neurological symptoms were due to clinically significant central nervous system involvement by chronic lymphocytic leukemia and another etiology. Median overall survival among patients with clinically significant central nervous system chronic lymphocytic leukemia and Richter syndrome was 12 and 11 months, respectively. In conclusion, clinically significant central nervous system involvement by chronic lymphocytic leukemia is a rare condition, and neurological symptoms in patients with chronic lymphocytic

  14. ACTIVATION MECHANISMS OF GUT-ASSOCIATED LYMPHOID TISSUE UNDER CHRONIC SOCIAL STRESS CONDITIONS

    Directory of Open Access Journals (Sweden)

    A. M. Kamyshnyi

    2015-01-01

    Full Text Available Stress-induced immune disregulation is a risk factor of autoimmune and inflammatory diseases, but, so far, the mechanisms for this effect are not fully known. Expression levels of specific mRNAs were assessed in gut-associated lymphoid tissue (GALT from Wistar rats subjected to chronic social stress (CSS. Gene expression was evaluated for NR3C1, Adrβ2, as well as IL-1β, IL-17α pro-inflammatory cytokines, and Nlrp, an inflammasome gene. Under the CSS conditions, we have shown altered distribution of RORγt +, FoxP3+, LMP2+, XBP1+ lymphocytes in GALT.The experiments were carried out with female Wistar rats aged 5–6 months. Specific mRNA expression for the target genes was determined by means of real-time PCR performed in a CFX96™ thermocycler («BioRadLaboratories, Inc»,USA. Relative levels of a target gene expression were quantified by the ΔΔCt method, being compared with rat GAPDH reference gene expression. Statistical analysis was performed with available «BioRad СFX Manager 3.1» software. Specific monoclonal rat antibodes were used for detection of immunopositive lymphocytes by means of indirect immunofluorescence technique.CSS development leads to decreased levels of mRNA expression for Nr3c1 and Adrβ2-genes in the GALT cells, being accompanied with unidirectional changes, i.e., increased transcription of pro-inflammatory cytokine mRNAs (IL-1β, IL-17α and Nlrp3-inflammasome genes. These changes are accompanied by decreased FoxP3+/RORγt + cell ratio and predominant Th17 differentiation accompanied by suppressor failure. In addition, CSS development was characterized by unidirectional tendency for increasing total number of LMP2+ lymphocytes and reduced ХВР1+ cell population density in lymphoid structures of rat ileum.The events observed in GALT cell populations under CSS conditions are opposing classical paradigm of the stress response. The CSS-associated effects do not promote immunosuppression, however, are able to cause

  15. Management of chronic myeloid leukemia in blast crisis.

    Science.gov (United States)

    Saußele, S; Silver, Richard T

    2015-04-01

    Due to the high efficacy of BCR-ABL tyrosine kinase inhibition (TKI) in chronic phase (CP) chronic myeloid leukemia (CML), the frequency of blast crisis (BC) is greatly reduced compared to the pre-TKI era. However, TKI treatment of BC has only marginally improved the number of favorable responses, including remissions, which for the most part have only been transitory. Occasionally, they provide a therapeutic window to perform an allogeneic stem cell transplantation (allo-SCT). The challenge remains to improve management of BC with the limited options available. We review and summarize articles pertaining to the treatment of BC CML published after 2002. Additionally, we will discuss whether there is a need for a new definition of BC and/or treatment failure.

  16. Therapy for chronic myeloid leukemia: Past, present and future

    International Nuclear Information System (INIS)

    Tothova, E.

    2012-01-01

    Although chronic myeloid leukemia (CML) was probably first described in the early nineteenth century, there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 1960. Subsequent important landmarks were the recognition that the Ph chromosome results from a t(9;22) translocation and subsequently of BCR-ABL fusion gene. Between 1980 and 2000, allo grafting, despite the risks of morbidity and mortality, was the recommended initial treatment for younger patients with HLA-matched donors. Therapy has now been „revolutionized“ by the introduction on imatinib mesylate (IM), the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998. This paper will attempt to define approaches to management of the newly diagnosed patient with CML in chronic phase that are favored in 2012, but it is most probable these recommendations will need to be updated as further experience in gained with the use of TKI. (author)

  17. Management of Advanced-Phase Chronic Myelogenous Leukemia.

    Science.gov (United States)

    Radich, Jerald P

    2016-05-01

    Chronic myelogenous leukemia represents the poster child of successful precision medicine in cancer, with amazing survival results achieved with targeted tyrosine kinase inhibitors (TKIs) in many patients with chronic-phase disease. Unfortunately, however, this good news has not extended to patients in blast crisis, for whom survival has not clearly been improved with TKIs. During his presentation at the NCCN 21st Annual Conference, Jerald P. Radich, MD, briefly explored the biology behind advanced-stage disease and several of the molecular findings in disease progression. He also reviewed some of the therapeutic options in advanced disease, emphasizing that transplantation, although fraught with some difficulties, offers the best long-term prognosis for patients in blast crisis. Copyright © 2016 by the National Comprehensive Cancer Network.

  18. Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia?

    Directory of Open Access Journals (Sweden)

    Avital F. Barak

    2011-12-01

    Full Text Available The outcome and quality of life of chronic myeloid leukemia (CML patients has remarkably changed with the treatment of tyrosine kinase inhibitors (TKIs. Currently, hematopoietic stem cell transplantation (HSCT is considered mainly as a third line salvage therapy in cases of TKIs resistance or intolerance. Here we describe a patient with chronic phase CML who developed both resistance and late occurrence of s severe thrombocytopenia on first and second generation TKIs and eventually underwent HSCT. Although the mechanism of the myelosuppression is not fully understood, we showed for the first time the development of dose dependent platelet antibodies in the presence of TKIs, suggesting the possibility of TKIs induced thrombocytopenia. Our case emphasizes that late development of severe myelosuppression during imatinib treatment is probably an important indication for consideration of early HSCT.

  19. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab

    Directory of Open Access Journals (Sweden)

    Smolej L

    2014-12-01

    Full Text Available Lukáš Smolej 4th Department of Internal Medicine – Hematology, University Hospital Hradec Králové and Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic Abstract: Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101 is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL. Keywords: chronic lymphocytic leukemia, anti-CD20 antibodies, chlorambucil, rituximab, ofatumumab, obinutuzumab, overall survival

  20. Morphologic identification of atypical chronic lymphocytic leukemia by digital microscopy.

    Science.gov (United States)

    Marionneaux, S; Maslak, P; Keohane, E M

    2014-08-01

    Atypical chronic lymphocytic leukemia (aCLL) is a morphologic variant found in approximately 25% of patients with chronic lymphocytic leukemia (CLL). Although aCLL has a more aggressive course compared to typical CLL (tCLL), it is not usually reported. This retrospective study used digital microscopy to morphologically classify CLL patients as aCLL or tCLL, and determined the prevalence of prognostic markers in each group. CellaVision AB (Lund, Sweden) was used to evaluate lymphocyte morphology on archived blood films of 97 CLL patients, and results of their prognostic marker analysis at diagnosis were obtained. The unpaired t-test, Chi-square, or Fisher's Exact test were used for statistical analysis. 27% of CLL cases were morphologically classified as aCLL. The aCLL group had a higher prevalence of trisomy 12, unmutated IgVH, and CD38 expression (markers associated with poor prognosis), and a lower prevalence of 13q14 deletions compared to tCLL; this was statistically significant. Using digital imaging to identify aCLL is feasible, economical, and may provide clinically relevant prognostic information at diagnosis and during periodic monitoring. Further study of a larger number of patients is needed to assess the clinical utility of reporting aCLL morphology. © 2013 John Wiley & Sons Ltd.

  1. Juvenile Myelomonocytic Leukemia

    Science.gov (United States)

    ... myeloproliferative neoplasms, leukemia , and other conditions . Chronic Myelomonocytic Leukemia Key Points Chronic myelomonocytic leukemia is a disease ... chance of recovery) and treatment options. Chronic myelomonocytic leukemia is a disease in which too many myelocytes ...

  2. The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia.

    Science.gov (United States)

    Manzoni, Delphine; Catallo, Régine; Chebel, Amel; Baseggio, Lucile; Michallet, Anne-Sophie; Roualdes, Olivier; Magaud, Jean-Pierre; Salles, Gilles; Ffrench, Martine

    2016-08-01

    New B-cell receptor-targeted therapies such as ibrutinib, a Bruton tyrosine kinase inhibitor, are now proposed for lymphoid pathologies. The putative benefits of its combination with glucocorticoids were evaluated here. We compared the effects of dexamethasone (DXM), ibrutinib and their in vitro combination on proliferation and metabolic stress markers in stimulated normal B-lymphocytes and in malignant lymphocytes from chronic lymphocytic leukemia (CLL) patients. In both cellular models, cell cycle progression was globally inhibited by DXM and/or ibrutinib. This inhibition was significantly amplified by DXM addition to ibrutinib and was related to a significant decrease in the expression of the cell cycle regulatory proteins CDK4 and cyclin E. Apoptosis increased especially with DXM/ibrutinib combination and was associated with a significant decrease in Mcl-1 expression. Treatment effects on metabolic stress were evaluated by DNA damage recognition after 53BP1 foci labeling. The percentage of cells with more than five 53BP1 foci decreased significantly with ibrutinib in normal and CLL lymphocytes. This decrease was strongly reinforced, in CLL, by DXM addition. Our data indicated that, in vitro, DXM potentiated antiproliferative effects of ibrutinib and decreased DNA damage in lymphoid B-cells. Thus their combination may be proposed for CLL treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. [Monoclonal antibodies ICO-02 to blast cell antigens in patients with chronic myeloleukemia in blast crisis].

    Science.gov (United States)

    Baryshnikov, A Iu

    1984-01-01

    Mice were immunized with blood cells of a patient with chronic granulocytic leukemia, and their cells were subsequently used for the preparation of hybridoma ICO-02. This hybridoma is continuously producing monoclonal antibodies which reacted with cells in 4 out of 13 patients with blastic crisis of chronic granulocytic leukemia and in 6 out of 38 patients with acute lymphoblastic leukemia. Antibodies reacted with blast cells in 2 out of 3 patients with undifferentiated blastic crisis of chronic myelocytic leukemia and in 2 out of 5 patients with lymphoid variant of blastic crisis of chronic granulocytic leukemia. Cells of 6 patients with acute lymphoblastic leukemia which reacted with the monoclonal antibodies had immunological markers of T lymphocytes bone-marrow precursors. Monoclonal antibodies did not react with cells of blood and bone marrow from healthy people and from patients with chronic lymphocytic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute monoblastic leukemia and lymphosarcoma.

  4. Dasatinib in the treatment of imatinib refractory chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Radhakrishnan Ramchandren

    2009-05-01

    Full Text Available Radhakrishnan Ramchandren, Charles A SchifferDivision of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USAAbstract: The development of imatinib for the treatment of chronic myeloid leukemia (CML has proven to be an example of medical success in the era of targeted therapy. However, imatinib resistance or intolerance occurs in a substantial number of patients. Additionally, patients who have progressed beyond the chronic phase of CML do relatively poorly with imatinib therapy. Mechanisms of imatinib resistance include BCR-ABL point mutations resulting in decreased imatinib binding, as well as mutation-independent causes of resistance such as SRC family kinase dysregulation, BCR-ABL gene amplification, drug influx/efflux mechanisms and other poorly understood processes. The options for therapy in these patients include stem cell transplantation, imatinib dose escalation as well as the use of second-generation tyrosine kinase inhibitors. Dasatinib is a second-generation multi-kinase inhibitor with several theoretical and mechanistic advantages over imatinib. Moreover, several studies have evaluated dasatinib in patients who have progressed on imatinib therapy with encouraging results. Other novel agents such as mTOR inhibitors, bosutinib and INNO 406 have also shown promise in this setting. Although treatment options have increased, the choice of second-line therapy in patients with CML is influenced by concerns surrounding the duration of response as well as toxicity. Consequently, there is no agreed upon optimal second-line agent. This paper reviews the current data and attempts to address these issues. Keywords: chronic myeloid leukemia (CML, dasatinib, imatinib, resistance (imatinib resistance, nilotinib, tyrosine kinase inhibitor

  5. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

    Science.gov (United States)

    Deininger, Michael W.; Rosti, Gianantonio; Hochhaus, Andreas; Soverini, Simona; Apperley, Jane F.; Cervantes, Francisco; Clark, Richard E.; Cortes, Jorge E.; Guilhot, François; Hjorth-Hansen, Henrik; Hughes, Timothy P.; Kantarjian, Hagop M.; Kim, Dong-Wook; Larson, Richard A.; Lipton, Jeffrey H.; Mahon, François-Xavier; Martinelli, Giovanni; Mayer, Jiri; Müller, Martin C.; Niederwieser, Dietger; Pane, Fabrizio; Radich, Jerald P.; Rousselot, Philippe; Saglio, Giuseppe; Saußele, Susanne; Schiffer, Charles; Silver, Richard; Simonsson, Bengt; Steegmann, Juan-Luis; Goldman, John M.; Hehlmann, Rüdiger

    2013-01-01

    Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved. PMID:23803709

  6. Diagnosis of chronic myeloid and acute lymphocytic leukemias by detection of leukemia-specific mRNA sequences amplified in vitro

    International Nuclear Information System (INIS)

    Kawasaki, E.S.; Clark, S.S.; Coyne, M.Y.; Smith, S.D.; Champlin, R.; Witte, O.N.; McCormick, F.P.

    1988-01-01

    The Philadelphia chromosome is present in more than 95% of chronic myeloid leukemia patients and 13% of acute lymphocytic leukemia patients. The Philadelphia translocation, t(9;22), fuses the BCR and ABL genes resulting in the expression of leukemia-specific, chimeric BCR-ABL messenger RNAs. To facilitate diagnosis of these leukemias, the authors have developed a method of amplifying and detecting only the unique mRNA sequences, using an extension of the polymerase chain reaction technique. Diagnosis of chronic myeloid and acute lymphocytic leukemias by this procedure is rapid, much more sensitive than existing protocols, and independent of the presence or absence of an identifiable Philadelphia chromosome

  7. Treatment of blastic transformation of chronic granulocytic leukemia by chemotherapy, total body irradiation and infusion of cryopreserved autologous marrow

    Energy Technology Data Exchange (ETDEWEB)

    Buckner, C D; Stewart, P; Clift, R A; Fefer, A; Neiman, P E; Singer, J; Storb, R; Thomas, E D [Washington Univ., Seattle (USA). School of Medicine; The United States Public Health Service Hospital; Providence Medical Center, and the Fred Hutchinson Cancer Research Center, Seattle, Washington, USA)

    1978-01-01

    We have previously reported attempts to reestablish the chronic phase of chronic granulocytic leukemia (CGL), in two patients with blastic transrormation, utilizing intensive therapy followed by the infusion of cryopreserved autologous marrow. This approach has now been attempted in a total of seven patients. Marrow was harvested on single or multiple occasions during the chronic phase of CGL and cryopreserved in 10% dimethylsulfoxide. All patients were treated with cyclophosphamide, 120 mg/kg, plus 1,000 rad of total body irradiation followed by infusion of stored marrow. Two patients failed to achieve marrow repopulation and died of infection after 29 and 48 days. Three patients had partial marrow recovery. Two of these achieved repopulation of myeloid, erythroid, and lymphoid elements but did not recover platelet function; one died of hemorrhage on day 55, and one died of cytomegalovirus interstitial pneumonitis on day 58. A third patient had delayed engraftment of all cell elements, most prominently lymphocytes, and died after 84 days of an iodopathic interstitial pneumonitis. Two patients achieved prompt and complete reestablishment of the chronic phase of CGL. One died on day 72 with a fungal pheumonitis and one developed blastic transformation within 4 months. These preliminary results indicate that this approach to the treatment of blastic transformation of CGL is feasible but difficult. Improvements in results may be achieved by more frequent storage of marrow and pheripheral blood stem cells and lymphocytes and further advances in pretransplant therapy.

  8. Report of chronic myeloid leukemia SMS Medical College Hospital, Jaipur.

    Science.gov (United States)

    Malhotra, Hemant; Sharma, Rajesh; Singh, Yogender; Chaturvedi, Hemant

    2013-07-01

    This is a retrospective analysis of patients of chronic myeloid leukemia (CML) registered and under treatment at the Leukemia Lymphoma Clinic at the Birla Cancer Center, SMS Medical College Hospital, Jaipur. Approximately, two-thirds of the patients are getting imatinib mesylate (IM) through the Glivec International Patient Assistance Program while the rest are on generic IM. In addition to comparison of hematological and molecular responses in the Glivec versus the genetic group, in this analysis, an attempt is also made to assess the socio-economic (SE) status of the patients and its effect on the response rates. Of the 213 patients studied, most (28.6%) are in the age group between 30 years and 40 years and the mean age of the patients in 39 years, a good decade younger that in the west. There is a suggestion that patients in lower SE class present with higher Sokal scores and with more disease burden. Possibly hematological responses are similar with both Glivec and generic IM. No comment can be made with regards to molecular response between the two groups as a significant number of patients in the Glivec arm (42%) do not have molecular assessment because of economic reasons. CML is a common and challenging disease in the developing world with patients presenting at an earlier age with more advanced disease. SE factors play a significant role in therapy and disease monitoring decision making and may impact on response rates and prognosis.

  9. Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia

    International Nuclear Information System (INIS)

    Patnaik, M M; Tefferi, A

    2016-01-01

    Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder associated with peripheral blood monocytosis and an inherent tendency to transform to acute myeloid leukemia. CMML has overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms. Clonal cytogenetic changes are seen in ~30%, whereas gene mutations are seen in >90% of patients. Common cytogenetic abnormalities include; trisomy 8, -Y, -7/del(7q), trisomy 21 and del(20q), with the Mayo–French risk stratification effectively risk stratifying patients based on cytogenetic abnormalities. Gene mutations frequently involve epigenetic regulators (TET2 ~60%), modulators of chromatin (ASXL1 ~40%), spliceosome components (SRSF2 ~50%), transcription factors (RUNX1 ~15%) and signal pathways (RAS ~30%, CBL ~15%). Of these, thus far, only nonsense and frameshift ASXL1 mutations have been shown to negatively impact overall survival. This has resulted in the development of contemporary, molecularly integrated (inclusive of ASXL1 mutations) CMML prognostic models, including Molecular Mayo Model and the Groupe Français des Myélodysplasies model. Better understanding of the prevalent genetic and epigenetic dysregulation has resulted in emerging targeted treatment options for some patients. The development of an integrated (cytogenetic and molecular) prognostic model along with CMML-specific response assessment criteria are much needed future goals

  10. Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia.

    Science.gov (United States)

    Fabbri, Giulia; Holmes, Antony B; Viganotti, Mara; Scuoppo, Claudio; Belver, Laura; Herranz, Daniel; Yan, Xiao-Jie; Kieso, Yasmine; Rossi, Davide; Gaidano, Gianluca; Chiorazzi, Nicholas; Ferrando, Adolfo A; Dalla-Favera, Riccardo

    2017-04-04

    Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates MYC via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of NOTCH1 in CLL pathogenesis, and have direct implications for specific therapeutic targeting.

  11. Trends in adult leukemia incidence and survival in Denmark, 1943-2003

    DEFF Research Database (Denmark)

    Thygesen, Lau Caspar; Nielsen, Ove Juul; Johansen, Christoffer

    2009-01-01

    The etiology of leukemia is largely unknown. Ecological data indicating trends in incidence and survival can provide information about changes in risk factors, can reflect underlying changes in diagnostic classification, and can measure therapeutic advances. From the records of the Danish Cancer...... Registry with registration starting from 1943, we calculated age-specific, period-specific, and age-standardized (world standard) incidence rates of chronic lymphoid leukemia (CLL), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML) for persons above the age...... of 18. Kaplan-Meier survival curves and median survival times were calculated. Between 1943 and 2003, there were 26,036 cases of leukemia reported. The age-specific incidence rates of CLL, CML, and AML were higher for older men and women, while the incidence rates of ALL by age were more homogeneous...

  12. Hairy cell leukemia-variant

    International Nuclear Information System (INIS)

    Quadri, Mohammad I.; Al-Sheikh, Iman H.

    2001-01-01

    Hairy cell leukaemia variant is a very rare chronic lymphoproliferative disorder and is closely related to hairy cell leukemia. We hereby describe a case of hairy cell leukaemia variant for the first time in Saudi Arabia. An elderly Saudi man presented with pallor, massive splenomegaly, and moderate hepatomegaly. Hemoglobin was 7.7 g/dl, Platelets were 134 x109/l and white blood count was 140x10 9/l with 97% being abnormal lymphoid cells with cytoplasmic projections. The morphology, cytochemistry, and immunophenotype of the lymphoid cells were classical of hairy cell leukaemia variant. The bone marrow was easily aspirated and findings were consistent with hairy cell leukaemia variant. (author)

  13. Dasatinib for the treatment of chronic myeloid leukemia: patient selection and special considerations.

    Science.gov (United States)

    Keskin, Dilek; Sadri, Sevil; Eskazan, Ahmet Emre

    2016-01-01

    Dasatinib is one of the second-generation tyrosine kinase inhibitors used in imatinib resistance and/or intolerance, as well as in the frontline setting in patients with chronic myeloid leukemia-chronic phase, and also in patients with advanced disease. It is also utilized in Philadelphia chromosome-positive acute lymphocytic leukemia. While choosing the appropriate tyrosine kinase inhibitor (ie, dasatinib) for each individual patient, comorbidities and BCR-ABL1 kinase domain mutations should always be taken into consideration, among other things. This review mainly focuses on patient selection prior to dasatinib administration in the treatment of chronic myeloid leukemia.

  14. REGULATORY T-CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Giovanni D'arena

    2012-08-01

    Full Text Available Regulatory T-cells (Tregs constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL. Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosis, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in either cancer and autoimmune disorders.

  15. Docosahexaenoic acid induces apoptosis in primary chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Romain Guièze

    2015-12-01

    Full Text Available Chronic lymphocytic leukemia is an indolent disorder with an increased infectious risk remaining one of the main causes of death. Development of therapies with higher safety profile is thus a challenging issue. Docosahexaenoic acid (DHA, 22:6 is an omega-3 fatty acid, a natural compound of normal cells, and has been shown to display antitumor potency in cancer. We evaluated the potential in vitro effect of DHA in primary CLL cells. DHA induces high level of in vitro apoptosis compared to oleic acid in a dose-dependent and time-dependent manner. Estimation of IC50 was only of 4.813 μM, which appears lower than those reported in solid cancers. DHA is highly active on CLL cells in vitro. This observation provides a rationale for further studies aiming to understand its mechanisms of action and its potent in vivo activity.

  16. The clinical safety of ibrutinib in chronic lymphocytic leukemia.

    Science.gov (United States)

    Molica, Stefano

    2015-10-01

    Ibrutinib , a targeted inhibitor of B-cell receptor signaling, achieved impressive clinical results for patients with chronic lymphocytic leukemia (CLL). These results allowed the approval of ibrutinib for the treatment of patients with CLL who have received at least one prior therapy and those with a 17p deletion regardless of line of therapy. Comprehensive data from either Phase I-II or randomized Phase III studies are analyzed in this article. In addition, we reviewed data on the prevalence and the clinical management of some peculiar toxicities ibrutinib related such as lymphocytosis, major bleeding and atrial fibrillation. Ibrutinib has radically changed the scenery of relapsed/refractory CLL treatment and established an important paradigm in the molecularly targeted approach of this disease. Discontinuation of ibrutinib is rarely due to adverse events related to the drug. Patients who discontinue treatment represent a challenge to the physicians because treatment options are very limited.

  17. Tetrasomy 8 in a patient with chronic lymphocytic leukemia.

    Science.gov (United States)

    de Oliveira, Fábio Morato; Brandão, Renata Amorim; Leite-Cueva, Sabrina Dias; de Paula Careta, Francisco; Simões, Belinda Pinto; Rego, Eduardo Magalhães; Falcão, Roberto Passetto

    2010-04-15

    We report a case of a 47-year-old man diagnosed with chronic lymphocytic leukemia (CLL) with two extra copies of chromosome 8. Classical cytogenetic analysis by the immunostimulatory combination of DSP30 and interleukin 2 showed tetrasomy of chromosome 8 in 60% of the metaphase cells (48,XY,+8,+8[12]/46,XY[8]). Spectral karyotype analysis confirmed the abnormality previously seen by G banding. Additionally, interphase fluorescence in situ hybridization using an LSI CEP 8 probe performed on peripheral blood cells without any stimulant agent showed tetrasomy of chromosome 8 in 54% of analyzed cells (108 of 200). To our knowledge, tetrasomy 8 as the sole chromosomal abnormality in CLL has not been previously described. The prognostic significance of tetrasomy 8 in CLL remains to be elucidated. However, the patient has been followed up in the outpatient hospital since 2004 without any therapeutic intervention and has so far remained stable. Copyright 2010 Elsevier Inc. All rights reserved.

  18. Immunological changes with kinase inhibitor therapy for chronic lymphocytic leukemia.

    Science.gov (United States)

    Pleyer, Christopher; Wiestner, Adrian; Sun, Clare

    2018-05-15

    Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment.

  19. Methylation status regulates lipoprotein lipase expression in chronic lymphocytic leukemia.

    Science.gov (United States)

    Abreu, Cecilia; Moreno, Pilar; Palacios, Florencia; Borge, Mercedes; Morande, Pablo; Landoni, Ana Inés; Gabus, Raul; Dighiero, Guillermo; Giordano, Mirta; Gamberale, Romina; Oppezzo, Pablo

    2013-08-01

    Among different prognostic factors in chronic lymphocytic leukemia (CLL), we previously demonstrated that lipoprotein lipase (LPL) is associated with an unmutated immunoglobulin profile and clinical poor outcome. Despite the usefulness of LPL for CLL prognosis, its functional role and the molecular mechanism regulating its expression are still open questions. Interaction of CLL B-cells with the tissue microenvironment favors disease progression by promoting malignant B-cell growth. Since tissue methylation can be altered by environmental factors, we investigated the methylation status of the LPL gene and the possibility that overexpression could be associated with microenvironment signals. Our results show that a demethylated state of the LPL gene is responsible for its anomalous expression in unmutated CLL cases and that this expression is dependent on microenvironment signals. Overall, this work proposes that an epigenetic mechanism, triggered by the microenvironment, regulates LPL expression in CLL disease.

  20. 3D protein-structure-oriented discovery of clinical relation across chronic lymphocytic leukemia patients

    DEFF Research Database (Denmark)

    Mochament, Konstantinos; Agathangelidis, Andreas; Polychronidou, Eleftheria

    2017-01-01

    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia with still unclear etiology. Indications of antigenic pressure have been hinted, using sequence and structure-based reasoning. The accuracy of such approaches, and in particular of the ones derived from 3D models obtained from t...

  1. Chronic myelomonocytic leukemia masquerading as cutaneous indeterminate dendritic cell tumor: Expanding the spectrum of skin lesions in chronic myelomonocytic leukemia.

    Science.gov (United States)

    Loghavi, Sanam; Curry, Jonathan L; Garcia-Manero, Guillermo; Patel, Keyur P; Xu, Jie; Khoury, Joseph D; Torres-Cabala, Carlos A; Nagarajan, Priyadharsini; Aung, Phyu P; Gibson, Bernard R; Goodwin, Brandon P; Kelly, Brent C; Korivi, Brinda R; Medeiros, L Jeffrey; Prieto, Victor G; Kantarjian, Hagop M; Bueso-Ramos, Carlos E; Tetzlaff, Michael T

    2017-12-01

    Chronic myelomonocytic leukemia (CMML) is a hematopoietic stem cell neoplasm exhibiting both myelodysplastic and myeloproliferative features. Cutaneous involvement by CMML is critical to recognize as it typically is a harbinger of disease progression and an increased incidence of transformation to acute myeloid leukemia. Cutaneous lesions of CMML exhibit heterogeneous histopathologic features that can be challenging to recognize as CMML. We describe a 67-year-old man with a 3-year history of CMML who had been managed on single-agent azacitidine with stable disease before developing splenomegaly and acute onset skin lesions. Examination of these skin lesions revealed a dense infiltrate of histiocytic cells morphologically resembling Langerhans type cells (lacking frank histopathologic atypia), and with the immunophenotype of an indeterminate cell histiocytosis (S100+ CD1a+ and langerin-). Given the history of CMML, next-generation sequencing studies were performed on the skin biopsy. These revealed a KRAS (p.G12R) mutation identical to that seen in the CMML 3 years prior, establishing a clonal relationship between the 2 processes. This case expands the spectrum for and underscores the protean nature of cutaneous involvement by CMML and underscores the importance of heightened vigilance when evaluating skin lesions of CMML patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Radotinib and its clinical potential in chronic-phase chronic myeloid leukemia patients: an update.

    Science.gov (United States)

    Eskazan, Ahmet Emre; Keskin, Dilek

    2017-09-01

    Although imatinib has dramatically improved major outcomes in patients with chronic myeloid leukemia (CML), there are newer tyrosine kinase inhibitors (TKIs) approved worldwide for the treatment of resistant cases, and two second-generation TKIs (dasatinib, nilotinib) are approved in some nations for treating patients in the upfront setting. Radotinib (IY5511HCL, Supect® ) is a novel and selective second-generation BCR-ABL1 TKI, which is currently approved in Korea for the treatment of patients with CML both in the upfront and salvage settings. This review mainly focuses on the clinical potential of radotinib in patients with CML in chronic phase in terms of efficacy and safety.

  3. Tyrosine kinase inhibition: A therapeutic target for the management of chronic-phase chronic myeloid leukemia

    Science.gov (United States)

    Jabbour, Elias J; Cortes, Jorge E; Kantarjian, Hagop M

    2014-01-01

    Chronic myeloid leukemia (CML) is a hematologic neoplasm with a progressive, ultimately terminal, disease course. In most cases, CML arises owing to the aberrant formation of a chimeric gene for a constitutively active tyrosine kinase. Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target transforming the prognosis of patients with CML. New tyrosine kinase inhibitors (TKIs) continue to improve the management of CML, offering alternative options for those resistant to or intolerant of standard TKIs. Here we review the pathobiology of CML and explore emerging strategies to optimize the management of chronic-phase CML, particularly first-line treatment. PMID:24236822

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

    Directory of Open Access Journals (Sweden)

    Ferdin

    2012-08-01

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

  5. The human CD38 monoclonal antibody daratumumab shows antitumor activity and hampers leukemia-microenvironment interactions in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Matas-Céspedes, Alba; Vidal-Crespo, Anna; Rodriguez, Vanina

    2017-01-01

    Purpose: To establish a proof-of-concept for the efficacy of the anti-CD38 antibody daratumumab in the poor prognosis CD38+ chronic lymphocytic leukemia (CLL) subtype. Experimental Design: The mechanism of action of daratumumab was assessed in CLL primary cells and cell lines using peripheral blo...

  6. [Function and modulation of type Ⅱ innate lymphoid cells and their role in chronic upper airway inflammatory diseases].

    Science.gov (United States)

    Liu, Y; Liu, Z

    2017-02-07

    Type Ⅱ innate lymphoid cells (ILC2) is a family of innate immune lymphocytes, which provide effective immune responses to cytokines. ILC2 are regulated by the nuclear transcription factor ROR alpha and GATA3, secreting cytokines IL-5 and IL-13, etc. Animal models have shown that ILC2 are involved in allergic diseases, such as asthma and atopic dermatitis, and also play a very important role in the metabolic balance. In addition, recent reports suggest that ILC2 not only play a role in the initial stages of the disease, but also can lead to chronic pathological changes in the disease, such as fibrosis, and may have an effect on acquired immunity. This paper mainly focus in the role and regulation of ILC2 cells, and review the research status of ILC2 in the field of chronic upper airway inflammatory diseases including allergic rhinitis and chronic rhinosinusitis.

  7. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Agathangelidis, Andreas; Darzentas, Nikos; Hadzidimitriou, Anastasia

    2012-01-01

    Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency...

  8. BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future

    NARCIS (Netherlands)

    Spaargaren, M.; de Rooij, M. F. M.; Kater, A. P.; Eldering, E.

    2015-01-01

    The treatment of chronic lymphocytic leukemia (CLL) with inhibitors targeting B cell receptor signaling and other survival mechanisms holds great promise. Especially the early clinical success of Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), has received widespread

  9. Ibrutinib Improves Survival in Patients with Previously Treated Chronic Lymphocytic Leukemia

    Science.gov (United States)

    A summary of results from an international phase III trial that compared ibrutinib (Imbruvica®) and ofatumumab (Arzerra®) for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

  10. Chronic myeloid leukemia in a child with IgA nephropathy.

    Science.gov (United States)

    Udani, Amish; Vijayakumar, Mahalingam; Prahlad, Nageswaran; Ekambaram, Sudha

    2012-08-01

    We report an 11 year old boy with IgA nephropathy developing chronic myeloid leukemia on follow-up. This association suggests that a B cell defect might be involved in the pathogenesis of these two conditions.

  11. Intrinsic functional defects of type 2 innate lymphoid cells impair innate allergic inflammation in promyelocytic leukemia zinc finger (PLZF)-deficient mice.

    Science.gov (United States)

    Verhoef, Philip A; Constantinides, Michael G; McDonald, Benjamin D; Urban, Joseph F; Sperling, Anne I; Bendelac, Albert

    2016-02-01

    The transcription factor promyelocytic leukemia zinc finger (PLZF) is transiently expressed during development of type 2 innate lymphoid cells (ILC2s) but is not present at the mature stage. We hypothesized that PLZF-deficient ILC2s have functional defects in the innate allergic response and represent a tool for studying innate immunity in a mouse with a functional adaptive immune response. We determined the consequences of PLZF deficiency on ILC2 function in response to innate and adaptive immune stimuli by using PLZF(-/-) mice and mixed wild-type:PLZF(-/-) bone marrow chimeras. PLZF(-/-) mice, wild-type littermates, or mixed bone marrow chimeras were treated with the protease allergen papain or the cytokines IL-25 and IL-33 or infected with the helminth Nippostrongylus brasiliensis to induce innate type 2 allergic responses. Mice were sensitized with intraperitoneal ovalbumin-alum, followed by intranasal challenge with ovalbumin alone, to induce adaptive TH2 responses. Lungs were analyzed for immune cell subsets, and alveolar lavage fluid was analyzed for ILC2-derived cytokines. In addition, ILC2s were stimulated ex vivo for their capacity to release type 2 cytokines. PLZF-deficient lung ILC2s exhibit a cell-intrinsic defect in the secretion of IL-5 and IL-13 in response to innate stimuli, resulting in defective recruitment of eosinophils and goblet cell hyperplasia. In contrast, the adaptive allergic inflammatory response to ovalbumin and alum was unimpaired. PLZF expression at the innate lymphoid cell precursor stage has a long-range effect on the functional properties of mature ILC2s and highlights the importance of these cells for innate allergic responses in otherwise immunocompetent mice. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.

  12. Night shift work and chronic lymphocytic leukemia in the MCC-Spain case-control study.

    Science.gov (United States)

    Costas, Laura; Benavente, Yolanda; Olmedo-Requena, Rocío; Casabonne, Delphine; Robles, Claudia; Gonzalez-Barca, Eva-Maria; de la Banda, Esmeralda; Alonso, Esther; Aymerich, Marta; Tardón, Adonina; Marcos-Gragera, Rafael; Gimeno-Vázquez, Eva; Gómez-Acebo, Inés; Papantoniou, Kyriaki; Castaño-Vinyals, Gemma; Aragonés, Nuria; Pollán, Marina; Kogevinas, Manolis; de Sanjosé, Silvia

    2016-11-01

    Chronic lymphocytic leukemia (CLL) has few known modifiable risk factors. Recently, circadian disruption has been proposed as a potential contributor to lymphoid neoplasms' etiology. Serum melatonin levels have been found to be significantly lower in CLL subjects compared with healthy controls, and also, CLL prognosis has been related to alterations in the circadian molecular signaling. We performed the first investigation of an association between night shift work and CLL in 321 incident CLL cases and 1728 population-based controls in five areas of Spain. Participants were interviewed face-to-face by trained interviewers to collect information on sociodemographic factors, familial, medical and occupational history, including work shifts and other lifestyle factors. We used logistic regression models adjusted for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). Seventy-nine cases (25%) and 339 controls (20%) had performed night work. Overall, working in night shifts was not associated with CLL (OR = 1.06; 95% CI = 0.78-1.45, compared with day work). However, long-term night shift (>20 years) was positively associated with CLL (OR(tertile 3 vs . day-work)  = 1.77; 95% = 1.14-2.74), although no linear trend was observed (P trend = 0.18). This association was observed among those with rotating (OR(tertile 3 vs . day-work)  = 2.29; 95% CI = 1.33-3.92; P trend = 0.07), but not permanent night shifts (OR(tertile 3 vs . day-work) = 1.16; 95% CI = 0.60-2.25; P trend = 0.86). The association between CLL and long-term rotating night shift warrants further investigation. © 2016 UICC.

  13. Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective.

    Science.gov (United States)

    Darwiche, Walaa; Gubler, Brigitte; Marolleau, Jean-Pierre; Ghamlouch, Hussein

    2018-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of small mature-looking CD19+ CD23+ CD5+ B-cells that accumulate in the blood, bone marrow, and lymphoid organs. To date, no consensus has been reached concerning the normal cellular counterpart of CLL B-cells and several B-cell types have been proposed. CLL B-cells have remarkable phenotypic and gene expression profile homogeneity. In recent years, the molecular and cellular biology of CLL has been enriched by seminal insights that are leading to a better understanding of the natural history of the disease. Immunophenotypic and molecular approaches (including immunoglobulin heavy-chain variable gene mutational status, transcriptional and epigenetic profiling) comparing the normal B-cell subset and CLL B-cells provide some new insights into the normal cellular counterpart. Functional characteristics (including activation requirements and propensity for plasma cell differentiation) of CLL B-cells have now been investigated for 50 years. B-cell subsets differ substantially in terms of their functional features. Analysis of shared functional characteristics may reveal similarities between normal B-cell subsets and CLL B-cells, allowing speculative assignment of a normal cellular counterpart for CLL B-cells. In this review, we summarize current data regarding peripheral B-cell differentiation and human B-cell subsets and suggest possibilities for a normal cellular counterpart based on the functional characteristics of CLL B-cells. However, a definitive normal cellular counterpart cannot be attributed on the basis of the available data. We discuss the functional characteristics required for a cell to be logically considered to be the normal counterpart of CLL B-cells.

  14. Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells

    Directory of Open Access Journals (Sweden)

    Ahmad Hamad

    2013-01-01

    Full Text Available Chronic myeloid leukemia (CML is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML that have the potential to target CML stem cells and potentially provide cure for CML.

  15. Leukemia

    Science.gov (United States)

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

  16. Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia.

    Science.gov (United States)

    Maddocks, Kami; Jones, Jeffrey A

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and remains incurable outside of the setting of allogeneic stem cell transplant. While the standard therapy for both initial and relapsed CLL has traditionally included monoclonal antibody therapy in combination with chemotherapy, there are patients with high-risk disease features including unmutated IgVH, del(11q22) and del(17p13) that are associated with poor overall responses to these therapies with short time to relapse and shortened overall survival. Additionally, many of these therapies have a high rate of infectious toxicity in a population already at increased risk. Targeting the B-cell receptor (BCR) signaling pathway has emerged as a promising therapeutic advance in a variety of B-cell malignancies, including CLL. Bruton agammaglobulinemia tyrosine kinase (Btk) is a tyrosine kinase in the BCR pathway critical to the survival of both normal and malignant B cells and inhibition of this kinase has shown to block the progression of CLL. Ibrutinib, a first in class oral inhibitor of Btk, has shown promise as a very effective agent in the treatment of CLL-in both relapsed and upfront therapy, alone and in combination with other therapies, and in patients of all-risk disease-which has led to its approval in relapsed CLL and as frontline therapy in patients with the high-risk del(17p13) disease. Several studies are ongoing to evaluate the efficacy and safety of ibrutinib in combination with chemotherapy as frontline treatment for CLL and investigation into newer-generation Btk inhibitors is also underway. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Paranasal Manifestations of Early Stage Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Ceren Günel

    2015-04-01

    Full Text Available OBJECTIVE: Chronic lymphocytic leukemia (CLL is the most common adult leukemia. A few studies have been reported about the relationship between CLL and paranasal sinuses. We aimed to investigate the paranasal manifestations of CLL and to determine the expression of nuclear factor-ĸB (NF-kB and tumor necrosis factor (TNF-α in the nasal mucosa in patients with CLL. MATERIALS AND METHODS: This study was a clinical trial that involved 40 patients. Group CLL (n=20 consisted of patients with early-stage CLL who were followed-up at the hematology clinic and who did not receive any treatment. The control group (n=20 consisted of patients who had undergone concha surgery because of nasal obstruction. Paranasal sinus computer tomography scans of all patients were taken, they were scored on the basis of the Lund–Mackay system, and sinusitis findings were recorded. The biopsy material taken from the inferior concha head of all patients was immunohistochemically stained with primary antibodies against NF-kB and TNF-α. RESULTS: There were no statistically significant differences between the two groups with respect to NF-κB (p=0.716 and TNF-α staining scores (p=1.000. The Lund–Mackay scores were significantly higher in the CLL group than in the control group (p=0.004. Fourteen patients had sinusitis at different locations, while the most common diagnosis was maxillary sinusitis (n=8 in the CLL group. CONCLUSION: This study showed that patients with early-stage CLL tend to have rhinosinusitis. However, NF-kB and TNF-α may not have a role in the inflammatory process involving the paranasal sinuses in patients with CLL.

  18. Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma and Chronic Lymphoblastic Leukemia.

    Science.gov (United States)

    Hsu, Jingmei; Artz, Andrew; Mayer, Sebastian A; Guarner, Danielle; Bishop, Michael R; Reich-Slotky, Ronit; Smith, Sonali M; Greenberg, June; Kline, Justin; Ferrante, Rosanna; Phillips, Adrienne A; Gergis, Usama; Liu, Hongtao; Stock, Wendy; Cushing, Melissa; Shore, Tsiporah B; van Besien, Koen

    2018-02-01

    Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin lymphoma (n = 9, 21%), CLL (n = 5, 12%) and non-Hodgkin lymphomas (n = 28, 67%), including 13 T cell lymphomas. Twenty-four patients (52%) had 3 or more lines of therapies. Six (14%) and 1 (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant 12 patients (29%) were in complete remission, 18 had chemotherapy-sensitive disease, and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%), and 24 (57%) patients had low, intermediate, and high disease risk index before transplant. Comorbidity index was evenly distributed among 3 groups, with 13 (31%), 14 (33%), and 15 (36%) patients scoring 0, 1 to 2, and ≥3. Median age for the cohort was 49 years (range, 23 to 71). All patients received fludarabine/melphalan/antithymocyte globulin conditioning regimen and post-transplant graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil. The median time to neutrophil engraftment was 11 days (range, 9 to 60) and to platelet engraftment 19.5 days (range, 11 to 88). Cumulative incidence of nonrelapse mortality was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival

  19. Immunoregulatory changes induced by total lymphoid irradiation. II. Development of thymus-leukemia antigen-positive and -negative suppressor T cells that differ in their regulatory function

    International Nuclear Information System (INIS)

    King, D.P.; Strober, S.

    1981-01-01

    BALB/c mice treated with total lymphoid irradiation (TLI) develop non-antigen-specific suppressor cells of the adoptive secondary antibody response and of the mixed leukocyte reaction. Suppressors of the adoptive anti-DNP response were eliminated by incubation of spleen cells with anti-Thy-1.2 or anti-thymus-leukemia (TL) antiserum and complement before cell transfer. Thymectomy before TLI prevented the appearance of the latter suppressor cells. On the other hand, suppressors of the MLR were eliminated by incubation of spleen cells with anti-Thy-1.2 but not anti-TL antiserum and complement. Thymectomy before TLI did not prevent their subsequent development. Thus, two subpopulations of suppressor T cells that differ in the expression of the TL surface antigen, dependence on the presence of the thymus, and in regulatory functions develop after TLI. The TL+, thymus-dependent cell suppresses the adoptive antibody response, and the TL-, thymus-independent cell suppresses the MLR

  20. Genetics Home Reference: PDGFRA-associated chronic eosinophilic leukemia

    Science.gov (United States)

    ... link) Genetic Testing Registry: Idiopathic hypereosinophilic syndrome Other Diagnosis and Management Resources (3 links) Cancer.Net: Leukemia - Eosinophilic: Treatment MedlinePlus Encyclopedia: Eosinophil Count - Absolute Seattle ...

