Fewer acute GvHD cases after stem-cell transplant with vorinostat

ATLANTA – The antilymphoma drug vorinostat may help to reduce the incidence of serious acute graft-versus-host disease in patients who have undergone blood and bone marrow transplants, said researchers at the annual meeting of the American Society of Hematology.

In a first-in-humans phase I/II trial, adults with hematologic malignancies who underwent hematopoietic stem-cell transplants (HSCTs) with reduced-intensity conditioning and also received vorinostat (Zolinza) before, during, and after transplant had significantly fewer episodes of graft-versus-host disease (GvHD) than did historical controls who received standard GvHD prophylaxis but not vorinostat, reported Dr. Pavan Reddy of the University of Michigan, Ann Arbor.

"From a biological standpoint, we found that using this drug, just as we did in our experimental mouse models, we were able to reduce inflammation." The results were based on measurement of different cytokines, as well as increased acetylation of certain proteins, said Dr. Reddy at a media briefing.

Vorinostat treatment also increased the population of regulatory T cells, "which really have salutary effects on graft-versus-host disease outcomes," he added.

Vorinostat is a histone deacetylase (HDAC) inhibitor approved as a third-line therapy for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

In animal studies, Dr. Reddy and his colleague Dr. Sung W. Choi, as well as other groups, have shown that HDAC inhibitors are effective against experimental GvHD, suppress the production of proinflammatory cytokines, and alter the immune response by modulating antigen-presenting cells and by enhancing the production and function of regulatory T cells.

With investigators at Washington University in St. Louis, the Michigan researchers enrolled adult patients scheduled to undergo allogeneic HSCT from donors matched by at least 7 of 8 HLA factors. The patients could be in either complete or partial remission or have progressive disease.

A total of 47 patients were available for the analysis presented at the meeting. In phase I, 10 patients received 100 mg of vorinostat twice daily, and nine additional patients underwent dose escalation to 200 mg twice daily. The remaining 28 patients were treated in phase II at the 100-mg b.i.d. dose. All patients also received standard GvHD prophylaxis with tacrolimus and mycophenolate mofetil. Patients received vorinostat beginning 10 days before transplant and continuing through day 100, when the incidence of grade 2-4 GvHD, the primary endpoint, was assessed.

Neil Osterweil/IMNG Medical Media

The results were compared with those of 25 historical controls. Both neutrophil and platelet engraftment occurred at a median of 12 days on study, compared with 11 days each for controls.

The cumulative incidence of grade 2-4 GvHD at day 100 was 22% for patients on vorinostat, compared with 48% for controls (P = .03). There was also a nonsignificant trend favoring vorinostat for prevention of grade 3-4 GvHD, Dr. Reddy noted.

There were nine cases of thrombocytopenia among patients on vorinostat, six among patients on the 200-mg b.i.d. dose, and three at the 100-mg b.i.d. dose. Ten patients on the drug had nausea. There were no significant differences in adverse event profiles, infectious complications, or causes of death between patients in the study and historical controls.

A hematologist who was not involved in the study commented that with vorinostat, investigators seemed to have found a balance between preventing serious GvHD, which significantly increases the risk of death, and mild or moderate GvHD, which is helpful for mounting an immune defense against malignant cells.

"We have seen in some biological studies that this kind of drug – and not only this drug but this group of drugs – can increase some cells in the blood of patients that will in fact decrease the probability of acute graft-versus-host disease and at the same time can also fight against the cancer cells," said Dr. Vanderson Rocha from the University of Oxford (England). Dr. Rocha moderated the briefing where Dr. Reddy presented the data.

The study was supported by the National Institutes of Health. Dr. Reddy, Dr. Choi, and Dr. Rocha all declared having no relevant conflicts of interest to disclose.

ATLANTA – The antilymphoma drug vorinostat may help to reduce the incidence of serious acute graft-versus-host disease in patients who have undergone blood and bone marrow transplants, said researchers at the annual meeting of the American Society of Hematology.

In a first-in-humans phase I/II trial, adults with hematologic malignancies who underwent hematopoietic stem-cell transplants (HSCTs) with reduced-intensity conditioning and also received vorinostat (Zolinza) before, during, and after transplant had significantly fewer episodes of graft-versus-host disease (GvHD) than did historical controls who received standard GvHD prophylaxis but not vorinostat, reported Dr. Pavan Reddy of the University of Michigan, Ann Arbor.

"From a biological standpoint, we found that using this drug, just as we did in our experimental mouse models, we were able to reduce inflammation." The results were based on measurement of different cytokines, as well as increased acetylation of certain proteins, said Dr. Reddy at a media briefing.

Vorinostat treatment also increased the population of regulatory T cells, "which really have salutary effects on graft-versus-host disease outcomes," he added.

Vorinostat is a histone deacetylase (HDAC) inhibitor approved as a third-line therapy for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

In animal studies, Dr. Reddy and his colleague Dr. Sung W. Choi, as well as other groups, have shown that HDAC inhibitors are effective against experimental GvHD, suppress the production of proinflammatory cytokines, and alter the immune response by modulating antigen-presenting cells and by enhancing the production and function of regulatory T cells.

With investigators at Washington University in St. Louis, the Michigan researchers enrolled adult patients scheduled to undergo allogeneic HSCT from donors matched by at least 7 of 8 HLA factors. The patients could be in either complete or partial remission or have progressive disease.

