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ORLANDO – Folinic acid does not prevent oral mucositis in patients who are receiving a calcineurin inhibitor and methotrexate for graft-vs.-host disease prophylaxis, results of a multicenter study from Israel suggest.
A randomized clinical trial to determine whether folinic acid rescue 24 hours after a methotrexate dose protects patients against severe oral mucositis was halted for futility after an interim analysis showed no advantage to adding folinic acid, reported Moshe Yeshrun, MD, of Rabin Medical Center at Tel Aviv University, Israel.
“Regarding the primary and secondary endpoints, we observed identical rates and duration of severe oral mucositis, as well as identical rates of oral mucositis of any grade in the folinic acid and placebo groups,” he said at the annual Transplantation and Cellular Therapy Meetings.
There were also no significant differences between the folinic acid and placebo control groups in time to neutrophil and platelet engraftment, rates of febrile neutropenia and bloodstream infections, veno-occlusive disease, need for opiates or total parenteral nutrition (TPN), or time from transplant to discharge, Dr. Yeshrun added at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Folinic acid therapy did not, however, appear to abrogate or interfere with the effects of methotrexate on prevention of either acute or chronic graft-vs-host disease (GVHD).
Severe adverse event
Oral mucositis can be a serious complication of therapy, associated with increased morbidity and mortality; significant pain; difficulty with eating or speaking; difficulty swallowing water, food, and medications; prolonged hospitalizations; and increased costs of care, Dr. Yeshrun noted.
The presence of oral mucositis sometimes leads clinicians to reduce or even skip methotrexate doses, thereby increasing risk for GVHD.
There are limited data from nonrandomized studies indicating that folinic acid (also called leucovorin) may reduce methotrexate-associated toxicities, and both the European Society for Blood and Marrow Transplantation and European LeukemiaNet working group recommend the use of folinic-acid rescue 24 hours following each methotrexate dose, Dr. Yeshrun said.
To see whether folinic acid rescue actually reduces the rate of methotrexate-induced toxicity and affects outcomes for patients who receive methotrexate post transplant for GVHD prophylaxis, Dr. Yeshrun and colleagues in three Israeli medical centers conducted a randomized, placebo-controlled trial.
The eligible study population included patients 18 and older with hematological malignancies in complete remission or minimal residual disease who underwent myeloablative conditioning and allogeneic transplant from HLA-matched or 1-antigen mismatched siblings or unrelated donors.
The patients were stratified by treatment center and intensity of the conditioning regimen, and then randomized on a 1:1 basis to receive folinic acid or placebo beginning 24 hours after each methotrexate dose, with the assigned medication given at a dose of 15 mg three times daily on the first day, and once daily on days 3 and 6.
Patients who received a transplant from an unrelated donor were also given anti-thymocyte globulin at a total dose of 15 mg/kg.
Supportive care included filgrastim (Neupogen) 5 mcg/kg from day 7 until neutrophil engraftment, infection prophylaxis, and ursodeoxycholic acid for prevention of veno-occlusive disease.
Trial stopped
Although the study was designed to enroll 116 patients to have a power of 80% to detect a 50% reduction in the rate of severe oral mucositis from an anticipated 50% in the placebo arm, a planned interim analysis conducted after approximately half of the target events occurred showed no difference in the rates of severe oral mucositis, and the trial was halted.
A total of 28 patients in the folinic acid group and 24 in the placebo group were available for the analysis.
The rate of grade 3 or 4 mucositis, the primary endpoint, was 46.6% in the folinic acid group, and 45.8% in the placebo group.
Respectively, the median duration of severe oral mucositis was 4 days in each group, days to neutrophil engraftment were a median of 12 and to platelet engraftment were a median of 13 days in each group, rates of febrile neutropenia were 57.1% and 58.3%, rates of bloodstream infections were 10.7% and 16.6%, rates of veno-occlusive disease were 7% and 12.5%, need for TPN occurred in 14.2% vs. 25%, need for opiates occurred in 78.5% vs. 66.6%, and median time to discharge was 18 and 19 days. As noted, none of the differences were statistically significant.
“These unequivocal interim results led to our decision to discontinue the study,” Dr. Yeshrun said.
Arnon Nagler, MD, MSc, from Sheba Medical Center Tel HaShomer at Tel Aviv University in Israel, who was not involved in the study, said in an interview “I think this is a very practical and important study, because we need evidence-based data such as this.”
Dr. Nagler, who comoderated the session where the data were presented, noted that the study was limited by the small number of patients and the lack of a subgroup analysis, but emphasized that the findings were important nonetheless.
His comoderator, Maria Gilleece, MD, director of the Yorkshire (England) Blood and Marrow Transplant Program, noted in an interview that folinic acid is frequently used in the United Kingdom for patients receiving high-dose methotrexate, ”and certainly, this study suggests that may be inappropriate.”
Rabin Medical Center sponsored the trial. Dr. Yeshrun, Dr. Nagler, and Dr. Gilleece reported no relevant conflicts of interest.
SOURCE: Yeshrun M. et al. TCT 2020. Abstract 61.
