Background
Phase 3, multicenter, randomized, 2×2 factorial trial (COG AALL0232). N=3,154 enrolled (2,914 randomly assigned), age 1–30 years, with newly diagnosed NCI high-risk B-ALL. Two independent randomized questions: (1) induction steroid — dexamethasone 10 mg/m²/day ×14d vs prednisone 60 mg/m²/day ×28d; and (2) interim maintenance MTX — high-dose methotrexate (HD-MTX 5 g/m² ×4 with leucovorin rescue) vs Capizzi-escalating MTX (C-MTX, no leucovorin) + PEG-asparaginase. Trial stopped early in 2011 for superiority of HD-MTX. Published JCO 2016.
Interventions and follow up
Arm A: High-dose methotrexate (HD-MTX 5 g/m² IV ×4 doses) during interim maintenance 1, with leucovorin rescue
Arm B: Capizzi escalating-dose methotrexate (C-MTX, starting 100 mg/m²) + PEG-asparaginase during interim maintenance 1, without leucovorin rescue
Primary endpoint: 5-year disease-free survival (DFS)
mFollow up: ~6 years
Arm B: Capizzi escalating-dose methotrexate (C-MTX, starting 100 mg/m²) + PEG-asparaginase during interim maintenance 1, without leucovorin rescue
Primary endpoint: 5-year disease-free survival (DFS)
mFollow up: ~6 years
Results
5-year DFS (HD-MTX vs C-MTX, primary): 91.7% vs 84.2%, P<.0001 — exceeded efficacy boundary, trial stopped early
5-year OS (HD-MTX vs C-MTX): HD-MTX superior, P<.001
Dexamethasone vs prednisone (induction steroid): No significant EFS difference overall; dexamethasone trend toward CNS protection but higher infection-related mortality in patients ≥10 years
CNS relapse: Lower with HD-MTX arm
5-year OS (HD-MTX vs C-MTX): HD-MTX superior, P<.001
Dexamethasone vs prednisone (induction steroid): No significant EFS difference overall; dexamethasone trend toward CNS protection but higher infection-related mortality in patients ≥10 years
CNS relapse: Lower with HD-MTX arm
Adverse events
HD-MTX arm: mucositis, transaminitis, delayed clearance in ~10% requiring leucovorin escalation
Steroid comparison: dexamethasone associated with higher infection-related deaths, hyperglycemia, and osteonecrosis (esp. age >10)
C-MTX arm: neurotoxicity (leukoencephalopathy) at higher dose levels; overall grade ≥3 AEs comparable between major arms
Steroid comparison: dexamethasone associated with higher infection-related deaths, hyperglycemia, and osteonecrosis (esp. age >10)
C-MTX arm: neurotoxicity (leukoencephalopathy) at higher dose levels; overall grade ≥3 AEs comparable between major arms
Conclusions
HD-MTX during interim maintenance significantly improved 5-year DFS (91.7% vs 84.2%) in children and young adults with NCI high-risk B-ALL, leading to early trial termination. HD-MTX is now the standard during interim maintenance for high-risk B-ALL in the US.
Key Limitations
The 2×2 factorial design assumes independence of the two randomizations — potential interaction effects. Trial stopped early for HD-MTX superiority; the dexamethasone vs prednisone question did not meet a definitive stopping boundary, so steroid conclusions are less certain. Age-related differential steroid effects (CNS benefit vs toxicity in older children/AYA). Enrolled 2004–2011; contemporary MRD-guided stratification and emerging immunotherapies (blinatumomab, tisagenlecleucel) have shifted the backbone context. Long-term data show high osteonecrosis rates with dexamethasone.
Clinical Context
AALL0232 established HD-MTX as the standard interim maintenance regimen for pediatric/AYA high-risk B-ALL, directly informing subsequent COG protocols (AALL1231, AALL1732). It also informed steroid choice: dexamethasone is preferred in young children for CNS penetration, while prednisone may be preferred in older patients (≥10 years) given infection/osteonecrosis risk. ESMO and COG frameworks incorporate HD-MTX into the standard high-risk B-ALL backbone.