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, Thomas Braun, Lawrence Chang, James L.M. Ferrara, Attaphol Pawarode, John M. Magenau, Guoqing Hou, Jan H. Beumer, John E. Levine, Steve Goldstein, Daniel R. Couriel, Keith Stockerl-Goldstein, Oleg I. Krijanovski, Carrie Kitko, Gregory A. Yanik, Michael H. Lehmann, Isao Tawara, Yaping Sun, Sophie Paczesny, Markus Y. MaparaCharles A. Dinarello, John F. DiPersio, Pavan Reddy

Research output: Contribution to journalArticle

66 Citations (Scopus)

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/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.

Original languageEnglish (US)
Pages (from-to)87-95
Number of pages9
JournalThe Lancet Oncology
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2014

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Stem Cell Transplantation
Tacrolimus
Graft vs Host Disease
Tissue Donors
Poisons
Incidence
Mycophenolic Acid
vorinostat
Busulfan
Mucositis
Histone Deacetylases
Hematologic Diseases
National Institutes of Health (U.S.)
Hyperglycemia
Thrombocytopenia
Electrolytes
Lymphoma
Leukemia
Neutrophils
Blood Platelets

ASJC Scopus subject areas

  • Oncology

Cite this

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. / Choi, Sung Won; Braun, Thomas; Chang, Lawrence; Ferrara, James L.M.; Pawarode, Attaphol; Magenau, John M.; Hou, Guoqing; Beumer, Jan H.; Levine, John E.; Goldstein, Steve; Couriel, Daniel R.; Stockerl-Goldstein, Keith; Krijanovski, Oleg I.; Kitko, Carrie; Yanik, Gregory A.; Lehmann, Michael H.; Tawara, Isao; Sun, Yaping; Paczesny, Sophie; Mapara, Markus Y.; Dinarello, Charles A.; DiPersio, John F.; Reddy, Pavan.

In: The Lancet Oncology, Vol. 15, No. 1, 01.01.2014, p. 87-95.

Research output: Contribution to journalArticle

Choi, SW, Braun, T, Chang, L, Ferrara, JLM, Pawarode, A, Magenau, JM, Hou, G, Beumer, JH, Levine, JE, Goldstein, S, Couriel, DR, Stockerl-Goldstein, K, Krijanovski, OI, Kitko, C, Yanik, GA, Lehmann, MH, Tawara, I, Sun, Y, Paczesny, S, Mapara, MY, Dinarello, CA, DiPersio, JF & Reddy, P 2014, '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, vol. 15, no. 1, pp. 87-95. https://doi.org/10.1016/S1470-2045(13)70512-6
Choi, Sung Won ; Braun, Thomas ; Chang, Lawrence ; Ferrara, James L.M. ; Pawarode, Attaphol ; Magenau, John M. ; Hou, Guoqing ; Beumer, Jan H. ; Levine, John E. ; Goldstein, Steve ; Couriel, Daniel R. ; Stockerl-Goldstein, Keith ; Krijanovski, Oleg I. ; Kitko, Carrie ; Yanik, Gregory A. ; Lehmann, Michael H. ; Tawara, Isao ; Sun, Yaping ; Paczesny, Sophie ; Mapara, Markus Y. ; Dinarello, Charles A. ; DiPersio, John F. ; Reddy, Pavan. / 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. In: The Lancet Oncology. 2014 ; Vol. 15, No. 1. pp. 87-95.
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TY - JOUR

T1 - Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation

T2 - A phase 1/2 trial

AU - Choi, Sung Won

AU - Braun, Thomas

AU - Chang, Lawrence

AU - Ferrara, James L.M.

AU - Pawarode, Attaphol

AU - Magenau, John M.

AU - Hou, Guoqing

AU - Beumer, Jan H.

AU - Levine, John E.

AU - Goldstein, Steve

AU - Couriel, Daniel R.

AU - Stockerl-Goldstein, Keith

AU - Krijanovski, Oleg I.

AU - Kitko, Carrie

AU - Yanik, Gregory A.

AU - Lehmann, Michael H.

AU - Tawara, Isao

AU - Sun, Yaping

AU - Paczesny, Sophie

AU - Mapara, Markus Y.

AU - Dinarello, Charles A.

AU - DiPersio, John F.

AU - Reddy, Pavan

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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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