Redefining the role of second transplantation in adult ALL with post-transplant relapse in the modern era of immuno-targeted therapies

Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains one of the most challenging events in adult acute lymphoblastic leukemia (ALL) and a leading cause of treatment failure [ 1 , 2 ]. Second allo-HCT has historically been regarded as the only potentially curative option for patients who regain complete remission (CR), supported by previous data preceding the era of newer therapeutic options showing superior survival over chemotherapy-based salvage [ 2 , 3 , 4 ]. However, such comparisons are confounded by selection and immortal-time bias, because only patients who achieve remission and remain fit enough proceed to a second transplant [ 4 ]. The contemporary adoption of immuno-targeted agents—later-generation tyrosine kinase inhibitors (TKI), bispecific T-cell engagers, antibody–drug conjugates, and chimeric antigen receptor T cells (CAR-T)—has substantially improved remission and survival, thereby raising the question of whether second allo-HCT should remain the default consolidation for all patients with post-transplant relapse [ 5 , 6 , 7 ]. In such a clinical context, we aimed to compare second allo-HCT with transplant-free immuno-targeted salvage in adult B-cell ALL relapsing after first allo-HCT, using time-dependent methods to mitigate treatment-allocation bias [ 8 ].