  1. Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells

    International Nuclear Information System (INIS)

    Askmyr, M; Ågerstam, H; Lilljebjörn, H; Hansen, N; Karlsson, C; Palffy, S von; Landberg, N; Högberg, C; Lassen, C; Rissler, M; Richter, J; Ehinger, M; Järås, M; Fioretos, T

    2014-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34 + cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML

  2. Complete suppression of viral gene expression is associated with the onset and progression of lymphoid malignancy: observations in Bovine Leukemia Virus-infected sheep

    Directory of Open Access Journals (Sweden)

    Burny Arsène

    2007-07-01

    Full Text Available Abstract Background During malignant progression, tumor cells need to acquire novel characteristics that lead to uncontrolled growth and reduced immunogenicity. In the Bovine Leukemia Virus-induced ovine leukemia model, silencing of viral gene expression has been proposed as a mechanism leading to immune evasion. However, whether proviral expression in tumors is completely suppressed in vivo was not conclusively demonstrated. Therefore, we studied viral expression in two selected experimentally-infected sheep, the virus or the disease of which had features that made it possible to distinguish tumor cells from their nontransformed counterparts. Results In the first animal, we observed the emergence of a genetically modified provirus simultaneously with leukemia onset. We found a Tax-mutated (TaxK303 replication-deficient provirus in the malignant B-cell clone while functional provirus (TaxE303 had been consistently monitored over the 17-month aleukemic period. In the second case, both non-transformed and transformed BLV-infected cells were present at the same time, but at distinct sites. While there was potentially-active provirus in the non-leukemic blood B-cell population, as demonstrated by ex-vivo culture and injection into naïve sheep, virus expression was completely suppressed in the malignant B-cells isolated from the lymphoid tumors despite the absence of genetic alterations in the proviral genome. These observations suggest that silencing of viral genes, including the oncoprotein Tax, is associated with tumor onset. Conclusion Our findings suggest that silencing is critical for tumor progression and identify two distinct mechanisms-genetic and epigenetic-involved in the complete suppression of virus and Tax expression. We demonstrate that, in contrast to systems that require sustained oncogene expression, the major viral transforming protein Tax can be turned-off without reversing the transformed phenotype. We propose that suppression

  3. Development of chronic myelocytic leukemia in atomic bomb survivors

    Energy Technology Data Exchange (ETDEWEB)

    Kamada, N; Oguma, N; Tanaka, R; Kuramoto, A; Ohkita, T [Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology

    1978-04-01

    On the basis of the evaluation of laboratory findings in 102 cases including 20 cases which were diagnosed as very early stage chronic myelogenic leukemia (CML), chronological orders of the histopathological pictures of CML were shown as follows; myeloid occupation with Ph/sup 1/-positive cells (leucocyte count 10/sup 10//L)--basophilic leucocytosis thrombocytosis and low activity of neutrocyte-AP (1 - 2 x 10/sup 10//L)--appearance of immature granulocytes more than 5% in the peripheral blood (2 x 10/sup 10//L)--increase of serum Vit. B/sub 12/ (2.5 x 10/sup 10//L)--splenomegaly (5 x 10/sup 10//L)--appearance of subjective symptoms (7 x 10/sup 10//L or more). The relation between an actual number of Ph/sup 1/-positive cells and time of their appearance (months) can be expressed as log Y = 0.053 + 10.023. It was estimated that it takes about 8 years since one Ph/sup 1/-positive cell appears in the body until the leucocyte count becomes 10/sup 11//L and the patient consult a doctor. The idea that Ph/sup 1/-positive cells can be transformed to more malignant clones is helpful to understand the pathological feature of acute transformation of CML.

  4. REGULATORY T-CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Giovanni D'arena

    2012-01-01

    Full Text Available

    Regulatory T-cells (Tregs constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL. Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosis, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in either cancer and autoimmune disorders.

  5. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia

    Science.gov (United States)

    Piazza, Rocco; Valletta, Simona; Winkelmann, Nils; Redaelli, Sara; Spinelli, Roberta; Pirola, Alessandra; Antolini, Laura; Mologni, Luca; Donadoni, Carla; Papaemmanuil, Elli; Schnittger, Susanne; Kim, Dong-Wook; Boultwood, Jacqueline; Rossi, Fabio; Gaipa, Giuseppe; De Martini, Greta P; di Celle, Paola Francia; Jang, Hyun Gyung; Fantin, Valeria; Bignell, Graham R; Magistroni, Vera; Haferlach, Torsten; Pogliani, Enrico Maria; Campbell, Peter J; Chase, Andrew J; Tapper, William J; Cross, Nicholas C P; Gambacorti-Passerini, Carlo

    2013-01-01

    Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases. PMID:23222956

  6. Quantitative analysis of DNA methylation in chronic lymphocytic leukemia patients.

    Science.gov (United States)

    Lyko, Frank; Stach, Dirk; Brenner, Axel; Stilgenbauer, Stephan; Döhner, Hartmut; Wirtz, Michaela; Wiessler, Manfred; Schmitz, Oliver J

    2004-06-01

    Changes in the genomic DNA methylation level have been found to be closely associated with tumorigenesis. In order to analyze the relation of aberrant DNA methylation to clinical and biological risk factors, we have determined the cytosine methylation level of 81 patients diagnosed with chronic lymphocytic leukemia (CLL). The analysis was based on DNA hydrolysis followed by derivatization of the 2'-desoxyribonucleoside-3'-monophosphates with BODIPY FL EDA. Derivatives were separated by micellar electrokinetic chromatography, and laser-induced fluorescence was used for detection. We analyzed potential correlations between DNA methylation levels and numerous patient parameters, including clinical observations and biological data. As a result, we observed a significant correlation with the immunoglobulin variable heavy chain gene (VH) mutation status. This factor has been repeatedly proposed as a reliable prognostic marker for CLL, which suggests that the methylation level might be a valuable factor in determining the prognostic outcome of CLL. We are now in the process of refining our method to broaden its application potential. In this context, we show here that the oxidation of the fluorescence marker in the samples and the evaporation of methanol in the electrolytes can be prevented by a film of paraffin oil. In summary, our results thus establish capillary electrophoresis as a valuable tool for analyzing the DNA methylation status of clinical samples.

  7. Hematopoietic stem cell transplantation for chronic lymphocytic leukemia.

    Science.gov (United States)

    Gladstone, Douglas E; Fuchs, Ephraim

    2012-03-01

    Although hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many aggressive hematologic malignancies, the role of HSCT in chronic lymphocytic leukemia (CLL) has remained controversial. Now in the era of improved conventional treatment and better prognostication of long-term outcome, a review of autologous and allogeneic HSCT in CLL treatment is warranted. Despite an improved disease-free survival in some patients, multiple, prospective, randomized autologous HSCT CLL trials fail to demonstrate an overall survival benefit as compared to conventional therapy. Allogeneic bone marrow transplantation, although limited by donor availability, can successfully eradicate CLL with adverse prognostic features. In the older CLL patients, nonmyeloablative allogeneic transplants are better tolerated than myeloablative transplants. Nonmyeloablative allogeneic transplants are less effective in heavily diseased burdened patients. Outside of a clinical protocol, autologous HSCT for CLL cannot be justified. Nonmyeloablative allogeneic transplantation should be considered in high-risk populations early in the disease process, when disease burden is most easily controlled. Alternative donor selection using haploidentical donors and posttransplantation cyclophosphamide has the potential to vastly increase the availability of curative therapy in CLL while retaining a low treatment-related toxicity.

  8. [Molecular genetics in chronic myeloid leukemia with variant Ph translocation].

    Science.gov (United States)

    Wu, Wei; Li, Jian-yong; Zhu, Yu; Qiu, Hai-rong; Pan, Jin-lan; Xu, Wei; Chen, Li-juan; Shen, Yun-feng; Xue, Yong-quan

    2007-08-01

    To explore the value of fluorescence in situ hybridization (FISH) and multiplex fluorescence in situ hybridization (M-FISH) techniques in the detection of genetic changes in chronic myeloid leukemia (CML) with variant Philadelphia translocation (vPh). Cytogenetic preparations from 10 CML patients with vPh confirmed by R banding were assayed with dual color dual fusion FISH technique. If only one fusion signal was detected in interphase cells, metaphase cells were observed to determine if there were derivative chromosome 9[der (9)] deletions. Meanwhile, the same cytogenetic preparations were assayed with M-FISH technique. Of the 10 CML patients with vPh, 5 were detected with der (9) deletions by FISH technique. M-FISH technique revealed that besides the chromosome 22, chromosomes 1, 3, 5, 6, 8, 10, 11 and 17 were also involved in the vPh. M-FISH technique also detected the abnormalities which were not found with conventional cytogenetics (CC), including two never reported abnormalities. The combination of CC, FISH and M-FISH technique could refine the genetic diagnosis of CML with vPh.

  9. Overview of recent developments in chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Preetesh Jain

    2012-01-01

    Full Text Available Multiple advances have been made in our understanding of pathobiology of chronic lymphocytic leukemia (CLL. These developments in the laboratory include new prognostic markers, risk stratification of the disease and newer therapeutic agents in CLL. These advances in CLL have come a long way in the past three decades since the development of Rai and Binet clinical staging systems. Important strides in the pathobiology, from defining mutational status of IGHV, to B-cell receptor (BCR signaling pathways and CLL microenvironment have made a major difference in our understanding of this disease. Mutational status of immunoglobulin heavy chain genes (IGHV, CD38 and Zap-70, chromosomal aberrations and newer mutations, are the most clinically relevant prognostic markers. Chemoimmunotherapy (CIT has become the treatment of choice for young and fit CLL patients. Various inhibitors of BCR signaling pathways and immunomodulatory drugs have shown efficacy in clinical trials. The most recent advance is the use of chimeric antigen receptor therapy (CAR based on autologous T-lymphocytes. Nevertheless, CLL remains an incurable disease today. Coordinated developments between laboratory and clinic will hopefully translate into a cure for CLL. This short review focuses on advances in prognostication and therapy in CLL.

  10. Managing chronic myeloid leukemia: a coordinated team care perspective.

    Science.gov (United States)

    Holloway, Stacie; Lord, Katharine; Bethelmie-Bryan, Beverly; Shepard, Marian W; Neely, Jessica; McLemore, Morgan; Reddy, Satyanarayan K; Montero, Aldemar; Jonas, William S; Gladney, Sara Pierson; Khanwani, Shyam L; Reddy, Silpa C; Lahiry, Anup K; Heffner, Leonard T; Winton, Elliott; Arellano, Martha; Khoury, Hanna Jean

    2012-04-01

    Treatment of chronic myeloid leukemia (CML) has seen dramatic progress in recent years with the development of tyrosine kinase inhibitors (TKIs). To take maximum advantage of therapy with TKIs, compliance and good understanding of monitoring response to therapy are essential. We established a team that included a hematologist, a physician assistant (PA), and a nurse who work closely with a social worker, a pharmacist, and a research coordinator to assist patients throughout their journey with CML. The patient and the referring community oncologist were incorporated into this team. This coordinated team care approach takes advantage of each member's specific skills to provide patients with education about CML, encourage patients' strong involvement in tracking/monitoring results/response to therapy, and support patients with issues that arise throughout the long course of the disease. A low rate of noncompliance with clinic visits (3%) was an indirect measure of the impact of this approach. The inclusion of the referring oncologist in the team extended the tracking of monitoring results to the community practice. We conclude that a coordinated team care approach is feasible in the management of patients with CML. This approach provided patients with education and a good understanding of response to therapy and improved relations with the health care team. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Red cell ferritin and iron stores in chronic granulocytic leukemia

    International Nuclear Information System (INIS)

    Cermak, J.; Neuwirth, J.; Voglova, J.; Brabec, V.; Chrobak, L.

    1994-01-01

    Basic red cell ferritin was investigated in 28 patients with different phases of chronic granulocytic leukemia (GCL). Red cell ferritin was significantly decreased in remission after busulphan treatment and significantly elevated in the blast crisis as compared to healthy controls. Bone marrow stainable iron was decreased or absent in 86% of patients in the initial phase at the time of diagnosis and in 92% of those in remission. Red cell ferritin correlated with serum ferritin, however, serum ferritin level remained above normal range during all phases of the disease. A negative correlation between red cell ferritin and hemoglobin (Hb) (r = -0.605, p < 0.001) suggested that red cell ferritin level reflected the rate of iron utilization for heme synthesis. Decrease red cell iron observed in the remission may be explained by regression of dyserythropoiesis and by restoration of normal Hb synthesis after busulphan treatment. A progressive dyserythropoiesis in the blast crisis may lead to an increased red cell ferritin level. (author)

  12. Diagnosis and Treatment of Chronic Myeloid Leukemia (CML) in 2015

    Science.gov (United States)

    Thompson, Philip A; Kantarjian, Hagop; Cortes, Jorge E

    2017-01-01

    Few neoplastic diseases have undergone a transformation in a relatively short period of time like chronic myeloid leukemia (CML) has in the last few years. In 1960, CML was the first cancer where a unique chromosomal abnormality, “a minute chromosome”,1 was identified and a pathophysiologic correlation suggested. Landmark work followed, recognizing the underlying translocation between chromosomes 9 and 22 that gave rise to this abnormality2 and shortly afterward, the specific genes involved3,4 and the pathophysiologic implications of this novel rearrangement.5–7 Fast-forward a few years, this knowledge has given us the most remarkable example of a specific therapy targeting the dysregulated kinase activity represented by this molecular change. The broad use of tyrosine kinase inhibitors has resulted in an improvement in the overall survival to the point where the life expectancy of patients today is nearly equal to that of the general population.8 Still, there are challenges and unanswered questions that define the reasons why the progress still escapes many patients, and the details that separate patients from ultimate “cure”. In this manuscript we review our current understanding of CML in 2015, present recommendations for optimal management, and discuss the unanswered questions and what could be done to answer them in the near future. PMID:26434969

  13. Phenotypic complexity of T regulatory subsets in patients with B-chronic lymphocytic leukemia.

    Science.gov (United States)

    Biancotto, Angélique; Dagur, Pradeep K; Fuchs, John C; Wiestner, Adrian; Bagwell, C Bruce; McCoy, J Philip

    2012-02-01

    Increased numbers of T regulatory (T(reg)) cells are found in B-chronic lymphocytic leukemia, but the nature and function of these T(regs) remains unclear. Detailed characterization of the T(regs) in chronic lymphocytic leukemia has not been performed and the degree of heterogeneity of among these cells has not been studied to date. Using 15-color flow cytometry we show that T(reg) cells, defined using CD4, CD25, and forkhead box P3 (FOXP3), can be divided into multiple complex subsets based on markers used for naïve, memory, and effector delineation as well as markers of T(reg) activation. Furthermore FOXP3(+) cells can be identified among CD4(+)CD25(-) as well as CD8(+)CD4(-) populations in increased proportions in patients with chronic lymphocytic leukemia compared with healthy donors. Significantly different frequencies of naïve and effector T(regs) populations are found in healthy donor controls compared with donors with chronic lymphocytic leukemia. A population of CCR7(+)CD39(+) T(regs) was significantly associated with chronic lymphocytic leukemia. This population demonstrated slightly reduced suppressive activity compared with total T(regs) or T(regs) of healthy donors. These data suggest that FOXP3-expressing cells, particularly in patients with chronic lymphocytic leukemia are much more complex for T(reg) sub-populations and transitions than previously reported. These findings demonstrate the complexity of regulation of T-cell responses in chronic lymphocytic leukemia and illustrate the use of high-dimensional analysis of cellular phenotypes in facilitating understanding of the intricacies of cellular immune responses and their dysregulation in cancer.

  14. O transplante de células-tronco hematopoéticas na leucemia linfoide crônica, uma proposta do I Encontro de Diretrizes do Transplante de Medula Óssea da Sociedade Brasileira de Transplante de Medula Óssea, Rio de Janeiro 2009 Hematopoietic stem cell transplantation in chronic lymphoid leukemia: a proposal by the Brazilian Consensus on Bone Marrow Transplantation of the Brazilian Society of Bone Marrow Transplantation, Rio de Janeiro 2009

    Directory of Open Access Journals (Sweden)

    Milton A. Ruiz

    2010-05-01

    Full Text Available Portadores de leucemia linfoide crônica (LLC apresentam curso clínico indolente e prolongado que devem ser diferenciados daqueles que têm doença de evolução agressiva e fatal. Pacientes mais jovens e com critérios de alto risco podem se beneficiar com tratamento mais agressivo como o transplante de células-tronco hemopoéticas (TCTH. O transplante autólogo apresenta casos com remissão citogenética e molecular, baixa taxa de mortalidade, mas não demonstram platô nas curvas de sobrevivência e alta taxa de recaídas. Os transplantes alogênicos com regime mieloablativos têm altos índices de toxicidade e mortalidade, mas evidenciam o efeito enxerto versus leucemia, que aumenta a possibilidade de cura destes indivíduos. Assim, a opção dos transplantes alogênicos está dirigida para os transplantes com regime de condicionamento não mieloablativo, que pode ser aplicado inclusive a pacientes mais idosos ou portadores de comorbidades, e manter o potencial efeito GVL. A identificação dos pacientes que podem ser beneficiados por esses procedimentos, caracterizar e apontar os novos marcadores prognósticos permanece objeto de muitos estudos clínicos e foi o objetivo do grupo responsável em discutir as diretrizes do TCTH no consenso da Sociedade Brasileira de Transplante de Medula Óssea - SBTMO. Assim, consideramos que o TCTH para a leucemia linfoide crônica (LLC deve seguir, para sua indicação, os critérios do European Group for Blood and Marrow Transplantation (EBMT e, quando houver disponibilidade de um doador aparentado, a opção deve ser do TCTH alogênico com regime não mieloablativo. O TCTH alogênico não aparentado e o autólogo devem ser considerados como opção secundária de indisponibilidade de doador, situações especiais e ensaios clínicos.Patients with chronic lymphocytic leukemia usually have an indolent and prolonged clinical course and need to be differentiated from those who have an aggressive and fatal

  15. Nilotinib induced avascular necrosis of femoral head in an adult chronic myeloid leukemia patient.

    Science.gov (United States)

    Thekkudan, Shinto Francis; Nityanand, Soniya

    2018-06-01

    We report a rare case of avascular necrosis of femoral head (AVNFH) in an adult chronic myeloid leukemia - chronic phase (CML-CP) patient during due course of therapy with second line Tyrosine Kinase Inhibitor (TKI), Nilotinib. A high index of clinical suspicion should be kept in any symptomatic CML patient on TKI's.

  16. Targeting of the BLT2 in chronic myeloid leukemia inhibits leukemia stem/progenitor cell function

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Meifang; Ai, Hongmei; Li, Tao [Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China); Rajoria, Pasupati; Shahu, Prakash [Department of Clinical Medicine, Medical School of Yangtze University, Jingzhou (China); Li, Xiansong, E-mail: lixiansongjz@hotmail.com [Department of Neurosurgery, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China)

    2016-04-15

    Imatinib, a tyrosine kinase inhibitor (TKI) has significantly improved clinical outcome for chronic myeloid leukemia (CML) patients. However, patients develop resistance when the disease progresses to the blast phase (BP) and the mechanisms are not well understood. Here we show that BCR-ABL activates BLT2 in hematopoietic stem/progenitor cells to promote leukemogenesis and this involves the p53 signaling pathway. Compared to normal bone marrow (NBM), the mRNA and protein levels of BLT2 are significantly increased in BP-CML CD34{sup +} stem/progenitor cells. This is correlated with increasing BCR-ABL expression. In contrast, knockdown of BCR-ABL or inhibition of its tyrosine kinase activity decreases Blt2 protein level. BLT2 inhibition induces apoptosis, inhibits proliferation, colony formation and self-renewal capacity of CD34{sup +} cells from TKI-resistant BP-CML patients. Importantly, the inhibitory effects of BCR-ABL TKI on CML stem/progenitor cells are further enhanced upon combination with BLT2 inhibition. We further show that BLT2 activation selectively suppresses p53 but not Wnt or BMP-mediated luciferase activity and transcription. Our results demonstrate that BLT2 is a novel pathway activated by BCR-ABL and critically involved in the resistance of BP-CML CD34{sup +} stem/progenitors to TKIs treatment. Our findings suggest that BLT2 and p53 can serve as therapeutic targets for CML treatment. - Highlights: • BCR-ABL regulates BLT2 expression to promote leukemogenesis. • BLT2 is essential to maintain CML cell function. • Activation of BLT2 suppresses p53 signaling pathway in CML cells. • Inhibition of BLT2 and BCR-ABL synergize in eliminating CML CD34{sup +} stem/progenitors.

  17. Endoscopic features of lymphoid follicles in Helicobacter pylori-associated chronic gastritis.

    Science.gov (United States)

    Hayashi, Seishu; Imamura, Jun; Kimura, Kiminori; Saeki, Shunichi; Hishima, Tsunekazu

    2015-01-01

    Small, round, yellowish-white nodules (YWN) are frequently observed in Helicobacter pylori-associated gastritis. The aim of the present study was to investigate the clinical significance of these YWN. Participants comprised 211 patients with H. pylori-associated gastritis, ranging in age from 23 to 86 years. YWN were detected in 23% of participants, more frequently in women (33%) than in men (12%; P gastritis, and represented histological lymphoid follicles. © 2014 The Authors. Digestive Endoscopy © 2014 Japan Gastroenterological Endoscopy Society.

  18. Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

    Science.gov (United States)

    Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah

    2016-07-01

    Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. © 2016 John Wiley & Sons A/S.

  19. Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)

    Science.gov (United States)

    2018-05-10

    B-Cell Chronic Lymphocytic Leukemia; Monoclonal B-Cell Lymphocytosis; Lymhoma, Small Lymphocytic; Chronic Lymphocytic Leukemia; Lymphoplasmacytic Lymphoma; Waldenstrom Macroglobulinemia; Splenic Marginal Zone Lymphoma

  20. Disturbance of the gut-associated lymphoid tissue is associated with disease progression in chronic HIV infection.

    Science.gov (United States)

    Hofer, Ursula; Speck, Roberto F

    2009-07-01

    Why and how HIV makes people sick is highly debated. Recent evidence implicates heightened immune activation due to breakdown of the gastrointestinal barrier as a determining factor of lentiviral pathogenesis. HIV-mediated loss of Th17 cells from the gut-associated lymphoid tissue (GALT) impairs mucosal integrity and innate defense mechanisms against gut microbes. Translocation of microbial products from the gut, in turn, correlates with increased immune activation in chronic HIV infection and may further damage the immune system by increasing viral and activation-induced T cell death, by reducing T cell reconstitution due to tissue scarring, and by impairing the function of other cell types, such as gammadelta T cells and epithelial cells. Maintaining a healthy GALT may be the key to reducing the pathogenic potential of HIV.

  1. Defective immunoregulatory T-cell function in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Han, T.; Ozer, H.; Henderson, E.S.; Dadey, B.; Nussbaum-Blumenson, A.; Barcos, M.

    1981-01-01

    Chronic lymphocytic leukemia (CLL) of B-cell origin results in the malignant proliferation of small immunoglobulin-bearing lymphocytes. There is currently a controversy in the literature regarding both the ability of this leukemic population to differentiate into mature plasma cells, as well as the ability of apparently normal T cells from these patients to regulate allogeneic B-cell differentiation. In the present study we have examined the lymphocytes of CLL patients in various clinical stages of their disease and with different surface phenotypes of their leukemic B-cell population. Our results show that leukemic CLL B cells from all 20 patients (including one patient with a monoclonal IgM paraprotein and another with a monoclonal IgG paraprotein) are incapable of further differentiation even in the absence of suppressor T cells and the presence of helper T lymphocytes. This lack of capacity to differentiate is unaffected by clinical stage, by therapy, or by the phenotype of the malignant population. Since the leukemic B population did not suppress normal allogeneic B-cell differentiation, the maturation deficit is evidently intrinsic to the leukemic clone rather than a result of activity of non-T suppressor cells. T helper function was also variably depressed in the blood of some patients with CLL, and this depression did not correlate with clinical stage, with therapy, or with the degree of lymphocytosis. Dysfunction of radiosensitive T suppressor cells was found to be the most consistent regulatory deficit of CLL T cells. Each of 11 patients whose leukemic cell population was of the μdelta, μα, or μ phenotype had both helper and suppressor cell defects

  2. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.

    Science.gov (United States)

    Byrd, John C; Furman, Richard R; Coutre, Steven E; Flinn, Ian W; Burger, Jan A; Blum, Kristie A; Grant, Barbara; Sharman, Jeff P; Coleman, Morton; Wierda, William G; Jones, Jeffrey A; Zhao, Weiqiang; Heerema, Nyla A; Johnson, Amy J; Sukbuntherng, Juthamas; Chang, Betty Y; Clow, Fong; Hedrick, Eric; Buggy, Joseph J; James, Danelle F; O'Brien, Susan

    2013-07-04

    The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).

  3. RhoA: A therapeutic target for chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Molli Poonam R

    2012-03-01

    Full Text Available Abstract Background Chronic Myeloid Leukemia (CML is a malignant pluripotent stem cells disorder of myeloid cells. In CML patients, polymorphonuclear leukocytes (PMNL the terminally differentiated cells of myeloid series exhibit defects in several actin dependent functions such as adhesion, motility, chemotaxis, agglutination, phagocytosis and microbicidal activities. A definite and global abnormality was observed in stimulation of actin polymerization in CML PMNL. Signalling molecules ras and rhoGTPases regulate spatial and temporal polymerization of actin and thus, a broad range of physiological processes. Therefore, status of these GTPases as well as actin was studied in resting and fMLP stimulated normal and CML PMNL. Methods To study expression of GTPases and actin, Western blotting and flow cytometry analysis were done, while spatial expression and colocalization of these proteins were studied by using laser confocal microscopy. To study effect of inhibitors on cell proliferation CCK-8 assay was done. Significance of differences in expression of proteins within the samples and between normal and CML was tested by using Wilcoxon signed rank test and Mann-Whitney test, respectively. Bivariate and partial correlation analyses were done to study relationship between all the parameters. Results In CML PMNL, actin expression and its architecture were altered and stimulation of actin polymerization was absent. Differences were also observed in expression, organization or stimulation of all the three GTPases in normal and CML PMNL. In normal PMNL, ras was the critical GTPase regulating expression of rhoGTPases and actin and actin polymerization. But in CML PMNL, rhoA took a central place. In accordance with these, treatment with rho/ROCK pathway inhibitors resulted in specific growth inhibition of CML cell lines. Conclusions RhoA has emerged as the key molecule responsible for functional defects in CML PMNL and therefore can be used as a

  4. Novel treatments for chronic lymphocytic leukemia and moving forward.

    Science.gov (United States)

    Brown, Jennifer R; Porter, David L; O'Brien, Susan M

    2014-01-01

    The last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These include the antibody obintutuzumab (GA-101), as well as small-molecule inhibitors of key pathways involved in the pathogenesis of CLL, specifically the B-cell receptor (BCR) pathway (especially Bruton's tyrosine kinase [BTK] and P13K), and the antiapoptotic pathway (especially BCL-2). We will consider each in turn, focusing on the molecules most advanced in clinical development. There has also been extensive development in rewiring the patient's own immune system to treat CLL. This has been done through modifying autologous T cells to express a chimeric antigen receptor (CAR). Thus far all CAR-T preparations have targeted the CD19 antigen. This is a good rational for B-cell malignancies as CD19 expression is limited to B-cell malignancies and normal B cells. The in vivo amplification of the transduced T cells relies on signaling and co-signaling domains and provides significant killing of CLL cells. As exciting as these novel agents and approaches are, they obviously beg the question, will chemotherapy as a treatment for CLL soon be obsolete? Although chemotherapy is associated with known short-term toxicities, it has the advantage of being completed in a short period of time and being relatively inexpensive in comparison to novel therapies. In addition, long-term follow-up of results with chemoimmunotherapy have now identified a group of patients whose remissions are maintained for more than 10 years. An important question that will arise going forward is how to incorporate novel agents without eliminating the long term benefits possible with chemoimmunotherapy in a subset of patients with CLL.

  5. Selecting the Best Frontline Treatment in Chronic Myeloid Leukemia

    Science.gov (United States)

    Yilmaz, Musa; Abaza, Yasmin; Jabbour, Elias

    2017-01-01

    With the discovery of Philadelphia chromosome, understanding of chronic myeloid leukemia (CML) pathobiology has tremendously increased. Development of tyrosine kinase inhibitors (TKI) targeting the BCR/ABL1 oncoprotein has changed the landscape of the disease. Today, the expected survival of CML patients, if properly managed, is likely to be similar to the general population. Imatinib is the first approved TKI in CML treatment, and for several years, it was the only option in the frontline setting. Four years ago, second generation TKIs (nilotinib and dasatinib) were approved as alternative frontline options. Now, clinicians are faced the challenge of making decision for which TKI to chose upfront. Second generation TKIs have been demonstrated to induce deeper and faster responses compared to imatinib, however, none of 3 TKIs have been shown to have a clear survival advantage, they all are reasonable options. In contrast, when considering therapy in individual patients, the case may be stronger for a specific TKI. Co-morbidities of the patient and side effect profile of the TKI of interest should be an important consideration in decision making. At present, the cost nilotinib or dasatinib is not remarkably different from imatinib. However, patent for imatinib is expected to expire soon, and it will be available as a generic. Clinicians, then, need to weigh the advantages some patients gain with nilotinib or dasatinib in the frontline setting against the difference in cost. Whatever TKI is chosen as frontline, intolerance, non-compliance or treatment failure should be recognized early as a prompt intervention increases the chance of achieving best possible response. PMID:25921387

  6. Interferon alpha induced cytogenetic remissions of chronic myelocytic leukemia

    International Nuclear Information System (INIS)

    Oguma, Nobuo; Shigeta, Chiharu; Tanaka, Kimio; Kamada, Nanao; Kuramoto, Atsushi; Ito, Chikako.

    1994-01-01

    In two heavily exposed A-bomb survivors, Philadelphia (Ph 1 ) chromosomes completed disappeared by the treatment with interferon (IFN)-α for chronic myelocytic leukemia (CML). One is a 55-year-old man exposed at 2.0 km in Hiroshima at the age of 13. Periodic mass screening in 1987 showed the presence of Ph 1 chromosomes, in addition to an increased number of leukocytes and the presence of neocytes. Subcutaneous injection of IFN-α (6,000,000 units/day) was started with a diagnosis of CML, and 5 months later Ph 1 chromosomes disappeared. Then, because Ph 1 chromosomes were found in 2.8% of 143 cells one year and 6 months after the termination of IFN-α, re-injection of IFN-α was started. The other patient is a 53-year-old woman exposed at 2.0 km in Hiroshima at the age of 6. She was pointed out to have leukocytosis in 1992; bone marrow examination showed the presence of Ph 1 chromosomes in 88.1% of 88 cells analyzed, leading to a diagnosis of CML. Subcutaneous injection of IFN-α (6,000,000 units/day) was started and 5 months later Ph 1 chromosomes disappeared. As of 11 months after the start of injection, no Ph 1 chromosomes were observed, but the patient is still treated with IFN-α injection. Effects of IFN-α and problems of residual Ph 1 chromosomes are discussed in a review of the literature. (N.K.)

  7. BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia.

    Science.gov (United States)

    Cuellar, Sandra; Vozniak, Michael; Rhodes, Jill; Forcello, Nicholas; Olszta, Daniel

    2017-01-01

    The management of chronic myeloid leukemia with BCR-ABL1 tyrosine kinase inhibitors has evolved chronic myeloid leukemia into a chronic, manageable disease. A patient-centered approach is important for the appropriate management of chronic myeloid leukemia and optimization of long-term treatment outcomes. The pharmacist plays a key role in treatment selection, monitoring drug-drug interactions, identification and management of adverse events, and educating patients on adherence. The combination of tyrosine kinase inhibitors with unique safety profiles and individual patients with unique medical histories can make managing treatment difficult. This review will provide up-to-date information regarding tyrosine kinase inhibitor-based treatment of patients with chronic myeloid leukemia. Management strategies for adverse events and considerations for drug-drug interactions will not only vary among patients but also across tyrosine kinase inhibitors. Drug-drug interactions can be mild to severe. In instances where co-administration of concomitant medications cannot be avoided, it is critical to understand how drug levels are impacted and how subsequent dose modifications ensure therapeutic drug levels are maintained. An important component of patient-centered management of chronic myeloid leukemia also includes educating patients on the significance of early and regular monitoring of therapeutic milestones, emphasizing the importance of adhering to treatment in achieving these targets, and appropriately modifying treatment if these clinical goals are not being met. Overall, staying apprised of current research, utilizing the close pharmacist-patient relationship, and having regular interactions with patients, will help achieve successful long-term treatment of chronic myeloid leukemia in the age of BCR-ABL1 tyrosine kinase inhibitors.

  8. Farmacogenética aplicada al tratamiento de la leucemia linfoide aguda Pharmacogenetics applied to the treatment of acute lymphoid leukemia

    Directory of Open Access Journals (Sweden)

    Yalena Prado Vizcaíno

    2011-09-01

    Full Text Available Las enzimas de biotransformación y eliminación de los fármacos en pacientes con leucemia linfoide aguda tienen una acción determinante en el efecto terapéutico de los medicamentos antineoplásicos. La presencia y actividad de estos complejos enzimáticos está codificada genéticamente y sujeta a variaciones alélicas, cuyas frecuencias son variables en las diferentes poblaciones humanas. Este polimorfismo genético influye sobre la efectividad terapéutica de los medicamentos y condiciona la carencia de toxicidad o presencia de esta, que en ocasiones puede ser fatal. Las enzimas tiopurin-metil-transferasa, metilén-tetrahidrofolato-reductasa y glutatión-tranferasa son sistemas destoxificadores de algunos de los quimioterápicos empleados en el tratamiento de la leucemia linfoide aguda. En este trabajo se revisan las características genéticas de estas enzimas, la frecuencia de sus polimorfismos y las implicaciones clínicas de su expresión. De igual modo se discute la importancia y los beneficios del genotipaje previo al inicio del tratamiento, con el fin de modificar las dosis de los medicamentos para optimizar su efecto terapéutico y disminuir su toxicidad. La farmacogenética constituye un área de creciente interés que ha tenido un desarrollo considerable en los últimos años, su conocimiento e implementación nos colocará en el camino de la medicina personalizada.The biotransformation and elimination enzymes of drugs in patients suffering from acute lymphoid leukemia play a decisive role on the therapeutical effect of anti-neoplastic drugs. The presence and activity of these enzymatic complexes are genetically coded and subjected to allele variations, the frequency of which is variable in the different human populations. This genetic polymorphism has an impact on the therapeutic effectiveness of drugs and determines the lack or the existence of toxicity that may sometimes become lethal. The enzymes called thiopurine

  9. Cryptochrome-1 expression: a new prognostic marker in B-cell chronic lymphocytic leukemia.

    Science.gov (United States)

    Lewintre, Eloisa Jantus; Martín, Cristina Reinoso; Ballesteros, Carlos García; Montaner, David; Rivera, Rosa Farrás; Mayans, José Ramón; García-Conde, Javier

    2009-02-01

    Chronic lymphocytic leukemia is an adult-onset leukemia with a heterogeneous clinical behavior. When chronic lymphocytic leukemia cases were divided on the basis of IgV(H) mutational status, widely differing clinical courses were revealed. Since IgV(H) sequencing is difficult to perform in a routine diagnostic laboratory, finding a surrogate for IgV(H) mutational status seems an important priority. In the present study, we proposed the use of Cryptochrome-1 as a new prognostic marker in early-stage chronic lymphocytic leukemia. Seventy patients (Binet stage A, without treatment) were included in the study. We correlated Cryptochrome-1 mRNA with well established prognostic markers such as IgV(H) mutations, ZAP70, LPL or CD38 expression and chromosomal abnormalities. High Cryptochrome-1 expression correlated with IgV(H) unmutated samples. In addition, Cryptochrome-1 was a valuable predictor of disease progression in early-stage chronic lymphocytic leukemia, therefore it can be introduced in clinical practice with the advantage of a simplified method of quantification.

  10. Ibrutinib: A New Frontier in the Treatment of Chronic Lymphocytic Leukemia by Bruton’s Tyrosine Kinase Inhibition

    Science.gov (United States)

    Dias, Ajoy Lawrence; Jain, Dharamvir

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of nonfunctional mature B cells in blood, bone marrow and lymphoid tissues. In the last decade, our understanding of CLL and consequently our diagnostic and therapeutic approaches have changed dramatically. Conventional fludarabine based chemotherapy has led to improved disease response and longer survival in young patients with CLL. However its application in elderly patients has been restricted by substantial myelosuppression and infection. Treatment of CLL is now moving towards targeted therapy. The success of new class of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further search for treatment agents with novel targets to inhibit. The B cell receptor activating pathway involving the Bruton’s tyrosine kinase (BTK) is crucial in B cell production and maintenance and is an attractive therapeutic target. Ibrutinib is an oral covalent inhibitor of the BTK pathway that induces apoptosis of B cells. Early phase studies with Ibrutinib either as a single agent or in combination regimens have shown promising results with an excellent safety profile in patients with high-risk, refractory or relapsed CLL and elderly treatment-naïve patients. This review summarizes the current knowledge of Ibrutinib in the treatment of CLL. PMID:24433470

  11. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Burger, Jan A; Tedeschi, Alessandra; Barr, Paul M; Robak, Tadeusz; Owen, Carolyn; Ghia, Paolo; Bairey, Osnat; Hillmen, Peter; Bartlett, Nancy L; Li, Jianyong; Simpson, David; Grosicki, Sebastian; Devereux, Stephen; McCarthy, Helen; Coutre, Steven; Quach, Hang; Gaidano, Gianluca; Maslyak, Zvenyslava; Stevens, Don A; Janssens, Ann; Offner, Fritz; Mayer, Jiří; O'Dwyer, Michael; Hellmann, Andrzej; Schuh, Anna; Siddiqi, Tanya; Polliack, Aaron; Tam, Constantine S; Suri, Deepali; Cheng, Mei; Clow, Fong; Styles, Lori; James, Danelle F; Kipps, Thomas J

    2015-12-17

    Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; PIbrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, Pibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall

  12. Successful Treatment For Chronic Eosinophilic Leukemia (CEL With Imatinib Mesylate

    Directory of Open Access Journals (Sweden)

    Rayane da Silva Souza

    2017-12-01

    Full Text Available We report a case of a patient with Chronic Eosinophilic Leukemia (CEL with mutation in alfa PDGFR gene exhibiting a satisfactory response to treatment with imatinib mesylate. A 25-year-old man presented in a hematology service with a persistent cough and hemogram alterations. His blood count showed a hemoglobin level of 12.5 g/dL and a white blood cell count of 94,030/mm3, eosinophils were 68% of all cells. Bone marrow aspiration and biopsy showed hypercellularity with marked eosinophilia (77% and erythroid differentiation series was hypocellular with normoblast maturation. The immunohistochemically of the bone biopsy was positive for myeloperoxidase and negative for CD34/CD99, consistent with CEL. Fluorescence in situ hybridization (FISH for the beta-fraction of platelet-derived growth factor (PDGFRβ and Philadelphia chromosome (Ph 1 were negative and the alfa PDGFR (Platelet-Derived Growth Factor was positive and showed heterozygosis in c.2531T>C on 18 Exon and homozygous in C.2562+1G>A at the region of the splicing site at the 18 intron. Treatment was initiated and maintained by administering 400mg/day imatinib mesylate. Laboratory findings returned to normal ranges, with clinical improvement and a hematological response observed after the second month of therapy. Currently, the patient’s blood count shows the white blood cell count (5,400 total leukocytes, eosinophils (8.6/mm3, hemoglobin (15.5 g/dl, hematocrit (45.4% and platelets (298,000/mm3 within normal ranges. The mutation search was negative in in peripheral blood one year after the initial treatment. Our work corroborates other studies on the efficacy of imatinib mesylate in the treatment of patients with CSF PDGFR alpha positive. We emphasize the importance of molecular studies, considering its relevance for the correct staging of the disease. Since CEL is a rare disease, it is important to define its etiology and anticipate its treatment, thus minimizing the damage induced by

  13. Cardiac Surgery Outcomes in Patients With Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Zhu, Yuanjia; Toth, Andrew J; Lowry, Ashley M; Blackstone, Eugene H; Hill, Brian T; Mick, Stephanie L

    2018-04-01

    Surgical outcomes of patients with chronic lymphocytic leukemia (CLL) undergoing cardiac surgery are limited. Our objectives were to investigate hospital morbidity and mortality after open cardiac surgery in CLL versus non-CLL patients. From May 1995 to May 2015, 157 patients with CLL and 55,917 without and older than 47 years underwent elective cardiac surgery at Cleveland Clinic. By Rai criteria, 79 CLL patients (56%) were low risk (class 0), 13 (9.1%) intermediate risk (classes I and II), and 38 (27%) high risk (classes III and IV); 12 (8.5%) were in remission. Mean age of CLL patients was 72 ± 9.0 years, and 18% were women. CLL patients were propensity-score matched to 3 non-CLL patients to compare surgical outcomes. High-risk CLL patients received more blood products than matched non-CLL patients (33/38 [87%] versus 74/114 [65%], p = 0.01), but were less likely to receive cryoprecipitate (0% versus 15/114 [13%], p = .02). Intermediate-risk CLL patients received more platelet units, mean 12 versus 4.6 (p = 0.008). Occurrence of deep sternal wound infection (0% versus 5/471 [1.1%]), septicemia (5/157 [3.2%] versus 14/471 [3.0%]), and hospital mortality (4/157 [2.5%] versus 14/471 [3.0%]) were similar (p > 0.3), independent of prior chemotherapy treatment for CLL. Although CLL patients did not have higher hospital mortality than non-CLL patients, high-risk CLL patients were more likely to receive blood products. Risks associated with transfusion should be considered when evaluating CLL patients for elective cardiac surgery. Appropriate preoperative management, such as blood product transfusions, and alternative treatment options that decrease blood loss, should be considered for high-risk patients. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  14. Treatment Options for Childhood Acute Myeloid Leukemia, Childhood Chronic Myelogenous Leukemia, Juvenile Myelomonocytic ...

    Science.gov (United States)

    ... can affect the blood and bone marrow. Transient abnormal myelopoiesis (TAM) TAM is a disorder of the bone marrow that can develop in ... is sometimes used to treat MDS or transient abnormal myelopoiesis (TAM). ... caused by the disease or its treatment. All patients with leukemia receive ...

  15. EBI2 overexpression in mice leads to B1 B-cell expansion and chronic lymphocytic leukemia-like B-cell malignancies.

    Science.gov (United States)

    Niss Arfelt, Kristine; Barington, Line; Benned-Jensen, Tau; Kubale, Valentina; Kovalchuk, Alexander L; Daugvilaite, Viktorija; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup; Egerod, Kristoffer L; Bassi, Maria R; Spiess, Katja; Schwartz, Thue W; Wang, Hongsheng; Morse, Herbert C; Holst, Peter J; Rosenkilde, Mette M

    2017-02-16

    Human and mouse chronic lymphocytic leukemia (CLL) develops from CD5 + B cells that in mice and macaques are known to define the distinct B1a B-cell lineage. B1a cells are characterized by lack of germinal center (GC) development, and the B1a cell population is increased in mice with reduced GC formation. As a major mediator of follicular B-cell migration, the G protein-coupled receptor Epstein-Barr virus-induced gene 2 ( EBI2 or GPR183 ) directs B-cell migration in the lymphoid follicles in response to its endogenous ligands, oxysterols. Thus, upregulation of EBI2 drives the B cells toward the extrafollicular area, whereas downregulation is essential for GC formation. We therefore speculated whether increased expression of EBI2 would lead to an expanded B1 cell subset and, ultimately, progression to CLL. Here, we demonstrate that B-cell-targeted expression of human EBI2 (hEBI2) in mice reduces GC-dependent immune responses, reduces total immunoglobulin M (IgM) and IgG levels, and leads to increased proliferation and upregulation of cellular oncogenes. Furthermore, hEBI2 overexpression leads to an abnormally expanded CD5 + B1a B-cell subset (present as early as 4 days after birth), late-onset lymphoid cancer development, and premature death. These findings are highly similar to those observed in CLL patients and identify EBI2 as a promoter of B-cell malignancies.

