Dasatinib-Associated Major Molecular Responses Are Rapidly Achieved in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Following Resistance, Suboptimal Response, or Intolerance on Imatinib.

Abstract Dasatinib (SPRYCEL®) is a highly potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. Qualitative and quantitative assessment of BCR-ABL transcripts by RT-PCR is the most sensitive method for assessing minimal residual disease in patients with CML. In the treatment of patients with CML in the first-line setting, achievement of a major molecular response (MMR) within 18 months of therapy is considered to be clinically important. Here, molecular responses to dasatinib in patients with CML-CP following resistance, suboptimal response, or intolerance to imatinib were analyzed using data from two phase II studies (CA180-013 [START-C], -017 [START-R]) and a phase III dose-optimization study (CA180-034). BCR-ABL mRNA levels were determined in peripheral blood samples using real-time quantitative PCR and results were standardized using the international scale. A MMR was defined as a reduction of BCR-ABL transcripts to ≤ 0.1%. Samples were assayed at one of four laboratories (Mannheim, Germany; Adelaide, Australia; or Seattle, USA for −013 and −017; and Wallingford, USA for −034). Of 1,158 patients with CML-CP who were randomized to (017) or treated with (013/034) dasatinib, 1,067 had a molecular assessment and were included in the analysis. After 3, 6, 12, and 24 months of follow-up, a MMR was achieved by 12%, 22%, 35%, and 40%, respectively, of all patients analyzed. The 24-month MMR rate among patients who had achieved or maintained a complete cytogenetic response was 72%. In patients with imatinib resistance/suboptimal response (n=829), overall MMR rates after 3, 6, 12, and 24 months were 10%, 18%, 29%, and 34%, respectively, and in patients with imatinib intolerance (n=238), MMR rates were 22%, 37%, 55%, and 63%, respectively. In patients treated during the 034 study with dasatinib 100 mg once daily, which is associated with fewer key side effects, MMR rates at different time points were similar to rates with other dose schedules (24-month MMR: 100 mg QD, 36%; other schedules, 38%). Among all patients who achieved a MMR, median time to MMR was 5.7 months (6.0 months with 100 mg QD), and after 18 months, 92% of responding patients were without loss of MMR (88% with 100 mg QD). Overall, the results of this analysis demonstrate that high rates of MMR are rapidly achieved in patients with CML-CP treated with dasatinib following resistance, suboptimal response, or intolerance to imatinib. Table Major molecular response (%) Follow-up (months) 3 6 12 24 All analyzed patients (n=1067) 12 22 35 40 Resistant/suboptimal response (n=829) 10 18 29 34 Intolerant (n=238) 22 37 55 63 Phase II studies (013/017) (n=467) 17 27 39 44 Resistant (n=373) 13 21 31 35 Intolerant (n=94) 33 50 69 78 Phase III dose-optimization study (034) (n=600) 9 19 32 38 Resistant/suboptimal response (n=456) 7 16 27 33 Intolerant (n=144) 15 29 46 54 Response by dose schedule 100 mg QD (n=154) 7 18 29 36 70 mg BID (n=146) 9 18 32 38 140 mg QD (n=144) 13 22 32 38 50 mg BID (n=156) 7 17 34 38

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