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Increased donor inhibitory KIR with known HLA interactions provide protection from relapse following HLA matched unrelated donor HCT for AML

Bone Marrow Transplantation volume 56, pages 2714–2722 (2021)Cite this article

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A Correction to this article was published on 15 October 2021

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Abstract

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated graft versus leukemia effect (GVL) after hematopoietic cell transplant (HCT) for AML. Accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity and GVL. A retrospective study of 2359 donor-recipient pairs (DRP) who underwent unrelated donor (URD) HCT for AML was performed. KIR-KIRL combinations were determined and associations with clinical outcomes examined. Relapse risk was reduced in DRP with both higher inhibitory KIR-KIRL (iKIR) and missing KIRL (mKIR) scores, with HR 0.86 (P = 0.01) & HR 0.84 (P = 0.02) respectively. The iKIR and mKIR score components were summed to give a maximal inhibitory KIR ligand (IM-KIR) score for each donor, which if it was 5, as opposed to <5, was also associated with a lower relapse risk, SHR 0.8 (P = 0.004). All IM = 5 donors possess KIR Haplotype B/x. Transplant-related mortality was increased among those with IM-KIR = 5, HR, 1.32 (P = 0.01). In a subset analysis of those transplanted with 8/8 HLA-matched DRP, anti-thymocyte globulin recipients with IM-KIR = 5, had a lower relapse rate HR, 0.61 (p = 0.001). This study demonstrates that HLA-matched unrelated donors with the highest inhibitory KIR content confer relapse protection, albeit with increased TRM. These donors all have KIR haplotype B. Clinical trials utilizing donors with a higher iKIR content in conjunction with novel strategies to reduce TRM should be considered for URD HCT in recipients with AML to optimize clinical outcomes.

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Fig. 1: Unadjusted and adjusted sub-distribution hazard and hazard ratios from competing risk and Cox proportional hazard models for the effect of iKIR, mKIR and aKIR on clinical outcomes following HCT for AML, depicting a beneficial effect of iKIR and mKIR on relapse risk.
Fig. 2: Unadjusted and adjusted sub-distribution hazard and hazard ratios from competing risk and Cox proportional hazard models for the effect of dichotomized IM-KIR Score* on clinical outcomes following HCT for AML, showing a relapse protection with IM = 5 donors in HCT for AML.
Fig. 3: Unadjusted cumulative incidence curves by IM-KIR scores for relapse, treatment-related mortality, and chronic graft versus host disease, as well as failure curves by IM-KIR scores for overall survival, relapse-free survival, and cGVHD-free, relapse-free survival.
Fig. 4: Unadjusted cumulative incidence curves depicting interaction between IM-KIR scores and in vivo T cell depletion with ATG depicting relapse, treatment-related mortality, and chronic graft versus host disease.

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Acknowledgements

The authors gratefully acknowledge Stephen Spellman and Tao Wang, Ph.D. for their help with data organization and for critical review of the manuscript. The analysis presented here was performed on data obtained from the Center for International Blood and Marrow Transplantation Research (CIBMTR, Milwaukee, WI). The CIBMTR is supported primarily by Public Health Service grant/cooperative agreement U24CA076518 with the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); grant/cooperative agreement U24HL138660 with NHLBI and NCI; grants R21HL140314 and U01HL128568 from the NHLBI; contract HHSH250201700006C with Health Resources and Services Administration (HRSA); grants N00014-18-1-2888, N00014-17-1-2850 and N00014-20-1-2705 from the Office of Naval Research; subaward from prime contract award SC1MC31881-01-00 with HRSA; subawards from prime grant awards R01HL131731 and R01HL126589 from NHLBI; subaward from prime grant award 5R01CA2151343 from NIH Cancer Institute. P01CA111412, R01CA152108, R01CA218285;R01CA231141, R01HL126589, R01HL129472, R01HL131731 and U01AI126612 from the NIH. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government. AT was supported by research funding from the NIH-NCI Cancer Center Support Grant (P30-CA016059; PI: Gordon Ginder, MD). Institutional Review Board at the Virginia Commonwealth University deemed that since data were completely deidentified, this analysis did not constitute human subjects research and according to Section 45 CFR 46.102(l) of the HHS Regulations for the Protection of Human Subjects did not require IRB scrutiny.

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  1. These authors contributed equally: Elizabeth Krieger, Rehan Qayyum.

Authors and Affiliations

  1. Department of Pediatrics, Virginia Commonwealth University, Richmond, VA, USA

    Elizabeth Krieger

  2. Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA

    Rehan Qayyum

  3. Princess Margaret Cancer Centre, Toronto, ON, Canada

    Armand Keating

  4. Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

    Amir Toor

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Contributions

EK: Designed study, developed KIR-KIRL scoring algorithm, analyzed data, wrote paper. RQ: Designed study, developed KIR-KIRL scoring algorithm, performed statistical analysis, wrote paper. AK: Critical review of the KIR-KIRL scoring algorithm and manuscript, wrote the paper. AT: Designed study, developed KIR-KIRL scoring algorithm, analyzed data, wrote paper.

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Correspondence to Amir Toor.

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The original online version of this article was revised: In the “Acknowledgements” section of this article, the grant numbers (CIDR) U24CA233032 from the NCI and the grant number OT3HL147741 from NHLBI were removed.

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Krieger, E., Qayyum, R., Keating, A. et al. Increased donor inhibitory KIR with known HLA interactions provide protection from relapse following HLA matched unrelated donor HCT for AML. Bone Marrow Transplant 56, 2714–2722 (2021). https://doi.org/10.1038/s41409-021-01393-9

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