THE INFLUENCE OF NK CELL ALLOREACTIVITY ON OUTCOME AFTER T-CELL-DEPLETED HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN PATIENTS WITH ACUTE LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Abrosimov A. 06/09/16; 133080; E1531
Mr. Andrey Abrosimov
Contributions
Contributions
Abstract
Abstract: E1531
Type: Eposter Presentation
Background
HSCT from human leukocyte antigen (HLA) haplotype-mismatched family members is the only curative option for patients with high-risk acute leukemia who do not have a matched donor. Natural killer (NK) cells are the first lymphoid cell population to reconstitute after allogeneic HSCT. It is believed that NK alloreactivity is regulated by quantitative differences in activating and inhibitory signals (mediated by activating and inhibitory killer cell immunoglobulin-like-receptors (KIRs), which recognize HLA class-I alleles (KIR ligands)). A number of studies demonstrated beneficial effects of donor activating KIRs and KIR-ligand mismatches on transplant outcome.
Aims
In the present study we tested if donor KIR haplotype, particular KIR genes and KIR-ligand mismatch have an effect on relapse incidence and event-free survival (EFS) in pediatric patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Methods
Fifty eight patients between 1/2012 and 6/2015 in complete remission with ALL(n=26) and AML(n=32) were included in this study. Patients received T-cell-depleted haploidentical transplants after myeloablative conditioning regimen and post-transplant tacrolimus (n=24) or bortezomib (n=34) as GVHD prophylaxis. In all cases GCSF-mobilized PBSC were depleted of TCR-alpha/beta and CD19+ cells with CliniMACS Plus. All samples were typed for HLA-A,-B,-C,-DRB1,-DQB1 by sequence-based typing. KIR genotype was performed by sequence-specific primers. “Receptor-ligand” model (at least one inhibitory KIR gene expressed in the donor in the abscence of the appropriate HLA-molecules in the recipient's ligand repertoire) was used to predict NK alloreactivity. The role of donor B vs A KIR haplotype and the number of total, inhibitory or activating KIR in the donor was evaluated. The effect of each individual KIR gene was analyzed. Cumulative incidence estimates were used for relapse and nonrelapse mortality, because they are competing risk. The Gray test compared univariate competing risk outcome. The Kaplan-Meier method evaluated EFS.
Results
All patients had primary engraftment (median 14 days for neutrophils and 15 days for platelets). The median number of total KIR genes in donor was 10(range, 7-15), activating 3(1-6), inhibitory 7(5-9). No significant effect of KIR genotype was found in patients treated with tacrolimus and in the whole cohort of patients. Incidence of relapse decreased for patients treated with bortezomib by: donor’s B/x haplotype compared to A/A, 12±6.5 vs 22.2±13.6, p=0.05; higher total number of KIR genes (total KIR, 0 vs 29.4 ±10.9, p=0.005; activating KIR, 0 vs 29.4 ±10.9, p=0.004; inhibitory KIR, 8.7±5.9 vs 27.3 ±13.2, p=0.014; Influence of particular KIR genes on the incidence of relapse was detected: KIR2DS2(10±6.7 vs 21.4±10.7, p=0.05); KIR2DS3(0 vs 22.7±8.8, p=0.028); KIR2DL2(10±6.7 vs 21.4±10.7, p=0.05); KIR2DL5B(0 vs 21.7±8.5, p=0.035). No significant influence was observed for other KIR genes. Based on clinical studies “receptor-ligand” model was analyzed in patients with AML. There was no correlation between KIR-ligand mismatch and relapse risk and EFS (p=0.97 and p=0.50 respectively).
Conclusion
There is increasing evidence that impact of donor NK alloreactivity and KIR genotype is dependent on the transplant protocol. Our results suggest that the use of bortezomib instead of prolonged tacrolimus may contribute to the beneficial effects of donor NK cells.
Session topic: E-poster
Keyword(s): Acute leukemia, Haploidentical stem cell transplantation, KIR, Pediatric
Type: Eposter Presentation
Background
HSCT from human leukocyte antigen (HLA) haplotype-mismatched family members is the only curative option for patients with high-risk acute leukemia who do not have a matched donor. Natural killer (NK) cells are the first lymphoid cell population to reconstitute after allogeneic HSCT. It is believed that NK alloreactivity is regulated by quantitative differences in activating and inhibitory signals (mediated by activating and inhibitory killer cell immunoglobulin-like-receptors (KIRs), which recognize HLA class-I alleles (KIR ligands)). A number of studies demonstrated beneficial effects of donor activating KIRs and KIR-ligand mismatches on transplant outcome.
