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Phase I trial of histone deacetylase inhibitor panobinostat in addition to glucocorticoids for primary therapy of acute graft-versus-host disease

Bone Marrow Transplantation volume 53, pages 1434–1444 (2018)Cite this article

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Abstract

Glucocorticoids for primary therapy of acute GVHD have limited responses. A phase I/II trial tested 4 weeks of deacetylase inhibitor panobinostat started within 48 h of glucocorticoids (1 mg/kg/day prednisone or equivalent) as primary treatment for patients with either classic acute GVHD (n = 16) or acute GVHD overlapping with chronic (n = 6). Four patients received 2.5 mg/m2 IV three times a week (TIW). Subsequent to discontinuation of IV panobinostat, patients received oral doses (PO). Two patients treated with 10 mg TIW (PO level 1) had progressive GVHD, after which patients were treated with 5 mg TIW (PO level −1; n = 16); 31/41 adverse events were possibly related, including thrombocytopenia (n = 13), leukopenia (n = 7), hypercholesterolemia (n = 3), hypertriglyceridemia (n = 5), anemia (n = 1), fatigue (n = 1), and hepatobiliary disorder (n = 1). GVHD responses were complete (n = 12) or partial (n = 3), with 1 progression at PO level −1. T-regulatory cells increased at day 8, CD4/CD8 and monocytes exhibited enhanced H3 acetylation, and CD4 or CD8 numbers remained unchanged with a decreased interleukin 12p40 plasma level. Panobinostat in combination with prednisone is safe and warrants further testing in GVHD.

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Acknowledgements

We thank Erika Elmer, Michele Burton, Jermaine Castro, and Carmen Patton for trial coordination/data acquisitions. We thank Sonya Smyk (Moffitt Cancer Center) for editorial assistance. Novartis Pharmaceuticals Corporation supported this trial and provided PANO.

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Author notes

  1. Hugo Fernandez

    Present address: Malignant Hematology & Cellular Therapy Department, Memorial Healthcare System, Pembroke Pines, FL, USA

  2. Pedro Horna

    Present address: Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN, USA

  3. Marcie Riches

    Present address: Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

  4. Alejandro Villagra

    Present address: Department of Biochemistry & Molecular Medicine, George Washington University, Washington, DC, USA

Authors and Affiliations

  1. Blood & Marrow Transplant & Cellular Immunotherapy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Lia Perez, Hugo Fernandez, Marcie Riches, Frederick Locke, Teresa Field, Asmita Mishra, Brian Betts, Mohamed Kharfan-Dabaja, Francisca Beato, Leonel Ochoa-Bayona, Joseph Pidala & Claudio Anasetti

  2. Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Pedro Horna

  3. Department of Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    John Powers, Eva Sahakian & Alejandro Villagra

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Perez, L., Fernandez, H., Horna, P. et al. Phase I trial of histone deacetylase inhibitor panobinostat in addition to glucocorticoids for primary therapy of acute graft-versus-host disease. Bone Marrow Transplant 53, 1434–1444 (2018). https://doi.org/10.1038/s41409-018-0163-z

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