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Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.
PLoS One. 2016; 11(6):e0158242.Plos

Abstract

BACKGROUND

Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT.

METHODS AND FINDINGS

The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42-4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11-2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10-0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17-0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants.

CONCLUSIONS

The present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

Authors+Show Affiliations

Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.Section of Pediatric Oncology, Blood and Marrow Transplant, Department of Oncology and Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, United States of America.Departments of Medicine and Oncology, Foothills Hospital and Tom Baker Cancer Centre, Calgary, Alberta, Canada.Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada. Calgary Laboratory Services, University of Calgary, Calgary, Alberta, Canada.Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada. Departments of Medicine and Oncology, Foothills Hospital and Tom Baker Cancer Centre, Calgary, Alberta, Canada.Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada. Calgary Laboratory Services, University of Calgary, Calgary, Alberta, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27341514

Citation

Faridi, Rehan Mujeeb, et al. "Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect Against Relapse After Myeloablative, HLA Matched Hematopoietic Cell Transplantation." PloS One, vol. 11, no. 6, 2016, pp. e0158242.
Faridi RM, Kemp TJ, Dharmani-Khan P, et al. Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation. PLoS One. 2016;11(6):e0158242.
Faridi, R. M., Kemp, T. J., Dharmani-Khan, P., Lewis, V., Tripathi, G., Rajalingam, R., Daly, A., Berka, N., Storek, J., & Masood Khan, F. (2016). Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation. PloS One, 11(6), e0158242. https://doi.org/10.1371/journal.pone.0158242
Faridi RM, et al. Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect Against Relapse After Myeloablative, HLA Matched Hematopoietic Cell Transplantation. PLoS One. 2016;11(6):e0158242. PubMed PMID: 27341514.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation. AU - Faridi,Rehan Mujeeb, AU - Kemp,Taylor J, AU - Dharmani-Khan,Poonam, AU - Lewis,Victor, AU - Tripathi,Gaurav, AU - Rajalingam,Raja, AU - Daly,Andrew, AU - Berka,Noureddine, AU - Storek,Jan, AU - Masood Khan,Faisal, Y1 - 2016/06/24/ PY - 2016/02/17/received PY - 2016/06/12/accepted PY - 2016/6/25/entrez PY - 2016/6/25/pubmed PY - 2017/7/25/medline SP - e0158242 EP - e0158242 JF - PloS one JO - PLoS One VL - 11 IS - 6 N2 - BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT. METHODS AND FINDINGS: The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42-4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11-2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10-0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17-0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants. CONCLUSIONS: The present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/27341514/Donor_Recipient_Matching_for_KIR_Genotypes_Reduces_Chronic_GVHD_and_Missing_Inhibitory_KIR_Ligands_Protect_against_Relapse_after_Myeloablative_HLA_Matched_Hematopoietic_Cell_Transplantation_ L2 - https://dx.plos.org/10.1371/journal.pone.0158242 DB - PRIME DP - Unbound Medicine ER -