Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia.

Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 × 10-13) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 × 10-6). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB1∗03:01, (OR 1.66, p = 1.52 × 10-7), DPB1∗10:01 (OR 2.12, p = 0.0003), and DPB1∗01:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 × 10-9) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.

Multiple functional variants in the IL1RL1 region are pretransplant markers for risk of GVHD and infection deaths.

Graft-versus-host disease (GVHD) and infections are the 2 main causes of death without relapse after allogeneic hematopoietic cell transplantation (HCT). Elevated soluble serum simulation-2 (sST2), the product of IL1RL1 in plasma/serum post-HCT, is a validated GVHD biomarker. Hundreds of SNPs at 2q12.1 have been shown to be strongly associated with sST2 concentrations in healthy populations. We therefore hypothesized that the donor genetic variants in IL1RL1 correlate with sST2 protein levels associated with patient survival outcomes after HCT. We used DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to 1-Year Mortality after Blood and Marrow Transplantation), a genomic study of >3000 donor-recipient pairs, to inform our hypothesis. We first measured pre-HCT plasma/serum sST2 levels in a subset of DISCOVeRY-BMT donors (n = 757) and tested the association of donor sST2 levels with donor single nucleotide polymorphisms (SNPs) in the 2q12.1 region. Donor SNPs associated with sST2 levels were then tested for association with recipient death caused by acute GVHD (aGVHD)-, infection-, and transplant-related mortality in cohorts 1 and 2. Meta-analyses of cohorts 1 and 2 were performed using fixed-effects inverse variance weighting, and P values were corrected for multiple comparisons. Donor risk alleles in rs22441131 (P meta = .00026) and rs2310241 (P meta = .00033) increased the cumulative incidence of aGVHD death up to fourfold and were associated with high sST2 levels. Donor risk alleles at rs4851601 (P meta = 9.7 × 10-7), rs13019803 (P meta = 8.9 × 10-6), and rs13015714 (P meta = 5.3 × 10-4) increased cumulative incidence of infection death to almost sevenfold and were associated with low sST2 levels. These functional variants are biomarkers of infection or aGVHD death and could facilitate donor selection, prophylaxis, and a conditioning regimen to reduce post-HCT mortality.

KIR Donor Selection: Feasibility in Identifying better Donors.

We previously reported that acute myelogenous leukemia (AML) transplants using killer cell immunoglobulin-type receptor (KIR) B haplotype better or best (≥2 B activating gene loci ± Cen B/B) unrelated donors (URDs) yield less relapse and better survival. In this prospective trial we evaluated 535 AML searches from 14 participating centers with centralized donor KIR genotyping for donor selection. This represented 3% to 48% of all AML searches (median 20%) per center, totaling 3 to 172 patients (median 22) per center. Donor KIR genotype was reported at a median of 14 days after request (≤26 days for 76% of searches). In 535 searches, 2080 donors were requested for KIR genotyping (mean 4.3 per search); and a median of 1.8 (range, 0 to 4.5) per search were KIR typed. Choosing more donors for confirmatory HLA and KIR haplotype identification enriched the likelihood of finding KIR better or best donors. The search process identified a mean of 30% KIR better or best donors; the success ranged from 24% to 38% in the 11 centers enrolling ≥8 patients. More donors requested for KIR genotyping increased the likelihood of identifying KIR better or best haplotype donors. Of the 247 transplants, 9.3% used KIR best, 19% used KIR better, and 48% used KIR neutral donors while 24% used a non-KIR-tested donor. KIR genotyping did not delay transplantation. The time from search to transplant was identical for transplants using a KIR-genotyped versus a non-KIR-genotyped donor. Prospective evaluation can rapidly identify KIR favorable genotype donors, but choosing more donors per search would substantially increase the likelihood of having a KIR best or better donor available for transplantation. Transplant centers and donor registries must both commit extra effort to incorporate new characteristics (beyond HLA, age, and parity) into improved donor selection. Deliberate efforts to present additional genetic factors for donor selection will require novel procedures.

The effect of NIMA matching in adult unrelated mismatched hematopoietic stem cell transplantation - a joint study of the Acute Leukemia Working Party of the EBMT and the CIBMTR.

