Impact of Imatinib Treatment on Renal Function in Chronic Myeloid Leukemia Patients

Abstract Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder; the molecular hallmark of the disease is the BCR-ABL gene rearrangement, which usually occurs as the result of a reciprocal translocation between chromosomes 9 and 22. Tyrosine kinase inhibitors (TKI) were the first drugs that targeted the constitutively active BCR-ABL kinase and it have become the standard frontline therapy for CML. Monitoring the treatment of CML patients with detection of bcr-abl transcript levels with real time qualitative polymerase chain reaction (RQ-PCR) is essential in evaluating the therapeutic response. Material and method: At the Clinical Hematology and BMT Unit Tîrgu Mureș, between 2008-2011, we performed the molecular monitoring of bcr-abl transcript levels with RQ-PCR in 16 patients diagnosed with CML. Results: We have 11 patients on imatinib treatment who achieved major molecular response. One patient lost the complete molecular response after 5 years of treatment. Two patients in blast crisis underwent allogeneic hematopoietic stem cell transplantation from identical sibling donors. The first patient is in complete molecular remission after 4 years of the transplant with mild chronic GVHD. The other patient had an early relapse with treatment refractory disease and died from evolution of the disease. Three patients with advanced phases of the disease present increasing transcript levels. We performed the dose escalation, and for two of them the switch to the second generation of TKI. Conclusions: Regular molecular monitoring of individual patients with CML is clearly desirable. It allows for a reassessment of the therapeutic strategy in cases of rising levels of BCR-ABL as an early indication of loss of response.

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The PERK-eIF2α phosphorylation arm is a pro-survival pathway of BCR-ABL signaling and confers resistance to imatinib treatment in chronic myeloid leukemia cells

Cell Cycle ◽

10.4161/cc.22387 ◽

2012 ◽

Vol 11 (21) ◽

pp. 4069-4078 ◽

Cited By ~ 35

Author(s):

Monika Kusio-Kobialka ◽

Paulina Podszywalow-Bartnicka ◽

Philippos Peidis ◽

Eliza Glodkowska-Mrowka ◽

Kamila Wolanin ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Leukemia Cells ◽

Imatinib Treatment ◽

Eif2α Phosphorylation ◽

Survival Pathway

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Chronic Myeloid Leukemia

Hematology ◽

10.1182/asheducation-2003.1.132 ◽

2003 ◽

Vol 2003 (1) ◽

pp. 132-152 ◽

Cited By ~ 65

Author(s):

Junia V. Melo ◽

Timothy P. Hughes ◽

Jane F. Apperley

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Molecular Mechanisms ◽

Treatment Options ◽

Philadelphia Chromosome ◽

Current Treatment ◽

Patient Specific ◽

Imatinib Treatment ◽

Molecular Monitoring ◽

Cytogenetic Analyses

Abstract Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a specific genetic lesion, the Philadelphia chromosome, harboring the BCR-ABL oncogene. Since then, it has become a paradigm for the discovery of molecular mechanisms and targeted therapeutic approaches in the field of hematologic neoplasias. The past 5 years or so have been particularly fruitful in the dissection of the signal transduction pathways abnormally activated in CML and in the translation of this knowledge to clinical practice. In this report, we discuss the biological basis for such translation and highlight the current and potential tools for the effective treatment of CML patients. The first part presents a review of the basic concepts on the biology of CML and their application to the design of targeted therapy. The mechanisms of action of the molecular-specific drugs currently used in clinical trials are discussed, with emphasis on the description of the most promising new compounds that are enhancing the potential for effective alternative or combination chemotherapy in CML. In the following section, we explain how molecular monitoring of response to imatinib mesylate in patients with CML can be used as a guide to clinical management. In particular, we discuss the relative value of regular quantitative RT/PCR and cytogenetic analyses, how responding patients should be monitored and managed, and how to investigate patients who are refractory or become resistant to imatinib treatment. In the last part of this report, a discussion on the possibility of managing CML with patient-specific strategies is presented. We review the current treatment options, highlight the factors impacting on decision making, discuss the range of possibilities for future therapeutic strategies and propose a systematic approach for individualizing treatment for patients in different disease categories.

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Russo D, Martinelli G, Malagola M, et al. Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. Blood. 2013;121(26):5138-5144.

