Combined Tyrosine Kinase Inhibitors and Chemotherapy Based on Minimal Residual Disease in Children With Ph⁺ Acute Lymphoblastic Leukemia: A Phase 2 Single-Arm Trial, JCCG ALL-Ph13

Background: Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) have a poor prognosis. In Ph+ALL04, allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) was indicated for all patients, and was performed in those who remained in CR at the scheduled time of transplantation, with 4-year event-free survival (EFS) and overall survival (OS) rates of 54% (95% confidence interval [CI]: 38%–68%) and 78% (95% CI: 62%–88%), respectively. Procedure: The Japan Children's Cancer Group conducted ALL-Ph13, a multicenter single-arm Phase 2 clinical trial, to improve outcomes and reduce HSCTs by using chemotherapy with tyrosine kinase inhibitors (TKIs) guided by minimal residual disease (MRD). The primary endpoint was the 3-year EFS rate. Results: Between 2013 and 2017, 41 of 43 enrolled patients with Ph⁺ ALL aged 1–19 years were eligible. Imatinib was started on Day 15 of induction and switched to dasatinib if MRD-positive after consolidation IB. TKIs were administered until the end of maintenance treatment (Week 104), with temporary discontinuation due to the severity of nonhematological adverse events and resumption at 80% of the original dose. When MRD was positive after the three HR blocks, HSCT was performed. Following four sepsis-related deaths, the protocol was amended in 2016, after which no such deaths occurred. Six patients (15%) underwent HSCT in the first CR, one per protocol indication and five without. The 3-year EFS and OS rates were 65% (95% CI: 48%–78%) and 85% (95% CI: 70%–93%), respectively. As several relapses occurred beyond 3 years, the 5-year EFS and OS rates were also calculated: 48% (95% CI: 30%–64%) and 85% (95% CI: 70%–93%), respectively. Conclusions: Compared with Ph+ALL04, HSCT was substantially reduced in ALL-Ph13 while maintaining comparable outcomes. Further optimization of treatment, particularly the duration of TKI administration, is needed to maintain long-term EFS.