HLA Haplotypes and Relapse After Hematopoietic Cell Transplantation.

PURPOSE: Recurrence of blood malignancy is the major cause of hematopoietic cell transplant failure. HLA class II molecules play a fundamental role in antitumor responses but the role of class II haplotypes is not known. METHODS: HLA-DR, -DQ, -DM, and -DO allele variation was determined in 1,629 related haploidentical transplants to study the clinical significance of individual molecules and haplotypes. RESULTS: Outcome correlated with patient and donor variation for HLA-DRß residue 86 (Gly/Val), HLA-DQ (G1/G2) heterodimers, and donor HLA-DM (DM11,11/nonDM11,11) molecules, and depended on patient-donor mismatching. Risks of relapse were lower for DRß-86 GlyGly patients when the donor was GlyVal (hazard ratio [HR], 0.46 [95% CI, 0.30 to 0.68]; P < .001); GlyVal patients benefited from HLA-DRB1-matched donors, whereas no donor was superior to another for ValVal patients. G1G2 patients with G1G2-mismatched donors had lower relapse. Transplantation from donors with DMα residue 184 ArgHis was associated with higher risk of relapse (HR, 1.60 [95% CI, 1.09 to 2.36]; P = .02) relative to ArgArg. Relapse and mortality risks differed across HLA-DR-DQ-DM haplotypes. CONCLUSION: HLA class II haplotypes may be functional constituents of the transplantation barrier, and their consideration in patients and donors may improve the success of transplantation.

Role of NKG2D ligands and receptor in haploidentical related donor hematopoietic cell transplantation.

The recurrence of malignancy after hematopoietic cell transplantation (HCT) is the primary cause of transplantation failure. The NKG2D axis is a powerful pathway for antitumor responses, but its role in the control of malignancy after HCT is not well-defined. We tested the hypothesis that gene variation of the NKG2D receptor and its ligands MICA and MICB affect relapse and survival in 1629 patients who received a haploidentical HCT for the treatment of a malignant blood disorder. Patients and donors were characterized for MICA residue 129, the exon 5 short tandem repeat (STR), and MICB residues 52, 57, 98, and 189. Donors were additionally defined for the presence of NKG2D residue 72. Mortality was higher in patients with MICB-52Asn relative to those with 52Asp (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.24-2.71; P = .002) and lower in those with MICA-STR mismatch than in those with STR match (HR, 0.66; 95% CI, 0.54-0.79; P = .00002). Relapse was lower with NKG2D-72Thr donors than with 72Ala donors (relapse HR, 0.57; 95% CI, 0.35-0.91; P = .02). The protective effects of patient MICB-52Asp with donor MICA-STR mismatch and NKG2D-72Thr were enhanced when all 3 features were present. The NKG2D ligand/receptor pathway is a transplantation determinant. The immunobiology of relapse is defined by the concerted effects of MICA, MICB, and NKG2D germ line variation. Consideration of NKG2D ligand/receptor pairings may improve survival for future patients.

Race and Survival in Unrelated Hematopoietic Cell Transplantation.

Survival after hematopoietic cell transplantation depends on race/ethnicity and histocompatibility (HLA) between the patient and transplant donor. HLA sequence variation is a genetic construct of continental populations, but its role in accounting for racial disparities of transplant outcome is unknown. To determine disparities in transplant survivorship among patients of diverse race while accounting for patient and donor HLA variation. A total of 26,945 self-described Japanese, U.S. Asian, White, Hispanic, and Black patients received an unrelated donor transplant for the treatment of a life-threatening blood disorder. The risk of mortality with and without adjustment for known HLA risk factors (number and location of donor mismatches; patient HLA-B leader genotype and HLA-DRß peptide-binding motif) was studied using multivariable models. Survival after HLA-matched transplantation for patients with optimal leader and peptide-binding features was estimated for each race, as was the improvement in survival over calendar-year time by considering year of transplantation as a continuous linear variable. The number, location, and nature of donor HLA mismatches and the frequency of patient HLA-B and HLA-DRB1 sequence motifs differed by race. Japanese patients had superior survival compared to other races without consideration of HLA. After HLA adjustment, three mortality risk strata were identified: Japanese and U.S. Asian (low-risk); White and Hispanic (intermediate-risk), and Black patients (high-risk). Survival for patients with optimal donor and HLA characteristics was superior for Japanese, intermediate for U.S. Asian, White, and Hispanic, and lowest for Black patients. Five-year increments of transplant year were associated with greater decreases in mortality hazards for Black and Hispanic patients than for Japanese, U.S. Asian and White patients. Transplant survivorship disparities are influenced by HLA as a genetic construct of race. A more complete understanding of the factors that influence transplant outcomes provides opportunities to narrow disparities for future patients.

HLA-DQ heterodimers in hematopoietic cell transplantation.

