A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on December 23, 2010 under Uncategorized | 
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Imatinib trough levels in chronic myelogenous leukemia: does one dose fit all?
Leuk Lymphoma. 2010 Dec 20;
Authors: Yeung DT, White DL
PMID: 21171867 [PubMed - as supplied by publisher]
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Relationship of serum imatinib trough level and response in CML patients: long term follow-up.
Leuk Res. 2010 Dec;34(12):1573-5
Authors: Awidi A, Ayed AO, Bsoul N, Magablah A, Mefleh R, Dweiri M, Ramahi M, Arafat E, Bishtawi M, Marie L
One hundred and three patients with Philadelphia chromosome or BCR-ABL positive chronic myeloid leukemia (CML) in chronic phase who were on oral imatinib were included in this study. The study aimed to assess the relationship between imatinib trough serum levels and clinical outcome (as determined by molecular response) in Jordanian CML patients who have been on imatinib therapy for at least 12 months. The mean trough imatinib serum level in the group with complete molecular response (CMR) was 2891±856 ng/ml, the group with major molecular response (MMR) was 2337±434 ng/ml, the group with complete cytogenetic response (CCyR) was 1817±563 ng/ml, and the group without CCyR was 1723±673 ng/ml. A receiver operating characteristic (ROC) curve was constructed after dividing patient sample into two groups, those with MMR or better and those without MMR, in order to estimate a threshold for imatinib level that correlates with a favorable response (the former group), and analysis yielded a value of 2158 ng/ml.
PMID: 20688395 [PubMed - indexed for MEDLINE]
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Successful management of pregnancy occurring in a patient with chronic myeloid leukemia on dasatinib.
Leuk Lymphoma. 2010 Sep;51(9):1751-3
Authors: Kroll T, Ames MB, Pruett JA, Fenske TS
PMID: 20629520 [PubMed - indexed for MEDLINE]
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Transcriptional down-regulation of the Wnt antagonist SFRP1 in haematopoietic cells of patients with different risk types of MDS.
Leuk Res. 2010 Dec;34(12):1610-6
Authors: Reins J, Mossner M, Neumann M, Platzbecker U, Schumann C, Thiel E, Hofmann WK
Secreted frizzled related protein 1 (SFRP1) is an extracellular antagonist of the Wnt signalling pathway that plays an important role in the pathogenesis of solid tumours and haematopoietic malignancies. SFRP1 has been observed to be transcriptionally down-regulated due to hypermethylation in acute and chronic leukaemia, but so far not in myelodysplastic syndrome (MDS). Moreover, it has been shown that the epigenetic inactivation of SFRP1 correlates with an overexpression of the Wnt receptor Frizzled 3 (Fzd3) in acute leukaemia. Using real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) we examined mRNA expression of SFRP1 and Fzd3 in bone marrow cells derived from 121 patients with different risk types of MDS, acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). We employed pyrosequencing to quantify promoter DNA methylation in MDS and acute leukaemia. We detected significant lower mRNA transcription of SFRP1 in MDS compared to healthy individuals. However, DNA sequence mutations or frequent elevated DNA methylation levels of the SFRP1 promoter could not be observed in MDS but in AML and ALL as previously reported. The expression levels of Fzd3 were up-regulated in both acute leukaemia and MDS. Our data show a significant transcriptional down-regulation of SFRP1 as a common event in AML, ALL and – as demonstrated for the first time – in MDS. An inactivation of SFRP1 and the transcriptional up-regulation of Fzd3 seem to be associated with an activation of the Wnt signalling pathway in these haematopoietic diseases.
PMID: 20471677 [PubMed - indexed for MEDLINE]
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Expression, epigenetic regulation, and humoral immunogenicity of cancer-testis antigens in chronic myeloid leukemia.
Leuk Res. 2010 Dec;34(12):1647-55
Authors: Luetkens T, Schafhausen P, Uhlich F, Stasche T, Akbulak R, Bartels BM, Hildebrandt Y, Gontarewicz A, Kobold S, Meyer S, Gordic M, Bartels K, Lajmi N, Cao Y, Kröger N, Bokemeyer C, Brümmendorf TH, Atanackovic D
Cancer-testis (CT) antigens represent attractive targets for tumor immunotherapy based on their tumor-restricted expression and immunogenicity. However, a broad picture of the expression of CT antigens and associated humoral immune responses in chronic myeloid leukemia (CML) is still missing.
PMID: 20409582 [PubMed - indexed for MEDLINE]
Posted by rob on December 21, 2010 under Uncategorized | Comments are off for this article
Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells.
