Significance of ABL Kinase Domain Mutation in Chronic Myeloid Leukemia under Imatinib Therapy

Background: Despite durable responses to imatinib in chronic myeloid leukaemia (CML), mutations in Bcr-Abl kinase domain (KD) are known to induce imatinib resistance and cause poor clinical outcome. Methods: We characterized Bcr-Abl KD mutations in 20 Egyptian CML patients with imatinib resistance (n = 12) or responsive (n = 8) using allele specific oligonucleotide polymerase chain reaction (PCR) and direct sequencing. The frequency of mutations in patients with increasing BCR-ABL transcript levels, and those with stable or decreasing levels was determined using allele specific oligonucleotide polymerase chain reaction (ASO-PCR). Results: Six out of the twelve patients with primary or secondary resistance had detectable mutations, whereas none of the eight responders who achieved suboptimal, complete or major response had any detectable mutation. The presence of a mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase / blast crisis and shorter survival. Patients harboring P-loop mutations showed poor overall survival compared with patients harboring non-P-loop mutations (93% vs 67% P=0.001). Conclusion: These data suggest that a rise in BCRABL transcript levels of > 2-fold can be used as a primary indicator to test patients for BCR-ABL kinase domain mutations and that ASO-PCR is a valuable tool allowing a timely detection of mutations. Moreover, early detection of BCR-ABL mutations may play a role in identifying patients who are likely to become resistant to imatinib therapy, for which alternative therapeutic options should be considered. [Amr A.Ghannam, Abdou S. M. and Mona Hatata. Clinical Significance of ABL Kinase Domain Mutation in Chronic Myeloid Leukemia under Imatinib Therapy Cancer Biology 2014;4(1):10-17]. (ISSN: 2150-1041): (ISSN: 2150-105X (online). http://www.cancerbio.net. 2