Influence of Differently Licensed KIR2DL1-Positive Natural Killer Cells in Transplant Recipients with Acute Leukemia: A Japanese National Registry Study

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Influence of Differently Licensed KIR2DL1-Positive Natural Killer Cells in Transplant Recipients with Acute Leukemia: A Japanese National Registry Study Nobuyoshi Arima, Fumiaki Nakamura, Toshio Yabe, Junji Tanaka, Shigeo Fuji, Kazuteru Ohashi, Takahiro Fukuda, Koichi Miyamura, Koji Iwato, Tetsuya Eto, Takehiko Mori, Naoki Kobayashi, Takumi Hoshino, Chiaki Kato, Heiwa Kanamori, Hirohisa Nakamae, Yoshiko Atsuta, Yasuo Morishima, Yoshinobu Kanda Biology of Blood and Marrow Transplantation Volume 22, Issue 3, Pages 423-431 (March 2016) DOI: 10.1016/j.bbmt.2015.09.029 Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Model of natural killer (NK) cellular recognition of donor HLA-C2 as a KIR2DL1-ligand. Upper: If donor cells express HLA-C2, KIR2DL1-positive donor NK cells will become licensed by self-major histocompatibility complexes and will attack recipient leukemia. Middle: Even if both donor and recipient do not exhibit HLA-C2, KIR2DL1-positive donor NK cells will be transiently alloreactive just after hematopoietic stem-cell transplantation (HSCT). Bottom: If recipient leukemia express HLA-C2, KIR2DL1-positive donor NK cells will become inhibited. Biology of Blood and Marrow Transplantation 2016 22, 423-431DOI: (10.1016/j.bbmt.2015.09.029) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Effect of the KIR2DL1-ligand group on relapse in recipients with acute myeloid leukemia (AML) (A) or acute lymphoblastic leukemia (ALL) (B). The cumulative incidence of relapse is shown for HLA-C1/HLA-C2 (dotted line) or HLA-C1/HLA-C1 (solid line) patients who received transplants from unrelated donors with HLA-A, -B, -C, and- DRB1 matched HLA alleles. Biology of Blood and Marrow Transplantation 2016 22, 423-431DOI: (10.1016/j.bbmt.2015.09.029) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Effect of the KIR2DL1-ligand group on overall survival in unrelated HSCT in C1/C1 or C1/C2 recipients with AML or ALL. All combinations of HLA-C groups were adjusted for recipient/donor age, recipient/donor sex, myeloablative/reduced intensity, performance status before transplantation, and disease risk. The adjusted overall survival is shown for recipients from HLA-matched donors (black line), HLA-C–mismatched licensed donors (red dotted line), an HLA-C–mismatched transiently alloreactive donors (green dashed line), or HLA-C–mismatched inhibited donors (blue dashed line). Biology of Blood and Marrow Transplantation 2016 22, 423-431DOI: (10.1016/j.bbmt.2015.09.029) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Algorithm for selecting how to appropriately choose HLA-C–mismatched donors in clinical practice. When recipients are expected to receive hematological stem cell transplantation, the differential diagnosis of their leukemia has priority. Then, HLA-Cs of each recipient should be grouped as HLA-C1 or HLA-C2 by their serotypes, leading the recommendation for a preferable donor. No data to recommend for HLA-C2C2 recipients exist in this study. Biology of Blood and Marrow Transplantation 2016 22, 423-431DOI: (10.1016/j.bbmt.2015.09.029) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions