JCCG ALL-B12: Evaluation of Intensified Therapies With Vincristine/Dexamethasone Pulses and Asparaginase and Augmented High-Dose Methotrexate for Pediatric B-ALL

Abstract

Purpose: The JCCG ALL-B12 clinical trial aimed to evaluate the effectiveness of unvalidated treatment phases for pediatric ALL and develop a safety-focused treatment framework.

Patients and methods: Patients age 1-19 years with newly diagnosed B-ALL were enrolled in this study. These patients were stratified into standard-risk (SR), intermediate-risk (IR), and high-risk (HR) groups. Randomized comparisons assessed the effectiveness of vincristine (VCR)/dexamethasone pulses in the SR group, evaluated the effects of L-asparaginase (ASP) intensification in the IR group, and compared standard consolidation including block-type treatment with experimental consolidation with high-dose methotrexate (HD-MTX) intensified with VCR and ASP in the HR group.

Results: Of 1,936 patients enrolled, 1,804 were eligible for the experimental treatment. The overall 5-year event-free survival and overall survival rates were 85.2% (95% CI, 83.5 to 86.8) and 94.3% (95% CI, 93.1 to 95.3), respectively. The cumulative incidence of relapse and postremission nonrelapse mortality was 13.2% (95% CI, 11.6 to 14.8) and 0.6% (95% CI, 0.3 to 1.0), respectively. Random assignment in the SR group showed no significant benefit from pulse therapy. In the IR group, ASP intensification had limited effects. In the HR group, standard block therapy and HD-MTX yielded equivalent outcomes.

Conclusion: The ALL-B12 trial achieved favorable outcomes in a nationwide cohort by stratifying treatment on the basis of risk and balancing treatment intensity. This study not only demonstrated that existing standard of care can be further refined but also indicated that improvement in outcomes with intensified chemotherapy has reached a plateau.

FIG 1.

CONSORT diagram of the ALL-B12 trial. The most common reason for exclusion was BCR::ABL1 positivity (n = 96). FAS, full analysis set; PPS, per-protocol set.

FIG 2.

Treatment outcomes of patients enrolled in the ALL-B12 trial. (A) EFS and (B) OS probabilities of the patients in the full analysis set. (C) EFS and (D) OS probabilities of the different risk groups. (E) EFS probability categorized according to MRD status at the end of induction (TP1). (F) EFS probability categorized according to MRD status at the end of consolidation (TP2). EFS, event-free survival; HR, high risk; IR, intermediate risk; MRD, minimal residual disease; OS, overall survival; SR, standard risk; TP1, time point 1; TP2, time point 2.

FIG 3.

Comparisons of the outcomes of treatment with or without VD pulses in the standard-risk group. (A) EFS of patients allocated to the treatment arms, all randomly assigned participants. The standard arm (arm A) is treatment without VD pulses, whereas the experimental arm (arm B) is treatment with VD pulses. (B) Frequency of adverse events in the treatment arms. This figure includes only grade 3 or higher adverse events that occurred at a frequency of ≥5% in either group. EFS, event-free survival; VD, vincristine/dexamethasone.

FIG 4.

Comparisons of the outcomes of treatment with or without intensification of ASP in the intermediate-risk group. (A) EFS of patients allocated to the treatment arms, all randomly assigned participants. Standard arm (arm A) is treatment without ASP intensification, and experimental arm (arm B) is treatment with ASP intensification. (B) Frequency of ASP-associated adverse events in the treatment arms. This figure includes only grade 3 or higher adverse events that occurred at a frequency of ≥5% in either group. ASP, asparaginase; EFS, event-free survival.

FIG 5.

Comparisons of outcomes of the consolidation regimen in the high-risk group. (A) EFS of patients allocated to the treatment arms, all randomly assigned participants. Arm A is conventional block-type consolidation, and arm B is experimental consolidation with HD-MTX/VL. (B) Frequency of adverse events in the treatment arms during block therapy or HD-MTX/VL. This figure includes only grade 3 or higher adverse events that occurred at a frequency of ≥5% in either group. EFS, event-free survival; HD-MTX/VL, high-dose methotrexate 5 g/m² over 24 hours intensified with vincristine and asparaginase.