Three Is Not Better Than One: Intrathecal Triple Therapy Is Not Superior to Intrathecal Methotrexate in Children With HR B-ALL

While survival rates for children with B-cell acute lymphoblastic leukemia (B-ALL) now approach 90 percent, patients with relapsed disease continue to have relatively poor prognosis.¹  Importantly, approximately 30 percent of patients with B-ALL relapse have detectable disease in the central nervous system (CNS), indicating a crucial need for progress in CNS-directed therapy.² 

AALL1131 was a Children’s Oncology Group (COG) –initiated phase III clinical trial for newly diagnosed high-risk (HR) B-ALL. In the manuscript featured here, Dr. Wanda L. Salzer and colleagues describe the results of the HR stratum of this study, which aimed to determine the optimal intrathecal (IT) agents for CNS prophylaxis: IT methotrexate (MTX) or IT triple therapy (ITT) with MTX, cytarabine, and hydrocortisone, on a modified Berlin-Frankfurt-Münster (mBFM) chemotherapy backbone.Patients with newly diagnosed National Cancer Institute (NCI) HR B-ALL were eligible for enrollment on AALL1131 from 2012 to 2018. The study included a two-staged consent. Patients first consented to induction chemotherapy and received a standard four-drug induction with corticosteroid (14 days of dexamethasone for age < 10 years, 28 days of prednisone for age ≥ 10 years), vincristine, daunorubicin, and PEG-asparaginase. At the end of induction, patients were stratified into risk groups, and eligible patients were consented for postinduction therapy and randomization. The HR stratum included NCI HR patients younger than 13 years at diagnosis without CNS disease or poor prognostic cytogenetic features (intrachromosomal amplification of chromosome 21, KMT2A gene rearrangement, or hypodiploidy) who achieved day 29 bone marrow (BM) minimal residual disease (MRD) less than 0.01 percent. Patients initially classified as having NCI standard-risk B-ALL and enrolled on COG AALL0932 (NCT01190930) were also eligible for the HR stratum of AALL1131 if they lacked favorable cytogenetics (trisomy of chromosomes 4 or 10, or ETV6-RUNX1 fusion) and had day 8 peripheral blood MRD of 1 percent or greater and day 29 BM MRD less than 0.01 percent, or if they had favorable cytogenetic features and day 29 BM MRD of 0.01 percent or greater.

After induction, 1,734 eligible patients were randomly assigned 1:1 to receive IT MTX (arm A) or ITT (arm B) for CNS prophylaxis. Girls received a total of 21 doses of postinduction IT therapy over two years from the start of interim maintenance, and boys received 26 doses over three years. Postrandomization therapy was otherwise identical for the two treatment arms, with a mBFM regimen including a single interim maintenance phase with systemic high-dose MTX and a single delayed intensification phase.^3,4  A total of 479 patients (aged 6-11 years) also consented to an embedded correlative neurocognitive study, Longitudinal Computerized Assessment of Neurocognitive Functioning, which included repeated assessments with a computerized cognitive evaluation (Cogstate) and parental questionnaire on cognitive and behavioral functioning (Behavior Rating Inventory of Executive Functioning, BRIEF).^5,6 

This study was closed to accrual in 2018 after interim analysis revealed a futility monitoring boundary had been crossed, indicating that ITT could not be shown to be superior to IT MTX. There was ultimately no difference in the primary outcome of five-year disease-free survival (93.2% vs. 90%) or in overall survival (96.3% vs. 96.7%) for patients receiving IT MTX versus ITT, respectively (Figure). The five-year cumulative incidence rates of relapse were also not different between the two randomized arms (5.6% with IT MTX vs. 7.0% with ITT), including when subdividing cumulative incidence rate by isolated BM relapse, isolated CNS relapse, and combined BM/CNS relapse.

There was no difference in postinduction neurologic toxicities between the randomized groups, including transient ischemic attack, stroke, encephalopathy (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥ 3), neuropathy interfering with activities of daily living, or seizure (CTCAE grade ≥ 2). Neurocognitive assessments through the end of maintenance cycle 6 (approximately 2 years postdiagnosis) showed no difference in scores for reaction time/processing speed, visual attention, or working memory for patients receiving IT MTX versus ITT. Rates of abnormal scores for reaction time and visual attention were higher for both groups compared to a normative standardization sample. Parent-reported rating of behavioral regulation and metacognition was comparable for patients in both treatment arms. Longer term post-therapy evaluation of cognitive differences over time was not reported.