Selecting the Best Donor for Haploidentical Transplant: Impact of HLA, Killer Cell Immunoglobulin-Like Receptor Genotyping, and Other Clinical Variables

Abstract

The use of post-transplant cyclophosphamide (PTCy)-based haploidentical (haplo) transplant is increasing worldwide. However, because multiple potential haplo donors are usually available, data-driven guidance is clearly needed to help transplant centers prioritize donors. To that end, we retrospectively analyzed 208 consecutive donor-recipient pairs receiving PTCy-based haplo transplant at a single institution. Median recipient and donor age were 52 years (range, 19 to 75) and 38 years (range, 15 to 73), peripheral blood stem cell was the stem cell source in 66%, and myeloablative conditioning was used in 41%. Median follow-up for surviving patients was 33 months (range, 7 to 130). Donor variables analyzed included age, sex, relationship, cytomegalovirus (CMV) status, ABO compatibility, HLA disparity, and several natural killer (NK) alloreactivity models. Multivariate Cox analysis was used to adjust for known patient, disease, and transplant covariates. Donor characteristics independently associated with improved survival included presence of HLA-DR mismatch, HLA-DP nonpermissive mismatch, killer cell immunoglobulin-like receptor (KIR) receptor-ligand mismatch, and KIR B/x haplotype with KIR2DS2. Donor characteristics associated with inferior survival included parental donor relationship and the use of a CMV-seronegative donor for a CMV-seropositive patient. Increased HLA disparity (≥4/10 HLA allelic mismatches [graft-versus-host direction]) resulted in relapse protection at the expense of increased nonrelapse mortality with no associated survival effect. We further propose a donor risk factor scoring system to permit a more evidence-based selection algorithm for potential haplo donors. This large, single-institution analysis demonstrates the importance of HLA-DR/HLA-DP disparity, NK alloreactivity, and other clinical variables in the haplo donor selection process and suggests that KIR and HLA-DP genotyping should be performed routinely for haplo donor selection.

Donor selection for haploidentical hematopoietic cell transplantation‐ practice guidance

“…Similarly, in haplo‐HCT with PTCy, Kasamon et al also found that greater HLA disparity did not appear to worsen overall outcomes . This has been further confirmed by a recent study by Solomon et al and other investigators from European Group for Blood and Marrow Transplantation (EBMT) . Therefore, recent retrospective studies have suggested that HLA disparity is not associated with prognosis after haplo‐HCT …”

“…However, some specific HLA loci have been shown to be associated with transplant outcomes. In haplo‐HCT using PTCy, Solomon et al suggested that HLA‐DP nonpermissive mismatch was associated with improved overall survival (OS; 71% vs 56%) and reduced relapse (16% vs 40%), whereas HLA‐DR mismatch was associated with a better OS (63% vs 47%) and reduced NRM (11% vs 46%) . In haplo‐HCT using the Beijing protocol, although the high degree of HLA allele mismatches did not adversely affect transplant outcomes in haplo‐HCT, each HLA allele mismatch had a different effect.…”

Haploidentical hematopoietic stem cell transplantation with post‐transplant high‐dose cyclophosphamide in high‐risk children: A single‐center study

“…We decided to preferentially select mothers as donors whenever possible due to a number of publications hypothesizing immunological tolerance between the mother and the fetus during pregnancy, producing a lifelong downregulation of immune responses, and thus development of tolerance, toward antigens of maternal origin . However, consistent with other previous reports, we observed no survival advantage linked to the gender of the donor parent, suggesting that neither alloreactivity encoded by the Y chromosome of the father or immunological tolerance between the mother and child plays a major role in the success of haploidentical transplantations with Post‐Cy.…”

“…Meanwhile, Solomon et al 19 reported that neither parent demonstrated a survival advantage over the other. We decided to preferentially select mothers as donors whenever possible due to a number of publications hypothesizing immunological tolerance between the mother and the fetus during pregnancy, producing a lifelong downregulation of immune responses, and thus development of tolerance, toward antigens of maternal origin.…”

Who is the best relative? Optimizing haploidentical donor transplantation in lymphoma

“…The obvious next challenge for the scientific community is to understand the variables that may make haplo-HCT safer and better. Multiple studies, editorials and algorithms later, this remain an area of active research and debate (Wang et al, 2014;Handgretinger, 2014;Chang et al, 2016;Solomon et al, 2018;McCurdy et al, 2018;Bacigalupo & Laurenti, 2018).…”