  16. Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Berthou Christian

    2010-12-01

    Full Text Available Abstract Background We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from Guttiferae trees, display in vitro antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL and leukemia B cell lines. Results Here, we investigated the in vivo therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (p = 0.0006 and p = 0.0141, respectively. The same treatment of mice which were not xenografted induced no mortality. Conclusion These data show for the first time the in vivo antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.

  17. [The role of genetic polymorphisms of interleukins in chronic lymphocytic leukemia in patients of different ages].

    Science.gov (United States)

    Sirotina, S S; Tikunova, T S; Proshchaev, K I; Efremova, O A; Batlutskaia, I V; Iakunchenko, T I; Sobianin, F I; Churnosov, M I; Alekseev, S M

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is a multifactorial disease, in which development the important role played the cytokine genes, in particular interleukins. This type of leukemia is more common in the elderly. The purpose of the study was to evaluate the association of genetic polymorphisms of interleukin with the development of chronic lymphocytic leukemia among residents of the Central Chernozem region of Russia. Genotyping of the -889C/T IL-1A, -590C/T IL-4 and VNTR IL-1 Ra was conducted in 206 patients with CLL and 307 individuals of the control group. The study found that the genetic risk factor for the development of CLL is allele -590T IL-4 (OR=-1,45). The development of thrombocytopenia in patients with CLL is associated with genetic variants -889T IL-1A (OR=1,95), -889TT IL-1A (OR=6,2) and IL-1Ra*1 (OR=-2,32).

  18. DNA apoptosis and stability in B-cell chronic lymphoid leukaemia: implication of the DNA double-strand breaks repair system by non homologous recombination

    International Nuclear Information System (INIS)

    Deriano, L.

    2005-01-01

    After an introduction presenting the diagnosis and treatment of chronic lymphoid leukaemia, its molecular and genetic characteristics, and its cellular origin and clonal evolution, this research thesis describes the apoptosis (definition and characteristics, cancer and chemotherapy, apoptotic ways induced by gamma irradiation), the genotoxic stresses, the different repair mechanisms for different damages, and the DNA repair processes. It reports how human chronic lymphocytic leukaemia B cells can escape DNA damage-induced apoptosis through the non-homologous end-joining DNA repair pathway, and presents non-homologous end-joining DNA repair as a potent mutagenic process in human chronic lymphocytic leukaemia B cells

  19. Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Gunnarsson, Rebeqa; Mansouri, Larry; Isaksson, Anders

    2011-01-01

    High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic...... profiles from sequential patients' samples allows detection of clonal evolution....

  20. Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia

    Science.gov (United States)

    TET2 enzymatically converts 5-methyl-cytosine to 5-hydroxymethyl-cytosine, possibly leading to loss of DNA methylation. TET2 mutations are common in myeloid leukemia and were proposed to contribute to leukemogenesis through DNA methylation. To expand on this concept, we studied chronic myelomonocyti...

  1. Cell lines generated from a chronic lymphocytic leukemia mouse model exhibit constitutive Btk and Akt signaling

    NARCIS (Netherlands)

    Singh, Simar Pal; Pillai, Saravanan Y.; de Bruijn, Marjolein J. W.; Stadhouders, Ralph; Corneth, Odilia B. J.; van den Ham, Henk Jan; Muggen, Alice; van Ijcken, Wilfred; Slinger, Erik; Kuil, Annemieke; Spaargaren, Marcel; Kater, Arnon P.; Langerak, Anton W.; Hendriks, Rudi W.

    2017-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature CD5(+) B cells in blood. Spontaneous apoptosis of CLL cells in vitro has hampered in-depth investigation of CLL pathogenesis. Here we describe the generation of three monoclonal mouse cell lines, EMC2, EMC4 and EMC6,

  2. Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Thijssen, Rachel; ter Burg, Johanna; Garrick, Brett; van Bochove, Gregor G. W.; Brown, Jennifer R.; Fernandes, Stacey M.; Rodríguez, María Solé; Michot, Jean-Marie; Hallek, Michael; Eichhorst, Barbara; Reinhardt, Hans Christian; Bendell, Johanna; Derks, Ingrid A. M.; van Kampen, Roel J. W.; Hege, Kristen; Kersten, Marie José; Trowe, Torsten; Filvaroff, Ellen H.; Eldering, Eric; Kater, Arnon P.

    2016-01-01

    Inhibition of B-cell receptor (BCR) signaling pathways in chronic lymphocytic leukemia (CLL) provides significant clinical benefit to patients, mainly by blocking adhesion of CLL cells in the lymph node microenvironment. The currently applied inhibitors ibrutinib and idelalisib have limited capacity

  3. The risk of chronic myeloid leukemia: Can the dose-response curve be U-shaped?

    Czech Academy of Sciences Publication Activity Database

    Radivoyevitch, T.; Kozubek, Stanislav; Sachs, R. K.

    2002-01-01

    Roč. 157, č. 1 (2002), s. 106-109 ISSN 0033-7587 R&D Projects: GA ČR GA202/01/0197; GA ČR GA301/01/0186; GA AV ČR IBS5004010 Keywords : radiation risk * chronic myeloid leukemia * chromosome translocation Subject RIV: BO - Biophysics Impact factor: 2.768, year: 2002

  4. Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Gunnarsson, Rebeqa; Mansouri, Larry; Isaksson, Anders

    2011-01-01

    High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic...

  5. Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation

    NARCIS (Netherlands)

    Mackus, W. J. M.; Kater, A. P.; Grummels, A.; Evers, L. M.; Hooijbrink, B.; Kramer, M. H. H.; Castro, J. E.; Kipps, T. J.; van Lier, R. A. W.; van Oers, M. H. J.; Eldering, E.

    2005-01-01

    We investigated the apoptosis gene expression profile of chronic lymphocytic leukemia (CLL) cells in relation to (1) normal peripheral and tonsillar B-cell subsets, (2) IgV(H) mutation status, and (3) effects of cytotoxic drugs. In accord with their noncycling, antiapoptotic status in vivo, CLL

  6. Clinical Practice Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL) in The Netherlands

    NARCIS (Netherlands)

    Kersting, Sabina; Neppelenbroek, Suzanne I. M.; Visser, Hein P. J.; van Gelder, Michel; Levin, Mark-David; Mous, Rogier; Posthuma, Ward; van der Straaten, Hanneke M.; Kater, Arnon P.

    2018-01-01

    In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukemia (CLL), and new potent drugs have become available. Therefore, the CLL working party revised the Dutch guidelines. Not only efficacy but also quality of life and socio-economic impact

  7. Simultaneous presence of two hematological malignancies: chronic lymphocytic leukemia and myelofibrosis in a patient.

    Science.gov (United States)

    Palta, Anshu; Garg, Shailja; Chauhan, Sandeep; Varma, Neelam

    2011-03-01

    Coexistence of chronic lymphocytic leukemia (CLL) with myelofibrosis is a rare association with only isolated case reports in the literature. We report an unusual case of CLL in which the cause of anemia was coexistent myelofibrosis. In a case of CLL presenting with refractory anemia, besides common causes like autoimmune hemolytic anemia and marrow infiltration, other causes like myelofibrosis should be searched for.

  8. p53-dependent non-coding RNA networks in chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Blume, C. J.; Hotz-Wagenblatt, A.; Hüllein, J.; Sellner, L.; Jethwa, A.; Stolz, T.; Slabicki, M.; Lee, K.; Sharathchandra, A.; Benner, A.; Dietrich, S.; Oakes, C. C.; Dreger, P.; te Raa, D.; Kater, A. P.; Jauch, A.; Merkel, O.; Oren, M.; Hielscher, T.; Zenz, T.

    2015-01-01

    Mutations of the tumor suppressor p53 lead to chemotherapy resistance and a dismal prognosis in chronic lymphocytic leukemia (CLL). Whereas p53 targets are used to identify patient subgroups with impaired p53 function, a comprehensive assessment of non-coding RNA targets of p53 in CLL is missing. We

  9. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Strefford, J C; Sutton, L-A; Baliakas, P

    2013-01-01

    Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B...

  10. Not all IGHV3-21 chronic lymphocytic leukemias are equal

    DEFF Research Database (Denmark)

    Baliakas, Panagiotis; Agathangelidis, Andreas; Hadzidimitriou, Anastasia

    2015-01-01

    An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue...

  11. Modeling of Chronic Myeloid Leukemia : An Overview of In Vivo Murine and Human Xenograft Models

    NARCIS (Netherlands)

    Sontakke, Pallavi; Jaques, Jenny; Vellenga, Edo; Schuringa, Jan Jacob

    2016-01-01

    Over the past years, a wide variety of in vivo mouse models have been generated in order to unravel the molecular pathology of Chronic Myeloid Leukemia (CML) and to develop and improve therapeutic approaches. These models range from (conditional) transgenic models, knock-in models, and murine bone

  12. Statistical Analysis of Competing Risks: Overall Survival in a Group of Chronic Myeloid Leukemia Patients

    Czech Academy of Sciences Publication Activity Database

    Fürstová, Jana; Valenta, Zdeněk

    2011-01-01

    Roč. 7, č. 1 (2011), s. 2-10 ISSN 1801-5603 Institutional research plan: CEZ:AV0Z10300504 Keywords : competing risks * chronic myeloid leukemia (CML) * overall survival * cause-specific hazard * cumulative incidence function Subject RIV: IN - Informatics, Computer Science http://www.ejbi.eu/images/2011-1/Furstova_en.pdf

  13. Improved survival for patients diagnosed with chronic lymphocytic leukemia in the era of chemo-immunotherapy

    DEFF Research Database (Denmark)

    da Cunha-Bang, C; Simonsen, J; Rostgaard, K

    2016-01-01

    The treatment of chronic lymphocytic leukemia (CLL) is in rapid transition, and during recent decades both combination chemotherapy and immunotherapy have been introduced. To evaluate the effects of this development, we identified all CLL patients registered in the nation-wide Danish Cancer...... for patients treated with chemo-immunotherapy demonstrated in clinical studies....

  14. Chronic myeloid leukemia and interferon-alpha : a study of complete cytogenetic responders

    NARCIS (Netherlands)

    Bonifazi, F; de Vivo, A; Rosti, G; Guilhot, F; Guilhot, J; Trabacchi, E; Hehlmann, R; Hochhaus, A; Shepherd, PCA; Steegmann, JL; Kluin-Nelemans, HC; Thaler, J; Simonsson, B; Louwagie, A; Reiffers, J; Mahon, FX; Montefusco, E; Alimena, G; Hasford, J; Richards, S; Saglio, G; Testoni, N; Martinelli, G; Tura, S; Baccarani, M

    2001-01-01

    Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CIVIL) with interferon-alpha (IFN-alpha), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the

  15. Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

    NARCIS (Netherlands)

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

    2010-01-01

    In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Having reported feasibility previously, we hereby

  16. Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

    NARCIS (Netherlands)

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

    2010-01-01

    Background In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Design and Methods Having reported

  17. Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

    NARCIS (Netherlands)

    Deenik, Wendy; Janssen, Jeroen J. W. M.; van der Holt, Bronno; Verhoef, Gregor E. G.; Smit, Willem M.; Kersten, Marie Jose; Daenen, Simon M. G. J.; Verdouck, Leo F.; Ferrant, Augustin; Schattenberg, Anton V. M. B.; Sonneveld, Pieter; Kooy, Marinus van Marwijk; Wittebol, Shulamit; Willemze, Roelof; Wijermans, Pierre W.; Beverloo, H. Berna; Lowenberg, Bob; Valk, Peter J. M.; Ossenkoppele, Gert J.; Cornelissen, Jan J.

    Background In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Design and Methods Having reported

  18. Not all IGHV3-21 chronic lymphocytic leukemias are equal: Prognostic considerations

    NARCIS (Netherlands)

    P. Baliakas (P.); A. Agathangelidis (Andreas); A. Hadzidimitriou (A.); L.-A. Sutton (L.); E. Minga (Evangelia); A. Tsanousa (Athina); L. Scarfó (L.); Z. Davis (Zadie); X.-J. Yan (Xiao-Jie); T. Shanafelt (Tait); K. Plevova (K.); Y. Sandberg (Yorick); F.J. Vojdeman (Fie Juhl); M. Boudjogra (Myriam); T. Tzenou (T.); M. Chatzouli (Maria); C.C. Chu (Charles C.); S. Veronese (Silvio); A. Gardiner (Anne); A. Mansouri (Ahmed); O. Smedby; L.B. Pedersen (Lone Bredo); D. Moreno (Denis); K. van Lom (Kirsten); V. Giudicelli (Veronique); H.S. Francova (Hana Skuhrova); F. Nguyen-Khac (Florence); P. Panagiotidis (P.); G. Juliusson (Gunnar); L. Angelis (Lefteris); C. Anagnostopoulos (Constantinos); M.-P. Lefranc (Marie-Paule); M. Facco (Monica); L. Trentin (Livio); M. Catherwood (M.); M. Montillo (Marco); C.H. Geisler (Christian); A.W. Langerak (Anton); D. Pospisilova (Dagmar); N. Chiorazzi (Nicholas); D.G. Oscier (David Graham); D.F. Jelinek (Diane F.); N. Darzentas (Nikos); C. Belessi (C.); F. Davi (Frédéric); P. Ghia (Paolo); R. Rosenquist (R.); K. Stamatopoulos (Kostas)

    2015-01-01

    textabstractAn unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised

  19. T-cell chronic lymphocytic leukemia in a double yellow-headed Amazon parrot (Amazona ochrocephala oratrix).

    Science.gov (United States)

    Osofsky, Anna; Hawkins, Michelle G; Foreman, Oded; Kent, Michael S; Vernau, William; Lowenstine, Linda J

    2011-12-01

    An adult, male double yellow-headed Amazon parrot (Amazona ochrocephala oratrix) was diagnosed with chronic lymphocytic leukemia based on results of a complete blood cell count and cytologic examination of a bone marrow aspirate. Treatment with oral chlorambucil was attempted, but no response was evident after 40 days. The bird was euthanatized, and the diagnosis of chronic lymphocytic leukemia was confirmed on gross and microscopic examination of tissues. Neoplastic lymphocytes were found in the bone marrow, liver, kidney, testes, and blood vessels. Based on CD3-positive immunocytochemical and immunohistochemical immunophenotyping, the chronic lymphocytic leukemia was determined to be of T-cell origin.

  20. High-Dose Busulfan and High-Dose Cyclophosphamide Followed By Donor Bone Marrow Transplant in Treating Patients With Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, or Recurrent Hodgkin or Non-Hodgkin Lymphoma

    Science.gov (United States)

    2010-08-05

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; 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 Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Burkitt Lymphoma; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myeloid Leukemia in Remission; Childhood Acute Myelomonocytic Leukemia (M4); Childhood Acute Promyelocytic Leukemia (M3); Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; De Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-Cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent

  1. PrPCWD lymphoid cell targets in early and advanced chronic wasting disease of mule deer

    NARCIS (Netherlands)

    Sigurdson, C.J.; Barillas-Mury, C.; Miller, M.W.; Oesch, B.; Keulen, van L.J.M.; Langeveld, J.P.M.; Hoover, E.A.

    2002-01-01

    Up to 15% of free-ranging mule deer in northeastern Colorado and southeastern Wyoming, USA, are afflicted with a prion disease, or transmissible spongiform encephalopathy (TSE), known as chronic wasting disease (CWD). CWD is similar to a subset of TSEs including scrapie and variant Creutzfeldt¿Jakob

  2. Spotlight on ibrutinib and its potential in frontline treatment of chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Khan M

    2017-03-01

    Full Text Available Maliha Khan, Jamie L Gibbons, Alessandra Ferrajoli Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: Chronic lymphocytic leukemia (CLL is the most prevalent leukemia in the adult population. Current efforts are focused on better understanding the intricate pathophysiology of the disease to develop successful targeted therapies. Ibrutinib is emerging as an important agent in this new age of targeted treatment for CLL. As a Bruton’s tyrosine kinase inhibitor, it blocks the signaling pathway that malignant B-lymphocytes need for growth and maturation. Ibrutinib’s role in therapy was further expanded recently when the US Food and Drug Administration approved its use in both frontline and salvage treatment for patients with CLL. This review assesses the effectiveness of ibrutinib in the frontline setting, its efficacy in various types of patients with CLL, and its safety and tolerability. Keywords: ibrutinib, CLL, frontline therapy

  3. Targeted Therapies in Hematology and Their Impact on Patient Care: Chronic and Acute Myeloid Leukemia

    Science.gov (United States)

    Cortes, Elias Jabbour Jorge; Ravandi, Farhad; O’Brien, Susan; Kantarjian, Hagop

    2014-01-01

    Advances in the genetic and molecular characterizations of leukemias have enhanced our capabilities to develop targeted therapies. The most dramatic examples of targeted therapy in cancer to date are the use of targeted BCR-ABL protein tyrosine kinase inhibitors (TKI) which has revolutionized the treatment of chronic myeloid leukemia (CML). Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target, transforming the prognosis of patients with CML. In contrast, acute myeloid leukemia (AML) is an extremely heterogeneous disease with outcomes that vary widely according to subtype of the disease. Targeted therapy with monoclonal antibodies and small molecule kinase inhibitors are promising strategies to help improve the cure rates in AML. In this review, we will highlight the results of recent clinical trials in which outcomes of CML and AML have been influenced significantly. Also, novel approaches to sequencing and combining available therapies will be covered. PMID:24246694

  4. Heme oxygenase-1: A new druggable target in the management of chronic and acute myeloid leukemia.

    Science.gov (United States)

    Salerno, Loredana; Romeo, Giuseppe; Modica, Maria N; Amata, Emanuele; Sorrenti, Valeria; Barbagallo, Ignazio; Pittalà, Valeria

    2017-12-15

    Heme oxygenase-1 (HO-1) is the enzyme catalyzing the rate-limiting oxidative degradation of cellular heme into free iron, carbon monoxide (CO), and biliverdin, which is then rapidly converted into bilirubin. By means of these catabolic end-products and by removal of pro-oxidant heme, HO-1 exerts antioxidant, antiapoptotic, and immune-modulating effects, leading to overall cytoprotective and beneficial functions in mammalian cells. Therefore, HO-1 is considered a survival molecule in various stress-related conditions. By contrast, growing evidence suggests that HO-1 is a survival-enhancing molecule also in various solid and blood cancers, such as various types of leukemia, promoting carcinogenesis, tumor progression, and chemo-resistance. Among leukemias, chronic myeloid leukemia (CML) is currently therapeutically well treated with tyrosine kinase inhibitors (TKIs) such as Imatinib (IM) and its congeners; nevertheless, resistance to all kinds of current drugs persist in a number of patients. Moreover, treatment outcomes for acute myeloid leukemia (AML) remain unsatisfactory, despite progress in chemotherapy and hematopoietic stem cell transplantation. Therefore, identification of new eligible targets that may improve leukemias therapy is of general interest. Several recent papers prove that inhibition of HO-1 through HO-1 inhibitors as well as modulation of other pathways involving HO-1 by a number of different new or known molecules, are critical for leukemia treatment. This review summarizes the current understanding of the pro-tumorigenic role of HO-1 and its potential as a molecular target for the treatment of leukemias. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Bone marrow transplantation in severe aplastic anemia and acute or chronic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Schaefer, U W; Mahmoud, H K; Beelen, D W; Hoffmann, W; Becher, R; Schmidt, C G; Bamberg, M; Quast, U; Haralambie, E; Linzenmeier, G

    1986-04-01

    In Essen 121 bone marrow transplantations were carried out. The indications were severe aplastic anemia, acute leukemia in relapse, acute leukemia in remission or chronic myeloid leukemia. The conditioning regimen consisted of cyclophosphamide or the combination of cyclophosphamide and total body irradiation. All patients were treated under strict gnotobiotic care. To mitigate the risk of CMV infections intravenous CMV-hyperimmunoglobulin and CMV-negative blood products have been applied routinely since two years. MTX was used as prophylaxis against GVH-disease. In case of severe aplastic anemia 13 patients (72%) are still alive with a median observation time of 24 months. In the prognostically unfavourable group of acute leukemia in relapse only one patient showed long term survival. In this patient leukemic relapse occurred six years after transplantation. The survival rate of AML patients grafted during the first remission is 55% with a median observation time of 40 months. For patients grafted in the first consecutive remission of ALL the survival rate is 42% with a maximal observation time of 29 months. Out of 37 patients grafted because of CML, eight were in an advanced stage of the disease. 13 patients are still alive, the maximal observation time is 37 months. The overall incidence of GVHD in patients at risk was 28% in aplastic anemia, 26% in AML, 9% in ALL and 63% in CML. In aplastic anemia no patient developed an interstitial pneumonia. In leukemia the risk of fatal interstitial pneumonia was 34%.

  6. Bone marrow transplantation in severe aplastic anemia and acute or chronic leukemia

    International Nuclear Information System (INIS)

    Schaefer, U.W.; Mahmoud, H.K.; Beelen, D.W.; Hoffmann, W.; Becher, R.; Schmidt, C.G.; Bamberg, M.; Quast, U.; Haralambie, E.; Linzenmeier, G.; Stollmann, B.; Grosse-Wilde, H.; Richter, H.J.; Hantschke, D.; Henneberg, K.; Luboldt, W.

    1986-01-01

    In Essen 121 bone marrow transplantations were carried out. The indications were severe aplastic anemia, acute leukemia in relapse, acute leukemia in remission or chronic myeloid leukemia. The conditioning regimen consisted of cyclophosphamide or the combination of cyclophosphamide and total body irradiation. All patients were treated under strict gnotobiotic care. To mitigate the risk of CMV infections intravenous CMV-hyperimmunoglobulin and CMV-negative blood products have been applied routinely since two years. MTX was used as prophylaxis against GVH-disease. In case of severe aplastic anemia 13 patients (72%) are still alive with a median observation time of 24 months. In the prognostically unfavourable group of acute leukemia in relapse only one patient showed long term survival. In this patient leukemic relapse occurred six years after transplantation. The survival rate of AML patients grafted during the first remission is 55% with a median observation time of 40 months. For patients grafted in the first consecutive remission of ALL the survival rate is 42% with a maximal observation time of 29 months. Out of 37 patients grafted because of CML, eight were in an advanced stage of the disease. 13 patients are still alive, the maximal observation time is 37 months. The overall incidence of GVHD in patients at risk was 28% in aplastic anemia, 26% in AML, 9% in ALL and 63% in CML. In aplastic anemia no patient developed an interstitial pneumonia. In leukemia the risk of fatal interstitial pneumonia was 34%. (orig.) [de

  7. Cytogenetic conversion following allogeneic bone marrow transplantation for advanced chronic myelogenous leukemia

    International Nuclear Information System (INIS)

    McGlave, P.B.; Miller, W.J.; Hurd, D.D.; Arthur, D.C.; Kim, T.

    1981-01-01

    We performed a pilot study to test the effectiveness of allogeneic bone marrow transplantation in the treatment of chronic myelogenous leukemia. Five patients in the advanced stages of chronic myelogenous leukemia (four in blast crisis, one in accelerated phase) with abnormal chromosomes underwent matched-sibling allogeneic bone marrow transplantation after preparation with busulfan, vincristine, cyclophosphamide, and fractionated total body irradiation. Engraftment and conversion to normal chromosome patterns after transplantation occurred in all five patients. None of the patients reverted to an abnormal chromosome pattern or demonstrated clinical or hematologic evidence of recurrent disease during the course of this study; however, longest survival from transplant was 248 days. Allogeneic bone marrow transplantation can eradicate the abnormal clone even in far advanced chronic myelogenous leukemia and can provide normal hematopoiesis. We suggest that clinical complications of chemotherapeutic toxicity and infection were responsible for the short survival in this group of patients, and that these complications could be decreased by performing transplantation in the chronic phase or early accelerated phase of the disease

  8. Allogeneic stem cell transplantation for acute myeloid leukemia with del(7q) following untreated chronic lymphocytic leukemia.

    Science.gov (United States)

    DeFilipp, Zachariah; Huynh, Donny V; Fazal, Salman; Sahovic, Entezam

    2012-01-01

    The development of hematologic malignancy in the presence of chronic lymphocytic leukemia (CLL) is rare. We present a case of acute myeloid leukemia (AML) with del(7q) occurring in a patient with a 4-year history of untreated CLL. Application of flow cytometry and immunohistochemistry allowed for characterization of two distinct coexisting malignant cell populations. After undergoing induction and consolidation chemotherapy, the patient achieved complete remission of AML with the persistence of CLL. Allogeneic transplantation was pursued given his unfavorable cytogenetics. Subsequent matched unrelated donor allogeneic stem cell transplantation resulted in full engraftment and complete remission, with no evidence of AML or CLL. Due to a scarcity of reported cases, insight into treatment and prognosis in cases of concurrent AML and CLL is limited. However, prognosis seems dependent on the chemosensitivity of AML. CLL did not have a detrimental effect on treatment or transplant outcome in our case. This is the first reported case of concomitant de novo AML and CLL to undergo allogeneic transplantation. The patient remained in complete hematologic and cytogenetic remission of both malignancies over a year after transplantation.

  9. Antileukemic Effect of Tualang Honey on Acute and Chronic Leukemia Cell Lines

    Directory of Open Access Journals (Sweden)

    Nik Muhd Khuzaimi Nik Man

    2015-01-01

    Full Text Available Complementary medicine using natural product as antitumor is on the rise. Much research has been performed on Tualang Honey and it was shown to have therapeutic potential in wound healing, and antimicrobial activity and be antiproliferative against several cancer models such as human osteosarcoma (HOS, human breast (MCF-7 and MDA-MB-231, and cervical (HeLa cancer cell lines. To date, there was limited study on antileukemic properties of Tualang (Koompassia excelsa Honey. The aim of this study was to evaluate the antileukemic effect of Tualang Honey on acute and chronic leukemia cell lines. Leukemia cell lines (K562 and MV4-11 and human mononuclear cell isolated from peripheral blood were grown in RPM1 1640 culture medium. The cells were incubated with increasing concentrations of Tualang Honey. After incubation, the evaluation of viability and apoptosis was performed. The morphological changes of leukemia cells were the presence of cytoplasmic blebs followed by apoptotic bodies and round shape of cells. IC50 against K562 and MV4-11 was determined. Tualang Honey gave 53.9% and 50.6% apoptosis activity on K562 and MV4-11, respectively, while on human mononuclear cell it was 37.4%. Tualang Honey has the apoptosis-inducing ability for acute and chronic myeloid leukemia (K562 and MV4-11 cell lines.

  10. Epidemiologic study on survival of chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation

    DEFF Research Database (Denmark)

    Nicolini, Franck E; Mauro, Michael J; Martinelli, Giovanni

    2009-01-01

    The BCR-ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP......), or blastic-phase (BP) and Philadelphia chromosome-positive (Ph)(+) acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation...

  11. Polycythemia vera treated with /sup 32/P and myleran: Development of chronic granulocytic leukemia with chromosomal abnormalities in one patient

    Energy Technology Data Exchange (ETDEWEB)

    Stavem, P; Sandnes, K [Rikshospitalet, Oslo (Norway); Hagen, C.B. van der [Oslo Univ. (Norway); Vogt, E [Statens Institutt for Folkehelse, Oslo, Norway

    1975-01-01

    Chronic granulocytic leukemia developed in a 59-year-old woman who had previously received a total of 21 mCl /sup 32/P for polycythemia vera. She was treated with Myleran (busulphan) for her chronic granulocytic leukemia. Cytogenetic studies revealed deletion of chromosomes No. 8 and 12, and translocation between 1 and 8. The patient also developed a severe autoimmune hemolytic anemia, for which she received prednisone treatment. She died with a perforated stomach ulcer. (INIS)

  12. Prior history of non-melanoma skin cancer is associated with increased mortality in patients with chronic lymphocytic leukemia

    Science.gov (United States)

    Toro, Jorge R.; Blake, Patrick W.; Björkholm, Magnus; Kristinsson, Sigurdur Y.; Wang, Zhuoqiao; Landgren, Ola

    2009-01-01

    We investigated whether a previous diagnosis of non-melanoma skin cancer among chronic lymphocytic leukemia patients is a predictor of poor outcome. Using the Swedish Cancer Registry, we conducted a population-based study to evaluate the survival patterns among chronic lymphocytic leukemia patients with and without non-melanoma skin cancer. Cox proportional hazards regression models were used and Kaplan-Meier curves were constructed. Of a total of 12,041 chronic lymphocytic leukemia cases identified, 236 cases, including 111 squamous cell cancer, had a prior history of non-melanoma skin cancer. Chronic lymphocytic leukemia patients with a prior history of non-melanoma skin cancer had a 1.29-fold (95% CI 1.10–1.52; p=0.0024) increased risk of dying; and those with a history of squamous cell cancer had a further elevated 1.86-fold (95% CI 1.46–2.36; p<0.0001) risk of dying. Kaplan-Meier plots showed that patients with a history of non-melanoma skin cancer, particularly those with squamous cell cancer, had significantly poorer survival than chronic lymphocytic leukemia patients without non-melanoma skin cancer (p<0.0001; log-rank test). Non-melanoma skin cancer may be a novel clinical predictor of worse chronic lymphocytic leukemia outcome. PMID:19794092

  13. Disfunción neurocognitiva en niños con leucemia linfoide aguda Neurocognitive disfunction in children with acute lymphoid leukemia

    Directory of Open Access Journals (Sweden)

    Raúl Martínez-Triana

    2013-03-01

    Full Text Available Introducción: se ha comunicado afectación neurocognitiva como secuela a largo plazo en pacientes curados de leucemia linfoide aguda que fueron irradiados durante el tratamiento. Más recientemente esto se plantea también para los tratados solo con quimioterapia. Sobre estos últimos no se conocen antecedentes en Cuba de estudios de este tipo. Métodos: se estudió el rendimiento intelectual de 77 pacientes entre 6 y 32 años (54 con tratamiento y 23 con sobrevida de más de 5 años que no recibieron radiaciones durante su tratamiento, y de un grupo (n=20 de adolescentes sanos. Se utilizó la escala de inteligencia de Wechsler para niños (Wisc y para adultos (Wais. Resultados: los resultados mostraron que las escalas totales, tanto de los enfermos como de los curados, se encontraba dentro de parámetros normales. Sin embargo, se obtuvieron notaciones significativamente más bajas en los pacientes curados que en los sanos en las pruebas de semejanzas, dígitos, ordenar figuras y diseño de bloques; también en el factor de distractibilidad. Los pacientes que se encontraban enfermos en la evaluación obtuvieron puntuación más baja que los normales solo en la prueba de dígitos. Conclusiones: estos resultados sugieren afectaciones subclínicas específicas relacionadas con la capacidad de asociación de conceptos verbales, memoria inmediata, capacidad de planeamiento estratégico, organización visoespacial, análisis y síntesis como procesos del pensamiento, así como una dificultad atencional en los pacientes curados como secuela de la quimioterapia.Introduction: neurocognitive disorders have been reported as long-term side effects in patients free from acute lymphoid leukemia that had undergone radiotherapy. These disorders have been likewise reported in those cases in which the patients had undergone chemotherapy. No antecedents about previous study on the latter in Cuba are known. Methods: the intellectual performance of 77 patients who

  14. Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia is a predictor of early death

    DEFF Research Database (Denmark)

    Andersen, Michael Asger; Vojdeman, Fie Juhl; Andersen, Mette Klarskov

    2016-01-01

    Hypogammaglobulinemia is the most common immune deficiency in chronic lymphocytic leukemia (CLL). However, the prognostic significance in terms of morbidity and mortality remains controversial. We here evaluate the significance of hypogammaglobulinemia in terms of infections, treatment-free survi......Hypogammaglobulinemia is the most common immune deficiency in chronic lymphocytic leukemia (CLL). However, the prognostic significance in terms of morbidity and mortality remains controversial. We here evaluate the significance of hypogammaglobulinemia in terms of infections, treatment......-free survival (TFS), and overall survival (OS). A total of 159 consecutive, newly diagnosed patients were included for analysis. Twenty-five patients (16%) had a moderate or severe infection within one year of diagnosis, but no associations were found between low immunoglobulin (Ig) levels and infections...

  15. Chronic myeloid leukemia and its induction by radiation

    International Nuclear Information System (INIS)

    Kozubek, S.; Lukasova, E.; Kozubek, M.; Bartova, E.; Skalnikova, M.; Kroha, V.

    1998-01-01

    Physical distance can play an important role in the process leading to the translocations that are responsible for oncogenic transformation of cells. Thus, e.g., one of the reasons of a high incidence of ABL/BCR fusion may be the physical closeness of ABL and BCR genes in cells. The average distance of ABL-BCR genes in interphase lymphocytes is only 24% of the nuclear radius; after stimulation, this distance increases to 35%. The mean value for randomly distributed genes in a sphere is 43%. This means that the mutual distance of the critical genes is largely smaller than the random distance. The distance between chromosomes 9 and 22 in prometaphase plates (rosettes) of human fibroblasts was also investigated. In many prometaphase rosettes, each copy of chromosome 9 was located near a copy of chromosome 22 and the pairs were located on opposite sides of the plate. Thus both in the interphase and in mitosis, the distance between ABL and BCR genes, located in chromosomes 9 and 22, is substantially shorter than the random value. This contributes to the observed incidence of leukemia. The positions of ABL and BCR genes in irradiated and stimulated lymphocytes are shifted to the centre of the nucleus. They are closer to each other, and also the distances between heterologous ABL and BCR genes are shorter. In 15% of the cell nuclei irradiated with gamma rays (5 Gy), the volume in which the genes appear is 6 times smaller than in control nuclei. Hence, the probability of interaction between ABL and CBR genes increases 6 2 x 0.15 = 5.4 times. Thus, radiation increases substantially the probability of induction of leukemia not only through DNA damage but also due to changes in the chromatin structure in irradiated cells, which concentrates the critical genes in a relatively small volume

  16. Human innate lymphoid cells.

    Science.gov (United States)

    Mjösberg, Jenny; Spits, Hergen

    2016-11-01

    Innate lymphoid cells (ILCs) are increasingly acknowledged as important mediators of immune homeostasis and pathology. ILCs act as early orchestrators of immunity, responding to epithelium-derived signals by expressing an array of cytokines and cell-surface receptors, which shape subsequent immune responses. As such, ILCs make up interesting therapeutic targets for several diseases. In patients with allergy and asthma, group 2 innate lymphoid cells produce high amounts of IL-5 and IL-13, thereby contributing to type 2-mediated inflammation. Group 3 innate lymphoid cells are implicated in intestinal homeostasis and psoriasis pathology through abundant IL-22 production, whereas group 1 innate lymphoid cells are accumulated in chronic inflammation of the gut (inflammatory bowel disease) and lung (chronic obstructive pulmonary disease), where they contribute to IFN-γ-mediated inflammation. Although the ontogeny of mouse ILCs is slowly unraveling, the development of human ILCs is far from understood. In addition, the growing complexity of the human ILC family in terms of previously unrecognized functional heterogeneity and plasticity has generated confusion within the field. Here we provide an updated view on the function and plasticity of human ILCs in tissue homeostasis and disease. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  17. Prostatic-Like Syndrome in a Woman with Chronic Lymphocytic Leukemia: Sequential Kinase Inhibitor Therapy

    Directory of Open Access Journals (Sweden)

    Diego Velasco-Rodríguez

    2017-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is an incurable lymphoproliferative disorder with a heterogeneous genetic and clinical course. Two kinase inhibitors, ibrutinib and idelalisib, have demonstrated achievement of complete and durable remissions in relapse/refractory genetically unselected CLL patients. We present a case of relapsed CLL with extensive disease and hourglass deformity of urinary bladder as a result of the compression of two extraperitoneal paravesical soft tissue bulky masses, with excellent response to sequential kinase inhibitor therapy.

  18. Chronic lymphocytic leukemia/small lymphocytic lymphoma presenting as septic arthritis of the shoulder

    Energy Technology Data Exchange (ETDEWEB)

    Donovan, Andrea; Schweitzer, Mark E.; Nomikos, George [NYU Hospital for Joint Diseases, New York, NY (United States); Garcia, Roberto A. [Bellevue Hospital Center, New York, NY (United States)

    2008-11-15

    We report a case of a 53-year-old man presenting with shoulder pain mimicking septic arthritis. Laboratory findings were atypical. Biopsy performed to assess for possible osteomyelitis demonstrated chronic lymphocytic leukemia/small lymphocytic lymphoma. Intra-articular lymphoma is a rare but important consideration in patients with atypical clinical presentation. Imaging alone may be insufficient to render diagnosis as lymphoma can mimic infection, synovial hypertrophic processes, and depositional arthropathy. (orig.)

  19. Renal Bleeding Due to Extramedullary Hematopoiesis in a Patient With Chronic Myelogenous Leukemia

    OpenAIRE

    Stephanie Zettner; Sandeep G. Mistry

    2014-01-01

    Chronic myelogenous leukemia (CML) is a myeloproliferative disorder that normally presents in middle-aged adults. Renal infiltration and extramedullary hematopoiesis in renal tissue has been rarely reported. This case report presents a patient with CML and renal insufficiency who developed gross hematuria. Efforts at controlling the hematuria led to a cascade of events propelled by the underlying disorder that ultimately led to a radical nephrectomy, multiorgan failure, and prolonged hospital...

  20. Progranulin Is a Novel Independent Predictor of Disease Progression and Overall Survival in Chronic Lymphocytic Leukemia

    OpenAIRE

    G?bel, Maria; Eisele, Lewin; M?llmann, Michael; H?ttmann, Andreas; Johansson, Patricia; Scholtysik, Ren?; Bergmann, Manuela; Busch, Raymonde; D?hner, Hartmut; Hallek, Michael; Seiler, Till; Stilgenbauer, Stephan; Klein-Hitpass, Ludger; D?hrsen, Ulrich; D?rig, Jan

    2013-01-01

    Progranulin (Pgrn) is a 88 kDa secreted protein with pleiotropic functions including regulation of cell cycle progression, cell motility, wound repair and tumorigenesis. Using microarray based gene expression profiling we have recently demonstrated that the gene for Pgrn, granulin (GRN), is significantly higher expressed in aggressive CD38(+)ZAP-70(+) as compared to indolent CD38(-)ZAP-70(-) chronic lymphocytic leukemia (CLL) cases. Here, we measured Pgrn plasma concentrations by enzyme-linke...

  1. Dasatinib-Induced Rhabdomyolysis in a 33-Year-Old Patient with Chronic Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Andrew Stevenson Joel Chandranesan

    2018-01-01

    Full Text Available Rhabdomyolysis is a life-threatening syndrome due to breakdown of the skeletal muscle. It can be caused by massive trauma and crush injuries or occur as a side effect of medications. Here, we describe a case of a 33-year-old male with human immunodeficiency virus (HIV and newly diagnosed chronic myeloid leukemia (CML with severe life-threatening rhabdomyolysis due to a rare offending agent.

  2. New Insights into Biology, Prognostic Factors, and Current Therapeutic Strategies in Chronic Lymphocytic Leukemia

    OpenAIRE

    Smolewski, Piotr; Witkowska, Magdalena; Korycka-Wołowiec, Anna

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by the clonal proliferation and accumulation of mature B lymphocytes. CLL cells show an antiapoptotic profile, suggesting the important role of apoptosis inhibition in the disease development. However, there is some population of proliferating CLL cells, which may also play a role in progression of the disease. There are several newer, biological prognostic factors in CLL. Currently, cytogenetic abnormalities with different prognostic values...

  3. Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib

    OpenAIRE

    Okamoto, Koh; Proia, Laurie A.; Demarais, Patricia L.

    2016-01-01

    Cryptococcus is a unique environmental fungus that can cause disease most often in immunocompromised individuals with defective cell-mediated immunity. Chronic lymphocytic leukemia (CLL) is not known to be a risk factor for cryptococcal disease although cases have been described mainly in patients treated with agents that suppress cell-mediated immunity. Ibrutinib is a new biologic agent used for treatment of CLL, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia. It acts by inhibitin...

  4. Ibrutinib as an antitumor immunomodulator in patients with refractory chronic lymphocytic leukemia

    OpenAIRE

    Cubillos-Zapata, Carolina; Avendaño-Ortiz, Jose; Córdoba, Raúl; Hernández-Jiménez, Enrique; Toledano, Victor; Pérez de Diego, Rebeca; López-Collazo, Eduardo

    2016-01-01

    Ibrutinib has emerged as a promising therapy for patients with chronic lymphocytic leukemia (CLL) who are nonresponsive to standard therapies. The refractory state of monocytes and T-cell exhaustion in patients with CLL could explain the morbidity and mortality reported in these patients. We studied the effect of ibrutinib on the immune response of four relapsed patients with CLL during the first treatment cycle. We observed the ability to recover the standard response against bacterial stimu...

  5. Tophaceous gout in an amputation stump in a patient with chronic myelogenous leukemia

    International Nuclear Information System (INIS)

    Chung, Christine B.; Mohana-Borges, Aurea; Pathria, Mini

    2003-01-01

    Gout is a common rheumatologic disorder that can have an unusual clinical presentation. This case report describes the development of a gouty tophus at a site of remote traumatic forearm amputation in a patient with chronic myelogenous leukemia (CML). It further addresses the imaging characteristics of tophaceous gout as well as the differential diagnostic considerations as regards both the imaging findings and the clinical presentation. (orig.)

  6. [Acute transformation of chronic myeloid leukemia: disappearance of the Philadelphia chromosome after autograft].

    Science.gov (United States)

    Reiffers, J; David, B; Bernard, P; Vezon, G; Marit, G; Moulinier, J; Broustet, A

    1984-04-12

    Two patients with chronic granulocytic leukemia (C.G.L.) undergoing transformation were treated by high dose chemotherapy and total body irradiation followed by autografting of hematopoietic stem cells collected and cryo-preserved at the time of diagnosis. Recovery of hematopoiesis was characterized by disappearance of the Philadelphia chromosome in most metaphases. A new approach of the management of C.G.L. is discussed.

  7. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia

    OpenAIRE

    Choi, Goda; van den Broek, Esther C; Stam, Olga CG; van Noesel, C.J.M.; Tonino, Sanne H.; Kater, Armon P.

    2015-01-01

    We present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compare...

  8. B-Cell Chronic Lymphocytic Leukemia with 11q22.3 Rearrangement in Patient with Chronic Myeloid Leukemia Treated with Imatinib

    Directory of Open Access Journals (Sweden)

    Krzysztof Lewandowski

    2016-01-01

    Full Text Available The coexistence of two diseases chronic myeloid leukemia (CML and B-cell chronic lymphocytic leukemia (B-CLL is a rare phenomenon. Both neoplastic disorders have several common epidemiological denominators (they occur more often in men over 50 years of age but different origin and long term prognosis. In this paper we described the clinical and pathological findings in patient with CML in major molecular response who developed B-CLL with 11q22.3 rearrangement and Coombs positive hemolytic anemia during the imatinib treatment. Due to the presence of the symptoms of autoimmune hemolytic anemia and optimal CML response to the imatinib treatment, the decision about combined therapy with prednisone and imatinib was made. During the follow-up, the normalization of complete blood count and resolution of peripheral lymphadenopathy were noted. The hematologic response of B-CLL was diagnosed. The repeated FISH analysis of cultured peripheral blood lymphocytes showed 2% of cells carrying 11q22.3 rearrangement. At the same time, molecular monitoring confirmed the deep molecular response of CML. The effectiveness of such combination in the described case raises the question about the best therapeutic option in such situation, especially in patients with good imatinib tolerance and optimal response.

  9. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: Recommendations for clinical practice from the French Chronic Myeloid Leukemia Study Group.

