Increased Relapse Risk of Acute Lymphoid Leukemia in Homozygous HLA-C1 Patients after HLA-Matched Allogeneic Transplantation: A Japanese National Registry Study

Nobuyoshi Arima; Junya Kanda; Toshio Yabe; Yasuo Morishima; Junji Tanaka; Shinichi Kako; Hirotoshi Sakaguchi; Motohiro Kato; Kazuteru Ohashi; Yukiyasu Ozawa; Takahiro Fukuda; Shuichi Ota; Takayoshi Tachibana; Makoto Onizuka; Tatsuo Ichinohe; Yoshiko Atsuta; Yoshinobu Kanda

doi:10.1016/j.bbmt.2019.10.032

Increased Relapse Risk of Acute Lymphoid Leukemia in Homozygous HLA-C1 Patients after HLA-Matched Allogeneic Transplantation: A Japanese National Registry Study

Biol Blood Marrow Transplant. 2020 Mar;26(3):431-437. doi: 10.1016/j.bbmt.2019.10.032. Epub 2019 Nov 6.

Authors

Nobuyoshi Arima¹, Junya Kanda², Toshio Yabe³, Yasuo Morishima⁴, Junji Tanaka⁵, Shinichi Kako⁶, Hirotoshi Sakaguchi⁷, Motohiro Kato⁸, Kazuteru Ohashi⁹, Yukiyasu Ozawa¹⁰, Takahiro Fukuda¹¹, Shuichi Ota¹², Takayoshi Tachibana¹³, Makoto Onizuka¹⁴, Tatsuo Ichinohe¹⁵, Yoshiko Atsuta¹⁶, Yoshinobu Kanda¹⁷

Affiliations

¹ Department of Hematology, Shinko Hospital, Kobe, Japan; Department of Hematology, Medical Research Institute Kitano Hospital, Osaka, Japan. Electronic address: [email protected].
² Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
³ Laboratory Department, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
⁴ Central Japan Cord Blood Bank, Seto, Japan.
⁵ Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
⁶ Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
⁷ Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross, Nagoya First Hospital, Nagoya, Japan.
⁸ Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
⁹ Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
¹⁰ Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
¹¹ Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
¹² Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan.
¹³ Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan.
¹⁴ Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.
¹⁵ Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
¹⁶ The Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹⁷ Division of Hematology, Jichi Medical University, Shimotsuke, Japan.

PMID: 31704471
DOI: 10.1016/j.bbmt.2019.10.032

Abstract

Natural killer (NK) cells expressing killer cell immunoglobulin-like receptors (KIRs) can recognize specific HLA class I molecules as their ligands. By studying a large Japanese transplant registry, we compared transplant outcomes between patients heterozygous for HLA-C^Asn80/C^Lys80 (HLA-C1/C2) and those homozygous for HLA-C1 (HLA-C1/C1) among patients who had undergone HLA-matched hematopoietic stem cell transplantation (HSCT). A high frequency of KIR2DL1 with strong HLA-C2 binding capacity and a low frequency of HLA-C2 and KIR haplotype B are characteristic of the Japanese population. In our previous report, HLA-C1/C1 patients with myeloid leukemia were less likely to relapse than HLA-C1/C2 patients. We newly assessed 2884 patients with acute lymphoblastic leukemia (ALL) who received HLA-matched allogeneic HSCT and analyzed their leukemia relapses by using adjusted competing-risk methods. HLA-C1/C1 patients with ALL experienced significantly higher relapse rates than HLA-C1/C2 patients (hazard ratio [HR] = 1.55, P = .003), contrary to our results in patients with myeloid leukemia. We allocated patients with ALL to several subgroups and found a higher frequency of relapse (HR >1.8) in the HLA-C1/C1 group than in the HLA-C1/C2 group among patients with Ph-negative ALL, those who had no cytomegalovirus reactivation, those who received transplants from donors who were aged 41 years or older, and those who experienced acute graft-versus-host disease, especially if it required systemic treatment. One interpretation of our results is that KIR2DL1-positive NK cells disrupt T cells, antigen-presenting cells, or both from working efficiently in transplant immunity in HLA-C1/C1 patients with ALL. Another is that KIR2DS1-positive NK cells directly attack HLA-C2-positive ALL blasts in HLA-C1/C2 patients. Whether HLA-C2 can cause recurrence to decrease or increase in patients depending on the disease (ALL or myeloid leukemia) will be a very important finding. We hope that our results will provide clues to the real mechanisms behind relapse after transplantation in patients with different HLA profiles.

Keywords: Allogeneic hematopoietic stem cell transplantation; Graft-versus-leukemia; HLA-C; Killer cell immunoglobulin-like receptor; Natural killer cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

HLA-C Antigens / genetics
Hematopoietic Stem Cell Transplantation*
Humans
Japan
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / therapy
Receptors, KIR
Recurrence
Registries
Transplantation, Homologous

Substances

HLA-C Antigens
Receptors, KIR