Blood ◽

10.1182/blood-2014-03-564971 ◽

2014 ◽

Vol 123 (18) ◽

pp. 2902-2902

Keyword(s):

Chronic Myeloid Leukemia ◽

Elderly Patients ◽

Myeloid Leukemia ◽

Imatinib Treatment

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Continuing Imatinib Treatment for Chronic Myeloid Leukemia Patients Who Had Serious Adverse Events at the Onset of Therapy

Acta Haematologica ◽

10.1159/000455035 ◽

2017 ◽

Vol 137 (3) ◽

pp. 158-162

Author(s):

Yufeng Li ◽

Chun-ling Wang ◽

Banhe Din ◽

Liang Yu ◽

Jiabin Zhu

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Imatinib Treatment ◽

Serious Adverse Events

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BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia

Haematologica ◽

10.3324/haematol.2018.189787 ◽

2018 ◽

Vol 103 (12) ◽

pp. 2026-2032 ◽

Cited By ~ 12

Author(s):

Ilaria S. Pagani ◽

Phuong Dang ◽

Ivar O. Kommers ◽

Jarrad M. Goyne ◽

Mario Nicola ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Genomic Dna ◽

Myeloid Leukemia ◽

Imatinib Treatment ◽

First Line ◽

Dna Pcr

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Denaturing-HPLC-Based Assay for Detection of ABL Mutations in Chronic Myeloid Leukemia Patients Resistant to Imatinib

Clinical Chemistry ◽

10.1373/clinchem.2004.031112 ◽

2004 ◽

Vol 50 (7) ◽

pp. 1205-1213 ◽

Cited By ~ 85

Author(s):

Simona Soverini ◽

Giovanni Martinelli ◽

Marilina Amabile ◽

Angela Poerio ◽

Michele Bianchini ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Large Scale ◽

Kinase Inhibitor ◽

Direct Sequencing ◽

Point Mutations ◽

Kinase Domain ◽

Imatinib Treatment ◽

Abl Tyrosine Kinase ◽

Reverse Transcription Pcr

Abstract Background: Despite the efficacy of the BCR-ABL tyrosine kinase inhibitor Imatinib mesylate for the treatment of chronic myeloid leukemia (CML), resistance has been observed in a proportion of cases, especially those with advanced stages of the disease. Point mutations within the ABL kinase domain are emerging as the most frequent mechanism for reactivation of kinase activity within the leukemic clone. Methods: We developed a denaturing-HPLC (D-HPLC)-based assay for screening for ABL point mutations. For each sample, two partially overlapping fragments of 393 and 482 bp corresponding to the kinase domain were amplified by nested reverse transcription-PCR and analyzed under selected temperature and acetonitrile gradient conditions. Fifty-one bone marrow and/or peripheral blood specimens from 27 CML patients who showed cytogenetic resistance to Imatinib were screened in parallel by D-HPLC and by direct sequencing. Results: In 12 of 27 (44%) patients, D-HPLC showed an abnormal elution profile suggesting the presence of a nucleotide change. Direct sequencing confirmed the presence of a point mutation in all cases. Conversely, all samples scored as wild type by D-HPLC showed no evidence of mutations by direct sequencing. In two cases, novel amino acid substitutions at codons already known for being hot-spots of mutation were identified (F311I and E355D). Conclusions: The proposed D-HPLC-based assay is highly specific and at least as sensitive as sequencing; with respect to the latter, it provides a much faster and less expensive semiautomated system for mutational screening. It may therefore potentially be a valuable tool for regular, large-scale testing of patients undergoing Imatinib treatment.

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Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment

Blood ◽

10.1182/blood-2007-07-103523 ◽

2008 ◽

Vol 111 (3) ◽

pp. 1039-1043 ◽

Cited By ~ 152

Author(s):

Andreas Hochhaus ◽

Brian Druker ◽

Charles Sawyers ◽

Francois Guilhot ◽

Charles A. Schiffer ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Imatinib Mesylate ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Interferon Α ◽

Imatinib Treatment ◽

Serious Adverse Events ◽

Response Level

Abstract Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-α (IFNα) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 months of starting imatinib; however, some patients achieved initial MCyR and CCyR more than 5 years after imatinib initiation. Estimated rates of freedom from progression to accelerated phase (AP) and blastic phase (BP) and overall survival at 6 years were 61% and 76%, respectively. Both freedom from progression to AP/BP and overall survival (OS) were associated with cytogenetic response level at 12 months. No increase in rates of serious adverse events was observed with continuous use of imatinib for up to 6.5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN.

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