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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

Association of KIR genotype mismatching with chronic GVHD was confirmed using a multivariate competing risks regression model.Effect of KIR genotype mismatching on aGVHD grade II-IV (left panel), cGVHD needing systemic therapy (middle panel) and relapse (right panel) was analyzed using multivariate competing risks regression model (Fine and Gray method) across discovery [A], validation [B] and combined [C] cohorts. Graft failure, relapse, second malignancy or death occurring before the onset of cGVHD was considered competing risks for cGVHD. Graft failure, second malignancy or non-relapse death occurring before the onset of relapse was considered competing risk for relapse. P values <0.05 were considered statistically significant. Favorable effect of KIR genotype matched donors on cGVHD (middle panel) was confirmed across discovery and validation cohorts in addition to all analyzed cases.
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pone.0158242.g002: Association of KIR genotype mismatching with chronic GVHD was confirmed using a multivariate competing risks regression model.Effect of KIR genotype mismatching on aGVHD grade II-IV (left panel), cGVHD needing systemic therapy (middle panel) and relapse (right panel) was analyzed using multivariate competing risks regression model (Fine and Gray method) across discovery [A], validation [B] and combined [C] cohorts. Graft failure, relapse, second malignancy or death occurring before the onset of cGVHD was considered competing risks for cGVHD. Graft failure, second malignancy or non-relapse death occurring before the onset of relapse was considered competing risk for relapse. P values <0.05 were considered statistically significant. Favorable effect of KIR genotype matched donors on cGVHD (middle panel) was confirmed across discovery and validation cohorts in addition to all analyzed cases.

Mentions: We first analyzed D-R pairs of the discovery cohort to assess the influence of KIR genotypes/matching on different HCT outcomes. A KIR genotype-matched transplant refers to one in which both donor and recipient were either KIR-AA or -B/x type. In univariate analyses, a significantly lower incidence of cGVHD was observed with D-R KIR genotype matched transplants compared to the KIR genotype-mismatched (B/x donor into AA recipients or vice-versa) transplants of the discovery cohort (25.0% [95%CI: 16.8–34.1%] vs. 54.0% [95%CI: 35.8–69.1%], p = 0.0005; Fig 1A, middle panel). Analyses of validation cohort further confirmed the observations as the incidence of cGVHD was lower among KIR genotype matched transplants compared to KIR-genotype mismatched transplants (26.7% [95%CI: 17.4–34.1%] vs. 50.1% [95%CI: 30.9–66.6%], p = 0.026, Fig 1B, middle panel). The multivariate competing risks regression analysis established a strong association of KIR genotype mismatching with cGVHD in patients of both discovery (p = 0.001, Table 3, Fig 2A, middle panel) and validation cohorts (p = 0.005, Table 3, Fig 2B, middle panel). Upon combining discovery and validation cohorts, the cumulative incidence of cGVHD in KIR genotype-matched versus mismatched transplants presented a sub-distributional hazard ratio of 2.67 (p<0.0001; Fig 2C, middle panel). Favorable cGVHD outcome through KIR genotype matching was contributed by both KIR-B/x and –AA genotype matching (p = 0.011 and 0.009 respectively, Table 3) and was applicable to both matched sibling and unrelated donor transplants (p = 0.009 and 0.004 respectively, Table 3).


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)

Association of KIR genotype mismatching with chronic GVHD was confirmed using a multivariate competing risks regression model.Effect of KIR genotype mismatching on aGVHD grade II-IV (left panel), cGVHD needing systemic therapy (middle panel) and relapse (right panel) was analyzed using multivariate competing risks regression model (Fine and Gray method) across discovery [A], validation [B] and combined [C] cohorts. Graft failure, relapse, second malignancy or death occurring before the onset of cGVHD was considered competing risks for cGVHD. Graft failure, second malignancy or non-relapse death occurring before the onset of relapse was considered competing risk for relapse. P values <0.05 were considered statistically significant. Favorable effect of KIR genotype matched donors on cGVHD (middle panel) was confirmed across discovery and validation cohorts in addition to all analyzed cases.
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pone.0158242.g002: Association of KIR genotype mismatching with chronic GVHD was confirmed using a multivariate competing risks regression model.Effect of KIR genotype mismatching on aGVHD grade II-IV (left panel), cGVHD needing systemic therapy (middle panel) and relapse (right panel) was analyzed using multivariate competing risks regression model (Fine and Gray method) across discovery [A], validation [B] and combined [C] cohorts. Graft failure, relapse, second malignancy or death occurring before the onset of cGVHD was considered competing risks for cGVHD. Graft failure, second malignancy or non-relapse death occurring before the onset of relapse was considered competing risk for relapse. P values <0.05 were considered statistically significant. Favorable effect of KIR genotype matched donors on cGVHD (middle panel) was confirmed across discovery and validation cohorts in addition to all analyzed cases.
Mentions: We first analyzed D-R pairs of the discovery cohort to assess the influence of KIR genotypes/matching on different HCT outcomes. A KIR genotype-matched transplant refers to one in which both donor and recipient were either KIR-AA or -B/x type. In univariate analyses, a significantly lower incidence of cGVHD was observed with D-R KIR genotype matched transplants compared to the KIR genotype-mismatched (B/x donor into AA recipients or vice-versa) transplants of the discovery cohort (25.0% [95%CI: 16.8–34.1%] vs. 54.0% [95%CI: 35.8–69.1%], p = 0.0005; Fig 1A, middle panel). Analyses of validation cohort further confirmed the observations as the incidence of cGVHD was lower among KIR genotype matched transplants compared to KIR-genotype mismatched transplants (26.7% [95%CI: 17.4–34.1%] vs. 50.1% [95%CI: 30.9–66.6%], p = 0.026, Fig 1B, middle panel). The multivariate competing risks regression analysis established a strong association of KIR genotype mismatching with cGVHD in patients of both discovery (p = 0.001, Table 3, Fig 2A, middle panel) and validation cohorts (p = 0.005, Table 3, Fig 2B, middle panel). Upon combining discovery and validation cohorts, the cumulative incidence of cGVHD in KIR genotype-matched versus mismatched transplants presented a sub-distributional hazard ratio of 2.67 (p<0.0001; Fig 2C, middle panel). Favorable cGVHD outcome through KIR genotype matching was contributed by both KIR-B/x and –AA genotype matching (p = 0.011 and 0.009 respectively, Table 3) and was applicable to both matched sibling and unrelated donor transplants (p = 0.009 and 0.004 respectively, Table 3).

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