Hematological malignancies can be cured by unrelated donor allogeneic HSCT and outcomes are optimized by high-resolution HLA matching at HLA-A, -B, -C, -DRB1 and -DQB1 (10/10 match). If a 10/10 match is unavailable, 9/10 matches may be suitable. Fetal exposure to non-inherited maternal antigens (NIMA) may impart lifelong NIMA tolerance modulating the immune response, as shown in adult haploidentical transplantation. In cord blood transplantation, NIMA matching lowered rates of aGvHD and TRM; in haploidentical transplantation, sibling donors with non-shared maternal antigens showed less grade II-IV aGvHD. This retrospective analysis examined if 9/10 matched unrelated donor HSCT benefits from NIMA matching. DKMS contacted 1,735 donors and obtained 733 (42%) maternal samples. NIMA-matched and -mismatched cases with a minimum follow-up of 1 year were compared by univariate and multivariate analyses adjusted for co-variates for OS, DFS, relapse, TRM and a/cGvHD. The study population (N = 445) comprised 31 NIMA-matched and 414 NIMA-mismatched cases. No significant differences between NIMA-matched and NIMA-mismatched groups were found for any outcomes with similar OS and TRM rates within both groups. This study provides the proof of principle that NIMA matching is possible in the unrelated donor HSCT setting; larger studies may be able to provide significant results.

Analysis of Single Nucleotide Polymorphisms in the Gamma Block of the Major Histocompatibility Complex in Association with Clinical Outcomes of Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Study.

HLA haplotype mismatches have been associated with an elevated risk of acute graft-versus-host disease (aGVHD) in patients undergoing HLA-matched unrelated donor (URD) hematopoietic cell transplantation (HCT). The gamma block (GB) is located in the central MHC region between beta and delta blocks (encoding HLA-B and -C and HLA-DQ and -DR antigens, respectively) and contains numerous inflammatory and immune regulatory genes, including Bf, C2, and C4 genes. A single-center study showed that mismatches in SNPs c.2918+98G, c.3316C, and c.4385C in the GB block (C4 SNPs) were associated with higher risk of grade III-IV aGVHD. We investigated the association of GB SNP (GBS) mismatches with outcomes after 10/10 and 9/10 URD HCT (n = 714). The primary outcome was acute GVHD. Overall survival, disease-free survival, transplantation-related mortality, relapse, chronic GVHD, and engraftment were also analyzed. DNA samples were GBS genotyped by identifying 338 SNPs across 20 kb using the Illumina NGS platform. The overall 100-day incidence of aGVHD grade II-IV and II-IV were 41% and 17%, respectively. The overall incidence of matching at all GBSs tested and at the C4 SNPs were 23% and 81%, respectively. Neither being matched across all GB SNPs tested (versus mismatched) nor having a higher number of GBS mismatches was associated with transplantation outcomes. There was no association between C4 SNP mismatches and outcomes except for an unexpected significant association between having 2 C4 SNP mismatches and a higher hazard ratio (HR) for relapse (association seen in 15 patients only; HR, 3.38, 95% confidence interval, 1.75 to 6.53; P = .0003). These data do not support the hypothesis that mismatching at GB is associated with outcomes after HCT.

Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis.

Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved overall survival (OS) were reduced-intensity conditioning (hazard ratio [HR] of death, .76) and good performance status (HR, .46), whereas alloHCT in nonremission (HR, 1.96) and mismatched donors (HR, 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A versus B/x KIR haplotypes and those with KIR gene content scores of 0 versus 1 versus ≥2 yielded similar rates of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival and OS. Relapse risk was not different for grafts from donors with KIR3DL1 transplanted into HLA C1/1 versus C2 recipients. This large analysis failed to demonstrate an association between URD KIR genotype and transplant outcome for patients with CLL, and thus KIR genotyping should not be used as a donor selection criterion in this setting.

