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Original Article


Benefits of the early detection of M351T mutation, by allele-specific oligonucleotide polymerase chain reaction, in imatinib-resistant chronic myelogenous leukemia (CML) - A retrospective analysis

Mukul A. Gharote1Harsha P. Panchal2Rakesh Rawal3Krupa Shah2Asha Anand2Apurva P. Patel2Sonia K. Parikh2
1Department of Medical Oncology, Mukta Cancer Clinic, Nashik, Maharashtra, India, 2Department of Medical Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India, 3Department of Molecular Biology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
Corresponding Author:

Mukul A. Gharote

Department of Medical Oncology, Mukta Cancer Clinic, Nashik, Maharashtra, India
E-mail: Mukul.gharote@gmail.com

Corresponding Author:

Mukul A. Gharote

Department of Medical Oncology, Mukta Cancer Clinic, Nashik, Maharashtra, India
E-mail: Mukul.gharote@gmail.com

DOI:10.18203/issn.2456-3994.IntJMolImmunoOncol20183226

ABSTRACT


Introduction: BCR-ABL kinase domain mutations represent the most important disease-related factor in chronic myelogenous leukemia (CML) resistance. Highly resistant clones may pre-exist and emerge rapidly. Patients with CML can acquire more than one BCR-ABL1 mutation, which may result in increased oncogenicity. Materials and Methods: Retrospective analysis of 50 patients of imatinib resistance was done in GCRI, from January 2014 to May 2014. Response to imatinib was defined according to the European LeukemiaNet 2009 criteria. Allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) was performed on genomic DNA, extracted from peripheral blood mononuclear cells. Results: Average age was 40.75 years, 33 were males and 17 females. 47 (94%) were in chronic phase, 2 (4%) in accelerated phase, and 1 (2%) in blastic crisis. 29/50 were having low EUTOS score, whereas SOKAL score was low in 20, intermediate in 21 while only 9 had high SOKAL at presentation. Median duration of imatinib was 48 months. 43/50 had one or more than 1 mutation, T315I mutation in 5 (10%) patients, and M351T in 32% (16/50). Conclusion: The presence of M351T mutation in mutant clone leads to the development of T315I mutations development, and the detection of M351T mutation in the initial months of the therapy has a prognostic significance. ASO-PCR is more sensitive method of the detection of such mutations as compared to direct sequencing. We report low cytogenetic response (25%) and durability of response to 600 mg of imatinib, even in M351T mutation, after 400 mg of imatinib for median period of 4 years.
Keywords: BCR-ABL kinase domain mutation, Imatinib resistance, M351T mutation

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