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Clin Lymphoma Myeloma Leuk. 2018 Mar;18(3):180-190.e2. doi: 10.1016/j.clml.2018.01.004. Epub 2018 Feb 2.

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

Author information

1
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL. Electronic address: jramos2@med.miami.edu.
2
Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
3
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD.
4
University of Arkansas for Medical Sciences, Little Rock, AR.
5
Weill Cornell Medicine, New York, NY.
6
University of California San Diego Moores Cancer Center, San Diego, CA.
7
Penn Hematology/Oncology Abramson Cancer Center, Pennsylvania Hospital, Philadelphia, PA.
8
Washington University School of Medicine, St. Louis, MO.
9
Virginia Mason Medical Center and University of Washington, Seattle, WA.
10
Johns Hopkins School of Medicine, Baltimore, MD.
11
David Geffen School of Medicine, Los Angeles (UCLA), Los Angeles, CA.
12
Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY.

Abstract

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.

KEYWORDS:

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

PMID:
29426719
DOI:
10.1016/j.clml.2018.01.004
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