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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.

Faridi RM, Kemp TJ, Dharmani-Khan P, Lewis V, Tripathi G, Rajalingam R, Daly A, Berka N, Storek J, Masood Khan F - PLoS ONE (2016)

Bottom Line: 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.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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.

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.

No MeSH data available.


Related in: MedlinePlus

Effect of KIR genotype matching on the survival outcomes.Estimates of cGVHD & relapse free survival (cGRFS, left panel), relapse-free survival (RFS, middle panel) and overall survival (OS, right panel) are presented across discovery [A], validation [B] and combined [C] cohorts. A multivariate Cox Proportional Hazards Regression at the end of follow-up revealed a significantly poorer (p-values <0.05) cGRFS in both discovery and validation cohorts in addition to a combined cohort (discovery + validation) when KIR genotype mismatched donors were used.
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pone.0158242.g005: Effect of KIR genotype matching on the survival outcomes.Estimates of cGVHD & relapse free survival (cGRFS, left panel), relapse-free survival (RFS, middle panel) and overall survival (OS, right panel) are presented across discovery [A], validation [B] and combined [C] cohorts. A multivariate Cox Proportional Hazards Regression at the end of follow-up revealed a significantly poorer (p-values <0.05) cGRFS in both discovery and validation cohorts in addition to a combined cohort (discovery + validation) when KIR genotype mismatched donors were used.

Mentions: Chronic GVHD & relapse free survival (cGRFS) was defined as one being free of cGVHD or relapse; whichever happened first, constituted the “failure event” and marked the end of follow-up for that patient. Multivariate analysis performed for cGRFS corrected for covariates for both GVHD and relapse showed that cGRFS is significantly improved in recipients of KIR genotype-matched transplants as compared to the recipients of KIR genotype-mismatched transplants in both discovery and validation cohorts (p = 0.002 and 0.026 respectively; Fig 5A and 5B, left panel). Upon combining the discovery and validation cohorts, a hazard ratio of 1.86 (95%CI: 1.32–2.59, p = 0.0001) was observed, where cGRFS was significantly lower in recipients of KIR genotype mismatched transplant as compared to those of KIR genotype matched transplant (18.8% [95%CI: 10.2–29.4%] vs. 40.6% [95%CI: 32.8–48.3%]; Fig 5C, left panel). None of the other tested definitions yielded any significant effect on cGRFS (data not shown). When a similar analysis was performed in ligand-specific cohort, the favorable cGRFS was observed exclusively in recipients carrying one or two C1 bearing HLA-C allotypes (p = 0.013, Fig 6A), receiving grafts from a KIR genotype matched donor. Matched sibling or unrelated donors, Bw4/x positive or negative recipients or A3/11 positive or negative recipients did not segregate the beneficiaries of KIR genotype matching in terms of improved cGRFS.


Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

Faridi RM, Kemp TJ, Dharmani-Khan P, Lewis V, Tripathi G, Rajalingam R, Daly A, Berka N, Storek J, Masood Khan F - PLoS ONE (2016)

Effect of KIR genotype matching on the survival outcomes.Estimates of cGVHD & relapse free survival (cGRFS, left panel), relapse-free survival (RFS, middle panel) and overall survival (OS, right panel) are presented across discovery [A], validation [B] and combined [C] cohorts. A multivariate Cox Proportional Hazards Regression at the end of follow-up revealed a significantly poorer (p-values <0.05) cGRFS in both discovery and validation cohorts in addition to a combined cohort (discovery + validation) when KIR genotype mismatched donors were used.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920429&req=5

pone.0158242.g005: Effect of KIR genotype matching on the survival outcomes.Estimates of cGVHD & relapse free survival (cGRFS, left panel), relapse-free survival (RFS, middle panel) and overall survival (OS, right panel) are presented across discovery [A], validation [B] and combined [C] cohorts. A multivariate Cox Proportional Hazards Regression at the end of follow-up revealed a significantly poorer (p-values <0.05) cGRFS in both discovery and validation cohorts in addition to a combined cohort (discovery + validation) when KIR genotype mismatched donors were used.
Mentions: Chronic GVHD & relapse free survival (cGRFS) was defined as one being free of cGVHD or relapse; whichever happened first, constituted the “failure event” and marked the end of follow-up for that patient. Multivariate analysis performed for cGRFS corrected for covariates for both GVHD and relapse showed that cGRFS is significantly improved in recipients of KIR genotype-matched transplants as compared to the recipients of KIR genotype-mismatched transplants in both discovery and validation cohorts (p = 0.002 and 0.026 respectively; Fig 5A and 5B, left panel). Upon combining the discovery and validation cohorts, a hazard ratio of 1.86 (95%CI: 1.32–2.59, p = 0.0001) was observed, where cGRFS was significantly lower in recipients of KIR genotype mismatched transplant as compared to those of KIR genotype matched transplant (18.8% [95%CI: 10.2–29.4%] vs. 40.6% [95%CI: 32.8–48.3%]; Fig 5C, left panel). None of the other tested definitions yielded any significant effect on cGRFS (data not shown). When a similar analysis was performed in ligand-specific cohort, the favorable cGRFS was observed exclusively in recipients carrying one or two C1 bearing HLA-C allotypes (p = 0.013, Fig 6A), receiving grafts from a KIR genotype matched donor. Matched sibling or unrelated donors, Bw4/x positive or negative recipients or A3/11 positive or negative recipients did not segregate the beneficiaries of KIR genotype matching in terms of improved cGRFS.

Bottom Line: 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.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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.

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.

No MeSH data available.


Related in: MedlinePlus