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Presence of donor-encoded centromeric KIR B content increases the risk of infectious mortality in recipients of myeloablative, T-cell deplete, HLA-matched HCT to treat AML

Bone Marrow Transplantation volume 55, pages 1975–1984 (2020)Cite this article

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Abstract

The reported influence of donor Killer-cell Immunoglobulin-like Receptor (KIR) genes on the outcomes of haematopoietic cell transplantation (HCT) are contradictory, in part due to diversity of disease, donor sources, era and conditioning regimens within and between different studies. Here, we describe the results of a retrospective clinical analysis establishing the effect of donor KIR motifs on the outcomes of 119 HLA-matched, unrelated donor HCT for adult acute myeloid leukaemia (AML) using myeloablative conditioning (MAC) in a predominantly T-cell deplete (TCD) cohort. We observed that HCT involving donors with at least one KIR B haplotype were more likely to result in non-relapse mortality (NRM) than HCT involving donors with two KIR A haplotypes (p = 0.019). Upon separation of KIR haplotypes into their centromeric (Cen) and telomeric (Tel) motif structures, we demonstrated that the Cen-B motif was largely responsible for this effect (p = 0.001). When the cause of NRM was investigated further, infection was the dominant cause of death (p = 0.006). No evidence correlating donor KIR B haplotype with relapse risk was observed. The results from this analysis confirm previous findings in the unrelated, TCD, MAC transplant setting and imply a protective role for donor-encoded Cen-A motifs against infection in allogeneic HCT recipients.

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Fig. 1: Charts demonstrating the proportions of different centromeric motif structures within donor subgroups.
Fig. 2: Donor KIR B genotype increases NRM.
Fig. 3: Effect of donor Cen-B is dose-dependent.

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Acknowledgements

This project was supported in part by funding provided by the National Institutes of Health (NIH, P01-CA-111412) whilst further funding and support was provided by Anthony Nolan.

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Authors and Affiliations

  1. Anthony Nolan Research Institute, Royal Free Hospital, London, UK

    Will P. Bultitude, Jennifer Schellekens, Richard M. Szydlo, Chloe Anthias, Marie C. Wilson, J. Alejandro Madrigal, Neema P. Mayor & Steven G. E. Marsh

  2. Cancer Institute, University College London, Royal Free Campus, London, UK

    Will P. Bultitude, Jennifer Schellekens, J. Alejandro Madrigal, Neema P. Mayor & Steven G. E. Marsh

  3. Imperial College London, London, UK

    Richard M. Szydlo

  4. Royal Marsden Hospital, Surrey, UK

    Chloe Anthias & Michael N. Potter

  5. Fate Therapeutics, San Diego, CA, USA

    Sarah A. Cooley

  6. Haematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

    Jeffrey S. Miller & Daniel J. Weisdorf

  7. CIBMTR and Froedtert and the Medical College of Wisconsin Clinical Cancer Center, Wisconsin, WI, USA

    Bronwen E. Shaw

  8. London School of Hygiene and Tropical Medicine, London, UK

    Chrissy h. Roberts

  9. Laboratorio de Genómica Viral y Humana, Facultad de Medicina, Universidad Autónoma de San Luis Potosi, San Luis Potosi, SLP, Mexico

    Christian A. Garcia-Sepulveda

  10. British Society of Blood and Marrow Transplantation and Cellular Therapy, Guy’s Hospital, London, UK

    Julia Lee, Rachel M. Pearce & Marie C. Wilson

  11. Nottingham University Hospital, Nottingham, UK

    Jenny L. Byrne & Nigel H. Russell

  12. University College London Hospitals NHS Foundation Trust, London, UK

    Stephen MacKinnon

  13. The Christie NHS Foundation Trust, Manchester, UK

    Adrian J. Bloor

  14. Liverpool University Hospital, Liverpool, UK

    Amit Patel

  15. West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, UK

    I. Grant McQuaker

  16. University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

    Ram Malladi

  17. Manchester University NHS Foundation Trust, Manchester, UK

    Eleni Tholouli

  18. University Hospital Southampton NHS Foundation Trust, Southampton, UK

    Kim Orchard

  19. Kings College Hospital, London, UK

    Victoria T. Potter

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  1. Will P. Bultitude
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Correspondence to Steven G. E. Marsh.

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Bultitude, W.P., Schellekens, J., Szydlo, R.M. et al. Presence of donor-encoded centromeric KIR B content increases the risk of infectious mortality in recipients of myeloablative, T-cell deplete, HLA-matched HCT to treat AML. Bone Marrow Transplant 55, 1975–1984 (2020). https://doi.org/10.1038/s41409-020-0858-9

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