Aims
In the present study we tested if donor KIR haplotype, particular KIR genes and KIR-ligand mismatch have an effect on relapse incidence and event-free survival (EFS) in pediatric patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Methods
Fifty eight patients between 1/2012 and 6/2015 in complete remission with ALL(n=26) and AML(n=32) were included in this study. Patients received T-cell-depleted haploidentical transplants after myeloablative conditioning regimen and post-transplant tacrolimus (n=24) or bortezomib (n=34) as GVHD prophylaxis. In all cases GCSF-mobilized PBSC were depleted of TCR-alpha/beta and CD19+ cells with CliniMACS Plus. All samples were typed for HLA-A,-B,-C,-DRB1,-DQB1 by sequence-based typing. KIR genotype was performed by sequence-specific primers. “Receptor-ligand” model (at least one inhibitory KIR gene expressed in the donor in the abscence of the appropriate HLA-molecules in the recipient's ligand repertoire) was used to predict NK alloreactivity. The role of donor B vs A KIR haplotype and the number of total, inhibitory or activating KIR in the donor was evaluated. The effect of each individual KIR gene was analyzed. Cumulative incidence estimates were used for relapse and nonrelapse mortality, because they are competing risk. The Gray test compared univariate competing risk outcome. The Kaplan-Meier method evaluated EFS.
Results
All patients had primary engraftment (median 14 days for neutrophils and 15 days for platelets). The median number of total KIR genes in donor was 10(range, 7-15), activating 3(1-6), inhibitory 7(5-9). No significant effect of KIR genotype was found in patients treated with tacrolimus and in the whole cohort of patients. Incidence of relapse decreased for patients treated with bortezomib by: donor’s B/x haplotype compared to A/A, 12±6.5 vs 22.2±13.6, p=0.05; higher total number of KIR genes (total KIR, 0 vs 29.4 ±10.9, p=0.005; activating KIR, 0 vs 29.4 ±10.9, p=0.004; inhibitory KIR, 8.7±5.9 vs 27.3 ±13.2, p=0.014; Influence of particular KIR genes on the incidence of relapse was detected: KIR2DS2(10±6.7 vs 21.4±10.7, p=0.05); KIR2DS3(0 vs 22.7±8.8, p=0.028); KIR2DL2(10±6.7 vs 21.4±10.7, p=0.05); KIR2DL5B(0 vs 21.7±8.5, p=0.035). No significant influence was observed for other KIR genes. Based on clinical studies “receptor-ligand” model was analyzed in patients with AML. There was no correlation between KIR-ligand mismatch and relapse risk and EFS (p=0.97 and p=0.50 respectively).
Conclusion
There is increasing evidence that impact of donor NK alloreactivity and KIR genotype is dependent on the transplant protocol. Our results suggest that the use of bortezomib instead of prolonged tacrolimus may contribute to the beneficial effects of donor NK cells.
Session topic: E-poster
Keyword(s): Acute leukemia, Haploidentical stem cell transplantation, KIR, Pediatric
Abstract: E1531
Type: Eposter Presentation
Background
HSCT from human leukocyte antigen (HLA) haplotype-mismatched family members is the only curative option for patients with high-risk acute leukemia who do not have a matched donor. Natural killer (NK) cells are the first lymphoid cell population to reconstitute after allogeneic HSCT. It is believed that NK alloreactivity is regulated by quantitative differences in activating and inhibitory signals (mediated by activating and inhibitory killer cell immunoglobulin-like-receptors (KIRs), which recognize HLA class-I alleles (KIR ligands)). A number of studies demonstrated beneficial effects of donor activating KIRs and KIR-ligand mismatches on transplant outcome.
Aims
In the present study we tested if donor KIR haplotype, particular KIR genes and KIR-ligand mismatch have an effect on relapse incidence and event-free survival (EFS) in pediatric patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Methods
Fifty eight patients between 1/2012 and 6/2015 in complete remission with ALL(n=26) and AML(n=32) were included in this study. Patients received T-cell-depleted haploidentical transplants after myeloablative conditioning regimen and post-transplant tacrolimus (n=24) or bortezomib (n=34) as GVHD prophylaxis. In all cases GCSF-mobilized PBSC were depleted of TCR-alpha/beta and CD19+ cells with CliniMACS Plus. All samples were typed for HLA-A,-B,-C,-DRB1,-DQB1 by sequence-based typing. KIR genotype was performed by sequence-specific primers. “Receptor-ligand” model (at least one inhibitory KIR gene expressed in the donor in the abscence of the appropriate HLA-molecules in the recipient's ligand repertoire) was used to predict NK alloreactivity. The role of donor B vs A KIR haplotype and the number of total, inhibitory or activating KIR in the donor was evaluated. The effect of each individual KIR gene was analyzed. Cumulative incidence estimates were used for relapse and nonrelapse mortality, because they are competing risk. The Gray test compared univariate competing risk outcome. The Kaplan-Meier method evaluated EFS.