    Science.gov (United States)

    Rea, Delphine; Ame, Shanti; Berger, Marc; Cayuela, Jean-Michel; Charbonnier, Aude; Coiteux, Valérie; Cony-Makhoul, Pascale; Dubruille, Viviane; Dulucq, Stéphanie; Etienne, Gabriel; Legros, Laurence; Nicolini, Franck; Roche-Lestienne, Catherine; Escoffre-Barbe, Martine; Gardembas, Martine; Guerci-Bresler, Agnès; Johnson-Ansah, Hyacinthe; Rigal-Huguet, Françoise; Rousselot, Philippe; Mahon, François-Xavier

    2018-05-03

    The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice. Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucémies Myéloïdes Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice. Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction. This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

  10. BCR-ABL1- positive chronic myeloid leukemia with erythrocytosis presenting as polycythemia vera: a case report.

    Science.gov (United States)

    Cornea, Mihaela I Precup; Levrat, Emmanuel; Pugin, Paul; Betticher, Daniel C

    2015-04-08

    The World Health Organization classification of chronic myeloproliferative disease encompasses eight entities of bone marrow neoplasms, among them Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1-positive chronic myeloid leukemia and polycythemia vera. Polycythemia vera requires, in the majority of cases (95%), the negativity of Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 rearrangement and the presence of the Janus kinase 2 mutation. We report a case of erythrocytosis as the primary manifestation of a chronic myeloid leukemia, with the presence of the Philadelphia chromosome and the Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion gene, and in the absence of any Janus kinase 2 mutation. A 68-year-old Caucasian woman, with a history of cigarette consumption and obstructive sleep apnoea syndrome (undergoing continuous positive airway pressure treatment) had presented to our institution with fatigue and a hemoglobin level of 18.6g/L, with slight leukocytosis at 16G/L, and no other anomalies on her complete blood cell count. Examination of her arterial blood gases found only a slight hypoxemia; erythropoietin and ferritin levels were very low and could not explain a secondary erythrocytosis. Further analyses revealed the absence of any Janus kinase 2 mutation, thus excluding polycythemia vera. Taken together with a high vitamin B12 level, we conducted a Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 gene analysis and bone marrow cytogenetic analysis, both of which returned positive, leading to the diagnosis of chronic myeloid leukemia. To date, this case is the first description of a Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1-positive chronic myeloid leukemia, presenting with erythrocytosis as the initial manifestation, and mimicking a Janus kinase 2 V617F-negative polycythemia vera. Her impressive response to imatinib

  11. Quantification of newly produced B and T lymphocytes in untreated chronic lymphocytic leukemia patients

    Directory of Open Access Journals (Sweden)

    Caimi Luigi

    2010-11-01

    Full Text Available Abstract Background The immune defects occurring in chronic lymphocytic leukemia are responsible for the frequent occurrence of infections and autoimmune phenomena, and may be involved in the initiation and maintenance of the malignant clone. Here, we evaluated the quantitative defects of newly produced B and T lymphocytes. Methods The output of B and T lymphocytes from the production and maturation sites was analyzed in chronic lymphocytic leukemia patients and healthy controls by quantifying kappa-deleting recombination excision circles (KRECs and T-cell receptor excision circles (TRECs by a Real-Time PCR assay that simultaneously detects both targets. T-lymphocyte subsets were analyzed by six-color flow cytometric analysis. Data comparison was performed by two-sided Mann-Whitney test. Results KRECs level was reduced in untreated chronic lymphocytic leukemia patients studied at the very early stage of the disease, whereas the release of TRECs+ cells was preserved. Furthermore, the observed increase of CD4+ lymphocytes could be ascribed to the accumulation of CD4+ cells with effector memory phenotype. Conclusions The decreased number of newly produced B lymphocytes in these patients is likely related to a homeostatic mechanism by which the immune system balances the abnormal B-cell expansion. This feature may precede the profound defect of humoral immunity characterizing the later stages of the disease.

  12. Efficiency of use endobronchial laser doppler-flowmetry in patients with chronic leukemia

    Science.gov (United States)

    Vanina, E. A.; Voitsekhovskiy, V. V.; Landyshev, Y. S.; Tkacheva, S. I.

    2016-11-01

    In this work indicatorsendobronchial microcirculation were investigated in patients with chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), polycythemia vera (PV), idiopathic myelofibrosis (IMF). A diagnostic bronchoscopy was performed using fibreoptic «Olympus» (Japan).Endobronchial laser Doppler flowmetry was carried out on the laser analyzer capillary blood LAK-02 (Russia). Laser Doppler flowmetry indicators such as parameter of microcirculation, the oscillation amplitude in the endothelial, neurogenic, myogenic, cardiac and respiratory ranges were calculated by continuous the Wavelet transforms. Reduced cardiac and respiratory amplitudes in CML and CLL are primarily due to the development leukostasis. If PV is the case, this is due to sludge syndrome. And when MM occurs, it is caused by protein stasis in the vessels of the bronchial tubes. Increased endothelial oscillation amplitudes in the range in CML, PV, IMF and their reduction in MM indicate the presence of endothelial dysfunction in these patients. Increasing the amplitude of oscillations in the range of neurogenic indicates the development of arteriolar vasodilation as a compensatory response to the violation of blood flow. Increasing the amplitude of oscillations of myogenic tone indicating decrease precapillaries as a compensatory reaction to improve blood flow. It is concluded that endobronchial laser Doppler flowmetry is an important method allowing diagnosing the pathology of the microvasculature of the bronchi in chronic leukemia.

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

    Directory of Open Access Journals (Sweden)

    Rohan Bhise

    2013-01-01

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

  14. Molecular relapse in chronic myelogenous leukemia patients after bone marrow transplantation detected by polymerase chain reaction

    International Nuclear Information System (INIS)

    Sawyers, C.L.; Timson, L.; Clark, S.S.; Witte, O.N.; Champlin, R.; Kawasaki, E.S.

    1990-01-01

    Relapse of chronic myelogenous leukemia after bone marrow transplantation can be detected by using clinical, cytogenetic, or molecular tools. A modification of the polymerase chain reaction can be used in patients to detect low levels of the BCR-ABL-encoded mRNA transcript, a specific marker for chronic myelogenous leukemia. Early detection of relapse after bone marrow transplantation could potentially alter treatment decisions. The authors prospectively evaluated 19 patients for evidence of molecular relapse, cytogenetic relapse, and clinical relapse after bone marrow transplantation. They used the polymerase chain reaction to detect residual BCR-ABL mRNA in patients followed up to 45 months after treatment and found 4 patients with BCR-ABL mRNA expression following bone marrow transplantation. Fifteen patients did not express detectable BCR-ABL mRNA. All 19 patients remain in clinical remission. In this prospective study of chronic myelogenous leukemia patients treated with bone marrow transplantation, molecular relapse preceded cytogenetic relapse in those patients who persistently express BCR-ABL mRNA. They recommend using standard clinical and cytogenetic testing to make patient care decisions until further follow-up determines the clinical outcome of those patients with residual BCR-ABL mRNA transcripts detected by polymerase chain reaction

  15. Outcomes for Patients with Chronic Lymphocytic Leukemia (CLL) and Acute Leukemia or Myelodysplastic Syndrome

    Science.gov (United States)

    Tambaro, Francesco Paolo; Garcia-Manero, Guillermo; O’Brien, Susan M.; Faderl, Stefan H.; Ferrajoli, Alessandra; Burger, Jan A.; Pierce, Sherry; Wang, Xuemei; Do, Kim-Anh; Kantarjian, Hagop M.; Keating, Michael J.; Wierda, William G.

    2016-01-01

    Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in CLL. We retrospectively identified 95 patients with CLL also diagnosed with AL (n=38) or MDS (n=57), either concurrently (n=5) or subsequent (n=90) to CLL diagnosis and report their outcomes. Median number of CLL treatments prior to AL and MDS was 2(0–9) and 1(0–8), respectively; the most common regimen was purine analogue combined with alkylating agent±CD20 mAb. Twelve had no prior CLL treatment. Among 38 with AL, 33 had AML, 3 had ALL (1Ph+), 1 had biphenotypic, and 1 had extramedullary (bladder) AML. Unfavorable AML karyotype was noted in 26, intermediate-risk in 7. There was no association between survival from AL and number of prior CLL regimens or karyotype. Expression of CD7 on blasts was associated with shorter survival. Among MDS cases, all IPSS were represented; karyotype was unfavorable in 36, intermediate in 6, and favorable in 12 patients; 10 experienced transformation to AML. Shorter survival from MDS correlated with higher-risk IPSS, poor-risk karyotype, and increased number of prior CLL treatments. Overall, outcomes for patients with CLL subsequently diagnosed with AL or MDS were poor; AL/MDS occurred without prior CLL treatment. Effective therapies for these patients are desperately needed. PMID:26290497

  16. Potential mechanisms of disease progression and management of advanced-phase chronic myeloid leukemia

    Science.gov (United States)

    Jabbour, Elias J.; Hughes, Timothy P.; Cortés, Jorge E.; Kantarjian, Hagop M.; Hochhaus, Andreas

    2014-01-01

    Despite vast improvements in treatment of Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated phase or blast crisis, remain notoriously difficult to treat. Treatments that are highly effective against CML-CP produce disappointing results against advanced disease. Therefore, a primary goal of therapy should be to maintain patients in CP for as long as possible, by (1) striving for deep, early molecular response to treatment; (2) using tyrosine kinase inhibitors that lower risk of disease progression; and (3) more closely observing patients who demonstrate cytogenetic risk factors at diagnosis or during treatment. PMID:24050507

  17. Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents

    DEFF Research Database (Denmark)

    Millot, Frédéric; Guilhot, Joëlle; Suttorp, Meinolf

    2017-01-01

    The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression ...

  18. Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents

    NARCIS (Netherlands)

    Millot, Frederic; Guilhot, Joelle; Suttorp, Meinolf; Gunes, Adalet Meral; Sedlacek, Petr; De Bont, Eveline; Li, Chi Kong; Kalwak, Krzysztof; Lausen, Birgitte; Culic, Srdjana; Dworzak, Michael; Kaiserova, Emilia; De Moerloose, Barbara; Roula, Farah; Biondi, Andrea; Baruchel, Andre

    2017-01-01

    The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression

  19. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers.

    Science.gov (United States)

    Palma, Marzia; Gentilcore, Giusy; Heimersson, Kia; Mozaffari, Fariba; Näsman-Glaser, Barbro; Young, Emma; Rosenquist, Richard; Hansson, Lotta; Österborg, Anders; Mellstedt, Håkan

    2017-03-01

    Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3 + cells and the CD8 + subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4 + and CD8 + cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients ( P =0.0003 and P =0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4 + and CD8 + subsets, with a significantly higher PD-1 expression. Higher numbers of CD4 + and CD8 + cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67 + ) and activated (CD69 + ) CD4 + and CD8 + cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls ( P leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways. Copyright© Ferrata Storti Foundation.

  20. Post-transplant outcome in chronic myeloid leukemia

    International Nuclear Information System (INIS)

    Raza, S.; Ullah, K.; Ahmed, P.; Kamal, M.K.

    2008-01-01

    To determine post-transplant survival in chronic myeloid leukaemia patients undergoing allogeneic stem cell transplant. All patients of chronic myeloid leukaemia in chronic phase having HLA identical donor and age under 55 years, normal hepatic, renal and cardiac functions with good performance status were selected. Patients in accelerated phase or blast crisis, poor performance status, impaired hepatic, renal, cardiac functions or pregnancy were excluded. Survival was calculated from the date of transplant to death or last follow-up according to Kaplan-Meier and Cox (proportional hazard) regression analysis methods. Thirty seven patients with chronic myeloid leukaemia underwent allogeneic stem cell transplant from HLA identical sibling donors. Thirty two patients were male and five were females. Median age of patients was 28 years. All patients and donors were CMV positive. Post-transplant complications encountered were acute GvHD (Grade II-IV) (n=13, 35.1%), chronic GvHD in 18.9% (n=7), Veno Occlusive Disease (VOD) in 5.4% (n=2), acute renal failure in 2.7% (n=1), haemorrhagic cystitis in 2.7% (n=1), bacterial infections in 40.5% (n=15), fungal infections in 16.2% (n=6), CMV infection in 5.4% (n=2), tuberculosis in 5.4% (n=2), Herpes Zoster infection 2.7% (n=1) and relapse in 2.7% (n=1). Mortality was observed in 27% (n=10). Major causes of mortality were GvHD, VOD, septicemia, CMV infection and disseminated Aspergillosis. Overall Disease Free Survival (DFS) was 73% with a median duration of follow-up of 47.4 + 12 months. DFS was 81% in standard risk and 54.5% in high-risk group. Results of allogeneic stem cell transplant in standard risk group CML patients were good and comparable with other international centres, however, results in high-risk CML patients need further improvement, although, number of patients in this group is small. (author)

  1. Omitting cytogenetic assessment from routine treatment response monitoring in chronic myeloid leukemia is safe.

    Science.gov (United States)

    Geelen, Inge G P; Thielen, Noortje; Janssen, Jeroen J W M; Hoogendoorn, Mels; Roosma, Tanja J A; Valk, Peter J M; Visser, Otto; Cornelissen, Jan J; Westerweel, Peter E

    2018-04-01

    The monitoring of response in chronic myeloid leukemia (CML) is of great importance to identify patients failing their treatment in order to adjust TKI choice and thereby prevent progression to advanced stage disease. Cytogenetic monitoring has a lower sensitivity, is expensive, and requires invasive bone marrow sampling. Nevertheless, chronic myeloid leukemia guidelines continue to recommend performing routine cytogenetic response assessments, even when adequate molecular diagnostics are available. In a population-based registry of newly diagnosed CML patients in the Netherlands, all simultaneous cytogenetic and molecular assessments performed at 3, 6, and 12 months were identified and response of these matched assessments was classified according to European Leukemia Net (ELN) recommendations. The impact of discrepant cytogenetic and molecular response classifications and course of patients with additional chromosomal abnormalities were evaluated. The overall agreement of 200 matched assessments was 78%. In case of discordant responses, response at 24 months was consistently better predicted by the molecular outcome. Cytogenetic response assessments provided relevant additional clinical information only in some cases of molecular "warning." The development of additional cytogenetic abnormalities was always accompanied with molecular failure. We conclude that it is safe to omit routine cytogenetics for response assessment during treatment and to only use molecular monitoring, in order to prevent ambiguous classifications, reduce costs, and reduce the need for invasive bone marrow sampling. Cytogenetic re-assessment should still be performed when molecular response is suboptimal. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Pattern of occurrence of leukemia at a teaching hospital in eastern region of Nepal - a six year study.

    Science.gov (United States)

    Kulshrestha, R; Sah, S P

    2009-01-01

    Pattern of leukemia is known to vary widely throughout the world. The characterization of distribution patterns of different subtypes of leukemia in Nepal needs further study. We wanted to study the leukemia pattern in our institute. A retrospective study of 196 cases of leukemia, diagnosed at BPKIHS, between January 1997 to December 2002 was done. We analyzed the pattern of leukemia at BPKIHS by morphological subtype, gender, age at diagnosis, time period of diagnosis (seasonality), and geographic distribution. Morphological sub typing showed that 121 cases were of acute leukemia and 75 of chronic leukemia. Chronic myeloid leukemia constituted the single largest group comprising 35.2 % of all cases, followed by acute myeloid leukemia (28.57 %) and acute lymphoid leukemia (19.9 %). Maximum numbers of cases were from the lowlands while least number of cases were from the mountain districts. Results were compared with literature from Nepal and other countries. This is the second series of leukemia from Nepal. The data published in this study reflects the leukemia pattern in the eastern region of Nepal. The pattern and distribution of AML, CML, ALL was similar to that in the developed western countries while the lesser frequency of CLL was similar to that in Southeast Asian region.

  3. Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections.

    Science.gov (United States)

    Hilal, Talal; Gea Banacloche, Juan C; Leis, Jose F

    2018-03-16

    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the world. Patient with CLL are at particular risk for infections due to inherent disease-related immune dysfunction in addition to the effect of certain systemic therapies on the immune system. The advent of B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib has led to a practice change that utilizes these targeted agents in the treatment of CLL, either in place of chemoimmunotherapy (CIT) or in later line settings. In this paper, we review the pathophysiology of immune dysfunction in CLL, the spectrum of immunodeficiency with the various therapeutic agents along with prevention strategies with a focus on targeted therapies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Chronic Disseminated Candidiasis Complicated by Immune Reconstitution Inflammatory Syndrome in Child with Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Olga Zając-Spychała

    2016-01-01

    Full Text Available Hepatosplenic candidiasis also known as chronic disseminated candidiasis is a rare manifestation of invasive fungal infection typically observed in patients with acute leukemia in prolonged, deep neutropenia. Immune reconstitution inflammatory syndrome (IRIS is an inflammatory disorder triggered by rapid resolution of neutropenia. Diagnosis and treatment of IRIS are still challenging due to a variety of clinical symptoms, lack of certain diagnostic criteria, and no standards of treatment. The diagnosis of IRIS is even more difficult in patients with hematological malignancies complicated by “probable” invasive fungal infection, when fungal pathogen is still uncertain. We report a case of probable hepatic candidiasis in 4-year-old boy with acute lymphoblastic leukemia. Despite proper antifungal therapy, there was no clinical and radiological improvement, so diagnosis of Candida-related IRIS was made and corticosteroid therapy was added to antifungal treatment achieving prompt resolution of infection symptoms.

  5. Treatment of chronic granulocytic leukemia by chemotherapy, total body irradiation and allogeneic bone marrow transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Doney, K; Buckner, C D; Sale, G E; Ramberg, R; Boyd, C; Thomas, E D [Fred Hutchinson Cancer Research Institute; Washington Univ., Seattle (USA). School of Medicine)

    1978-01-01

    Fourteen patients with chronic granulocytic leukemia received bone marrow grafts from HLA identical siblings. Ten patients were in blast crisis prior to grafting, three were in an accelerated phase of their disease, and one was aplastic secondary to chemotherapy. Prior to transplant all patients were conditioned with chemotherapy including cyclophosphamide plus 1,000 rad of total body irradiation. Ten patients achieved engraftment while four died 1 to 26 days after marrow infusion without functioning grafts. Two patients reveived a second infusion of donor marrow because of delayed engraftment. Neither marrow cell dose nor presence of myelofibrosis correlated with succesful engraftment. Three out of ten engrafted patients developed graft-versus-host disease. Interstitial pneumonia occurred in seven patients. The immediate cause of death was bacterial septicemia in six patients. All evidence of leukemia disappeared in nine out of ten evaluable patients. The median survival was 43 days. One patient had a complete remission of 16 months duration.

  6. Treatment of chronic granulocytic leukemia by chemotherapy, total body irradiation and allogeneic bone marrow transplantation

    International Nuclear Information System (INIS)

    Doney, K.; Buckner, C.D.; Sale, G.E.; Ramberg, R.; Boyd, C.; Thomas, E.D.; Washington Univ., Seattle

    1978-01-01

    Fourteen patients with chronic granulocytic leukemia received bone marrow grafts from HLA identical siblings. Ten patients were in blast crisis prior to grafting, three were in an accelerated phase of their disease, and one was aplastic secondary to chemotherapy. Prior to transplant all patients were conditioned with chemotherapy including cyclophosphamide plus 1,000 rad of total body irradiation. Ten patients achieved engraftment while four died 1 to 26 days after marrow infusion without functioning grafts. Two patients reveived a second infusion of donor marrow because of delayed engraftment. Neither marrow cell dose nor presence of myelofibrosis correlated with succesful engraftment. Three out of ten engrafted patients developed graft-versus-host disease. Interstitial pneumonia occurred in seven patients. The immediate cause of death was bacterial septicemia in six patients. All evidence of leukemia disappeared in nine out of ten evaluable patients. The median survival was 43 days. One patient had a complete remission of 16 months duration. (Author)

  7. AUTOIMMUNE CYTOPENIAS IN CHRONIC LYMPHOCYTIC LEUKEMIA, FACTS AND MYTHS

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    Pavankumar Tandra

    2013-11-01

    Full Text Available CLL has been defined as presence of more than 5000 small mature appearing monoclonal B lymphocytes with a specific immunophenotype in peripheral blood. It is a well-known fact that CLL is associated with autoimmune cytopenias. CLL cells are CD5+ B lymphocytes, and usually are not the “guilty” cells which produce autoantibodies. T cell defect is another characteristic of CLL and the total number of T cells is increased, and there is inversion of the CD4/CD8 ratio. Autoimmune hemolytic anemia (AIHA is the most common autoimmune complication of CLL and has been reported in 10-25% of CLL patients. However, the stage-adjusted estimated rate of AIHA in CLL is about 5%. Conversely, CLL is three times more common in patients who present with AIHA. Direct agglutinin test (DAT is positive in 7-14% of CLL patients but AIHA may also occur in DAT negative patients. Autoimmune thrombocytopenia (AIT is the second most common complication of CLL and has been reported in 2-3% of patients. DAT is positive in AIT but presence of antiplatelet antibodies is neither diagnostic nor reliable. Autoimmune neutropenia (AIN and pure red cell aplasia (PRCA are very rare complications of CLL and like other autoimmune complications of CLL may occur at any clinical stage. It is believed that most case reports of AIN and PRCA in CLL actually belong to large granular lymphocytic leukemia (LGL. Non-hematologic autoimmune complications of CLL including cold agglutinin disease (CAD, paraneoplastic pemphigus (PNP, acquired angioedema, and anti-myelin associated globulin are rare. Before starting any treatment, clinicians should distinguish between autoimmune cytopenias and massive bone marrow infiltration since autoimmune complications of CLL are not necessarily equal to advanced disease with poor prognosis. According to IWCLL guideline, steroids are the mainstay of treatment of simple autoimmunity. Intravenous immunoglobulin (IVIg, cyclosporine, and rituximab are used in

  8. 'Real-life' study of imatinib therapy in chronic phase-chronic myeloid leukemia: A novel retrospective observational longitudinal analysis.

    Science.gov (United States)

    Merante, Serena; Ferretti, Virginia; Elena, Chiara; Calvello, Celeste; Rocca, Barbara; Zappatore, Rita; Cavigliano, Paola; Orlandi, Ester

    2017-01-01

    Imatinib is a cornerstone of treatment of chronic myeloid leukemia. It remains unclear whether transient treatment discontinuation or dose changes affect outcome and this approach has not yet been approved for use outside clinical trials. We conducted a retrospective single-institution observational study to evaluate factors affecting response in 'real-life' clinical practice in 138 chronic myeloid leukemia patients in chronic phase treated with imatinib. We used a novel longitudinal data analytical model, with a generalized estimating equation model, to study BCR-ABL variation according to continuous standard dose, change in dose or discontinuation; BCR-ABL transcript levels were recorded. Treatment history was subdivided into time periods for which treatment was given at constant dosage (total 483 time periods). Molecular and cytogenetic complete response was observed after 154 (32%) and 358 (74%) time periods, respectively. After adjusting for length of time period, no association between dose and cytogenetic complete response rate was observed. There was a significantly lower molecular complete response rate after time periods at a high imatinib dosage. This statistical approach can identify individual patient variation in longitudinal data collected over time and suggests that changes in dose or discontinuation of therapy could be considered in patients with appropriate biological characteristics.

  9. B cell markers in Ph1-positive acute lymphoblastic leukemia.

    Science.gov (United States)

    Alimena, G; De Rossi, G; Gastaldi, R; Guglielmi, C; Mandelli, F

    1980-01-01

    A case of acute lymphoblastic leukemia (ALL) where the blast cells had B cell markers and displayed the presence of a typical Ph1 chromosome, originated by a standard t (9;22) translocation, is reported. Cytological and clinical aspects during the entire course of the disease were consistent with the diagnosis of ALL. Evidence of differentiation along a well-defined lymphoid cell line in a Ph1-positive cell confirms the presence of the Ph1 chromosome in conditions other than chronic granulocytic leukemia and shows that it possibly does not occur in an exclusively undifferentiated totipotent stem cell.

  10. Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells.

    Science.gov (United States)

    Velu, Vijayakumar; Mylvaganam, Geetha Hanna; Gangadhara, Sailaja; Hong, Jung Joo; Iyer, Smita S; Gumber, Sanjeev; Ibegbu, Chris C; Villinger, Francois; Amara, Rama Rao

    2016-09-01

    Chronic HIV infection is associated with accumulation of germinal center (GC) T follicular helper (Tfh) cells in the lymphoid tissue. The GC Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages, such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC Tfh cells in the lymphoid tissue and its association with viral persistence and Ab production during chronic SIV/HIV infection are not known. To address this, we characterized the expression of CXCR3, CCR4, and CCR6 on GC Tfh cells in lymph nodes following SIVmac251 infection in rhesus macaques. In SIV-naive rhesus macaques, only a small fraction of GC Tfh cells expressed CXCR3, CCR4, and CCR6. However, during chronic SIV infection, the majority of GC Tfh cells expressed CXCR3, whereas the proportion of CCR4(+) cells did not change, and CCR6(+) cells decreased. CXCR3(+), but not CXCR3(-), GC Tfh cells produced IFN-γ (Th1 cytokine) and IL-21 (Tfh cytokine), whereas both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4(+)IFN-γ(+) T cells within the hyperplastic follicles during chronic SIV infection. CXCR3(+) GC Tfh cells also expressed higher levels of ICOS, CCR5, and α4β7 and contained more copies of SIV DNA compared with CXCR3(-) GC Tfh cells. However, CXCR3(+) and CXCR3(-) GC Tfh cells delivered help to B cells in vitro for production of IgG. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC Tfh cells, which are phenotypically and functionally distinct from conventional GC Tfh cells and contribute to hypergammaglobulinemia and viral reservoirs. Copyright © 2016 by The American Association of Immunologists, Inc.

  11. Development of venetoclax for therapy of lymphoid malignancies

    Directory of Open Access Journals (Sweden)

    Zhu H

    2017-03-01

    Full Text Available Huayuan Zhu,1,2 Alexandru Almasan1 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 2Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People’s Republic of China Abstract: B-cell lymphoma-2 (BCL-2 family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199 is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications. Keywords: BCL-2, BCL-xL, chronic lymphocytic leukemia, MCL-1, venetoclax

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  13. Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes.

    Science.gov (United States)

    Stagno, Fabio; Stella, Stefania; Spitaleri, Antonio; Pennisi, Maria Stella; Di Raimondo, Francesco; Vigneri, Paolo

    2016-01-01

    The tyrosine kinase inhibitor Imatinib Mesylate has dramatically improved the clinical outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease, generating unprecedented rates of complete hematologic and cytogenetic responses and sustained reductions in BCR-ABL transcripts. Here, we present an overview on the efficacy and safety of Imatinib and describe the most important clinical studies employing this drug for the frontline treatment of chronic phase CML. We also discuss recent reports describing the long-term outcome of patients receiving Imatinib for their disease. The imminent availability of generic forms of Imatinib coupled with the approval of expensive second-generation tyrosine kinase inhibitors underlines an unmet need for early molecular parameters that may distinguish CML patients likely to benefit from the drug from those that should receive alternative forms of treatment.

  14. Studies on N5-methyltetrahydrofolate-homocystein methyltransferase in normal and leukemia leukocytes.

    Science.gov (United States)

    Peytremann, R; Thorndike, J; Beck, W S

    1975-11-01

    A cobalamin-dependent N5-methyltetra-hydrofolate-homocysteine methyltransferase (methyl-transferase) was demonstrated in unfractioned extracts of human normal and leukemia leukocytes. Activity was substantially reduced in the absence of an added cobalamin derivative. Presumably, this residual activity reflects the endogeneous level of holoenzyme. Enzyme activity was notably higher in lymphoid cells than in myeloid cells. Thus, mean specific activities (+/-SD) were: chronic lymphocytic leukemia lymphocytes, 2.15+/-1.16; normal lymphocytes, 0.91+/-0.59; normal mature granulocytes, 0.15+/-0.10; chronic myelocytic leukemia granulocytes, barely detectable activity. Properties of leukocytes enzymes resembled those of methyltransferases previously studied in bacteria and other animal cells. Granulocytes and chronic myelocytic leukemia cells contain a factor or factors that inhibits Escherichia coli enzyme. The data suggest that the prominence of this cobalamin-dependent enzyme in lymphocytes and other mononuclear cell types may be related to their potential for cell division.

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

    Directory of Open Access Journals (Sweden)

    Keller-von Amsberg G

    2013-03-01

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

  16. Rationale and motivating factors for treatment-free remission in chronic myeloid leukemia.

    Science.gov (United States)

    Caldemeyer, Lauren; Akard, Luke P

    2016-12-01

    With BCR-ABL1 tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, many patients with chronic myeloid leukemia in chronic phase (CML-CP) can expect to live near-normal life spans. Current treatment recommendations of the National Comprehensive Cancer Network and the European LeukemiaNet state that patients with CML-CP should remain on TKI therapy indefinitely. However, there is increasing evidence from clinical trials that some patients with sustained deep molecular responses may be able to achieve treatment-free remission (TFR), whereby they can suspend TKI therapy without losing previously achieved responses. With many patients achieving deep molecular responses to TKI therapy, there is growing interest in whether such patients can achieve TFR. In addition, adverse events (AEs) with long-term TKI therapy, including both the potential for later-emerging AEs and chronic, low-grade AEs, represent a major motivator for oncologists and their patients to investigate the feasibility of TFR. In this review, we provide an overview of data from TFR clinical trials, discuss the importance of achieving a deep molecular response to TKI treatment, and consider potential reasons for investigating TFR following TKI therapy.

  17. Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia.

    Science.gov (United States)

    Weiss, Lukas; Melchardt, Thomas; Egle, Alexander; Grabmer, Christoph; Greil, Richard; Tinhofer, Inge

    2011-05-15

    Early stage chronic lymphocytic leukemia is characterized by a highly variable course of disease. Because it is believed that regulatory T cells (T(regs) ) are potent suppressors of antitumor immunity, the authors hypothesized that increased T(regs) may favor disease progression. T(reg) levels (cluster of differentiation 3 [CD3]-positive, [CD4]-positive, CD25-positive, and CD127-negative) in peripheral blood from 102 patients were analyzed by flow cytometry. Statistical analysis was used to evaluate correlations with clinical data. The relative T(reg) numbers in CD4-positive T cells were significantly greater in patients with chronic lymphocytic leukemia compared with the numbers in a control group of 170 healthy individuals (P = .001). Patients were divided into 2 groups using a median T(reg) value of 9.7% (the percentage of CD4-positive T cells). Patients with higher T(reg) levels had a significantly shorter time to initial treatment (median, 5.9 years) compared with patients who had lower T(reg) levels (median, 11.7 years; log-rank P = .019). Furthermore, T(reg) levels (the percentage of CD4-positive T cells) had significant prognostic power to predict the time to initial treatment in univariate analysis (P = .023) and in multivariate Cox regression analysis that included the variables Rai stage, immunoglobulin heavy-chain variable region gene mutational status, chromosomal aberrations, and CD38 expression (P = .028). Higher T(reg) levels had significant and independent prognostic power for predicting the time to initial treatment in patients with low to intermediate stage chronic lymphocytic leukemia. 2010 American Cancer Society.

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

    Directory of Open Access Journals (Sweden)

    Olga Meltem Akay

    2016-05-01

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

  19. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

    OpenAIRE

    Berndt, S.I.; Skibola, C.F.; Joseph, V.; Camp, N.J.; Nieters, A.; Wang, Z.; Cozen, W.; Monnereau, A.; Wang, S.S.; Kelly, R.S.; Lan, Q.; Teras, L.R.; Chatterjee, N.; Chung, C.C.; Yeager, M.

    2013-01-01

    Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 × 10...

  20. Erythema multiforme in a patient with recurrent non-hodgkins lymphoma/chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Siva Kumara Shankari

    2012-01-01

    Full Text Available Erythema multiforme major (EMM is a hypersensitivity reaction usually secondary to medications, viruses or other infections. Its presentation is fairly typical with a symmetrical distribution of vesicles, bullae or targeted lesions on the upper body, arms, legs, palms, feet and oral mucosa. The authors present a delineated case of EMM in association with chronic lymphocytic leukemia (CLL and non-Hodgkin′s lymphoma (NHL with a very unusual clinical presentation evolving overtime into a unique, almost dermatomal distribution. Typical therapies were not initially helpful and intravenous immunoglobulin antibody had to be administered.

  1. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Cross, N. C. P.; White, H. E.; Colomer, D.

    2015-01-01

    Treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors has advanced to a stage where many patients achieve very low or undetectable levels of disease. Remarkably, some of these patients remain in sustained remission when treatment is withdrawn, suggesting that they may be at ...... of sensitivity. Here we present detailed laboratory recommendations, developed as part of the European Treatment and Outcome Study for CML (EUTOS), to enable testing laboratories to score MR in a reproducible manner for CML patients expressing the most common BCR-ABL1 variants....

  2. Treatment Sequencing in a Chronic Lymphocytic Leukemia Patient with Central Nervous System Involvement

    Directory of Open Access Journals (Sweden)

    Filipa Mousinho

    2018-01-01

    Full Text Available Early-stage chronic lymphocytic leukemia (CLL with neurologic involvement is a rare condition and should require a careful follow-up. Although no standard protocol exists for this condition, intrathecal chemotherapy, combined with systemic chemoimmunotherapy, has been used previously. This case describes the treatment of a patient with CLL and symptomatic compromise of the central nervous system. Our results suggest that a combination of chemotherapy, radiotherapy, and ibrutinib, administered sequentially over a 2-year period, led to a near-complete resolution of the cerebral spinal fluid neoplastic infiltration. Importantly, this response has been maintained with ibrutinib monotherapy for more than 12 months.

  3. No evidence of transmission of chronic lymphocytic leukemia through blood transfusion

    DEFF Research Database (Denmark)

    Hjalgrim, Henrik; Rostgaard, Klaus; Vasan, Senthil K

    2015-01-01

    Monoclonal B-cell lymphocytosis (MBL) is a precursor of chronic lymphocytic leukemia (CLL). Observations of MBL in blood donors raise concern that transmitted MBL may cause recipient CLL. Using a database with health information on 1.5 million donors and 2.1 million recipients, we compared CLL...... of 0.94 (95% confidence interval, 0.52-1.71). Analyses using the entire database showed no evidence of CLL clustering among recipients of blood from individual donors. In conclusion, when donor MBL was approximated by subsequent donor CLL diagnosis, data from 2 countries' entire computerized...

  4. Renal Bleeding Due to Extramedullary Hematopoiesis in a Patient With Chronic Myelogenous Leukemia

    Directory of Open Access Journals (Sweden)

    Stephanie Zettner

    2014-11-01

    Full Text Available Chronic myelogenous leukemia (CML is a myeloproliferative disorder that normally presents in middle-aged adults. Renal infiltration and extramedullary hematopoiesis in renal tissue has been rarely reported. This case report presents a patient with CML and renal insufficiency who developed gross hematuria. Efforts at controlling the hematuria led to a cascade of events propelled by the underlying disorder that ultimately led to a radical nephrectomy, multiorgan failure, and prolonged hospitalization. We suggest that management of gross hematuria in clinically stable patients with CML, suspected of having extramedullary hematopoiesis, should prioritize treatment of the myeloproliferative disorder over efforts to control bleeding.

  5. Renal Bleeding Due to Extramedullary Hematopoiesis in a Patient With Chronic Myelogenous Leukemia.

    Science.gov (United States)

    Zettner, Stephanie; Mistry, Sandeep G

    2014-11-01

    Chronic myelogenous leukemia (CML) is a myeloproliferative disorder that normally presents in middle-aged adults. Renal infiltration and extramedullary hematopoiesis in renal tissue has been rarely reported. This case report presents a patient with CML and renal insufficiency who developed gross hematuria. Efforts at controlling the hematuria led to a cascade of events propelled by the underlying disorder that ultimately led to a radical nephrectomy, multiorgan failure, and prolonged hospitalization. We suggest that management of gross hematuria in clinically stable patients with CML, suspected of having extramedullary hematopoiesis, should prioritize treatment of the myeloproliferative disorder over efforts to control bleeding.

  6. An Urologic Face of Chronic Lymphocytic Leukemia:Sequential Prostatic and Penis Localization

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2013-01-01

    Full Text Available We report a patient with chronic lymphocytic leukemia (CLL in whom a leukemic involvement of prostate and penis occurred in the advanced phase of his disease. Obstructive urinary symptoms were indicative of prostatic CLL infiltration, followed by the occurrence of an ulcerative lesion on the glans. Histologic examination confirmed  the  neoplastic B-cell infiltration. Both localizations responded to conventional treatments. A review of the literature confirms that leukemic involvement of the genito-urinary system is   uncommon in CLL patients. However, such an involvement should be considered in CLL patients with urologic symptoms and a long history of the disease.

  7. Role of the B-cell receptor in chronic lymphocytic leukemia: where do we stand?

    Science.gov (United States)

    Fais, Franco; Bruno, Silvia; Ghiotto, Fabio

    2010-01-01

    The past 15 years have witnessed an enormous effort in studying B-cell Chronic Lymphocytic Leukemia. A great number of researches brought significant novel information and a better understanding of the natural history of this disease. This mini review will focus on the studies related to the Immunoglobulin variable (IgV) genes rearrangements that compose the B-cell receptor (BcR) of the leukemic clones. These studies have defined a role for the antigen(s) in the paths that lead to leukemic clone generation/expansion and underscore the informative value represented by BcR analyses.

  8. Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Lanemo Myhrinder, Anna; Hellqvist, Eva; Bergh, Ann-Charlotte

    2013-01-01

    Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface...... a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA...

  9. Interesting coincidence of atypical TSH-secreting pituitary adenoma and chronic lymphocytic leukemia.

    Science.gov (United States)

    Bolanowski, Marek; Zieliński, Grzegorz; Jawiarczyk-Przybyłowska, Aleksandra; Maksymowicz, Maria; Potoczek, Stanisław; Syrycka, Joanna; Podgórski, Jan K

    2014-01-01

    Thyrotropin-secreting adenomas (TSH-oma) are very rare pituitary tumours. They are macroadenomas usually presenting with signs and symptoms of hyperthyroidism, and mass effects. They can co-secrete other hormones such as growth hormone or prolactin. Different malignancies, including haematological ones, are reported in patients with pituitary diseases. Chronic lymphocytic leukemia (CLL) occurs mostly in older patients, more often in males. CLL is associated with increased risk of second malignancies such as other blood neoplasms, skin and solid tumours. We present a successful neurosurgical outcome in a patient with an interesting coincidence of atypical TSH-oma and asymptomatic CLL.

  10. Second case of chronic granulocytic leukemia with karyotypic evolution at acute crisis, occurring in so-called Nishiyama district

    Energy Technology Data Exchange (ETDEWEB)

    Yao, E; Tomonaga, Yu; Nishino, K; Matsunaga, M; Sadamori, N [Nagasaki Univ. (Japan). School of Medicine

    1978-09-01

    The whole process of a second case of chronic granulocytic leukemia in Nishiyama district where a very small amount of radiation existed for a long time was reported together with data measured by a human counter and the results of chromosomal analysis. No significantly high K or /sup 137/Cs values were measured by a human counter immediately after the onset. Chromosomal division aberration and chromosomal aberration, which seemed to be induced by radiation, also were not observed. However, granulocytic leukemia was diagnosed after chromosomal analysis of peripheral blood revealed Ph/sup 1/ chromosomes, white cell count increased, juvenile cells appeared, and basophil cells increased. Clinical features of typical chronic granulocytic leukemia in the exposed were observed during the chronic stage (7 years). In the acute stage, abnormal clones were discovered in all 16 chromosomes analyzed. Much karyotypic evolution identical to that in persons directly exposed to the A-bomb was also observed.

  11. Considering baseline factors and early response rates to optimize therapy for chronic myeloid leukemia in chronic phase.

    Science.gov (United States)

    Akard, Luke P; Bixby, Dale

    2016-05-01

    Multiple BCR-ABL tyrosine kinase inhibitors (TKIs) are available for the treatment of chronic myeloid leukemia in chronic phase (CML-CP), and several baseline and on-treatment predictive factors have been identified that can be used to help guide TKI selection for individual patients. In particular, early molecular response (EMR; BCR-ABL ≤10% on the International Scale at 3 months) has become an accepted benchmark for evaluating whether patients with CML-CP are responding optimally to frontline TKI therapy. Failure to achieve EMR is considered an inadequate initial response according to the National Comprehensive Cancer Network guidelines and a warning response according to the European LeukemiaNet recommendations. Here we review data supporting the importance of achieving EMR for improving patients' long-term outcomes and discuss key considerations for selecting a frontline TKI in light of these data. Because a higher proportion of patients achieve EMR with second-generation TKIs such as nilotinib and dasatinib than with imatinib, these TKIs may be preferable for many patients, particularly those with known negative prognostic factors at baseline. We also discuss other considerations for frontline TKI choice, including toxicities, cost-effectiveness, and the emerging goals of deep molecular response and treatment-free remission.

  12. Monocytic leukemias.

    Science.gov (United States)

    Shaw, M T

    1980-05-01

    The monocytic leukemias may be subdivided into acute monocytic leukemia, acute myelomonocytic leukemia, and subacute and chronic myelomonocytic leukemia. The clinical features of acute monocytic and acute myelomonocytic leukemias are similar and are manifestations of bone marrow failure. Gingival hypertrophy and skin infiltration are more frequent in acute monocytic leukemia. Cytomorphologically the blast cells in acute monocytic leukemia may be undifferentiated or differentiated, whereas in the acute myelomonocytic variety there are mixed populations of monocytic and myeloblastic cells. Cytochemical characteristics include strongly positive reactions for nonspecific esterase, inhibited by fluoride. The functional characteristics of acute monocytic and acute myelomonocytic cells resemble those of monocytes and include glass adherence and phagocytoses, the presence of Fc receptors for IgG and C'3, and the production of colony stimulating activity. Subacute and chronic myelomonocytic leukemias are insidious and slowly progressive diseases characterized by anemia and peripheral blood monocytosis. Atypical monocytes called paramyeloid cells are characteristic. The drugs used in the treatment of acute monocytic and acute myelomonocytic leukemias include cytosine arabinoside, the anthracyclines, and VP 16-213. Drug therapy in subacute and chronic myelomonocytic leukemias is not usually indicated, although VP 16-213 has been claimed to be effective.

  13. Conditional survival in patients with chronic myeloid leukemia in chronic phase in the era of tyrosine kinase inhibitors.

    Science.gov (United States)

    Sasaki, Koji; Kantarjian, Hagop M; Jain, Preetesh; Jabbour, Elias J; Ravandi, Farhad; Konopleva, Marina; Borthakur, Gautam; Takahashi, Koichi; Pemmaraju, Naveen; Daver, Naval; Pierce, Sherry A; O'Brien, Susan M; Cortes, Jorge E

    2016-01-15

    Tyrosine kinase inhibitors (TKIs) significantly improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). Conditional probability provides survival information in patients who have already survived for a specific period of time after treatment. Cumulative response and survival data from 6 consecutive frontline TKI clinical trials were analyzed. Conditional probability was calculated for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS) according to depth of response within 1 year of the initiation of TKIs, including complete cytogenetic response, major molecular response, and molecular response with a 4-log or 4.5-log reduction. A total of 483 patients with a median follow-up of 99.4 months from the initiation of treatment with TKIs were analyzed. Conditional probabilities of FFS, TFS, EFS, and OS for 1 additional year for patients alive after 12 months of therapy ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively. Conditional FFS for 1 additional year did not improve with a deeper response each year. Conditional probabilities of TFS, EFS, and OS for 1 additional year were maintained at >95% during the period. In the era of TKIs, patients with chronic myeloid leukemia in chronic phase who survived for a certain number of years maintained excellent clinical outcomes in each age group. Cancer 2016;122:238-248. © 2015 American Cancer Society. © 2015 American Cancer Society.

  14. JAK2V617F mutation in chronic myeloid leukemia predicts early disease progression

    International Nuclear Information System (INIS)

    Pahore, Z.A.A.; Shamsi, T.S.; Taj, M.; Farzana, T.; Ansari, S.H.; Nadeem, M.; Ahmad, M.; Naz, A.

