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Optimum antithymocyte globulin exposure after allogeneic hemopoietic cell transplantation (HTC) is associated with a higher probability of survival as a result of reductions in transplant-related and relapse-related deaths, based on findings from a retrospective multicenter cohort study.
The findings come from a pharmacokinetic-pharmacodynamic analysis of data from 146 patients with acute lymphoid leukemia, acute myeloid leukemia, or myelodysplastic syndrome. All were receiving their first T cell–repleted allogeneic peripheral blood stem cell HCT with antithymocyte globulin (ATG) as part of their nonmyeloablative conditioning regimen. Based on hazard ratios for overall survival, nonrelapse mortality, and relapse-related mortality, the optimum range of ATG exposure was 60-95 arbitrary units per day/mL, Rick Admiraal, MD, of the University Medical Centre Utrecht, Netherlands, and his colleagues reported in the Lancet Haematology (Lancet Haematol. 2017 Apr;4[4]:e183-91).
The estimated 5-year survival was significantly greater with optimum ATG exposure than with below-optimum exposure (69% vs. 32%; hazard ratio, 2.41) or with above-optimum exposure (69% vs. 48%; hazard ratio, 2.11).
Optimum ATG exposure also was associated with a greater likelihood of event-free survival: The hazard ratio was 2.54 for those with below-optimum exposure and 1.83 for those with above-optimum exposure, the researchers said. Further, above-optimum exposure was associated with higher relapse-related mortality (hazard ratio, 2.66). Below-optimum exposure was associated with higher non-relapse mortality (hazard ratio, 4.36) as well as with a higher risk for grade 3-4 acute graft-versus-host disease (hazard ratio, 3.09), but not for chronic graft-versus-host disease (hazard ratio, 2.38).
Optimum target attainment was better with modeled dosing based on absolute lymphocyte counts than with weight-based dosing, the authors said.
The findings underscore the importance of optimum ATG dosing, as “survival after HCT is highly affected by ATG exposure after HCT,” and they suggest that survival chances may be improved with individualized dosing based on lymphocyte counts–a finding that requires assessment in a prospective study, they concluded.
This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no relevant disclosures.
The study by Dr. Admiraal and his associates introduces important concepts regarding ATG dosing, but the suggestion that dosing should be individualized based on lymphocyte count and should target the area under the time-versus-thymoglobulin-concentration curve of 60-95 arbitrary units per day/mL after HCT should not yet become the standard of care.
“As the authors correctly point out, first a prospective study is needed,” Dr. Storek wrote.
However, even if such a study confirms this approach – which the authors previously showed to be of benefit in children – it would apply only to the setting in which it was developed. The problem is that there are numerous HCT settings, each requiring a different dose. Further, there is no universally accepted assay for measuring thymoglobulin concentrations, he noted.
“Following the seminal observations in the paper … much work remains to be done,” he wrote.
Jan Storek, MD, is with the University of Calgary (Alta.) and Alberta Health Services, Calgary. He made his comments in an editorial (Lancet Haematol. 2017 Apr;4[4]:e154-5) published with the study and reported having no disclosures.
The study by Dr. Admiraal and his associates introduces important concepts regarding ATG dosing, but the suggestion that dosing should be individualized based on lymphocyte count and should target the area under the time-versus-thymoglobulin-concentration curve of 60-95 arbitrary units per day/mL after HCT should not yet become the standard of care.
“As the authors correctly point out, first a prospective study is needed,” Dr. Storek wrote.
However, even if such a study confirms this approach – which the authors previously showed to be of benefit in children – it would apply only to the setting in which it was developed. The problem is that there are numerous HCT settings, each requiring a different dose. Further, there is no universally accepted assay for measuring thymoglobulin concentrations, he noted.
“Following the seminal observations in the paper … much work remains to be done,” he wrote.
Jan Storek, MD, is with the University of Calgary (Alta.) and Alberta Health Services, Calgary. He made his comments in an editorial (Lancet Haematol. 2017 Apr;4[4]:e154-5) published with the study and reported having no disclosures.
The study by Dr. Admiraal and his associates introduces important concepts regarding ATG dosing, but the suggestion that dosing should be individualized based on lymphocyte count and should target the area under the time-versus-thymoglobulin-concentration curve of 60-95 arbitrary units per day/mL after HCT should not yet become the standard of care.
“As the authors correctly point out, first a prospective study is needed,” Dr. Storek wrote.
However, even if such a study confirms this approach – which the authors previously showed to be of benefit in children – it would apply only to the setting in which it was developed. The problem is that there are numerous HCT settings, each requiring a different dose. Further, there is no universally accepted assay for measuring thymoglobulin concentrations, he noted.
“Following the seminal observations in the paper … much work remains to be done,” he wrote.