Chromosome Y-encoded antigens associate with acute graft-versus-host disease in sex-mismatched stem cell transplant.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a curative option for blood cancers, but the coupled effects of graft-versus-tumor and graft-versus-host disease (GVHD) limit its broader application. Outcomes improve with matching at HLAs, but other factors are required to explain residual risk of GVHD. In an effort to identify genetic associations outside the major histocompatibility complex, we conducted a genome-wide clinical outcomes study on 205 acute myeloid leukemia patients and their fully HLA-A-, HLA-B-, HLA-C-, HLA-DRB1-, and HLA-DQB1-matched (10/10) unrelated donors. HLA-DPB1 T-cell epitope permissibility mismatches were observed in less than half (45%) of acute GVHD cases, motivating a broader search for genetic factors affecting clinical outcomes. A novel bioinformatics workflow adapted from neoantigen discovery found no associations between acute GVHD and known, HLA-restricted minor histocompatibility antigens (MiHAs). These results were confirmed with microarray data from an additional 988 samples. On the other hand, Y-chromosome-encoded single-nucleotide polymorphisms in 4 genes (PCDH11Y, USP9Y, UTY, and NLGN4Y) did associate with acute GVHD in male patients with female donors. Males in this category with acute GVHD had more Y-encoded variant peptides per patient with higher predicted HLA-binding affinity than males without GVHD who matched X-paralogous alleles in their female donors. Methods and results described here have an immediate impact for allo-HCT, warranting further development and larger genomic studies where MiHAs are clinically relevant, including cancer immunotherapy, solid organ transplant, and pregnancy.

Patient HLA Germline Variation and Transplant Survivorship.

Purpose HLA mismatching increases mortality after unrelated donor hematopoietic cell transplantation. The role of the patient's germline variation on survival is not known. Patients and Methods We previously identified 12 single nucleotide polymorphisms within the HLA region as markers of transplantation determinants and tested these in an independent cohort of 1,555 HLA-mismatched unrelated transplants. Linkage disequilibrium mapping across class II identified candidate susceptibility features. The candidate gene was confirmed in an independent cohort of 3,061 patients. Results Patient rs429916AA/AC was associated with increased transplantation-related mortality compared with rs429916CC (hazard ratio [HR], 1.39; 95% CI, 1.12 to 1.73; P = .003); rs429916A positivity was a proxy for DOA*01:01:05. Mortality increased with one (HR, 1.17; 95% CI, 1.0 to 1.36; P = .05) and two (HR, 2.51; 95% CI, 1.41 to 4.45; P = .002) DOA*01:01:05 alleles. HLA-DOA*01:01:05 was a proxy for HLA-DRB1 alleles encoding FEY ( P < 10E-15) and FDH ( P < 10E-15) amino acid substitutions at residues 26/28/30 that influence HLA-DRß peptide repertoire. FEY- and FDH-positive alleles were positively associated with rs429916A ( P < 10E-15); FDY-positive alleles were negatively associated. Mortality was increased with FEY (HR, 1.66; 95% CI, 1.29 to 2.13; P = .00008) and FDH (HR, 1.40; 95% CI, 1.02 to 1.93; P = .04), whereas FDY was protective (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). Of the three candidate motifs, FEY was validated as the susceptibility determinant for mortality (HR, 1.29; 95% CI, 1.00 to 1.67; P = .05). Although FEY was found frequently among African and Hispanic Americans, it increased mortality independently of ancestry. Conclusion Patient germline HLA-DRB1 alleles that encode amino acid substitutions that influence the peptide repertoire of HLA-DRß predispose to increased death after transplantation. Patient germline variation informs transplantation outcomes across US populations and may provide a means to reduce risks for high-risk patients through pretransplantation screening and evaluation.

Chromosomal Aberrations and Survival after Unrelated Donor Hematopoietic Stem Cell Transplant in Patients with Fanconi Anemia.

Studies of chromosomal aberrations in blood or bone marrow of patients with Fanconi anemia (FA) have focused on their associations with leukemic transformation. The role of such abnormalities on outcomes after hematopoietic cell transplantation (HCT) is unclear. We used genome-wide single nucleotide polymorphism arrays to identify chromosomal aberrations in pre-HCT blood samples from 73 patients with FA who received unrelated donor HCT for severe aplastic anemia between 1991 and 2007. Outcome data and blood samples were available through the Center for International Blood and Marrow Transplant Research. For survival analyses, we used the Kaplan-Meier estimator to calculate the survival probabilities and the exact log-rank test to compare the survival differences across groups. Chromosomal aberrations were detected in 16 (22%) patients; most frequent were clonal copy loss in chromosome 7 (9.6%), clonal copy gains in the long arm (q) of chromosome 1 (chr1q+) (8.2%), and clonal or complete copy gains in the q arm of chromosome 3 (chr3q+) (8.2%). Seven (9.6%) patients had alterations in 3 or more chromosomes. Poor post-HCT overall survival (OS) was noted in patients with chr3q+ (P = .04), or those with abnormalities in ≥3 chromosomes (P = .03). The 1-year OS was 0% versus 45% in patients with either alteration versus its absence. No statistically significant differences in OS were noted in patients carrying deletions in chr7 (1-year OS = 29% versus 42%; log-rank P = .74). The study is limited by the small sample size. A larger, prospective study is warranted to validate our findings in light of recent improvement in transplant modalities and outcomes.

