Despite the considerable improvements witnessed over the last few decades in the feasibility and safety of allogeneic hematopoietic cell transplantation (allo-HCT) for hematological malignancies, disease relapse continues to represent a frequent occurrence, with largely unsatisfactory salvage options. Recent studies have shed new light on the biology of posttransplantation relapses, demonstrating that they can frequently be explained using an evolutionary perspective: The changes in disease clonal structure and immunogenicity that are often documented at relapse may in fact represent the end results of a process of selection, allowing the outgrowth of variants that are more capable of resisting the therapeutic control of allo-HCT. This review provides an overview of the mechanisms forming the basis of relapse, including clonal evolution, gain of tropism for privileged sites, genomic and nongenomic changes in the HLA asset, and enforcement of immune checkpoints. Finally, this review discusses how these mechanisms may combine in complex patterns and how understanding and untangling these interactions may provide key knowledge for the selection of personalized therapeutic approaches.

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