Comprehensive evaluation of time-to-response parameter as a predictor of treatment failure following imatinib therapy in chronic phase chronic myeloid leukemia: Which parameter at which time-point does matter?

Posted by rob on October 1, 2010 under Uncategorized | Comments are off for this article

Comprehensive evaluation of time-to-response parameter as a predictor of treatment failure following imatinib therapy in chronic phase chronic myeloid leukemia: Which parameter at which time-point does matter?

Am J Hematol. 2010 Aug 23;

Authors: Kim DH, Sriharsha L, Jung CW, Kamel-Reid S, Radich JP, Lipton JH

Early recognition of high-risk patient is important to improve long-term outcomes following imatinib therapy for chronic myeloid leukemia (CML). Some controversy surrounds the question, which of short-term response parameters at which time-point, including complete cytogenetic response (CCyR) or major molecular response (MMR) at 6 or 12 months, is the best predictor for treatment outcomes. In this comprehensive analysis, we adopted landmark analysis method, time-dependent Cox’s proportional hazard model, and receiver-operating characteristics (ROC) method to analyze time-to-response parameter as predictor of long-term outcomes in 187 chronic phase (CP) CML patients. Regardless of the methods of analysis, earlier achievement of short-term response such as CCyR or MMR could predict the higher probability of achieving better interim outcome (such as treatment failure or loss of response [LOR]). Similar to the findings from other studies, our ROC analysis provided cutoff time points for MMR (18-36 months) and CCyR (6-12 months) that were the best predictors for LOR or treatment failure, which can be an indirect evidence supporting the ELN recommendation. The patient who achieves short-term response rapidly will have a lower risk of losing response or failing after imatinib therapy in CML patients. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc.

PMID: 20882527 [PubMed - as supplied by publisher]

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Dorsolateral Midbrain MRI Abnormalities and Ocular Motor Deficits Following Cytarabine-Based Chemotherapy for Acute Myelogenous Leukemia.

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Dorsolateral Midbrain MRI Abnormalities and Ocular Motor Deficits Following Cytarabine-Based Chemotherapy for Acute Myelogenous Leukemia.

J Neuroophthalmol. 2010 Sep 25;

Authors: Doan T, Lacayo N, Fisher PG, Liao YJ

PMID: 20881617 [PubMed - as supplied by publisher]

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Overdose with 16,000 mg of imatinib mesylate.

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Overdose with 16,000 mg of imatinib mesylate.

Leuk Res. 2010 Oct;34(10):e286-7

Authors: Dehours E, Riu B, Valle B, Chatelut E, Recher C, Fourcade O, Huguet F

PMID: 20627383 [PubMed - indexed for MEDLINE]

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ABVD associated with imatinib for coexisting chronic myeloid leukaemia and relapsed Hodgkin lymphoma.

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ABVD associated with imatinib for coexisting chronic myeloid leukaemia and relapsed Hodgkin lymphoma.

Leuk Res. 2010 Oct;34(10):e280-1

Authors: Ferrario A, Radaelli F, Goldaniga M, F FG, Olivero B, Rossi F, Baldini L

PMID: 20605208 [PubMed - indexed for MEDLINE]

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BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review.

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BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review.

Leuk Res. 2010 Oct;34(10):1255-68

Authors: An X, Tiwari AK, Sun Y, Ding PR, Ashby CR, Chen ZS

Chronic Myeloid Leukemia (CML) is a clonal disease characterized by the presence of the Philadelphia (Ph+) chromosome and its oncogenic product, BCR-ABL, a constitutively active tyrosine kinase, that is present in >90% of the patients. Epidemiologic data indicates that almost 5000 new cases are reported every year and 10% of these patients eventually succumb to the disease. The treatment of CML was revolutionized by the introduction of imatinib mesylate (IM, Gleevec), a BCR-ABL tyrosine kinase inhibitor (TKI). The clinical use of specific BCR-ABL inhibitors has resulted in a significantly improved prognosis, response rate, overall survival, and patient outcome in CML patients compared to previous therapeutic regimens. However, the complete eradication of CML in patients receiving imatinib was limited by the emergence of resistance mostly due to mutations in the ABL kinase domain and to a lesser extent by molecular residual disease after treatment. The second-generation BCR-ABL TKIs nilotinib (Tasigna) and dasatinib (Sprycel), showed significant activity in clinical trials in patients intolerant or resistant to imatinib therapy, except in those patients with the T315I BCR-ABL mutation. Identifying key components involved in the CML pathogenesis may lead to the exploration of new approaches that might eventually overcome resistance mediated to the BCR-ABL TKIs. Here, we present an overview about the current treatment of Ph+ CML patients with the TKIs and the obstacles to successful treatment with these drugs.

PMID: 20537386 [PubMed - indexed for MEDLINE]

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In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib.

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In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib.

