High-sensitivity detection of M351T, F317L, and F311C BCR-ABL kinase domain mutation in chronic myeloid leukemia patients treated with novel tyrosine kinase inhibitors (TKIs) imatinib and dasatinib

Abstract

7061 Objectives: (1) To study the detection of M351T, F317L, and F311C ABL kinase domain mutation in CML patients treated with TKIs (imatinib and dasatinib). (2) To evaluate the effect of imatinib dose esculation in the CML patients carrying M351T mutations. Methods: One hundred CML patients were treated with imatinib at 400 mg/day from 2 to 4 years .They were diagnosed by RT-PCR for BCR-ABL transcripts. Early screening for the M351T, F317L, and F311C mutations was performed by allele specific-oligonucleotide-PCR (ASO-PCR). Results: We evaluated 100 CML patients for kinase domain mutation by ASO-PCR after three years of imatinib initiation. Patients were categorized into three groups. Group A All 100 CML patients were treated with imatinib at conventional dose of 400 mg/day and were screened for M351T mutation after three years of imatinib initiation. (40%) 40/100 were positive for M351T mutation consequently 20/40 were treated with high dose imatinib at 600 to 800 or 1,000 mg/day. After 11 months of dose escalation, 15/20 lost M351T mutation but remaining five who resist M351T mutation, developed a more fatal mutation called gate keeper mutation T315I. 2/5 died, three progressed to advanced disease. Group B All 100 CML patients were screened for F311C mutation after three years of imatinib initiation and (10%) 10/100 were positive. After 10 months, 4/10 developed a more fatal mutation in 315 and consequently 2/4 died and one progressed to advanced disease. Group C It included 12 imatinib-resistant CML patients treated with dasatinib at 70 to 100 mg/day. At the initiation of dasatinib, no one was positive for F317L and T315I mutation. After 10 months of dasatinib treatment, all were screened for F317L/ T315I mutation by ASO-PCR, 4/12 were positive for F317L mutation and no one was positive for T315I mutation. After 6 months of mutation detection 2/4 progressed to blast crisis, and 1/4 died. Conclusions: ASO-PCR proved to be a very economical, sensitive, and rapid technique for detection of KD mutations M351T, F317L, and F311C ABL mutation and is more sensitive than mutation detection by sequencing. The detection of M351T, F317L, and F311C -ABL mutation at any stage has prognostic significance. No significant financial relationships to disclose.