How I select hematopoietic cell donors in the era of posttransplant cyclophosphamide

Selection of a hematopoietic progenitor cell donor for allogeneic hematopoietic cell transplantation (HCT) is essential for treatment planning; however, the parameters that define an "optimal" donor in the modern era are not well defined. Historically, donor-recipient HLA mismatching correlated strongly with risk for graft-versus-host disease (GVHD) and reduced survival. For this reason, donor selection was typically hierarchical: HLA-matched related and unrelated donors were evaluated first, followed by HLA-mismatched donors (or deferral of HCT altogether) in patients lacking an HLA-matched donor. The advent of posttransplant cyclophosphamide (PTCy)-based GVHD prevention has changed this paradigm. Survival outcomes after HLA-mismatched donor HCT with PTCy, including from related haploidentical or HLA-mismatched unrelated donors, approach those in HLA-matched donor recipients in recent clinical trials and retrospective studies. These encouraging results present a new challenge: In the PTCy era, how should donors be prioritized among the many potential sources available? Herein, we review HLA and non-HLA parameters that inform adult donor selection, address disease-specific considerations, and discuss approaches to increase donor availability, including use of match probability-based donor search. Case vignettes focusing on concepts that may be adapted to heterogeneous clinical scenarios are presented.