PD-1 GENOTYPE OF THE DONOR AND ACUTE GRAFT-VERSUS-HOST DISEASE AFTER HLA-IDENTICAL SIBLING DONOR STEM CELL TRANSPLANTATION
(Abstract release date: 05/19/16)
EHA Library. Santos N. 06/11/16; 135277; S521
Dr. Nazly Santos
Contributions
Contributions
Abstract
Abstract: S521
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Room H5
Background
Both T cell receptor (TCR) and co-signalling molecules are required for T cell activation. Programmed death 1 molecule (PD-1) triggers an immune checkpoint and co-inhibitory signalling that leads to peripheral tolerance. Some PD-1 polymorphisms (SNPs) have been described and associated with autoimmune disease or cancer predisposition. Monoclonal antibodies target co-inhibitory molecules enhance the immune response against malignancies.
Aims
Establish the relevance of the PD-1 SNPs on the clinical outcome after allogeneic-hematopoietic stem cell transplantation (allo-HSCT).
Methods
We accomplished a retrospective analysis of the SNPs PD-1.1G/A (promoter) and PD-1.3G/A (4 intron) genotypes of the donor in a cohort of 1485 HLA-identical sibling transplants (SIB) from Spanish transplant centers performed between 1991 and 2013. T-cell depleted graft recipes were not included. PD-1 genotyping determined by allelic discrimination assays and detection system Life Technologies on DNA samples obtained from peripheral blood. Written informed consent was obtained. Statistical cumulative incidence was estimated for aGVHD, relapse and transplant related mortality (TRM) according to PD-1 donor’s genotype. TRM was defined as death due other causes but relapse. Overall survival (OS) and relapse-free survival (RFS) were analyzed through Kaplan Meier method comparing curves by the log-rank test. Multivariate analysis was performed by Cox regression model.
Results
PD-1 allele and haplotype frequencies were comparable to other Caucasian populations. The haplotype PD-1.1G/PD-1.3G was the predominant (86.3%). There were statistical differences on age and gender demographic features in donors genotyped as PD-1AG or AA. The remaining clinical variables were comparable between these both genotype groups and between PD-1.3AA or PD-1.3AG/GG cohorts as well, except for the high proportion of myeloablative transplants on the last one. The aGVHD grades II-IV cumulative incidence was higher in recipes receiving grafts from homozygous PD-1.1G (p: 0.027) and PD-1.3A (p: 0.003) donors. Both genotypes were independent risk factors in multivariate analysis for grades II-IV aGVHD (p:0.033; HR2.2; 95%CI: 1.1 to 4.8 and p<0.001; HR4.5; 95%CI: 2 to 10.1 respectively). PD-1.3AA remained as independent risk factors for sever III-IV aGVHD (p<0.001; HR7.22; 95%CI: 2.6 to 19.7). The cumulative incidence for aGVHD grades II-IV was 64% in patients with “high risk” genotypes (PD-1.1GG/PD1.3AA), 32.6% for PD-1.1GG/PD-1.3AG or GG genotypes and 18% in those with of at least one A-allele at PD-1.1 position (p:0.001 and p:0.029). Despite the increased risk of aGVHD, we did not detect any influence of the PD-1 genotype and the secondary clinical endpoints (chronic GVHD, TRM, OS and relapse). We inferred the relative frequencies of genotypes and haplotypes for CTLA-4/PD-1 combinations so, on 883 donors we found that the most frequent matched observed (42.6%) involves the A alleles at both CTLA-4 SNPs coexisting with G allele at PD-1.1 and PD-1.3, without any association between CTLA-4 and PD-1 SNPs.
Conclusion
PD-1 genotypes carrying with the “high risk” alleles are independent risk factors for grades III- IV aGVHD. Other genotypes seem to be protective as it has been describe in other autoimmune mediated diseases. There were no statistically differences with the other clinical endpoints, suggesting that PD-1 should be relevant in the initial process of allorecognition, but not on prevention of relapses. These preliminary results should be confirmed by other studies. Financed by PI11/01690 and PI14/01646 and MTV3/120210.
