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 - 31/12/13

Doi : 10.1016/S1470-2045(13)70512-6

Sung Won Choi, MD ^a, Thomas Braun, ProfPhD ^b, Lawrence Chang, MD ^a, James L M Ferrara, ProfMD ^a, Attaphol Pawarode, MD ^a, John M Magenau, MD ^a, Guoqing Hou, PhD ^a, Jan H Beumer, PhD ^d, John E Levine, ProfMD ^a, Steve Goldstein, MD ^a, Daniel R Couriel, ProfMD ^a, Keith Stockerl-Goldstein, MD ^e, Oleg I Krijanovski, MD ^f, Carrie Kitko, MD ^a, Gregory A Yanik, ProfMD ^a, Michael H Lehmann, ProfMD ^c, Isao Tawara, MD ^g, Yaping Sun, MD ^a, Sophie Paczesny, MD ^h, Markus Y Mapara, ProfMD ⁱ, Charles A Dinarello, ProfMD ^j,^k, John F DiPersio, ProfMD ^c, Pavan Reddy, ProfMD ^a,^⁎

^a Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA

^b Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

^c Department of Cardiology, University of Michigan, Ann Arbor, MI, USA

^d Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA

^e Blood and Marrow Transplantation Program, Washington University, St Louis, MO, USA

^f Sutter East Bay Medical Foundation, Berkeley, CA, USA

^g Hematology-Oncology, Mie University Hospital, Mie, Japan

^h Pediatric Hematology Oncology, Indiana University, Indianapolis, IN, USA

ⁱ Blood and Marrow Transplantation Program, Columbia University, New York, NY, USA

^j Department of Medicine, University of Colorado, Aurora, CO, USA

^k Department of Medicine, University Medical Center Nijmegen, Netherlands

^* Correspondence to: Prof Pavan Reddy, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI 48109, USA

Summary

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/m² 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.

Findings

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.

Interpretation

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.

Funding

Merck, Leukemia and Lymphoma Society, National Institutes of Health, St Baldrick’s Foundation, Michigan Institute for Clinical and Health Research.

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Vol 15 - N° 1

P. 87-95 - janvier 2014 Retour au numéro

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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 - 31/12/13

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