Selection of Cord Blood Unit by CD34+ Cell and GM-CFU Numbers and Allele-Level HLA Matching in Single Cord Blood Transplantation.

In Japan, only single-unit cord blood transplantations (CBTs) are typically performed, and their number has increased over the last 23 years, with ongoing improvement in results. In most cases, CBTs with multiple HLA mismatches are used, owing to a low HLA barrier, and lower engraftment rate is a problem that must be overcome. Here, as part of an effort to improve guidelines for the selection and processing of CB units for transplantation, we sought to assess the present status of CBT in Japan and to elucidate factors contributing to the favorable outcomes, focusing in particular on selection by cell components of CB unit and HLA allele matching. We conducted a nationwide study analyzing 13,443 patients who underwent first CBT between in Japan between December 1997 and December 2019 using multivariate regression analysis. Both patient- and transplantation-related variables, such as age and Hematopoietic Cell Transplantation Comorbidity Index, as well as selected CB unit characteristics, were included in the analysis. The interaction analysis elucidated that CB unit selection favoring higher counts of CD34+ cells and granulocyte macrophage colony-forming units (GM-CFU)/kg, but not of total nucleated cells, contributed to improved engraftment after transplantation. Moreover, a higher CD34+ cell dose was associated with improved overall survival (OS). Distinctive HLA allele matching was observed. A 0 or 1 HLA allele mismatch between patient and donor had favorable engraftment and carried significantly lower risks of acute GVHD and chronic GVHD but had a significantly higher leukemia relapse rate, compared with a 3-HLA allele mismatch. HLA-DRB1 mismatches were associated with reduced risk of leukemia relapse. Notably, the number of HLA allele mismatches had no incremental effect on engraftment, acute and chronic GVHD, or relapse incidence. As a result, 5-year overall survival did not differ significantly among patients receiving CB units with 0 to 7 HLA allele mismatches. The main points of CB unit selection are as follows. First, selection according to a higher number of CD34+ cells/kg and then of CFU-GM/kg is recommended to obtain favorable engraftment. A unit with .5 × 105 CD34+ cells/kg is minimally acceptable. For units with a CD34+ cell dose of .5 to 1.0 × 105 cells/kg, applying the parameter of ≥20 to 50 × 103 GM-CFU/kg (66.5% of transplanted CB units in this cohort) is associated with a neutrophil engraftment rate of approximately 90%. A unit with ≥1.0 × 105 CD34+ cells/kg can achieve a ≥90% mean neutrophil engraftment rate. Subsequently, HLA allele matching of HLA-A, -B, -C, and -DRB1 at the 2-field level should be searched for units with 0 or 1 HLA allele mismatch in the host-versus-graft direction for favorable engraftment. Units with 2 to 6 HLA allele mismatches are acceptable in patients age ≥15 years and units with 2 to 4 HLA allele mismatches are acceptable in patients age ≤14 years. Units with HLA-DRB1 and/or -B allele mismatch(es) might not be preferable owing to an increased GVHD risk. Our analysis demonstrates that single-unit CBT with the selection of adequate CD34+/kg and GM-CFU/kg and HLA allele matching showed favorable outcomes in both pediatric and adult patients.

Long-term follow-up after R-High CHOP/CHASER/LEED with Auto-PBSCT in untreated mantle cell lymphoma-Final analysis of JCOG0406.

Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.

Sequence Variations Within HLA-G and HLA-F Genomic Segments at the Human Leukocyte Antigen Telomeric End Associated With Acute Graft-Versus-Host Disease in Unrelated Bone Marrow Transplantation.

