title: Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.
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.
  
  
  RESULTS
  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.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Rehan Mujeeb
authors.initials: RM
authors.lastname: Faridi
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Kemp
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Poonam
authors.initials: P
authors.lastname: Dharmani-Khan
authors.affiliation: Section of Pediatric Oncology, Blood and Marrow Transplant, Department of Oncology and Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Lewis
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Gaurav
authors.identifier: http://orcid.org/0000-0002-1820-6547
authors.initials: G
authors.lastname: Tripathi
authors.affiliation: Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Raja
authors.initials: R
authors.lastname: Rajalingam
authors.affiliation: Departments of Medicine and Oncology, Foothills Hospital and Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Andrew
authors.identifier: http://orcid.org/0000-0001-7513-1062
authors.initials: A
authors.lastname: Daly
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.|Calgary Laboratory Services, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Noureddine
authors.initials: N
authors.lastname: Berka
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Storek
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.|Calgary Laboratory Services, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Faisal
authors.initials: F
authors.lastname: Masood Khan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D002908:Chronic Disease; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000209:etiology* / Q000517:prevention & control*; D006680:HLA Antigens / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000627:therapeutic use; D063868:Patient Outcome Assessment; D011817:Rabbits; D054340:Receptors, KIR / Q000235:genetics*; D035781:Siblings; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods; D014184:Transplantation, Homologous; D061349:Unrelated Donors
chemical_list: D000961:Antilymphocyte Serum; D006680:HLA Antigens; D008024:Ligands; D019653:Myeloablative Agonists; D054340:Receptors, KIR