INBIOSUR   25013
INSTITUTO DE CIENCIAS BIOLOGICAS Y BIOMEDICAS DEL SUR
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Detection of BCR-ABL kinase domain mutations in a cohort of Argentine patients with chronic myeloid leukemia to imatinib mesylate resistance
Autor/es:
MJL ZANELLA; SANDOVAL MJ
Lugar:
Miami
Reunión:
Congreso; 20th Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy.; 2018
Resumen:
Imatinib (IM), the first targeted therapy for patients with chronic myeloid leukemia (CML), has led to a meaningful prolongation of their lives. Nonetheless, a 30% of these patients fail therapy. Mutations within the ABL kinase domain (KD) of BCR-ABL are the most frequent mechanism of IM resistance. Several publications show the clinical relevance of mutations assay to guide the treatment.The aim of the study was to evaluate the clinical relevance of the mutations assay in patients with CML resistant to IM treatment and, to describe the main mutations harbored in our population.It work includes 71 CML patients resistant to IM (400 mg, for at least 6 months) or with suboptimal responses, according to the European LeukemiaNet (ELN) guidelines. Peripheral blood samples were collected on EDTA. RNA was isolated by TRIzol method and total RNA was reverse transcribed. The PCR product was amplified in a seminested reaction and then sequenced in both directions. The sequences were compared to the wild-type ABL sequence (GenBank accession number X16416). T315I screening was performed in all cases (AS-RT-PCR assay). Statistical analysis was carried out using SPSS software (version 15.0).At the time of mutation study, 55/71 (77.5%) were in chronic phase (CF), 4/71 (5.6%) in accelerated phase (AP), and 12/71 (16.9%) in blast crisis phase (BP). Mutations were detected in 30/71 patients (42%) and the frequencies in CP, AP, and BP were 29% (16/55), 100% (4/4) and 75% (9/12), respectively. We found 14 types of mutations and nobody presented multiple mutations. We detected: T315I (n= 8), F317L (n= 6), G250E (n= 3); Y253H, E255K and exon 7 deletion (n= 2); E453K, E459K, F359V, L248V, L387M, M327V, T272A and T315V (n= 1). The P-loop and T315I mutations were observed in 17/30 patients (56.6%). Regarding the perfil of sensibility, in 25/30 (83%) cases had had an appropriated alternative therapeutic option based on the BCR-ABL KD mutation status. The median patient follow up was 30 months (1?74). The progression free survival (PFS) and the overall survival (OS) at five years were lower in mutated than in non-mutated patients 58 vs 84% (p