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4982 Donor NK Cell Education By KIR3DL1 and HLA-B Associates with Reduced Relapse in Unrelated Bone Marrow Transplantation for Adult T-Cell Leukemia

Program: Oral and Poster Abstracts
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical Research
Monday, December 11, 2023, 6:00 PM-8:00 PM

Mari Morita-Fujita, MD1,2*, Takero Shindo, MD, PhD3*, Shuji Kawaguchi, PhD2*, Kiyotaka Izumi, MD, PhD1*, Yuichi Inadomi, PhD2*, Masakazu Shimizu, PhD2*, Ai Murano2*, Akiyo Morinibu2*, Meiko Takahashi, PhD2*, Junya Kanda, MD, PhD1*, Taro Tsujimura, PhD4*, Takuya Yamamoto, PhD4*, Koji Kato, M.D., Ph.D.5, Hidenori Tanaka, PhD6*, Nobuaki Nakano, M.D.7*, Tetsuya Eto, MD, PhD8*, Yasuhiko Miyazaki, MD, PhD9*, Kazunori Imada, MD, PhD10*, Youko Suehiro, MD, PhD11*, Toshiro Kawakita, MD, PhD12*, Tatsuo Ichinohe, MD, PhD13*, Takahiro Fukuda, MD, PhD14*, Makoto Onizuka, MD, PhD15, Yoshiko Atsuta, MD, PhD16*, Fumihiko Matsuda, PhD2* and Akifumi Takaori-Kondo, MD, PhD3

1Department of Hematology / Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
2Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
3Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
4Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
5Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
6HLA Foundation Laboratory, Kyoto, Japan
7Department of Hematology, Imamura General Hospital, Kagoshima, Japan
8Department of Hematology, Hamanomachi Hospital, Fukuoka, JPN
9Department of Hematology, Oita Prefectural Hospital, Oita, JPN
10Department of Hematology, Japanese Red Cross Osaka Hospital, Osaka, Japan
11Department of Hematology and Cell Therapy, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
12Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan
13Department of Hematology and Oncology, Research Institute For Radiation Biology and Medicine, Hiroshima University, Hiroshima, JPN
14Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
15Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan
16Japanese Data Center For Hematopoietic Cell Transplantation, Nagakute, Japan

