Triple Intrathecal Therapy (Methotrexate/Hydrocortisone/Cytarabine) Does Not Improve Disease-Free Survival Versus Intrathecal Methotrexate Alone in Children with High Risk B-Lymphoblastic Leukemia: Results of Children's Oncology Group Study AALL1131

Background: With current multi-agent chemotherapy, 88-90% of children diagnosed with High Risk B-Acute Lymphoblastic Leukemia (HR B-ALL) will be cured. However, for those patients who relapse, ~ 1/3 will have central nervous system (CNS) involvement. Thus, adequate CNS disease control for children with HR B-ALL remains a challenge. AALL1131 was designed to determine if the administration of post-Induction age-adjusted triple intrathecal therapy (ITT) with methotrexate, hydrocortisone, and cytarabine, on a modified augmented Berlin-Frankfurt-Münster (MBFM) backbone, would improve 5-year disease free survival (DFS) of children with HR B-ALL compared to age-adjusted intrathecal methotrexate (IT MTX) alone.

Methods: Patients with HR B-ALL included: National Cancer Institute (NCI) HR patients <13 years of age at diagnosis without adverse prognostic features [CNS leukemia at diagnosis (≥ 5 white blood cells in the cerebral spinal fluid with blasts on cytospin and/or clinical signs of CNS leukemia), iAMP21, KMT2A (MLL) rearrangement, or hypodiploidy (<44 chromosomes and/or DNA index <0.81)] who had bone marrow minimal residual disease (BM MRD) <0.01% on Induction day 29; and NCI standard risk (SR) patients lacking favorable cytogenetics (ETV6-RUNX1 fusion or trisomy of chromosomes 4 and 10) who had peripheral blood MRD ≥1% on day 8 and BM MRD <0.01% on Induction day 29, and NCI SR B-ALL patients with favorable cytogenetics who had BM MRD ≥0.01% on Induction day 29. Newly diagnosed children with HR B-ALL were randomized post-Induction in a 1:1 fashion to receive ITT versus IT MTX. A total of 21-26 doses of post-Induction intrathecal therapy was administered during Consolidation (n=4), Interim Maintenance (n=2), Delayed Intensification (n=3), and Maintenance (n=12 for girls, n=16 for boys).

Results: The post-Induction HR B-ALL randomization was closed to accrual on March 19, 2018 following planned interim monitoring that revealed a futility boundary was crossed, concluding the inability to show the superiority of ITT compared to IT MTX. Five-year DFS rates for IT MTX versus ITT were 93±3.8% and 90±4.3%, p value=0.86. The corresponding estimated hazard ratio (HR) of IT MTX vs ITT is 1.285; 95% CI of (0.822, 2.01). There were no differences in toxicities observed in patients receiving ITT compared to IT MTX. As such, the study was amended to prescribe IT MTX to all patients.

Conclusion:

The administration of post-induction age adjusted ITT did not improve 5-year DFS of children with HR B-ALL without CNS leukemia. IT MTX remains the standard of care for CNS prophylaxis.