    2011-01-01

    Objective: To determine the association of JAK2V617F mutation along with BCR-ABL translocation or Philadelphia chromosome in chronic myeloid leukemia with early disease progression to advanced stages (accelerated phase or blast crisis) and poor outcome. Study Design: Case series. Place and Duration of Study: National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, from February 2008 to August 2009. Methodology: All the newly diagnosed cases of BCR-ABL or Philadelphia positive CML were tested for JAK2V617F mutation by Nested PCR. Demographic data, spleen size, hemoglobin levels, white blood cell and platelet counts were recorded. Independent sample t-test was used for age, haemoglobin level and spleen size. Fisher's exact test was applied to compare disease progression in JAK2V617F mutation positive and negative cases. Results: Out of 45 newly diagnosed cases of CML, 40 were in chronic phase, 01 in accelerated phase and 04 in blast crisis. JAK2V617F mutation was detected in 12 (26.7%) patients; 09 (22.5%) in chronic phase, none in accelerated phase and 03 (75%) in blast crisis. During a mean follow-up of 8 months, 03 patients in chronic phase transformed in blast crisis and 02 into accelerated phase. Overall 08 out of 11 (73%) JAK2V617F positive patients either had advanced disease or showed disease progression. Only 2 of 20 (10%) available patients, negative for the mutation, showed disease progression by transforming into blast crisis (p < 0.001). No statistically significant difference was seen in the age, spleen size, haemoglobin levels, white blood cells and platelets counts in JAK2V617F positive patients. Conclusion: JAK2V617F mutation was detected in 26.7% cases of chronic myeloid leukemia. A significant proportion of them showed early disease progression. (author)

  15. Silenced B-Cell Receptor Response To Autoantigen In A Poor-Prognostic Subset Of Chronic Lymphocytic Leukemia

    DEFF Research Database (Denmark)

    Bergh, Ann-Charlotte; Evaldsson, Chamilly; Pedersen, Lone Bredo

    2014-01-01

    Chronic lymphocytic leukemia B cells express auto/xeno antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde that is present on low-density lipoprotein......-cell receptor unresponsiveness to cognate self-antigen on its own in poor-prognostic subset #1 chronic lymphocytic leukemia, indicating that these cells proliferate by other mechanisms that may override B-cell receptor silencing brought about in a context of self-tolerance/anergy. These novel findings have...

  16. Magnetic resonance imaging may simulate progressive multifocal leucoencephalopathy in a patient with chronic lymphocytic leukemia after fludarabine therapy

    Directory of Open Access Journals (Sweden)

    Kalita J

    2008-01-01

    Full Text Available A 60-year-old male with chronic lymphatic leukemia (CLL after 6 months of fludarabine therapy was admitted with status epilepticus and developed left hemiplegia. His magnetic resonance imaging revealed multiple T2 hyperintense lesions in the right frontal and left parieto-occipital lesion, simulating progressive multifocal leucoencephalopathy (PML. Cerebrospinal fluid Polymerase Chain Reaction (PCR for JC virus was negative. We suggest the possible role of fludarabine in producing PML-like lesions in patients with Chronic Lymphocytic Leukemia (CLL.

  17. Evaluation of multielements in human serum of patients with chronic myelogenous leukemia (CML) using SRTXRF

    International Nuclear Information System (INIS)

    Leitao, Catarine Canellas Gondim

    2005-04-01

    In this work, trace elements were analyzed in serum of patients with chronic myelogenous leukemia (CML) by Total Reflection X-Ray Fluorescence using synchrotron radiation (SRTXRF). Chronic myelogenous leukemia (CML) affects the myeloid cells in the blood and affects 1 to 2 people per 100,000 and accounts for 7-20% cases of leukemia. Sixty patients with CML and sixty healthy volunteers (control group) were studied. Blood was collected into vacutainers without additives. Directly after collection, each blood sample was centrifuged at 3000 rev/min for 10 min in order to separate blood cells and suspended particles from blood serum. Sera were transferred into polyethylene tubes and stored in a freezer at 253 K. A 500 m u L serum quantity was spiked with Ga (50 m u L ) as internal standard. 10 m u L aliquots were pipetted on Perspex sample carrier. After deposition, the samples were left to dry under an infrared lamp. The measurements were performed at the X-Ray Fluorescence Beamline at Brazilian National Synchrotron Light Laboratory (LNLS), using a polychromatic beam. Standard solutions with gallium as internal standard were prepared for calibration system. It was possible to determine the concentrations of the following elements: P, S, Cl, K, Ca, Cr, Mn, Fe, Ni, Cu, Zn, Br and Rb. Starting from the ANOVA test was observed that the elements P, S, Ca, Cr, Mn, Fe, Cu and Rb presented real significant differences (α = 0.05) between groups (healthy subjects and CML patients) and Sex (males and females). (author)

  18. Chronic lymphocytic leukemia-associated chromosomal abnormalities and miRNA deregulation

    Directory of Open Access Journals (Sweden)

    Kiefer Y

    2012-03-01

    Full Text Available Yvonne Kiefer1, Christoph Schulte2, Markus Tiemann2, Joern Bullerdiek11Center for Human Genetics, University of Bremen, Bremen, Germany; 2Hematopathology Hamburg, Hamburg, GermanyAbstract: Chronic lymphocytic leukemia is the most common leukemia in adults. By cytogenetic investigations major subgroups of the disease can be identified that reflect different routes of tumor development. Of these chromosomal deviations, trisomy 12 and deletions of parts of either the long arm of chromosome 13, the long arm of chromosome 11, or the short arm of chromosome 17 are most commonly detected. In some of these aberrations the molecular target has been identified as eg, ataxia telangiectasia mutated (ATM in case of deletions of chromosomal region 11q22~23 and the genes encoding microRNAs miR-15a/16-1 as likely targets of deletions of chromosomal band 13q14.3. Of note, these aberrations do not characterize independent subgroups but often coexist within the metaphases of one tumor. Generally, complex aberrations are associated with a worse prognosis than simple karyotypic alterations. Due to smaller sizes of the missing segment the detection of recurrent deletions is not always possible by means of classical cytogenetics but requires more advanced techniques as in particular fluorescence in situ hybridization (FISH. Nevertheless, at this time it is not recommended to replace classical cytogenetics by FISH because this would miss additional information given by complex or secondary karyotypic alterations. However, the results of cytogenetic analyses allow the stratification of prognostic and predictive groups of the disease. Of these, the group characterized by deletions involving TP53 is clinically most relevant. In the future refined methods as eg, array-based comparative genomic hybridization will supplement the existing techniques to characterize CLL. Keywords: chronic lymphocytic leukemia, chromosomal abnormality, miRNA deregulation

  19. Combined Population Dynamics and Entropy Modelling Supports Patient Stratification in Chronic Myeloid Leukemia

    Science.gov (United States)

    Brehme, Marc; Koschmieder, Steffen; Montazeri, Maryam; Copland, Mhairi; Oehler, Vivian G.; Radich, Jerald P.; Brümmendorf, Tim H.; Schuppert, Andreas

    2016-04-01

    Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer progression, biomarker identification and the design of individualized therapies. Using chronic myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patient-derived gene expression entropy separated established CML progression stages and uncovered additional heterogeneity within disease stages. Importantly, our patient data informed model enables quantitative approximation of individual patients’ disease history within chronic phase (CP) and significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized and genome-informed disease progression risk assessment that is independent and complementary to conventional measures of CML disease burden and prognosis.

  20. Deep molecular responses for treatment-free remission in chronic myeloid leukemia.

    Science.gov (United States)

    Dulucq, Stéphanie; Mahon, Francois-Xavier

    2016-09-01

    Several clinical trials have demonstrated that some patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieve sustained deep molecular responses on tyrosine kinase inhibitor (TKI) therapy can safely suspend therapy and attempt treatment-free remission (TFR). Many TFR studies to date have enrolled imatinib-treated patients; however, the feasibility of TFR following nilotinib or dasatinib has also been demonstrated. In this review, we discuss available data from TFR trials and what these data reveal about the molecular biology of TFR. With an increasing number of ongoing TFR clinical trials, TFR may become an achievable goal for patients with CML-CP. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  1. Anti-mutagenic and Pro-apoptotic Effects of Apigenin on Human Chronic Lymphocytic Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Mehrdad Hashemi

    2010-09-01

    Full Text Available "nDiet can play a vital role in cancer prevention. Nowadays the scientists are looking for food materials which can potentially prevent the cancer occurrence. The purpose of this research is to examine anti-mutagenic and apoptotic effects of apigenin in human lymphoma cells. In present study human chronic lymphocytic leukemia (Eheb cell line were cultured in RPMI 1640 (Sigma, supplemented with 10% fetal calf serum, penicillin-streptomycin, L-glutamine and incubated at 37 ºC for 2 days. In addition cancer cell line was treated by and apigenin and cellular vital capacity was determined by MTT assay. Then effect of apigenin in human lymphoma B cells was examined by flow cytometry techniques. The apigenin was subsequently evaluated in terms of anti-mutagenic properties by a standard reverse mutation assay (Ames test. This was performed with histidine auxotroph strain of Salmonella typhimurium (TA100. Thus, it requires histidine from a foreign supply to ensure its growth. The aforementioned strain gives rise to reverted colonies when expose to sodium azide as a carcinogen substance. During MTT assay, human chronic lymphocytic leukemia revealed to have a meaningful cell death when compared with controls (P<0.01 Apoptosis was induced suitably after 48 hours by flow cytometry assay. In Ames test apigenin prevented the reverted mutations and the hindrance percent of apigenin was 98.17%.These results have revealed apigenin induced apoptosis in human lymphoma B cells in vitro.

  2. Anti-mutagenic and Pro-apoptotic Effects of Apigenin on Human Chronic Lymphocytic Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Mehrdad Hashemi

    2010-10-01

    Full Text Available Diet can play a vital role in cancer prevention. Nowadays the scientists are looking for food materials which can potentially prevent the cancer occurrence. The purpose of this research is to examine anti-mutagenic and apoptotic effects of apigenin in human lymphoma cells. In present study human chronic lymphocytic leukemia (Eheb cell line were cultured in RPMI 1640 (Sigma, supplemented with 10% fetal calf serum, penicillin-streptomycin, L-glutamine and incubated at 37 ºC for 2 days. In addition cancer cell line was treated by and apigenin and cellular vital capacity was determined by MTT assay. Then effect of apigenin in human lymphoma B cells was examined by flow cytometry techniques. The apigenin was subsequently evaluated in terms of anti-mutagenic properties by a standard reverse mutation assay (Ames test. This was performed with histidine auxotroph strain of Salmonella typhimurium (TA100. Thus, it requires histidine from a foreign supply to ensure its growth. The aforementioned strain gives rise to reverted colonies when expose to sodium azide as a carcinogen substance. During MTT assay, human chronic lymphocytic leukemia revealed to have a meaningful cell death when compared with controls (P

  3. The top ten clues to understand the origin of chronic lymphocytic leukemia (CLL).

    Science.gov (United States)

    García-Muñoz, Ricardo; Feliu, Jesús; Llorente, Luis

    2015-01-01

    The fundamental task of the immune system is to protect the individual from infectious organisms without serious injury to self. The essence of acquired immunity is molecular self/non self discrimination. Chronic lymphocytic leukemia is characterized by a global failure of immune system that begins with the failure of immunological tolerance mechanisms (autoimmunity) and finish with the incapacity to response to non-self antigens (immunodeficiency). Immunological tolerance mechanisms are involved in chronic lymphocytic leukemia (CLL) development. During B cell development some self-reactive B cells acquire a special BCR that recognize their own BCR. This self-autoantibody-self BCR interaction promotes survival, differentiation and proliferation of self-reactive B cells. Continuous self-autoantibody-self BCR interaction cross-linking induces an increased rate of surface BCR elimination, CD5+ expression, receptor editing and anergy. Unfortunately, some times this mechanisms increase genomic instability and promote additional genetic damage that immortalize self-reactive B cells and convert them into CLL like clones with the capability of clonal evolution and transformed CLL B cells. This review summarizes the immunological effects of continuous self-autoantibody-self BCR interaction cross-linking in the surface of self-reactive B cells and their role in CLL development. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Martin Henkes

    2008-03-01

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

  5. Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia

    Science.gov (United States)

    Laidlaw, Kamilla M.E.; Berhan, Samuel; Liu, Suhu; Silvestri, Giovannino; Holyoake, Tessa L.; Frank, David A.; Aggarwal, Bharat; Bonner, Michael Y.; Perrotti, Danilo

    2016-01-01

    The use of tyrosine kinase inhibitors (TKI), including nilotinib, has revolutionized the treatment of chronic myeloid leukemia (CML). However current unmet clinical needs include combating activation of additional survival signaling pathways in persistent leukemia stem cells after long-term TKI therapy. A ubiquitous signaling alteration in cancer, including CML, is activation of reactive oxygen species (ROS) signaling, which may potentiate stem cell activity and mediate resistance to both conventional chemotherapy and targeted inhibitors. We have developed a novel nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, imipramine blue (IB) that targets ROS generation. ROS levels are known to be elevated in CML with respect to normal hematopoietic stem/progenitor cells and not corrected by TKI. We demonstrate that IB has additive benefit with nilotinib in inhibiting proliferation, viability, and clonogenic function of TKI-insensitive quiescent CD34+ CML chronic phase (CP) cells while normal CD34+ cells retained their clonogenic capacity in response to this combination therapy in vitro. Mechanistically, the pro-apoptotic activity of IB likely resides in part through its dual ability to block NF-κB and re-activate the tumor suppressor protein phosphatase 2A (PP2A). Combining BCR-ABL1 kinase inhibition with NADPH oxidase blockade may be beneficial in eradication of CML and worthy of further investigation. PMID:27438151

  6. The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis

    DEFF Research Database (Denmark)

    Nicolini, Franck E; Ibrahim, Amr R; Soverini, Simona

    2013-01-01

    The BCR-ABL T315I mutation confers resistance to currently licensed tyrosine kinase inhibitors in chronic myelogenous leukemia. However, the impact of this mutation on survival in early stages of disease, in chronic phase, has never been detailed. Using matched pair analysis, a cohort of 64...... patients with chronic phase chronic myelogenous leukemia harboring a T315I mutation and resistant to imatinib mesylate was compared to a similar cohort of 53 chronic phase patients resistant to imatinib, but with no detectable T315I mutation, in the pre-ponatinib era. These patients were matched according...... to age at diagnosis, interval between disease diagnosis and start of imatinib treatment, and duration of imatinib therapy. Kaplan-Meier survival analyses demonstrated the significant negative impact of the presence of the T315I mutation on overall survival (since imatinib-resistance: 48.4 months for T315...

  7. Radiogenic leukemia risk analysis for the Techa River Cohort members

    International Nuclear Information System (INIS)

    Krestinina, L.Y.; Epifanova, S.B.; Akleyev, A.V.; Preston, D.; Davis, F.; Ron, E.

    2008-01-01

    Full text: Members of the Techa River Cohort have been exposed to a long-term external and internal irradiation due to releases of radioactive waste from the Mayak Production Association into the Techa River. Since internal exposure resulted primarily from incorporation of 90 Sr in the bone structure, the bone marrow was the principal target. The maximum dose to the red bone marrow accumulated over 50 years in cohort members reached 2 Gy, and the mean dose was 0.3 Gy. The epidemiological analysis of radiogenic risk of leukemia development was conducted based on the retrospective cohort study approach and regression analysis using the Epicure statistical packet. The extended Techa River Cohort (ETRC) includes about 30 thousand people of the two genders, various ages and different ethnicity (mostly Russians, Tartars and Bashkirs). The catchment area for leukemia mortality and incidence follow-up includes the whole Chelyabinsk and Kurgan Oblasts. The previous analysis of leukemia mortality risk for a 50-year follow-up period pointed out statistically significant dose dependence. The presentation will for the first time describe the results of leukemia incidence risk analyses for the period from 1953 through 2004. Over this 52-year follow-up period 92 leukemia cases (42 in men and 50 in women) were registered among ETRC members resident in the catchment area. Among those 92 cases there were 22 cases attributed to chronic lymphoid leukemia (12 in men and 10 in women). The preliminary analysis of leukemia incidence risk showed a statistically significant linear dependence on dose for total leukemias (p = 0.006), as well as for leukemias with CLL excluded (p < 0.001). The point value of the total leukemia incidence ERR was 2.0/Gy (95% CI: 0.4-15.4) and for leukemia with CLL excluded the ERR was 4.5/Gy (95% CI: 1.1-14.7). More than 57% of leukemia cases (excluding CLL) registered in ETRC members could be related to the radiogenic factor. Analyses of chronic lymphoid

  8. Additional cytogenetic abnormalities and variant t(9;22) at the diagnosis of childhood chronic myeloid leukemia : The experience of the International Registry for Chronic Myeloid Leukemia in Children and Adolescents

    NARCIS (Netherlands)

    Millot, Frederic; Dupraz, Christelle; Guilhot, Joelle; Suttorp, Meinolf; Brizard, Francoise; Leblanc, Thierry; Gunes, Adalet Meral; Sedlacek, Petr; De Bont, Evelyne; Li, Chi Kong; Kalwak, Krzysztof; Lausen, Birgitte; Culic, Srdjana; Dworzak, Michael; Kaiserova, Emilia; De Moerloose, Barbara; Roula, Farah; Biondi, Andrea; Baruchel, Andre; Guilhot, Francois

    2017-01-01

    BACKGROUND: In the adult population with newly diagnosed chronic myeloid leukemia (CML), variant translocations are usually not considered to be impairing the prognosis, whereas some additional cytogenetic abnormalities (ACAs) are associated with a negative impact on survival. Because of the rarity

  9. Chronic Stress Induces Structural Alterations in Splenic Lymphoid Tissue That Are Associated with Changes in Corticosterone Levels in Wistar-Kyoto Rats

    Directory of Open Access Journals (Sweden)

    María Eugenia Hernandez

    2013-01-01

    Full Text Available Major depressive disorder patients present chronic stress and decreased immunity. The Wistar-Kyoto rat (WKY is a strain in which the hypothalamic-pituitary-adrenal axis is overactivated. To determine whether chronic stress induces changes in corticosterone levels and splenic lymphoid tissue, 9-week-old male rats were subject to restraint stress (3 h daily, chemical stress (hydrocortisone treatment, 50 mg/Kg weight, mixed stress (restraint plus hydrocortisone, or control treatment (without stress for 1, 4, and 7 weeks. The serum corticosterone levels by RIA and spleens morphology were analyzed. Corticosterone levels as did the structure, size of the follicles and morphology of the parenchyma (increase in red pulp in the spleen, varied depending on time and type of stressor. These changes indicate that chronic stress alters the immune response in the spleen in WKY rats by inducing morphological changes, explaining in part the impaired immunity that develops in organisms that are exposed to chronic stress.

  10. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

    OpenAIRE

    Bergomas, Francesca; Grizzi, Fabio; Doni, Andrea; Pesce, Samantha; Laghi, Luigi; Allavena, Paola; Mantovani, Alberto; Marchesi, Federica

    2011-01-01

    Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of ly...

  11. Occupation and leukemia in Nordic countries

    DEFF Research Database (Denmark)

    Talibov, Madar; Kautiainen, Susanna; Martinsen, Jan Ivar

    2012-01-01

    We studied occupational variation of the risk of acute myeloid leukemia, chronic lymphocytic leukemia, and other leukemia in Nordic countries.......We studied occupational variation of the risk of acute myeloid leukemia, chronic lymphocytic leukemia, and other leukemia in Nordic countries....

  12. Effect of total lymphoid irradiation on functional status in chronic multiple sclerosis: importance of lymphopenia early after treatment--the pros

    International Nuclear Information System (INIS)

    Devereux, C.; Troiano, R.; Zito, G.

    1988-01-01

    To determine whether immunosuppression by total lymphoid irradiation (TLI) slowed deterioration of chronic progressive multiple sclerosis (MS), functional impairment score and blood lymphocyte counts were compared at 6-month intervals through 4 years following treatment of MS patients by either TLI (n = 27) or sham irradiation (n = 21). At each interval, 20 to 30% fewer TLI-treated patients had deteriorated (p less than 0.05 at 6, 12, and 18 months), and the difference in mean functional impairment score between groups became progressively greater (p less than 0.01 at 42 and 48 months). Benefit accrued principally to the 17 TLI-treated patients with absolute blood lymphocyte counts less than 900/mm3 3 months after treatment, whose mean functional impairment score remained within 0.6 units of baseline (p = NS), whereas the ten TLI patients with higher post-treatment lymphocyte counts had progressive deterioration (p less than 0.05 to p less than 0.001 versus TLI-treated patients with lower lymphocyte counts at all intervals except 30 months) and had deteriorated by more than 5 functional scale units by 42 and 48 months. Side effects were minor and complications rare in TLI-treated patients, but one TLI-treated patient developed staphylococcal sepsis. Thus, TLI slows deterioration of chronic progressive MS, with what appears to be enduring benefit through 4 years compartmented to patients with greater induced lymphopenia. Modification of lymphoid irradiation regimens to increase the proportion of MS patients who achieve a favorable degree of lymphopenia and to avert functional hyposplenism may further improve the benefit/risk ratio

  13. Chronic lymphocytic leukemia disease progression is accelerated by APRIL-TACI interaction in the TCL1 transgenic mouse model

    NARCIS (Netherlands)

    Lascano, Valeria; Guadagnoli, Marco; Schot, Jan G.; Luijks, Dieuwertje M.; Guikema, Jeroen E. J.; Cameron, Katherine; Hahne, Michael; Pals, Steven; Slinger, Erik; Kipps, Thomas J.; van Oers, Marinus H. J.; Eldering, Eric; Medema, Jan Paul; Kater, Arnon P.

    2013-01-01

    Although in vitro studies pointed to the tumor necrosis factor family member APRIL (a proliferation-inducing ligand) in mediating survival of chronic lymphocytic leukemia (CLL) cells, clear evidence for a role in leukemogenesis and progression in CLL is lacking. APRIL significantly prolonged in

  14. Enhanced formation and survival of CD4+ CD25hi Foxp3+ T-cells in chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Jak, Margot; Mous, Rogier; Remmerswaal, Ester B. M.; Spijker, René; Jaspers, Annelieke; Yagüe, Adriana; Eldering, Eric; van Lier, René A. W.; van Oers, Marinus H. J.

    2009-01-01

    Recently, it has been described that patients with chronic lymphocytic leukemia (CLL) have increased numbers of regulatory T (T(reg)) cells. In the present study, we analysed the mechanism behind T(reg) cells expansion in CLL. Neither analysis of the T-cell receptor repertoire nor CD45 isoform

  15. Mitochondrial DNA copy number and chronic lymphocytic leukemia/small lymphocytic lymphoma risk in two prospective studies

    NARCIS (Netherlands)

    Kim, Christopher; Bassig, Bryan A; Seow, Wei Jie; Hu, Wei; Purdue, Mark P; Huang, Wen-Yi; Liu, Chin-San; Cheng, Wen-Ling; Männistö, Satu; Vermeulen, Roel; Weinstein, Stephanie J; Lim, Unhee; Hosgood, H Dean; Bonner, Matthew R; Caporaso, Neil E; Albanes, Demetrius; Lan, Qing; Rothman, Nathaniel

    BACKGROUND: Mitochondrial DNA copy number (mtDNA CN) may be modified by mitochondria in response to oxidative stress. Previously, mtDNA CN was associated with non-Hodgkin lymphoma (NHL) risk, particularly chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We conducted a replication

  16. Effect of IL-4 and IL-6 on the proliferation and differentiation of B-chronic lymphocytic leukemia cells

    NARCIS (Netherlands)

    van Kooten, C.; Rensink, I.; Aarden, L.; van Oers, R.

    1993-01-01

    The proliferation and differentiation of purified malignant B cells from nine patients with chronic lymphocytic leukemia (B-CLL) were studied in vitro. We have demonstrated before that tumour necrosis factor alpha (TNF-alpha), in combination with low dose phorbol myristic acid (PMA) (0.1 ng/ml), can

  17. Acute lymphoblastic leukemia in a patient with chronic granulomatous disease and a novel mutation in CYBB: First report

    NARCIS (Netherlands)

    Wolach, Baruch; Ash, Shifra; Gavrieli, Ronit; Stark, Batia; Yaniv, Isaac; Roos, Dirk

    2005-01-01

    We report for the first time a child with chronic granulomatous disease (CGD) who developed acute lymphoblastic leukemia (ALL). The diagnosis of CGD was made at the age of 4 months, by studies of his neutrophil functions. The superoxide production of the cells was negligible, as was the bactericidal

  18. Interleukin-4 inhibits both paracrine and autocrine tumor necrosis factor-alpha-induced proliferation of B chronic lymphocytic leukemia cells

    NARCIS (Netherlands)

    van Kooten, C.; Rensink, I.; Aarden, L.; van Oers, R.

    1992-01-01

    The proliferative response of purified malignant B cells from 26 patients with chronic lymphocytic leukemia (CLL) was investigated in vitro. In the majority of these patients, a proliferative response could be induced by the combination of tumor necrosis factor (TNF)-alpha and PMA. The concentration

  19. Granulocyte Colony-stimulating Factor-primed Bone Marrow: An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Yuhang Li

    2015-01-01

    Full Text Available Background: Steady-state bone marrow (SS-BM and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation. Here, we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA-identical sibling transplantation. Methods: A total of 226 patients (acute myelogenous leukemia-complete remission 1, chronic myelogenous leukemia-chronic phase 1 received SS-BM, G-BM, or G-PBSC from an HLA-identical sibling. Clinical outcomes (graft-versus-host disease [GVHD], overall survival, transplant-related mortality [TRM], and leukemia-free survival [LFS] were analyzed. Results: When compared to SS-BM, G-BM gave faster recovery time to neutrophil or platelet (P 0.05. Conclusions: G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM. We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

  20. AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations.

    Science.gov (United States)

    Leuenberger, Mona; Frigerio, Simona; Wild, Peter J; Noetzli, Franziska; Korol, Dimitri; Zimmermann, Dieter R; Gengler, Carole; Probst-Hensch, Nicole M; Moch, Holger; Tinguely, Marianne

    2010-02-01

    The biological behavior of chronic lymphocytic leukemia and small lymphocytic lymphoma is unpredictable. Nonetheless, non-mutated IgV(H) gene rearrangement, ATM (11q22-23) and p53 (17p13) deletion are recognized as unfavorable prognosticators in chronic lymphocytic leukemia. The mRNA expression of activation-induced cytidine deaminase (AID), an enzyme indispensable for somatic hypermutation processes, was claimed to be predictive of non-mutated chronic lymphocytic leukemia cells in blood. Here, we evaluated AID protein expression compared with known molecular and immunohistochemical prognostic indicators in 71 chronic lymphocytic leukemia/small lymphocytic lymphoma patients using a tissue microarray approach. We found AID heterogeneously expressed in tumor cells as shown by colocalization analysis for CD5 and CD23. Ki-67 positive paraimmunoblasts of the proliferation centers displayed the highest expression. This observation is reflected by a significant association of AID positivity with a high proliferation rate (P=0.012). ATM deletion was detected in 10% (6/63) of patients and p53 deletion in 19% (13/67) of patients. Moreover, both ATM (P=0.002) and p53 deletion (P=0.004) were significantly associated with AID. IgV(H) gene mutation was seen in 45% (27/60) of patients. Twenty-five percent (17/69) of patients with AID-positive chronic lymphocytic leukemia/small lymphocytic lymphoma displayed a shorter survival than AID-negative chronic lymphocytic leukemia/small lymphocytic lymphoma patients (61 vs 130 months, P=0.001). Although there was a trend, we could not show an association with the IgV(H) gene mutation status. Taken together, our study shows that AID expression is an indicator of an unfavorable prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma patients, although it is not a surrogate marker for the IgV(H) status. Furthermore, the microenvironment of proliferation centers seems to influence AID regulation and might be an initiating factor

  1. Therapy related-chronic myelomonocytic leukemia (CMML): Molecular, cytogenetic, and clinical distinctions from de novo CMML.

    Science.gov (United States)

    Patnaik, Mrinal M; Vallapureddy, Rangit; Yalniz, Fevzi F; Hanson, Curtis A; Ketterling, Rhett P; Lasho, Terra L; Finke, Christy; Al-Kali, Aref; Gangat, Naseema; Tefferi, Ayalew

    2018-01-01

    Therapy related myeloid neoplasms (t-MN) including therapy related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t-CMML. T-CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t-CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t-MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t-CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t-CMML in comparison to d-CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t-CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4-3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5-3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5-3.7). In summary, we highlight the unique genetics and independent prognostic impact of t-CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t-MN. © 2017 Wiley Periodicals, Inc.

  2. Novel human polyomaviruses, Merkel cell polyomavirus and human polyomavirus 9, in Japanese chronic lymphocytic leukemia cases

    Directory of Open Access Journals (Sweden)

    Imajoh Masayuki

    2012-06-01

    Full Text Available Abstract Background Chronic lymphocytic leukemia (CLL is the rarest adult leukemia in Japan, whereas it is the most common leukemia in the Western world. Recent studies from the United States and Germany suggest a possible etiological association between Merkel cell polyomavirus (MCPyV and CLL, although no data have been reported from Eastern countries. To increase the volume of relevant data, this study investigated the prevalence and DNA loads of MCPyV and human polyomavirus 9 (HPyV9, another lymphotropic polyomavirus, in Japanese CLL cases. Findings We found that 9/27 CLL cases (33.3 % were positive for MCPyV using quantitative real-time polymerase chain reaction analysis. The viral DNA loads ranged from 0.000017 to 0.0012 copies per cell. All cases were negative for HPyV9. One MCPyV-positive CLL case was evaluated by mutational analysis of the large T (LT gene, which indicated the presence of wild-type MCPyV without a nucleotide deletion. DNA sequence analysis of the entire small T (ST gene and the partial LT gene revealed that a Japanese MCPyV isolate, designated CLL-JK, had two nucleotide gaps when compared with the reference sequence of the North American isolate MCC350. Conclusions This study provides the first evidence that MCPyV is present in a subset of Japanese CLL cases with low viral DNA loads. MCPyV and HPyV9 are unlikely to contribute directly to the development of CLL in the majority of Japanese cases. MCPyV isolated from the Japanese CLL cases may constitute an Asian group and its pathogenicity needs to be clarified in future studies.

  3. Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial.

    Science.gov (United States)

    Gore, Lia; Kearns, Pamela R; de Martino, Maria Lucia; Lee; De Souza, Carmino Antonio; Bertrand, Yves; Hijiya, Nobuko; Stork, Linda C; Chung, Nack-Gyun; Cardos, Rocio Cardenas; Saikia, Tapan; Fagioli, Franca; Seo, Jong Jin; Landman-Parker, Judith; Lancaster, Donna; Place, Andrew E; Rabin, Karen R; Sacchi, Mariana; Swanink, Rene; Zwaan, C Michel

    2018-05-01

    Purpose Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias. Methods CA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest. Results Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients. Conclusion In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported.

  4. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance : Minimum 24-month follow-up

    NARCIS (Netherlands)

    Gambacorti-Passerini, Carlo; Brümmendorf, Tim H; Kim, Dong-Wook; Turkina, Anna G; Masszi, Tamas; Assouline, Sarit; Durrant, Simon; Kantarjian, Hagop M; Khoury, H Jean; Zaritskey, Andrey; Shen, Zhi-Xiang; Jin, Jie; Vellenga, Edo; Pasquini, Ricardo; Mathews, Vikram; Cervantes, Francisco; Besson, Nadine; Turnbull, Kathleen; Leip, Eric; Kelly, Virginia; Cortes, Jorge E

    Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib

  5. Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation

    NARCIS (Netherlands)

    Millot, F; Guilhot, J; Nelken, B; Leblanc, T; De Bont, ES; Bekassy, AN; Gadner, H; Sufliarska, S; Stary, J; Gschaidmeier, H; Guilhot, F; Suttorp, M

    A multicentric phase 2 study was conducted to determine the efficiency and the tolerance of imatinib mesylate in children with chronic myelogenous leukemia (CML) in advanced phase of the disease, in relapse after stem cell transplantation, or in case of failure to an interferon a-based regimen. In

  6. Sensitive DNA impedance biosensor for detection of cancer, chronic lymphocytic leukemia, based on gold nanoparticles/gold modified electrode

    International Nuclear Information System (INIS)

    Ensafi, Ali A.; Taei, M.; Rahmani, H.R.; Khayamian, T.

    2011-01-01

    Highlights: → Chronic lymphocytic leukemia causes an increase in the number of white blood cells. → We introduced a highly sensitive biosensor for the detection of chronic lymphocytic leukemia. → A suitable 25-mer ssDNA probe was immobilized on the surface of the gold nanoparticles. → We used electrochemical impedance spectroscopy as a suitable tool for the detection. → Detection of chronic lymphocytic leukemia in blood sample was checked using the sensor. - Abstract: A simple and sensitive DNA impedance sensor was prepared for the detection of chronic lymphocytic leukemia. The DNA electrochemical biosensor is worked based on the electrochemical impedance spectroscopic (EIS) detection of the sequence-specific DNA related to chronic lymphocytic leukemia. The ssDNA probe was immobilized on the surface of the gold nanoparticles. Compared to the bare gold electrode, the gold nanoparticles-modified electrode could improve the density of the probe DNA attachment and hence the sensitivity of the DNA sensor greatly. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy were performed in a solution containing 1.0 mmol L -1 K 3 [Fe(CN) 6 ]/K 4 [Fe(CN) 6 ] and 50 mmol L -1 phosphate buffer saline pH 6.87 plus 50 mmol L -1 KCl. In the CV studied, the potential was cycled from 0.0 to +0.65 V with a scan rate of 50 mV s -1 . Using EIS, the difference of the electron transfer resistance (ΔR et ) was linear with the logarithm of the complementary oligonucleotides sequence concentrations in the range of 7.0 x 10 -12 -2.0 x 10 -7 mol L -1 , with a detection limit of 1.0 x 10 -12 mol L -1 . In addition, the DNA sensor showed a good reproducibility and stability during repeated regeneration and hybridization cycles.

  7. Understanding Leukemia

    Science.gov (United States)

    ... for as long as they take it. Allogeneic stem cell transplantation is another treatment option that is only done if CML is not responding as expected to drug therapy. Chronic Lymphocytic Leukemia (CLL) . Some CLL patients do not need treatment ...

  8. Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Yin, Qingsong; Sivina, Mariela; Robins, Harlan; Yusko, Erik; Vignali, Marissa; O'Brien, Susan; Keating, Michael J; Ferrajoli, Alessandra; Estrov, Zeev; Jain, Nitin; Wierda, William G; Burger, Jan A

    2017-02-15

    The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4 + and CD8 + T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell-related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution. Copyright © 2017 by The American Association of Immunologists, Inc.

  9. B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292

    Directory of Open Access Journals (Sweden)

    Arnason JE

    2014-01-01

    Full Text Available Jon E Arnason,1 Jennifer R Brown21Beth Israel Deaconess Medical Center, 2CLL Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Chronic lymphocytic leukemia (CLL is the most common adult leukemia. The current treatment paradigm involves the use of chemoimmunotherapy, when patients develop an indication for therapy. With this strategy, a majority of patients will obtain a remission, though cure remains elusive. While treatable, the majority of CLL patients will die of complications of their disease. Recent advances in the understanding of the importance of the B cell receptor (BCR pathway in CLL have led to the development of a number of agents targeting this pathway. In this review, we discuss recent developments in the targeting of the BCR pathway, with a focus on CC-292. CC-292 covalently binds to Bruton's tyrosine kinase, a key mediator of BCR signaling, and has demonstrated preclinical and clinical activity in CLL, with acceptable tolerability. Based on the success of CC-292 and other inhibitors of the BCR pathway, these agents are being investigated in combination with standard therapy, with the hope that they will increase the depth and length of response, without significant toxicity.Keywords: Bruton's tyrosine kinase inhibitor, ibrutinib

  10. Changing trends of chronic myeloid leukemia in greater Mumbai, India over a period of 30 years

    Science.gov (United States)

    Dikshit, Rajesh P.; Nagrani, Rajini; Yeole, Balkrishna; Koyande, Shravani; Banawali, Shripad

    2011-01-01

    Background: Little is known about burden of chronic myeloid leukemia (CML) in India. There is a recent interest to observe incidence and mortality because of advent of new diagnostic and treatment policies for CML. Materials and Methods: We extracted data from the oldest population-based cancer registry of Mumbai for 30 years period from 1976−2005 to observe incidence and mortality rates of CML. We classified the data into four age groups 0–14, 15–29, 30–54 and 55–74 to observe incidence rates in the respective age groups. Results: The age specific rates were highest for the age group of 55–74 years. No significant change in trends of CML was observed for 30 years period. However, there was a significant reduction in incidence rate for recent 15-years period (Estimated average annual percentage change=-3.9). No significant reduction in mortality rate was observed till 2005. Conclusion: The study demonstrates that age-specific rates for CML are highest in age group of 55-74 years, although they are lower compared to western populations. Significant reduction in incidence of CML in recent periods might be because of reduced misclassification of leukemias. The data of CML has to be observed for another decade to witness reduction in mortality because of changes in treatment management. PMID:22174498

  11. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia.

    Science.gov (United States)

    Such, Esperanza; Germing, Ulrich; Malcovati, Luca; Cervera, José; Kuendgen, Andrea; Della Porta, Matteo G; Nomdedeu, Benet; Arenillas, Leonor; Luño, Elisa; Xicoy, Blanca; Amigo, Mari L; Valcarcel, David; Nachtkamp, Kathrin; Ambaglio, Ilaria; Hildebrandt, Barbara; Lorenzo, Ignacio; Cazzola, Mario; Sanz, Guillermo

    2013-04-11

    The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich Heine University Hospital, Düsseldorf, Germany, and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. CPSS was able to segregate patients into 4 clearly different risk groups for OS (P < .001) and risk of AML evolution (P < .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics, and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.

  12. Laboratory tools for diagnosis and monitoring response in patients with chronic myeloid leukemia.

    Science.gov (United States)

    Tohami, Tali; Nagler, Arnon; Amariglio, Ninette

    2012-08-01

    Chronic myeloid leukemia (CML) is a clonal hematological disease that represents 15-20% of all adult leukemia cases. The study and treatment of CML has contributed pivotal advances to translational medicine and cancer therapy. The discovery that a single chromosomal abnormality, the Philadelphia (Ph) chromosome, is responsible for the etiology of this disease was a milestone for treating and understanding CML. Subsequently, CML became the first disease for which allogeneic bone marrow transplantation is the treatment of choice. Currently, CML is one of the few diseases where treatment targeted against the chromosomal abnormality is the sole frontline therapy for newly diagnosed patients. The use of directed therapy for CML challenged disease monitoring during treatment and led to the development of definitions that document response and predict relapse sooner than the former routine methods. These methods relied on classical cytogenetics through molecular cytogenetics (FISH) and, finally, on molecular monitoring assays. This review discusses the laboratory tools used for diagnosing CML, for monitoring during treatment, and for assessing remission or relapse. The advantages and disadvantages of each test, the common definition of response levels, and the efforts to standardize molecular monitoring for CML patient management are discussed.

  13. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias

    Science.gov (United States)

    Calin, George Adrian; Liu, Chang-Gong; Sevignani, Cinzia; Ferracin, Manuela; Felli, Nadia; Dumitru, Calin Dan; Shimizu, Masayoshi; Cimmino, Amelia; Zupo, Simona; Dono, Mariella; Dell'Aquila, Marie L.; Alder, Hansjuerg; Rassenti, Laura; Kipps, Thomas J.; Bullrich, Florencia; Negrini, Massimo; Croce, Carlo M.

    2004-01-01

    Little is known about the expression levels or function of micro-RNAs (miRNAs) in normal and neoplastic cells, although it is becoming clear that miRNAs play important roles in the regulation of gene expression during development [Ambros, V. (2003) Cell 113, 673–676; McManus, M. T. (2003) Semin. Cancer Biol. 13, 253–258]. We now report the genomewide expression profiling of miRNAs in human B cell chronic lymphocytic leukemia (CLL) by using a microarray containing hundreds of human precursor and mature miRNA oligonucleotide probes. This approach allowed us to identify significant differences in miRNome expression between CLL samples and normal CD5+ B cells; data were confirmed by Northern blot analyses and real-time RT-PCR. At least two distinct clusters of CLL samples can be identified that were associated with the presence or absence of Zap-70 expression, a predictor of early disease progression. Two miRNA signatures were associated with the presence or absence of mutations in the expressed Ig variableregion genes or with deletions at 13q14, respectively. These data suggest that miRNA expression patterns have relevance to the biological and clinical behavior of this leukemia. PMID:15284443

  14. Non-codingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancer.

    Science.gov (United States)

    Wojcik, Sylwia E; Rossi, Simona; Shimizu, Masayoshi; Nicoloso, Milena S; Cimmino, Amelia; Alder, Hansjuerg; Herlea, Vlad; Rassenti, Laura Z; Rai, Kanti R; Kipps, Thomas J; Keating, Michael J; Croce, Carlo M; Calin, George A

    2010-02-01

    Cancer is a genetic disease in which the interplay between alterations in protein-coding genes and non-coding RNAs (ncRNAs) plays a fundamental role. In recent years, the full coding component of the human genome was sequenced in various cancers, whereas such attempts related to ncRNAs are still fragmentary. We screened genomic DNAs for sequence variations in 148 microRNAs (miRNAs) and ultraconserved regions (UCRs) loci in patients with chronic lymphocytic leukemia (CLL) or colorectal cancer (CRC) by Sanger technique and further tried to elucidate the functional consequences of some of these variations. We found sequence variations in miRNAs in both sporadic and familial CLL cases, mutations of UCRs in CLLs and CRCs and, in certain instances, detected functional effects of these variations. Furthermore, by integrating our data with previously published data on miRNA sequence variations, we have created a catalog of DNA sequence variations in miRNAs/ultraconserved genes in human cancers. These findings argue that ncRNAs are targeted by both germ line and somatic mutations as well as by single-nucleotide polymorphisms with functional significance for human tumorigenesis. Sequence variations in ncRNA loci are frequent and some have functional and biological significance. Such information can be exploited to further investigate on a genome-wide scale the frequency of genetic variations in ncRNAs and their functional meaning, as well as for the development of new diagnostic and prognostic markers for leukemias and carcinomas.

  15. Dasatinib Induced Avascular Necrosis of Femoral Head in Adult Patient with Chronic Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Mohamed A. Yassin

    2015-01-01

    Full Text Available Chronic myeloid leukemia (CML is a myeloproliferative neoplasm characterized by the presence of the Philadelphia (Ph chromosome resulting from the reciprocal translocation t(9;22(q34;q11. The molecular consequence of this translocation is the generation of the BCR-ABL fusion gene, which encodes a constitutively active protein tyrosine kinase. The oncogenic protein tyrosine kinase, which is located in the cytoplasm, is responsible for the leukemia phenotype through the constitutive activation of multiple signaling pathways involved in the cell cycle and in adhesion and apoptosis. Avascular necrosis of the femoral head (AVNFH is not a specific disease. It occurs as a complication or secondary to various causes. These conditions probably lead to impaired blood supply to the femoral head. The diagnosis of AVNFH is based on clinical findings and is supported by specific radiological manifestations. We reported a case of a 34-year-old Sudanese female with CML who developed AVNFH after receiving dasatinib as a second-line therapy. Though the mechanism by which dasatinib can cause avascular necrosis (AVN is not clear, it can be postulated because of microcirculatory obstruction of the femoral head. To the best of our knowledge and after extensive literature search, this is the first reported case of AVNFH induced by dasatinib in a patient with CML.