A total of 47 patients were available for the analysis presented at the meeting. In phase I, 10 patients received 100 mg of vorinostat twice daily, and nine additional patients underwent dose escalation to 200 mg twice daily. The remaining 28 patients were treated in phase II at the 100-mg b.i.d. dose. All patients also received standard GvHD prophylaxis with tacrolimus and mycophenolate mofetil. Patients received vorinostat beginning 10 days before transplant and continuing through day 100, when the incidence of grade 2-4 GvHD, the primary endpoint, was assessed.

Neil Osterweil/IMNG Medical Media

The results were compared with those of 25 historical controls. Both neutrophil and platelet engraftment occurred at a median of 12 days on study, compared with 11 days each for controls.

The cumulative incidence of grade 2-4 GvHD at day 100 was 22% for patients on vorinostat, compared with 48% for controls (P = .03). There was also a nonsignificant trend favoring vorinostat for prevention of grade 3-4 GvHD, Dr. Reddy noted.

There were nine cases of thrombocytopenia among patients on vorinostat, six among patients on the 200-mg b.i.d. dose, and three at the 100-mg b.i.d. dose. Ten patients on the drug had nausea. There were no significant differences in adverse event profiles, infectious complications, or causes of death between patients in the study and historical controls.

A hematologist who was not involved in the study commented that with vorinostat, investigators seemed to have found a balance between preventing serious GvHD, which significantly increases the risk of death, and mild or moderate GvHD, which is helpful for mounting an immune defense against malignant cells.

"We have seen in some biological studies that this kind of drug – and not only this drug but this group of drugs – can increase some cells in the blood of patients that will in fact decrease the probability of acute graft-versus-host disease and at the same time can also fight against the cancer cells," said Dr. Vanderson Rocha from the University of Oxford (England). Dr. Rocha moderated the briefing where Dr. Reddy presented the data.

The study was supported by the National Institutes of Health. Dr. Reddy, Dr. Choi, and Dr. Rocha all declared having no relevant conflicts of interest to disclose.

ATLANTA – The antilymphoma drug vorinostat may help to reduce the incidence of serious acute graft-versus-host disease in patients who have undergone blood and bone marrow transplants, said researchers at the annual meeting of the American Society of Hematology.

In a first-in-humans phase I/II trial, adults with hematologic malignancies who underwent hematopoietic stem-cell transplants (HSCTs) with reduced-intensity conditioning and also received vorinostat (Zolinza) before, during, and after transplant had significantly fewer episodes of graft-versus-host disease (GvHD) than did historical controls who received standard GvHD prophylaxis but not vorinostat, reported Dr. Pavan Reddy of the University of Michigan, Ann Arbor.

"From a biological standpoint, we found that using this drug, just as we did in our experimental mouse models, we were able to reduce inflammation." The results were based on measurement of different cytokines, as well as increased acetylation of certain proteins, said Dr. Reddy at a media briefing.

Vorinostat treatment also increased the population of regulatory T cells, "which really have salutary effects on graft-versus-host disease outcomes," he added.

Vorinostat is a histone deacetylase (HDAC) inhibitor approved as a third-line therapy for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

In animal studies, Dr. Reddy and his colleague Dr. Sung W. Choi, as well as other groups, have shown that HDAC inhibitors are effective against experimental GvHD, suppress the production of proinflammatory cytokines, and alter the immune response by modulating antigen-presenting cells and by enhancing the production and function of regulatory T cells.

With investigators at Washington University in St. Louis, the Michigan researchers enrolled adult patients scheduled to undergo allogeneic HSCT from donors matched by at least 7 of 8 HLA factors. The patients could be in either complete or partial remission or have progressive disease.

A total of 47 patients were available for the analysis presented at the meeting. In phase I, 10 patients received 100 mg of vorinostat twice daily, and nine additional patients underwent dose escalation to 200 mg twice daily. The remaining 28 patients were treated in phase II at the 100-mg b.i.d. dose. All patients also received standard GvHD prophylaxis with tacrolimus and mycophenolate mofetil. Patients received vorinostat beginning 10 days before transplant and continuing through day 100, when the incidence of grade 2-4 GvHD, the primary endpoint, was assessed.

Neil Osterweil/IMNG Medical Media

The results were compared with those of 25 historical controls. Both neutrophil and platelet engraftment occurred at a median of 12 days on study, compared with 11 days each for controls.

The cumulative incidence of grade 2-4 GvHD at day 100 was 22% for patients on vorinostat, compared with 48% for controls (P = .03). There was also a nonsignificant trend favoring vorinostat for prevention of grade 3-4 GvHD, Dr. Reddy noted.

There were nine cases of thrombocytopenia among patients on vorinostat, six among patients on the 200-mg b.i.d. dose, and three at the 100-mg b.i.d. dose. Ten patients on the drug had nausea. There were no significant differences in adverse event profiles, infectious complications, or causes of death between patients in the study and historical controls.

A hematologist who was not involved in the study commented that with vorinostat, investigators seemed to have found a balance between preventing serious GvHD, which significantly increases the risk of death, and mild or moderate GvHD, which is helpful for mounting an immune defense against malignant cells.

"We have seen in some biological studies that this kind of drug – and not only this drug but this group of drugs – can increase some cells in the blood of patients that will in fact decrease the probability of acute graft-versus-host disease and at the same time can also fight against the cancer cells," said Dr. Vanderson Rocha from the University of Oxford (England). Dr. Rocha moderated the briefing where Dr. Reddy presented the data.

The study was supported by the National Institutes of Health. Dr. Reddy, Dr. Choi, and Dr. Rocha all declared having no relevant conflicts of interest to disclose.