Optimal donor selection for transplant to reduce GVHD risk and augment graft-versus-malignancy efficacy

Allogeneic hematopoietic cell transplantation (alloHCT) is curative for many patients with high-risk, hematologic malignancies. AlloHCT depends on a graft versus malignancy (GVM) phenomenon, whereby donor-derived immune cells recognize and eradicate malignant host cells. Successful GVM correlates with the risk of alloreactivity against healthy tissues (graft-vs-host disease [GVHD]). HLA genes are central to immunologic recognition of self and mediate both GVM and GVHD. Historically, HLA-mismatched alloHCT was limited by the high incidence of severe GVHD. This led to a strong preference for HLA-matched donors, limiting access to HCT in patients without an HLA-matched donor. More recent advances in the prevention of GVHD, such as post-transplant cyclophosphamide, resulted in improved outcomes after HLA-mismatched donor HCT. New possibilities now exist to select donors for strategies designed to exploit GVM without significant GVHD. Here, we discuss the practical applications of donor selection to improve the overall efficacy of alloHCT.