  16. Re-emergence of interferon-α in the treatment of chronic myeloid leukemia

    Science.gov (United States)

    Talpaz, M; Hehlmann, R; Quintás-Cardama, A; Mercer, J; Cortes, J

    2013-01-01

    Treatment for chronic myeloid leukemia (CML) has evolved from chemotherapy (busulfan, hydroxyurea) to interferon-α (IFNα), and finally to tyrosine kinase inhibitors such as imatinib. Although imatinib has profoundly improved outcomes for patients with CML, it has limitations. Most significantly, imatinib cannot eradicate CML primitive progenitors, which likely accounts for the high relapse rate when imatinib is discontinued. IFNα, unlike imatinib, preferentially targets CML stem cells. Early studies with IFNα in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFNα were able to sustain durable remissions after discontinuing therapy and were probably cured. The mechanisms by which IFNα exerts its antitumor activity in CML are not well understood; however, activation of leukemia-specific immunity may have a role. Some clinical studies have demonstrated that the combination of imatinib and IFNα is superior to either therapy alone, perhaps because of their different mechanisms of action. Nonetheless, the side effects of IFNα often impede its administration, especially in combination therapy. Here, we review the role of IFNα in CML treatment and the recent developments that have renewed interest in this once standard therapy for patients with CML. PMID:23238589

  17. [Effectiveness of azacitidine in chronic myelomonocytic leukemia harboring del(20q) - a case report].

    Science.gov (United States)

    Manabe, Masahiro; Okita, Junya; Takakuwa, Teruhito; Harada, Naonori; Aoyama, Yasutaka; Kumura, Takeo; Ohta, Tadanobu; Furukawa, Yoshio; Mugitani, Atsuko

    2014-06-01

    A 7 1-year-old man was admitted to our hospital with leukocytosis and anemia. Chronic myelomonocytic leukemia (CMML)harboring del(20q)was diagnosed by peripheral blood examination and bone marrow aspiration. The patient was subsequently treated with azacitidine, which resulted in rapid disappearance of monocytosis and resolved his dependency on red cell transfusion. With regard to the chromosomal abnormality, although del(20q)is estimated to be encountered in approximately 0.7-1.0% of all CMML cases, its significance in prognosis has not been fully analyzed. Hence, more such cases need to be evaluated to elucidate the therapeutic outcome of CMML involving del(20q). In addition, the Wilms tumor-1(WT 1)level in the patient gradually decreased after the initiation of azacitidine therapy. This phenomenon of WT1 decrease synchronizing with the patient's clinical improvement might reflect therapeutic efficacy with regard to the clinical course, as had been observed in acute myeloid leukemia and myelodysplastic syndrome.

  18. Non-Hodgkin's lymphoma in a chronic myelocytic leukemia patient treated with imatinib

    Directory of Open Access Journals (Sweden)

    Semra Paydaş

    2011-09-01

    Full Text Available Imatinib is an important example of tyrosine kinase inhibitors (TKIs used in clinical practice. Imatinib blocks the ATP binding site of the Bcr-Abl fusion protein and selectively inhibits Bcr-Abl tyrosine kinase (TK activity. Treatment of chronic myelocytic leukemia (CML with imatinib is encouraging and it has an acceptable toxicity profile, and as such has changed the management of CML during the last decade. As with all drugs used in clinical practice, side effects of imatinib have been reported in studies with extended follow-up periods. In addition, some neoplastic disorders have been reported to occur during imatinib therapy. Herein we present a CML case that developed non-Hodgkin’s lymphoma (NHL while receiving imatinib treatment.

  19. The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy.

    Science.gov (United States)

    Landau, Dan A; Sun, Clare; Rosebrock, Daniel; Herman, Sarah E M; Fein, Joshua; Sivina, Mariela; Underbayev, Chingiz; Liu, Delong; Hoellenriegel, Julia; Ravichandran, Sarangan; Farooqui, Mohammed Z H; Zhang, Wandi; Cibulskis, Carrie; Zviran, Asaf; Neuberg, Donna S; Livitz, Dimitri; Bozic, Ivana; Leshchiner, Ignaty; Getz, Gad; Burger, Jan A; Wiestner, Adrian; Wu, Catherine J

    2017-12-19

    Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling. Known and previously undescribed mutations in BTK and PLCG2, or uncommonly, other candidate alterations are present in seventeen subjects at the time of progression. Thus, the frequently observed clonal shifts during the early treatment period and its potential association with adverse outcome may reflect greater evolutionary capacity, heralding the emergence of drug-resistant clones.

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

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    Vihang Patel

    2017-05-01

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

  1. Bilateral Proliferative Retinopathy as the Initial Presentation of Chronic Myeloid Leukemia

    Science.gov (United States)

    Macedo, Mafalda S. F.; Figueiredo, Ana R. M.; Ferreira, Natália N.; Barbosa, Irene M. A.; Furtado, Maria João F. B. S.; Correia, Nuno F. C. B. A.; Gomes, Miguel P.; Lume, Miguel R. B.; Menéres, Maria João S.; Santos, Marinho M. N.; Meireles S., M. Angelina C.

    2013-01-01

    The authors report a rare case of a 48-year-old male with chronic myeloid leukemia (CML) who initially presented with a bilateral proliferative retinopathy. The patient complained of recent visual loss and floaters in both eyes (BE). Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 20/50 in the right eye and 20/200 in the left eye (LE). Fundoscopy showed the presence of bilateral peripheral capillary dropout with multiple retinal sea fan neovascularisations, which were confirmed on fluorescein angiography. Full blood count revealed hyperleukocytosis, thrombocytosis, anemia, and hyperuricemia. Bone marrow aspiration and biopsy showed the reciprocal chromosomal translocation t (9;22), diagnostic of CML. The patient was started on hydroxyurea, allopurinol and imatinib mesylate. He received bilateral panretinal laser photocoagulation and a vitrectomy was performed in the LE. The patient has been in complete hematologic, cytogenetic, and major molecular remission while on imatinib and his BCVA is 20/25 in BE. PMID:24339689

  2. EFFECTIVENESS OF VENETOСLAX IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (LITERATURE REVIEW

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    V. V. Strugov

    2017-01-01

    Full Text Available Currently we are facing a revolution in therapy of chronic lymphocytic leukemia, related to the development of novel target drugs, which have markedly improved treatment results in all groups of patients. While inhibitors of Bruton’s tyrosine kinase (ibrutinib, acalabrutinib etc. and phosphatidylinositol-3 kinase isoforms (idelalisib, umbralisib etc. are currently in the spotlight, much less attention is paid to antiapoptotic protein inhibitors such as venetoclax. In this review we summarize the results of venetoclax clinical studies in CLL as monotherapy and in combinations. The drug is distinguished by a high rate of complete responses and minimal residual disease eradication in high risk CLL patients, as well as a favorable toxicity profile. This makes it an ideal component of non-genotoxic regimens, aimed at the cure of the disease.

  3. Cryptococcal infections in two patients receiving ibrutinib therapy for chronic lymphocytic leukemia.

    Science.gov (United States)

    Stankowicz, Matthew; Banaszynski, Megan; Crawford, Russell

    2018-01-01

    Cryptococcal infections are responsible for significant morbidity and mortality in immunocompromised patients. Reports of these infections in patients on small molecular kinase inhibitors have not been widely reported in clinical trials. We describe one case of cryptococcal meningoencephalitis and one case of cryptococcal pneumonia in two patients who were receiving ibrutinib for chronic lymphocytic leukemia. Despite different sites of cryptococcal infection, both patients had similar presentations of acute illness. Patient 1 was worked up for health care-associated pneumonia, as well as acute sinusitis prior to the diagnosis of cryptococcal meningoencephalitis. He also had a more complex past medical history than patient 2. Patient 2 developed atrial fibrillation from ibrutinib prior to admission for presumed health care-associated pneumonia. Cryptococcal antigen testing was done sooner in this patient due to patient receiving high-dose steroids for the treatment of underlying hemolytic anemia. We conclude that patients who develop acute illness while receiving ibrutinib should be considered for cryptococcal antigen testing.

  4. Detection of Hodgkin Transformation in a Case of Chronic Lymphocytic Leukemia by PET/CT

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    Sabire Yılmaz

    2014-06-01

    Full Text Available Richter’s transformation (RT represents the development of high grade lymphoma, most commonly diffuse large B-cell lymphoma, in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL. CLL/SLL may convert also to Hodgkin’s lymphoma, the so-called Hodgkin’s variant of Richter transformation. Histopathological proof is needed to confirm a definitive diagnosis. Patients with RT generally have a poor prognosis, with prompt recognition optimise clinical management. Whole-body PET scan with 18F-FDG can be used for detection of RT of CLL/SLL. We describe the case of 64-year-old woman with CLL/SLL who developed Hodgkin lymphoma detected with PET/CT.

  5. Variants forms of Philadelphia translocation in two patients with chronic myeloid leukemia

    International Nuclear Information System (INIS)

    Valent, A.; Zamecnikova, A.; Krizan, P.; Karlic, H.; Nowotny, H.

    1996-01-01

    During a 4-year period (December 1990-December 1994), among other diagnoses hundred cases of chronic myeloid leukemia (CML) were analyzed in our departments. We focused our attention on two cases with a variant form of Philadelphia translocation. Cytogenetic and molecular genetic studies were performed to resolve the status of BCR and ABL in the bone marrow or peripheral blood cells of the two CML patients with complex translocations involving chromosomes, 3, 9, 22 and 9, 12, 22 respectively. In the first case the presence of Ph chromosome was detected cytogenetically, BCR-ABL translocation was detected by Southern hybridization. In the second phase, only the PCR method showed BCR-ABL rearrangement. The second case, with a random variant form of Ph translocation, could be detected using different methods of clinical molecular genetics. (author)

  6. [CpG-oligodeoxynucleotide stimulation improves the success for karyotypic analysis of chronic lymphocytic leukemia cells].

    Science.gov (United States)

    Liu, Qiong; Xu, Wei; Qiu, Hai-rong; Wang, Rong; Yu, Hui; Fan, Lei; Miao, Kou-rong; Li, Jian-yong

    2009-09-01

    To explore the effect of CpG-oligodeoxynucleotides (ODN) in chromosome study of chronic lymphocytic leukemia (CLL). Blood or bone marrow cells of 70 CLL patients were cultured for 72 h with PHA, CpG-ODN and CpG-ODN combined with IL-2, respectively. Routine karyotype analysis with R banding technique and interphase fluorescence in situ hybridization (FISH) were performed. The metaphase number>or=20 was considered as successful stimulation, which in PHA, CpG-ODN and CpG-ODN combined IL-2 groups were 90.0%, 68.6% and 68.6%, respectively, and the detection rates of chromosome aberrations were 3.2%, 43.6% and 43.6%, respectively. The aberrations rates detected by interphase FISH with a panel of probes was 64.3%. CpG-ODN DSP30 can effectively raise the detection rate of chromosome aberrations in CLL patients.

  7. Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia.

    Science.gov (United States)

    Wang, Jiguang; Khiabanian, Hossein; Rossi, Davide; Fabbri, Giulia; Gattei, Valter; Forconi, Francesco; Laurenti, Luca; Marasca, Roberto; Del Poeta, Giovanni; Foà, Robin; Pasqualucci, Laura; Gaidano, Gianluca; Rabadan, Raul

    2014-12-11

    Cancer is a clonal evolutionary process, caused by successive accumulation of genetic alterations providing milestones of tumor initiation, progression, dissemination, and/or resistance to certain therapeutic regimes. To unravel these milestones we propose a framework, tumor evolutionary directed graphs (TEDG), which is able to characterize the history of genetic alterations by integrating longitudinal and cross-sectional genomic data. We applied TEDG to a chronic lymphocytic leukemia (CLL) cohort of 70 patients spanning 12 years and show that: (a) the evolution of CLL follows a time-ordered process represented as a global flow in TEDG that proceeds from initiating events to late events; (b) there are two distinct and mutually exclusive evolutionary paths of CLL evolution; (c) higher fitness clones are present in later stages of the disease, indicating a progressive clonal replacement with more aggressive clones. Our results suggest that TEDG may constitute an effective framework to recapitulate the evolutionary history of tumors.

  8. Dose Dependent Survival Response in Chronic Myeloid Leukemia under Continuous and Pulsed Targeted Therapy

    International Nuclear Information System (INIS)

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

    2010-01-01

    A simulative study of cancer growth dynamics in patients affected by Chronic Myeloid Leukemia (CML), under the effect of a targeted dose dependent continuous or pulsed therapy, is presented. We have developed a model for the dynamics of CML in which the stochastic evolution of white blood cell populations are simulated by adopting a Monte Carlo approach. Several scenarios in the evolutionary dynamics of white blood cells, as a consequence of the efficacy of the different modelled therapies, pulsed or continuous, are described. The best results, in terms of a permanent disappearance of the leukemic phenotype, are achieved with a continuous therapy and higher dosage. However, our findings demonstrate that an intermittent therapy could represent a valid choice in patients with high risk of toxicity, when a long-term therapy is considered. A suitably tuned pulsed therapy can enhance the treatment efficacy and reduce the percentage of patients developing resistance. (authors)

  9. Complex Variant t(9;22 Chromosome Translocations in Five Cases of Chronic Myeloid Leukemia

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    Ana Valencia

    2009-01-01

    Full Text Available The Philadelphia (Ph1 chromosome arising from the reciprocal t(9;22 translocation is found in more than 90% of chronic myeloid leukemia (CML patients and results in the formation of the chimeric fusion gene BCR-ABL. However, a small proportion of patients with CML have simple or complex variants of this translocation, involving various breakpoints in addition to 9q34 and 22q11. We report five CML cases carrying variant Ph translocations involving both chromosomes 9 and 22 as well as chromosomes 3, 5, 7, 8, or 10. G-banding showed a reciprocal three-way translocation involving 3q21, 5q31, 7q32, 8q24, and 10q22 bands. BCR-ABL fusion signal on der(22 was found in all of the cases by FISH.

  10. Bone and bone-marrow blood flow in chronic granulocytic leukemia and primary myelofibrosis

    International Nuclear Information System (INIS)

    Lahtinen, R.; Lahtinen, T.; Romppanen, T.

    1982-01-01

    Blood flow in hematopoietic bone marrow and in nonhematopoietic bone has been measured with a Xe-133 washout method in 20 patients with chronic granulocytic leukemia (CGL) and in seven with primary myelofibrosis. Age-matched healthy persons served as controls. Bone-marrow blood flow in CGL was dependent upon the phase of the disease. In the metamorphosis phase, bone-marrow blood flow was high compared with that in the well-controlled phase. Apart from the initial phase, the mean values for bone blood flow in CGL were increased compared with the values of the healthy controls. In myelofibrosis the bone blood flow was also increased. Bone-marrow blood flow in these diseases was dependent upon the cellularity of bone marrow as measured morphometrically

  11. NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells

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    Mauro Di Ianni

    2018-04-01

    Full Text Available To investigate chronic lymphocytic leukemia (CLL-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs. In NOTCH1-mutated CLL, we detected subclonal mutations in 57% CD34+/CD38− HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38− and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

  12. Where does allogeneic stem cell transplantation fit in the treatment of chronic lymphocytic leukemia?

    Science.gov (United States)

    Dreger, Peter; Montserrat, Emili

    2015-03-01

    Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (CLL) (i.e., refractory to purine analogs, short response (CLL treatment armamentarium. These signal transduction inhibitors (STI) will change the algorithms of high-risk CLL (HR-CLL) management. Despite the limited body of evidence, there is sufficient rationale for withholding alloHSCT in patients with 17p-/TP53mut CLL in first remission. In contrast, the perspectives of patients with relapsed 17p-/TP53mut CLL remain uncertain even if responding to STI. The same accounts for patients with HR-CLL progressing under STI. In both scenarios, it is reasonable to consider alloHSCT, ideally after response to alternative STI regimens.

  13. NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells.

    Science.gov (United States)

    Di Ianni, Mauro; Baldoni, Stefano; Del Papa, Beatrice; Aureli, Patrizia; Dorillo, Erica; De Falco, Filomena; Albi, Elisa; Varasano, Emanuela; Di Tommaso, Ambra; Giancola, Raffaella; Accorsi, Patrizia; Rotta, Gianluca; Rompietti, Chiara; Silva Barcelos, Estevão Carlos; Campese, Antonio Francesco; Di Bartolomeo, Paolo; Screpanti, Isabella; Rosati, Emanuela; Falzetti, Franca; Sportoletti, Paolo

    2018-01-01

    To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1- mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

  14. Cutaneous Mucormycosis Following a Bullous Pemphigoid Flare in a Chronic Lymphocytic Leukemia Patient on Ibrutinib.

    Science.gov (United States)

    Stein, Matthew K; Karri, Saradasri; Reynolds, Jackson; Owsley, Jeff; Wise, Austin; Martin, Mike G; Zare, Fereshteh

    2018-04-01

    While the recent development of novel therapeutics in oncology, such as small molecule kinase inhibitors (SMKIs), has enabled our ability to target disease-specific molecular pathways, the prolonged impact of these agents on the immune system and infectious risk remains to be seen. We present a 68-year-old male with refractory chronic lymphocytic leukemia (CLL) on ibrutinib monotherapy for 3 years who developed extensive cutaneous mucormycosis following a severe bullous pemphigoid (BP) flare. He received amphotericin B for 4 weeks and was continued on posaconazole with resolution of his mucormycosis infection. Consistent with a growing evidence of literature identifying opportunistic fungal infections in patients on ibrutinib therapy, providers should be cognizant of medical comorbidities that may predispose to such infections and explore methods of prevention before starting ibrutinib and other SMKIs.

  15. Nutritional support for chronic myelogenous and other leukemias: a review of the scientific literature.

    Science.gov (United States)

    Steriti, Ronald

    2002-10-01

    Chronic myelogenous leukemia (CML) is a slowly progressive disease characterized by the overproduction of granulocytes (neutrophils, eosinophils, and basophils). A blood smear shows moderate elevations in white blood cell counts that may persist for years and be benign. Platelets are increased in number, although their function is impaired, resulting in symptoms of easy bleeding (purpura, swollen gums). Conventional medical treatment is a marrow transplant and alkylating agents, which are usually prescribed only during crisis. Several nutrients and botanicals have been studied for use in CML, including vitamin A and all-trans retinoic acid (Retin-A), vitamin D3, vitamin E, vitamin B12, indirubin (found in herbs including Indigofera tinctoria and Isatis tinctoria), and Curcuma longa. This article briefly reviews the scientific literature on the therapeutic use of these nutrients for CML.

  16. Locally disordered methylation forms the basis of intra-tumor methylome variation in chronic lymphocytic leukemia

    Science.gov (United States)

    Landau, Dan A.; Clement, Kendell; Ziller, Michael J.; Boyle, Patrick; Fan, Jean; Gu, Hongcang; Stevenson, Kristen; Sougnez, Carrie; Wang, Lili; Li, Shuqiang; Kotliar, Dylan; Zhang, Wandi; Ghandi, Mahmoud; Garraway, Levi; Fernandes, Stacey M.; Livak, Kenneth J.; Gabriel, Stacey; Gnirke, Andreas; Lander, Eric S.; Brown, Jennifer R.; Neuberg, Donna; Kharchenko, Peter V.; Hacohen, Nir; Getz, Gad; Meissner, Alexander; Wu, Catherine J.

    2014-01-01

    SUMMARY Intra-tumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLL). Compared to 26 normal B cell samples, CLLs consistently displayed higher intra-sample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories. PMID:25490447

  17. Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.

    Science.gov (United States)

    Landau, Dan A; Clement, Kendell; Ziller, Michael J; Boyle, Patrick; Fan, Jean; Gu, Hongcang; Stevenson, Kristen; Sougnez, Carrie; Wang, Lili; Li, Shuqiang; Kotliar, Dylan; Zhang, Wandi; Ghandi, Mahmoud; Garraway, Levi; Fernandes, Stacey M; Livak, Kenneth J; Gabriel, Stacey; Gnirke, Andreas; Lander, Eric S; Brown, Jennifer R; Neuberg, Donna; Kharchenko, Peter V; Hacohen, Nir; Getz, Gad; Meissner, Alexander; Wu, Catherine J

    2014-12-08

    Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLLs). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Familial chronic lymphocytic leukemia in Norway and Denmark. Comments on pleiotropy and birth order.

    Science.gov (United States)

    Jønsson, Viggo; Tjønnfjord, Geir E; Johannesen, Tom B; Ly, Bernt; Olsen, Jørgen H; Yuille, Martin

    2010-01-01

    To investigate the genetics of chronic lymphocytic leukemia (CLL). In 56 (7%) out of 800 CLL patients with concomitant malignant hematological disease, 51 families and 141 cases were ascertained. 106 cases (75%) of CLL, 27 cases (19%) of nonCLL and 8 cases (6%) of myeloproliferative disorders. Paternal disease was transmitted primarily to the youngest sons in the sibship while maternal disease was transmitted equally to all sibs, demonstrated by means of matrix conjugation and confirmed with Cox regression on parity and birth order (maternal-offspring combination: relative risk (RR), 95% confidence interval (CI)=1.47 (0.89 - 2.43), p=0.12, compared with paternal-offspring combination: RR=3.25, 95% CI=(1.57-6.72), p<0.001). The B-cell expression in familial and sporadic CLL was indistinguishable. Parental genomic imprinting is pointed out as one possible mechanism behind this non-Mendelian genomic output.

  19. Treatment of chronic myeloid leukemia: assessing risk, monitoring response, and optimizing outcome.

    Science.gov (United States)

    Shanmuganathan, Naranie; Hiwase, Devendra Keshaorao; Ross, David Morrall

    2017-12-01

    Over the past two decades, tyrosine kinase inhibitors have become the foundation of chronic myeloid leukemia (CML) treatment. The choice between imatinib and newer tyrosine kinase inhibitors (TKIs) needs to be balanced against the known toxicity and efficacy data for each drug, the therapeutic goal being to maximize molecular response assessed by BCR-ABL RQ-PCR assay. There is accumulating evidence that the early achievement of molecular targets is a strong predictor of superior long-term outcomes. Early response assessment provides the opportunity to intervene early with the aim of ensuring an optimal response. Failure to achieve milestones or loss of response can have diverse causes. We describe how clinical and laboratory monitoring can be used to ensure that each patient is achieving an optimal response and, in patients who do not reach optimal response milestones, how the monitoring results can be used to detect resistance and understand its origins.

  20. The concept of treatment-free remission in chronic myeloid leukemia

    Science.gov (United States)

    Saußele, S; Richter, J; Hochhaus, A; Mahon, F-X

    2016-01-01

    The advent of tyrosine kinase inhibitors (TKI) into the management of patients with chronic myeloid leukemia (CML) has profoundly improved prognosis. Survival of responders is approaching that of the general population but lifelong treatment is still recommended. In several trials, TKI treatment has been stopped successfully in approximately half of the patients with deep molecular response. This has prompted the development of a new concept in the evaluation of CML patients known as ‘treatment-free remission'. The future in CML treatment will be to define criteria for the safe and most promising discontinuation of TKI on one hand, and, on the other, to increase the number of patients available for such an attempt. Until safe criteria have been defined, discontinuation of therapy is still experimental and should be restricted to clinical trials or registries. This review will provide an overview of current knowledge as well as an outlook on future challenges. PMID:27133824

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

    Science.gov (United States)

    Leitner, A A; Hehlmann, R

    2011-02-01

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

  2. Aberrant DNA Methylation in Chronic Myeloid Leukemia: Cell Fate Control, Prognosis, and Therapeutic Response.

    Science.gov (United States)

    Behzad, Masumeh Maleki; Shahrabi, Saeid; Jaseb, Kaveh; Bertacchini, Jessika; Ketabchi, Neda; Saki, Najmaldin

    2018-01-31

    Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy characterized by the expression of the BCR-ABL1 fusion gene with different chimeric transcripts. Despite the crucial impact of constitutively active tyrosine kinase in CML pathogenesis, aberrant DNA methylation of certain genes plays an important role in disease progression and the development of drug resistance. This article reviews recent findings relevant to the effect of DNA methylation pattern of regulatory genes on various cellular activities such as cell proliferation and survival, as well as cell-signaling molecules in CML. These data might contribute to defining the role of aberrant DNA methylation in disease initiation and progression. However, further studies are needed on the validation of specific aberrant methylation markers regarding the prognosis and prediction of response among the CML patients.

  3. Turkish Chronic Myeloid Leukemia Study: Retrospective Sectional Analysis of CML Patients

    Directory of Open Access Journals (Sweden)

    Fahri Şahin

    2013-12-01

    Full Text Available OBJECTIVE: here have been tremendous changes in treatment and follow-up of patients with chronic myeloid leukemia (CML in the last decade. Especially, regular publication and updating of NCCN and ELN guidelines have provided enermous rationale and base for close monitorization of patients with CML. But, it is stil needed to have registry results retrospectively to evaluate daily CML practices. METHODS: In this article, we have evaluated 1133 patients’ results with CML in terms of demographical features, disease status, response, resistance and use of second-generation TKIs. RESULTS: The response rate has been found relatively high in comparison with previously published articles, and we detected that there was a lack of appropriate and adequate molecular response assessment. CONCLUSION: We concluded that we need to improve registry systems and increase the availability of molecular response assessment to provide high-quality patient care.

  4. Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Malignancies.

    Science.gov (United States)

    Varughese, Tilly; Taur, Ying; Cohen, Nina; Palomba, M Lia; Seo, Susan K; Hohl, Tobias M; Redelman-Sidi, Gil

    2018-03-02

    Ibrutinib is a Bruton's tyrosine kinase inhibitor that is used for the treatment of lymphoid malignancies, including chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia and mantle cell lymphoma (MCL). Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. We reviewed the electronic medical records of patients with lymphoid malignancies at Memorial Sloan Kettering Cancer Center who received ibrutinib during a five-year period from January 1, 2012 to December 31, 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by univariate and multivariate analyses. 378 patients with lymphoid malignancies who received ibrutinib were analyzed. The most common underlying malignancies were CLL and MCL. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Of these, 23 (53.5%) developed invasive bacterial infections, and 16 (37.2%) developed invasive fungal infections (IFI). The majority of those who developed IFI on ibrutinib therapy (62.5%) lacked classical clinical risk factors for fungal infection (i.e., neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in six of the 43 patients (14%). Patients with lymphoid malignancies receiving ibrutinib treatment are at risk for serious infections, including IFI.

  5. A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Tucker DL

    2015-06-01

    Full Text Available David L Tucker, Simon A Rule Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK Abstract: Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL and chronic lymphocytic leukemia (CLL, small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase, which functions by irreversible inhibition of the downstream signaling pathway of the B-cell receptor, which normally promotes cell survival and proliferation. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile even in elderly and multiply pretreated patient cohorts. Although the majority of disease responses tend to be partial, efficacy data have also been encouraging with more than two-thirds of patients with CLL and MCL demonstrating a durable response, even in the high-risk disease setting. Resistance mechanisms are only partially understood and appear to be multifactorial, including the binding site mutation C481S, and escape through other common cell-signaling pathways. This article appraises the currently available data on safety and efficacy from clinical trials of ibrutinib in the management of MCL and CLL, both as a single agent and in combination with other therapies, and considers how this drug is likely to be used in future clinical practice. Keywords: ibrutinib, mantle cell lymphoma, chronic lymphocytic leukemia, Bruton’s tyrosine kinase, lymphoproliferative disorders

  6. Anticancer activity of Pupalia lappacea on chronic myeloid leukemia K562 cells.

    Science.gov (United States)

    Ravi, Alvala; Alvala, Mallika; Sama, Venkatesh; Kalle, Arunasree M; Irlapati, Vamshi K; Reddy, B Madhava

    2012-12-05

    Cancer is one of the most prominent human diseases which has enthused scientific and commercial interest in the discovery of newer anticancer agents from natural sources. Here we demonstrated the anticancer activity of ethanolic extract of aerial parts of Pupalia lappacea (L) Juss (Amaranthaceae) (EAPL) on Chronic Myeloid Leukemia K562 cells. Antiproliferative activity of EAPL was determined by MTT assay using carvacrol as a positive control. Induction of apoptosis was studied by annexin V, mitochondrial membrane potential, caspase activation and cell cycle analysis using flow cytometer and modulation in protein levels of p53, PCNA, Bax and Bcl2 ratio, cytochrome c and cleavage of PARP were studied by Western blot analysis. The standardization of the extract was performed through reverse phase-HPLC using Rutin as biomarker. The results showed dose dependent decrease in growth of K562 cells with an IC50 of 40 ± 0.01 μg/ml by EAPL. Induction of apoptosis by EAPL was dose dependent with the activation of p53, inhibition of PCNA, decrease in Bcl2/Bax ratio, decrease in the mitochondrial membrane potential resulting in release of cytochrome c, activation of multicaspase and cleavage of PARP. Further HPLC standardization of EAPL showed presence 0.024% of Rutin. Present study significantly demonstrates anticancer activity of EAPL on Chronic Myeloid Leukemia (K562) cells which can lead to potential therapeutic agent in treating cancer. Rutin, a known anti cancer compound is being reported and quantified for the first time from EAPL.

  7. Potentiation of luteolin cytotoxicity by flavonols fisetin and quercetin in human chronic lymphocytic leukemia cell lines.

    Science.gov (United States)

    Sak, Katrin; Kasemaa, Kristi; Everaus, Hele

    2016-09-14

    Despite numerous studies chronic lymphocytic leukemia (CLL) still remains an incurable disease. Therefore, all new compounds and novel strategies which are able to eradicate CLL cells should be considered as valuable clues for a potential future remedy against this malignancy. In the present study, the cytotoxic profiles of natural flavonoids were described in two human CLL cell lines, HG-3 and EHEB, indicating the flavone luteolin as the most potent flavonoid with half-maximal inhibitory constants (IC50) of 37 μM and 26 μM, respectively. Luteolin significantly increased the apoptotic cell population in both cell lines by increasing the activities of caspases-3 and -9 and triggering the intrinsic apoptotic pathway. Two flavonols, fisetin and quercetin, were somewhat less efficient in suppressing cellular viability, whereas baicalein, chrysin, (+)-catechin and hesperetin exerted only a small or no response at doses as high as 100 μM. Both fisetin and quercetin were able to augment the cytotoxic activity of luteolin in both cell lines by reducing the IC50 values up to four fold. As a result of this, luteolin displayed cytotoxicity activity already at low micromolar concentrations that could potentially be physiologically achievable through oral ingestion. No other tested flavonoids were capable of sensitizing CLL cells to luteolin pointing to a specific binding of fisetin and quercetin to the cellular targets which interfere with the signaling pathways induced by luteolin. Although further molecular studies to unravel this potentiating mechanism are certainly needed, this phenomenon could contribute to future remedies for prevention and treatment of chronic lymphocytic leukemia.

  8. Effect of low dose radiation on expression of p16 gene in chronic myelogenous leukemia cells

    International Nuclear Information System (INIS)

    Zhang Longzhen; Ding Xin; Li Xiangyang; Cen Jiannong; Shen Hongjie; Chen Zixing

    2010-01-01

    Objective: To investigate the effect of low dose radiation on the expression on p16 gene in chronic myelogenous leukemia. Methods: Leukemic stem cells (LSCs) which expressed CD34 +, CD38 - and CD123 + were isolated from bone marrow cells obtained from twenty patients newly-diagnosedas chronic myeloid leukemia with EasySep TM magnet beads. Hematopoietic stem cells (HSCs) which expressed CD34 + and CD38 - were isolated from human cord blood cells obtained from twenty full-term deliveries with EasySep TM magnet beads as control. HSCs vs LSCs samples were further divided into three dose groups, including 0, 12.5 and 50 cGy, respectively. RT-PCR and real-time quantitative reverse transcription-polymerase chain reaction methods were used to detect mRNA expression of p16 gene in HSCs and LSCs after irradiation. Cells were harvested at different time for detection of cell cycle and apoptosis by flow cytometer. Results: p16 mRNA level in CML-LSCs was increased slightly at 12.5 cGy, and significantly increased at 50 cGy (Z=-3.39, P 0 /G 1 stagewas increased 48 h after 12.5 cGy irradiation, and 72 h post-irradiation with 50 cGy. The apoptosis rate of CML-LSCs was gradually raised after LDR, especially at 72 h post-irradiation of 50 cGy [(17.75±11.760% vs (6.13±4.71)%, Z=-2.37, P<0.01]. Conclusions: p16 gene transcription could be up-regulated by low dose radiation, which might provide a theoretical evidence for CML therapy and LDR in leukemic clinical application. (authors)

  9. Prognostic value of regulatory T cells in newly diagnosed chronic myeloid leukemia patients.

    Science.gov (United States)

    Zahran, Asmaa M; Badrawy, Hosny; Ibrahim, Abeer

    2014-08-01

    Chronic myeloid leukemia (CML) is a clonal disease, characterized by a reciprocal t(9, 22) that results in a chimeric BCR/ABL fusion gene. Regulatory T cells (Tregs) constitute the main cell population that enables cancer cells to evade immune surveillance. The purpose of our study was to investigate the level of Tregs in newly diagnosed CML patients and to correlate it with the patients' clinical, laboratory and molecular data. We also aimed to assess the effect of treatment using tyrosine kinase inhibitor (TKI) on Treg levels. Tregs were characterized and quantified by flow cytometry in 63 newly diagnosed CML patients and 40 healthy controls. TKI was used in 45 patients with chronic phase CML, and the response to therapy was correlated with baseline Treg levels. The percentages of Tregs were significantly increased in CML patients compared to the controls. Treg numbers were significantly lower in patients with chronic phase CML versus the accelerated and blast phases, and were significantly lower in patients with complete molecular remission (CMR) compared to those patients without CMR. Tregs may play a role in the maintenance of CML. Moreover, the decrease of their levels in patients with CMR suggests that Tregs might have a clinical value in evaluating the effects of therapy.

  10. Total Body Irradiation for Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia

    International Nuclear Information System (INIS)

    Chung, Su Mi; Choi, Ihl Bohng; Kang, Ki Mun; Kim, In Ah; Shinn, Kyung Sub; Kim, Choon Choo; Kim, Dong Jip

    1994-01-01

    Between July 1987 and December 1992, we treated 22 patients with chromic myelogenous leukemia; 14 in the chronic phase and 8 with more advanced disease. All were received with allogeneic bone marrow transplantation from HLA-identical sibling donors after a total body irradiation (TBI) cyclophosphamide conditioning regimen. Patients were non-randomly assigned to either 1200 cGy/6 fractions/3 days (6 patients) or 1320 cGy/8 fractions/4 days (16 patients) by dose of TBI. Of the 22 patients, 8 were prepared with cyclophosphamide alone, 14 were conditioned with additional adriamycin or daunorubicin. To prevent graft versus host disease, cyclosporine was given either alone or in conjunction with methotrexate. The actuarial survival and leukemic-free survival at four years were 58.5% and 41.2%, respectively, and the relapse rate was 36% among 22 patients. There was a statistically significant difference in survival between the patients in chronic phase and more advanced phase (76% vs 33%, p=0.05). The relapse rate of patients receiving splenectomy was higher than that of patients receiving splenic irradiation (50% vs 0%, p=0.04). We conclude that the probability of cure is highest if transplantation is performed while the patient remains in the chronic phase

  11. Total Body Irradiation for Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Su Mi; Choi, Ihl Bohng; Kang, Ki Mun; Kim, In Ah; Shinn, Kyung Sub; Kim, Choon Choo; Kim, Dong Jip [Catholic University College of Medicine, Seoul (Korea, Republic of)

    1994-06-15

    Between July 1987 and December 1992, we treated 22 patients with chromic myelogenous leukemia; 14 in the chronic phase and 8 with more advanced disease. All were received with allogeneic bone marrow transplantation from HLA-identical sibling donors after a total body irradiation (TBI) cyclophosphamide conditioning regimen. Patients were non-randomly assigned to either 1200 cGy/6 fractions/3 days (6 patients) or 1320 cGy/8 fractions/4 days (16 patients) by dose of TBI. Of the 22 patients, 8 were prepared with cyclophosphamide alone, 14 were conditioned with additional adriamycin or daunorubicin. To prevent graft versus host disease, cyclosporine was given either alone or in conjunction with methotrexate. The actuarial survival and leukemic-free survival at four years were 58.5% and 41.2%, respectively, and the relapse rate was 36% among 22 patients. There was a statistically significant difference in survival between the patients in chronic phase and more advanced phase (76% vs 33%, p=0.05). The relapse rate of patients receiving splenectomy was higher than that of patients receiving splenic irradiation (50% vs 0%, p=0.04). We conclude that the probability of cure is highest if transplantation is performed while the patient remains in the chronic phase.

  12. Additional cytogenetic abnormalities and variant t(9;22) at the diagnosis of childhood chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Millot, Frédéric; Dupraz, Christelle; Guilhot, Joelle

    2017-01-01

    for Chronic Myeloid Leukemia in Children and Adolescents. RESULTS: Overall, 19 children (6.3%) presented with additional cytogenetic findings at diagnosis: 5 children (1.7%) had a variant t(9;22) translocation, 13 children (4.3%) had ACAs, and 1 had both. At 3 years, for children with a classic translocation......BACKGROUND: In the adult population with newly diagnosed chronic myeloid leukemia (CML), variant translocations are usually not considered to be impairing the prognosis, whereas some additional cytogenetic abnormalities (ACAs) are associated with a negative impact on survival. Because of the rarity...... of CML in the pediatric population, such abnormalities have not been investigated in a large group of children with CML. METHODS: The prognostic relevance of variant t(9;22) and ACAs at diagnosis was assessed in 301 children with CML in the chronic phase who were enrolled in the International Registry...

  13. Two cases of chronic myelogenous leukemia (CML) treated with Iminitab (Glivec) in different phases

    International Nuclear Information System (INIS)

    Davoli, R.; Ciarlo, S.; Acosta, I.; Perez, S.; Lagorio, S.; Pratti, A.A.

    2003-01-01

    Full text: IMINITAB, inhibitor of cytoplasmic transduction signs, and hindering neoplastic cells growth, is a new therapeutic agent for chronic myelogenous leukemia (CML). It is a tyrosine kinase bcrabl inhibitor, inhibiting also the c-kit receptor protein in gastrointestinal neoplasia and small cells lung cancer. The aim of the present work was to evaluate the effect of this agent in CML patients in two different time-periods, namely the chronic phase and the acute one. We hereby present two patients: 1) a 48 years old patient with radioactive contamination history, and 2) a 19 years old patient. In both cases diagnosis was confirmed by BM and BM biopsy, neutrophile alkaline phosphatase, and Ph chromosome t(9;22) (q34;q11). There were non-compatible BM donors available. Both patients were treated with hydroxyurea, hydroxyurea plus interferon, and one of them adding ARAC. Since there was no favorable response an Iminitab course was started. Patient (2) with blastic crisis remitted for 12 month until subsequent relapse and death. Patient (1) treated during chronic phase is still in remission. Neither of them attained negative Ph chromosome. Up to now, current reports show a high percentage of relapse in patients treated during the acute phase, while the chronic ones present a smaller number of relapses. It is to be noted the importance of the follow up during the chronic phase, due to the short time drug utilization in our country (May 2001). Good tolerance and sustained remission in CML patients allows being optimistic regarding this therapeutic agent. (author)

  14. The acute monocytic leukemias: multidisciplinary studies in 45 patients.

    Science.gov (United States)

    Straus, D J; Mertelsmann, R; Koziner, B; McKenzie, S; de Harven, E; Arlin, Z A; Kempin, S; Broxmeyer, H; Moore, M A; Menendez-Botet, C J; Gee, T S; Clarkson, B D

    1980-11-01

    The clinical and laboratory features of 37 patients with variants of acute monocytic leukemia are described. Three of these 37 patients who had extensive extramedullary leukemic tissue infiltration are examples of true histiocytic "lymphomas." Three additional patients with undifferentiated leukemias, one patient with refractory anemia with excess of blasts, one patient with chronic myelomonocytic leukemia, one patient with B-lymphocyte diffuse "histiocytic" lymphoma and one patient with "null" cell, terminal deoxynucleotidyl transferase-positive lymphoblastic lymphoma had bone marrow cells with monocytic features. Another patient had dual populations of lymphoid and monocytoid leukemic cells. The true monocytic leukemias, acute monocytic leukemia (AMOL) and acute myelomonocytic leukemia (AMMOL), are closely related to acute myelocytic leukemia (AML) morphologically and by their response to chemotherapy. like AML, the leukemic cells from the AMMOL and AMOL patients form leukemic clusters in semisolid media. Cytochemical staining of leukemic cells for nonspecific esterases, presence of Fc receptor on the cell surface, phagocytic ability, low TdT activity, presence of surface "ruffles" and "ridges" on scanning EM, elevations of serum lysozyme, and clinical manifestations of leukemic tissue infiltration are features which accompanied monocytic differentiation in these cases.

  15. Treating the chronic-phase chronic myeloid leukemia patient: which TKI, when to switch and when to stop?

    Science.gov (United States)

    Patel, Ami B; Wilds, Brandon W; Deininger, Michael W

    2017-07-01

    With the discovery of imatinib mesylate nearly 20 years ago, tyrosine kinase inhibitors (TKIs) were found to be effective in chronic myeloid leukemia (CML). TKI therapy has since revolutionized the treatment of CML and has served as a paradigm of success for targeted drug therapy in cancer. Several new TKIs for CML have been approved over the last two decades that exhibit improved potency over imatinib and have different off-target profiles, providing options for individualized therapy selection. Areas covered: Current management of chronic phase CML, including guidance on the sequential use of imatinib and newer-generation TKIs and evolving treatment strategies such as TKI discontinuation. Relevant literature was identified by searching biomedical databases (i.e. PubMed) for primary research material. Expert commentary: Although survival outcomes have drastically improved for CML patients, treatment for CML has grown more complex with the introduction of next-generation TKIs and the advent of treatment-free remissions (TFR). Goals of therapy have shifted accordingly, with increased focus on improving quality of life, managing patient expectations and optimizing patient adherence.

  16. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era

    DEFF Research Database (Denmark)

    Warlick, Erica; Ahn, Kwang Woo; Pedersen, Tanya L

    2012-01-01

    Tyrosine kinase inhibitors (TKIs) and reduced intensity conditioning (RIC)/nonmyeloablative (NMA) conditioning hematopoietic cell transplants (HCTs) have changed the therapeutic strategy for chronic myelogenous leukemia (CML) patients. We analyzed post-HCT outcomes of 306 CML patients reported to...

  17. Incidence of second primary malignancies and related mortality in patients with imatinib-treated chronic myeloid leukemia.

    Science.gov (United States)

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Albano, Francesco; Iurlo, Alessandra; Intermesoli, Tamara; Abruzzese, Elisabetta; Levato, Luciano; D'Adda, Mariella; Pregno, Patrizia; Cavazzini, Francesco; Stagno, Fabio; Martino, Bruno; La Barba, Gaetano; Sorà, Federica; Tiribelli, Mario; Bigazzi, Catia; Binotto, Gianni; Bonifacio, Massimiliano; Caracciolo, Clementina; Soverini, Simona; Foà, Robin; Cavo, Michele; Martinelli, Giovanni; Pane, Fabrizio; Saglio, Giuseppe; Baccarani, Michele; Rosti, Gianantonio

    2017-09-01

    The majority of patients with chronic myeloid leukemia are successfully managed with life-long treatment with tyrosine kinase inhibitors. In patients in chronic phase, other malignancies are among the most common causes of death, raising concerns on the relationship between these deaths and the off-target effects of tyrosine kinase inhibitors. We analyzed the incidence of second primary malignancies, and related mortality, in 514 chronic myeloid leukemia patients enrolled in clinical trials in which imatinib was given as first-line treatment. We then compared the observed incidence and mortality with those expected in the age- and sex-matched Italian general population, calculating standardized incidence and standardized mortality ratios. After a median follow-up of 74 months, 5.8% patients developed second primary malignancies. The median time from chronic myeloid leukemia to diagnosis of the second primary malignancies was 34 months. We did not find a higher incidence of second primary malignancies compared to that in the age- and sex-matched Italian general population, with standardized incidence ratios of 1.06 (95% CI: 0.57-1.54) and 1.61 (95% CI: 0.92-2.31) in males and females, respectively. Overall, 3.1% patients died of second primary malignancies. The death rate in patients with second primary malignancies was 53% (median overall survival: 18 months). Among females, the observed cancer-related mortality was superior to that expected in the age- and sex-matched Italian population, with a standardized mortality ratio of 2.41 (95% CI: 1.26 - 3.56). In conclusion, our analysis of patients with imatinib-treated chronic myeloid leukemia did not reveal a higher incidence of second primary malignancies; however, the outcome of second primary malignancies in such patients was worse than expected. Clinicaltrials.gov: NCT00514488, NCT00510926. Copyright© 2017 Ferrata Storti Foundation.

