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Reduced leukemia relapse through cytomegalovirus reactivation in killer cell immunoglobulin-like receptor-ligand-mismatched cord blood transplantation

Bone Marrow Transplantation volume 56, pages 1352–1363 (2021)Cite this article

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Abstract

Cytomegalovirus (CMV) reactivation in cord blood transplantation (CBT) may result in the proliferation and maturation of natural killer (NK) cells. Similarly, a mismatch of the killer cell immunoglobulin-like receptor (KIR)-ligand induces NK cell activation. Therefore, if CMV reactivation occurs in the presence of KIR-ligand mismatch, it might improve CBT outcomes. We assessed the difference in the effect of CMV reactivation in the presence of KIR-ligand mismatch on disease relapse in the graft-versus-host direction. A total of 2840 patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and chronic myeloid leukemia were analyzed. Among those with a HLA-Bw4/A3/A11 (KIR3DL-ligand) mismatch, CMV reactivation up to 100 days following CBT had a favorable impact on relapse (18.9% vs. 32.9%, P = 0.0149). However, this effect was not observed in cases without the KIR3DL-ligand mismatch or in those with or without a HLA-C1/C2 (KIR2DL-ligand) mismatch. The multivariate analysis suggested that CMV reactivation had a favorable effect on relapse only in cases with a KIR3DL-ligand mismatch (hazard ratio 0.54, P = 0.032). Moreover, the interaction effect between CMV reactivation and KIR3DL-ligand mismatch on relapse was significant (P = 0.039). Thus, our study reveals the association between KIR-ligand mismatches and CMV reactivation, which will enhance CBT outcomes.

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Fig. 1: Flowchart depicting the patient selection process.
Fig. 2: Effect of CMV reactivation on relapse following CBT in patients with or without a KIR-ligand mismatch.
Fig. 3: Multivariate analysis assessing the effect of CMV reactivation on relapse and NRM following CBT based on each type of KIR-ligand mismatch and identification of the interaction effect between KIR-ligand mismatch and CMV reactivation.
Fig. 4: Effect of CMV reactivation on NRM following CBT in patients with or without a KIR-ligand mismatch.
Fig. 5: Effect of CMV reactivation on OS following CBT in patients with or without a KIR-ligand mismatch.
Fig. 6: Multivariate analysis assessing the effect of CMV reactivation on outcomes following CBT in patients with AML and ALL having a KIR3DL-ligand mismatch.
Fig. 7: Effect of CMV reactivation on CBT outcomes in patients with or without KIR3DL-ligand mismatch, which was assessed by multivariate analysis for the cohort that excluded patients developing aGVHD II–IV.

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Acknowledgements

The authors would like to thank all the physicians and data managers who delivered valuable data to the Japan Society for Hematopoietic Cell Transplantation (JSHCT). The authors would also like to thank the staff at the Data Center, JSHCT for their contributions.

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Authors and Affiliations

  1. Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Hisayuki Yokoyama

  2. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Junya Kanda

  3. Department of Pediatrics, Jichi Medical University School of Medicine, Shimotsuke, Japan

    Yuta Kawahara

  4. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan

    Naoyuki Uchida

  5. Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan

    Masatsugu Tanaka

  6. Division of Molecular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Satoshi Takahashi

  7. Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan

    Makoto Onizuka

  8. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Yuma Noguchi

  9. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Yukiyasu Ozawa

  10. Department of Hematology, National Hospital Organization Sendai Medical Center, Sendai, Japan

    Yuna Katsuoka

  11. Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan

    Shuichi Ota

  12. Department of Hematology, Kitakyushu City Hospital Organization, Kitakyushu Municipal Medical Center, Kitakyushu, Japan

    Takanori Ohta

  13. Preparation Department, Japanese Red Cross Kinki Block Blood Center, Ibaraki, Japan

    Takafumi Kimura

  14. Division of Hematology, Jichi Medical University, Shimotsuke, Japan

    Yoshinobu Kanda

  15. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Tatsuo Ichinohe

  16. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Yoshiko Atsuta

  17. Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta

  18. Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan

    Hideki Nakasone

  19. Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan

    Satoko Morishima

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  1. Hisayuki Yokoyama
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Yokoyama, H., Kanda, J., Kawahara, Y. et al. Reduced leukemia relapse through cytomegalovirus reactivation in killer cell immunoglobulin-like receptor-ligand-mismatched cord blood transplantation. Bone Marrow Transplant 56, 1352–1363 (2021). https://doi.org/10.1038/s41409-020-01203-8

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