Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8431263 | Biology of Blood and Marrow Transplantation | 2015 | 7 Pages |
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 â8 to â3). Gemcitabine was infused continuously at 10 mg/m2/minute over 4.5 hours (days â8 and â3). Busulfan dosing targeted 4000 μM-minute/day (days â8 to â5). Melphalan was infused at 60 mg/m2/day (days â3 and â2). Patients with CD20+ tumors received rituximab (375 mg/m2, 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.
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Authors
Yago Nieto, Benigno C. Valdez, Peter F. Thall, Sairah Ahmed, Roy B. Jones, Chitra Hosing, Uday Popat, Elizabeth J. Shpall, Muzaffar Qazilbash, Alison Gulbis, Paolo Anderlini, Amin Alousi, Nina Shah, Qaiser Bashir, Yan Liu, Yasuhiro Oki,