The last 20 years witnessed relevant clinical advancements in the field of hematopoietic cell transplantation (HCT) for leukemia patients. The introduction of novel conditioning regimens, a better prophylaxis and management of graft- versus-host disease, and an ameliorated posttransplant support system improved safety and, therefore, outcomes. On the other hand, leukemia relapse remains the major cause of allogeneic HCT failure. Efforts have been made to understand the mechanisms of leukemia relapse, and new insights that clarify how donor immunity exerts graft-versus- leukemia (GVL) activity are available. Such studies set the base to design novel transplant strategies that can improve disease control. In our review we begin by discussing the most relevant criteria to choose a donor that provides a strong GVL effect. We also report some of the novel conditioning regimens that aim to deliver and extend myeloablation in order to reduce the disease burden at time of graft infusion. Finally, we discuss how the graft can be manipulated to limit the use of immune suppression and ensure potent antileukemic activity.

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