Donor telomere length and causes of death after unrelated hematopoietic cell transplantation in patients with marrow failure.

Previous studies have suggested that longer donor leukocyte telomere length (TL) is associated with improved survival after hematopoietic cell transplantation (HCT) in severe aplastic anemia (SAA). This study aimed to determine whether cell-specific lymphocyte TL is associated with certain post-HCT causes of death. We used flow cytometry and fluorescence in situ hybridization to measure TL in donor total lymphocytes and subsets: naïve enriched T cells (CD45RA+CD20-), memory enriched T cells (CD45RA-CD20-), natural killer (NK) fully differentiated T cells (CD45RA+CD57+), and B cells (CD45RA+CD20+). Competing risk survival regression was used for cause-specific death analyses. Clinical data and biospecimens were available from the Center for International Blood and Marrow Transplant Research database and biorepository. The study included 197 patients who underwent unrelated-donor HCT for SAA between 1988 and 2004. The median age at HCT was 15 years (range, 0.5-40 years), and the median follow-up was 5 years (range, <1 month to 20.7 years). Longer donor TL in all cell subsets was associated with lower risk of all-cause mortality (P < .01). In cause-specific mortality analyses, longer TL in B cells (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.46-0.87; P = .006) and possibly NK fully differentiated T cells (HR, 0.7; 95% CI, 0.51 to 0.97; P = .03) was associated with lower risk of infection-related death. Donor TL in other tested lymphocyte subsets was not statistically significantly associated with death resulting from graft-versus-host disease or graft failure (P > .05). However, a trend toward excess risk of graft-versus-host mortality was noted (HR for total lymphocyte TL, 1.26; P = .15). In conclusion, longer donor TL was associated with reduced rate of infection-related deaths after HCT for SAA.

No association between donor telomere length and outcomes after allogeneic unrelated hematopoietic cell transplant in patients with acute leukemia.

Recent studies suggest improved survival in patients with severe aplastic anemia receiving hematopoietic cell transplant (HCT) from unrelated donors with longer telomeres. Here, we tested whether this effect is generalizable to patients with acute leukemia. From the Center for International Blood and Marrow Transplant Research (CIBMTR®) database, we identified 1097 patients who received 8/8 HLA-matched unrelated HCT for acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) between 2004 and 2012 with myeloablative conditioning, and had pre-HCT blood sample from the donor in CIBMTR repository. The median age at HCT for recipients was 40 years (range ≤1-68), and 32 years for donors (range = 18-61). We used qPCR for relative telomere length (RTL) measurement, and Cox proportional hazard models for statistical analyses. In a discovery cohort of 300 patients, longer donor RTL (>25th percentile) was associated with reduced risks of relapse (HR = 0.62, p = 0.05) and acute graft-versus-host disease II-IV (HR = 0.68, p = 0.05), and possibly with a higher probability of neutrophil engraftment (HR = 1.3, p = 0.06). However, these results did not replicate in two validation cohorts of 297 and 488 recipients. There was one exception; a higher probability of neutrophil engraftment was observed in one validation cohort (HR = 1.24, p = 0.05). In a combined analysis of the three cohorts, no statistically significant associations (all p > 0.1) were found between donor RTL and any outcomes.

Impact of HLA Alleles on Outcomes of Allogeneic Transplantation for B Cell Non-Hodgkin Lymphomas: A Center for International Blood and Marrow Transplant Research Analysis.

