DONOR KIR HAPLOTYPE B EXACERBATES ACUTE GVHD IN HLA-MISMATCHED HEMATOPOIETIC CELL TRANSPLANTATION: A SINGLE-CENTER RETROSPECTIVE ANALYSIS
(Abstract release date: 05/19/16)
EHA Library. Hosokai R. 06/09/16; 133061; E1512
Dr. Ryosuke Hosokai
Contributions
Contributions
Abstract
Abstract: E1512
Type: Eposter Presentation
Background
Following allogeneic hematopoietic stem cell transplantation (allo-HSCT), natural killer (NK) cells play a role in immune responses such as graft versus tumor (GVT) and graft versus host disease (GVHD). Killer-cell immunoglobulin-like receptors (KIR) regulate the function of NK cells by interacting with MHC class I molecules. KIR haplotype A contains only one stimulatory KIR (2DS4), whereas haplotype B contains 2 to 5 stimulatory KIR genes. Previous studies have demonstrated the effect of donor KIR haplotypes on allo-HSCT outcomes. Some investigators showed that donor KIR haplotype B augmented GVT and suppressed GVHD, consequently improving survival. However, the association between donor KIR haplotypes and clinical outcomes after allo-HSCT remains controversial.
Aims
To investigate the impact of donor KIR haplotypes on clinical outcomes in a Japanese cohort from a single center.
Methods
We retrospectively analyzed the clinical outcomes of patients with hematological malignancies who underwent allo-HSCTs at Niigata University. From 1989 to 2011, 304 HSCTs were performed. DNA samples were available for 152 donor KIR haplotypes. Of these 152, HSCTs from HLA-haploidentical family donors, umbilical cord blood, and unrelated donors with administration of anti-thymocyte globulin (ATG), as well as HSCTs for non-malignant hematologic disorders, were excluded. The remaining 106 cases, including 44 AML, 28 ALL, 14 CML, 11 NHL, and 9 MDS, were enrolled. HLA-matched sibling donors and 10/10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele-matched unrelated donors were defined as the HLA full-match group. Donors with at least one HLA allele mismatch were defined as the HLA mismatch group. KIR genotyping was performed with a PCR-rSSO kit.
Results
There were 61 donors with KIR haplotype A (57.5%) and 45 with KIR haplotype B (42.5%). The distribution of KIR haplotypes in this cohort was similar to that previously reported in the Japanese population. A comparison of the two groups of donors with KIR haplotypes A and B revealed no significant differences in the overall survival, cumulative incidence of relapse, and non-relapse mortality, possibly due to the small sample size and the dominance of non-AML malignancies. The cumulative incidence of grade II-IV acute (a)GVHD was not significantly different (16.4% vs 33.3%; P=0.051). However, grade III-IV aGVHD was significantly more frequent in patients receiving grafts from KIR haplotype B donors (4.9% vs 20.0%; P=0.02). The cumulative incidence of severe aGVHD was evaluated according to the degree of HLA matching. In the HLA full-match group, there was no significant difference between KIR haplotype A and B in the cumulative incidence of grade III-IV aGVHD (5.7% vs 8.7%; P=0.68). In contrast, in the HLA mismatch group, the cumulative incidence of grade III-IV aGVHD was significantly higher in patients receiving grafts from KIR haplotype B donors (5.3% vs 37.5%; P=0.02). In multivariate analysis, donor KIR haplotype B was the only significant risk factor for grade III-IV aGVHD (hazard ratio 3.92; CI, 1.04-14.75; P=0.04).
Conclusion
These findings demonstrated that donor KIR haplotype B was an independent risk factor for severe aGVHD in HLA-mismatched HSCTs using conditioning regimens without ATG. This observation suggests that genetic determinants of the functional properties of donor NK cells can affect the severity of aGVHD, which is thought to be solely induced by donor T-cells. Furthermore, it indicates that under strong T-cell alloreactivity, NK cells may have a role in worsening aGVHD.
Session topic: E-poster
Keyword(s): Acute graft-versus-host disease, Allogeneic hematopoietic stem cell transplant, Killer immunoglobulin receptors (KIR), NK cell
Type: Eposter Presentation
Background
Following allogeneic hematopoietic stem cell transplantation (allo-HSCT), natural killer (NK) cells play a role in immune responses such as graft versus tumor (GVT) and graft versus host disease (GVHD). Killer-cell immunoglobulin-like receptors (KIR) regulate the function of NK cells by interacting with MHC class I molecules. KIR haplotype A contains only one stimulatory KIR (2DS4), whereas haplotype B contains 2 to 5 stimulatory KIR genes. Previous studies have demonstrated the effect of donor KIR haplotypes on allo-HSCT outcomes. Some investigators showed that donor KIR haplotype B augmented GVT and suppressed GVHD, consequently improving survival. However, the association between donor KIR haplotypes and clinical outcomes after allo-HSCT remains controversial.
Aims
To investigate the impact of donor KIR haplotypes on clinical outcomes in a Japanese cohort from a single center.
