Publications by authors named "Yasuo Morishima"

214 Publications

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

Cancers (Basel) 2021 Jun 1;13(11). Epub 2021 Jun 1.

Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.

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, , , , and , and two SNPs in the methylase genes, and , 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 ( > 0.005). This result questions the usefulness of these immune checkpoint gene polymorphisms for predicting post-BMT outcomes. However, the recipient histone methyltransferase gene SNP, which encodes the D185H substitution, exhibited a low -value in regression analysis of grade 2-4 acute graft-versus-host disease ( = 0.010). Due to a low minor allele frequency, this SNP warrants further investigation in a larger-scale study.
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http://dx.doi.org/10.3390/cancers13112752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199545PMC
June 2021

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

Leuk Lymphoma 2021 Jun 15:1-10. Epub 2021 Jun 15.

Central Japan Cord Blood Bank, Seto, Japan.

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,  = .002), possibly due to the graft-versus-leukemia effect of HLA-DPB1 mismatches. A lower CD34 cell dose (<.50 × 10/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.
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http://dx.doi.org/10.1080/10428194.2021.1929958DOI Listing
June 2021

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.

Transplant Cell Ther 2021 May 5. Epub 2021 May 5.

Japan Marrow Donor Program, Aichi Medical University School of Medicine, Nagakute, Japan.

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.
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http://dx.doi.org/10.1016/j.jtct.2021.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098035PMC
May 2021

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

Genes Immun 2021 May 24;22(1):35-43. Epub 2021 Feb 24.

Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

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.
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http://dx.doi.org/10.1038/s41435-021-00122-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903020PMC
May 2021

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

Bone Marrow Transplant 2021 03 9;56(3):646-654. Epub 2020 Oct 9.

Central Japan Cord Blood Bank, Seto, Japan.

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.
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http://dx.doi.org/10.1038/s41409-020-01070-3DOI Listing
March 2021

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

Int J Hematol 2020 Dec;112(6):907

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s12185-020-03018-1.
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http://dx.doi.org/10.1007/s12185-020-03018-1DOI Listing
December 2020

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

Cancer Sci 2020 Oct 11;111(10):3770-3779. Epub 2020 Sep 11.

National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

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).
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http://dx.doi.org/10.1111/cas.14604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540987PMC
October 2020

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

Front Immunol 2020 29;11:941. Epub 2020 May 29.

Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan.

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 (, and ) 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 and ) showed strong significant differences ( < 2.1 × 10). 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.
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http://dx.doi.org/10.3389/fimmu.2020.00941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272581PMC
April 2021

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

Blood 2020 07;136(3):362-369

Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD; and.

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.
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http://dx.doi.org/10.1182/blood.2020005743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365916PMC
July 2020

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

J Clin Oncol 2020 08 1;38(24):2712-2718. Epub 2020 Jun 1.

Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD.

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; = .001) and severe acute GVHD (OR, 1.32; = .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.
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http://dx.doi.org/10.1200/JCO.20.00265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430213PMC
August 2020

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

Bone Marrow Transplant 2020 07 14;55(7):1367-1378. Epub 2020 Apr 14.

Department of Hematology and ErasmusMC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.

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.
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http://dx.doi.org/10.1038/s41409-020-0886-5DOI Listing
July 2020

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

Cancers (Basel) 2020 Feb 12;12(2). Epub 2020 Feb 12.

Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan.

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 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 expression levels than the T allele. We investigated the influence of the 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%; = 0.03) and 5 year disease-free survival (35% vs. 22%; = 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 rs2071746 genotyping could be useful for selecting donors and tailoring transplant strategies for patients with high-risk hematologic malignancies.
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http://dx.doi.org/10.3390/cancers12020424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072481PMC
February 2020

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

Int J Hematol 2020 Feb 16;111(2):256-266. Epub 2019 Nov 16.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

