Molecular Response According to Type of Preexisting BCR-ABL Mutations after Second Line Dasatinib Therapy in Chronic Phase CML Patients

Dasatinib (SPRYCEL®) has demonstrated significant efficacy in a high proportion of imatinib-resistant or -intolerant chronic phase CML patients (pts) concerning achievement of hematologic and cytogenetic responses. We sought to establish a relationship between type of preexisting BCR-ABL mutations associated with imatinib resistance and achievement of major molecular response (MMR, BCR-ABL ≤0.1% according to International Scale, IS) after 12 months of dasatinib therapy in pts with chronic phase CML. We have investigated 1,605 peripheral blood samples from 202 pts (n=62 imatinib-intolerant, n=140 imatinib-resistant; 52% male, median age 60 yrs, range 21–78) who had been enrolled in an international phase II study (START-C study, CA180–013) investigating the activity of 70mg dasatinib BID after imatinib failure. Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. During follow up, pts were monitored in 3-monthly intervals by RQ-PCR for BCR-ABL mRNA transcripts and by mutation analysis to determine the quantitative course of the preexisting mutation or the emergence of new mutations. Prior to dasatinib therapy, 34 different BCR-ABL mutations involving 29 amino acids were detected in 85/202 pts (42%) with a striking predominance in imatinib-resistant (77/140 pts, 55%) over imatinib-intolerant pts (8/62 pts, 13%). 75 pts showed one, 8 pts two and 2 pts three mutations. RQ-PCR data after 12 months of therapy was available from 154 pts (76%), samples from 48 pts (24%) were not available for monitoring after one year due to progressive disease. MMR was achieved in 28 imatinib-intolerant (45%) and 19 imatinib-resistant pts (14%, p1,000nM). Of 85 pts without sufficient molecular response to dasatinib (BCR-ABL IS >5%) after 12 months (median, range 9–15) mutation analysis revealed the emergence of new mutations in 17 formerly imatinib-resistant pts (T315I, n=2; T315A, n=1; F317L, n=6; V299L, n=2; M351T, n=2; L248V, n=1; G250E, n=1; K271R, n=1; Y320C, n=1). We conclude that dasatinib is capable of inducing high rates of major molecular response after one year treatment particularly in imatinib-intolerant pts. Response dynamics depend on the individual type of mutation which may be a basis for individual dose adjustment according to the mutation pattern.