Methods
We retrospectively analyzed the clinical outcomes of patients with hematological malignancies who underwent allo-HSCTs at Niigata University. From 1989 to 2011, 304 HSCTs were performed. DNA samples were available for 152 donor KIR haplotypes. Of these 152, HSCTs from HLA-haploidentical family donors, umbilical cord blood, and unrelated donors with administration of anti-thymocyte globulin (ATG), as well as HSCTs for non-malignant hematologic disorders, were excluded. The remaining 106 cases, including 44 AML, 28 ALL, 14 CML, 11 NHL, and 9 MDS, were enrolled. HLA-matched sibling donors and 10/10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele-matched unrelated donors were defined as the HLA full-match group. Donors with at least one HLA allele mismatch were defined as the HLA mismatch group. KIR genotyping was performed with a PCR-rSSO kit.
Results
There were 61 donors with KIR haplotype A (57.5%) and 45 with KIR haplotype B (42.5%). The distribution of KIR haplotypes in this cohort was similar to that previously reported in the Japanese population. A comparison of the two groups of donors with KIR haplotypes A and B revealed no significant differences in the overall survival, cumulative incidence of relapse, and non-relapse mortality, possibly due to the small sample size and the dominance of non-AML malignancies. The cumulative incidence of grade II-IV acute (a)GVHD was not significantly different (16.4% vs 33.3%; P=0.051). However, grade III-IV aGVHD was significantly more frequent in patients receiving grafts from KIR haplotype B donors (4.9% vs 20.0%; P=0.02). The cumulative incidence of severe aGVHD was evaluated according to the degree of HLA matching. In the HLA full-match group, there was no significant difference between KIR haplotype A and B in the cumulative incidence of grade III-IV aGVHD (5.7% vs 8.7%; P=0.68). In contrast, in the HLA mismatch group, the cumulative incidence of grade III-IV aGVHD was significantly higher in patients receiving grafts from KIR haplotype B donors (5.3% vs 37.5%; P=0.02). In multivariate analysis, donor KIR haplotype B was the only significant risk factor for grade III-IV aGVHD (hazard ratio 3.92; CI, 1.04-14.75; P=0.04).
Conclusion
These findings demonstrated that donor KIR haplotype B was an independent risk factor for severe aGVHD in HLA-mismatched HSCTs using conditioning regimens without ATG. This observation suggests that genetic determinants of the functional properties of donor NK cells can affect the severity of aGVHD, which is thought to be solely induced by donor T-cells. Furthermore, it indicates that under strong T-cell alloreactivity, NK cells may have a role in worsening aGVHD.
Session topic: E-poster
Keyword(s): Acute graft-versus-host disease, Allogeneic hematopoietic stem cell transplant, Killer immunoglobulin receptors (KIR), NK cell
Abstract: E1512
Type: Eposter Presentation
Background
Following allogeneic hematopoietic stem cell transplantation (allo-HSCT), natural killer (NK) cells play a role in immune responses such as graft versus tumor (GVT) and graft versus host disease (GVHD). Killer-cell immunoglobulin-like receptors (KIR) regulate the function of NK cells by interacting with MHC class I molecules. KIR haplotype A contains only one stimulatory KIR (2DS4), whereas haplotype B contains 2 to 5 stimulatory KIR genes. Previous studies have demonstrated the effect of donor KIR haplotypes on allo-HSCT outcomes. Some investigators showed that donor KIR haplotype B augmented GVT and suppressed GVHD, consequently improving survival. However, the association between donor KIR haplotypes and clinical outcomes after allo-HSCT remains controversial.
Aims
To investigate the impact of donor KIR haplotypes on clinical outcomes in a Japanese cohort from a single center.
Methods
We retrospectively analyzed the clinical outcomes of patients with hematological malignancies who underwent allo-HSCTs at Niigata University. From 1989 to 2011, 304 HSCTs were performed. DNA samples were available for 152 donor KIR haplotypes. Of these 152, HSCTs from HLA-haploidentical family donors, umbilical cord blood, and unrelated donors with administration of anti-thymocyte globulin (ATG), as well as HSCTs for non-malignant hematologic disorders, were excluded. The remaining 106 cases, including 44 AML, 28 ALL, 14 CML, 11 NHL, and 9 MDS, were enrolled. HLA-matched sibling donors and 10/10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele-matched unrelated donors were defined as the HLA full-match group. Donors with at least one HLA allele mismatch were defined as the HLA mismatch group. KIR genotyping was performed with a PCR-rSSO kit.