Session topic: Stem cell transplantation - Clinical 1
Keyword(s): Allogeneic hematopoietic stem cell transplant, Costimulatory molecues, Immunotherapy
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Room H5
Background
Both T cell receptor (TCR) and co-signalling molecules are required for T cell activation. Programmed death 1 molecule (PD-1) triggers an immune checkpoint and co-inhibitory signalling that leads to peripheral tolerance. Some PD-1 polymorphisms (SNPs) have been described and associated with autoimmune disease or cancer predisposition. Monoclonal antibodies target co-inhibitory molecules enhance the immune response against malignancies.
Aims
Establish the relevance of the PD-1 SNPs on the clinical outcome after allogeneic-hematopoietic stem cell transplantation (allo-HSCT).
Methods
We accomplished a retrospective analysis of the SNPs PD-1.1G/A (promoter) and PD-1.3G/A (4 intron) genotypes of the donor in a cohort of 1485 HLA-identical sibling transplants (SIB) from Spanish transplant centers performed between 1991 and 2013. T-cell depleted graft recipes were not included. PD-1 genotyping determined by allelic discrimination assays and detection system Life Technologies on DNA samples obtained from peripheral blood. Written informed consent was obtained. Statistical cumulative incidence was estimated for aGVHD, relapse and transplant related mortality (TRM) according to PD-1 donor’s genotype. TRM was defined as death due other causes but relapse. Overall survival (OS) and relapse-free survival (RFS) were analyzed through Kaplan Meier method comparing curves by the log-rank test. Multivariate analysis was performed by Cox regression model.
Results
PD-1 allele and haplotype frequencies were comparable to other Caucasian populations. The haplotype PD-1.1G/PD-1.3G was the predominant (86.3%). There were statistical differences on age and gender demographic features in donors genotyped as PD-1AG or AA. The remaining clinical variables were comparable between these both genotype groups and between PD-1.3AA or PD-1.3AG/GG cohorts as well, except for the high proportion of myeloablative transplants on the last one. The aGVHD grades II-IV cumulative incidence was higher in recipes receiving grafts from homozygous PD-1.1G (p: 0.027) and PD-1.3A (p: 0.003) donors. Both genotypes were independent risk factors in multivariate analysis for grades II-IV aGVHD (p:0.033; HR2.2; 95%CI: 1.1 to 4.8 and p<0.001; HR4.5; 95%CI: 2 to 10.1 respectively). PD-1.3AA remained as independent risk factors for sever III-IV aGVHD (p<0.001; HR7.22; 95%CI: 2.6 to 19.7). The cumulative incidence for aGVHD grades II-IV was 64% in patients with “high risk” genotypes (PD-1.1GG/PD1.3AA), 32.6% for PD-1.1GG/PD-1.3AG or GG genotypes and 18% in those with of at least one A-allele at PD-1.1 position (p:0.001 and p:0.029). Despite the increased risk of aGVHD, we did not detect any influence of the PD-1 genotype and the secondary clinical endpoints (chronic GVHD, TRM, OS and relapse). We inferred the relative frequencies of genotypes and haplotypes for CTLA-4/PD-1 combinations so, on 883 donors we found that the most frequent matched observed (42.6%) involves the A alleles at both CTLA-4 SNPs coexisting with G allele at PD-1.1 and PD-1.3, without any association between CTLA-4 and PD-1 SNPs.
Conclusion
PD-1 genotypes carrying with the “high risk” alleles are independent risk factors for grades III- IV aGVHD. Other genotypes seem to be protective as it has been describe in other autoimmune mediated diseases. There were no statistically differences with the other clinical endpoints, suggesting that PD-1 should be relevant in the initial process of allorecognition, but not on prevention of relapses. These preliminary results should be confirmed by other studies. Financed by PI11/01690 and PI14/01646 and MTV3/120210.
