Background
Phase 2, multicenter single-group trial (GRAALL-2014, NCT02617004/NCT02619630). N=743 patients aged 18–59 with newly diagnosed Philadelphia-negative ALL (489 B-cell, 254 T-cell). GRAALL-2014 introduced two modifications over GRAALL-2005: (1) age-adapted intensity — patients ≥45 received reduced corticosteroids, asparaginase, and anthracycline to lower non-relapse mortality; and (2) MRD-guided transplant allocation — only patients with poor early MRD response were allocated to allo-HSCT in CR1, targeting a 50% reduction in transplant use. Compared against the GRAALL-2005 historical control. Published Blood 2025.
Interventions and follow up
Regimen: Pediatric-inspired chemotherapy backbone (GRAALL-2005) with age-adapted dose attenuation for patients ≥45, rituximab for CD20+ B-ALL, in adults aged 18–59 with Ph-negative ALL
Transplant allocation: Allo-HSCT in CR1 restricted to patients with poor MRD response (MRD-guided)
Primary endpoint: 4-year overall survival vs GRAALL-2005 historical control
Median follow-up: ~4 years
Transplant allocation: Allo-HSCT in CR1 restricted to patients with poor MRD response (MRD-guided)
Primary endpoint: 4-year overall survival vs GRAALL-2005 historical control
Median follow-up: ~4 years
Results
CR: ~90% (consistent with prior GRAALL trials)
4-year OS (all): 71.7% (95% CI 67.7–76.0) vs 65.5% in GRAALL-2005, P=.031
4-year OS (age ≥45): 59.5% vs 49.6% in GRAALL-2005, P=.011 — significant improvement in older patients
4-year DFS: 57.1% vs 58.8% in GRAALL-2005 — unchanged; OS gain driven by reduced NRM
Non-relapse mortality: Significantly reduced, P<.0001, particularly in patients ≥45
Allo-HSCT in CR1: 50% reduction in transplant use vs GRAALL-2005
4-year OS (all): 71.7% (95% CI 67.7–76.0) vs 65.5% in GRAALL-2005, P=.031
4-year OS (age ≥45): 59.5% vs 49.6% in GRAALL-2005, P=.011 — significant improvement in older patients
4-year DFS: 57.1% vs 58.8% in GRAALL-2005 — unchanged; OS gain driven by reduced NRM
Non-relapse mortality: Significantly reduced, P<.0001, particularly in patients ≥45
Allo-HSCT in CR1: 50% reduction in transplant use vs GRAALL-2005
Adverse events
Asparaginase-related: Hypersensitivity, pancreatitis, and thrombosis reduced in older patients owing to dose attenuation
Corticosteroid-related: Fewer complications (hyperglycemia, myopathy, infections) with age-adapted dosing
Treatment-related mortality: Lower than GRAALL-2005, confirming that age-adapted intensity reduces NRM without increasing relapse
Corticosteroid-related: Fewer complications (hyperglycemia, myopathy, infections) with age-adapted dosing
Treatment-related mortality: Lower than GRAALL-2005, confirming that age-adapted intensity reduces NRM without increasing relapse
Conclusions
GRAALL-2014 demonstrated that age-adapted chemotherapy intensity and MRD-guided transplant restriction significantly improved OS in adults with Ph-negative ALL — primarily by reducing non-relapse mortality, especially in patients ≥45. Restricting allo-HSCT to MRD-positive patients cut transplant use by 50% without apparent detriment to outcomes.
Key Limitations
Single-group trial compared against a historical GRAALL-2005 control rather than a concurrent randomized comparator, vulnerable to era effects (improved supportive care, salvage options). DFS was unchanged, so the OS gain reflects reduced NRM rather than improved disease control. MRD-guided transplant allocation assumes accurate, standardized MRD assessment. Limited follow-up (~4 years) for a curative-intent ALL population. Predates routine frontline incorporation of blinatumomab/inotuzumab.
Clinical Context
GRAALL-2014 supports two important refinements in adult Ph-negative ALL: tailoring chemotherapy intensity by age to reduce toxic deaths, and using MRD response to restrict allo-HSCT to those most likely to benefit. These principles are consistent with ESMO and ELN recommendations emphasizing MRD-directed risk stratification. The findings reinforce that reducing treatment-related mortality — not just intensifying therapy — can improve survival in older adults with ALL.