ORIGINAL ARTICLE Impact of HLA allele mismatch on the clinical outcome in serologically matched related hematopoietic SCT S Fuji 1 , J Kanda 2 , S Kato 3 , K Ikegame 4 , S Morishima 5 , T Miyamoto 6 , M Hidaka 7 , K Kubo 8 , K Miyamura 9 , K Ohashi 10 , H Kobayashi 11 , Y Maesako 12 , S Adachi 13 , T Ichinohe 14 , Y Atsuta 15 , Y Kanda 2 on behalf of the HLA Working Group of the Japan Society for Hematopoietic Cell Transplantation In unrelated hematopoietic SCT (HSCT), HLA allele mismatch has been shown to have a significant role. To clarify the importance of HLA allele mismatch in the GVH direction in related HSCT, we retrospectively evaluated 2377 patients who received stem cells from an HLA serologically matched related donor in the GVH direction using the database of the Japan Society for Hematopoietic Cell Transplantation. The cumulative incidences of grade II–IV and grade III–IV acute GVHD in patients with an HLA allele-mismatched donor (n = 133, 5.6%) were significantly higher than those in patients with an HLA allele-matched donor. Multivariate analyses showed that the presence of HLA allele mismatch was associated with increased risks of grade II–IV and grade III–IV acute GVHD. In particular, HLA-B mismatch and multiple allele mismatches were associated with an increased risk of acute GVHD. The presence of HLA allele mismatch was associated with an inferior OS owing to an increased risk of non-relapse mortality (NRM). In conclusion, the presence of HLA allele mismatch in the GVH direction in related HSCT was associated with increased risks of GVHD and NRM, which led to an inferior OS. HLA allele typing is recommended in related HSCT. Bone Marrow Transplantation (2014) 49, 1187–1192; doi:10.1038/bmt.2014.141; published online 7 July 2014 INTRODUCTION Previous studies have shown that HLA allele mismatch signifi- cantly affects the clinical outcome after unrelated hematopoietic SCT (HSCT). 1,2 Several retrospective studies have demonstrated that the presence of HLA allele mismatch is associated with an increased risk of GVHD in unrelated HSCT. 3–5 Although the disparity of HLA molecules in HLA antigen mismatch is greater than that in HLA allele mismatch without HLA antigen mismatch, the impact of HLA mismatch on the clinical outcome was considered to be, for practical purposes, similar between antigen mismatch and allele mismatch, as reported previously. 4,6,7 Although the impact of an HLA mismatch at each locus varied among the studies, there is a consensus that an HLA mismatch at any locus, including A, B, C and DRB1, is in general associated with a poor clinical outcome. 2 In related HSCT, the importance of HLA allele mismatch has not yet been well established, because an HLA antigen-matched sibling is in most cases an HLA allele fully matched donor. In Japan, HLA compatibility in related HSCT is usually assessed serologically or by low-resolution DNA typing at three loci, including HLA-A, -B and -DR. However, when the donor is not a sibling, such as a parent or child, the probability of HLA allele mismatch between the recipient and the donor is expected to be higher than that between siblings. Furthermore, there may also be an HLA allele mismatch with a sibling if we consider recombina- tion and mutation. The presence of one HLA antigen mismatch has been reported to be associated with a poor overall clinical outcome in related HSCT. 8–10 Therefore, if the impact of allele mismatch is similar to that of antigen mismatch in related HSCT, as it is in unrelated HSCT, we could assume that the presence of HLA allele mismatch adversely affects the clinical outcome in related HSCT. In this study, we assessed the impact of HLA allele mismatch on the clinical outcome in related HSCT using the database of the Japan Society for Hematopoietic Cell Transplantation (JSHCT), including patients without serological HLA mismatch in the GVH direction. PATIENTS AND METHODS Data collection Data for all patients who received a first allogeneic HSCT from a serologically HLA-A, -B and -DR matched related donor in the GVH direction, irrespective of the number of mismatches in the HVG direction, between 1 January 2000 and 31 December 2011 were obtained from the Transplant Registry Unified Management Program, which includes data from the JSHCT. 11 We excluded patients who lacked data on survival status. Overall, 7089 patients satisfied the above criteria. In further analyses, we considered only 2377 patients (33.5%) for whom information 1 Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan; 2 Division of Hematology, Saitama Medical Center, Saitama, Japan; 3 Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Kanagawa, Japan; 4 Division of Hematology, Department of Internal Medicine, Hyogo Medical College, Hyogo, Japan; 5 Department of Hematology, Fujita Health University School of Medicine, Nagoya, Japan; 6 Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka, Japan; 7 Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan; 8 Department of Hematology, Aomori Prefectural Central Hospital, Aomori, Japan; 9 Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan; 10 Hematology Division, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan; 11 Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan; 12 Department of Hematology, Tenri Hospital, Nara, Japan; 13 Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; 14 Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan and 15 Department of HSCT Data Management and Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Correspondence: Dr Y Kanda, Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma Town, Omiya Ward, Saitama City, Saitama 330-8503, Japan. E-mail: ycanda-tky@umin.ac.jp Received 17 December 2013; revised 3 March 2014; accepted 22 April 2014; published online 7 July 2014 Bone Marrow Transplantation (2014) 49, 1187 – 1192 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt