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1311 Frequent Loss of HLA-B*40:02 from Leukocytes in Male Patients with Hepatitis-Associated Aplastic Anemia

Program: Oral and Poster Abstracts
Session: 508. Bone Marrow Failure: Acquired: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Acquired Marrow Failure Syndromes, Translational Research, Bone Marrow Failure Syndromes, Aplastic Anemia, Diseases
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Rio Takahashi1*, Yoshitaka Zaimoku, MD, PhD2, Kohei Hosokawa, MD, PhD 2, Seishi Ogawa, MD, PhD3,4,5, Yoshiyuki Takahashi6, Takako Miyamura7, Yasushi Onishi, MD, PhD8*, Takashi Koike9*, Tetsuya Nishida10*, Naoyuki Uchida11, Noriko Doki12, Masatsugu Tanaka13*, Tetsuya Eto14*, Mitsuhiro Itagaki15*, Masashi Sawa16*, Yuta Hasegawa17*, Takahiro Fukuda18*, Makoto Onizuka19, Yoshiko Atsuta20,21*, Shinji Nakao, MD, PhD2 and Takamasa Katagiri22*

1Department of Clinical Laboratory Science, Kanazawa University, Kanazawa, ISH, Japan
2Department of Hematology, Kanazawa University, Kanazawa, Japan
3Kyoto University, Sakyoku, KYO, Japan
4Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
5Department of Medicine, Karolinska Institute, Stockholm, Sweden
6Department of Pediatrics, Nagoya University, Nagoya, Japan
7Department of Pediatrics, Osaka University Hospital, Osaka, Japan
8Department of Hematology, Tohoku University Hospital, Sendai, Japan
9Department of Pediatrics, Tokai University, Isehara, Japan
10Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
11Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations TORANOMON HOSPITAL, Tokyo, Japan
12Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
13Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
14Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
15Department of Hematology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan
16Department of Hematology and Oncology, Anjo Kosei Hospital, Anjyo, Japan
17Department of Hematology, Hokkaido University Hospital, Sapporo, Japan
18Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
19Department of Hematology/Oncology, Tokai University, Isehara, Japan
20Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University, Nagakute, Japan
21The Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
22Department of Clinical Laboratory Science, Kanazawa University, Kanazawa, Japan

Background: Hepatitis-associated aplastic anemia (HAAA), a rare variant of idiopathic aplastic anemia (iAA), is a potentially life-threatening complication of acute hepatitis. Although it has been proposed that several hepatitis viruses are linked to the disease, the exact pathogenic factor underlying this disease is currently unknown. We previously reported somatic loss of HLA class I allele expression as a result of either loss of heterozygosity in chromosome 6p (6pLOH) or somatic loss-of-function mutations in hematopoietic stem progenitor cells (HSPCs) in a subset of patients with iAA. We also found that the missing HLA alleles in HLA class I allele-lacking leukocytes (HLA-LLs) were strikingly skewed toward certain HLA subtypes, which are associated with the risk of developing iAA. These findings provided perhaps the most robust evidence for the autoimmune nature of iAA, since the appearance of HLA-LLs suggests that HSPCs with somatic loss of HLA class I allele expression escape the attack of cytotoxic T lymphocytes that are specific for autoantigens presented by the missing HLA class I alleles. In this study, the correlation between this genomic alteration and the clinical features of HAAA was investigated, and the prevalence of certain high-risk HLA alleles was elucidated.

Methods: A total of 19 patients with HAAA aged 1-53 (median: 25, a male/female ratio [M/F]: 1.7) and 205 patients with iAA aged 6-88 (median: 54, M/F: 1.1) were examined for the prevalence of somatic loss of HLA class I allele expression by analysis of allele-specific copy numbers using GeneChip 500K arrays and flow cytometry. In addition, HLA data from 33,733 patients, including 97 patients with HAAA aged 1-53 (median: 14, M/F: 2.2), 1,273 patients with iAA aged 0-75 (median: 18, M/F: 1.1), and 32,363 patients with other hematological diseases aged 0-82 (median: 57, M/F: 1.4) (18,329 with acute myeloid leukemia, 8,428 with acute lymphoblastic leukemia, and 5,606 with myelodysplastic syndromes), who received allogeneic bone marrow transplantation through the Japan Marrow Donor Program (JMDP) were collected from the Japanese Data Center for Hematopoietic Cell Transplantation for analysis of high-risk HLA allele frequency.