ORLANDO – Folinic acid does not prevent oral mucositis in patients who are receiving a calcineurin inhibitor and methotrexate for graft-vs.-host disease prophylaxis, results of a multicenter study from Israel suggest.
A randomized clinical trial to determine whether folinic acid rescue 24 hours after a methotrexate dose protects patients against severe oral mucositis was halted for futility after an interim analysis showed no advantage to adding folinic acid, reported Moshe Yeshrun, MD, of Rabin Medical Center at Tel Aviv University, Israel.
“Regarding the primary and secondary endpoints, we observed identical rates and duration of severe oral mucositis, as well as identical rates of oral mucositis of any grade in the folinic acid and placebo groups,” he said at the annual Transplantation and Cellular Therapy Meetings.
There were also no significant differences between the folinic acid and placebo control groups in time to neutrophil and platelet engraftment, rates of febrile neutropenia and bloodstream infections, veno-occlusive disease, need for opiates or total parenteral nutrition (TPN), or time from transplant to discharge, Dr. Yeshrun added at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Folinic acid therapy did not, however, appear to abrogate or interfere with the effects of methotrexate on prevention of either acute or chronic graft-vs-host disease (GVHD).
Severe adverse event
Oral mucositis can be a serious complication of therapy, associated with increased morbidity and mortality; significant pain; difficulty with eating or speaking; difficulty swallowing water, food, and medications; prolonged hospitalizations; and increased costs of care, Dr. Yeshrun noted.
The presence of oral mucositis sometimes leads clinicians to reduce or even skip methotrexate doses, thereby increasing risk for GVHD.
There are limited data from nonrandomized studies indicating that folinic acid (also called leucovorin) may reduce methotrexate-associated toxicities, and both the European Society for Blood and Marrow Transplantation and European LeukemiaNet working group recommend the use of folinic-acid rescue 24 hours following each methotrexate dose, Dr. Yeshrun said.
To see whether folinic acid rescue actually reduces the rate of methotrexate-induced toxicity and affects outcomes for patients who receive methotrexate post transplant for GVHD prophylaxis, Dr. Yeshrun and colleagues in three Israeli medical centers conducted a randomized, placebo-controlled trial.
The eligible study population included patients 18 and older with hematological malignancies in complete remission or minimal residual disease who underwent myeloablative conditioning and allogeneic transplant from HLA-matched or 1-antigen mismatched siblings or unrelated donors.
The patients were stratified by treatment center and intensity of the conditioning regimen, and then randomized on a 1:1 basis to receive folinic acid or placebo beginning 24 hours after each methotrexate dose, with the assigned medication given at a dose of 15 mg three times daily on the first day, and once daily on days 3 and 6.
Patients who received a transplant from an unrelated donor were also given anti-thymocyte globulin at a total dose of 15 mg/kg.
Supportive care included filgrastim (Neupogen) 5 mcg/kg from day 7 until neutrophil engraftment, infection prophylaxis, and ursodeoxycholic acid for prevention of veno-occlusive disease.
Trial stopped
Although the study was designed to enroll 116 patients to have a power of 80% to detect a 50% reduction in the rate of severe oral mucositis from an anticipated 50% in the placebo arm, a planned interim analysis conducted after approximately half of the target events occurred showed no difference in the rates of severe oral mucositis, and the trial was halted.
A total of 28 patients in the folinic acid group and 24 in the placebo group were available for the analysis.
The rate of grade 3 or 4 mucositis, the primary endpoint, was 46.6% in the folinic acid group, and 45.8% in the placebo group.
Respectively, the median duration of severe oral mucositis was 4 days in each group, days to neutrophil engraftment were a median of 12 and to platelet engraftment were a median of 13 days in each group, rates of febrile neutropenia were 57.1% and 58.3%, rates of bloodstream infections were 10.7% and 16.6%, rates of veno-occlusive disease were 7% and 12.5%, need for TPN occurred in 14.2% vs. 25%, need for opiates occurred in 78.5% vs. 66.6%, and median time to discharge was 18 and 19 days. As noted, none of the differences were statistically significant.
“These unequivocal interim results led to our decision to discontinue the study,” Dr. Yeshrun said.
Arnon Nagler, MD, MSc, from Sheba Medical Center Tel HaShomer at Tel Aviv University in Israel, who was not involved in the study, said in an interview “I think this is a very practical and important study, because we need evidence-based data such as this.”
Dr. Nagler, who comoderated the session where the data were presented, noted that the study was limited by the small number of patients and the lack of a subgroup analysis, but emphasized that the findings were important nonetheless.
His comoderator, Maria Gilleece, MD, director of the Yorkshire (England) Blood and Marrow Transplant Program, noted in an interview that folinic acid is frequently used in the United Kingdom for patients receiving high-dose methotrexate, ”and certainly, this study suggests that may be inappropriate.”
Rabin Medical Center sponsored the trial. Dr. Yeshrun, Dr. Nagler, and Dr. Gilleece reported no relevant conflicts of interest.
SOURCE: Yeshrun M. et al. TCT 2020. Abstract 61.
