Type: Oral
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Donor and Conditioning Regimen Selection
Hematology Disease Topics & Pathways:
Research, Clinical Research, registries
Methods: Clinical data of 10,569 patients who underwent single-unit CBT for acute myeloid leukemia (AML, n=5,518), myelodysplastic syndrome (MDS, n=1,483), acute lymphoblastic leukemia (ALL, n=2,020), and lymphoma (n=1,548) between 2008 – 2021 were provided by the Japanese Data Center for Hematopoietic Cell Transplantation. HLA-A, -B, -C, and –DRB1 typing was performed at least at the antigen level. The leader genotype is defined based on the two HLA-B allotypes. All patients were not used ATG for GVHD prophylaxis. Study outcomes were overall survival (OS), cumulative incidences of relapse, NRM, and grade II-IV acute GVHD (aGVHD). Multivariable Cox regression analysis including covariables; disease risk index (DRI), myeloablative/reduced-intensity conditioning, presence of total body irradiation as a conditioning regimen, short-term methotrexate or mycophenolate mofetil for GVHD prophylaxis, recipient cytomegalovirus serostatus. All statistical analyses were performed with EZR.
Results: The median patient’s age was 53 (range 0-88) years. The numbers of patients with HLA-B leader TT, MT, and MM genotype were 7,639 (72.3 %), 2,707 (25.6 %), and 223 (2.1 %), respectively. To classify HLA-B match/mismatch status, we stratify “HLA-B one locus mismatched (GVH direction)” and HLA-B matched (no GVH direction mismatch)“. First, we focused on HLA-B one antigen mismatched (HLA 5/6 antigen matched, n = 1172) setting as shown in the previous literature. Recipient MM genotype showed significantly worse OS and relapse in the multivariate analysis compared to MT or TT genotype (Tx) (Figure) (OS: hazard ratio [HR] 0.543 [95% CI, 0.311 – 0.947]; p = 0.032, relapse: [HR] 2.863 [95% CI, 1.330 – 6.165]; p = 0.007). Recipient MM didn’t relate to relapse and grade II-IV aGVHD.
Next, we explored the impacts of HLA-B leaders in HLA-B antigen-matched CBT (3/6 – 6/6 matched, n = 3995). Donor MM genotype demonstrated a negative impact for OS and NRM, not relapse and aGVHD, compared to Tx donor (Figure) (OS: [HR] 0.738 [95% CI, 0.542 – 1.000]; p 0.050, NRM: [HR] 1.695 [95% CI, 1.097 – 2.621]; p = 0.018). Especially, OS and NRM of donor MM genotype were significantly inferior to Tx in HLA 6/6 matched (n = 914) CBT (OS: [HR] 0.311 [95% CI, 0.187 – 0.518]; p < 0.001, NRM: [HR] 3.216 [95% CI, 1.931 – 5.356]; p = 0.034).
Conclusions: ATG would affect immune dynamics strongly in CBT via in-vivo T cell depletion, yet the current study demonstrated the HLA-B leader was still a significant risk factor in CBT without ATG for the first time. Recipient MM genotype in HLA-B one locus mismatched (HLA 5/6 matched) and donor MM genotype in HLA-B matched were the risk factors for worse CBT outcomes. We concluded MM genotype donors would be avoided to decrease NRM in HLA-B matched CBT. The precise mechanism of negative impact in CBT outcomes in patients or donor MM genotype remains to be clarified, however, we assume higher level HLA-E expression may be crucial in terms of NKG2A inhibitory signaling to T cells/NK cells and T-cell direct recognition for peptide/HLA-E complex in CBT.
Disclosures: Kanaya: Meiji Seika Pharma Co., Ltd: Honoraria; Sanofi K.K.: Honoraria; JANSSEN PHARMACEUTICAL K.K.: Honoraria; Chugai Pharmaceutical Co., Ltd. l: Honoraria; Astellas Pharma Inc.: Honoraria. Hashimoto: Daiichi Sankyo Inc: Honoraria; Ono Pharma: Honoraria; Janssen Pharma: Honoraria; Kyowa-Kirin: Honoraria; Chugai Pharmaceutical: Honoraria; LUCA Science: Patents & Royalties; Astellas Pharma: Honoraria. Tanaka: Astellas Phrama: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Kyowa-Kirin: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; MSD: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Pfizer: Speakers Bureau; Sumitomo Pharma: Speakers Bureau; Asahi Kasei Pharma: Speakers Bureau; Abbvie: Speakers Bureau. Takahashi: Daiichi Sankyo RD Novare, Otsuka Pharmaceutical: Research Funding; Nippon Sinyaku: Honoraria; Novartis: Honoraria; Chugai Pharmaceutical: Honoraria; Asahi Kasei Pharma: Honoraria; AstraZeneca: Honoraria; Terumo: Honoraria; Kyowa Kirin: Honoraria; JCR pharma: Honoraria. Sawa: Sanofi: Honoraria; Janssen: Honoraria. Ichinohe: Repertoire Genesis: Research Funding. Atsuta: JCR Pharmaceuticals Co., Ltd.: Consultancy; Novartis Pharma KK: Speakers Bureau; Meiji Seika Pharma Co, Ltd.: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd: Speakers Bureau. Morishima: Chugai Pharma: Honoraria; Abbvie: Honoraria; Kyowa Kirin: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria; Sanofi: Honoraria; Janssen: Honoraria.