Acute graft-versus-host disease (aGVHD) is defined as a syndrome of an immunological response of graft to the host that occurs early after allogeneic hematopoietic stem cell transplantation (HCT). This disease is frequently observed even in HCT matched for human leukocyte antigen (HLA) alleles at multiple gene loci. Although the HLA region represents complex and diverse genomic characteristics, detailed association analysis is required for the identification of uncharacterized variants that are strongly associated with aGVHD. We genotyped three loci, OR2H2, HLA-F-AS1, and HLA-G, that are located in the 460 kb of HLA telomeric region and statistically analyzed the genotypes including HLA-DPB1 with clinical and transplantation outcomes using 338 unrelated bone marrow transplantation (UR-BMT) patient-donor pairs who were matched for HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 (HLA-10/10). Multivariate analyses demonstrated that HLA-F-AS1 and HLA-DPB1 mismatches were associated with grade II-IV aGVHD (hazard ratio (HR), 1.76; 95% CI, 1.07-2.88; p = 0.026; and HR, 1.59; CI, 1.02-2.49; p = 0.042, respectively). There was no confounding between HLA-F-AS1 and HLA-DPB1 (p = 0.512), suggesting that the HLA-F-AS1 mismatch has a strong effect on aGVHD independently of HLA-DPB1. Moreover, a stratified analysis suggested possible associations of HLA-F-AS1, HLA-DPB1, and/or HLA-G mismatches with grade II-IV aGVHD and the more severe grade III-IV aGVHD. These findings provide new insights into understanding the molecular mechanism of aGVHD caused by HLA-matched UR-BMT.

Effect of Cryopreservation in Unrelated Bone Marrow and Peripheral Blood Stem Cell Transplantation in the Era of the COVID-19 Pandemic: An Update from the Japan Marrow Donor Program.

During the COVID-19 pandemic, donor grafts are frequently cryopreserved to ensure that a graft is available before starting a conditioning regimen. However, there have been conflicting reports on the effect of cryopreservation on transplantation outcomes. Also, the impact of cryopreservation may differ in bone marrow (BM) transplantation (BMT) and peripheral blood stem cell (PBSC) transplantation (PBSCT). In this retrospective study, we analyzed the clinical data of both cryopreserved unrelated BMTs (n = 235) and PBSCTs (n = 118) and compared these with data from a large control cohort without cryopreservation including 4133 BMTs and 720 PBSCTs. Among the patients with cryopreserved grafts, 10 BMT recipients (4.3%) and 3 PBSCT recipients (2.5%) did not achieve neutrophil engraftment after transplantation, including 4 of the former and all 3 of the latter who died early before engraftment. In a multivariate analysis, cryopreservation was not associated with neutrophil engraftment in BMT but significantly delayed neutrophil engraftment in PBSCT (hazard ratio [HR], .82; 95% confidence interval [CI], .69 to .97; P = .023). There was an interaction with borderline significance between cryopreservation and the stem cell source (P = .067). Platelet engraftment was delayed by cryopreservation after both BMT and PBSCT. Only 2 cryopreserved grafts (<1%) were unused during the study period. The cryopreservation of unrelated donor BM and PBSC grafts is associated with a slight delay in neutrophil and platelet engraftment but an acceptable rate of graft failure. PBSC grafts may be more sensitive to cryopreservation than BM grafts. Cryopreservation is a reasonable option during COVID-19 pandemic, provided that the apheresis and transplantation centers are adept at cryopreservation. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

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.

Analysis of Relationships between Immune Checkpoint and Methylase Gene Polymorphisms and Outcomes after Unrelated Bone Marrow Transplantation.

Unrelated bone marrow transplantation (uBMT) is performed to treat blood disorders, and it uses bone marrow from an unrelated donor as the transplant source. Although the importance of HLA matching in uBMT has been established, that of other genetic factors, such as single-nucleotide polymorphisms (SNPs), remains unclear. The application of immunoinhibitory receptors as anticancer drugs has recently been attracting attention. This prompted us to examine the importance of immunoinhibitory receptor SNPs in uBMT. We retrospectively genotyped five single-nucleotide polymorphisms (SNPs) in the immune checkpoint genes, BTLA, PD-1, LAG3, and CTLA4, and two SNPs in the methylase genes, DNMT1 and EZH2, in 999 uBMT donor-recipient pairs coordinated through the Japan Marrow Donor Program matched at least at HLA-A, -B, and -DRB1. No correlations were observed between these SNPs and post-uBMT outcomes (p > 0.005). This result questions the usefulness of these immune checkpoint gene polymorphisms for predicting post-BMT outcomes. However, the recipient EZH2 histone methyltransferase gene SNP, which encodes the D185H substitution, exhibited a low p-value in regression analysis of grade 2-4 acute graft-versus-host disease (p = 0.010). Due to a low minor allele frequency, this SNP warrants further investigation in a larger-scale study.

