Highlights
– GRAALL‑2014 tested an age‑adapted, intensive protocol for adults (18–59 years) with Philadelphia chromosome‑negative ALL, reducing treatment intensity for patients ≥45 years and using MRD to guide alloHSCT decisions.
– Among 743 enrolled patients, early mortality fell and complete remission rates rose in older adults compared with the previous GRAALL‑2005 cohort; MRD‑guided decision making halved alloHSCT indications without a significant reduction in disease‑free survival (4‑year DFS 57.1%, 95% CI 53.4–61.1).
– Four‑year overall survival improved significantly versus historical controls: younger patients 65.5% → 71.7% (p=0.031); older patients 49.6% → 59.5% (p=0.011).
Background and Unmet Need
Adult Philadelphia chromosome‑negative acute lymphoblastic leukemia (Ph‑negative ALL) remains a therapeutically challenging disease. Pediatric‑inspired, dose‑intensive regimens have improved outcomes in adolescents and young adults but can provoke excessive toxicity in older adults. The previous GRAALL‑2005 program found high treatment‑related mortality in older patients and suggested that early good responders might not benefit from routine allogeneic hematopoietic stem cell transplantation (alloHSCT). At the same time, measurable residual disease (MRD) has emerged as one of the most powerful prognostic markers in ALL and a logical tool to individualize consolidation strategies. The GRAALL‑2014 trial was designed to reconcile efficacy and safety by adapting chemotherapy intensity to age and using MRD to restrict alloHSCT to those with poor molecular responses.
Study Design
GRAALL‑2014 (ClinicalTrials.gov: NCT02617004, NCT02619630) was a prospective, multicenter trial enrolling adults aged 18–59 years with newly diagnosed Ph‑negative ALL. The protocol retained a pediatric‑inspired backbone for younger adults while formally reducing certain intensities and/or cumulative exposures in patients aged ≥45 years to lower toxicity. Treatment allocation and transplant recommendations were guided by MRD assessments performed during and after induction; patients with poor MRD clearance were directed to alloHSCT, whereas those with favorable MRD kinetics were spared transplant when feasible. The trial enrolled 743 patients; outcomes were compared against the historical GRAALL‑2005 cohort to assess the impact of the age‑adapted and MRD‑oriented strategy on remission rates, toxicity, transplant utilization, relapse, disease‑free survival (DFS), and overall survival (OS).
Key Findings
Overall outcomes and DFS
Across the study population, the 4‑year disease‑free survival was 57.1% (95% CI, 53.4–61.1). Importantly, despite intentional reductions in chemotherapy intensity for older patients and a substantial reduction in transplant use, DFS compared favorably with historical outcomes from GRAALL‑2005 across age subgroups, with no significant loss of DFS observed.
Remission rates and early mortality
The GRAALL‑2014 regimen was associated with higher complete remission (CR) rates and reduced early mortality in patients aged ≥45 years compared with the GRAALL‑2005 experience. The trial demonstrates that tailoring intensity to age can reduce the short‑term harms previously observed with pediatric‑inspired regimens in older adults while still achieving strong remission rates.
MRD‑guided transplant utilization
Using MRD to guide transplant decision making substantially decreased the number of patients recommended for alloHSCT—by approximately 50%—compared with broader, less selective transplant policies. This reduction in transplant indications translated into fewer procedure‑related risks and long‑term sequelae for many patients, without clear compromise in DFS at the cohort level.
Relapse patterns and age effects
Older patients experienced a higher cumulative incidence of relapse than younger counterparts; however, because of lower early mortality and preserved DFS, overall outcomes still improved in the older subgroup. This suggests that the age‑adapted reductions in toxicity allowed more patients to receive and recover from therapy, partially offsetting the higher relapse risk associated with older age.
Overall survival
Four‑year overall survival improved significantly in both age strata relative to historical comparators. In younger adults, 4‑year OS rose from 65.5% (95% CI, 61.7–69.8) to 71.7% (95% CI, 67.7–76.0) (p=0.031). In older adults, OS improved from 49.6% (95% CI, 43.5–56.5) to 59.5% (95% CI, 53.5–66.3) (p=0.011). These gains imply that the combined strategy of age‑adaptation and MRD‑directed transplant can improve survival endpoints that matter most to patients.
Safety and treatment‑related toxicity
GRAALL‑2014 succeeded in reducing early mortality and treatment‑related toxicities in older adults. While the trial report summarizes the aggregate safety improvements, detailed adverse‑event profiles (specific organ toxicities, infection rates, transplant‑related mortality) were not reproduced in full here; the key clinical message is that modifying intensity for older patients meaningfully enhanced tolerability.