Blood. 2010 Aug 26;116(8):1329-35

Authors: Sobrinho-Simões M, Wilczek V, Score J, Cross NC, Apperley JF, Melo JV

It is not clear if absence of BCR-ABL transcripts–complete molecular response (CMR)–is synonymous with, or required for, cure of chronic myeloid leukemia (CML). Some patients achieve CMR with imatinib (IM), but most relapse shortly after treatment discontinuation. Furthermore, most patients in long-term remission (LTR) post-stem cell transplantation (SCT) are considered functionally cured, although some remain occasionally positive for low-level BCR-ABL mRNA. Interpretation of the latter is complicated because it has been observed in healthy subjects. We designed a patient-specific, highly sensitive, DNA quantitative polymerase chain reaction to test follow-up samples for the original leukemic clone, identified by its unique genomic BCR-ABL fusion (gBCR-ABL). In 5 IM-treated patients in CMR, gBCR-ABL was detected in transcript-negative samples; 4 patients became gBCR-ABL-negative with continuing IM therapy. In contrast, of 9 patients in LTR (13-27 years) post-SCT, gBCR-ABL was detected in only 1, despite occasional transcript-positive samples in 8 of them. In conclusion, in IM-treated patients, absence of transcripts should not be interpreted as absence of the leukemic clone, although continuing IM after achievement of CMR may lead to further reduction of residual disease. Post-SCT, we found little evidence that the transcripts occasionally detected originate from the leukemic clone.

PMID: 20462961 [PubMed - indexed for MEDLINE]

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Abnormal phenotype of bone marrow plasma cells in patients with chronic myeloid leukemia undergoing therapy with Imatinib.

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Abnormal phenotype of bone marrow plasma cells in patients with chronic myeloid leukemia undergoing therapy with Imatinib.

Leuk Res. 2010 Oct;34(10):1336-9

Authors: Carulli G, Cannizzo E, Ottaviano V, Cervetti G, Buda G, Galimberti S, Baratè C, Marini A, Petrini M

Imatinib induces several effects on the immune system, including hypogammaglobulinemia and has been associated with multiple myeloma in some patients. We studied the phenotype of plasma cells from patients with chronic myeloid leukemia (CML) undergoing therapy with Imatinib mesylate (Glivec). Bone marrow samples from 30 CML patients were evaluated and plasma cells were identified by multiparametric flow cytometry. In 21 patients an abnormal plasma cell phenotype, characterized by the absence of CD19, was registered, with 12 patients expressing also the CD56 molecule. A significant correlation between abnormal plasma cell phenotype and reduced gamma-globulin levels was found. Immunofixation was always negative. Therapy with Imatinib for CML seems to induce a plasma cell phenotype with the same characteristics as monoclonal gammapathies. These findings deserve further studies and suggest to monitor plasma protein electrophoresis and gamma-globulin levels in all patients treated with Imatinib.

PMID: 20149455 [PubMed - indexed for MEDLINE]

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Down-regulation of mitochondrial ATPase by hypermethylation mechanism in chronic myeloid leukemia is associated with multidrug resistance.

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Down-regulation of mitochondrial ATPase by hypermethylation mechanism in chronic myeloid leukemia is associated with multidrug resistance.

Ann Oncol. 2010 Jul;21(7):1506-14

Authors: Li RJ, Zhang GS, Chen YH, Zhu JF, Lu QJ, Gong FJ, Kuang WY

BACKGROUND: To identify novel proteins involved in multidrug resistance in chronic myeloid leukemia (CML). MATERIALS AND METHODS: Comparative proteomics was used to screen multidrug resistance-related proteins from K562 and K562/A02; the differently expressed proteins were further confirmed by western blot and real-time PCR. short hairpin RNA (shRNA) assay was applied to determine the relationship between candidate protein and adriamycin resistance. Bisulfite sequencing was carried out to assess methylation status of candidate multidrug resistance-related gene promoter. K562/A02 was treated with 5-azacytidine or trichostatin A (TSA); multidrug resistance phenotype and corresponding protein or gene changes were detected. RESULTS: Seventeen proteins with altered abundances of more than twofold were detected, among which mitochondrial ATPase in K562/A02 was significantly down-regulated. Suppressing mitochondrial ATPase by shRNA could enhance adriamycin resistance and antiapoptosis activity of K562. The promoter hypermethylation in mitochondrial ATPase was found to be attributed to the adriamycin-resistant phenotype of both K562/A02 (methylated frequency 18.18%) and CML primary cells in accelerated phase (methylated frequency 7.95%) or blast crisis (methylated frequency 26.59%). Inhibition of hypermethylation increased adriamycin sensitivity of K562/A02. A synergistic effect on reversing adriamycin-resistant phenotype was obtained when 5-azacytidine was combined with TSA. CONCLUSION: Down-regulation of mitochondrial ATPase can lead to adriamycin resistance in CML and the mechanism is associated with DNA methylation regulation.

PMID: 20038517 [PubMed - indexed for MEDLINE]

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