  18. Correlation of Cadmium and Magnesium in the Blood and Serum Samples of Smokers and Non-Smokers Chronic Leukemia Patients.

    Science.gov (United States)

    Khan, Noman; Afridi, Hasan Imran; Kazi, Tasneem Gul; Arain, Muhammad Balal; Bilal, Muhammad; Akhtar, Asma; Khan, Mustafa

    2017-03-01

    It was studied that cancer-causing processes are related with the disproportions of essential and toxic elements in body tissues and fluid. The purpose of the current study was to evaluate the levels of magnesium (Mg) and cadmium (Cd) in serum and blood samples of smokers and nonsmokers who have chronic myeloid (CML) and lymphocytic (CLL) leukemia, age ranged 31-50 years. For comparative study, age-matched smokers and nonsmoker males were chosen as controls/referents. The levels of elements in patient were analyzed before any treatment by atomic absorption spectrophotometer, after microwave assisted acid digestion. The validation of the method was done by using certified reference materials of serum and blood samples. The resulted data indicated that the adult male smokers and nonsmokers have two- to fourfold higher levels of Cd in the blood and sera samples as compared to the referents (p blood and serum samples of both types of leukemia patients as related to referent values. The resulted data indicates significant negative correlation among Mg and Cd in leukemia patients and smoker referents. Further studies are needed to clarify the role of these elements in pathogenesis of chronic leukemia.

  19. Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib

    Directory of Open Access Journals (Sweden)

    Ronan Swords

    2009-03-01

    Full Text Available Ronan Swords, Devalingam Mahalingam, Swaminathan Padmanabhan, Jennifer Carew, Francis GilesInstitute for Drug Development, Cancer Therapy and Research Centre, University of Texas Health Science Centre at San Antonio, USAAbstract: Chronic myeloid leukemia (CML is the consequence of a single balanced translocation that produces the BCR-ABL fusion oncogene which is detectable in over 90% of patients at presentation. The BCR-ABL inhibitor imatinib mesylate (IM has improved survival in all phases of CML and is the standard of care for newly diagnosed patients in chronic phase. Despite the very significant therapeutic benefits of IM, a small minority of patients with early stage disease do not benefit optimally while IM therapy in patients with advanced disease is of modest benefit in many. Diverse mechanisms may be responsible for IM failures, with point mutations within the Bcr-Abl kinase domain being amongst the most common resistance mechanisms described in patients with advanced CML. The development of novel agents designed to overcome IM resistance, while still primarily targeted on BCR-ABL, led to the creation of the high affinity aminopyrimidine inhibitor, nilotinib. Nilotinib is much more potent as a BCR-ABL inhibitor than IM and inhibits both wild type and IM-resistant BCR-ABL with significant clinical activity across the entire spectrum of BCR-ABL mutants with the exception of T315I. The selection of a second generation tyrosine kinase inhibitor to rescue patients with imatinib failure will be based on several factors including age, co-morbid medical problems and ABL kinase mutational profile. It should be noted that while the use of targeted BCR-ABL kinase inhibitors in CML represents a paradigm shift in CML management these agents are not likely to have activity against the quiescent CML stem cell pool. The purpose of this review is to summarize the pre-clinical and clinical data on nilotinib in patients with CML who have failed prior

  20. Clinical roundtable monograph: Emerging treatment options for TKI-resistant chronic myelogenous leukemia.

    Science.gov (United States)

    Cortes, Jorge; Radich, Jerald; Mauro, Michael J

    2012-10-01

    The development of tyrosine kinase inhibitors (TKIs) that inhibit signaling of the constitutive BCR-ABL protein revolutionized the treatment of chronic myelogenous leukemia (CML). These agents have dramatically changed the treatment landscape for CML, shifting the use of allogeneic stem cell transplantation to selected patients in the salvage setting. Four BCR-ABL TKIs are now commercially available for the treatment of CML: the first-generation TKI imatinib, and the second-generation TKIs dasatinib, nilotinib, and bosutinib. Continuous treatment with these agents induces durable responses in a high proportion of patients with chronic-phase CML. Research is focused on identifying which patients can discontinue therapy without a recurrence of disease. For the group of patients with resistance to TKIs, multiple alternative therapies are being evaluated. The third-generation TKI ponatinib is a BCR-ABL inhibitor that has demonstrated significant activity, including in patients with the TKI resistance mutation T315I. The homoharringtonine derivative omacetaxine mepesuccinate, which inhibits protein synthesis, has also demonstrated clinical activity in CML, including in patients with TKI resistance due to T315I and in patients who have TKI resistance despite no evidence of ABL mutations. It is essential that clinicians implement these new agents with care and change therapies only when appropriate in order to preserve as many options as possible for future use if needed.

  1. Circulating endothelial cells are increased in chronic myeloid leukemia blast crisis

    Directory of Open Access Journals (Sweden)

    C.R.T. Godoy

    2015-06-01

    Full Text Available We measured circulating endothelial precursor cells (EPCs, activated circulating endothelial cells (aCECs, and mature circulating endothelial cells (mCECs using four-color multiparametric flow cytometry in the peripheral blood of 84 chronic myeloid leukemia (CML patients and 65 healthy controls; and vascular endothelial growth factor (VEGF by quantitative real-time PCR in 50 CML patients and 32 healthy controls. Because of an increase in mCECs, the median percentage of CECs in CML blast crisis (0.0146% was significantly higher than in healthy subjects (0.0059%, P0.05. In addition, VEGF gene expression was significantly higher in all phases of CML: 0.245 in blast crisis, 0.320 in the active phase, and 0.330 in chronic phase patients than it was in healthy subjects (0.145. In conclusion, CML in blast crisis had increased levels of CECs and VEGF gene expression, which may serve as markers of disease progression and may become targets for the management of CML.

  2. Planned Pregnancy in a Chronic Myeloid Leukemia Patient in Molecular Remission

    Science.gov (United States)

    Pavlovsky, Carolina; Giere, Isabel; Van Thillo, Germán

    2012-01-01

    Excellent response rates and a good quality of life have been observed since the introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment. Consequently, some challenges began to appear in CML women in child-bearing age wishing to become pregnant. Currently, many women around the world are in stable major/complete molecular response MMR/CMR (MMR: <0.1% BCR-ABL/ABL and CMR: undetectable BCR-ABL mRNA by RQ-PCR transcript levels on the international scale). The condition of stable MMR/CMR is linked to a long-term virtual absence of progression to the accelerated and blastic phase and to the possibility of stopping the TKI treatment with the maintenance of a condition of CMR in a proportion of cases. Imatinib teratogenic and prescribing information prohibits the use of it during pregnancy. We describe the case of a 36-year-old female patient with CML in chronic phase who stopped imatinib after 2 years in major molecular response (MMR) to plan a pregnancy. Molecular monitoring by RQ-PCR was performed quarterly. She achieved a safe pregnancy and delivery maintaining an optimal molecular response throughout the pregnancy. Isolated literature reports have been described, but no formal advice has been described at present time. PMID:22928126

  3. Insights into the management of chronic myeloid leukemia in resource-poor settings: a Mexican perspective.

    Science.gov (United States)

    Gomez-de-León, Andrés; Gómez-Almaguer, David; Ruiz-Delgado, Guillermo J; Ruiz-Arguelles, Guillermo J

    2017-09-01

    The arrival of targeted therapy for chronic myeloid leukemia (CML) was revolutionary. However, due to the high cost of tyrosine kinase inhibitors, access to this highly effective therapy with strict monitoring strategies is limited in low to middle-income countries. In this context, following standard recommendations proposed by experts in developed countries is difficult. Areas covered: This review aims to provide an insight into the management of patients with CML living in a resource-limited setting. It addresses several issues: diagnosis, initial treatment, disease monitoring, and additional treatment alternatives including allogeneic hematopoietic stem cell transplantation. Expert commentary: Imatinib is probably the most cost-effective TKI for initial treatment in developing and underdeveloped countries. Generic imatinib preparations should be evaluated before considering their widespread use. Adherence to treatment should be emphasized. Adequate monitoring can be performed through several methods successfully and is important for predicting outcomes, particularly early in the first year, and if treatment suspension is being considered. Access to further therapeutic alternatives should define our actions after failure or intolerance to imatinib, preferring additional TKIs if possible. Allogeneic transplantation in chronic phase is a viable option in this context.

  4. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia.

    Science.gov (United States)

    Giustacchini, Alice; Thongjuea, Supat; Barkas, Nikolaos; Woll, Petter S; Povinelli, Benjamin J; Booth, Christopher A G; Sopp, Paul; Norfo, Ruggiero; Rodriguez-Meira, Alba; Ashley, Neil; Jamieson, Lauren; Vyas, Paresh; Anderson, Kristina; Segerstolpe, Åsa; Qian, Hong; Olsson-Strömberg, Ulla; Mustjoki, Satu; Sandberg, Rickard; Jacobsen, Sten Eirik W; Mead, Adam J

    2017-06-01

    Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.

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

    Science.gov (United States)

    Bixby, Dale L

    2013-05-01

    The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib are the standard of care for treating patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML). Compared with interferon-based treatment, the previous standard of care, imatinib is associated with significantly higher cytogenetic response rates and prolonged overall survival. Nilotinib and dasatinib, both newer and more potent TKIs, significantly improve cytogenetic and molecular response rates compared with imatinib. Despite significant advances in CML treatment enabled by the TKIs, a fraction of patients who receive frontline treatment with a TKI demonstrate inadequate response. The reasons for this vary, but in many cases, inadequate response can be attributed to non-adherence to the treatment regimen, intolerance to the drug, intrinsic or acquired resistance to the drug, or a combination of reasons. More often than not, strategies to improve response necessitate a change in treatment plan, either a dose adjustment or a switch to an alternate drug, particularly in the case of drug intolerance or drug resistance. Improved physician-patient communication and patient education are effective strategies to address issues relating to adherence and intolerance. Because inadequate response to TKI treatment correlates with poor long-term outcomes, it is imperative that patients who experience intolerance or who fail to achieve appropriate responses are carefully evaluated so that appropriate treatment modifications can be made to maximize the likelihood of positive long-term outcome. Copyright © 2012. Published by Elsevier Ltd.

  6. Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

    Science.gov (United States)

    Burchert, A; Saussele, S; Eigendorff, E; Müller, M C; Sohlbach, K; Inselmann, S; Schütz, C; Metzelder, S K; Ziermann, J; Kostrewa, P; Hoffmann, J; Hehlmann, R; Neubauer, A; Hochhaus, A

    2015-06-01

    A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

  7. Expression, prognostic significance and mutational analysis of protein tyrosine phosphatase SHP-1 in chronic myeloid leukemia.

    Science.gov (United States)

    Papadopoulou, Vasiliki; Kontandreopoulou, Elina; Panayiotidis, Panayiotis; Roumelioti, Maria; Angelopoulou, Maria; Kyriazopoulou, Lydia; Diamantopoulos, Panagiotis T; Vaiopoulos, George; Variami, Eleni; Kotsianidis, Ioannis; Athina Viniou, Nora

    2016-05-01

    The protein tyrosine phosphatase SHP-1 dephosphorylates BCR-ABL1, thereby serving as a potential control mechanism of BCR-ABL1 kinase activity. Pathways regulating SHP-1 expression, which could be exploited in the therapeutics of TKI-resistant chronic myeloid leukemia (CML), remain unknown. Moreover, the questions of whether there is any kind of SHP-1 deregulation in CML, contributing to disease initiation or evolution, as well as the question of prognostic significance of SHP-1, have not been definitively answered. This study shows moderately lower SHP-1 mRNA expression in chronic phase CML patients in comparison to healthy individuals and no change in SHP-1 mRNA levels after successful TKI treatment. Mutational analysis of the aminoterminal and phosphatase domains of SHP-1 in patients did not reveal genetic lesions. This study also found no correlation of SHP-1 expression at diagnosis with response to treatment, although a trend for lower SHP-1 expression was noted in the very small non-responders' group of the 3-month therapeutic milestone.

  8. Investigation of selected trace elements in Sudanese patients with leukemia using NAA

    International Nuclear Information System (INIS)

    Elradi, M. M. M.

    2010-10-01

    In the present study, the concentrations of Co, Cr, Fe, Hg, Rb, Se, Zn in the serum of 103 adult patients with newly diagnosed of leukemia (before treatment) were studied. Samples were collected from Radiation of Isotopes Center-Khartoum (RICK) and Institute of Nuclear Medicine and Molecular Biology-Aljazeera State. Samples were freeze-dried and analyzed using Neutron Activation Analysis (NAA). Serum levels of these elements were compared with the contents found in healthy group samples. The patients were divided into 4 groups: 1- Acute Lymphoid Leukemia (ALL), 2- Acute Myeloid Leukemia (AML), 3- Chronic Lymphoid Leukemia (CLL), 4- Chronic Myeloid Leukemia (CML). The control group was formed of 40 healthy subjects, data analysis was performed using the T-tests. partial correlation was used to study a relationship between two variables. It was found that, In group I (ALL ): higher concentration of Cr, Fe, Hg, Rb, Zn, were found in the serum of patients with significant difference as compared to healthy group (p 0.05), the level of selenium was statistically lower than in the control group (p 0.05). Similar result was obtained in Co. The level of selenium was statistically lower than in the control group (p< 0.05). (Author)

  9. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.

    Science.gov (United States)

    Ryan, Christine E; Sahaf, Bita; Logan, Aaron C; O'Brien, Susan; Byrd, John C; Hillmen, Peter; Brown, Jennifer R; Dyer, Martin J S; Mato, Anthony R; Keating, Michael J; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R; Styles, Lori; Coutre, Steven E; Miklos, David B

    2016-12-22

    Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. © 2016 by The American Society of Hematology.

  10. Using gene co-expression network analysis to predict biomarkers for chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Borlawsky Tara B

    2010-10-01

    Full Text Available Abstract Background Chronic lymphocytic leukemia (CLL is the most common adult leukemia. It is a highly heterogeneous disease, and can be divided roughly into indolent and progressive stages based on classic clinical markers. Immunoglobin heavy chain variable region (IgVH mutational status was found to be associated with patient survival outcome, and biomarkers linked to the IgVH status has been a focus in the CLL prognosis research field. However, biomarkers highly correlated with IgVH mutational status which can accurately predict the survival outcome are yet to be discovered. Results In this paper, we investigate the use of gene co-expression network analysis to identify potential biomarkers for CLL. Specifically we focused on the co-expression network involving ZAP70, a well characterized biomarker for CLL. We selected 23 microarray datasets corresponding to multiple types of cancer from the Gene Expression Omnibus (GEO and used the frequent network mining algorithm CODENSE to identify highly connected gene co-expression networks spanning the entire genome, then evaluated the genes in the co-expression network in which ZAP70 is involved. We then applied a set of feature selection methods to further select genes which are capable of predicting IgVH mutation status from the ZAP70 co-expression network. Conclusions We have identified a set of genes that are potential CLL prognostic biomarkers IL2RB, CD8A, CD247, LAG3 and KLRK1, which can predict CLL patient IgVH mutational status with high accuracies. Their prognostic capabilities were cross-validated by applying these biomarker candidates to classify patients into different outcome groups using a CLL microarray datasets with clinical information.

  11. [A clinical study of chronic disseminated candidiasis in patients with acute leukemia].

    Science.gov (United States)

    Xu, Bing; Guo, Xu-Tao; Wei, Yong-Qiang; Meng, Fan-Yi; Liu, Qi-Fa; Zhou, Shu-Yun

    2008-06-01

    To deepen the understanding of chronic disseminated candidiasis (CDC) in patients with acute leukemia (AL). CDC was investigated in 119 AL patients who received induction chemotherapy from August 2004 to May 2005. Clinical manifestations, laboratory tests, imaging modalities, diagnosis and treatment were investigated retrospectively. Three patients (2.5%) were identified to be suffering from CDC. All the three patients had an absolute neutrophil count (ANC) nodular patchy shadows in lungs. Nuclear magnetic resonance imaging showed multiple abnormal signal in liver, spleen and kidneys in one of the patients. Two patients had positive bleed fungal cultures and histologic examination in one of the patients were positive for Candida tropicalis. Two patients received amphotericin B therapy empirically, but it was replaced by amphotericin B colloid dispersion (ABCD) later in one and combined with voriconazole in another because of unresponsiveness to the drug. One patient took a favorable turn after receiving ABCD therapy for 45 d, which was replaced by voriconazole because of the emergence of fever after discontinuation of ABCD. All the three patients received further chemotherapy smoothly after the diagnosis of CDC. The diagnosis of CDC remains difficult. Fungal blood cultures and histologic examination have been considered in many studies as the golden standard for the diagnosis of CDC. Amphotericin B is the cornerstone of treatment in patients with CDC and lipid formulations of amphotericin B can be used in CDC patients who are intolerant of or refractory to conventional amphotericin B. Voriconazole has a favorable response for refractory/relapse patients and could be used for second line treatment. The development of CDC in patients with acute leukemia does not preclude further chemotherapy.

  12. Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143 in chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Manoj K. Kashyap

    2017-05-01

    Full Text Available Abstract Background The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL. Methods Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model. Results PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD. PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC and complement-dependent cytotoxicity activity (CDC. PF-06747143 had significant combinatorial effect with standard of care (SOC agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A, ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy

  13. The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era

    Directory of Open Access Journals (Sweden)

    Ilana Zalcberg Renault

    2011-12-01

    Full Text Available Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging.

  14. The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era

    Science.gov (United States)

    Renault, Ilana Zalcberg; Scholl, Vanesa; Hassan, Rocio; Capelleti, Paola; de Lima, Marcos; Cortes, Jorge

    2011-01-01

    Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging. PMID:23049363

  15. Chronic lymphocytic leukemia: assessing pathogenesis and prognosis by modern molecular cytogenetic studies and microRNAs expression

    OpenAIRE

    Saccenti, Elena

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is a B-cell clonal lymphoprolipherative disorder characterized by the accumulation of small lymphocytes in the peripheral blood, bone marrow and lymph nodes deriving from the transformation of CD5+ B-cell. Despite a homogeneous immunophenotype consisting of CD19+, CD20+, CD5+ and CD23+, CLL is clinically heterogeneous. Several adverse prognostic features have been identified including stage, CD38 positivity, the unmutated configuration of the ...

  16. Real world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

    Science.gov (United States)

    Mato, Anthony R; Thompson, Meghan; Allan, John N; Brander, Danielle M; Pagel, John M; Ujjani, Chaitra S; Hill, Brian T; Lamanna, Nicole; Lansigan, Frederick; Jacobs, Ryan; Shadman, Mazyar; Skarbnik, Alan P; Pu, Jeffrey J; Barr, Paul M; Sehgal, Alison R; Cheson, Bruce D; Zent, Clive S; Tuncer, Hande H; Schuster, Stephen J; Pickens, Peter V; Shah, Nirav N; Goy, Andre; Winter, Allison M; Garcia, Christine; Kennard, Kaitlin; Isaac, Krista; Dorsey, Colleen; Gashonia, Lisa M; Singavi, Arun K; Roeker, Lindsey E; Zelenetz, Andrew; Williams, Annalynn; Howlett, Christina; Weissbrot, Hanna; Ali, Naveed; Khajavian, Sirin; Sitlinger, Andrea; Tranchito, Eve; Rhodes, Joanna; Felsenfeld, Joshua; Bailey, Neil; Patel, Bhavisha; Burns, Timothy F; Yacur, Melissa; Malhotra, Mansi; Svoboda, Jakub; Furman, Richard R; Nabhan, Chadi

    2018-06-07

    Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with CLL treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients , the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study. Copyright © 2018, Ferrata Storti Foundation.

  17. A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease

    OpenAIRE

    Bagnara, Davide; Kaufman, Matthew S.; Calissano, Carlo; Marsilio, Sonia; Patten, Piers E. M.; Simone, Rita; Chum, Philip; Yan, Xiao-Jie; Allen, Steven L.; Kolitz, Jonathan E.; Baskar, Sivasubramanian; Rader, Christoph; Mellstedt, Hakan; Rabbani, Hodjattallah; Lee, Annette

    2011-01-01

    Chronic lymphocytic leukemia (CLL) is an incurable adult disease of unknown etiology. Understanding the biology of CLL cells, particularly cell maturation and growth in vivo, has been impeded by lack of a reproducible adoptive transfer model. We report a simple, reproducible system in which primary CLL cells proliferate in nonobese diabetes/severe combined immunodeficiency/γcnull mice under the influence of activated CLL-derived T lymphocytes. By cotransferring autologous T lymphocytes, activ...

  18. BCR SIGNALING INHIBITORS: AN OVERVIEW OF TOXICITIES ASSOCIATED WITH IBRUTINIB AND IDELALISIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

    OpenAIRE

    Lorenzo Falchi; Jessica M Baron; Carrie Anne Orlikowski; Alessandra Ferrajoli

    2016-01-01

    The B-cell receptor signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment landscape of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in trea...

  19. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

    DEFF Research Database (Denmark)

    Sutton, Lesley-Ann; Young, Emma; Baliakas, Panagiotis

    2016-01-01

    We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations...... subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s)....

  20. Estimating outcomes and cost effectiveness using a single-arm clinical trial: ofatumumab for double-refractory chronic lymphocytic leukemia

    OpenAIRE

    Hatswell, Anthony J.; Thompson, Gwilym J.; Maroudas, Penny A.; Sofrygin, Oleg; Delea, Thomas E.

    2017-01-01

    Background Ofatumumab (Arzerra?, Novartis) is a treatment for chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab [double refractory (DR-CLL)]. Ofatumumab was licensed on the basis of an uncontrolled Phase II study, Hx-CD20-406, in which patients receiving ofatumumab survived for a median of 13.9?months. However, the lack of an internal control arm presents an obstacle for the estimation of comparative effectiveness. Methods The objective of the study was to present a metho...

  1. Pleural effusion as the initial manifestation of chronic myeloid leukemia: Report of a case with clinical and cytologic correlation

    Directory of Open Access Journals (Sweden)

    Paras Nuwal

    2012-01-01

    Full Text Available Pleural effusion in patients with chronic myeloid leukemia (CML is very rare and poorly understood. We report here a 26-year-old male patient having CML and presenting with pleural effusion as the first clinical sign. The possible mechanism of pleural effusion in CML, the cytological interpretive problem and the clinical significance of finding immature leucocytes in pleural fluid are also briefly discussed.

  2. Chronic intravascular coagulation associated with chronic myelocytic leukemia. Use of heparin in connection with a surgical procedure.

    Science.gov (United States)

    German, H J; Smith, J A; Lindenbaum, J

    1976-10-01

    A women with Philadelphia chromosome-positive chronic myelocytic leukemia lived nearly 12 years from the time of diagnosis. During most of this period she received no therapy, and marked cyclic oscillations in the white blood cell count were documented. The last two years of her illness were marked by a hemorrhagic disorder associated with hypofibrinogenemia, thrombocytopenia, increased plasma fibrinopeptide A concentration and markedly elevated serum levels of fibrin degradation products. The coagulation disorder was rapidly reversible on several occasions with heparin therapy. After treatment with heparin and platelet transfusions, the patient underwent successful resection of a large ovarian cyst with excellent hemostasis during the procedure. Postoperatively, the administration of heparin and platelets was discontinued and a large wound hematoma developed. After resumption of therapy with heparin and platelets, the remainder of her postoperative course was uneventful. The literature on the subject is reviewed and tentative guidelines are offered concerning the management of patients with intravascular coagulation who require diagnostic or therapeutic surgical procedures.

  3. Association between regular molecular monitoring and tyrosine kinase inhibitor therapy adherence in chronic myelogenous leukemia in the chronic phase.

    Science.gov (United States)

    Guérin, Annie; Chen, Lei; Dea, Katherine; Wu, Eric Q; Goldberg, Stuart L

    2014-07-01

    Adherence with oral tyrosine kinase inhibitor (TKI) therapy over prolonged timeframes is required for successful outcomes among patients with chronic phase chronic myelogenous leukemia (CP-CML). Since quantitative polymerase chain reaction (qPCR) monitoring may identify early suboptimal responses, and thereby permit detection of non-adherence to therapy, we sought to assess the association between frequency of molecular monitoring and medication adherence. This is a retrospective cohort study design of diagnosed CP-CML obtained from two large US administrative claims databases. Patients were grouped into cohorts based on the number of qPCR tests they had. Adherence was assessed both by medication possession ratio (MPR) and proportion of days covered (PDC) and was compared between qPCR cohorts. A sensitivity analysis was performed by adjusting for the number of oncology outpatient visits not due to routine molecular monitoring. Over the 12 month study period, 1205 CML patients met the selection criteria; 41.0% had no qPCR tests, 31.9% had 1-2 tests, and 27.1% had 3-4 tests; 88.9% of patients were initiated on imatinib. Patients in the 3-4 qPCR tests cohort had an average MPR that was 10.22 (p sensitivity analysis were consistent with core analysis findings, excluding number of physician visits as a potential driver of adherence. These findings demonstrate an association, not causation, between molecular monitoring frequency and adherence. Frequent molecular monitoring (3-4 times per year as recommended in current guidelines) is associated with greater TKI treatment adherence for patients diagnosed with CML. Since TKI adherence >80% has been associated with better clinical outcomes, this study underscores the importance of molecular monitoring.

  4. PTCH1 is a reliable marker for predicting imatinib response in chronic myeloid leukemia patients in chronic phase.

    Directory of Open Access Journals (Sweden)

    Juan M Alonso-Dominguez

    Full Text Available Patched homolog 1 gene (PTCH1 expression and the ratio of PTCH1 to Smoothened (SMO expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72. In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF, which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013, probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02, and proportions of early molecular failure (14% vs. 43%, P = 0.015. Every progression to an advanced phase (n = 3 and CML-related death (n = 2 occurred in the low PTCH1 group (P<0.001 for both comparisons. PTCH1 was an independent prognostic factor for the prediction of IF. We also validated previously published thresholds for PTCH1 expression. Therefore, we confirmed that PTCH1 expression can predict the imatinib response in CML patients in CP by applying a more rigorous statistical analysis. Thus, PTCH1 expression is a promising molecular marker for predicting the imatinib response in CML patients in CP.

  5. Analysis of Th17 and Tc17 Frequencies and Antiviral Defenses in Gut-Associated Lymphoid Tissue of Chronic HIV-1 Positive Patients.

    Science.gov (United States)

    d'Ettorre, Gabriella; Ceccarelli, Giancarlo; Andreotti, Mauro; Selvaggi, Carla; Giustini, Noemi; Serafino, Sara; Schietroma, Ivan; Nunnari, Giuseppe; Antonelli, Guido; Vullo, Vincenzo; Scagnolari, Carolina

    2015-01-01

    The complex relationship between both the Th1/Th17 and Tc1/Tc17 axis and innate defences in the intestinal mucosa during HIV-1 infection has not been well characterized. This study examined the frequency, phenotype, and functional status of T cell populations in the gut-associated lymphoid tissue and peripheral blood of virologically suppressed HIV-1-infected patients on therapy, focusing on the Th1, Th17, Tc1, and Tc17 cell subsets. We found a persistent immune cell activation (CD38 and HLADR expression) into the GALT despite the higher levels of Th17 and Tc17 in respect to peripheral blood. An upregulation of type I IFN response in GALT compared to the peripheral blood compartment was also recorded. Furthermore, IFN-α/β levels were negatively related to the frequencies of Th1 naïve cells and Tc1 cell subsets (naïve, central memory, and effector memory) in the GALT. In contrast, no relationships between type I IFN response and Th1 or Tc1 cell subsets in peripheral blood compartment and between IFN-α/β and Th17/Tc17 in both GALT and peripheral blood district were recorded. These data indicate that prolonged antiretroviral treatment improves GALT immune function despite the persistence of immune activation and type I IFN response in chronic HIV-1 positive patients.

  6. Analysis of Th17 and Tc17 Frequencies and Antiviral Defenses in Gut-Associated Lymphoid Tissue of Chronic HIV-1 Positive Patients

    Directory of Open Access Journals (Sweden)

    Gabriella d’Ettorre

    2015-01-01

    Full Text Available The complex relationship between both the Th1/Th17 and Tc1/Tc17 axis and innate defences in the intestinal mucosa during HIV-1 infection has not been well characterized. This study examined the frequency, phenotype, and functional status of T cell populations in the gut-associated lymphoid tissue and peripheral blood of virologically suppressed HIV-1-infected patients on therapy, focusing on the Th1, Th17, Tc1, and Tc17 cell subsets. We found a persistent immune cell activation (CD38 and HLADR expression into the GALT despite the higher levels of Th17 and Tc17 in respect to peripheral blood. An upregulation of type I IFN response in GALT compared to the peripheral blood compartment was also recorded. Furthermore, IFN-α/β levels were negatively related to the frequencies of Th1 naïve cells and Tc1 cell subsets (naïve, central memory, and effector memory in the GALT. In contrast, no relationships between type I IFN response and Th1 or Tc1 cell subsets in peripheral blood compartment and between IFN-α/β and Th17/Tc17 in both GALT and peripheral blood district were recorded. These data indicate that prolonged antiretroviral treatment improves GALT immune function despite the persistence of immune activation and type I IFN response in chronic HIV-1 positive patients.

  7. The -137G/C Polymorphism in Interleukin-18 Gene Promoter Contributes to Chronic Lymphocytic and Chronic Myelogenous Leukemia Risk in Turkish Patients

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    Serap Yalçın

    2015-12-01

    Full Text Available Objective: Interleukin-18 (IL-18 is a cytokine that belongs to the IL-1 superfamily and is secreted by various immune and nonimmune cells. Evidence has shown that IL-18 has both anticancer and procancer effects. The aim of this study was to evaluate the relationship between IL-18 gene polymorphisms and susceptibility to chronic lymphocytic leukemias (CLL and chronic myelogenous leukemias (CML in Turkish patients. Materials and Methods: The frequencies of polymorphisms (rs61667799(G/T, rs5744227(C/G, rs5744228(A/G, and rs187238(G/C were studied in 20 CLL patients, 30 CML patients, and 30 healthy individuals. The genotyping was performed by polymerase chain reaction and DNA sequencing analysis. Results: Significant associations were detected between the IL-18 rs187238(G/C polymorphism and chronic leukemia. A higher prevalence of the C allele was found in CML cases with respect to controls. The GC heterozygous and CC homozygous genotypes were associated with risk of CML when compared with controls. However, prevalence of the C allele was not significantly high in CLL cases with respect to controls. There was only a significant difference between the homozygous CC genotype of CLL patients and the control group; thus, it can be concluded that the CC genotype may be associated with the risk of CLL. Based on our data, there were no significant associations between the IL-18 rs61667799(G/T, rs5744227(C/G, or rs5744228(A/G polymorphisms and CLL or CML. Conclusions: IL-18 gene promoter rs187238(G/C polymorphism is associated with chronic leukemia in the Turkish population. However, due to the limited number of studied patients, these are preliminary results that show the association between -137G/C polymorphism and patients (CLL and CML. Further large-scale studies combined with haplotype and expression analysis are required to validate the current findings.

  8. Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease

    Science.gov (United States)

    Aims: Chronic wasting disease (CWD) is a naturally-occurring, fatal neurodegenerative disease of cervids. We previously demonstrated that disease-associated prion protein (PrPSc) can be detected in the brain and retina from pigs challenged intracranially or orally with the CWD agent. In that study,...

  9. The option value of innovative treatments in the context of chronic myeloid leukemia.

    Science.gov (United States)

    Sanchez, Yuri; Penrod, John R; Qiu, Xiaoli Lily; Romley, John; Thornton Snider, Julia; Philipson, Tomas

    2012-11-01

    To quantify in the context of chronic myeloid leukemia (CML) the additional value patients receive when innovative treatments enable them to survive until the advent of even more effective future treatments (ie, the "option value"). Observational study using data from the Surveillance, Epidemiology and End Results (SEER) cancer registry comprising all US patients with CML diagnosed between 2000 and 2008 (N = 9,760). We quantified the option value of recent breakthroughs in CML treatment by first conducting retrospective survival analyses on SEER data to assess the effectiveness of TKI treatments, and then forecasting survival from CML and other causes to measure expected future medical progress. We then developed an analytical framework to calculate option value of innovative CML therapies, and used an economic model to value these gains. We calculated the option value created both by future innovations in CML treatment and by medical progress in reducing background mortality. For a recently diagnosed CML patient, the option value of innovative therapies from future medical innovation amounts to 0.76 life-years. This option value is worth $63,000, equivalent to 9% of the average survival gains from existing treatments. Future innovations in CML treatment jointly account for 96% of this benefit. The option value of innovative treatments has significance in the context of CML and, more broadly, in disease areas with rapid innovation. Incorporating option value into traditional valuations of medical innovations is both a feasible and a necessary practice in health technology assessment.

  10. PROGNOSTIC VALUE OF TUMOR NECROSIS FACTOR-ALPHA IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

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    E. N. Zotina

    2016-01-01

    Full Text Available The prognostic value of tumor necrosis factor-alfa (TNFα, a pro-inflammatory cytokine was studied in 140 patients with a newly diagnosed chronic lymphocytic leukemia (CLL. TNFα contents in blood serum was determined using ELISA method. A significant increase of serum TNFα was shown in patients with newly diagnosed CLL, as compared to healthy individuals. Dependence of the cytokine concentration on clnical stage and course of disease was revealed: the highest levels of serum TNFα were registered in patients with advanced disease and/or CLL progression. Distinct correlations were revealed between the studied cytokine amounts and clinical laboratory parameters reflecting the cell proliferative activity and tumor clone size. Immunochemotherapy was accompanied by a significant reduction of TNFα levels. According to the data from multivariate regression analysis. TNFα level of at the time of the diagnosis was an independent predictor of overall survival. Hence, TNFα plays an important role in CLL pathogenesis and may be used as an additional predictive factor for CLL outcomes.

  11. Rhabdomyolysis Associated with Fenofibrate Monotherapy in a Patient with Chronic Myelogenous Leukemia

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    Kazuya Kato

    2011-08-01

    Full Text Available Rhabdomyolysis associated with fenofibrate monotherapy is extremely rare. Here, we report a rare case of rhabdomyolysis of the psoas muscle in an 82-year-old man with chronic myelogenous leukemia (CML. He was prescribed fenofibrate because of a hypertriglyceridemia. The patient reported generalized muscle pain and right abdominal pain while receiving fenofibrate monotherapy. An abdominal computed tomography scan and an abdominal ultrasound showed a large and low attenuation and high echogenicity, respectively, in the right middle abdominal area. Laboratory values included a serum creatine concentration of 4.1 mg/dl and a creatinine phosphokinase concentration of 5,882 IU/l. During laparotomy, a large hematoma and necrotic mass was identified in the right psoas muscle. Histological examination revealed that the resected specimens were of the psoas muscle with irregular fiber sizes, degenerating fibers surrounding the inflammatory reaction, and fiber necrosis that is typical for polymyositis. Based on these findings and the clinical history, a diagnosis of fenofibrate-induced rhabdomyolysis was made. To the best of our knowledge, no patient has ever been diagnosed with fulminant psoas rhabdomyolysis due to a fenofibrate monotherapy. This report details the rare case of rhabdomyolysis in a patient with CML associated with fenofibrate monotherapy and offers a review of the literature.

  12. CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells.

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    Deaglio, Silvia; Capobianco, Andrea; Bergui, Luciana; Dürig, Jan; Morabito, Fortunato; Dührsen, Ulrich; Malavasi, Fabio

    2003-09-15

    The prognosis for patients with B-cell chronic lymphocytic leukemia (B-CLL) is generally less favorable for those expressing CD38. Our working hypothesis is that CD38 is not merely a marker in B-CLL, but that it plays a receptor role with pathogenetic potential ruling the proliferation of the malignant clone. CD38 levels were generally low in the patients examined and monoclonal antibody (mAb) ligation was inefficient in signaling. Other cellular models indicated that molecular density and surface organization are critical for CD38 functionality. Interleukin 2 (IL-2) induced a marked up-modulation and surface rearrangement of CD38 in all the patients studied. On reaching a specific expression threshold, CD38 becomes an efficient receptor in purified B-CLL cells. Indeed, mAb ligation is followed by Ca2+ fluxes and by a markedly increased proliferation. The unsuitability of CD38 to perform as a receptor is obviated through close interaction with the B-cell-receptor (BCR) complex and CD19. On mAb binding, CD38 translocates to the membrane lipid microdomains, as shown by a colocalization with the GM1 ganglioside and with CD81, a raft-resident protein. Finally, CD38 signaling in IL-2-treated B-CLL cells prolonged survival and induced the appearance of plasmablasts, providing a pathogenetic hypothesis for the occurrence of Richter syndrome.

  13. Regulatory T cells in chronic lymphocytic leukemia: implication for immunotherapeutic interventions.

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    Jadidi-Niaragh, Farhad; Ghalamfarsa, Ghasem; Yousefi, Mehdi; Tabrizi, Mina Hajifaraj; Shokri, Fazel

    2013-08-01

    Identification of regulatory T cells (Tregs) has led to breaking the dichotomy of the Th1/Th2 axis in the immunopathology of several diseases such as autoimmune diseases and cancer. Despite the presence of extensive information about immunobiology of Tregs in pathogenesis of autoimmune diseases, little is known about the frequency and function of these cells in hematologic malignancies, particularly chronic lymphocytic leukemia (CLL). Recent data have demonstrated increased frequency and intact functional capacity of CD4(+) Tregs in CLL patients. However, the precise role of these cells in the immunopathology of CLL is not well known. While targeting Tregs in cancer diseases seems to be an interesting immunotherapeutic approach, such therapeutic interventions in CLL might be deleterious due to suppression of the tumor-specific adaptive and innate immune responses. Thus, the precise biological and regulatory functions of all Tregs subsets should be carefully investigated before planning any immunotherapeutic interventions based on targeting of Tregs. In this communication, we review the recent data published on immunobiology of Tregs in CLL and discuss about the possibility of targeting Tregs in CLL.

  14. Quantitative and qualitative analysis of regulatory T cells in B cell chronic lymphocytic leukemia.

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    Mpakou, Vassiliki E; Ioannidou, Heleni-Dikaia; Konsta, Eugene; Vikentiou, Myrofora; Spathis, Aris; Kontsioti, Frieda; Kontos, Christos K; Velentzas, Athanassios D; Papageorgiou, Sotiris; Vasilatou, Diamantina; Gkontopoulos, Konstantinos; Glezou, Irene; Stavroulaki, Georgia; Mpazani, Efthimia; Kokkori, Stella; Kyriakou, Elias; Karakitsos, Petros; Dimitriadis, George; Pappa, Vasiliki

    2017-09-01

    Accumulated data indicate a significant role of T cell dysfunction in the pathogenesis of chronic lymphocytic leukemia. In CLL, regulatory T cells are significantly higher and show lower apoptotic levels compared to healthy donors. We demonstrate that CLL derived CD4 + CD25 - CD127 - and CD4 + CD25 low CD127 - subpopulations share a common immunophenotypic profile with conventional Tregs and are associated with advanced stage disease. We further provide evidence that the increased number of Tregs contributes indirectly to the proliferation of the CLL clone, by suppressing the proliferation of Teffs which in turn suppress CLL cells. These data are further supported by our observations that CLL derived Tregs appear rather incapable of inducing apoptosis of both normal B cells and CLL cells, in contrast to normal Tregs, suggesting an immunoediting effect of CLL cells on Tregs which negatively affects the functionality of the latter and contributes to the failure of Tregs in CLL to efficiently eliminate the abnormal clone. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Clinical roundtable monograph: unmet needs in the treatment of chronic lymphocytic leukemia: integrating a targeted approach.

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    O'Brien, Susan M; Furman, Richard R; Byrd, John C; Smith, Ashbel

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is the most frequently diagnosed hematologic malignancy in the United States. Although several features can be useful in the diagnosis of CLL, the most important is the immunophenotype.Two staging systems--the Binet system and the Rai classification--are used to assess risk. After diagnosis, the first major therapeutic decision is when to initiate therapy, as a watchful waiting approach is often appropriate for patients with asymptomatic disease. Once a patient has met the criteria for treatment, the choice of therapy is the next major decision. Younger patients (<65 years) often receive more aggressive treatment that typically consists of cytotoxic chemotherapy. There is a great unmet need concerning treatment of older patients with CLL, who often present with more comorbid conditions that can decrease their ability to tolerate particular regimens. The current standard of care for older patients with CLL is rituximab plus chlorambucil. The concept of targeted agents is currently an area of intense interest in CLL. The Bruton’s tyrosine kinase inhibitor ibrutinib is the targeted agent that is furthest along in clinical development. It is associated with an overall survival rate of 83%. Idelalisib targets the phosphatidyl inositol 3-kinase and is under evaluation in pivotal trials. Targeted agents offer much promise in terms of efficacy, toxicity, and oral availability. They will change the management of patients with CLL.

  16. Clinical roundtable monograph: Unmet needs in the management of chronic myelogenous leukemia.

    Science.gov (United States)

    Jabbour, Elias J; Bixby, Dale; Akard, Luke P

    2012-12-01

    Approximately 5,000 cases of chronic myelogenous leukemia (CML) are diagnosed each year in the United States. The introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved survival time for many CML patients. Current first-line treatment options include imatinib and the second-generation agents nilotinib and dasatinib. Second- and third-line agents include nilotinib, dasatinib, bosutinib, and the new agent ponatinib. Despite the effectiveness of TKIs, some patients develop resistance or intolerance to these agents. A number of mutations of the BCR-ABL gene have been identified and are associated with TKI resistance. Patients may benefit from switching to a second-line TKI, undergoing hematopoietic stem cell transplant, or receiving newly emerging agents. Although early response is associated with improved patient outcome, clinicians lack tests that can determine which patients will benefit from which therapies. To ensure adequate response, patients should be monitored by both polymerase chain reaction and cytogenetic analysis of the bone marrow. This roundtable monograph reviews key unmet needs in patients with CML related to disease management and treatment options.

  17. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.

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    Hing, Zachary A; Mantel, Rose; Beckwith, Kyle A; Guinn, Daphne; Williams, Erich; Smith, Lisa L; Williams, Katie; Johnson, Amy J; Lehman, Amy M; Byrd, John C; Woyach, Jennifer A; Lapalombella, Rosa

    2015-05-14

    Despite the therapeutic efficacy of ibrutinib in chronic lymphocytic leukemia (CLL), complete responses are infrequent, and acquired resistance to Bruton agammaglobulinemia tyrosine kinase (BTK) inhibition is being observed in an increasing number of patients. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We previously showed that the XPO1 inhibitor selinexor is proapoptotic in CLL cells and disrupts B-cell receptor signaling via BTK depletion. Herein we show the combination of selinexor and ibrutinib elicits a synergistic cytotoxic effect in primary CLL cells and increases overall survival compared with ibrutinib alone in a mouse model of CLL. Selinexor is effective in cells isolated from patients with prolonged lymphocytosis following ibrutinib therapy. Finally, selinexor is effective in ibrutinib-refractory mice and in a cell line harboring the BTK C481S mutation. This is the first report describing the combined activity of ibrutinib and selinexor in CLL, which represents a new treatment paradigm and warrants further evaluation in clinical trials of CLL patients including those with acquired ibrutinib resistance. © 2015 by The American Society of Hematology.

