title: 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.
abstract: BACKGROUND
  Acute graft-versus-host disease (GVHD) remains a barrier to more widespread application of allogeneic haemopoietic stem-cell transplantation. Vorinostat is an inhibitor of histone deacetylases and was shown to attenuate GVHD in preclinical models. We aimed to study the safety and activity of vorinostat, in combination with standard immunoprophylaxis, for prevention of GVHD in patients undergoing related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation.
  
  
  METHODS
  Between March 31, 2009, and Feb 8, 2013, we did a prospective, single-arm, phase 1/2 study at two centres in the USA. We recruited adults (aged ≥18 years) with high-risk haematological malignant diseases who were candidates for reduced-intensity conditioning haemopoietic stem-cell transplantation and had an available 8/8 or 7/8 HLA-matched related donor. All patients received a conditioning regimen of fludarabine (40 mg/m(2) daily for 4 days) and busulfan (3.2 mg/kg daily for 2 days) and GVHD immunoprophylaxis of mycophenolate mofetil (1 g three times a day, days 0-28) and tacrolimus (0.03 mg/kg a day, titrated to a goal level of 8-12 ng/mL, starting day -3 until day 180). Vorinostat (either 100 mg or 200 mg, twice a day) was initiated 10 days before haemopoietic stem-cell transplantation until day 100. The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD by day 100. This trial is registered with ClinicalTrials.gov, number NCT00810602.
  
  
  RESULTS
  50 patients were assessable for both toxic effects and response; eight additional patients were included in the analysis of toxic effects. All patients engrafted neutrophils and platelets at expected times after haemopoietic stem-cell transplantation. The cumulative incidence of grade 2-4 acute GVHD by day 100 was 22% (95% CI 13-36). The most common non-haematological adverse events included electrolyte disturbances (n=15), hyperglycaemia (11), infections (six), mucositis (four), and increased activity of liver enzymes (three). Non-symptomatic thrombocytopenia after engraftment was the most common haematological grade 3-4 adverse event (nine) but was transient and all cases resolved swiftly.
  
  
  CONCLUSIONS
  Administration of vorinostat in combination with standard GVHD prophylaxis after related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation is safe and is associated with a lower than expected incidence of severe acute GVHD. Future studies are needed to assess the effect of vorinostat for prevention of GVHD in broader settings of haemopoietic stem-cell transplantation.
  
  
  BACKGROUND
  Merck, Leukemia and Lymphoma Society, National Institutes of Health, St Baldrick's Foundation, Michigan Institute for Clinical and Health Research.
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chang
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: James L M
authors.initials: JL
authors.lastname: Ferrara
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Attaphol
authors.initials: A
authors.lastname: Pawarode
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Magenau
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Hou
authors.affiliation: Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Goldstein
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Couriel
authors.affiliation: Blood and Marrow Transplantation Program, Washington University, St Louis, MO, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Stockerl-Goldstein
authors.affiliation: Sutter East Bay Medical Foundation, Berkeley, CA, USA.
authors.forename: Oleg I
authors.initials: OI
authors.lastname: Krijanovski
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Kitko
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.affiliation: Department of Cardiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Lehmann
authors.affiliation: Hematology-Oncology, Mie University Hospital, Mie, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Tawara
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Pediatric Hematology Oncology, Indiana University, Indianapolis, IN, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Paczesny
authors.affiliation: Blood and Marrow Transplantation Program, Columbia University, New York, NY, USA.
authors.forename: Markus Y
authors.initials: MY
authors.lastname: Mapara
authors.affiliation: Department of Medicine, University of Colorado, Aurora, CO, USA; Department of Medicine, University Medical Center Nijmegen, Netherlands.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Cardiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA. Electronic address: reddypr@umich.edu.
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007166:Immunosuppressive Agents; D000077337:Vorinostat; D009173:Mycophenolic Acid; D016559:Tacrolimus