To investigate the use of high-dose therapy and autologous stem cell transplantation (ASCT) for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL) between 1990 and 2007, we conducted a nationwide survey using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Of the 1222 patients in the database, 576 (47%) received ASCT in first complete remission (CR1), 140 (12%) in first partial remission, 281 (23%) in sensitive relapse, 150 (12%) in resistant or sensitivity-unknown relapse, and 75 (6%) in primary refractory status. With a median follow-up of 22 months, the 2-year overall survival (OS) and progression-free survival rates were 71% and 68%, respectively. The cumulative incidences of 2-year non-relapse mortality and relapse/progression were 6% and 26%, respectively. Relapse/progression after ASCT in the rituximab era (2002-2007) was significantly lower than that in the pre-rituximab era (1990-2001; P < 0.001). Older age, male gender, poor performance status at ASCT, non-CR1 at ASCT, ASCT performed in 1990-2001, and LEED or MCEC regimen were adverse predictors of OS. Because ASCT for newly diagnosed high-risk DLBCL has not been performed recently, a registry database study to assess the impact of ASCT for relapsed or refractory DLBCL in the rituximab era is warranted.
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http://dx.doi.org/10.1007/s12185-019-02772-1DOI Listing
February 2020

Impact of HLA Allele Mismatch at HLA-A, -B, -C, and -DRB1 in Single Cord Blood Transplantation.

Biol Blood Marrow Transplant 2020 03 9;26(3):519-528. Epub 2019 Nov 9.

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

The impact of allele-level HLA mismatch on outcomes of cord blood transplantation has not been well established. We retrospectively analyzed the effects of HLA allele matching at HLA-A, -B, -C, and -DRB1 in cord blood transplantation for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome. In multivariate analysis, overall survival (OS) significantly deteriorated in the 4-allele or higher mismatch in pediatric cases (hazard ratio, 1.8 for 4/8 match [reference, 6/8 match] and 2.85 for 3-1/8 match) and the 5-allele or higher mismatch in adult cases (hazard ratio, 1.23 for 3-0/8 match). Incidence of grade Ⅲ to Ⅳ acute graft-versus-host disease was low in the 8/8 match and 1-allele mismatch in pediatric cases (hazard ratio, 0.19 for 8/8 match and 0.41 for 7/8 match) and the 8/8 match in adult cases (hazard ratio, 0.41 for 8/8 match). On the other hand, a higher incidence of relapse was noted in the 8/8 match in adults (hazard ratio, 1.53). The incidence of neutrophil and platelet engraftment decreased in the 3-allele or higher mismatch in adults. In subgroup analysis of graft-versus-host disease prophylaxis in adult cases, a deteriorating effect on OS of HLA 5-allele or higher mismatch was more significant in cases with calcineurin inhibitor with methotrexate than with mycophenolate mofetil. These results suggest that allele-level HLA mismatch affects the outcomes of cord blood transplantation. Information on HLA allele matching at HLA-A, -B, -C, and -DRB1 may be useful for cord blood unit selection.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.001DOI Listing
March 2020

Increased Relapse Risk of Acute Lymphoid Leukemia in Homozygous HLA-C1 Patients after HLA-Matched Allogeneic Transplantation: A Japanese National Registry Study.

Biol Blood Marrow Transplant 2020 03 6;26(3):431-437. Epub 2019 Nov 6.

Division of Hematology, Jichi Medical University, Shimotsuke, Japan.

Natural killer (NK) cells expressing killer cell immunoglobulin-like receptors (KIRs) can recognize specific HLA class I molecules as their ligands. By studying a large Japanese transplant registry, we compared transplant outcomes between patients heterozygous for HLA-C/C (HLA-C1/C2) and those homozygous for HLA-C1 (HLA-C1/C1) among patients who had undergone HLA-matched hematopoietic stem cell transplantation (HSCT). A high frequency of KIR2DL1 with strong HLA-C2 binding capacity and a low frequency of HLA-C2 and KIR haplotype B are characteristic of the Japanese population. In our previous report, HLA-C1/C1 patients with myeloid leukemia were less likely to relapse than HLA-C1/C2 patients. We newly assessed 2884 patients with acute lymphoblastic leukemia (ALL) who received HLA-matched allogeneic HSCT and analyzed their leukemia relapses by using adjusted competing-risk methods. HLA-C1/C1 patients with ALL experienced significantly higher relapse rates than HLA-C1/C2 patients (hazard ratio [HR] = 1.55, P = .003), contrary to our results in patients with myeloid leukemia. We allocated patients with ALL to several subgroups and found a higher frequency of relapse (HR >1.8) in the HLA-C1/C1 group than in the HLA-C1/C2 group among patients with Ph-negative ALL, those who had no cytomegalovirus reactivation, those who received transplants from donors who were aged 41 years or older, and those who experienced acute graft-versus-host disease, especially if it required systemic treatment. One interpretation of our results is that KIR2DL1-positive NK cells disrupt T cells, antigen-presenting cells, or both from working efficiently in transplant immunity in HLA-C1/C1 patients with ALL. Another is that KIR2DS1-positive NK cells directly attack HLA-C2-positive ALL blasts in HLA-C1/C2 patients. Whether HLA-C2 can cause recurrence to decrease or increase in patients depending on the disease (ALL or myeloid leukemia) will be a very important finding. We hope that our results will provide clues to the real mechanisms behind relapse after transplantation in patients with different HLA profiles.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.032DOI Listing
March 2020

