A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on June 13, 2010 under Uncategorized | 
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[Molecular targeting therapy for leukemia]
Gan To Kagaku Ryoho. 2010 May;37(5):806-10
Authors: Miyazaki Y
PMID: 20524248 [PubMed - indexed for MEDLINE]
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Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase.
Blood. 2010 May 20;115(20):4018-20
Authors: Pavlů J, Kew AK, Taylor-Roberts B, Auner HW, Marin D, Olavarria E, Kanfer EJ, MacDonald DH, Milojkovic D, Rahemtulla A, Rezvani K, Goldman JM, Apperley JF, Szydlo RM
Outstanding results have been obtained in the treatment of chronic myeloid leukemia (CML) with first-line imatinib therapy. However, approximately 35% of patients will not obtain long-term benefit with this approach. Allogeneic hematopoietic stem cell transplantation (HCT) is a valuable second- and third-line therapy for appropriately selected patients. To identify useful prognostic indicators of transplantation outcome in postimatinib therapeutic interventions, we investigated the role of the HCT comorbidity index (HCT-CI) together with levels of C-reactive protein (CRP) before HCT in 271 patients who underwent myeloablative HCT for CML in first chronic phase. Multivariate analysis showed both an HCT-CI score higher than 0 and CRP levels higher than 9 mg/L independently predict inferior survival and increased nonrelapse mortality at 100 days after HCT. CML patients without comorbidities (HCT-CI score 0) with normal CRP levels (0-9 mg/L) may therefore be candidates for early allogeneic HCT after failing imatinib.
PMID: 20304808 [PubMed - indexed for MEDLINE]
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Generation of iPSCs from cultured human malignant cells.
Blood. 2010 May 20;115(20):4039-42
Authors: Carette JE, Pruszak J, Varadarajan M, Blomen VA, Gokhale S, Camargo FD, Wernig M, Jaenisch R, Brummelkamp TR
Induced pluripotent stem cells (iPSCs) can be generated from various differentiated cell types by the expression of a set of defined transcription factors. So far, iPSCs have been generated from primary cells, but it is unclear whether human cancer cell lines can be reprogrammed. Here we describe the generation and characterization of iPSCs derived from human chronic myeloid leukemia cells. We show that, despite the presence of oncogenic mutations, these cells acquired pluripotency by the expression of 4 transcription factors and underwent differentiation into cell types derived of all 3 germ layers during teratoma formation. Interestingly, although the parental cell line was strictly dependent on continuous signaling of the BCR-ABL oncogene, also termed oncogene addiction, reprogrammed cells lost this dependency and became resistant to the BCR-ABL inhibitor imatinib. This finding indicates that the therapeutic agent imatinib targets cells in a specific epigenetic differentiated cell state, and this may contribute to its inability to fully eradicate disease in chronic myeloid leukemia patients.
PMID: 20233975 [PubMed - indexed for MEDLINE]
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Why doesn’t imatinib cure chronic myeloid leukemia?
Oncologist. 2010;15(2):182-6
Authors: Redner RL
Imatinib mesylate has transformed the treatment for chronic myeloid leukemia (CML). The vast majority of patients obtain hematologic remission, with a low probability of progression of disease. Yet imatinib rarely cures CML, and current recommendations dictate lifelong treatment with imatinib. In this review we analyze the biology behind the failure of imatinib to fully eradicate CML. We review evidence that indicates that the leukemic stem cell for CML is inherently resistant to imatinib, and that imatinib treatment itself may enhance this resistance.
PMID: 20124443 [PubMed - indexed for MEDLINE]
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Abstract: To characterize the molecular mechanisms involved in the transition from the chronic phase to blast crisis in chronic myelogenous leukemia (CML), gene expression profiles of leukemic cells from patients in the chronic and blast crisis phases were analyzed using an 8.7K cDNA chip and real-time PCR. A transient transfection analysis was conducted to evaluate the role of FLT3, which was significantly upregulated in the blast crisis patients. Abl and c-Kit induction was detected in K562 cells transfected with FLT3 cDNA (K562/FLT3), and Abl and c-Kit levels were reduced in K562/FLT3 cells transfected with FLT3-siRNA (K562/FLT3-siRNA). The induction of FLT3 in CML cells attenuated imatinib-induced apoptosis. The opposite effect was observed in K562/FLT3-siRNA cells. An increased level …
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Despite the development of intensive combination chemotherapy, many leukemia patients still succumb to drug-resistant leukemia. In contrast to the success of ‘targeted’ tyrosine kinase inhibitor (TKI) therapy in BCR-ABL-driven chronic myelogenous leukemia (CML) [particularly in chronic phase (CP)], BCR-ABL-driven acute lymphoblastic leukemias (including ‘de novo’ Ph+ ALLs, and CML patients in lymphoid blast-crisis [LBC]) invariably relapse while on single-agent tyrosine kinase inhibitor therapy . In these TKI-resistant leukemias, a number of well-characterized drug-resistant BCR-ABL Kinase Domain (KD) mutations frequently emerge in the dominant drug-resistant leukemic clone(s) . While tyrosine kinase inhibitors can be safely added to intensive combination chemotherapy regimens and …
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We present the results of numerous simulated treatment programs in which imatinib treatment is temporarily stopped to stimulate and leverage the anti-leukemia immune response to combat CML. The simulations presented in this paper imply that treatment programs that involve strategic treatment interruptions may prevent leukemia from relapsing and may prevent remission for significantly longer than continuous imatinib treatment. Moreover, in many cases, strategic treatment interruptions may completely eliminate leukemic cells from the body. Thus, strategic treatment interruptions may be a feasible clinical approach to enhancing the effects of imatinib treatment for CML. We study the effects of both the timing and the duration of the treatment interruption on the results of the treatment. We a…
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Authors: Etienne G, Milpied B, Réa D, Rigal-Huguet F, Tulliez M, Nicolini FE
Nilotinib (Tasigna(R)) is a second-generation BCR-ABL kinase inhibitor, recently introduced and used for the treatment of chronic or accelerated phase CML patients, intolerant or resistant to imatinib. This treatment represents and important step forward for the disease control of such patients but can lead to side effects, sometimes serious, which can limit its optimal use. We propose here some guidelines that might be of help in daily practice, in order to manage properly these side effects.
PMID: 20529767 [PubMed - as supplied by publisher] (Source: Bulletin du Cancer)
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