Efficacy of dasatinib in chronic phase chronic myelogenous leukemia patients after imatinib failure according to baseline BCR- ABL mutations

Abstract

7023 Background: Dasatinib is an oral, multi-targeted BCR-ABL and SRC kinase inhibitor with preclinical activity against 20/21 imatinib (Im) resistant BCR-ABL mutations. Clinical efficacy was demonstrated in phase I, II, and III studies in patients (pts) with chronic myelogenous leukemia (CML) in all phases of the disease and BCR-ABL positive acute lymphoblastic leukemia (ALL). We sought to establish a relationship between type of BCR-ABL mutations associated with Im resistance and efficacy of dasatinib in chronic phase (CP) CML pts. Methods: Between 10/03 and 03/06, dasatinib was commenced in 1,093 CP-CML pts recruited for three consecutive trials and administered for a median of 8.7 months (range <1–25.9). BCR-ABL mRNA was screened for mutations of amino acids 207–517 by D-HPLC and/or regular sequencing and data are available from 961 cases (88%). ABL polymorphisms K247R and E499E were excluded from analysis. Results: Prior to dasatinib, 75 different BCR-ABL mutations involving 56 amino acids were detected in 18/240 Im intolerant (7.5%) and 324/721 (45%) Im resistant pts. 267 pts showed one, 53 pts two, 16 pts three, and six pts four mutations. In Im resistant pts, response was not different between 370 pts with and 351 pts without baseline mutations: Complete hematologic response (CHR) was achieved in 89% vs 92%; major cytogenetic response (MCR) in 48% vs 52% being complete (CCR) in 38 vs 36%, respectively. Response dynamics were associated with preclinical activity of dasatinib: classifying mutations for IC50 values <2, 2–20 and >1,000nM (T315I), CHR was achieved in 93, 85 and 28%; MCR in 48, 42 and 0%; and CCR in 37, 35 and 0% of cases, respectively. During follow up, new mutations were detected in 30 cases, predominantly T315I (n=10), Y253H/F (n=4), and F317L (n=3). Conclusions: We conclude that dasatinib is capable of inducing hematologic and cytogenetic remissions in a significant proportion of Im resistant pts associated with BCR-ABL mutations, except T315I, but also in pts with BCR-ABL independent causes of resistance. Quality of response depends on the individual type of the mutation which is consistent with preclinical observations. No significant financial relationships to disclose.