Homozygous HLA-C1 is Associated with Reduced Risk of Relapse after HLA-Matched Transplantation in Patients with Myeloid Leukemia

Nobuyoshi Arima; Junya Kanda; Junji Tanaka; Toshio Yabe; Yasuo Morishima; Sung-Won Kim; Yuho Najima; Yukiyasu Ozawa; Tetsuya Eto; Heiwa Kanamori; Takehiko Mori; Naoki Kobayashi; Tadakazu Kondo; Hirohisa Nakamae; Naoyuki Uchida; Masami Inoue; Takahiro Fukuda; Tatsuo Ichinohe; Yoshiko Atsuta; Yoshinobu Kanda

doi:10.1016/j.bbmt.2017.11.029

Homozygous HLA-C1 is Associated with Reduced Risk of Relapse after HLA-Matched Transplantation in Patients with Myeloid Leukemia

Biol Blood Marrow Transplant. 2018 Apr;24(4):717-725. doi: 10.1016/j.bbmt.2017.11.029. Epub 2017 Dec 27.

Authors

Nobuyoshi Arima¹, Junya Kanda², Junji Tanaka³, Toshio Yabe⁴, Yasuo Morishima⁵, Sung-Won Kim⁶, Yuho Najima⁷, Yukiyasu Ozawa⁸, Tetsuya Eto⁹, Heiwa Kanamori¹⁰, Takehiko Mori¹¹, Naoki Kobayashi¹², Tadakazu Kondo², Hirohisa Nakamae¹³, Naoyuki Uchida¹⁴, Masami Inoue¹⁵, Takahiro Fukuda⁶, Tatsuo Ichinohe¹⁶, Yoshiko Atsuta¹⁷, Yoshinobu Kanda¹⁸

Affiliations

¹ Department of Hematology, Medical Research Institute Kitano Hospital, Osaka, Japan. Electronic address: n-arima@kitano-hp.or.jp.
² Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
³ Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
⁴ Hematology Division, Japanese Red Cross Tokyo Metropolitan Blood Center, Tokyo, Japan.
⁵ Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁶ Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.
⁷ Hematology Division, Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
⁸ Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
⁹ Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan.
¹⁰ Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan.
¹¹ Department of Hematology, Keio University School of Medicine, Tokyo, Japan.
¹² Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan.
¹³ Department of Hematology, Osaka City University Hospital, Osaka, Japan.
¹⁴ Department of Hematology, Toranomon Hospital, Tokyo, Japan.
¹⁵ Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.
¹⁶ Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
¹⁷ Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹⁸ Devision of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.

PMID: 29197675
DOI: 10.1016/j.bbmt.2017.11.029

Abstract

Natural killer (NK) cells assume graft-versus-leukemia alloreactivity after hematopoietic stem cell transplantation (HSCT) through their inhibitory killer cell immunoglobulin-like receptors (KIRs). KIR2D family members recognize HLA-C alleles with Asn80 (HLA-C1) or Lys80 (HLA-C2). The predominance of HLA-C1 over HLA-C2 and the frequent presence of KIR2DL1 are characteristic of Japanese people. We compared clinical outcomes among homozygous HLA-C1 (HLA-C1/C1) patients and heterozygous HLA-C1/C2 patients who underwent HLA-matched HSCT for hematologic malignancies by assessing the data of 10,638 patients from the Japanese national registry. HLA-C1/C1 recipients had a lower rate of relapse than HLA-C1/C2 recipients after transplantation for acute myelogenous leukemia (AML) (hazard ratio [HR], .79; P = .006) and chronic myelogenous leukemia (CML) (HR, .48; P = .025), but not for acute lymphoblastic leukemia (HR, 1.36), lymphoma (HR, .97), or low-grade myelodysplastic syndrome (HR, 1.40). We then grouped AML and CML patients together and divided them into several subgroups. Advantages of HLA-C1/C1 recipients over HLA-C1/C2 recipients regarding relapse were observed irrespective of donor relation (related: HR, .79, P = .069; unrelated: HR, .77, P = .022), preparative regimen (myeloablative: HR, .79, P = .014; reduced intensity: HR, .73, P = .084), and occurrence of acute graft-versus-host disease (yes: HR, .70, P = .122; no, HR .71, P = .026) or cytomegalovirus reactivation (reactivated: HR .67,P = .054; nonreactivated: HR .71, P = .033); however, these advantages were not observed in recipients with a delay in achieving complete chimerism (HR, 1.06). The advantage of decreasing relapse and extending relapse-free survival of C1/1 over C1/2 KIR-ligand status was most pronounced in T cell-depleted HSCT (HR, .27; P < .001 and HR, .30; P = .002, respectively) and in children age <15 years (HR, .29; P < .001 and HR .31; P < .001, respectively). Our findings represent an important mechanism responsible for the immunity against HLA-C2-negative myeloid leukemia cells after HLA-matched transplantation.

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

Publication types

Clinical Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles*
HLA-C Antigens* / genetics
HLA-C Antigens* / immunology
Homozygote*
Humans
Japan
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / immunology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / mortality
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / immunology
Leukemia, Myeloid, Acute* / mortality
Leukemia, Myeloid, Acute* / therapy
Middle Aged
Recurrence
Registries*
Risk Factors

Substances

HLA-C Antigens