Results
All patients had primary engraftment (median 14 days for neutrophils and 15 days for platelets). The median number of total KIR genes in donor was 10(range, 7-15), activating 3(1-6), inhibitory 7(5-9). No significant effect of KIR genotype was found in patients treated with tacrolimus and in the whole cohort of patients. Incidence of relapse decreased for patients treated with bortezomib by: donor’s B/x haplotype compared to A/A, 12±6.5 vs 22.2±13.6, p=0.05; higher total number of KIR genes (total KIR, 0 vs 29.4 ±10.9, p=0.005; activating KIR, 0 vs 29.4 ±10.9, p=0.004; inhibitory KIR, 8.7±5.9 vs 27.3 ±13.2, p=0.014; Influence of particular KIR genes on the incidence of relapse was detected: KIR2DS2(10±6.7 vs 21.4±10.7, p=0.05); KIR2DS3(0 vs 22.7±8.8, p=0.028); KIR2DL2(10±6.7 vs 21.4±10.7, p=0.05); KIR2DL5B(0 vs 21.7±8.5, p=0.035). No significant influence was observed for other KIR genes. Based on clinical studies “receptor-ligand” model was analyzed in patients with AML. There was no correlation between KIR-ligand mismatch and relapse risk and EFS (p=0.97 and p=0.50 respectively).
Conclusion
There is increasing evidence that impact of donor NK alloreactivity and KIR genotype is dependent on the transplant protocol. Our results suggest that the use of bortezomib instead of prolonged tacrolimus may contribute to the beneficial effects of donor NK cells.
Session topic: E-poster
Keyword(s): Acute leukemia, Haploidentical stem cell transplantation, KIR, Pediatric
Type: Eposter Presentation
Background
HSCT from human leukocyte antigen (HLA) haplotype-mismatched family members is the only curative option for patients with high-risk acute leukemia who do not have a matched donor. Natural killer (NK) cells are the first lymphoid cell population to reconstitute after allogeneic HSCT. It is believed that NK alloreactivity is regulated by quantitative differences in activating and inhibitory signals (mediated by activating and inhibitory killer cell immunoglobulin-like-receptors (KIRs), which recognize HLA class-I alleles (KIR ligands)). A number of studies demonstrated beneficial effects of donor activating KIRs and KIR-ligand mismatches on transplant outcome.
Aims
In the present study we tested if donor KIR haplotype, particular KIR genes and KIR-ligand mismatch have an effect on relapse incidence and event-free survival (EFS) in pediatric patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Methods
Fifty eight patients between 1/2012 and 6/2015 in complete remission with ALL(n=26) and AML(n=32) were included in this study. Patients received T-cell-depleted haploidentical transplants after myeloablative conditioning regimen and post-transplant tacrolimus (n=24) or bortezomib (n=34) as GVHD prophylaxis. In all cases GCSF-mobilized PBSC were depleted of TCR-alpha/beta and CD19+ cells with CliniMACS Plus. All samples were typed for HLA-A,-B,-C,-DRB1,-DQB1 by sequence-based typing. KIR genotype was performed by sequence-specific primers. “Receptor-ligand” model (at least one inhibitory KIR gene expressed in the donor in the abscence of the appropriate HLA-molecules in the recipient's ligand repertoire) was used to predict NK alloreactivity. The role of donor B vs A KIR haplotype and the number of total, inhibitory or activating KIR in the donor was evaluated. The effect of each individual KIR gene was analyzed. Cumulative incidence estimates were used for relapse and nonrelapse mortality, because they are competing risk. The Gray test compared univariate competing risk outcome. The Kaplan-Meier method evaluated EFS.
Results
All patients had primary engraftment (median 14 days for neutrophils and 15 days for platelets). The median number of total KIR genes in donor was 10(range, 7-15), activating 3(1-6), inhibitory 7(5-9). No significant effect of KIR genotype was found in patients treated with tacrolimus and in the whole cohort of patients. Incidence of relapse decreased for patients treated with bortezomib by: donor’s B/x haplotype compared to A/A, 12±6.5 vs 22.2±13.6, p=0.05; higher total number of KIR genes (total KIR, 0 vs 29.4 ±10.9, p=0.005; activating KIR, 0 vs 29.4 ±10.9, p=0.004; inhibitory KIR, 8.7±5.9 vs 27.3 ±13.2, p=0.014; Influence of particular KIR genes on the incidence of relapse was detected: KIR2DS2(10±6.7 vs 21.4±10.7, p=0.05); KIR2DS3(0 vs 22.7±8.8, p=0.028); KIR2DL2(10±6.7 vs 21.4±10.7, p=0.05); KIR2DL5B(0 vs 21.7±8.5, p=0.035). No significant influence was observed for other KIR genes. Based on clinical studies “receptor-ligand” model was analyzed in patients with AML. There was no correlation between KIR-ligand mismatch and relapse risk and EFS (p=0.97 and p=0.50 respectively).
Conclusion
There is increasing evidence that impact of donor NK alloreactivity and KIR genotype is dependent on the transplant protocol. Our results suggest that the use of bortezomib instead of prolonged tacrolimus may contribute to the beneficial effects of donor NK cells.
Session topic: E-poster
Keyword(s): Acute leukemia, Haploidentical stem cell transplantation, KIR, Pediatric
{{ help_message }}
{{filter}}