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

Lancet Haematol 2020 Jan 25;7(1):e50-e60. Epub 2019 Oct 25.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

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.
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http://dx.doi.org/10.1016/S2352-3026(19)30208-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948919PMC
January 2020

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

Biol Blood Marrow Transplant 2020 03 9;26(3):509-518. Epub 2019 Oct 9.

Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

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.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.035DOI Listing
March 2020

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

Biol Blood Marrow Transplant 2020 01 12;26(1):132-138. Epub 2019 Sep 12.

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.009DOI Listing
January 2020

Recipient Single-Nucleotide Polymorphism Predicts Relapse after Unrelated Bone Marrow Transplantation for Hematologic Malignancy.

Int J Mol Sci 2019 Jan 8;20(1). Epub 2019 Jan 8.

Department of Clinical Laboratory Science, Kanazawa University School of Medical Sciences, Kanazawa 920-0942, Japan.

Relapse remains a major obstacle to the survival of patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation. A disintegrin-like and metalloprotease with a thrombospondin type 1 motif (ADMATS13), which cleaves von Willebrand factor multimers into less active fragments, is encoded by the gene and has a functional single-nucleotide polymorphism (SNP) rs2285489 (C > T). We retrospectively examined whether rs2285489 affected the transplant outcomes in a cohort of 281 patients who underwent unrelated human leukocyte antigen (HLA)-matched bone marrow transplantation for hematologic malignancies. The recipient C/C genotype, which putatively has low inducibility, was associated with an increased relapse rate (hazard ratio [HR], 3.12; 95% confidence interval [CI], 1.25⁻7.77; = 0.015), resulting in a lower disease-free survival rate in the patients with a recipient C/C genotype (HR, 1.64; 95% CI, 1.01⁻2.67; = 0.045). Therefore, rs2285489 genotyping in transplant recipients may be a useful tool for evaluating pretransplantation risks.
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http://dx.doi.org/10.3390/ijms20010214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337246PMC
January 2019

Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial.

Lancet Haematol 2018 Nov;5(11):e520-e531

Department of Haematology, National Cancer Center Hospital East, Chiba, Japan.

Background: Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial.

Methods: In the phase 2-3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1-3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m], given on day 1, plus cyclophosphamide [750 mg/m], doxorubicin [50 mg/m], vincristine [1·4 mg/m, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3-7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121.

Findings: Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25-41; R-CHOP-14 39%, 31-47; hazard ratio 0·89, 95% CI 0·67-1·17). In 248 patients with grade 1-3a follicular lymphoma, progression-free survival was 39% (33-45) at 8 years and 36% (30-42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5-6·0) at 5 years, 8·5% (5·4-12·4) at 8 years, and 9·3% (6·1-13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1-12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3-5·5).

Interpretation: R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up-both of which could lead to death.

Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.
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http://dx.doi.org/10.1016/S2352-3026(18)30155-8DOI Listing
November 2018

Reference Grade Characterization of Polymorphisms in Full-Length HLA Class I and II Genes With Short-Read Sequencing on the ION PGM System and Long-Reads Generated by Single Molecule, Real-Time Sequencing on the PacBio Platform.

Front Immunol 2018 4;9:2294. Epub 2018 Oct 4.

Division of Basic Medical Science and Molecular Medicine, Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan.