Session topic: Stem cell transplantation - Clinical 1
Keyword(s): Allogeneic hematopoietic stem cell transplant, Costimulatory molecues, Immunotherapy
Abstract: S521
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Room H5
Background
Both T cell receptor (TCR) and co-signalling molecules are required for T cell activation. Programmed death 1 molecule (PD-1) triggers an immune checkpoint and co-inhibitory signalling that leads to peripheral tolerance. Some PD-1 polymorphisms (SNPs) have been described and associated with autoimmune disease or cancer predisposition. Monoclonal antibodies target co-inhibitory molecules enhance the immune response against malignancies.
Aims
Establish the relevance of the PD-1 SNPs on the clinical outcome after allogeneic-hematopoietic stem cell transplantation (allo-HSCT).
Methods
We accomplished a retrospective analysis of the SNPs PD-1.1G/A (promoter) and PD-1.3G/A (4 intron) genotypes of the donor in a cohort of 1485 HLA-identical sibling transplants (SIB) from Spanish transplant centers performed between 1991 and 2013. T-cell depleted graft recipes were not included. PD-1 genotyping determined by allelic discrimination assays and detection system Life Technologies on DNA samples obtained from peripheral blood. Written informed consent was obtained. Statistical cumulative incidence was estimated for aGVHD, relapse and transplant related mortality (TRM) according to PD-1 donor’s genotype. TRM was defined as death due other causes but relapse. Overall survival (OS) and relapse-free survival (RFS) were analyzed through Kaplan Meier method comparing curves by the log-rank test. Multivariate analysis was performed by Cox regression model.
Results
PD-1 allele and haplotype frequencies were comparable to other Caucasian populations. The haplotype PD-1.1G/PD-1.3G was the predominant (86.3%). There were statistical differences on age and gender demographic features in donors genotyped as PD-1AG or AA. The remaining clinical variables were comparable between these both genotype groups and between PD-1.3AA or PD-1.3AG/GG cohorts as well, except for the high proportion of myeloablative transplants on the last one. The aGVHD grades II-IV cumulative incidence was higher in recipes receiving grafts from homozygous PD-1.1G (p: 0.027) and PD-1.3A (p: 0.003) donors. Both genotypes were independent risk factors in multivariate analysis for grades II-IV aGVHD (p:0.033; HR2.2; 95%CI: 1.1 to 4.8 and p<0.001; HR4.5; 95%CI: 2 to 10.1 respectively). PD-1.3AA remained as independent risk factors for sever III-IV aGVHD (p<0.001; HR7.22; 95%CI: 2.6 to 19.7). The cumulative incidence for aGVHD grades II-IV was 64% in patients with “high risk” genotypes (PD-1.1GG/PD1.3AA), 32.6% for PD-1.1GG/PD-1.3AG or GG genotypes and 18% in those with of at least one A-allele at PD-1.1 position (p:0.001 and p:0.029). Despite the increased risk of aGVHD, we did not detect any influence of the PD-1 genotype and the secondary clinical endpoints (chronic GVHD, TRM, OS and relapse). We inferred the relative frequencies of genotypes and haplotypes for CTLA-4/PD-1 combinations so, on 883 donors we found that the most frequent matched observed (42.6%) involves the A alleles at both CTLA-4 SNPs coexisting with G allele at PD-1.1 and PD-1.3, without any association between CTLA-4 and PD-1 SNPs.
Conclusion
PD-1 genotypes carrying with the “high risk” alleles are independent risk factors for grades III- IV aGVHD. Other genotypes seem to be protective as it has been describe in other autoimmune mediated diseases. There were no statistically differences with the other clinical endpoints, suggesting that PD-1 should be relevant in the initial process of allorecognition, but not on prevention of relapses. These preliminary results should be confirmed by other studies. Financed by PI11/01690 and PI14/01646 and MTV3/120210.
