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Clinical Trial
. 2014 Jan;15(1):87-95.
doi: 10.1016/S1470-2045(13)70512-6. Epub 2013 Nov 30.

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

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Clinical Trial

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

Sung Won Choi et al. Lancet Oncol. .
Free PMC article

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.

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.

Conflict of interest statement

CONFLICTS OF INTEREST

All authors declared no conflicts of interest.

Figures

Figure 1
Figure 1. Clinical Outcomes of Acute GVHD, Relapse, Non-Relapse Mortality (NRM), and Overall Survival
Cumulative incidence of Grade 2–4 and Grade 3–4 acute GVHD (Panel A), Relapse (Panel B), GVHD-related NRM and overall NRM (Panel C), and Overall Survival (Panel D). The study population consisted of 50 patients whom underwent matched related donor, reduced intensity conditioning transplant with vorinostat combined with tacrolimus and mycophenolate mofetil for GVHD prevention.
Figure 2
Figure 2. Pharmacodynamic Studies
Shown are controls (formula image)versus study patients (formula image). Panel A shows the results of Western blot analyses of histone acetylation in peripheral blood mononuclear cells (acetylated H3 formula imagen = 14, formula imagen = 26; acetylated H4 formula imagen = 13, formula imagen = 27). Panel B shows plasma pro-inflammatory cytokines as assessed by enzyme-linked immunosorbent (TNFR1 formula imagecontrol n = 20, formula imagestudy n = 45) assay and by flow cytometry (TNF-αformula imagen = 6, formula imagen = 10). Panel C shows the flow cytometric detection of CD4+ (formula imagen = 22, formula imagen = 36) and CD8+ (formula imagen = 22, formula imagen = 36) counts. Panel D shows the flow cytometric detection of absolute lymphocyte counts (formula imagen = 22, formula imagen = 36) and CD4+25+127 Treg counts (formula imagen = 22, formula imagen = 36). Panel D shows FoxP3 (formula imagen = 20, formula imagen = 35) and indoleamine-2,3-dioxygenase (IDOformula imagecontrol n = 19, formula imagen = 30) expression as assessed by RT-PCR. All studies were conducted at day 30 post-transplant.
Figure 2
Figure 2. Pharmacodynamic Studies
Shown are controls (formula image)versus study patients (formula image). Panel A shows the results of Western blot analyses of histone acetylation in peripheral blood mononuclear cells (acetylated H3 formula imagen = 14, formula imagen = 26; acetylated H4 formula imagen = 13, formula imagen = 27). Panel B shows plasma pro-inflammatory cytokines as assessed by enzyme-linked immunosorbent (TNFR1 formula imagecontrol n = 20, formula imagestudy n = 45) assay and by flow cytometry (TNF-αformula imagen = 6, formula imagen = 10). Panel C shows the flow cytometric detection of CD4+ (formula imagen = 22, formula imagen = 36) and CD8+ (formula imagen = 22, formula imagen = 36) counts. Panel D shows the flow cytometric detection of absolute lymphocyte counts (formula imagen = 22, formula imagen = 36) and CD4+25+127 Treg counts (formula imagen = 22, formula imagen = 36). Panel D shows FoxP3 (formula imagen = 20, formula imagen = 35) and indoleamine-2,3-dioxygenase (IDOformula imagecontrol n = 19, formula imagen = 30) expression as assessed by RT-PCR. All studies were conducted at day 30 post-transplant.

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