Background
Sequential French GRAALL trials in adults with Philadelphia-negative ALL. GRAALL-2003 (phase 2, N=225, age 15–60) established that a pediatric-inspired backbone (≥10 asparaginase doses, high corticosteroid intensity, polychemotherapy) was feasible and effective in adults (CR 93.5%, 42-month OS 60%). GRAALL-2005 (phase 2/3, N=940, age 15–59) continued the backbone with two nested randomizations: (1) high-dose cyclophosphamide (hyper-C) intensification vs standard, and (2) in CD20+ B-ALL, rituximab (16–18 doses, 375 mg/m²) vs none. Published JCO 2018.
Interventions and follow up
Backbone: Pediatric-inspired chemotherapy (prednisone, vincristine, daunorubicin, cyclophosphamide, L-asparaginase) induction, then consolidation and maintenance; allo-HSCT for high-risk patients in CR1
Hyper-C randomization (GRAALL-2005): Intensified hyperfractionated cyclophosphamide vs standard cyclophosphamide
Rituximab randomization (GRAALL-2005, CD20+ B-ALL): Rituximab added to chemotherapy vs chemotherapy alone
Primary endpoint: Event-free survival and overall survival
Median follow-up: 5.2 years
Hyper-C randomization (GRAALL-2005): Intensified hyperfractionated cyclophosphamide vs standard cyclophosphamide
Rituximab randomization (GRAALL-2005, CD20+ B-ALL): Rituximab added to chemotherapy vs chemotherapy alone
Primary endpoint: Event-free survival and overall survival
Median follow-up: 5.2 years
Results
Overall CR (GRAALL-2005): 91.9%
5-year EFS (all): 52.2%
5-year OS (all): 58.5%
Rituximab in CD20+ B-ALL (GRAALL-2005-R, prior report): Improved EFS (HR ~0.66, P=.021) and OS (HR ~0.60, P=.018) — first randomized evidence of rituximab benefit in adult B-ALL
Hyper-C randomization: No significant EFS or OS benefit; higher toxicity
5-year EFS (all): 52.2%
5-year OS (all): 58.5%
Rituximab in CD20+ B-ALL (GRAALL-2005-R, prior report): Improved EFS (HR ~0.66, P=.021) and OS (HR ~0.60, P=.018) — first randomized evidence of rituximab benefit in adult B-ALL
Hyper-C randomization: No significant EFS or OS benefit; higher toxicity
Adverse events
Treatment-related mortality: Deaths in remission (non-relapse mortality) ~9%, higher in older patients
Asparaginase-related: Allergy, pancreatitis, grade ≥3 hepatotoxicity, and venous thromboembolism — the principal challenge of pediatric-inspired regimens in adults
Rituximab: Added minimal additional toxicity over the chemotherapy backbone
Asparaginase-related: Allergy, pancreatitis, grade ≥3 hepatotoxicity, and venous thromboembolism — the principal challenge of pediatric-inspired regimens in adults
Rituximab: Added minimal additional toxicity over the chemotherapy backbone
Conclusions
GRAALL-2003/2005 established the pediatric-inspired chemotherapy backbone as effective in adults with Ph-negative ALL (~91% CR, ~58% 5-year OS). Within GRAALL-2005, rituximab significantly improved EFS and OS in CD20+ B-precursor ALL — one of the first randomized demonstrations of benefit in adult B-ALL — whereas the hyper-C question was negative.
Key Limitations
GRAALL-2003 was single-arm; the pediatric-inspired backbone conclusion rests on historical/comparative rather than randomized data. Substantial non-relapse mortality (~9%), driven largely by asparaginase toxicity in older adults, limits applicability to patients ≥45–55. Pre-dates routine MRD-guided allocation and modern immunotherapy (blinatumomab, inotuzumab). The rituximab and hyper-C questions applied only to subsets of GRAALL-2005, reducing statistical power for each.
Clinical Context
GRAALL-2003/2005 helped establish pediatric-inspired chemotherapy as a standard approach for adults and adolescents/young adults with Ph-negative ALL, an approach endorsed by ESMO and ELN frameworks. The rituximab finding supported incorporation of anti-CD20 therapy into CD20+ B-ALL regimens. These trials provided the backbone subsequently refined by age-adaptation and MRD-guided strategies in GRAALL-2014.