A drug currently approved for treatment of refractory cutaneous T-cell lymphoma has given promising results in reducing the incidence of graft-versus-host disease (GVHD) in bone marrow transplant patients. The study on the histone deacetylase inhibitor vorinostat was carried out by researchers in the University of Michigan Comprehensive Cancer Centre and published in The Lancet Oncology.
Vorinostat is a member of the family of histone deacetylase inhibitors (HDACi) which have both anti-cancer and anti-inflammatory properties. Many of these HDACi are in clinical trials for various cancers, including belinostat, abexinostat, SB939, resminostat, givinostat, quisinostat, pentobinostat, CUDC-101, with vorinostat (SAHA) having won FDA approval for cutaneous T-cell lymphoma (CTCL). HDACi compounds work by inducing histone lysine tails acetylation in chromatin and thereby modifying expression of genes involved in regulating processes relevant to cancer development, including cell survival, proliferation, differentiation and apoptosis. Vorinostat inhibits tumour cell growth and the production of pro-inflammatory cytokines. It was the anti-inflammatory effects of HDACi and their immunomodulatory function relating to balance of immune activation versus tolerance that prompted the study on vorinostat in GVHD. Acute GVHD remains highly problematic in using more general use of haemopoietic stem-cell transplantation.
Vorinostat had already been shown to attenuate GVHD in pre-clinical animal models. In the current study, a prospective, single-arm, phase 1/2 study was carried out at two centres in the USA on a cohort of 50 patients with high-risk haematological malignant diseases undergoing related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation. Vorinostat was administered in combination with standard GVHD prophylaxis after transplantation. The primary end-point set for the study was cumulative incidence of grade 2—4 acute GVHD by day 100. Encouragingly, this was recorded at 22% of patients receiving vorinostat, compared to 42% who typically develop GVHD with standard medications alone. In terms of safety, the most common haematological grade 3—4 adverse event was non-symptomatic thrombocytopenia after engraftment but it was transient and quickly resolved in all cases.
The study’s authors caution that further studies are needed on this potential new application for vorinostat, for example in settings where haemopoietic stem-cell transplantation is carried out using non-related donors. They are however cautiously optimistic about the potential as the drug both because of its immunomodulatory function in reduction of GVHD coupled to its anti-cancer effects which may help in prevention of cancer relapse.Caution is also needed in any attempt to more generally apply HDACi compounds in treatment of GVHD as another study in mice unexpectedly showed that another HDACi, LBH589, accelerated GVHD.
Sources
CHOI, S.W., BRAUN, T., CHANG, L., FERRARA, J.L.M., PAWARODE, A., MAGENAU, J.M., HOU, G., BEUMER, J.H., LEVINE, J.E., GOLDSTEIN, S., COURIEL, D.R., STOCKERL-GOLDSTEIN, K., KRIJANOVSKI, O.I., KITKO, C., YANIK, G.A., LEHMANN, M.H., TAWARA, I., SUN, Y., PACZESNY, S., MAPARA, M.Y., DINARELLO, C.A., DIPERSIO, J.F. and REDDY, P., 2013. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. The Lancet Oncology, 2013; DOI: 10.1016/S1470-2045(13)70512-6
IWAMOTO, M., FRIEDMAN, E.J., SANDHU, P., AGRAWAL, N.G.B., RUBIN, E.H. and WAGNER, J.A., 2013. Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor. Cancer chemotherapy and pharmacology, 72(3), pp. 493-508.
LICCIARDI, P.V., VERVERIS, K., TANG, M.L., EL-OSTA, A. and KARAGIANNIS, T.C., 2013. Immunomodulatory effects of histone deacetylase inhibitors. Current Molecular Medicine, 13(4), pp. 640-647.
RAJAK, H., SINGH, A., RAGHUWANSHI, K., KUMAR, R., DEWANGAN, P.K., VEERASAMY, R., SHARMA, P.C., DIXIT, A. and MISHRA, P., 2013. A Structural Insight into Hydroxamic Acid Based Histone Deacetylase Inhibitors for the Presence of Anticancer Activity. Current medicinal chemistry, 2013.
REDDY, P., DE LIMA, M. and KORETH, J., 2012. Emerging therapies in hematopoietic stem cell transplantation. Biology Of Blood And Marrow Transplantation: Journal Of The American Society For Blood And Marrow Transplantation, 18(1), pp. S125-S131.
WANG, D., ICLOZAN, C., LIU, C., XIA, C., ANASETTI, C. and YU, X., 2012. LBH589 enhances T cell activation in vivo and accelerates graft-versus-host disease in mice. Biology Of Blood And Marrow Transplantation: Journal Of The American Society For Blood And Marrow Transplantation, 18(8), pp. 1182-1190.e1.