Combined impact of HLA-allele matching and the CD34-positive cell dose on optimal unit selection for single-unit cord blood transplantation in adults.

The combined effects of HLA-allele matching at six-loci (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) and CD34+ cell dose on clinical outcomes were analyzed in 1,226 adult cases with single-unit unrelated cord blood transplantation. In the six-loci analysis, low HLA-allele matches did not significantly increase the overall mortality compared to higher matches, whereas in the five-loci analysis excluding HLA-DPB1, they caused a higher overall mortality (HR 1.42, p = .002), possibly due to the graft-versus-leukemia effect of HLA-DPB1 mismatches. A lower CD34+ cell dose (<.50 × 105/kg) resulted in higher mortality and lower engraftment; these inferior outcomes were offset by high HLA-allele matches (7-10/10 match), while the inferior outcomes of low HLA-allele matches were improved by increasing the CD34+ cell dose. Consideration of the combined effects of the CD34+ cell dose and HLA matching may expand the options for transplantable units when HLA matching or the CD34+ cell dose is inadequate.

Cryopreservation of Unrelated Hematopoietic Stem Cells from a Blood and Marrow Donor Bank During the COVID-19 Pandemic: A Nationwide Survey by the Japan Marrow Donor Program.

During the COVID-19 pandemic, donor hematopoietic stem cell grafts are frequently cryopreserved to ensure the availability of graft before starting a conditioning regimen. However, the safety of cryopreservation has been controversial in unrelated hematopoietic stem cell transplantation (HSCT), especially for bone marrow (BM) grafts. In addition, in unrelated HSCT, the effect of the time from harvest to cryopreservation of donor grafts required for the transportation of donor graft has not been fully clarified. In this study, we retrospectively analyzed the first 112 patients with available data who underwent cryopreserved unrelated blood and marrow transplantation through the Japan Marrow Donor Program during the COVID-19 pandemic. There were 112 patients, including 83 who received BM grafts and 29 who received peripheral blood stem cell (PBSC) grafts. The median time from stem cell harvest to cryopreservation was 9.9 hours (range, 2.6 to 44.0 hours), and the median time from cryopreservation to infusion was 231.2 hours. The incidence of neutrophil engraftment at day 28 after HSCT was 91.1%, and among 109 patients (excluding 3 patients with early death), all but 1 patient achieved neutrophil engraftment within 60 days after HSCT. The time to neutrophil engraftment and time to platelet engraftment were shorter in PBSC transplantation compared with BM transplantation (BMT), but the differences were not statistically significant (P = .064 and .18). Multivariate analysis among BM recipients revealed that a higher number of frozen nucleated cells and the absence of HLA mismatch were associated with faster neutrophil engraftment. The time to neutrophil engraftment after unrelated cryopreserved BMT was not different from that after unrelated BMT without cryopreservation. Our findings suggest that unrelated donor BM and PBSC grafts can be safely cryopreserved even after transit from the harvest center to the transplantation center. In the current COVID-19 pandemic, cryopreservation can be considered as an option while balancing the risks and benefits of the procedure.

Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation.

UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.

Individual HLAs influence immunological events in allogeneic stem cell transplantation from HLA-identical sibling donors.