Although NGS technologies fuel advances in high-throughput HLA genotyping methods for identification and classification of HLA genes to assist with precision medicine efforts in disease and transplantation, the efficiency of these methods are impeded by the absence of adequately-characterized high-frequency HLA allele reference sequence databases for the highly polymorphic HLA gene system. Here, we report on producing a comprehensive collection of full-length HLA allele sequences for eight classical HLA loci found in the Japanese population. We augmented the second-generation short read data generated by the Ion Torrent technology with long amplicon spanning consensus reads delivered by the third-generation SMRT sequencing method to create reference grade high-quality sequences of HLA class I and II gene alleles resolved at the genomic coding and non-coding level. Forty-six DNAs were obtained from a reference set used previously to establish the HLA allele frequency data in Japanese subjects. The samples included alleles with a collective allele frequency in the Japanese population of more than 99.2%. The HLA loci were independently amplified by long-range PCR using previously designed HLA-locus specific primers and subsequently sequenced using SMRT and Ion PGM sequencers. The mapped long and short-reads were used to produce a reference library of consensus HLA allelic sequences with the help of the reference-aware software tool LAA for SMRT Sequencing. A total of 253 distinct alleles were determined for 46 healthy subjects. Of them, 137 were novel alleles: 101 SNVs and/or indels and 36 extended alleles at a partial or full-length level. Comparing the HLA sequences from the perspective of nucleotide diversity revealed that HLA-DRB1 was the most divergent among the eight HLA genes, and that the HLA-DPB1 gene sequences diverged into two distinct groups, DP2 and DP5, with evidence of independent polymorphisms generated in exon 2. We also identified two specific intronic variations in HLA-DRB1 that might be involved in rheumatoid arthritis. In conclusion, full-length HLA allele sequencing by third-generation and second-generation technologies has provided polymorphic gene reference sequences at a genomic allelic resolution including allelic variations assigned up to the field-4 level for a stronger foundation in precision medicine and HLA-related disease and transplantation studies.
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http://dx.doi.org/10.3389/fimmu.2018.02294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180199PMC
October 2019

Comparison of HLA Allele Mismatch and Antigen Mismatch in Unrelated Bone Marrow Transplantation in Patients with Leukemia.

Biol Blood Marrow Transplant 2019 03 8;25(3):436-442. Epub 2018 Oct 8.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan. Electronic address:

We compared the effect of HLA single-antigen and single-allele mismatched unrelated bone marrow transplantation (UBMT) without in vivo/ex vivo T cell depletion. Becasue a single DRB1 mismatch is preferred among 1-allele or 1-antigen mismatched donors, we performed mismatched allele- or antigen-specific analyses with a single DRB1 mismatch as the reference. In adjusted comparison by multivariate analyses, an HLA-DRB1 single-allele mismatch resulted in a decreased risk of nonrelapse mortality (NRM; relative risk [RR], 1.33; 95% confidence interval [CI], 1.08 to 1.63, P = .006) compared with an HLA-DR single-antigen mismatch and conferred a decreased risk of NRM (RR, 1.25; 95% CI, 1.01 to 1.57; P = .025) and overall mortality (RR, 1.16; 95% CI, 1.00 to 1.37; P = .046) compared with an HLA-C single-antigen mismatch. Relative to an HLA-DRB1 single-allele mismatch, 2-mismatch transplants, including those with 1 or more antigen mismatches, resulted in a significantly increased risk of NRM (1-antigen/1-allele mismatch: RR, 1.68; 95% CI, 1.03 to 2.05; P < .001; 2-antigen mismatch: RR, 1.58; 95% CI, 1.04 to 2.02; P = .001) and overall mortality (1-antigen/1-allele mismatch: RR, 1.27; 95% CI, 1.09 to 1.47; P = .002; 2-antigen mismatch: RR, 1.27; 95% CI, 1.03 to 1.57; P = .02). NRM correlated with the combined number of mismatches and allele or antigen mismatches, with rates of 22%, 27%, 32%, 31%, and 38% at 4years for full match, single-allele mismatch, single-antigen mismatch, 2-allele mismatch, and 2 mismatches that included an antigen mismatch, respectively. Our results support the preference for an allele mismatch rather than an antigen mismatch in unrelated bone marrow donors with 1 DR mismatch or 2 mismatches for T cell-replete UBMT.
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http://dx.doi.org/10.1016/j.bbmt.2018.10.002DOI Listing
March 2019

R-High-CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY.

Cancer Sci 2018 Sep 28;109(9):2830-2840. Epub 2018 Jul 28.

Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.

