Long-Term Efficacy of Dasatinib in Chronic-Phase CML: Results from the Phase I Trial (CA180002).

Imatinib resistance in CML is frequently associated with BCR-ABL mutations. Such kinase domain mutations are emerging as a common mechanistic theme in cases of acquired resistance to kinase inhibitor therapy. Five-year follow-up from the IRIS trial indicates that the incidence of hematologic resistance to imatinib is 17% and >30% of patients have discontinued imatinib therapy on study. Preclinical studies reveal that dasatinib (SPRYCEL®), a novel BCR-ABL inhibitor, is 325-fold more potent than imatinib in inhibiting the kinase activity of BCR-ABL, as well as demonstrating activity against all imatinib-resistant BCR-ABL mutations tested to date, with the exception of T315I. Here we present an update of a Phase-I dose-escalation study, with enrollment between November 2003 and April 2005, of dasatinib in imatinib-resistant or -intolerant patients with CML or Ph+ ALL; this report focuses on the long-term follow-up of the 45 patients (56% male) with late chronic-phase disease. Dasatinib was administered at doses of 15–180 mg/day on a QD or BID schedule. Median duration of CML prior to entry was 8 years (range 1–17). Median age was 63 years (range 28–79). Prior therapy included interferon-α in 91% of patients and stem-cell transplantation in 4%; 62% had received prior imatinib doses >600 mg. With a minimum follow-up of 27 months, the rate of complete hematologic response (CHR) was 91% (41/45). Major cytogenetic responses (MCyR) were attained in 51% of patients (23/45), with complete CyR (CCyR) in 44% (20/45). The rates of CCyR for the QD and BID schedules were 45% (10/22) and 43% (10/23), respectively. The median duration of CHR and MCyR have not been reached with a median duration of treatment of 28 months. In a landmark analysis, the 36-month progression-free survival (PFS) rate was 87% and overall survival (OS) was 94% for patients who achieved a MCyR within the first year of dasatinib therapy. For patients who did not achieve a MCyR within the first year, the 36-month PFS figure was 28% and OS was 68%. These long-term data confirm the durability and depth of hematologic and cytogenetic response associated with dasatinib in patients who have failed treatment with imatinib. Evidence is also provided to substantiate that the significant response rates observed with dasatinib therapy in this population translate into prolonged progression-free and overall survival. Dasatinib therefore has the potential to positively impact on the natural history of CML.