KIR2DS4 and Its Variant KIR1D in KIR-AA Genotype Donors Showed Differential Survival Impact in Patients with Lymphoid Disease after HLA-Matched Unrelated Hematopoietic Stem Cell Transplantation

Sowmya Gowdavally; Chrysanthi Tsamadou; Uwe Platzbecker; Elisa Sala; Thomas Valerius; Stefan Klein; Nicolaus Kröger; Gerald Wulf; Hermann Einsele; Lorenz Thurner; Kerstin Schaefer-Eckart; Sebastian Freitag; Jochen Casper; Mareike Dürholt; Martin Kaufmann; Bernd Hertenstein; Mark Ringhoffer; Sandra Schmeller; Christine Neuchel; Immanuel Rode; Elisa Maria Amann; Anita Richter; Hubert Schrezenmeier; Joannis Mytilineos; Daniel Fuerst

doi:10.1016/j.jtct.2023.04.006

KIR2DS4 and Its Variant KIR1D in KIR-AA Genotype Donors Showed Differential Survival Impact in Patients with Lymphoid Disease after HLA-Matched Unrelated Hematopoietic Stem Cell Transplantation

Transplant Cell Ther. 2023 Jul;29(7):457.e1-457.e10. doi: 10.1016/j.jtct.2023.04.006. Epub 2023 May 6.

Authors

Sowmya Gowdavally¹, Chrysanthi Tsamadou¹, Uwe Platzbecker², Elisa Sala³, Thomas Valerius⁴, Stefan Klein⁵, Nicolaus Kröger⁶, Gerald Wulf⁷, Hermann Einsele⁸, Lorenz Thurner⁹, Kerstin Schaefer-Eckart¹⁰, Sebastian Freitag¹¹, Jochen Casper¹², Mareike Dürholt¹³, Martin Kaufmann¹⁴, Bernd Hertenstein¹⁵, Mark Ringhoffer¹⁶, Sandra Schmeller¹⁷, Christine Neuchel¹, Immanuel Rode¹, Elisa Maria Amann¹, Anita Richter¹, Hubert Schrezenmeier¹, Joannis Mytilineos¹⁸, Daniel Fuerst¹⁹

Affiliations

¹ Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross and University Hospital Ulm, Germany; Institute of Transfusion Medicine, University of Ulm, Germany.
² Department of Hematology/Oncology, University of Leipzig, Germany.
³ Department of Internal Medicine III, University of Ulm, Germany.
⁴ Section for Stem Cell Transplantation and Immunotherapy, Department of Medicine II, Christian Albrechts University, Kiel, Germany.
⁵ Medical Clinic III, Universitätsmedizin Mannheim, Mannheim, Germany.
⁶ Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
⁷ Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany.
⁸ Department of Internal Medicine II, University Hospital Würzburg, Germany.
⁹ Department Internal Medicine I, Universitätsklinikum des Saarlandes, Homburg, Germany.
¹⁰ Medical Clinic 5: Hematology, Oncology, Nuremberg Hospital, Germany.
¹¹ Department of Medicine III, Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
¹² Department of Oncology and Hematology, Klinikum Oldenburg, University Clinic, Oldenburg, Germany.
¹³ Hematology/Oncology, Evangelic Clinic Essen-Werden, Essen, Germany.
¹⁴ Second Department of Internal Medicine, Oncology and Hematology, Robert Bosch Hospital, Stuttgart, Germany.
¹⁵ Hematology/Oncology, Klinikum Bremen-Mitte, Bremen, Germany.
¹⁶ Medical Clinic III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
¹⁷ German Registry for Stem Cell Transplantation, Ulm, Germany.
¹⁸ German Registry for Stem Cell Transplantation, Ulm, Germany; Zentrales Knochenmarkspender-Register für Deutschland, German National Bone Marrow Donor Registry, Ulm, Germany.
¹⁹ Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross and University Hospital Ulm, Germany; Institute of Transfusion Medicine, University of Ulm, Germany. Electronic address: d.fuerst@blutspende.de.

PMID: 37150297
DOI: 10.1016/j.jtct.2023.04.006

Abstract

Previous studies have illustrated associations between the presence of activating killer cell immunoglobulin-like receptor (KIR) genes and lower susceptibility to hematologic malignancies in humans. In addition, favorable hematopoietic stem cell transplantation (HSCT) outcomes have been reported in patients who received transplants from donors with KIR genotypes dominant for activating KIR receptors. However, the association of activating KIR genes on an allelic level with disease and their impact on HSCT outcome has been little investigated to date. To this end, we genotyped a large transplantation cohort for KIR 2 Ig domains and short cytoplasmic tail 4 (KIR2DS4) polymorphisms and investigated their association with disease. We next investigated the impact of KIR-AA genotype donor KIR2DS4 polymorphisms (AA/KIR2DS4 versus AA/ KIR 1 Ig domain [KIR1D]) on clinical outcomes of HSCT in myeloid versus lymphoid patient subgroups. Among 2810 transplantation donor-recipient pairs, 68.8% (n = 1934) were 10/10 HLA-matched and 31.2% (n = 876) were 9/10 HLA-matched. The distribution of KIR1D was equal in patients and donors (P = .205). Multivariate analysis in 10/10 HLA-matched patients with lymphoid disease showed improved HSCT outcomes when they received grafts from AA/KIR1D donors (overall survival: hazard ratio [HR], .62, P = .002; disease free survival: HR, .70, P = .011; graft-versus-host disease-free and relapse-free survival: HR, .67, P = .002; nonrelapse mortality: HR, .55, P < .001). This effect was not seen in either 9/10 HLA-matched patients with lymphoid disease or patients with myeloid disease. Our study indicates that the presence of KIR1D alleles is not associated with disease in patients, and, interestingly, using grafts from AA/KIR1D donors translated into beneficial survival outcomes in 10/10 HLA-matched patients with lymphoid disease.

Keywords: Hematopoietic Stem Cell tTransplantation; KIR alloreactivity; KIR-Receptor; KIR1D; KIR2DS4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Genotype
Hematopoietic Stem Cell Transplantation* / adverse effects
Humans
Neoplasm Recurrence, Local* / etiology
Receptors, KIR / genetics
Tissue Donors

Substances

Receptors, KIR
KIR2DS4 protein, human