Although induction immunochemotherapy including high-dose cytarabine and rituximab followed by high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R-High-CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20-65 years. Patients received 1 cycle of R-High-CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R-High-CHOP/CHASER. Primary endpoint was 2-year progression-free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38-65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty-five patients completed ASCT. Two-year PFS was 77% (80% CI 68-84), which met the primary endpoint. Five-year PFS and overall survival were 52% (95% CI 34-68%) and 71% (95% CI 51-84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R-High-CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.
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http://dx.doi.org/10.1111/cas.13719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125440PMC
September 2018

Risk of HLA Homozygous Cord Blood Transplantation: Implications for Induced Pluripotent Stem Cell Banking and Transplantation.

Stem Cells Transl Med 2018 02 23;7(2):173-179. Epub 2017 Dec 23.

Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.

Clinical application of induced pluripotent stem cells (iPS) in autologous settings has just begun. To overcome the high time and cost barriers in the individual production of autologous iPS, the use of allogeneic iPS with a homozygous human leukocyte antigen (HLA) haplotype (HLA-homo HP) has been proposed. Cord blood transplantation (CBT) is a suitable model for evaluating the allogeneic immunogenicity of iPS transplantation from HLA-homo donors. We analyzed 1,374 Japanese single cord blood transplant pairs who were retrospectively typed as HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1. Among these, six pairs with donor HLA homo-patient-HLA hetero (homo-hetero) were found, all of which showed favorable neutrophil engraftment. Multivariate analysis revealed a significantly elevated engraftment risk (HR = 1.59) compared with hetero-hetero pairs with HLA 1-2 locus mismatch (789 pts) and comparative risk (HR = 1.23) compared with hetero-hetero pairs with 0 mismatch (104 pts). These results for CBT with HLA-homo HP cord blood carry an important implication, namely the possibility that HLA-homo iPS transplantation results in favorable engraftment. Furthermore, we obtained detailed information on HLA alleles and haplotypes of HLA-homo. All donor HLA-homo HPs had a common specific ethnicity and high conservation of the HLA region, and one of two patient heterogeneous HPs invariably shared the same HP as donor HLA-homo HP, and another non-shared patient HP was mismatched with 1 to 4 HLA alleles of HLA-A, -B, -C, and -DRB1 loci in the GVH direction. These findings indicate that patients possessing a single common HLA haplotype have a higher chance of yielding HLA-homo iPS. Stem Cells Translational Medicine 2018;7:173-179.
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http://dx.doi.org/10.1002/sctm.17-0169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788882PMC
February 2018

Evolutionary basis of HLA-DPB1 alleles affects acute GVHD in unrelated donor stem cell transplantation.

Blood 2018 02 15;131(7):808-817. Epub 2017 Dec 15.

Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan.

HLA-DPB1 T-cell epitope (TCE) mismatching algorithm and rs9277534 SNP at the 3' untranslated region (3'UTR) in the HLA-DPB1 gene are key factors for transplant-related events in unrelated hematopoietic cell transplantation (UR-HCT). However, the association of these 2 mechanisms has not been elucidated. We analyzed 19 frequent HLA-DPB1 alleles derived from Japanese healthy subjects by next-generation sequencing of the entire HLA-DPB1 gene region and multi-SNP data of the HLA region in 1589 UR-HCT pairs. The risk of acute graft-versus-host disease (aGVHD) was analyzed in 1286 patients with single HLA-DPB1 mismatch UR-HCT. The phylogenetic tree constructed using the entire gene region demonstrated that HLA-DPB1 alleles were divided into 2 groups, HLA-DP2 and HLA-DP5. Although a phylogenetic relationship in the genomic region from exon 3 to 3'UTR (Ex3-3'UTR) obviously supported the division of HLA-DP2 and HLA-DP5 groups, which in exon 2 showed intermingling of HLA-DPB1 alleles in a non-HLA-DP2 and non-HLA-DP5-group manner. Multi-SNP data also showed 2 discriminative HLA-DPB1 groups according to Ex3-3'UTR. Risk of grade 2-4 aGVHD was significantly higher in patient HLA-DP5 group mismatch than patient HLA-DP2 group mismatch (hazard ratio, 1.28; = .005), regardless of donor mismatch HLA-DP group. Regarding TCE mismatch, increasing risk of aGVHD in patient HLA-DP5 group mismatch and TCE-nonpermissive mismatch were observed only in patients with TCE-permissive mismatch and patient HLA-DP2 group mismatch, respectively. Evolutionary analysis revealed that rs9277534 represented a highly conserved HLA-DPB1 Ex3-3'UTR region and may provoke aGVHD differently to TCE mismatching algorithm, reflecting exon 2 polymorphisms. These findings enrich our understanding of the mechanism of aGVHD in HLA-DPB1 mismatch UR-HCT.
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http://dx.doi.org/10.1182/blood-2017-08-801449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824334PMC
February 2018

Homozygous HLA-C1 is Associated with Reduced Risk of Relapse after HLA-Matched Transplantation in Patients with Myeloid Leukemia.