Jan Storek, MD, is with the University of Calgary (Alta.) and Alberta Health Services, Calgary. He made his comments in an editorial (Lancet Haematol. 2017 Apr;4[4]:e154-5) published with the study and reported having no disclosures.
Optimum antithymocyte globulin exposure after allogeneic hemopoietic cell transplantation (HTC) is associated with a higher probability of survival as a result of reductions in transplant-related and relapse-related deaths, based on findings from a retrospective multicenter cohort study.
The findings come from a pharmacokinetic-pharmacodynamic analysis of data from 146 patients with acute lymphoid leukemia, acute myeloid leukemia, or myelodysplastic syndrome. All were receiving their first T cell–repleted allogeneic peripheral blood stem cell HCT with antithymocyte globulin (ATG) as part of their nonmyeloablative conditioning regimen. Based on hazard ratios for overall survival, nonrelapse mortality, and relapse-related mortality, the optimum range of ATG exposure was 60-95 arbitrary units per day/mL, Rick Admiraal, MD, of the University Medical Centre Utrecht, Netherlands, and his colleagues reported in the Lancet Haematology (Lancet Haematol. 2017 Apr;4[4]:e183-91).
The estimated 5-year survival was significantly greater with optimum ATG exposure than with below-optimum exposure (69% vs. 32%; hazard ratio, 2.41) or with above-optimum exposure (69% vs. 48%; hazard ratio, 2.11).
Optimum ATG exposure also was associated with a greater likelihood of event-free survival: The hazard ratio was 2.54 for those with below-optimum exposure and 1.83 for those with above-optimum exposure, the researchers said. Further, above-optimum exposure was associated with higher relapse-related mortality (hazard ratio, 2.66). Below-optimum exposure was associated with higher non-relapse mortality (hazard ratio, 4.36) as well as with a higher risk for grade 3-4 acute graft-versus-host disease (hazard ratio, 3.09), but not for chronic graft-versus-host disease (hazard ratio, 2.38).
Optimum target attainment was better with modeled dosing based on absolute lymphocyte counts than with weight-based dosing, the authors said.
The findings underscore the importance of optimum ATG dosing, as “survival after HCT is highly affected by ATG exposure after HCT,” and they suggest that survival chances may be improved with individualized dosing based on lymphocyte counts–a finding that requires assessment in a prospective study, they concluded.
This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no relevant disclosures.
Optimum antithymocyte globulin exposure after allogeneic hemopoietic cell transplantation (HTC) is associated with a higher probability of survival as a result of reductions in transplant-related and relapse-related deaths, based on findings from a retrospective multicenter cohort study.
The findings come from a pharmacokinetic-pharmacodynamic analysis of data from 146 patients with acute lymphoid leukemia, acute myeloid leukemia, or myelodysplastic syndrome. All were receiving their first T cell–repleted allogeneic peripheral blood stem cell HCT with antithymocyte globulin (ATG) as part of their nonmyeloablative conditioning regimen. Based on hazard ratios for overall survival, nonrelapse mortality, and relapse-related mortality, the optimum range of ATG exposure was 60-95 arbitrary units per day/mL, Rick Admiraal, MD, of the University Medical Centre Utrecht, Netherlands, and his colleagues reported in the Lancet Haematology (Lancet Haematol. 2017 Apr;4[4]:e183-91).
The estimated 5-year survival was significantly greater with optimum ATG exposure than with below-optimum exposure (69% vs. 32%; hazard ratio, 2.41) or with above-optimum exposure (69% vs. 48%; hazard ratio, 2.11).
Optimum ATG exposure also was associated with a greater likelihood of event-free survival: The hazard ratio was 2.54 for those with below-optimum exposure and 1.83 for those with above-optimum exposure, the researchers said. Further, above-optimum exposure was associated with higher relapse-related mortality (hazard ratio, 2.66). Below-optimum exposure was associated with higher non-relapse mortality (hazard ratio, 4.36) as well as with a higher risk for grade 3-4 acute graft-versus-host disease (hazard ratio, 3.09), but not for chronic graft-versus-host disease (hazard ratio, 2.38).
Optimum target attainment was better with modeled dosing based on absolute lymphocyte counts than with weight-based dosing, the authors said.
The findings underscore the importance of optimum ATG dosing, as “survival after HCT is highly affected by ATG exposure after HCT,” and they suggest that survival chances may be improved with individualized dosing based on lymphocyte counts–a finding that requires assessment in a prospective study, they concluded.
This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no relevant disclosures.
FROM THE LANCET HAEMATOLOGY
Key clinical point:
Major finding: The estimated 5-year survival with optimum ATG exposure was 69% vs. 32% and 48% with below- and above-optimum exposure (hazard ratios, 2.41 and 2.11, respectively).
Data source: A retrospective cohort study of 146 patients receiving their first T-cell repleted allogeneic peripheral blood stem cell HCT.
Disclosures: This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no disclosures.