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.


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.


Burke:Shire: Speakers Bureau; JAZZ: Speakers Bureau; AMGEN: Speakers Bureau.

Author notes


Asterisk with author names denotes non-ASH members.