Abstract

Patients with Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) generally have a rapid disease course and a poor overall prognosis that is compounded by resistance to imatinib. Dasatinib is a novel multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, with in vitro potency some 325-fold greater than imatinib against BCR-ABL and proven efficacy in this patient population. START-L is an open-label, international, multicenter study in which patients with imatinib-resistant or -intolerant Ph+ ALL enrolled from January through July 2005 were treated with dasatinib 70 mg BID. Dose escalation to 100 mg BID and reduction to 50 or 40 mg BID were allowed for inadequate response and toxicity, respectively. At the time of this update, all 46 treated patients (median age 48 years; 59% male) had a minimum follow-up of 12 mo. 96% of patients were imatinib-resistant; 46% had received doses of imatinib >600 mg/d, and 52% had received imatinib therapy for >12 mo. Median time from the initial Ph+ ALL diagnosis was 18 mo (range 3–163) and 37% had undergone prior stem-cell transplantation (SCT). BCR-ABL mutations were present at baseline in 78% of patients. The overall major hematologic response rate (MaHR) was 41% with a complete HR rate of 33%. Major cytogenetic response (MCyR) was achieved in 57% of patients with a complete CyR attained in all but one of these patients (54%). Response rates were consistent irrespective of pre-existing BCR-ABL mutations. The median duration of MCyR was 6.9 mo. Median overall survival (OS) was 8.0 mo and 22% of patients remained alive and progression-free after 1 year of treatment. Outcome was favorable for patients with prior SCT: median OS of 9.0 mo (5.8 mo for patients without prior SCT). As expected in these pre-treated patients, grade 3–4 cytopenias were significant with 78% of patients experiencing severe thrombocytopenia and neutropenia. Non-hematologic side-effects included diarrhea in 33% of patients (grade 3–4 in 9%), pleural effusion in 24% (grade 3–4 in 7%), nausea in 22% (no grade 3-4), and pyrexia in 22% (grade 3–4 in 2%). The dose of dasatinib was reduced in 30% of patients and interrupted in 43%; this was primarily attributable to non-hematologic toxicities. This resulted in a median of the average daily dose of 143 mg. Dasatinib continues to show impressive efficacy in this poor-prognosis patient population with Ph+ ALL after the failure of imatinib. Updated analyses corresponding to a minimum follow-up of 2 years will be presented.

Author notes

Disclosure:Employment: Felix Garzon - Bristol-Myers Squibb; Jan Van Tornout - Bristol-Myers Squibb; Chao Zhu - Bristol-Myers Squibb. Consultancy: Oliver Ottmann - Novartis; Kimmo Porkka - Bristol-Myers Squibb and Novartis. Ownership Interests:; Felix Garzon - Bristol-Myers Squibb; Jan Van Tornout - Bristol-Myers Squibb; Chao Zhu - Bristol-Myers Squibb. Research Funding: Herve Dombret - Bristol-Myers Squibb; Richard Larson - Bristol-Myers Squibb; Oliver Ottmann - Bristol-Myers Squibb and Novartis; Bengt Simonsson - Bristol-Myers Squibb. Honoraria Information: Herve Dombret - Bristol-Myers Squibb; Oliver Ottmann - Bristol-Myers Squibb and Novartis; Bengt Simonsson - Bristol-Myers Squibb and Novartis. Membership Information: Bengt Simonsson - Advisory Boards - Bristol-Myers Squibb and Novartis.