University of Michigan Health System. "New drug cuts risk of deadly transplant side effect in half." ScienceDaily, 2 Dec. 2013. [Accessed 4 Dec. 2013].
Vorinostat is a member of the family of histone deacetylase inhibitors (HDACi) which have both anti-cancer and anti-inflammatory properties. Many of these HDACi are in clinical trials for various cancers, including belinostat, abexinostat, SB939, resminostat, givinostat, quisinostat, pentobinostat, CUDC-101, with vorinostat (SAHA) having won FDA approval for cutaneous T-cell lymphoma (CTCL). HDACi compounds work by inducing histone lysine tails acetylation in chromatin and thereby modifying expression of genes involved in regulating processes relevant to cancer development, including cell survival, proliferation, differentiation and apoptosis. Vorinostat inhibits tumour cell growth and the production of pro-inflammatory cytokines. It was the anti-inflammatory effects of HDACi and their immunomodulatory function relating to balance of immune activation versus tolerance that prompted the study on vorinostat in GVHD. Acute GVHD remains highly problematic in using more general use of haemopoietic stem-cell transplantation.
Vorinostat had already been shown to attenuate GVHD in pre-clinical animal models. In the current study, a prospective, single-arm, phase 1/2 study was carried out at two centres in the USA on a cohort of 50 patients with high-risk haematological malignant diseases undergoing related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation. Vorinostat was administered in combination with standard GVHD prophylaxis after transplantation. The primary end-point set for the study was cumulative incidence of grade 2—4 acute GVHD by day 100. Encouragingly, this was recorded at 22% of patients receiving vorinostat, compared to 42% who typically develop GVHD with standard medications alone. In terms of safety, the most common haematological grade 3—4 adverse event was non-symptomatic thrombocytopenia after engraftment but it was transient and quickly resolved in all cases.
The study’s authors caution that further studies are needed on this potential new application for vorinostat, for example in settings where haemopoietic stem-cell transplantation is carried out using non-related donors. They are however cautiously optimistic about the potential as the drug both because of its immunomodulatory function in reduction of GVHD coupled to its anti-cancer effects which may help in prevention of cancer relapse.Caution is also needed in any attempt to more generally apply HDACi compounds in treatment of GVHD as another study in mice unexpectedly showed that another HDACi, LBH589, accelerated GVHD.
Sources
CHOI, S.W., BRAUN, T., CHANG, L., FERRARA, J.L.M., PAWARODE, A., MAGENAU, J.M., HOU, G., BEUMER, J.H., LEVINE, J.E., GOLDSTEIN, S., COURIEL, D.R., STOCKERL-GOLDSTEIN, K., KRIJANOVSKI, O.I., KITKO, C., YANIK, G.A., LEHMANN, M.H., TAWARA, I., SUN, Y., PACZESNY, S., MAPARA, M.Y., DINARELLO, C.A., DIPERSIO, J.F. and REDDY, P., 2013. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. The Lancet Oncology, 2013; DOI: 10.1016/S1470-2045(13)70512-6
IWAMOTO, M., FRIEDMAN, E.J., SANDHU, P., AGRAWAL, N.G.B., RUBIN, E.H. and WAGNER, J.A., 2013. Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor. Cancer chemotherapy and pharmacology, 72(3), pp. 493-508.
LICCIARDI, P.V., VERVERIS, K., TANG, M.L., EL-OSTA, A. and KARAGIANNIS, T.C., 2013. Immunomodulatory effects of histone deacetylase inhibitors. Current Molecular Medicine, 13(4), pp. 640-647.
RAJAK, H., SINGH, A., RAGHUWANSHI, K., KUMAR, R., DEWANGAN, P.K., VEERASAMY, R., SHARMA, P.C., DIXIT, A. and MISHRA, P., 2013. A Structural Insight into Hydroxamic Acid Based Histone Deacetylase Inhibitors for the Presence of Anticancer Activity. Current medicinal chemistry, 2013.
REDDY, P., DE LIMA, M. and KORETH, J., 2012. Emerging therapies in hematopoietic stem cell transplantation. Biology Of Blood And Marrow Transplantation: Journal Of The American Society For Blood And Marrow Transplantation, 18(1), pp. S125-S131.
WANG, D., ICLOZAN, C., LIU, C., XIA, C., ANASETTI, C. and YU, X., 2012. LBH589 enhances T cell activation in vivo and accelerates graft-versus-host disease in mice. Biology Of Blood And Marrow Transplantation: Journal Of The American Society For Blood And Marrow Transplantation, 18(8), pp. 1182-1190.e1.
University of Michigan Health System. "New drug cuts risk of deadly transplant side effect in half." ScienceDaily, 2 Dec. 2013. [Accessed 4 Dec. 2013].
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