Dasatinib and dexamethasone followed by hematopoietic cell transplantation for adults with Ph-positive ALL.

Abstract

Post-remission strategies after dasatinib-corticosteroid induction in adults with Ph-positive acute lymphoblastic leukemia (ALL) are not well studied. We evaluated the feasibility and efficacy of dasatinib and dexamethasone induction then protocol-defined post-remission therapies, including hematopoietic cell transplantation (HCT). Adults (N=65) with Ph-positive ALL received dasatinib and dexamethasone induction, methotrexate-based central nervous system (CNS) prophylaxis, reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or chemotherapy alone based on age and donor availability, and dasatinib-based maintenance. Key efficacy endpoints were disease-free survival (DFS) and overall survival (OS). The median age was 60 years (range, 22-87). The complete remission rate was 98.5%. With a median follow up of 59 months, 5-year DFS and OS were 37% (median, 30 months) and 48% (median, 56 months), respectively. For patients receiving RIC allogeneic HCT, autologous HCT, or chemotherapy, 5-year DFSs were 49%, 29%, and 34% and 5-year OSs were 62%, 57%, and 46%, respectively. Complete molecular response rate after CNS prophylaxis was 40%. Relative to the p190 isoform, p210 had shorter DFS (median 10 vs 34 months, P=0.002) and OS (median 16 months vs not reached, P=0.05). Relapse occurred in 25% of allogeneic HCT, 57% of autologous HCT, and 36% of chemotherapy patients. T315I mutation was detected in 6 of 8 marrow relapses. Dasatinib CNS concentrations were low. Dasatinib and dexamethasone followed by RIC allogeneic HCT, autologous HCT, or chemotherapy was feasible and efficacious, especially with RIC allogeneic HCT. Future studies should address the major causes of treatment failure: T315I mutation, the p210 BCR-ABL1 isoform, and CNS relapse.