HLA-DQ heterodimers increase the susceptibility to autoimmune diseases, but their role in hematopoietic cell transplantation is unknown. We tested the hypothesis that outcome after HLA-matched and HLA-DQ-mismatched hematopoietic cell transplantation is influenced by HLA-DQ heterodimers. Heterodimers were defined in 5164 HLA-matched and 520 HLA-DQ-mismatched patients and their transplant donors according to well-established crystallographic criteria. Group 1 (G1) heterodimers are any DQA1*02/03/04/05/06α paired with any DQB1*02/03/04ß. Group 2 (G2) heterodimers are DQA1*01α paired with any DQB1*05/06ß. Multivariable models identified significantly higher relapse risk in G1G2 and G2G2 compared with G1G1 HLA-matched patients with malignant disease; risk increased with an increasing number of G2 molecules. In HLA-DQ-mismatched transplantation for malignant diseases, matching or mismatching for G2 increased relapse risk. G2 lowered disease-free survival after both HLA-matched and HLA-DQ-mismatched transplantation. A paradigm based on HLA-DQ heterodimers provides a functional definition of the hematopoietic cell transplantation barrier and a means to lower risks for future patients.

HLA informs risk predictions after haploidentical stem cell transplantation with posttransplantation cyclophosphamide.

Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence, and survival after haploidentical donor transplantation with posttransplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1 mismatching with HLA-DQB1 matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-nonpermissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1, and -DPB1 predicted disease-free survival, as did patient and donor cytomegalovirus serostatus, patient age, and comorbidity index. A web-based tool was developed to facilitate selection of the best haploidentical-related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.

Use of the HLA-B leader to optimize cord blood transplantation

Cord-blood transplantation (CBT) can cure life-threatening blood disorders. The HLA-B leader affects the success of unrelated donor transplantation but its role in CBT is unknown. We tested the hypothesis that the HLA-B leader influences CBT outcomes in unrelated single-unit cord-blood transplants performed by Eurocord/European Blood and Marrow Transplant (EBMT) centers between 1990 and 2018 with data reported to Eurocord. Among 4822 transplants, 2178 had one HLA-B mismatch of which 1013 were HLA-A and HLA-DRB1-matched. The leader (M or T) was determined for each HLA-B allele in patients and units to define the genotype. Among single HLA-B-mismatched transplants, the patient/unit mismatched alleles were defined as leader-matched if they encoded the same leader, or leader-mismatched if they encoded different leaders; the leader encoded by the matched (shared) allele was determined. The risks of GVHD, relapse, non-relapse mortality and overall mortality were estimated for various leaderdefined groups using multivariable regression models. Among the 1013 HLA-A, -DRB1- matched transplants with one HLA-B mismatch, increasing numbers of cord-blood unit M-leader alleles was associated with increased risk of relapse (hazard ratio [HR] for each increase in one M-leader allele 1.30, 95% confidence interval [CI] 1.05 to 1.60, P 0.02). Furthermore, leader mismatching together with an M-leader of the shared HLA-B allele lowered non-relapse mortality (HR 0.44, 95% CI 0.23 to 0.81; P 0.009) relative to leader-matching and a shared T-leader allele. The HLA-B leader may inform relapse and non-relapse mortality risk after CBT. Future patients might benefit from the appropriate selection of units that consider the leader.

Role of HLA-DP Expression in Graft-Versus-Host Disease After Unrelated Donor Transplantation.

PURPOSE: The main aim of this study was to evaluate the significance of HLA-DPB1 expression in acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) from HLA-A, -B, -C, -DRB1, -DQB1-matched and -mismatched unrelated donors. PATIENTS AND METHODS: Between January 1, 2017, and January 10, 2019, we assessed 19,136 patients who received HCT from an HLA-A, -B, -C, -DRB1, -DQB1-matched or -mismatched unrelated donor performed in Australia, the European Union, Japan, North America, and the United Kingdom between 1988 and 2016. Among transplant recipients with one HLA-DPB1 mismatch, the patient's mismatched HLA-DPB1 allotype was defined as low or high expression. Multivariable regression models were used to assess risks of GVHD associated with high expression relative to low expression HLA-DPB1 mismatches. The effect of increasing numbers of HLA-DPB1 mismatches on clinical outcome was assessed in HLA-mismatched transplant recipients. RESULTS: In HLA-A, -B, -C, -DRB1,-DQB1-matched transplant recipients, donor mismatching against one high-expression patient HLA-DPB1 increased moderate (odds ratio [OR], 1.36; P = .001) and severe acute GVHD (OR, 1.32; P = .0016) relative to low-expression patient mismatches, regardless of the expression level of the donor's mismatched HLA-DPB1. Among transplant recipients with one HLA-A, -B, -C, -DRB1, or -DQB1 mismatch, the odds of acute GVHD increased with increasing numbers of HLA-DPB1 mismatches (OR, 1.23 for one; OR, 1.40 for two mismatches relative to zero mismatches for moderate GVHD; OR, 1.19 for one; OR, 1.40 for two mismatches relative to zero for severe GVHD), but not with the level of expression of the patient's mismatched HLA-DPB1 allotype. CONCLUSION: The level of expression of patient HLA-DPB1 mismatches informs the risk of GVHD after HLA-A, -B, -C, -DRB1, -DQB1-matched unrelated HCT, and the total number of HLA-DPB1 mismatches informs the risk of GVHD after HLA-mismatched unrelated HCT. Prospective consideration of HLA-DPB1 may help to lower GVHD risks after transplantation.

HLA-B leader and survivorship after HLA-mismatched unrelated donor transplantation.

Hematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B-mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1-mismatched MM patients compared with HLA-DQB1-mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1-mismatched MM or MT patients compared with HLA-DRB1-mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.

Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study.

BACKGROUND: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. METHODS: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. FINDINGS: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype. INTERPRETATION: The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials. FUNDING: The National Institutes of Health, USA.