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

ABSTRACT: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL)-2014 trial evaluated an intensive, age-adapted protocol for adults aged 18 to 59 years with Philadelphia chromosome negative acute lymphoblastic leukemia. 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 (allo-HSCT) among 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 allo-HSCT to patients with poor measurable residual disease (MRD) responses. A total of 743 patients were included, and outcomes were compared with those of GRAALL-2005 trial. The GRAALL-2014 study demonstrated reduced early mortality and higher complete remission rates in patients aged ≥45 years. MRD-guided transplantation decisions reduced allo-HSCT indications by ∼50%. Although older patients experienced a higher cumulative incidence of relapse, no significant difference in disease-free survival (DFS) was observed compared with historical cohorts across age subgroups. The overall 4-year DFS was 57.1% (95% confidence interval [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 = .031) and from 49.6% (95% CI, 43.5-56.5) to 59.5% (95% CI, 53.5-66.3) in older patients (P = .011). These findings highlight the value of individualized treatment strategies that balance efficacy and safety. Future studies should investigate the integration of immunotherapy to further reduce treatment intensity and improve outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02617004 and #NCT02619630.