Dasatinib-based 2-step induction for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia

Abstract

The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

© 2022 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

Figure 1.

Patient flow and conditions. AE, adverse event; CNSR, central nervous system relapse; HR, hematological relapse; MR, molecular relapse.

Figure 2.

Frequency of grade 3/4 toxicities. (A) Hematological toxicities and infections. (B) Nonhematological toxicities other than infections. No grade 3/4 pleural effusion or QTc elongation were reported. CMV, XXX; DIC, disseminated intravascular coagulopathy; PN, peripheral neuropathy; Tbil, total bilirubin; TLS, tumor lysis syndrome.

Figure 3.

Survival curves. EFS and OS of the 78 eligible patients (A) and of the 58 patients who underwent HSCT in CR1 (B).

Figure 4.

Impact of additional CAs and type of BCR-ABL1 transcript on survival outcomes. (A) EFS curves of patients with additional CAs and isolated Ph positivity; 3-year EFS rates from enrollment were 61.8% (95% confidence interval [CI], 46.8-73.7) and 77.8% (95% CI, 51.1-91.0), respectively. (B) OS curves of patients with additional CAs and isolated Ph positivity; 3-year OS rates from enrollment were 73.9% (95% CI, 59.3-83.9) and 100%, respectively. (C) EFS curves of patients with major BCR-ABL1 and minor BCR-ABL1 transcripts; 3-year EFS rates from enrollment were 75.9% (95% CI, 51.4-89.2) and 62.4% (95% CI, 48.4-73.7), respectively. (D) OS curves of patients with major BCR-ABL1 and minor BCR-ABL1 transcripts; 3-year OS rates from enrollment were 90.5% (95% CI, 67.0-97.5) and 76.7% (95% CI, 63.3-85.8), respectively.

Figure 5.

Impact of conditioning intensity for HSCT and MRD status at HSCT in CR1 on survival outcomes. (A) EFS for patients who received MAC or RIC. (B) OS for patients who received MAC or RIC. (C) EFS for patients who were MRD− or MRD+. (D) OS for patients who were MRD− or MRD+.