Cancer Sci. 2010 Nov 27;
Authors: Takeuchi M, Ashihara E, Yamazaki Y, Kimura S, Nakagawa Y, Tanaka R, Yao H, Nagao R, Hayashi Y, Hirai H, Maekawa T
Treatment with Abl tyrosine kinase inhibitors (TKI) drastically improves the prognosis of chronic myelogenous leukemia (CML) patients. However, quiescent CML cells are insensitive to TKI and can lead to relapse of the disease. Thus, research is needed to elucidate the properties of these quiescent CML cells, including their microenvironment, in order to effectively target them. Hypoxia is known to be a common feature of solid tumors that contributes to therapeutic resistance. Leukemic cells are also able to survive and proliferate in severely hypoxic environments. The hypoxic conditions in the bone marrow (BM) allow leukemic cells that reside there to become insensitive to cell death stimuli. To target leukemic cells in hypoxic conditions, we focused on the hypoxia-selective cytotoxin, Rakicidin A. A previous report showed that Rakicidin A, a natural product produced by the Micromonospora strain, induced hypoxia-selective cytotoxicity in solid tumors. Here, we describe Rakicidin A-induced cell death in hypoxia-adapted (HA)-CML cells with stem cell-like characteristics. Interestingly, apoptosis was induced via caspase-dependent and -independent pathways. In addition, treatment with Rakicidin A in combination with the TKI, imatinib, resulted in synergistic cytotoxicity against HA-CML cells. In conclusion, Rakicidin A is a promising compound for targeting TKI-resistant quiescent CML stem cells in the hypoxic BM environment. (Cancer Sci, doi: 10.1111/j.1349-7006.2010.01813.x, 2010).
PMID: 21166958 [PubMed - as supplied by publisher]
Posted by rob on December 20, 2010 under Uncategorized | Comments are off for this article
The Hedgehog (Hh) signaling pathway is critical for cell growth and differentiation during embryogenesis and early development. While it is mostly quiescent in adults, inappropriate reactivation of the Hh pathway has been shown to be involved in the development of cancer. A number of tumor types rely on overexpression of Hh ligands to activate the pathway in a paracrine manner from the tumor to the surrounding stroma. Alternatively, Hh ligands may act on cancer stem cells in some hematopoietic cancers, such as chronic myelogenous leukemia. However, the role of the Hh pathway is best established in tumors, such as basal cell carcinoma and medulloblastoma, where the pathway is activated via mutations. Understanding the contribution of Hh signaling in these various tumor types will be critica…
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Posted by rob on December 18, 2010 under Uncategorized | Comments are off for this article
A small molecule significantly inhibits the bcr/abl fusion gene at the mRNA level in human chronic myelogenous leukemia.
Leuk Res. 2010 Dec 14;
Authors: He Q, Dong J, Zhen H, Ying Y, Zhang J, Li Q, Li B, Zhou Y
Bcr/abl fusion gene is the marker gene in chronic myelogenous leukemia (CML) and becomes the target for CML therapy. Although Imatinib opened a new way to treat CML, the resistance to the drug caused by bcr/abl fusion protein mutation stimulated search for new molecules to inhibit bcr/abl expression. In our research, it was found that a novel 2-aminosteroid (H89465) possessed special mechanism in treating CML. H89465 inhibits the proliferation of both non-resistant and resistant CML cells such as K562, Meg-01 and clinical primary CML cells. It prolongs the survival time of NOD/SCID mice inoculated with K562 leukemia cells. The mechanism underlying the effects is concerned with down-regulation of bcr/abl mRNA expression followed by decreasing the BCR/ABL protein expression and tyrosine kinase activity in CML cells. Our results demonstrate that H89465 possesses the therapeutic potential in treating human CML.
PMID: 21163528 [PubMed - as supplied by publisher]
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[The 2nd generation of TKIs for chronic myeloid leukemia].
Rinsho Ketsueki. 2010 Oct;51(10):1386-94
Authors: Matsumura I
PMID: 20962471 [PubMed - indexed for MEDLINE]
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[Management of chronic myeloid leukemia by imatinib].
Rinsho Ketsueki. 2010 Oct;51(10):1377-85
Authors: Kizaki M
PMID: 20962470 [PubMed - indexed for MEDLINE]
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[CML stem cell biology].
Rinsho Ketsueki. 2010 Oct;51(10):1367-76
Authors: Tauchi T
PMID: 20962469 [PubMed - indexed for MEDLINE]
Posted by rob on December 17, 2010 under Uncategorized | Comments are off for this article
Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS).
