Age‐adapted chemotherapy and MRD‐oriented transplant for Ph-negative acute lymphoblastic leukemia: the GRAALL-2014 trial Available to Purchase

• In patients over 45 years old, age-adapted protocol improved complete remission rate and decreased non-relapse mortality

• MRD-based transplant decisions reduced transplant indications and ensured the procedure was limited to patients most likely to benefit

The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL)-2014 trial (ClinicalTrials.gov: NCT02617004, NCT02619630) evaluated an intensive, age-adapted protocol for adults aged 18-59 years with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL). The trial was motivated by findings from the previous GRAALL-2005 study, which reported excessive toxicity from pediatric-inspired therapy in older patients and no added benefit from allogeneic hematopoietic stem cell transplantation (alloHSCT) in those with an early favorable response to treatment. Thus, the GRAALL-2014 protocol aimed to reduce treatment-related toxicity in patients aged ≥45 years and to limit alloHSCT to patients with poor measurable residual disease (MRD) responses. A total of 743 patients was included, and outcomes were compared to those of the GRAALL-2005 trial. The GRAALL-2014 demonstrated reduced early mortality and higher complete remission rates in patients aged ≥45 years. MRD-guided transplant decisions reduced alloHSCT indications by approximately 50%. While older patients experienced a higher cumulative incidence of relapse, no significant difference in disease-free survival (DFS) was observed compared to historical cohorts across age subgroups. The overall 4-year DFS was 57.1% (95% CI, 53.4-61.1). Notably, 4-year overall survival improved significantly, from 65.5% (95%CI, 61.7-69.8) to 71.7% (95%CI, 67.7-76.0) in younger patients (p=0.031) and from 49.6% (95%CI, 43.5-56.5) to 59.5% (95%CI, 53.5-66.3) in older patients (p=0.011). These findings highlight the value of individualized treatment strategies, balancing efficacy and safety. Future studies should investigate the integration of immunotherapy to further reduce treatment intensity and improve outcomes.