In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the effects of patient and donor human leukocyte antigen (HLA) matching status on graft-versus-host disease (GVHD) have been extensively elucidated, but the effects of specific HLAs on acute GVHD remain unclear. Using data from a Japanese registry, we retrospectively analyzed 4392 patients with leukemia or myelodysplastic syndrome who received transplants from HLA-identical sibling donors to investigate the effects of HLAs on acute GVHD. From unbiased searches of HLA-A, -B, and -DR, HLA-B60 was significantly associated with an increased risk of grades II-IV acute GVHD (HR, 1.34; 95% CI, 1.13-1.59; P = 0.001). In contrast, HLA-B62 was significantly associated with a decreased risk of grades II-IV (HR, 0.73; 95% CI, 0.62-0.87; P < 0.001) and III-IV acute GVHD (HR, 0.63; 95% CI, 0.46-0.87; P = 0.005). The risk of leukemia relapse was significantly higher in HLA-B62-positive patients than in HLA-B62-negative patients (HR, 1.23; 95% CI, 1.05-1.43; P = 0.01). Both HLA-B60 and -B62 did not affect overall survival. The findings of this study may by implication suggest the possibility that the effects of specific HLAs on transplant outcomes may reflect inherent biological features, and thus consideration of specific HLAs may be helpful to predict transplant outcomes.

Retraction Note to: High-dose therapy and autologous stem cell transplantation for relapsed or high-risk diffuse large B-cell lymphoma: a nationwide survey.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s12185-020-03018-1.

R-CHOP-14 versus R-CHOP-14/CHASER for upfront autologous transplantation in diffuse large B-cell lymphoma: JCOG0908 study.

The efficiency of upfront consolidation with high-dose chemotherapy/autologous stem-cell transplantation (HDCT/ASCT) for newly diagnosed high-risk diffuse large B-cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high-risk DLBCL patients having an age-adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R-CHOP-14 (arm A) or 3 cycles of R-CHOP-14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2-y progression-free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow-up of 40.3 mo, 2-y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%-81.2%) and 66.7% (95% CI: 48.8%-79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%-85.7%) and 83.3% (95% CI: 66.6%-92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non-hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R-CHOP-14 showed higher 2-y PFS and less toxicity compared with R-CHOP-14/CHASER in patients with high-risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN-CTR, UMIN000003823).

Capturing Differential Allele-Level Expression and Genotypes of All Classical HLA Loci and Haplotypes by a New Capture RNA-Seq Method.

The highly polymorphic human major histocompatibility complex (MHC) also known as the human leukocyte antigen (HLA) encodes class I and II genes that are the cornerstone of the adaptive immune system. Their unique diversity (>25,000 alleles) might affect the outcome of any transplant, infection, and susceptibility to autoimmune diseases. The recent rapid development of new next-generation sequencing (NGS) methods provides the opportunity to study the influence/correlation of this high level of HLA diversity on allele expression levels in health and disease. Here, we describe the NGS capture RNA-Seq method that we developed for genotyping all 12 classical HLA loci (HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4, and HLA-DRB5) and assessing their allelic imbalance by quantifying their allele RNA levels. This is a target enrichment method where total RNA is converted to a sequencing-ready complementary DNA (cDNA) library and hybridized to a complex pool of RNA-specific HLA biotinylated oligonucleotide capture probes, prior to NGS. This method was applied to 161 peripheral blood mononuclear cells and 48 umbilical cord blood cells of healthy donors. The differential allelic expression of 10 HLA loci (except for HLA-DRA and HLA-DPA1) showed strong significant differences (P < 2.1 × 10-15). The results were corroborated by independent methods. This newly developed NGS method could be applied to a wide range of biological and medical questions including graft rejections and HLA-related diseases.

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.

Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus-host disease in conjunction with the CMV status.

Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1 and MICA loci. HLA-DP typing was further available. MICB98 mismatches were significantly associated with an increased incidence of acute (grade II-IV: HR, 1.20; 95% CI, 1.15 to 1.24; P < 0.001; grade III-IV: HR, 2.28; 95% CI, 1.56 to 3.34; P < 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P < 0.001). MICB98 matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98 mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P < 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.

Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients.