Background: Adult T-cell leukemia/lymphoma (ATL) derives from human T-cell leukemia virus-1 (HTLV-1)-infected T cells, and its prognosis is still dismal. Whereas allogeneic stem cell transplant (allo-HSCT) may lead to long-term remission, 1-year relapse rate is still high at 35–47% (Muranushi et al, Bone Marrow Transplant. 2021). As for NK cell modulation against ATL, polymorphisms of killer-cell immunoglobulin-like receptors (KIRs) are of interest. NK cell inhibition by donor KIR/patient HLA interaction and NK cell education status have been reported to affect the prognosis of allo-HSCT, but no consensus has been reached. Furthermore, the effects of entire KIR haplotypes have not been extensively studied.
Aim: Using high-resolution genotyping of all 15 functional KIR genes based on long-range PCR and long-read sequencer, correlations between KIR/HLA polymorphisms and relapses in unrelated bone marrow transplantation (UR-BMT) for ATL were evaluated.
Methods: DNAs and clinical data of 264 transplants performed between 2007 and 2016 were obtained. Alleles of 15 KIRs, HLA-A, B, C, DRB1, DPB1 and DQB1 were genotyped for patients and donors. Prognostic factors for relapse were evaluated using the Fine–Gray proportional-hazards models.
Results: Donor KIR3DL1 and patient HLA-B combination predictive of strong interaction (n=74) showed a trend for a lower relapse rate than weak or non-interactive combinations (n=145) (HR, 0.64; p=0.100), raising the beneficial impact of donor NK cell education at KIR3DL1/HLA-B interaction. Comprehensive analysis focusing on amino acids of donors’ KIRs/HLAs specified combinations of HLA-B isoleucine 80 (80I)/KIR3DL2 aspartic acid 42 and HLA-B threonine 80 (80T)/KIR3DL2 glutamic acid 42 (n=76) associated with decreased relapse (HR, 0.35; 95%CI, 0.19-0.65; p=0.00087). On the other hand, combinations of HLA-B glutamic acid 152 (152E)/KIR2DL4 cysteine 30 and HLA-B valine 152 (152V)/KIR2DL4 tyrosine 30 (n=27) were associated with increased relapse (HR, 11.79; 95%CI, 1.6-86.58; p=0.015). Given that KIR3DL2/KIR2DL4 do not bind HLA-B and are closely linked to KIR3DL1/S1 in KIR haplotypes, specific KIR3DL1/S1 alleles were further explored by subgroup analyses. As a result, combinations of HLA-B 80I/KIR3DL1*015&KIR3DL2*002 and HLA-B 80T/KIR3DL1∗001, ∗005, ∗007, ∗020, ∗038, ∗097 (n=60) were defined as the group at low risk for relapse (adjusted HR, 0.21; 95%CI, 0.09-0.48; p=0.00026) (Figure 1A), and combinations of HLA-B 152E/KIR3DS1 and HLA-B 152V/KIR3DL1∗001, ∗007, ∗015, ∗020, ∗029, ∗038 (n=176) were defined as the group at high-risk for relapse (adjusted HR, 5.31; 95%CI, 1.72-16.39; p=0.0037) (Figure 1B). The cases in the low-risk group and/or not in the high-risk group (n=84) had a lower relapse rate (adjusted HR, 0.20; 95%CI, 0.10-0.40; p=0.0000059) (Figure 1C) and a higher overall survival (adjusted HR, 0.66; 95%CI, 0.46-0.95; p=0.0265389) (Figure 1D) than the remaining cases (n=130). In spite of reduced relapse rate, the former showed a lower rate of grades II-IV acute GVHD (HR 0.65; p=0.049). Finally, CD107a degranulation of NK cells was measured following coincubation of HLA-null K562 cells and PBMCs from healthy donors with or without genotypes of the low-risk group. KIR3DL1(+) NK cells showed increased CD107a degranulation compared with KIR3DL1(−) NK cells in healthy donors with the low-risk group genotype (p=0.031), but this difference was not apparent in healthy donors without the low-risk group genotype (p=0.28) (Figure 2).
Conclusions: Allelic genotyping of KIRs enabled to specify donors associated with reduced relapses. Donor NK cell education status at HLA-B/KIR3DL1 interaction might confer enhanced GVT effects and better prognosis in UR-BMT against ATL.

Disclosures: Kanda: Sanofi K.K.: Honoraria; AbbVie Pharma: Honoraria; Novartis Pharma K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Amgen: Ended employment in the past 24 months, Honoraria; Megakaryon Co.: Honoraria; Eisai Co.: Research Funding. Kato: AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Chugai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Eisai: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; MSD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono: Honoraria, Research Funding. Imada: Sanofi K.K.: Honoraria; AbbVie GK.: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Nippon Kayaku Co., Ltd.: Honoraria; AstraZeneca K.K.: Honoraria; Towa Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Meiji Seika Pharma Co. Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Otuka Pharmaceutical Co. Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Co. Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Amgen K.K.: Honoraria. Suehiro: Meiji Pharma: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Nippon Shinyaku: Honoraria; Kyowa Kirin: Research Funding; Incyte: Research Funding; Otsuka: Research Funding; Amgen: Research Funding; BMS: Honoraria; Abbvie: Honoraria, Research Funding; Teijin: Research Funding; Nippon Kayaku: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Chugai: Honoraria, Research Funding. Ichinohe: Repertoire Genesis Inc.: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Kyowa Kirin Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co.: Research Funding. Atsuta: Otsuka Pharmaceutical Co., Ltd: Speakers Bureau; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau; Meiji Seika Pharma Co, Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Consultancy; Novartis Pharma KK: Speakers Bureau. Takaori-Kondo: Shionogi Pharma: Other; AbbVie: Other; Kinshikouraininjin: Other; Ohara Pharmaceutical: Other; Eisai: Other; Chugai Pharmaceutical: Other; Kyowa Kirin: Other: Subsidies ; Takeda Pharmaceutical: Other: Subsidies; Pharma Essentia Japan: Research Funding; DKS Co. Ltd.: Research Funding; COGNANO: Research Funding; Ono Pharmaceutical: Research Funding; Megakaryon: Honoraria; Otsuka Pharmaceutical: Honoraria, Other: Subsidies ; Janssen Pharmaceutical K.K: Honoraria; Bristol Myers Squibb: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria, Other: Subsidies; ASAHI KASEI PHARMA: Other.

*signifies non-member of ASH