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

Matthew J Wieduwilt, Jun Yin, Meir Wetzler, Geoffrey L Uy, Bayard L Powell, Jonathan E Kolitz, Michaela Liedtke, Wendy Stock, Jan H Beumer, Ryan J Mattison, Elizabeth Storrick, Susan M Christner, Lionel D Lewis, Steven Devine, Richard M Stone, Richard A Larson, Matthew J Wieduwilt, Jun Yin, Meir Wetzler, Geoffrey L Uy, Bayard L Powell, Jonathan E Kolitz, Michaela Liedtke, Wendy Stock, Jan H Beumer, Ryan J Mattison, Elizabeth Storrick, Susan M Christner, Lionel D Lewis, Steven Devine, Richard M Stone, Richard A Larson

Abstract

Post-remission strategies after dasatinib-corticosteroid induction in adult Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) are not well studied. We evaluated dasatinib and dexamethasone induction then protocol-defined post-remission therapies, including hematopoietic cell transplantation (HCT). Adults (N = 65) with Ph-positive ALL received dasatinib-dexamethasone induction, methotrexate-based central nervous system (CNS) prophylaxis, reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or chemotherapy alone, and dasatinib-based maintenance. Key end points were disease-free survival (DFS) and overall survival (OS). The median age was 60 years (range, 22-87 years). 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 DFS were 49%, 29%, and 34%, and 5-year OS 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 = .002) and OS (median 16 months vs not reached, P = .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-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 failure: T315I mutation, the p210 BCR-ABL1 isoform, and CNS relapse. This study was registered at www.clinicaltrials.gov as #NCT01256398.

© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Treatment schema. CIV, continuous IV; G-CSF, granulocyte colony-stimulating factor; PO, by mouth; QPCR, quantitative RT-PCR.
Figure 2.
Figure 2.
Patient disposition. MI, myocardial infarction.
Figure 3.
Figure 3.
OS and DFS. OS (A) and DFS (B) for the entire cohort. OS (C) and DFS (D) by p190 vs p210 BCR-ABL1 isoform status. OS (E) and DFS (F) by plasma dasatinib levels.

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