Donor C1 Group KIR-ligand inferiority is linked to increased mortality in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide.

Background Aims: In HLA-identical hematopoietic stem cell transplantation (HSCT), HLA-C1 group killer cell immunoglobulin-like receptor (KIR) ligands have been linked to graft-versus-host disease, whereas C2 homozygosity was associated with increased relapses. The differential impact of the recipients versus the donor's HLA-C KIR ligands cannot be determined in HLA-identical HSCT but may be elucidated in the haploidentical setting, in which HLA-C (including the HLA-C KIR ligand group) mismatching is frequently present.

Methods: We retrospectively investigated the effect of recipient versus donor C1 ligand content on survival and complications in post-transplant cyclophosphamide (PTCy)-based haploidentical HSCT (n = 170). HSCTs were categorized as donor C1 supremacy (n = 34), C1 balance (n = 98), or donor C1 inferiority (n = 38).

Results: Following HSCT from C1-inferior donors, overall mortality (hazard ratio, 2.84; P = 0.002) and non-relapse mortality (sub-hazard ratio [SHR], 3.86; P = 0.007) were significantly increased. Following HSCT from C1-superior donors, a low 1-year relapse incidence and favorable 1-year progression-free survival were observed. C1 supremacy did not significantly impact acute or chronic graft-versus-host disease, natural killer cell reconstitution, or day 21 chimerism. Infection was a more common cause of death among recipients with a C1-inferior donor compared with C1-superior or C1-balanced donors.

Conclusions: These findings suggest an increased risk for NRM, particularly infection-related deaths, associated with C1-inferior donors. Upon independent confirmation, C1-inferior donors should be avoided in PTCy-based haploidentical HSCT.