Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas

Biol Blood Marrow Transplant. 2015 Nov;21(11):1914-20. doi: 10.1016/j.bbmt.2015.06.003. Epub 2015 Jun 11.

Abstract

More active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days -8 to -3). Gemcitabine was infused continuously at 10 mg/m(2)/minute over 4.5 hours (days -8 and -3). Busulfan dosing targeted 4000 μM-minute/day (days -8 to -5). Melphalan was infused at 60 mg/m(2)/day (days -3 and -2). Patients with CD20(+) tumors received rituximab (375 mg/m(2), days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography-positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation. This trial was registered at ClinicalTrials.gov (NCI-2011-02891).

Trial registration: ClinicalTrials.gov NCT01421173.

Keywords: Autologous stem-cell transplantation; High-dose chemotherapy; Lymphoma; Phase 1 trial; Vorinostat.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Busulfan / therapeutic use
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Gemcitabine
  • Hematopoietic Stem Cell Transplantation*
  • Hodgkin Disease / immunology
  • Hodgkin Disease / mortality
  • Hodgkin Disease / pathology
  • Hodgkin Disease / therapy*
  • Humans
  • Hydroxamic Acids / therapeutic use*
  • Lymphoma, Large B-Cell, Diffuse / immunology
  • Lymphoma, Large B-Cell, Diffuse / mortality
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Lymphoma, Large B-Cell, Diffuse / therapy*
  • Lymphoma, T-Cell / immunology
  • Lymphoma, T-Cell / mortality
  • Lymphoma, T-Cell / pathology
  • Lymphoma, T-Cell / therapy*
  • Male
  • Melphalan / therapeutic use
  • Middle Aged
  • Recurrence
  • Survival Analysis
  • Transplantation Conditioning / methods*
  • Transplantation, Autologous
  • Vorinostat

Substances

  • Hydroxamic Acids
  • Deoxycytidine
  • Vorinostat
  • Busulfan
  • Melphalan
  • Gemcitabine

Associated data

  • ClinicalTrials.gov/NCT01421173