Haploidentical transplantation: An optimal platform for graft manipulation and cellular therapies

Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a curative therapeutic option for patients with high-risk hematologic malignancies. When a fully matched donor is unavailable, haploidentical hematopoietic stem cell transplantation (haplo-HCT) provides a viable alternative. Over time, haplo-HCT procedures have significantly evolved, improving outcomes in treatment related mortality (TRM), especially in graft-versus-host disease (GvHD). However, challenges such as delayed immune reconstitution and disease relapse persist. Advances in in vivo graft manipulation techniques, such as post-transplant cyclophosphamide (PTCy) and ex vivo approaches, including TCRα/β and CD19 depletion, have shown promise in reducing the risk of severe GvHD without increasing the relapse rates. Innovative strategies, such as haploidentical donor lymphocyte infusions, "suicide-switch" mechanisms, ORCA-Q product infusions, and CAR based therapies offer potential to further optimize outcomes. This review examines the graft manipulation modalities in the haplo-HCT setting, highlighting their role in advancing cellular therapies and providing new hope in the fight against life-threatening diseases.