Dasatinib Time to and Durability of Major and Complete Cytogenetic Response (MCyR and CCyR) in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Dasatinib (SPRYCEL^®) is a potent BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. In this analysis, time to, duration, and rates of cytogenetic responses to dasatinib were determined using Kaplan-Meier analysis in patients recruited to phase II trials in imatinib-resistant or -intolerant CML-CP (START-C and -R), which have more than 2 years of follow-up. In both trials, patients received dasatinib at the previous dose of 70 mg twice daily (the approved dose in CML-CP is now 100 mg once daily following phase III dose optimization demonstrating improved tolerability). In START-C, imatinib-resistant and -intolerant patients were recruited, and separate analyses were performed for each group. In START-R, a randomized trial of dasatinib vs escalated-dose imatinib, only imatinib-resistant patients were recruited and patients from the dasatinib arm were analyzed prior to cross over. In all dasatinib trials, MCyRs and CCyRs were determined using conventional bone marrow cytogenetic assessment. Progression was defined as increasing white blood cell count, loss of complete hematologic response, loss of MCyR, transformation to accelerated or blast phase, or death. Among imatinib-resistant patients treated in START-C, a MCyR had been achieved at 3, 6, and 12 months by 29%, 40%, and 51%, and a CCyR had been achieved by 18%, 28%, and 39%, respectively (Table). At 24 months, MCyR and CCyR had been achieved by 55% and 44%, respectively. Among responding patients, median time to MCyR was 2.9 months and to CCyR was 5.5 months. In resistant patients who had achieved a MCyR, 94% and 84% had maintained this response 12 and 24 months after it had been initially achieved. For CCyR, 95% and 86% had maintained their response at 12 and 24 months, respectively. Progression-free survival (PFS) at 12 and 24 months for imatinib-resistant patients was 88% and 75%. In START-R, dasatinib response rates and durability were similar to those observed in the imatinib-resistant population of START-C, and median times to MCyR and CCyR were 2.8 and 4.1 months, respectively. Among imatinib-intolerant patients treated in START-C, MCyRs had been achieved at 3, 6, and 12 months by 62%, 74%, and 80%, and CCyRs by 44%, 65%, and 74%, respectively. Rates at 24 months had reached 82% for MCyR and 78% for CCyR. Median times to achieve MCyR and CCyR in the intolerant population were both 2.8 months. Among responding patients, 99% and 97% of intolerant patients were without loss of MCyR 12 and 24 months after responding, and 100% and 98% were without loss of CCyR, respectively. The 12- and 24-month PFS rates were 98% and 94%. In conclusion, dasatinib treatment results in high rates of durable MCyRs and CCyRs in patients with imatinib-resistant or -intolerant CML-CP, and responses are achieved rapidly in most patients.

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