Expert Commentary and Interpretation
The GRAALL‑2014 results reinforce several practical principles for contemporary management of adult Ph‑negative ALL.
First, treatment must balance disease control and toxicity: pediatric‑inspired intensity improves disease control but carries disproportionate harms in older adults; age‑adapted regimens can mitigate these harms while preserving efficacy at the population level.
Second, MRD remains the most robust biomarker to individualize consolidation intensity. By restricting alloHSCT to MRD‑positive or slow‑clearing patients, GRAALL‑2014 reduced exposure to transplant‑related morbidity and mortality for many patients without a detectable decrement in DFS.
Third, the improved OS in both age groups suggests that reduced early toxicity yields downstream survival benefits, even where relapse risk increases modestly in older adults. This underscores the importance of early tolerability for enabling patients to receive full planned therapy and potential salvage interventions.
Limitations and generalizability
Comparisons to GRAALL‑2005 are historical rather than randomized, so unmeasured secular trends and supportive‑care improvements may contribute to the observed gains. The MRD methods and thresholds used to guide transplant decisions are central to interpretation; harmonization of MRD assays and reporting is essential if centers wish to replicate GRAALL‑2014 decisions. Furthermore, the trial excluded patients older than 59 years, so conclusions do not extend to elderly populations where comorbidity and frailty further shape risk–benefit tradeoffs.
Biological plausibility and mechanistic insights
MRD negativity reflects effective clearance of leukemic clones and correlates with lower relapse risk. Sparing MRD‑negative patients from alloHSCT avoids transplant‑related immune and organ toxicities while preserving the option of transplant at relapse when indicated. Age‑adaptation likely decreases cumulative myelotoxic and non‑hematologic toxicities that drive early mortality, allowing improved delivery of consolidation and maintenance therapy.
Future directions: integrating immunotherapies
GRAALL‑2014 sets the stage for integrating targeted and immune‑based agents (for example bispecific T‑cell engagers, antibody–drug conjugates, and cellular therapies) to further reduce cytotoxic intensity while preserving or improving remission durability. A rational pathway is using immunotherapies to treat MRD‑positive patients or to substitute parts of intensive chemotherapy backbones—a strategy that could lower both relapse risk and late toxicity. Prospective trials are needed to test whether combining age‑adaptation, MRD risk stratification, and immunotherapies can further improve long‑term survival and quality of life.
Conclusions and Clinical Implications
The GRAALL‑2014 trial provides strong, practice‑relevant evidence that age‑adapted chemotherapy combined with MRD‑guided transplant selection improves early safety and overall survival in adults with Ph‑negative ALL, while preserving disease control at the cohort level. Clinicians should consider MRD‑directed decision making when contemplating alloHSCT and tailor chemotherapy intensity to age and fitness to reduce early harms. Future trials should evaluate how to incorporate targeted and immune therapies into this strategy to further reduce treatment intensity and improve outcomes.
Funding and ClinicalTrials.gov
ClinicalTrials.gov identifiers: NCT02617004, NCT02619630.
Reference
Boissel N, Chevret S, Rigal‑Huguet F, Leguay TT, Hunault M, Graux C, Chalandon Y, Delabesse E, Hicheri Y, Chevallier P, Balsat M, Pastoret C, Escoffre‑Barbe M, Pasquier F, Joris M, Thiebaut A, Huynh A, Dhedin N, Lemasle E, Bonmati C, Maury S, Guillerm G, Berceanu A, Schanz U, Cluzeau T, Turlure P, Rousselot P, De Prijck B, Grardel N, Béné MC, Lafage‑Pochitaloff M, Cuccuini W, Ifrah NH, Lheritier V, Asnafi V, Clappier E, Dombret H. Age‑adapted chemotherapy and MRD‑oriented transplant for Ph‑negative acute lymphoblastic leukemia: the GRAALL‑2014 trial. Blood. 2025 Oct 24: blood.2025029611. doi: 10.1182/blood.2025029611. Epub ahead of print. PMID: 41135009.
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A confident hematologist in a modern hospital reviewing MRD flow cytometry plots on a widescreen monitor, with a schematic overlay showing an adult patient silhouette, chemotherapy infusion bag, and stylized DNA helix; cool clinical color palette, high realism, 3:2 aspect ratio.