Even in the modern era of targeted therapies, allogeneic hematopoietic stem cell transplantation (allo-HCT) can offer a chance of extended survival in B cell non-Hodgkin lymphoma (B-NHL) patients who relapse after or are deemed ineligible for autologous transplantation. A better understanding of the factors influencing the graft-versus-lymphoma (GVL) response would be useful in identifying B-NHL patients who may benefit from allo-HCT. Based on prior single-center reports, we hypothesized that certain HLA alleles, or haplotypes, may be associated with superior GVL compared with others after allo-HCT. To test this possibility we retrospectively evaluated whether the presence of HLA-A2, HLA-C1C1, HLA-DRB1*01:01, or HLA-DRB1*13 alleles or the presence of HLA-A1+, HLA-A2-, and HLA-B44- haplotypes is associated with outcomes in a cohort of 1314 HLA-8/8 matched sibling or unrelated donor HCT for relapsed/refractory B-NHL. We observed no significant association between any HLA allele or haplotype and overall survival or any of the secondary endpoints. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-NHL patients based on HLA type. Identification of other variables will be required to delineate the immunologic impact of donor-host interactions on outcomes of allo-HCT for B-NHL.

KIR3DL1/HLA-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation.

Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells-upregulated in the post-HCT environment-signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity. We hypothesized that varied strengths of inhibition among subtypes of the ubiquitous KIR3DL1 and its cognate ligand, HLA-B, would titrate NK reactivity against acute myelogenous leukemia (AML). Patients and Methods By using an algorithm that was based on polymorphism-driven expression levels and specificities, we predicted and tested inhibitory and cytotoxic NK potential on the basis of KIR3DL1/HLA-B subtype combinations in vitro and evaluated their impact in 1,328 patients with AML who underwent HCT from 9/10 or 10/10 HLA-matched unrelated donors. Results Segregated by KIR3DL1 subtype, NK cells demonstrated reproducible patterns of strong, weak, or noninhibition by target cells with defined HLA-B subtypes, which translated into discrete cytotoxic hierarchies against AML. In patients, KIR3DL1 and HLA-B subtype combinations that were predictive of weak inhibition or noninhibition were associated with significantly lower relapse (hazard ratio [HR], 0.72; P = .004) and overall mortality (HR, 0.84; P = .030) compared with strong inhibition combinations. The greatest effects were evident in the high-risk group of patients with all KIR ligands (relapse: HR, 0.54; P < .001; and mortality: HR, 0.74; P < .008). Beneficial effects of weak and noninhibiting KIR3DL1 and HLA-B subtype combinations were separate from and additive to the benefit of donor activating KIR2DS1. Conclusion Consideration of KIR3DL1-mediated inhibition in donor selection for HLA-matched HCT may achieve superior graft versus leukemia effects, lower risk for relapse, and an increase in survival among patients with AML.

Relative Telomere Length before Hematopoietic Cell Transplantation and Outcome after Unrelated Donor Hematopoietic Cell Transplantation for Acute Leukemia.

Telomeres are tandem nucleotide repeats and a protein complex located at the end of the chromosomes maintaining genomic stability. Their potential as a predictive biomarker for outcomes after allogeneic hematopoietic cell transplant (HCT) in hematologic malignancies is still unclear. From the Center for International Blood and Marrow Transplant Research we randomly selected 536 acute leukemia patients from those who underwent myeloablative 8/8 HLA-matched unrelated donor HCT between 2005 and 2012 and who had an available pre-HCT blood sample in the repository. Relative telomere length (RTL) was measured by real-time quantitative PCR. We used Kaplan-Meier and competing risk estimators to calculate survival probability and cumulative incidence, respectively, across patient RTL tertiles. Cox proportional hazard regression was used for adjusted analyses. The study included 396 acute myeloid leukemia (AML) and 140 acute lymphoblastic leukemia (ALL) patients. Median age at HCT was 41 years (range, .5 to 66), and median follow-up for survivors was 5.1 years (range, .4 to 8.3). Significant inverse correlations between age and RTL were observed in patients with AML (r = -.44, P < .0001) and ALL (r = -.48, P < .0001). Patients with ALL had longer RTL than those with AML (.48 versus .43, respectively); the difference was not statistically significant after adjusting for patient age (P = .96). Pre-HCT RTL in acute leukemia patients was not statistically significantly associated with overall survival (HR for longest RTL compared with shortest, .91; 95% CI, .65 to 1.28), disease-free survival (HR, .90; 95% CI, .64 to 1.25), transplant-related mortality (HR, .97; 95% CI, .60 to 1.59), incidence of relapse (HR, .89; 95% CI, .56 to 1.40), neutrophil engraftment (HR, 1.06; 95% CI, .85 to 1.32), or grades II to IV acute graft-versus-host disease (HR, 1.11; 95% CI, .81 to 1.53), grades III-IV acute graft-versus-host disease (HR, .92; 95% CI, .54 to 1.59), and chronic graft-versus-host disease (HR, 1.10; 95% CI, .81 to 1.50). In this study, recipient pre-HCT RTL had no prognostic role in post-transplant outcomes in acute leukemia patients.