Biol Blood Marrow Transplant 2018 04 27;24(4):717-725. Epub 2017 Dec 27.

Devision of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.

Natural killer (NK) cells assume graft-versus-leukemia alloreactivity after hematopoietic stem cell transplantation (HSCT) through their inhibitory killer cell immunoglobulin-like receptors (KIRs). KIR2D family members recognize HLA-C alleles with Asn80 (HLA-C1) or Lys80 (HLA-C2). The predominance of HLA-C1 over HLA-C2 and the frequent presence of KIR2DL1 are characteristic of Japanese people. We compared clinical outcomes among homozygous HLA-C1 (HLA-C1/C1) patients and heterozygous HLA-C1/C2 patients who underwent HLA-matched HSCT for hematologic malignancies by assessing the data of 10,638 patients from the Japanese national registry. HLA-C1/C1 recipients had a lower rate of relapse than HLA-C1/C2 recipients after transplantation for acute myelogenous leukemia (AML) (hazard ratio [HR], .79; P = .006) and chronic myelogenous leukemia (CML) (HR, .48; P = .025), but not for acute lymphoblastic leukemia (HR, 1.36), lymphoma (HR, .97), or low-grade myelodysplastic syndrome (HR, 1.40). We then grouped AML and CML patients together and divided them into several subgroups. Advantages of HLA-C1/C1 recipients over HLA-C1/C2 recipients regarding relapse were observed irrespective of donor relation (related: HR, .79, P = .069; unrelated: HR, .77, P = .022), preparative regimen (myeloablative: HR, .79, P = .014; reduced intensity: HR, .73, P = .084), and occurrence of acute graft-versus-host disease (yes: HR, .70, P = .122; no, HR .71, P = .026) or cytomegalovirus reactivation (reactivated: HR .67,P = .054; nonreactivated: HR .71, P = .033); however, these advantages were not observed in recipients with a delay in achieving complete chimerism (HR, 1.06). The advantage of decreasing relapse and extending relapse-free survival of C1/1 over C1/2 KIR-ligand status was most pronounced in T cell-depleted HSCT (HR, .27; P < .001 and HR, .30; P = .002, respectively) and in children age <15 years (HR, .29; P < .001 and HR .31; P < .001, respectively). Our findings represent an important mechanism responsible for the immunity against HLA-C2-negative myeloid leukemia cells after HLA-matched transplantation.
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http://dx.doi.org/10.1016/j.bbmt.2017.11.029DOI Listing
April 2018

Associations of interactions between NLRP3 SNPs and HLA mismatch with acute and extensive chronic graft-versus-host diseases.

Sci Rep 2017 10 12;7(1):13097. Epub 2017 Oct 12.

Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan.

HLA matching is a well-known genetic requirement for successful bone marrow transplantation (BMT). However, the importance of non-HLA single-nucleotide polymorphisms (SNPs) remains poorly understood. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of innate immunity, is associated with multiple diseases. We retrospectively genotyped SNPs of NLRP1-3 and caspase recruitment domain family member 8 (CARD8), which are implicated in the interleukin 1β (IL-1β) signaling, in 999 unrelated BMT donor-recipient pairs. We identified an association of the interaction between the recipient NLRP3 SNP CC genotype and total HLA mismatches with grade 2-4 acute graft-versus-host disease (AGVHD), and an association of the interaction between the donor NLRP3 SNP T allele and HLA-C mismatch with extensive chronic GVHD (ECGVHD), in both adjusted and unadjusted regressions (P < 0.005). Importantly, the ECGVHD risk associated with HLA-C mismatch was not elevated when the donor NLRP3 genotype was CC. We also identified an association of the interaction between recipient NLRP3 SNP and donor cytomegalovirus seropositivity with overall survival in adjusted regressions (P < 0.005). These results suggest the importance of certain SNP-covariate interactions in unrelated BMT. The three identified interactions may be useful for donor selection or outcome prediction.
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http://dx.doi.org/10.1038/s41598-017-13506-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638959PMC
October 2017

The recipient CCR5 variation predicts survival outcomes after bone marrow transplantation.