Session topic: Stem cell transplantation - Clinical 1
Keyword(s): Allogeneic hematopoietic stem cell transplant, Costimulatory molecues, Immunotherapy
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Room H5
Background
Both T cell receptor (TCR) and co-signalling molecules are required for T cell activation. Programmed death 1 molecule (PD-1) triggers an immune checkpoint and co-inhibitory signalling that leads to peripheral tolerance. Some PD-1 polymorphisms (SNPs) have been described and associated with autoimmune disease or cancer predisposition. Monoclonal antibodies target co-inhibitory molecules enhance the immune response against malignancies.
Aims
Establish the relevance of the PD-1 SNPs on the clinical outcome after allogeneic-hematopoietic stem cell transplantation (allo-HSCT).
Methods
We accomplished a retrospective analysis of the SNPs PD-1.1G/A (promoter) and PD-1.3G/A (4 intron) genotypes of the donor in a cohort of 1485 HLA-identical sibling transplants (SIB) from Spanish transplant centers performed between 1991 and 2013. T-cell depleted graft recipes were not included. PD-1 genotyping determined by allelic discrimination assays and detection system Life Technologies on DNA samples obtained from peripheral blood. Written informed consent was obtained. Statistical cumulative incidence was estimated for aGVHD, relapse and transplant related mortality (TRM) according to PD-1 donor’s genotype. TRM was defined as death due other causes but relapse. Overall survival (OS) and relapse-free survival (RFS) were analyzed through Kaplan Meier method comparing curves by the log-rank test. Multivariate analysis was performed by Cox regression model.
Results
PD-1 allele and haplotype frequencies were comparable to other Caucasian populations. The haplotype PD-1.1G/PD-1.3G was the predominant (86.3%). There were statistical differences on age and gender demographic features in donors genotyped as PD-1AG or AA. The remaining clinical variables were comparable between these both genotype groups and between PD-1.3AA or PD-1.3AG/GG cohorts as well, except for the high proportion of myeloablative transplants on the last one. The aGVHD grades II-IV cumulative incidence was higher in recipes receiving grafts from homozygous PD-1.1G (p: 0.027) and PD-1.3A (p: 0.003) donors. Both genotypes were independent risk factors in multivariate analysis for grades II-IV aGVHD (p:0.033; HR2.2; 95%CI: 1.1 to 4.8 and p<0.001; HR4.5; 95%CI: 2 to 10.1 respectively). PD-1.3AA remained as independent risk factors for sever III-IV aGVHD (p<0.001; HR7.22; 95%CI: 2.6 to 19.7). The cumulative incidence for aGVHD grades II-IV was 64% in patients with “high risk” genotypes (PD-1.1GG/PD1.3AA), 32.6% for PD-1.1GG/PD-1.3AG or GG genotypes and 18% in those with of at least one A-allele at PD-1.1 position (p:0.001 and p:0.029). Despite the increased risk of aGVHD, we did not detect any influence of the PD-1 genotype and the secondary clinical endpoints (chronic GVHD, TRM, OS and relapse). We inferred the relative frequencies of genotypes and haplotypes for CTLA-4/PD-1 combinations so, on 883 donors we found that the most frequent matched observed (42.6%) involves the A alleles at both CTLA-4 SNPs coexisting with G allele at PD-1.1 and PD-1.3, without any association between CTLA-4 and PD-1 SNPs.
Conclusion
PD-1 genotypes carrying with the “high risk” alleles are independent risk factors for grades III- IV aGVHD. Other genotypes seem to be protective as it has been describe in other autoimmune mediated diseases. There were no statistically differences with the other clinical endpoints, suggesting that PD-1 should be relevant in the initial process of allorecognition, but not on prevention of relapses. These preliminary results should be confirmed by other studies. Financed by PI11/01690 and PI14/01646 and MTV3/120210.
Session topic: Stem cell transplantation - Clinical 1
Keyword(s): Allogeneic hematopoietic stem cell transplant, Costimulatory molecues, Immunotherapy
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