Investigating the Association of Genetic Admixture and Donor/Recipient Genetic Disparity with Transplant Outcomes.

Disparities in survival after allogeneic hematopoietic cell transplantation have been reported for some race and ethnic groups, despite comparable HLA matching. Individuals' ethnic and race groups, as reported through self-identification, can change over time because of multiple sociological factors. We studied the effect of 2 measures of genetic similarity in 1378 recipients who underwent myeloablative first allogeneic hematopoietic cell transplantation between 1995 and 2011 and their unrelated 10 of 10 HLA-A, -B, -C, -DRB1, and-DQB1- matched donors. The studied factors were as follows (1) donor and recipient genetic ancestral admixture and (2) pairwise donor/recipient genetic distance. Increased African genetic admixture for either transplant recipients or donors was associated with increased risk of overall mortality (hazard ratio [HR], 2.26; P = .005 and HR, 3.09; P = .0002, respectively) and transplant-related mortality (HR, 3.3; P = .0003 and HR, 3.86; P = .0001, respectively) and decreased disease-free survival (HR, 1.9; P = .02 and HR, 2.46; P = .002 respectively). The observed effect, albeit statistically significant, was relevant to a small subset of the studied population and was notably correlated with self-reported African-American race. We were not able to control for other nongenetic factors, such as access to health care or other socioeconomic factors; however, the results suggest the influence of a genetic driver. Our findings confirm what has been previously reported for African-American recipients and show similar results for donors. No significant association was found with donor/recipient genetic distance.

Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation.

BACKGROUND: Genetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after allogeneic hematopoietic stem-cell transplantation. METHODS: We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014. We evaluated the association of mutations with transplantation outcomes, including overall survival, relapse, and death without relapse. RESULTS: TP53 mutations were present in 19% of the patients and were associated with shorter survival and a shorter time to relapse than was the absence of TP53 mutations, after adjustment for significant clinical variables (P<0.001 for both comparisons). Among patients 40 years of age or older who did not have TP53 mutations, the presence of RAS pathway mutations was associated with shorter survival than was the absence of RAS pathway mutations (P=0.004), owing to a high risk of relapse, and the presence of JAK2 mutations was associated with shorter survival than was the absence of JAK2 mutations (P=0.001), owing to a high risk of death without relapse. The adverse prognostic effect of TP53 mutations was similar in patients who received reduced-intensity conditioning regimens and those who received myeloablative conditioning regimens. By contrast, the adverse effect of RAS pathway mutations on the risk of relapse, as compared with the absence of RAS pathway mutations, was evident only with reduced-intensity conditioning (P<0.001). In young adults, 4% of the patients had compound heterozygous mutations in the Shwachman-Diamond syndrome-associated SBDS gene with concurrent TP53 mutations and a poor prognosis. Mutations in the p53 regulator PPM1D were more common among patients with therapy-related MDS than those with primary MDS (15% vs. 3%, P<0.001). CONCLUSIONS: Genetic profiling revealed that molecular subgroups of patients undergoing allogeneic hematopoietic stem-cell transplantation for MDS may inform prognostic stratification and the selection of conditioning regimen. (Funded by the Edward P. Evans Foundation and others.).

Recipient HLA-C Haplotypes and microRNA 148a/b Binding Sites Have No Impact on Allogeneic Hematopoietic Cell Transplantation Outcomes.

