Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV-associated Non-Hodgkin's Lymphoma (AMC-075)

Juan C. Ramos, Joseph A. Sparano, Michelle A. Rudek, Page C. Moore, Ethel Cesarman, Erin G. Reid, David Henry, Lee Ratner, David Aboulafia, Jeanette Y. Lee, Richard F. Ambinder, Ronald Mitsuyasu, Ariela Noy

Research output: Contribution to journalArticlepeer-review

Abstract

We performed a phase I trial of vorinostat (VOR) given on days 1 to 5 with R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) in patients with aggressive HIV-associated non-Hodgkin lymphoma. VOR was tolerable at 300 mg and seemingly efficacious with chemotherapy with complete response rate of 83% and 1-year event-free survival of 83%. VOR did not significantly alter chemotherapy steady-state concentrations, CD4 + cell counts, or HIV viral loads. Introduction: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV + ) or human herpesvirus-8-positive (HHV-8 + ) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). Patients and Methods: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV + ), 1 EBV + /HHV-8 + primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. Results: The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%). Conclusion: VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL.

Original languageEnglish (US)
Pages (from-to)180-190.e2
JournalClinical Lymphoma, Myeloma and Leukemia
Volume18
Issue number3
DOIs
StatePublished - Mar 2018

Keywords

  • AIDS-related malignancies
  • Chemotherapy
  • Epstein-Barr virus
  • Histone deacetylase inhibitors
  • Lytic-inducing therapies

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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