Results
There were 61 donors with KIR haplotype A (57.5%) and 45 with KIR haplotype B (42.5%). The distribution of KIR haplotypes in this cohort was similar to that previously reported in the Japanese population. A comparison of the two groups of donors with KIR haplotypes A and B revealed no significant differences in the overall survival, cumulative incidence of relapse, and non-relapse mortality, possibly due to the small sample size and the dominance of non-AML malignancies. The cumulative incidence of grade II-IV acute (a)GVHD was not significantly different (16.4% vs 33.3%; P=0.051). However, grade III-IV aGVHD was significantly more frequent in patients receiving grafts from KIR haplotype B donors (4.9% vs 20.0%; P=0.02). The cumulative incidence of severe aGVHD was evaluated according to the degree of HLA matching. In the HLA full-match group, there was no significant difference between KIR haplotype A and B in the cumulative incidence of grade III-IV aGVHD (5.7% vs 8.7%; P=0.68). In contrast, in the HLA mismatch group, the cumulative incidence of grade III-IV aGVHD was significantly higher in patients receiving grafts from KIR haplotype B donors (5.3% vs 37.5%; P=0.02). In multivariate analysis, donor KIR haplotype B was the only significant risk factor for grade III-IV aGVHD (hazard ratio 3.92; CI, 1.04-14.75; P=0.04).
Conclusion
These findings demonstrated that donor KIR haplotype B was an independent risk factor for severe aGVHD in HLA-mismatched HSCTs using conditioning regimens without ATG. This observation suggests that genetic determinants of the functional properties of donor NK cells can affect the severity of aGVHD, which is thought to be solely induced by donor T-cells. Furthermore, it indicates that under strong T-cell alloreactivity, NK cells may have a role in worsening aGVHD.
Session topic: E-poster
Keyword(s): Acute graft-versus-host disease, Allogeneic hematopoietic stem cell transplant, Killer immunoglobulin receptors (KIR), NK cell
Type: Eposter Presentation
Background
Following allogeneic hematopoietic stem cell transplantation (allo-HSCT), natural killer (NK) cells play a role in immune responses such as graft versus tumor (GVT) and graft versus host disease (GVHD). Killer-cell immunoglobulin-like receptors (KIR) regulate the function of NK cells by interacting with MHC class I molecules. KIR haplotype A contains only one stimulatory KIR (2DS4), whereas haplotype B contains 2 to 5 stimulatory KIR genes. Previous studies have demonstrated the effect of donor KIR haplotypes on allo-HSCT outcomes. Some investigators showed that donor KIR haplotype B augmented GVT and suppressed GVHD, consequently improving survival. However, the association between donor KIR haplotypes and clinical outcomes after allo-HSCT remains controversial.
Aims
To investigate the impact of donor KIR haplotypes on clinical outcomes in a Japanese cohort from a single center.
Methods
We retrospectively analyzed the clinical outcomes of patients with hematological malignancies who underwent allo-HSCTs at Niigata University. From 1989 to 2011, 304 HSCTs were performed. DNA samples were available for 152 donor KIR haplotypes. Of these 152, HSCTs from HLA-haploidentical family donors, umbilical cord blood, and unrelated donors with administration of anti-thymocyte globulin (ATG), as well as HSCTs for non-malignant hematologic disorders, were excluded. The remaining 106 cases, including 44 AML, 28 ALL, 14 CML, 11 NHL, and 9 MDS, were enrolled. HLA-matched sibling donors and 10/10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele-matched unrelated donors were defined as the HLA full-match group. Donors with at least one HLA allele mismatch were defined as the HLA mismatch group. KIR genotyping was performed with a PCR-rSSO kit.
Results
There were 61 donors with KIR haplotype A (57.5%) and 45 with KIR haplotype B (42.5%). The distribution of KIR haplotypes in this cohort was similar to that previously reported in the Japanese population. A comparison of the two groups of donors with KIR haplotypes A and B revealed no significant differences in the overall survival, cumulative incidence of relapse, and non-relapse mortality, possibly due to the small sample size and the dominance of non-AML malignancies. The cumulative incidence of grade II-IV acute (a)GVHD was not significantly different (16.4% vs 33.3%; P=0.051). However, grade III-IV aGVHD was significantly more frequent in patients receiving grafts from KIR haplotype B donors (4.9% vs 20.0%; P=0.02). The cumulative incidence of severe aGVHD was evaluated according to the degree of HLA matching. In the HLA full-match group, there was no significant difference between KIR haplotype A and B in the cumulative incidence of grade III-IV aGVHD (5.7% vs 8.7%; P=0.68). In contrast, in the HLA mismatch group, the cumulative incidence of grade III-IV aGVHD was significantly higher in patients receiving grafts from KIR haplotype B donors (5.3% vs 37.5%; P=0.02). In multivariate analysis, donor KIR haplotype B was the only significant risk factor for grade III-IV aGVHD (hazard ratio 3.92; CI, 1.04-14.75; P=0.04).
Conclusion
These findings demonstrated that donor KIR haplotype B was an independent risk factor for severe aGVHD in HLA-mismatched HSCTs using conditioning regimens without ATG. This observation suggests that genetic determinants of the functional properties of donor NK cells can affect the severity of aGVHD, which is thought to be solely induced by donor T-cells. Furthermore, it indicates that under strong T-cell alloreactivity, NK cells may have a role in worsening aGVHD.
Session topic: E-poster
Keyword(s): Acute graft-versus-host disease, Allogeneic hematopoietic stem cell transplant, Killer immunoglobulin receptors (KIR), NK cell
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