In this issue of Blood, Petersdorf et al demonstrate a new paradigm for unrelated HLA mismatch donor selection for hematopoietic cell transplantation (HCT). When the HLA-B leader is matched and the patient has a threonine (T) leader, the rates of graft-versus-host disease (GVHD) and mortality and the transplant mortality are lowered.1 

Proposed algorithm for the selection according to the patient’s HLA-B leader genotype in unrelated donors for hematopoietic cell transplantation.

Proposed algorithm for the selection according to the patient’s HLA-B leader genotype in unrelated donors for hematopoietic cell transplantation.

Survival after allogeneic HCT has constantly improved since the experimental days of transplantation in the 1950s.2  In allogeneic HCT, donor-derived hematopoietic cells provide alloimmunity that provides a graft-versus-tumor effect to eradicate residual disease and prevent malignant relapse. However, alloimmunity toward normal host tissues also gives rise to GVHD, particularly in recipients of unrelated donor grafts. GVHD accounts for >20% of deaths.3,4  A major reason for the improved survival after unrelated donor grafts is better HLA matching of the patients and the donors at HLA-A, -B, -C, -DRB1, and -DQB.5,6  However, this is not always possible, particularly for patients of non-Caucasian background who are not well represented in the donor registries. HCT from a donor with an HLA mismatch followed by standard GVHD prophylaxis can be performed, but often results in severe acute GVHD and lower survival.5,6  Petersdorf et al have recently described a novel region of the HLA gene that harbors clinically relevant variations. The mature HLA class I molecule expressed on the cell surface is encoded by exons 2 to 7. Sequence variation in exons 2, 3, and 4 provide the basis for the tissue type of the class I molecule, or “allotype.” Exon 1 of class I genes encodes a separate leader peptide, which is not a structural moiety of the mature class I molecule, but can be bound and presented by class I, notably HLA-E.7  HLA-A and -C leader sequences are largely invariant, and encode methionine (M) at the −21 position.3  HLA-B exon 1 that has a sequence dimorphism at −21 gives rise to leader peptides encoding either M or T at the second position of the leader . This results in 3 potential genotypes: TT, MT, or MM. In HLA-B mismatched, unrelated HCT, GVHD and mortality risk increased when the patient has HLA-B M leaders (MM or MT) and when the mismatched patient/donor HLA-B allotypes have different leaders.8 

In this issue of the Blood, the authors extend their analysis to HLA-B matched but HLA-A, -C, -DRB1, or -DQB1 mismatched, unrelated HCT. Indeed, the question remains: Is HLA-B mismatching necessary for the leader to have an effect on transplant outcome? If that is the case, the leader will provide information on transplant outcome after unrelated donor transplantation in the setting of HLA-B matching but HLA-A, -C, -DRB1, or -DQB1 mismatching. It will allow for a novel algorithm to select HLA mismatched donors, and inform risks that have previously been attributed to the HLA mismatch itself.

The authors conducted a retrospective cohort analysis of 10 415 patients who received a transplant from an unrelated donor with 1 HLA-A, -C, -DRB1, or -DQB1 mismatch between 1988 and 2016, and whose HLA and clinical data were contributed by members of the International Histocompatibility Working Group in HCT. The 10 415 HLA-B matched pairs with 1 HLA-A, -C, -DRB1, or -DQB1 mismatch were analyzed alongside the 1457 previously studied single HLA-B mismatched pairs.8  The current study pairs are all HLA-B matched; therefore, the patient and donor have the same leader genotype. The patients’ leader frequencies in this cohort were 55.7% for TT, 38.1% for MT, and 6.2% for MM, which were similar to those of HLA-B mismatched patients and donors in the previous study.8  First, and contrary to the association of the patients’ leader genotype with acute GVHD, they found that in single HLA-B mismatches, the patients’ leader genotype did not increase the risk of acute GVHD in HLAA, -C, -DRB1, or -DQB1 mismatched unrelated HCT. This suggests that the patients’ leader genotype had a different effect in HLA-B matched vs mismatched HCT. Next, they looked at the impact of patients’ leader genotype on other outcomes among those with single mismatches at loci other than HLA-B. They found that survival decreased with increasing numbers of M leaders. This suggests that the mortality risk increases from TT to MT to MM after HLA-A, -C, -DRB1, or -DQB1-mismatched HCT. In a third set of analysis, the authors addressed the weight of the association of the patient’s leader genotype with outcomes (acute GVHD and mortality) across the different HLA mismatched loci. They showed that the statistical interaction was not the same between HLA locus and, specifically, mortality was increased when patients’ leader genotype was MM if the mismatch was at HLA-DQB1 (hazard ratio, 1.35; 95% confidence interval, 1.08-1.70; P = .01 for MM patients compared with TT patients). Acute GVHD risk was slightly increased with the MM genotype when the mismatch was at HLA-DRB1 (odds ratio, 2.52; 95% confidence interval, 0.90-7.04; P = .08). Together, these results suggest that the risk of mortality and GVHD escalate with M leaders’ genotype and change depending on the specific mismatched HLA locus.

Petersdorf et al further our understanding of permissive and nonpermissive HLA-B mismatches with this report and allow clinicians to use a leader-based algorithm to select the best donor. Such an algorithm is presented in the figure. Furthermore, and beyond the immediate clinical implications of the leader for donor selection, the information will give mechanistic insights in pathways involved in graft-versus-host allorecognition in transplantation. It would also be interesting to understand the role of HLA-B leader in HLA haploidentical HCT. In view of several recent findings in HLA as well as GVHD prophylaxis,9,10  an updated consensus on donor selection could be established.

Conflict-of-interest: The author declares no competing financial interests.

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