Blood. 2010 Nov 11;116(19):3758-65
Authors: Hughes TP, Hochhaus A, Branford S, Müller MC, Kaeda JS, Foroni L, Druker BJ, Guilhot F, Larson RA, O’Brien SG, Rudoltz MS, Mone M, Wehrle E, Modur V, Goldman JM, Radich JP,
This study examines the prognostic significance of early molecular response using an expanded dataset in chronic myeloid leukemia patients enrolled in the International Randomized Study of Interferon and STI571 (IRIS). Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time. Analyses of event-free survival (EFS) and time to progression to accelerated phase/blast crisis (AP/BC) at 7 years were based on molecular responses using the international scale (IS) at 6-, 12-, and 18-month landmarks. Patients with BCR-ABL transcripts > 10% at 6 months and > 1% at 12 months had inferior EFS and higher rate of progression to AP/BC compared with all other molecular response groups. Conversely, patients who achieved major molecular response [MMR: BCR-ABL (IS) ? 0.1%] by 18 months enjoyed remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 years. The probability of loss of complete cytogenetic response by 7 years was only 3% for patients in MMR at 18 months versus 26% for patients with complete cytogenetic response but not MMR (P < .001). This study shows a strong association between the degree to which BCR-ABL transcript numbers are reduced by therapy and long-term clinical outcome, supporting the use of time-dependent molecular measures to determine optimal response to therapy. This study is registered at www.clinicaltrials.gov as NCT00006343.
PMID: 20679528 [PubMed - indexed for MEDLINE]
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Resolution of platelet function defects with imatinib therapy in a patient with chronic myeloid leukaemia in chronic phase.
Blood Coagul Fibrinolysis. 2009 Jan;20(1):81-3
Authors: Ng AP, Servadei P, Tuckfield A, Friedhuber A, Grigg A
Platelet function defects are frequently found in patients with chronic myeloid leukaemia. Major clinical bleeding, however, is a rare and infrequently reported complication. Platelet function abnormalities have also not been previously correlated with molecular monitoring of BCR-ABL in chronic myeloid leukaemia. We report a case of a patient with major clinical bleeding as a presenting feature of chronic myeloid leukaemia. The patient developed compartment syndrome of the thigh secondary to a haematoma developing after minor trauma. Fasciotomy was complicated by severe bleeding requiring massive transfusion. Haemostasis was only obtained after activated recombinant factor VII was administered. Laboratory investigations revealed a platelet function defect with reduced platelet aggregation to collagen, epinephrine and arachidonic acid. As imatinib therapy commenced, molecular response was associated with near-normalization of platelet function, which subsequently became significantly abnormal with molecular relapse. Electron microscopy demonstrated normal platelet ultrastructure. We conclude that dysregulated Abelson kinase plays a pathogenic role in platelet function defects associated with chronic myeloid leukaemia, and discuss the management of clinically significant bleeding in patients with platelet function defects associated with myeloproliferative disorders.
PMID: 20523168 [PubMed - indexed for MEDLINE]
Posted by rob on December 16, 2010 under Uncategorized | Comments are off for this article
[A Case of t(3;3)(q21;q26.2) Associated with Severe Multilineage Dysplasia and Multi-drug Resistance in Blastic Crisis of Chronic Myelogenous Leukemia.]
Korean J Lab Med. 2010 Dec;30(6):595-599
Authors: Lee SA, Lim J, Kim M, Kim Y, Han K
The t(3;3)(q21;q26.2) is known to be mainly observed in hematologic myeloid malignancies, as a form of 3q21q26 syndrome. Cytogenetic abnormalities of 3q21q26 syndrome result in RPN1-EVI1 fusion transcripts involving ecotropic viral integration site-1 (EVI1) at 3q26.2 and ribophorin I (RPN1) at 3q21, and the fusion transcripts play an important role in leukemogenesis and disease progression. They are usually associated with dysplasia, especially of megakaryocytes. Patients with these cytogenetic abnormalities show extremely poor prognosis even with aggressive anti-leukemic therapy. We report a case of blastic crisis of CML with both t(3;3)(q21;q26.2) and t(9;22)(q34;q11.2) and associated severe multilineage dysplasia. The patient showed a poor response to imatinib, dasatinib and aggressive induction therapy. When both t(3;3)(q21;q26.2) and t(9;22)(q34;q11.2) are observed in cases of leukemia with increased blasts, they are best considered as aggressive phases of CML with t(3;3)(q21;q26.2), rather than AML with t(9;22)(q34;q11.2) by 2008 WHO classification.
PMID: 21157145 [PubMed - as supplied by publisher]
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Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2R?c-deficient mice.