Natural killer cells are important in graft-versus-leukemia responses after hematopoietic cell transplantation (HCT). A variety of surface receptors dictates natural killer cell function, including killer cell immunoglobulin-like receptor recognition of HLA-C. Previous single-center studies show that HLA-C epitopes, designated C1 and C2, were associated with allogeneic HCT outcomes; specifically, recipients homozygous for the C1 epitope (C1/C1) experienced a survival benefit. Additionally, mismatching at HLA-C was beneficial in recipients possessing at least 1 C2 allele, whereas the opposite was true for homozygous C1 (C1/C1) recipients where HLA-C mismatching resulted in worse outcomes. In this analysis we aimed to validate these findings in a large multicenter study. We also set out to determine whether surface expression of recipient HLA-C, determined by polymorphism in a microRNA (miR-148a/b) binding site within the 3'-region of the HLA-C transcript, was associated with transplant outcomes. In this large registry cohort, we were unable to confirm the prior findings regarding recipient HLA-C epitope status and outcome. Additionally, HLA-C surface expression (ie, surface density), as predicted by the miR-148a/b binding single nucleotide polymorphism, was also not with associated transplant outcomes. Collectively, neither HLA-C surface expression, as determined by miR-148a/b, nor recipient HLA-C epitopes (C1, C2) are associated with allogeneic HCT outcomes.

Effect of Recipient Age and Stem Cell Source on the Association between Donor Telomere Length and Survival after Allogeneic Unrelated Hematopoietic Cell Transplantation for Severe Aplastic Anemia.

We previously showed an association between donor leukocyte relative telomere length (RTL) and post-hematopoietic cell transplantation (HCT) survival in patients with severe aplastic anemia (SAA) who received bone marrow grafts at ages <40 years. Here, we tested the generalizability of the prior findings in an independent validation cohort and by recipient age and stem cell source in the combined discovery and validation cohorts. We used monoplex quantitative real-time PCR to measure RTL in: (1) a new SAA validation cohort of 428 patients (age range, .2 to 77 years) with available pretransplantation donor blood samples in the Center for International Blood and Marrow Transplant Research repository, and (2) 278 patients from the original cohort who had sufficient DNA to repeat RTL testing. We used Cox proportional hazard models to calculate hazard ratios (HRs), and 95% confidence intervals (CIs) across categories of donor RTL. Data from the validation cohort showed no association between donor RTL and patient survival, but further analysis identified differences by recipient age and stem cell source as the likely explanation. In patients <40 years, the HR comparing longest with shortest and middle RTL tertiles = .75; 95% CI, .44 to 1.30 versus HR = 1.05; 95% CI, .59 to 1.89 for patients ≥40 years, P interaction = .37. In bone marrow recipients, the HR = .68; 95% CI, .72 to 1.10 versus HR = 1.29; 95% CI, .64 to 2.62 for peripheral blood stem cell grafts; P interaction = .88. Analyses using data from the 2 cohorts showed a statistically significant survival benefit only in <40-year-old patients receiving bone marrow graft (HR comparing longest and middle RTL tertiles with shortest = .69; 95% CI, .50 to .95, P = .02). The study suggested that the association between donor RTL and post-HCT outcomes in recipients with SAA may vary by recipient age and stem cell source. A larger study is needed to account for multiple comparisons and to further test the generalizability of our findings.

Donor KIR B Genotype Improves Progression-Free Survival of Non-Hodgkin Lymphoma Patients Receiving Unrelated Donor Transplantation.

Donor killer immunoglobulin-like receptor (KIR) genotypes are associated with relapse protection and survival after allotransplantation for acute myelogenous leukemia. We examined the possibility of a similar effect in a cohort of 614 non-Hodgkin lymphoma (NHL) patients receiving unrelated donor (URD) T cell-replete marrow or peripheral blood grafts. Sixty-four percent (n = 396) of donor-recipient pairs were 10/10 allele HLA matched and 26% were 9/10 allele matched. Seventy percent of donors had KIR B/x genotype; the others had KIR A/A genotype. NHL patients receiving 10/10 HLA-matched URD grafts with KIR B/x donors experienced significantly lower relapse at 5 years (26%; 95% confidence interval [CI], 21% to 32% versus 37%; 95% CI, 27% to 46%; P = .05) compared with KIR A/A donors, resulting in improved 5-year progression-free survival (PFS) (35%; 95% CI, 26% to 44% versus 22%; 95% CI, 11% to 35%; P = .007). In multivariate analysis, use of KIR B/x donors was associated with significantly reduced relapse risk (relative risk [RR], .63, P = .02) and improved PFS (RR, .71, P = .008). The relapse protection afforded by KIR B/x donors was not observed in HLA-mismatched transplantations and was not specific to any particular KIR-B gene. Selecting 10/10 HLA-matched and KIR B/x donors should benefit patients with NHL receiving URD allogeneic transplantation.