Vorinostat for GVHD prevention in unrelated donor myeloblative conditioning BMT

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Allogeneic blood and marrow transplantation (BMT) is a potentially curative therapy for many hematologic and non-hematologic diseases. However, the success of allogeneic BMT is limited by non-relapse mortality (NRM), particularly when non-family member (unrelated) donors are used. Graft-versus-host disease (GVHD) remains a critical barrier to the wider application of allogeneic BMT because it contributes significantly to increased risk for NRM. Current pharmacologic agents for GVHD prevention and treatment primarily target an essential effector for GVHD, donor T cells. Other key effectors for GVHD, and therefore potential therapeutic targets, are antigen presenting cells (APCs). Therefore, agents that target the allostimulatory functions of APCs may be an innovative therapeutic potential in the GVH process. Histone deacetylase (HDAC) inhibitors are novel anti-tumor agents that appear to be well-tolerated in human clinical trials. However, their immunomodulatory effects have thus far been largely unrecognized. We have published preclinical data demonstrating that HDAC inhibitors pharmacologically target APCs and reduce GVHD. Dr. Choi has translated these experimental observations in a proof-of-concept phase 1/2 clinical trial showing that vorinostat has activity in the prevention of GVHD following related donor reduced intensity conditioning BMT. She would now like to expand the use of vorinostat in the unrelated donor BMT setting where the need is greater, which forms the justification for this proposal. Knowing that most patients lack a suitable, related donor and that the risks of GVHD and its NRM are increased following unrelated donor BMT, it is the logical next step to study the use of vorinostat in GVHD prevention in this high-risk population. Therefore, Dr. Choi will study the effect of an HDAC inhibitor, vorinostat, combined with standard immunosuppression to reduce the severity of GVHD following unrelated donor myeloablative conditioning BMT. She will correlate the clinical observations with appropriate laboratory studies in order to gain greatr insight on the molecular and cellular effects of HDAC inhibition in human BMT. The findings generated from this proposal will provide necessary data to design a future full-scale clinical trial. Dr. Choi's primary objective is to reduce grade 2-4 acute GVHD by day 100 after unrelated donor myeloablative conditioning BMT using vorinostat combined with standard immunosuppression. This study could allow for the development of a novel class of immunomodulatory drugs for attenuating GVHD in a high-risk population wherein the majority of allogeneic BMT is being performed. The Specific Aims (SA) of this proposal are: SA1. To conduct a phase 2 clinical trial using an HDAC inhibitor, vorinostat, combined with standard immunosuppression for GVHD prevention after unrelated donor BMT. SA2. To correlate laboratory studies with patient outcomes after HDAC inhibition.