An observational study reviewing the CIBMTR® (Center for International Blood and Marrow Transplant Research®) database for over 1400 patients who received a haploidentical related donor hematopoietic stem cell transplant (HCT) with post-transplant cyclophosphamide (PTCy) was published in Blood. This study represents the largest retrospective analysis on the effect of individual and combined HLA locus-mismatching in haploidentical HCT, which was used to create an online risk calculation tool to aid in the prospective selection of the optimal haploidentical donor based on predicted disease-free survival (DFS).
Improvements in HLA-haploidentical HCT have increased its safety and efficacy for treating life-threatening hematologic cancers. Notably, the use of PTCy after hematopoietic cell infusion has substantially reduced severe acute and chronic graft-versus-host disease (GVHD) risk associated with HLA mismatching and is now the most widely used GVHD-prevention strategy in haploidentical transplantation.
A haploidentical family member shares one complete HLA haplotype with the patient and differs for various alleles on the non-shared haplotype. A patient's probability of having at least one haploidentical family member exceeds 90% because biological parents and children are haploidentical. In addition, siblings and more distant relatives may be haploidentical. Haploidentical transplantation also provides an alternative donor option for ethnically diverse patients with a lower likelihood of identifying a suitable unrelated donor. In 2019, the number of haploidentical transplantations performed in the U.S. approached that of HLA matched siblings.
Most of the information on the importance of HLA in hematopoietic cell transplantation comes from analyses of the results of unrelated donor HCT without PTCy. In that context, increasing numbers of donor HLA mismatches are detrimental to survival, and the clinical implications of specific HLA mismatches depend on the locus and sequence features of the mismatched alleles. In contrast, haploidentical donors are currently selected based on non-HLA factors but information on the role of HLA in haploidentical transplantation is still emerging. Furthermore, it is unknown whether HLA mismatches in haploidentical transplantation confer similar effects on GVHD, relapse, and mortality, such as those observed in unrelated donor transplantation. Therefore, the goal of the study was to identify functional HLA characteristics that could help guide donor selection to improve the overall success of haploidentical HCT.
Results showed that HLA-B mismatches classified by B leader sequence matching (a conserved region of the gene) were associated with lower transplant-related mortality (TRM) and overall survival (OS). HLA-DRB1 mismatching in the graft-versus-host (GVH) direction was associated with lower relapse. HLA-DPB1 mismatches classified as T-cell epitope non-permissive mismatches were associated with improved overall survival compared to matched and permissive mismatches. Other factors were also reviewed, such as donor age and CMV status. Optimal outcomes of haploidentical transplantation with PTCy when the donor is HLA-B leader matched, HLA-DRB1-mismatched and HLA-DQB1-matched and non-permissive TCE HLA-DPB1 mismatched. Further exploration into the effects of mismatching in unrelated donor transplantation using PTCy should also expand using future studies relating HLA factors to donor selection and outcomes.
It’s difficult to simultaneously consider all HLA and clinical factors. The study team developed an online calculator to aid prospective selection of haploidentical donors for patients undergoing PTCy-based haploidentical HCT for acute leukemia or myelodysplastic syndrome . Based on the patient and donor information entered, 1- and 2-year disease-free survivals are estimated from the haploidentical transplants in the current study, aiding in the prioritization of candidate donors (see Figure 1 below). This tool can help to prioritize haploidentical donor options based on the findings from the study.
Online risk calculator: http://haplodonorselector.b12x.org/v1.0/