Results: SNP array analysis showed the presence of 6pLOH(+) clones in 6 (31.6%), all of whom were male (P=0.04, vs. male patients with 6pLOH[-] HAAA), of the 19 HAAA patients, a significantly higher frequency compared with 28 (13.7%), 19 of whom were male (P=0.06, vs. male patients with 6pLOH[-] iAA), of the 205 iAA patients (P=0.048). The genetic loss of HLA haplotypes was explicitly confirmed in all 6 HAAA patients with 6pLOH by analyzing the cell surface expression of HLA-A proteins on leukocytes. Notably, the lost haplotype in all 6 6pLOH(+) HAAA patients carried HLA-B*40:02 at a significantly higher frequency than in patients with iAA (P=0.02), whereas only 12 (42.9%) of the 28 6pLOH(+) iAA patients carried HLA-B*40:02. Furthermore, whether HLA-B*40:02 is associated with an increase in the risk of developing HAAA was analyzed by evaluating a large dataset including 33,733 JMDP registrants. These analyses showed a significantly higher frequency of the HLA-B*40:02 allele in 97 patients with HAAA (25.8%) compared with that in 1,273 patients with iAA (15.2%, P=0.012) and those with other hematological diseases (14.3%, P=0.005), with odds ratios (ORs) of 1.94 (95% CI: 1.2-3.14) and 2.08 (95% CI: 1.32-3.29), respectively. It is noteworthy that the significantly higher frequency of HLA-B*40:02 in HAAA patients (26.9%) than in those with iAA (16.0%, P=0.04, OR: 1.93 [95% CI: 1.08-3.45]) and other hematological diseases (14.4%, P=0.007, OR: 2.18 [95% CI: 1.27-3.75]) was observed only in male patients, whereas the frequency was comparable among female patients with HAAA, iAA, and other hematological diseases when the frequency was compared by sex.

Conclusions: This study demonstrated for the first time a higher frequency of 6pLOH, with the missing HLA alleles in HLA-LLs notably skewed toward only HLA-B*40:02 in male patients with HAAA. Our findings for HAAA not only shed light on the characteristics of HAAA patients, and the underlying immunopathological mechanisms, but also offer intriguing insights into the specific HLA allele, HLA-B*40:02, which is most closely associated with the pathogenesis of HAAA, and narrow down the candidate antigens presented by HLA-B*40:02 on HSPCs to those shared with hepatocytes.

Disclosures: Hosokawa: Bristol-Myers Squibb K.K.: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Novartis Pharma K.K.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria. Ogawa: Nihonshinyaku Co., Ltd.: Other: Donation; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Asahi Genomics Inc: Current equity holder in publicly-traded company; Nanpuh Hospital: Other: Endowed chair; Chordia Therapeutics Inc.: Consultancy, Other: Endowed chair, Research Funding; Eisai Co., Ltd.: Consultancy, Research Funding. Onishi: Kissei: Honoraria; Sanofi: Honoraria; IQVIA: Honoraria; Nippon Shinyaku: Honoraria; Symbio: Honoraria; Daiichi Sankyo: Honoraria; Asteras: Honoraria; Chugai: Honoraria; Kyowa Kirin: Honoraria; AsahiKasei: Honoraria; Shionogi: Research Funding; Incyte: Research Funding; Meiji Seika: Research Funding; Sumitomo: Research Funding; Abbvie: Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; JCR pharma: Research Funding; Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; MSD: Honoraria; Amgen: Honoraria. Uchida: Novartis Pharma Co.: Honoraria; AstraZeneca: Honoraria; CSL Behring: Honoraria; JCR Pharmaceuticals Co.: Research Funding; Takeda Pharmaceutical Co.: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Astellas Pharma Inc.: Honoraria; MSD (Merck & Co. Inc.): Honoraria; Kyowa Kirin Co.: Honoraria; SymBio Pharmaceuticals: Honoraria; Nippon Shinyaku Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Daiichi Sankyo Co.: Honoraria; Takeda Pharmaceutical Co.: Consultancy; Chugai Pharmaceutical Co.: Research Funding; Fuji Pharma Co.: Research Funding; Sumitomo Pharma Co.: Research Funding; Nippon Boehringer Ingelheim Co.: Research Funding; Asahi Kasei Pharma Co.: Honoraria; AbbVie GK: Honoraria; Astellas Pharma Inc.: Consultancy. Sawa: Kyowa Kirin Co., Ltd.: Honoraria. Atsuta: JCR Pharmaceuticals Co., Ltd.: Consultancy; Otsuka Pharmaceutical Co., Ltd: Speakers Bureau; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Janssen Pharmaceutical K.K.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria. Nakao: Alexion Pharmaceuticals, Inc.: Honoraria; SymBio Pharmaceuticals Ltd: Honoraria; Sobi Japan: Honoraria; Asahi Kasei Co: Honoraria; Pfizer Japan: Honoraria; Sanofi K.K.: Honoraria; Novartis Pharma K.K.: Honoraria; Kyowa Kirin Co: Honoraria.

*signifies non-member of ASH