  18. New developments in the management of chronic lymphocytic leukemia: role of ofatumumab

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    Laurenti L

    2016-01-01

    Full Text Available Luca Laurenti,1 Idanna Innocenti,1 Francesco Autore,1 Simona Sica,1 Dimitar G Efremov2 1Department of Hematology, Catholic University of the Sacred Heart, Rome, 2Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Monterotondo, Italy Abstract: Ofatumumab is one of the three anti-CD20 monoclonal antibodies currently available for the treatment of chronic lymphocytic leukemia (CLL. The US Food and Drug Administration (FDA approved the use of ofatumumab in patients with CLL refractory to fludarabine and alemtuzumab in 2009, and the European Medicines Agency (EMA granted approval for the same indication in 2010. Subsequent positive results of ofatumumab in combination with chlorambucil in treatment-naïve patients led the FDA in April 2014 to approve the use of this combination for first-line treatment of patients with CLL for whom fludarabine-based therapy is considered inappropriate. Later that year, the EMA approved the use of ofatumumab in combination with chlorambucil or bendamustine for the same indication. Ofatumumab has also shown potential as maintenance therapy for patients with relapsed CLL; an application to broaden the label for ofatumumab as maintenance therapy was submitted earlier this year to the EMA and FDA. Finally, ofatumumab has shown promising activity in combination with ibrutinib or idelalisib in relapsed/refractory CLL patients; combinations of ofatumumab with B-cell-receptor pathway inhibitors could represent another potential use of this antibody in the near future. Keywords: CLL, ofatumumab, monoclonal antibodies, immunotherapy

  19. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Brown, Jennifer R; Barrientos, Jacqueline C; Barr, Paul M; Flinn, Ian W; Burger, Jan A; Tran, Anh; Clow, Fong; James, Danelle F; Graef, Thorsten; Friedberg, Jonathan W; Rai, Kanti; O'Brien, Susan

    2015-05-07

    The safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent ibrutinib. The overall response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135. © 2015 by The American Society of Hematology.

  20. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia.

    Science.gov (United States)

    Rogers, K A; Ruppert, A S; Bingman, A; Andritsos, L A; Awan, F T; Blum, K A; Flynn, J M; Jaglowski, S M; Lozanski, G; Maddocks, K J; Byrd, J C; Woyach, J A; Jones, J A

    2016-02-01

    Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.

  1. Experience with ibrutinib for first-line use in patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Itchaki, Gilad; Brown, Jennifer R

    2018-01-01

    Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations. Moreover, compared with standard chemoimmunotherapy (CIT) for adults, ibrutinib causes fewer cytopenias and infections, while having its own unique toxicity profile. Its efficacy in relapsed patients as well as its tolerability have led to its increased use in previously untreated patients, especially in those with poor prognostic markers and/or the elderly. This review elaborates on ibrutinib's unique toxicity profile and the mechanisms of acquired resistance leading to progression on ibrutinib, since both are critical for understanding the obstacles to its first-line use. We will further evaluate the data from ongoing clinical trials in this setting and explore future options for combination therapy.

  2. State-of-the-Art Treatment and Novel Agents in Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Cramer, Paula; Hallek, Michael; Eichhorst, Barbara

    2016-01-01

    Chemoimmunotherapy is the established first-line treatment of patients with chronic lymphocytic leukemia (CLL) who do not display the high-risk genetic features del(17p) and/or TP53 mutation: Physically fit patients without or with only mild comorbidities should receive fludarabine, cyclophosphamide and rituximab, while bendamustine and rituximab can be considered in fit elderly patients of over 65 years and in patients with a higher risk of infections. Patients with relevant coexisting conditions should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. Patients with a del(17p) and/or TP53 mutation respond poorly to conventional chemo(immuno)therapies. However, the recently approved BTK and PI3K inhibitors ibrutinib and idelalisib have the best efficacy ever documented in patients with these high-risk genomic alterations and/or refractory CLL. The choice between ibrutinib and idelalisib should be based on the patients' comorbidities and concomitant medications since both agents have a distinct toxicity profile, although they are generally well tolerated in the majority of patients. For treatment of patients with a late relapse, chemoimmunotherapy instead of kinase inhibitors is still a reasonable approach, but has to be determined for every patient individually. Further targeted drugs and their combinations are currently being evaluated in clinical trials and have the potential to eradicate all residual CLL cells and thus lead to a cure of CLL. © 2016 S. Karger GmbH, Freiburg.

  3. The Next Generation of Targeted Molecules for the Treatment of Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Jeyakumar, Deepa; O'Brien, Susan

    2016-11-15

    With the recent approval of several new targeted therapies for chronic lymphocytic leukemia (CLL), there are now multiple options for its treatment. Inhibitors of Bruton tyrosine kinase (with ibrutinib being the first-in-class US Food and Drug Administration-approved agent) and phosphoinositide 3-kinase (with idelalisib as the first-in-class approved agent) are promising because they are generally well tolerated and highly effective against this malignancy. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and subsequent infections) associated with chemoimmunotherapy. As a class of medications, B-cell receptor inhibitors have some unique side effects, including redistribution lymphocytosis. Toxicities associated specifically with ibrutinib include increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities: transaminitis, colitis, and pneumonitis. Targeted therapies recently approved for use in CLL include the novel anti-CD20 monoclonal antibodies obinutuzumab and ofatumumab, and the B-cell lymphoma 2 inhibitor venetoclax. This article describes the clinical data that led to approval of these B-cell receptor inhibitors for the treatment of CLL, and highlights newer agents in clinical development that target the same kinases as the currently available therapies.

  4. Evaluation of chronic lymphocytic leukemia by BAC-based microarray analysis

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    McDaniel Lisa D

    2011-02-01

    Full Text Available Abstract Background Chronic lymphocytic leukemia (CLL is a highly variable disease with life expectancies ranging from months to decades. Cytogenetic findings play an integral role in defining the prognostic significance and treatment for individual patients. Results We have evaluated 25 clinical cases from a tertiary cancer center that have an established diagnosis of CLL and for which there was prior cytogenetic and/or fluorescence in situ hybridization (FISH data. We performed microarray-based comparative genomic hybridization (aCGH using a bacterial artificial chromosome (BAC-based microarray designed for the detection of known constitutional genetic syndromes. In 15 of the 25 cases, aCGH detected all copy number imbalances identified by prior cytogenetic and/or FISH studies. For the majority of those not detected, the aberrations were present at low levels of mosaicism. Furthermore, for 15 of the 25 cases, additional abnormalities were detected. Four of those cases had deletions that mapped to intervals implicated in inherited predisposition to CLL. For most cases, aCGH was able to detect abnormalities present in as few as 10% of cells. Although changes in ploidy are not easily discernable by aCGH, results for two cases illustrate the detection of additional copy gains and losses present within a mosaic tetraploid cell population. Conclusions Our results illustrate the successful evaluation of CLL using a microarray optimized for the interrogation of inherited disorders and the identification of alterations with possible relevance to CLL susceptibility.

  5. Primary cutaneous follicle center lymphoma in the setting of chronic lymphocytic leukemia

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    S Konda

    2011-01-01

    Full Text Available Primary cutaneous malignancies arising in association with chronic lymphocytic leukemia (CLL are notable for their atypical clinical and histological presentation. We report a 69-year-old man with a 17-year history of CLL who presented for evaluation of a well-defined red to violaceous nodule with a central depressed scar on the left lower extremity. Microscopic examination of a punch biopsy revealed an infiltrate of predominantly small lymphocytes with scattered large, atypical epithelioid cells. Immunohistochemical stains revealed diffuse positive staining of the lesional cells with CD20+ and bcl-6+ and focal positive staining with bcl-2+ (negative CD10 and CD23, findings which, in conjunction with the histology, were most compatible with a diagnosis of primary cutaneous follicle center lymphoma (PCFCL. A review of the clinical charts revealed several prior biopsies with varied diagnoses. In light of the most recent biopsy findings, all previous biopsies were re-reviewed and interpreted as PCFCL arising in the setting of CLL. Features contributing to the diagnostic conundrum in this case included an atypical clinical and histological presentation, lack of pertinent clinical history and multiple presentations at different institutions.

  6. Telomere length analysis in monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia Binet A

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    F.M. Furtado

    Full Text Available Monoclonal B-cell lymphocytosis (MBL is an asymptomatic clinical entity characterized by the proliferation of monoclonal B cells not meeting the diagnosis criteria for chronic lymphocytic leukemia (CLL. MBL may precede the development of CLL, but the molecular mechanisms responsible for disease progression and evolution are not completely known. Telomeres are usually short in CLL and their attrition may contribute to disease evolution. Here, we determined the telomere lengths of CD5+CD19+ cells in MBL, CLL, and healthy volunteers. Twenty-one CLL patients, 11 subjects with high-count MBL, and 6 with low-count MBL were enrolled. Two hundred and sixty-one healthy volunteers aged 0 to 88 years were studied as controls. After diagnosis confirmation, a flow cytometry CD19+CD5+-based cell sorting was performed for the study groups. Telomere length was determined by qPCR. Telomere length was similar in the 3 study groups but shorter in these groups compared to normal age-matched subjects that had been enrolled in a previous study from our group. These findings suggest that telomere shortening is an early event in CLL leukemogenesis.

  7. Automatic detection of axillary lymphadenopathy on CT scans of untreated chronic lymphocytic leukemia patients

    Science.gov (United States)

    Liu, Jiamin; Hua, Jeremy; Chellappa, Vivek; Petrick, Nicholas; Sahiner, Berkman; Farooqui, Mohammed; Marti, Gerald; Wiestner, Adrian; Summers, Ronald M.

    2012-03-01

    Patients with chronic lymphocytic leukemia (CLL) have an increased frequency of axillary lymphadenopathy. Pretreatment CT scans can be used to upstage patients at the time of presentation and post-treatment CT scans can reduce the number of complete responses. In the current clinical workflow, the detection and diagnosis of lymph nodes is usually performed manually by examining all slices of CT images, which can be time consuming and highly dependent on the observer's experience. A system for automatic lymph node detection and measurement is desired. We propose a computer aided detection (CAD) system for axillary lymph nodes on CT scans in CLL patients. The lung is first automatically segmented and the patient's body in lung region is extracted to set the search region for lymph nodes. Multi-scale Hessian based blob detection is then applied to detect potential lymph nodes within the search region. Next, the detected potential candidates are segmented by fast level set method. Finally, features are calculated from the segmented candidates and support vector machine (SVM) classification is utilized for false positive reduction. Two blobness features, Frangi's and Li's, are tested and their free-response receiver operating characteristic (FROC) curves are generated to assess system performance. We applied our detection system to 12 patients with 168 axillary lymph nodes measuring greater than 10 mm. All lymph nodes are manually labeled as ground truth. The system achieved sensitivities of 81% and 85% at 2 false positives per patient for Frangi's and Li's blobness, respectively.

  8. Prognostic Value of Lipoprotein Lipase Expression Among Egyptian B-Chronic Lymphocytic Leukemia Patients

    International Nuclear Information System (INIS)

    SAAD, A.A.; EL-SHENNAWY, D.; HAMED, A.I.; EL-FEKY, M.A.; ISMAIL, M.A.; EL-HAGRACY, R.S.

    2008-01-01

    Background: B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease with a highly variable clinical course. Some patients may survive for years without need for therapy while others, although they had early treatment, the outcome is unsatisfactory. The motive to find more reliable prognostic factors apart from stage, age, tumor volume and immunoglobulin heavy chain mutations is of clinical interest. Material and Methods: The study was carried out on 25 CLL patients attending Hematology Clinic at Ain Shams University Hospitals. Peripheral blood sample was taken from each patient for surface CD38 and cytoplasmic zeta-chain-associated protein tyrosine kinase (ZAP-70) by flow cytometry and lipoprotein lipase (LPL) expression by real time PCR. Results: We demonstrated statistically significant association between high level of LPL expression and significantly high LDH level, poor cytogenetic risk, ZAP- 70 expression and response to therapy ( p =0.01, 0.02, 0.04 and 0.001 respectively). Conclusion: LPL expression can serve as a new surrogate prognostic factor for CLL patients and can be used to detect patients who need early treatment

  9. Helical tomotherapy for extramedullary hematopoiesis involving the pericardium in a patient with chronic myeloid leukemia.

    Science.gov (United States)

    Toms, Daniel R; Cannick, Leander; Stuart, Robert K; Jenrette, Joseph M; Terwiliger, Lacy

    2010-07-01

    Extramedullary hematopoiesis (EMH) refers to the development of foci of hematopoiesis outside its normal location in the bone marrow. This occurs normally during fetal development but is abnormal postpartum. The most common sites of EMH are the spleen and liver. The phenomenon occurs in a number of disease states, notably in myelofibrosis, thalassemia, immune thrombocytopenic purpura, sickle cell anemia, polycythemia vera, and myelodysplastic syndrome. Affected patients often develop symptoms related to the location of the EMH. Reported treatments include red blood cell transfusions, surgical excision, decompressive laminectomy in cases of cord compression, chemotherapy, and irradiation. Radiation therapy is highly effective for treating hematopoietic tissue because such tissues are extremely radiosensitive. Megavoltage helical tomotherapy is a technical advance in the delivery of radiation therapy, allowing more conformal and precise treatments. The present case report describes a patient with the diagnosis of atypical chronic myeloid leukemia and myelofibrosis who subsequently developed EMH of the pericardium with effusion and tamponade. By utilizing tomotherapy we were able to treat the pericardium while sparing much of the myocardium. The patient tolerated treatment well without acute adverse effects. His symptoms were alleviated, but he died approximately 1 year later.

  10. MicroRNA expression profiling identifies activated B cell status in chronic lymphocytic leukemia cells.

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    Shuqiang Li

    2011-03-01

    Full Text Available Chronic lymphocytic leukemia (CLL is thought to be a disease of resting lymphocytes. However, recent data suggest that CLL cells may more closely resemble activated B cells. Using microRNA (miRNA expression profiling of highly-enriched CLL cells from 38 patients and 9 untransformed B cells from normal donors before acute CpG activation and 5 matched B cells after acute CpG activation, we demonstrate an activated B cell status for CLL. Gene set enrichment analysis (GSEA identified statistically-significant similarities in miRNA expression between activated B cells and CLL cells including upregulation of miR-34a, miR-155, and miR-342-3p and downregulation of miR-103, miR-181a and miR-181b. Additionally, decreased levels of two CLL signature miRNAs miR-29c and miR-223 are associated with ZAP70(+ and IgV(H unmutated status and with shorter time to first therapy. These data indicate an activated B cell status for CLL cells and suggest that the direction of change of individual miRNAs may predict clinical course in CLL.

  11. Analysis of chronic lymphotic leukemia transcriptomic profile: differences between molecular subgroups.

    Science.gov (United States)

    Jantus Lewintre, Eloisa; Reinoso Martín, Cristina; Montaner, David; Marín, Miguel; José Terol, María; Farrás, Rosa; Benet, Isabel; Calvete, Juan J; Dopazo, Joaquín; García-Conde, Javier

    2009-01-01

    B cell chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder with a variable clinical course. Patients with unmutated IgV(H) gene show a shorter progression-free and overall survival than patients with immunoglobulin heavy chain variable regions (IgV(H)) gene mutated. In addition, BCL6 mutations identify a subgroup of patients with high risk of progression. Gene expression was analysed in 36 early-stage patients using high-density microarrays. Around 150 genes differentially expressed were found according to IgV(H) mutations, whereas no difference was found according to BCL6 mutations. Functional profiling methods allowed us to distinguish KEGG and gene ontology terms showing coordinated gene expression changes across subgroups of CLL. We validated a set of differentially expressed genes according to IgV(H) status, scoring them as putative prognostic markers in CLL. Among them, CRY1, LPL, CD82 and DUSP22 are the ones with at least equal or superior performance to ZAP70 which is actually the most used surrogate marker of IgV(H) status.

  12. The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Kanduri, M; Tobin, G [Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala (Sweden); Åleskog, A [Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala (Sweden); Nilsson, K; Rosenquist, R [Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala (Sweden)

    2011-03-01

    Nuclear factor-κB (NF-κB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8–48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-κB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo.

  13. The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Kanduri, M; Tobin, G; Åleskog, A; Nilsson, K; Rosenquist, R

    2011-01-01

    Nuclear factor-κB (NF-κB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8–48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-κB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo

  14. The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia

    Science.gov (United States)

    Kanduri, M; Tobin, G; Åleskog, A; Nilsson, K; Rosenquist, R

    2011-01-01

    Nuclear factor-κB (NF-κB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8–48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-κB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo. PMID:22829125

  15. Posaconazole-Induced Adrenal Insufficiency in a Case of Chronic Myelomonocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Ann Miller

    2018-01-01

    Full Text Available Introduction. Posaconazole is an azole used in treatment and prophylaxis of a broad spectrum of fungal infections. Antifungals such as ketoconazole have been shown to cause primary adrenal insufficiency (AI as a result of direct inhibition on the steroidogenesis pathway. There is only one reported case of primary AI induced by posaconazole in a patient with mucormycosis. We report a case of posaconazole-related primary AI. Case. A 63-year-old man with chronic myelomonocytic leukemia was admitted for fatigue and intermittent nausea and vomiting. He had recently discontinued prophylactic posaconazole 300 mg daily. He was assessed for AI with a morning cortisol of 1.9 mcg/dL followed by a failed cosyntropin stimulation (CS test. Adrenocorticotropic hormone (ACTH level was 154.6 pg/mL with negative 21-hydroxylase antibodies. The patient’s symptoms improved with initiation of hydrocortisone and fludrocortisone. One year after discontinuation of posaconazole, he underwent a repeat CS test which showed normal adrenal function with normal ACTH at 34.1 pg/mL. Conclusion. In this case, we demonstrate that prolonged use of posaconazole is associated with primary AI. As use of posaconazole increases, knowledge of the potential risk of AI is important and must be included in the differential diagnosis when these patients present with hypotension, hypoglycemia, and failure to thrive.

  16. Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib.

    Science.gov (United States)

    Miller, Cecelia R; Ruppert, Amy S; Heerema, Nyla A; Maddocks, Kami J; Labanowska, Jadwiga; Breidenbach, Heather; Lozanski, Gerard; Zhao, Weiqiang; Gordon, Amber L; Jones, Jeffrey A; Flynn, Joseph M; Jaglowski, Samantha M; Andritsos, Leslie A; Blum, Kristie A; T Awan, Farrukh; Rogers, Kerry A; Grever, Michael R; Johnson, Amy J; Abruzzo, Lynne V; Hertlein, Erin K; Blachly, James S; Woyach, Jennifer A; Byrd, John C

    2017-08-22

    Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL). However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 ( P = .03), deletion 17p ( P = .03), and complex karyotype ( P = .01). Near-tetraploidy was also associated with ibrutinib discontinuation due to Richter transformation ( P transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95% CI, 3.83-19.59; P transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib.

  17. Novel therapies and their integration into allogeneic stem cell transplant for chronic lymphocytic leukemia.

    Science.gov (United States)

    Jaglowski, Samantha M; Byrd, John C

    2012-01-01

    Over the past decade, numerous advances have been made in elucidating the biology of and improving treatment for chronic lymphocytic leukemia (CLL). These studies have led to identification of select CLL patient groups that generally have short survival dating from time of treatment or initial disease relapse who benefit from more aggressive therapeutic interventions. Allogeneic transplantation represents the only potentially curative option for CLL, but fully ablative regimens applied in the past have been associated with significant morbidity and mortality. Reduced-intensity preparative regimens has made application of allogeneic transplant to CLL patients much more feasible and increased the number of patients proceeding to this modality. Arising from this has been establishment of guidelines where allogeneic stem cell transplantation should be considered in CLL. Introduction of new targeted therapies with less morbidity, which can produce durable remissions has the potential to redefine where transplantation is initiated in CLL. This review briefly summarizes the field of allogeneic stem cell transplant in CLL and the interface of new therapeutics with this modality. Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. New insights into hematopoietic stem cell transplantation for chronic lymphocytic leukemia: a 2015 perspective.

    Science.gov (United States)

    McClanahan, Fabienne; Gribben, John

    2015-09-01

    A considerable body of evidence demonstrates that allogeneic hematopoietic stem cell transplantation (HSCT) offers the only potentially curative treatment option for patients with chronic lymphocytic leukemia (CLL). However, this approach is suitable for only a minority of CLL patients, owing to its significant treatment-related mortality and morbidity. Until recently, internationally accepted guidelines suggested that HSCT should be considered in physically fit CLL patients who carry poor-risk features, such as TP53 abnormalities, or who had a short response to previous immunochemotherapy. However, several new agents and alternative treatment strategies are available that demonstrate impressive and durable responses, even in CLL patients who previously might have been candidates for transplant. The decision about which patients merit HSCT therefore remains important, and HSCT must now be considered in light of other less toxic therapies. Until data on the long-term efficacy of novel treatment approaches mature, the choice of HSCT vs alternative strategies must be assessed on a patient-by-patient basis, and treatment in the setting of randomized clinical trials should be pursued whenever possible.

  19. Clinical Practice Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL) in The Netherlands.

    Science.gov (United States)

    Kersting, Sabina; Neppelenbroek, Suzanne I M; Visser, Hein P J; van Gelder, Michel; Levin, Mark-David; Mous, Rogier; Posthuma, Ward; van der Straaten, Hanneke M; Kater, Arnon P

    2018-01-01

    In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukemia (CLL), and new potent drugs have become available. Therefore, the CLL working party revised the Dutch guidelines. Not only efficacy but also quality of life and socio-economic impact were taken into account in the formulation of treatment recommendations. The working party discussed a set of questions regarding diagnostic tests and treatment and wrote the draft guideline. This was evidence-based whenever possible, but in cases of low evidence, an expert-based recommendation was formulated with input of the entire working party. The draft guideline was sent to all hematologists in the Netherlands for comment and was subsequently approved. Recommendations were formulated on diagnostic tests and work-up before treatment. Also, recommendations were made for treatment with fludarabine-cyclophosphamide-rituximab, bendamustine-rituximab, chlorambucil with anti-CD20 antibody, ibrutinib, idelalisib-rituximab, venetoclax, and allogeneic stem cell transplantation. In the revised Dutch CLL guidelines, chemo-immunotherapy is still the cornerstone of CLL treatment with novel targeted drugs for specific risk groups. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN THE TREATMENT OF CHRONIC LYMPHOCITIC LEUKEMIA : WHY AND WHEN ?

    Directory of Open Access Journals (Sweden)

    Maria L. Delioukina

    2010-06-01

    Full Text Available Chronic lymphocytic leukemia (CLL is the most common hematologic malignancy in adults with an incidence rate of 4.2 per 100,000 per year. CLL frequently takes an indolent course, with some patients not requiring treatment for years, yet is incurable by currently available chemo- and immuno-therapeutic modalities. Despite high initial response rates, particularly to purine analogues, patients invariably relapse and subsequently develop resistance to therapy. The traditional “watchful waiting” approach to CLL is being challenged by data showing that treatments used early in the disease course impact long-term overall and progression-free survivals . The only curative treatment for CLL currently, is allogeneic hematopoeietic cell transplantation (alloHCT. In contrast to autologous transplant, myeloablative alloHCT for CLL patients generates durable remissions with promising survival plateaus; however, significant transplant related mortality (TRM is also observed (25-50% . At present the fact remains that for poor-risk CLL, alloHCT is the only treatment with the potential of providing long-term disease control. Future combinations with emerging low-toxicity therapies may further enhance the curative potential of allogeniec hematopoietic cell transplant. New drugs can also potentially enable refractory patients to attain response as a bridge to more effective stem cell transplantation.

  1. Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Hurtado, A M; Chen-Liang, T-H; Przychodzen, B; Hamedi, C; Muñoz-Ballester, J; Dienes, B; García-Malo, M D; Antón, A I; Arriba, F de; Teruel-Montoya, R; Ortuño, F J; Vicente, V; Maciejewski, J P; Jerez, A

    2015-01-01

    An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one ‘sub-Sanger' TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as β2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring

  2. Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib

    Directory of Open Access Journals (Sweden)

    Koh Okamoto

    2016-01-01

    Full Text Available Cryptococcus is a unique environmental fungus that can cause disease most often in immunocompromised individuals with defective cell-mediated immunity. Chronic lymphocytic leukemia (CLL is not known to be a risk factor for cryptococcal disease although cases have been described mainly in patients treated with agents that suppress cell-mediated immunity. Ibrutinib is a new biologic agent used for treatment of CLL, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia. It acts by inhibiting Bruton’s tyrosine kinase, a kinase downstream of the B-cell receptor critical for B-cell survival and proliferation. Ibrutinib use has not been associated previously with cryptococcal disease. However, recent evidence suggested that treatments aimed at blocking the function of Bruton’s tyrosine kinase could pose a higher risk for cryptococcal infection in a mice model. Here, we report the first case of disseminated cryptococcal disease in a patient with CLL treated with ibrutinib. When evaluating possible infection in CLL patients receiving ibrutinib, cryptococcal disease, which could be life threatening if overlooked, could be considered.

  3. Ibrutinib as an antitumor immunomodulator in patients with refractory chronic lymphocytic leukemia.

    Science.gov (United States)

    Cubillos-Zapata, Carolina; Avendaño-Ortiz, Jose; Córdoba, Raúl; Hernández-Jiménez, Enrique; Toledano, Victor; Pérez de Diego, Rebeca; López-Collazo, Eduardo

    2016-01-01

    Ibrutinib has emerged as a promising therapy for patients with chronic lymphocytic leukemia (CLL) who are nonresponsive to standard therapies. The refractory state of monocytes and T-cell exhaustion in patients with CLL could explain the morbidity and mortality reported in these patients. We studied the effect of ibrutinib on the immune response of four relapsed patients with CLL during the first treatment cycle. We observed the ability to recover the standard response against bacterial stimulus in CD14 + cells, improving levels of phospho-Erk1/2 and antigen presentation. Meanwhile, ibrutinib drove Th1-selective pressure in T lymphocytes, thus, reducing the PD-1 and PDL-1 expression. Our data suggest the impact of BTK inhibition along with immunomodulation on the innate immune response and a switch to the specific adaptive immune response, which might help to decrease infectious complications. The potential effect of ibrutinib on CLL patient outcomes is worthy of further study, because infections could be reduced with the use of ibrutinib.

  4. Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib.

    Science.gov (United States)

    Okamoto, Koh; Proia, Laurie A; Demarais, Patricia L

    2016-01-01

    Cryptococcus is a unique environmental fungus that can cause disease most often in immunocompromised individuals with defective cell-mediated immunity. Chronic lymphocytic leukemia (CLL) is not known to be a risk factor for cryptococcal disease although cases have been described mainly in patients treated with agents that suppress cell-mediated immunity. Ibrutinib is a new biologic agent used for treatment of CLL, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. It acts by inhibiting Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor critical for B-cell survival and proliferation. Ibrutinib use has not been associated previously with cryptococcal disease. However, recent evidence suggested that treatments aimed at blocking the function of Bruton's tyrosine kinase could pose a higher risk for cryptococcal infection in a mice model. Here, we report the first case of disseminated cryptococcal disease in a patient with CLL treated with ibrutinib. When evaluating possible infection in CLL patients receiving ibrutinib, cryptococcal disease, which could be life threatening if overlooked, could be considered.

  5. Igs expressed by chronic lymphocytic leukemia B cells show limited binding-site structure variability.

    Science.gov (United States)

    Marcatili, Paolo; Ghiotto, Fabio; Tenca, Claudya; Chailyan, Anna; Mazzarello, Andrea N; Yan, Xiao-Jie; Colombo, Monica; Albesiano, Emilia; Bagnara, Davide; Cutrona, Giovanna; Morabito, Fortunato; Bruno, Silvia; Ferrarini, Manlio; Chiorazzi, Nicholas; Tramontano, Anna; Fais, Franco

    2013-06-01

    Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated.

  6. Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia

    Science.gov (United States)

    Ghiotto, Fabio; Fais, Franco; Valetto, Angelo; Albesiano, Emilia; Hashimoto, Shiori; Dono, Mariella; Ikematsu, Hideyuki; Allen, Steven L.; Kolitz, Jonathan; Rai, Kanti R.; Nardini, Marco; Tramontano, Anna; Ferrarini, Manlio; Chiorazzi, Nicholas

    2004-01-01

    Studies of B cell antigen receptors (BCRs) expressed by leukemic lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that B lymphocytes with some level of BCR structural restriction become transformed. While analyzing rearranged VHDJH and VLJL genes of 25 non–IgM-producing B-CLL cases, we found five IgG+ cases that display strikingly similar BCRs (use of the same H- and L-chain V gene segments with unique, shared heavy chain third complementarity-determining region [HCDR3] and light chain third complementarity-determining region [LCDR3] motifs). These H- and L-chain characteristics were not identified in other B-CLL cases or in normal B lymphocytes whose sequences are available in the public databases. Three-dimensional modeling studies suggest that these BCRs could bind the same antigenic epitope. The structural features of the B-CLL BCRs resemble those of mAb’s reactive with carbohydrate determinants of bacterial capsules or viral coats and with certain autoantigens. These findings suggest that the B lymphocytes that gave rise to these IgG+ B-CLL cells were selected for this unique BCR structure. This selection could have occurred because the precursors of the B-CLL cells were chosen for their antigen-binding capabilities by antigen(s) of restricted nature and structure, or because the precursors derived from a B cell subpopulation with limited BCR heterogeneity, or both. PMID:15057307

  7. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Bruno, Silvia; Ledda, Bernardetta; Tenca, Claudya; Ravera, Silvia; Orengo, Anna Maria; Mazzarello, Andrea Nicola; Pesenti, Elisa; Casciaro, Salvatore; Racchi, Omar; Ghiotto, Fabio; Marini, Cecilia; Sambuceti, Gianmario; DeCensi, Andrea; Fais, Franco

    2015-09-08

    B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease. 1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients. Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts. At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis. In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules. Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process.

  8. Kinetics of lymphohematopoiesis and leukemia induction in chronically whole-body irradiated RF/J mice

    International Nuclear Information System (INIS)

    Cain, G.R.; Stitzel, K.A.; Fox, L.A.; Klein, A.K.; Dyck, J.A.; Shimizu, J.A.; Rosenblatt, L.S.

    1982-01-01

    Lymphohematopoietic progenitor cell populations (bone marrow CFU-GM, splenic CFU-BL) were quantitated in unirradiated and in chronically irradiated (17.5 R/day for 4 weeks) RF/J mice and control CAF 1 mice. RF/J mice were found capable of making substantial numbers of bone marrow CFU-GM but less so than the control strain CAF 1 . Significant strain differences were also seen in ability to form splinic B lymphocyte progenitor cells (CFU-BL). Unirradiated and irradiated RF mice produced over three times as many CFU-BL as CAF 1 mice. Throughout the period of protracted irradiation, followed by a twelve week recovery period, CFU-BL and CFU-GM were depressed less in the RF strain than the CAF 1 strain. This was due to an overcompensatory regenerative response which surpassed homostatic baseline levels. Despite strain and strain x dose differences in CFU-BL and CFU-GM, no significant strain x dose relationships were seen in circulati leukocyte counts. The increased susceptibility of RF mice to radiation-induced leukemia may be related to either inherent depressed regulatory control or the persistence of progenitor cell compartments. An apparent increased cell turnover rate in both CFU-BL and CFU-GM in RF mice following radiation damage may likewise play a contributory role

  9. Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability

    KAUST Repository

    Marcatili, P.

    2013-05-01

    Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated. Copyright © 2013 by The American Association of Immunologists, Inc.

  10. GENOMIC PROFILING BY MULTIPLEX LIGATION - DEPENDENT PROBE AMPLIFICATION IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS

    Directory of Open Access Journals (Sweden)

    Georgiana-Emilia Grigore

    2013-11-01

    Full Text Available The clinical management of severe pathological conditions, such as B-cell chronic lymphocytic leukemia (B-CLL, is subject to continuous optimization and re-evaluation. Patients may fully benefit from rapid, standardized laboratory tools designed to facilitate their early stratification according to disease risk, stage and prognosis. Such technologies may also aid the clinician in selecting the therapeutic option with the greatest chances of success. The presence of specific genetic abnormalities are frequently associated with the clinical outcome of oncologic patients in general, and B-CLL patients in particular. In the current study, a group of 58 B-CLL patients were evaluated for the detection of gene copy number alterations (deletions or duplication/ amplifications within 45 distinct genetic targets, by means of a novel molecular methodology, Multiplex Ligation - Dependent Probe Amplification (MLPA. Simple or complex genetic defects were identified in 67% of cases, and the most common aberrations observed were: deletion of the short arm of chromosome 13 in 33% of cases, deletion of the long arm of chromosome 11 in 16% of cases, trisomy 12 in 16% of cases, and deletion of the short arm of chromosome 17 in 7% of cases. The main conclusion of the study presented here points towards MLPA as a potential key step of clinical management protocols in B-CLL, providing that it will be fully standardised for routine diagnosis.

  11. An "age"-structured model of hematopoietic stem cell organization with application to chronic myeloid leukemia.

    Science.gov (United States)

    Roeder, Ingo; Herberg, Maria; Horn, Matthias

    2009-04-01

    Previously, we have modeled hematopoietic stem cell organization by a stochastic, single cell-based approach. Applications to different experimental systems demonstrated that this model consistently explains a broad variety of in vivo and in vitro data. A major advantage of the agent-based model (ABM) is the representation of heterogeneity within the hematopoietic stem cell population. However, this advantage comes at the price of time-consuming simulations if the systems become large. One example in this respect is the modeling of disease and treatment dynamics in patients with chronic myeloid leukemia (CML), where the realistic number of individual cells to be considered exceeds 10(6). To overcome this deficiency, without losing the representation of the inherent heterogeneity of the stem cell population, we here propose to approximate the ABM by a system of partial differential equations (PDEs). The major benefit of such an approach is its independence from the size of the system. Although this mean field approach includes a number of simplifying assumptions compared to the ABM, it retains the key structure of the model including the "age"-structure of stem cells. We show that the PDE model qualitatively and quantitatively reproduces the results of the agent-based approach.

  12. Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability

    KAUST Repository

    Marcatili, P.; Ghiotto, F.; Tenca, C.; Chailyan, A.; Mazzarello, A. N.; Yan, X.-J.; Colombo, M.; Albesiano, E.; Bagnara, D.; Cutrona, G.; Morabito, F.; Bruno, S.; Ferrarini, M.; Chiorazzi, N.; Tramontano, A.; Fais, F.

    2013-01-01

    Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated. Copyright © 2013 by The American Association of Immunologists, Inc.

  13. Overexpression of Hiwi Inhibits the Growth and Migration of Chronic Myeloid Leukemia Cells.

    Science.gov (United States)

    Wang, Yalin; Jiang, Yan; Ma, Ning; Sang, Bailu; Hu, Xiaolin; Cong, Xiaofeng; Liu, Ziling

    2015-09-01

    Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by dysregulated growth and proliferation of hematopoietic stem/progenitor cells in bone marrow and excessive expansion of hematopoietic compartments in peripheral blood. Expression deletion of Hiwi, a human Piwi homolog, has been reported to be implicated in leukemogenesis. We here explored Hiwi's role in CML pathogenesis by determining how and whether its forced overexpression could affect CML cell growth and migration. The present results showed that lentivirus-mediated overexpression of Hiwi significantly suppressed cell proliferation and induced obvious apoptosis in K562 cells, a CML line cell line. Tumors in BALB/c nude mice generated by the K562 cells expressing Hiwi were much smaller than those formed by the control cells. Like in vitro, Hiwi upregulation induced cell apoptosis in the tumor tissues in vivo. Additionally, Hiwi elevation suppressed K562 cell migration and inhibited the activity and expression of matrix metalloproteinase-2 and -9. In summary, our study demonstrates that Hiwi overexpression inhibits CML cell growth and migration, providing insights into its role in CML pathogenesis.

  14. Chronic adult T-cell Leukemia in a young male after blood transfusion as a newborn

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    Magali Colucci

    2016-06-01

    Full Text Available Human T-cell Lymphotropic virus type 1 (HTLV-1 is the etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HTM/TSP. Areas of extremely high HTLV-1 prevalence are surrounded by areas of middle or very low prevalence. ATLL is an aggressive lymphoproliferative malignancy of peripheral T cells, with an incidence of less than 5% in HTLV-1-infected individuals. ATLL developed in the majority of cases in individuals who were infected with HTLV-1 by their mothers due to prolonged breastfeeding. In non-endemic areas, ATLL is usually limited to immigrants, their sexual partners and descendants from endemic regions. Very few cases of ATLL have been diagnosed in recipient patients few years after an organ transplantation or blood transfusion worldwide. Achieving an accurate and fast diagnosis of ATLL can be challenging due to the lack of professional experience, delayed consultation and difficulty in its sub-classification. We present a case of a delayed onset of a chronic ATLL in an 18-years-old male who was transfused with blood components as a premature newborn in Buenos Aires, a non-endemic city of South America.

  15. Correlation of total body potassium and leukemic cell mass in patients with chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Chandra, P.; Sawitsky, A.; Chanana, A.D.; Chikkappa, G.; Cohn, S.H.; Rai, K.R.; Cronkity, E.P.

    1979-01-01

    Total body leukemic mass in patients with chronic lymphocytic leukemia (CLL) was measured by quantitation of total body potassium (TBK) with a whole-body counter. In addition, the predicted normal total body potassium (Kp) for each patient was calculated from an empirically derived relationship involving height, weight age, and sex. Both the absolute TBK and the relative excess of total body potassium (TBK/Kp) were related to the stage of disease. Patients in the early stages of CLL were found to have lower TBK and TBK/Kp than patients in the late stages of disease. Both of these parameters increased with the successively advanced stages of the disease. The clinically monitored reduction of leukemic cell mass following therapy was accompanied by reductions in TBK and TBK/Kp. Data presented support the notion that TBK/Kp is a useful indicator of the total body leukemic mass. Futhermore, the results of these studies quantitatively validate the proposed clinical staging system for CLL. Quantitation of TBK by a whole-body counter is an accurate and noninvasive procedure and does not require administration of isotopes

  16. Heterogeneity of BCR-ABL rearrangement in patients with chronic myeloid leukemia in Pakistan.

    Science.gov (United States)

    Tabassum, Najia; Saboor, Mohammad; Ghani, Rubina; Moinuddin, Moinuddin

    2014-07-01

    Breakpoint cluster region-Abelson (BCR-ABL) rearrangement or Philadelphia (Ph) chromosome in Chronic Myeloid Leukemia (CML) is derived from a reciprocal chromosomal translocation between ABL gene on chromosome 9 and BCR gene on chromosome 22. This chimeric protein has various sizes and therefore different clinical behaviour. The purpose of this study was to determine the heterogeneity of BCR-ABL rearrangement in patients with Ph(+)CML in Pakistan. The study was conducted at Civil Hospital and Baqai Institute of Hematology (BIH) Karachi. Blood samples from 25 patients with CML were collected. Multiplex reverse transcription polymerase chain reaction (RT-PCR) was performed to identify various BCR-ABL transcripts. All 25 samples showed BCR-ABL rearrangements. Out of these, 24 (96%) patients expressed p210 BCR-ABL rearrangements i.e. 60% (n=15) had b3a2 and 32% (n=8) had b2a2 rearrangements. Co-expression of b3a2 /b2a2 rearrangement and p190 (e1a3) rearrangement was also identified in two patients. It is apparent that majority of the patients had p210 BCR-ABL rearrangements. Frequency of co-expression and rare fusion transcripts was very low.

  17. How I Treat Elderly or Comorbid Patients with Chronic Lymphocytic Leukemia

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    Lukáš Smolej

    2010-01-01

    Full Text Available Treatment of chronic lymphocytic leukemia (CLL has recently undergone several major changes. Most importantly, large randomized trials (CLL-8 in first line and REACH in relapse clearly demonstrated superiority of chemoimmunotherapy consisting of fludarabine, cyclophosphamide and rituximab (FCR over fludarabine and cyclophosphamide (FC alone, thus establishing FCR regimen as the new gold standard in younger and physically fit patients. However, management of elderly and/or comorbid patients is still a challenging task because they cannot be treated with agressive approaches due to high risk of unacceptable toxicity. To date, no randomized trials in this patient population have improved therapeutic results over chlorambucil; therefore, this agent remains the backbone of treatment against which the new protocols should be tested. When deciding about the intensity of treatment, performance status, biological age and number as well as severity of comorbidities should be taken into account. Emerging treatment concepts for elderly/comorbid patients include combination of chlorambucil with monoclonal antibodies (rituximab, ofatumumab, GA-101, fludarabine-based regimens in reduced doses or protocols based on bendamustine and lenalidomide. Combination of highdose steroids with rituximab represent a promising option in relapsed/refractory CLL; however, infectious toxicity remains a serious issue. Finally, ofatumumab monotherapy appears to be a safe and effective therapy for heavily pretreated patients with CLL. This article reviews the current and future possibilities in the treatment of elderly and comorbid patients with CLL.

  18. How I treat elderly or comorbid patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Smolej, Lukás

    2010-01-01

    Treatment of chronic lymphocytic leukemia (CLL) has recently undergone several major changes. Most importantly, large randomized trials (CLL-8 in first line and REACH in relapse) clearly demonstrated superiority of chemoimmunotherapy consisting of fludarabine, cyclophosphamide and rituximab (FCR) over fludarabine and cyclophosphamide (FC) alone, thus establishing FCR regimen as the new gold standard in younger and physically fit patients. However, management of elderly and/or comorbid patients is still a challenging task because they cannot be treated with agressive approaches due to high risk of unacceptable toxicity. To date, no randomized trials in this patient population have improved therapeutic results over chlorambucil; therefore, this agent remains the backbone of treatment against which the new protocols should be tested. When deciding about the intensity of treatment, performance status, biological age and number as well as severity of comorbidities should be taken into account. Emerging treatment concepts for elderly/comorbid patients include combination of chlorambucil with monoclonal antibodies (rituximab, ofatumumab, GA-101), fludarabine-based regimens in reduced doses or protocols based on bendamustine and lenalidomide. Combination of high-dose steroids with rituximab represent a promising option in relapsed/refractory CLL; however, infectious toxicity remains a serious issue. Finally, ofatumumab monotherapy appears to be a safe and effective therapy for heavily pretreated patients with CLL. This article reviews the current and future possibilities in the treatment of elderly and comorbid patients with CLL.

  19. Familial chronic lymphocytic leukemia in Israel: A disproportionate distribution among Ashkenazi Jews.

    Science.gov (United States)

    Zada, Mor; Lerner, Daniele; Piltz, Yuval; Perry, Chava; Avivi, Irit; Herishanu, Yair

    2017-07-01

    Relatives of patients with chronic lymphocytic leukemia (CLL) are at increased risk of developing CLL. Familial CLL is defined as more than one case of CLL among blood relatives, a phenomenon reported in approximately 5%-10% of all CLL patients. Given the known predisposition of CLL among Ashkenazi Jews, we studied the features of familial CLL in an Israeli population. This is a retrospective study, in which we reviewed the demographics, clinical characteristics, and outcomes of a total of 332 patients with CLL/small lymphocytic lymphoma. Familial CLL was recorded in 41 cases (12.3%) of the patients. The age at diagnosis was younger in patients with familial CLL (by almost 3.5 years). Familial CLL was strongly associated with Ashkenazi Jewish origin. Patients with familial CLL more commonly presented with higher hemoglobin and lower serum β-2-microglobulin levels. No significant differences were detected between sporadic and familial CLL in disease stage, time to treatment, second cancers, or overall survival. Familial cases of CLL in an Israeli population show a disproportionate ethnic distribution toward Jews of Ashkenazi origin. The clinical characteristics and the overall outcome are not substantially different from sporadic cases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Towards Comprehension of the ABCB1/P-Glycoprotein Role in Chronic Myeloid Leukemia

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    Raquel C. Maia

    2018-01-01

    Full Text Available Abstract: The introduction of imatinib (IM, a BCR-ABL1 tyrosine kinase inhibitor (TKI, has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML. However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to this drug. Both resistance and intolerance have also been observed in treatment with the second-generation TKIs—dasatinib, nilotinib, and bosutinib—and the third-generation TKI—ponatinib. The mechanisms of resistance to TKIs may be BCR-ABL1-dependent and/or BCR-ABL1-independent. Although the role of efflux pump P-glycoprotein (Pgp, codified by the ABCB1 gene, is unquestionable in drug resistance of many neoplasms, a longstanding question exists about whether Pgp has a firm implication in TKI resistance in the clinical scenario. The goal of this review is to offer an overview of ABCB1/Pgp expression/activity/polymorphisms in CML. Understanding how interactions, associations, or cooperation between Pgp and other molecules—such as inhibitor apoptosis proteins, microRNAs, or microvesicles—impact IM resistance risk may be critical in evaluating the response to TKIs in CML patients. In addition, new non-TKI compounds may be necessary in order to overcome the resistance mediated by Pgp in CML.