J Clin Invest. 2010 Dec 13;
Authors: Sarry JE, Murphy K, Perry R, Sanchez PV, Secreto A, Keefer C, Swider CR, Strzelecki AC, Cavelier C, Récher C, Mansat-De Mas V, Delabesse E, Danet-Desnoyers G, Carroll M
Human leukemic stem cells, like other cancer stem cells, are hypothesized to be rare, capable of incomplete differentiation, and restricted to a phenotype associated with early hematopoietic progenitors or stem cells. However, recent work in other types of tumors has challenged the cancer stem cell model. Using a robust model of xenotransplantation based on NOD/SCID/IL2R?c-deficient mice, we confirmed that human leukemic stem cells, functionally defined by us as SCID leukemia-initiating cells (SL-ICs), are rare in acute myelogenous leukemia (AML). In contrast to previous results, SL-ICs were found among cells expressing lineage markers (i.e., among Lin+ cells), CD38, or CD45RA, all markers associated with normal committed progenitors. Remarkably, each engrafting fraction consistently recapitulated the original phenotypic diversity of the primary AML specimen and contained self-renewing leukemic stem cells, as demonstrated by secondary transplants. While SL-ICs were enriched in the Lin-CD38- fraction compared with the other fractions analyzed, SL-ICs in this fraction represented only one-third of all SL-ICs present in the unfractionated specimen. These results indicate that human AML stem cells are rare and enriched but not restricted to the phenotype associated with normal primitive hematopoietic cells. These results suggest a plasticity of the cancer stem cell phenotype that we believe has not been previously described.
PMID: 21157036 [PubMed - as supplied by publisher]
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Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations.
Blood. 2010 Dec 14;
Authors: Jabbour E, Cortes J, Santos FP, Jones D, O’Brien S, Rondon G, Popat U, Giralt S, Kebriaei P, Kantarjian H, Champlin R, De Lima M
Hematopoietic stem cell transplantation (HSCT) is effective therapy for patients with chronic myelogenous leukemia (CML), but is now mostly indicated for patients who develop resistance to tyrosine kinase inhibitors (TKI), which can be associated with point mutations in BCR-ABL1. We reviewed the outcomes of Imatinib-resistant CML patients (chronic phase [CP]=34, accelerated phase [AP]=9, blast phase [BP]=4) who underwent HSCT and had BCR-ABL1 sequencing. Mutations were found in 19 patients (40%) (15/19 had advanced CML (AP+BP+2nd CP)). Patients with mutations were more likely to transform to AP/BP at time of imatinib failure (69% vs 35%, p=0.03). Forty-two patients (89%) responded to HSCT: 32 (68%) had at least a major molecular response. The 2-year event-free survival was 36% and 58% (P=0.05) for the mutant and non-mutant groups, respectively and the 2-year overall survival was 44% and 76% (P=0.02), respectively. HSCT is an important salvage option for TKI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT. HSCT should be considered early for patients deemed to have a low probability of responding to 2nd-generation TKI.
PMID: 21156844 [PubMed - as supplied by publisher]
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Proceedings of the third global workshop on chronic myeloid leukemia.
Clin Lymphoma Myeloma Leuk. 2010 Dec 1;10(6):443-51
Authors: Saglio G, Kantarjian H, Holyoake T, Ranganathan A, Cortés JE
Tyrosine kinase inhibitor (TKI) therapy has resulted in unprecedented responses and survival rates in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) that are durable for years. However, a third of patients either fail to respond or respond suboptimally to imatinib therapy, while some others are intolerant to imatinib. Increased understanding of the molecular basis of imatinib resistance has led to rational development of second-generation TKIs as effective second-line treatment options for imatinib-resistant patients. However, persistence of minimal residual disease (MRD) and development of resistance against TKI therapy are proving to be significant challenges. Treatment options are evolving for patients with CML and the promising results with several novel agents showing activity in CML, including in patients with the T315I mutation, are encouraging advancements in the field. Recently, a panel of global experts in CML deliberated on the imminent approval of second-generation TKIs in the frontline setting, ways to improve on frontline therapy, integration of new agents in current treatment algorithms, and design of future clinical trials; the proceedings of the discussion are summarized in this article.
PMID: 21156461 [PubMed - in process]
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Response to Zaccaria regarding the article “Chromosome abnormalities additional to the Philadelphia chromosome at the diagnosis of chronic myelogenous leukemia: pathogenetic and prognostic implications”.
Cancer Genet Cytogenet. 2010 Dec;203(2):358
Authors: Najfeld V
PMID: 21156262 [PubMed - in process]
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Response to the letter by Najfeld regarding the article “Chromosome abnormalities additional to the Philadelphia chromosome at the diagnosis of chronic myelogenous leukemia: pathogenetic and prognostic implications”.
Cancer Genet Cytogenet. 2010 Dec;203(2):357
Authors: Zaccaria A
PMID: 21156261 [PubMed - in process]
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Letter to the Editor regarding the article “Chromosome abnormalities additional to the Philadelphia chromosome at the diagnosis of chronic myelogenous leukemia: pathogenic and prognostic implications”.
Cancer Genet Cytogenet. 2010 Dec;203(2):355-6
Authors: Najfeld V
PMID: 21156260 [PubMed - in process]