Transpl Immunol 2017 06 6;42:34-39. Epub 2017 May 6.

Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan. Electronic address:

The chemokine receptor CCR5 plays roles in the trafficking of effector cells towards the site of inflammation. We retrospectively examined the impact of the CCR5 variation (rs1800023, -2086A>G) on transplant outcomes in a cohort of 329 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. A multivariate analysis showed that the recipient CCR5 -2086A/A genotype was significantly associated with a lower relapse rate but not with the development of graft-versus-host disease (GVHD) or transplant-related mortality, thereby resulting in better disease-free and overall survival rates than other variations. The donor CCR5 -2086A/A genotype was associated with a lower incidence of grades 3-4 acute GVHD, which did not improve the survival outcomes. These findings suggest that the recipient CCR5 -2086A/A genotype affects the induction of the graft-versus-tumor effect without augmenting the development of GVHD. CCR5 genotyping in transplant recipients may therefore be a useful tool for evaluating pretransplantation risks.
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http://dx.doi.org/10.1016/j.trim.2017.05.003DOI Listing
June 2017

Toll-like receptor genetic variations in bone marrow transplantation.

Oncotarget 2017 Jul;8(28):45670-45686

Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

The Toll-like receptor family mediates the innate immune system through recognizing the molecular patterns of microorganisms and self-components and leading the synthesis of the inflammatory mediators. We retrospectively examined whether or not genetic variations in toll-like receptor 1 (rs5743551, -7202GQ>A), toll-like receptor 2 (rs7656411, 22215G>T), and toll-like receptor 4 (rs11536889, +3725G>C) affected transplant outcomes in a cohort of 365 patients who underwent unrelated HLA-matched bone marrow transplantation (for hematologic malignancies through the Japan Marrow Donor Program. Only donor toll-like receptor 4 variation significantly improved the survival outcomes. A multivariate analysis showed that the donor toll-like receptor 4 +3725G/G genotype was significantly associated with a better 5-year progression-free survival and a lower 5-year transplant-related mortality than other variations. Furthermore, the donor toll-like receptor 4 +3725G/G genotype was associated with a significantly lower incidence of fatal infections than other variations. The validation study of 502 patients confirmed that the donor toll-like receptor 4 +3725G/G genotype was associated with better survival outcomes. Toll-like receptor4 genotyping in transplant donors may therefore be a useful tool for optimizing donor selection and evaluating pretransplantation risks.
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http://dx.doi.org/10.18632/oncotarget.17315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542217PMC
July 2017

Role of Genetic Polymorphism of ALDH2 in Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2017 Aug 4;23(8):1374-1380. Epub 2017 Apr 4.

Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan; Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Aldehyde dehydrogenase 2 (ALDH2) is involved in critically important biological processes, such as the metabolism of aldehydes and aldehyde-induced genotoxicity in hematopoietic stem cells. Given its role in these biological processes, we hypothesized that a functional ALDH2 polymorphism could affect transplantation outcomes after hematopoietic stem cell transplantation. Here, we analyzed the Japanese national registry data for 409 patients who underwent allogeneic bone marrow transplantation (BMT) from HLA-matched unrelated donors. To evaluate the impact of the recipient and donor ALDH2 polymorphism on transplantation outcomes, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for potential confounders. The recipient ALDH2 Lys/Lys genotype was significantly associated with higher transplantation-related mortality (TRM), with an HR relative to Glu/Glu genotype of 2.45 (95% CI,  1.22 to 4.90). The recipient Lys/Lys genotype also tended to be associated with delayed platelet engraftment (HR, .66; 95% CI, .43 to 1.03). In conclusion, we observed increased TRM among recipients with the ALDH2 Lys/Lys genotype in HLA fully matched BMT. We also observed a suggestive association with delayed platelet engraftment, which warrants further examination. These results may suggest that the recipient ALDH2 genotype affects the metabolism of endogenous aldehydes, leading to a significant impact on transplantation outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2017.03.033DOI Listing
August 2017