ORLANDO – Folinic acid does not prevent oral mucositis in patients who are receiving a calcineurin inhibitor and methotrexate for graft-vs.-host disease prophylaxis, results of a multicenter study from Israel suggest.
A randomized clinical trial to determine whether folinic acid rescue 24 hours after a methotrexate dose protects patients against severe oral mucositis was halted for futility after an interim analysis showed no advantage to adding folinic acid, reported Moshe Yeshrun, MD, of Rabin Medical Center at Tel Aviv University, Israel.
“Regarding the primary and secondary endpoints, we observed identical rates and duration of severe oral mucositis, as well as identical rates of oral mucositis of any grade in the folinic acid and placebo groups,” he said at the annual Transplantation and Cellular Therapy Meetings.
There were also no significant differences between the folinic acid and placebo control groups in time to neutrophil and platelet engraftment, rates of febrile neutropenia and bloodstream infections, veno-occlusive disease, need for opiates or total parenteral nutrition (TPN), or time from transplant to discharge, Dr. Yeshrun added at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Folinic acid therapy did not, however, appear to abrogate or interfere with the effects of methotrexate on prevention of either acute or chronic graft-vs-host disease (GVHD).
Severe adverse event
Oral mucositis can be a serious complication of therapy, associated with increased morbidity and mortality; significant pain; difficulty with eating or speaking; difficulty swallowing water, food, and medications; prolonged hospitalizations; and increased costs of care, Dr. Yeshrun noted.
The presence of oral mucositis sometimes leads clinicians to reduce or even skip methotrexate doses, thereby increasing risk for GVHD.
There are limited data from nonrandomized studies indicating that folinic acid (also called leucovorin) may reduce methotrexate-associated toxicities, and both the European Society for Blood and Marrow Transplantation and European LeukemiaNet working group recommend the use of folinic-acid rescue 24 hours following each methotrexate dose, Dr. Yeshrun said.
To see whether folinic acid rescue actually reduces the rate of methotrexate-induced toxicity and affects outcomes for patients who receive methotrexate post transplant for GVHD prophylaxis, Dr. Yeshrun and colleagues in three Israeli medical centers conducted a randomized, placebo-controlled trial.
The eligible study population included patients 18 and older with hematological malignancies in complete remission or minimal residual disease who underwent myeloablative conditioning and allogeneic transplant from HLA-matched or 1-antigen mismatched siblings or unrelated donors.
The patients were stratified by treatment center and intensity of the conditioning regimen, and then randomized on a 1:1 basis to receive folinic acid or placebo beginning 24 hours after each methotrexate dose, with the assigned medication given at a dose of 15 mg three times daily on the first day, and once daily on days 3 and 6.
Patients who received a transplant from an unrelated donor were also given anti-thymocyte globulin at a total dose of 15 mg/kg.
Supportive care included filgrastim (Neupogen) 5 mcg/kg from day 7 until neutrophil engraftment, infection prophylaxis, and ursodeoxycholic acid for prevention of veno-occlusive disease.
Trial stopped
Although the study was designed to enroll 116 patients to have a power of 80% to detect a 50% reduction in the rate of severe oral mucositis from an anticipated 50% in the placebo arm, a planned interim analysis conducted after approximately half of the target events occurred showed no difference in the rates of severe oral mucositis, and the trial was halted.
A total of 28 patients in the folinic acid group and 24 in the placebo group were available for the analysis.
The rate of grade 3 or 4 mucositis, the primary endpoint, was 46.6% in the folinic acid group, and 45.8% in the placebo group.
Respectively, the median duration of severe oral mucositis was 4 days in each group, days to neutrophil engraftment were a median of 12 and to platelet engraftment were a median of 13 days in each group, rates of febrile neutropenia were 57.1% and 58.3%, rates of bloodstream infections were 10.7% and 16.6%, rates of veno-occlusive disease were 7% and 12.5%, need for TPN occurred in 14.2% vs. 25%, need for opiates occurred in 78.5% vs. 66.6%, and median time to discharge was 18 and 19 days. As noted, none of the differences were statistically significant.
“These unequivocal interim results led to our decision to discontinue the study,” Dr. Yeshrun said.
Arnon Nagler, MD, MSc, from Sheba Medical Center Tel HaShomer at Tel Aviv University in Israel, who was not involved in the study, said in an interview “I think this is a very practical and important study, because we need evidence-based data such as this.”
Dr. Nagler, who comoderated the session where the data were presented, noted that the study was limited by the small number of patients and the lack of a subgroup analysis, but emphasized that the findings were important nonetheless.
His comoderator, Maria Gilleece, MD, director of the Yorkshire (England) Blood and Marrow Transplant Program, noted in an interview that folinic acid is frequently used in the United Kingdom for patients receiving high-dose methotrexate, ”and certainly, this study suggests that may be inappropriate.”
Rabin Medical Center sponsored the trial. Dr. Yeshrun, Dr. Nagler, and Dr. Gilleece reported no relevant conflicts of interest.
SOURCE: Yeshrun M. et al. TCT 2020. Abstract 61.
REPORTING FROM TCT 2020