Who Is the Best Donor for the Second Transplant?: HLA Discrepancy between Graft and Host Rather Than That Graft and First Donor May Impact the Second Transplant Outcome from the JSHCT
Authors: Maeda Yoshinobu , Ugai Tomotaka , Kondo Eisei , Ikegame Kazuhiro , Murata Makoto , Uchida Naoyuki , Miyamoto Toshihiro , Takahashi Satoshi , Ohashi Kazuteru , Nakamae Hirohisa , Hirokawa Makoto , Ichinohe Tatsuo , Atsuta Yoshiko , Kanda Yoshinobu , Kanda Junya 
Published: October 2019

Abstract
For patients with malignant hematological diseases that relapse after allogeneic hematopoietic stem cell transplantation (HSCT), a second HSCT is thought to be a curative option. A second donor is usually searched for due to HLA discrepancy between the graft and the host. However, it is unclear whether HLA discrepancy between the graft and the first donor has an impact on the outcome of second HSCT. To address this issue, we focused on second HSCT patients who had received first HSCT from an HLA-mismatched (MM) donor and compared the effects of HLA discrepancy between graft and first donor with those between graft and host.
We retrospectively analyzed 646 patients receiving second HSCT between 1994 and 2016 after an initial HLA-MM transplantation. With regard to the graft versus host results, the one-allele mismatch (1 MM) group (relative risk [RR], 1.88; 95% confidence interval [CI], 0.79-4.45; p=0.163) and more than one-allele mismatch group (≥ 2 MM) (RR, 1.84; 95% CI, 0.75-4.51; p=0.182) had higher risks of grade III-IV acute GVHD compared to the HLA-matched (0 MM) group, although the results were not significant. In contrast, almost no difference in risk of acute GVHD was found among the 0, 1, and ≥ 2 MM group with respect to graft vs. first donor. Furthermore, with regard to graft vs. host, the ≥ 2 MM group showed a significantly higher risk of treatment-related mortality (TRM) (RR, 1.90; 95% CI, 1.04-3.50; p=0.038) compared to the 0 MM group. In contrast, the risk of relapse was slightly lower in the ≥ 2 MM group (RR, 068; 95% CI, 0.44-1.06; p=0.086). Consequently, no significant difference in OS was found among the three groups. In the analysis of each HLA allele MM, B allele MM between graft and host was associated with an increased risk of grade III-IV acute GVHD (RR 2.87; 95% CI, 1.42-5.79; p=0.003) and DR allele MM between graft and host was associated with a lower risk of relapse (RR, 0.75; 95% CI, 0.58-0.95; p=0.018) and higher risk of TRM (RR, 1.44; 95% CI, 1.03-2.00; p=0.033). In contrast, with regard to graft vs. first donor, there were no significant differences in relapse, TRM, or OS among the three groups, and also analysis of each HLA allele MM indicated no associations with relapse, TRM, or OS. These findings suggested that HLA discrepancy between graft and host, rather than between graft and first donor may induce transplant-related immunological responses in second HSCT leading to an increase in TRM.
In conclusion, HLA-MM donor is an option after initial HLA-MM transplantation, however, TRM remains a challenge, particularly with a ≥ 2 MM donor regarding to graft versus host. In this study, the biological effects of HLA discrepancy between the graft and the first donor on the outcome appeared negligible, and our findings shed light on the role of nonhematopoietic APCs on transplant-related immunological responses.
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Disclosures
Nakamae: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding. Ichinohe:Mundipharma: Honoraria; Eisai Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Zenyaku Kogyo Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; CSL Behring: Research Funding; Novartis.: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding. Kanda:Ono: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; Taisho-Toyama: Research Funding; MSD: Research Funding; Novartis: Research Funding; Tanabe-Mitsubishi: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; CSL Behring: Research Funding; Asahi-Kasei: Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.