Heme oxygenase-1 (HO-1), an intracellular enzyme that catalyzes the degradation of heme into biliverdin, free iron, and carbon monoxide, exerts anti-inflammatory and cytoprotective effects against endothelial cell injury. The HO-1 promoter gene has one important single-nucleotide polymorphism (SNP) rs2071746 (-413A>T) that is functional, and the A allele has been reported to be associated with higher HO-1 expression levels than the T allele. We investigated the influence of the HO-1 rs2071746 SNP on the transplant outcomes in 593 patients with hematological malignancies undergoing unrelated, human leukocyte antigen (HLA)-matched, T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. In patients with high-risk diseases, the donor A/A or A/T genotype was associated with better 5 year overall survival (35% vs. 25%; p = 0.03) and 5 year disease-free survival (35% vs. 22%; p = 0.0072), compared to the donor T/T genotype. These effects were not observed in patients with low-risk diseases. The current findings therefore indicate that HO-1 rs2071746 genotyping could be useful for selecting donors and tailoring transplant strategies for patients with high-risk hematologic malignancies.

Impact of Homozygous Conserved Extended HLA Haplotype on Single Cord Blood Transplantation: Lessons for Induced Pluripotent Stem Cell Banking and Transplantation in Allogeneic Settings.

Induced pluripotent stem cells (iPSCs) have been applied to clinical regenerative cell therapy. Recently, an iPSC banking system to collect HLA haplotype (HP) homozygous (homo) cells for iPSC transplantation in allogeneic settings was proposed, and tissue transplantation generated from iPSC through banking has just began. We analyzed 5017 single cord blood transplantation (CBT) pairs with HLA-A, -B, -C, -DRB1 allele typing data and found 39 donor HLA homo donor to patient HLA heterozygous (hetero) pairs. Of note, all 39 HLA homo to hetero pairs engrafted neutrophils, except 1 early death pair, and all 30 assessable pairs engrafted platelets. Acute graft-versus-host disease (GVHD) grades II to IV and grades III to IV occurred in 17 and 3 of 38 assessable pairs, respectively. Competing risk regression analysis revealed a favorable risk of neutrophil engraftment and higher risk of acute GVHD compared with HLA-matched CBTs. Thirty-seven of 39 homo to hetero pairs had conserved extended HLA HPs (HP-1, n = 18; HP-2, n = 8; HP-3, n = 7; HP-4, n = 4; HP-5, n = 1) that were ethnicity-specific, and at least 1 of 2 patient HLA-A, -B, -C, and -DRB1 alleles in each locus were invariably shared with the same donor HP in 35 pairs. These findings confirmed our preliminary results with 6 HLA homo CBTs, and a trend of high incidence of acute GVHD was newly observed. Importantly, they imply the possibility that HLA-homo iPSC transplantation provides favorable engraftment and accordingly imply the merit of banking iPSC with homozygous major conserved extended HLA HPs.

Effects of Haplotype Matching on Outcomes after Adult Single-Cord Blood Transplantation.

It remains unclear whether the HLA haplotype of unrelated cord blood (UCB) should be matched to that of the patient in single UCB transplantation. Thus, using data from a Japanese registry, we analyzed the effect of haplotype matching on outcomes. Patients with hematologic diseases aged 16 years or older who had undergone their first transplant were included (N = 1347). The effects of haplotype matching and high-frequency HLA haplotype on outcomes were analyzed. Median patient age was 55 years. The cumulative incidences of neutrophil engraftment among groups with 0, 1, and 2 HLA haplotype matches were 79%, 82%, and 88%, respectively (P = .008). In a multivariate analysis, the group with 0 haplotype matches was marginally associated with worse neutrophil engraftment (P = .087) and significantly associated with platelet engraftment (P = .044) compared with the group with 1 haplotype match. Two-haplotype matches were associated with a higher risk of relapse. In the group with 1 haplotype match, the top 3 shared haplotypes were "A*24:02-B*52:01-C*12:02-DRB1*15:02" (HP-P1), "A*33:03-B*44:03-C*14:03-DRB1*13:02" (HP-P2), and "A*24:02-B*07:02-C*07:02-DRB1*01:01" (HP-P3). The presence of HP-P2 but not HP-P1 or HP-P3 was associated with a decreased risk of grades II to IV acute graft-versus-host disease (hazard ratio, .56; P = .001) but an increased risk of relapse (hazard ratio, 1.35; P = .045). HLA haplotype matching might be considered to improve engraftment. Two-haplotype matches should be avoided if the relapse risk is high. The haplotype itself may have an effect on the risk of acute graft-versus-host disease and relapse.

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.