A Phase 2 Study of Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma. A California Cancer Consortium Study.

Background: The indolent (follicular, marginal zone and mantle cell) lymphomas tend to recur with decreasing intervals of remission after standard chemotherapy. New modalities of treatment are necessary. Vorinostat (SAHA) is an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deacetylases with preclinical and clinical activity against various forms of lymphoma.

Methods: We report the results of a phase II study of oral vorinostat in patients with relapsed or refractory (to chemotherapy and/or rituximab) follicular, marginal zone, or mantle cell lymphoma. Vorinostat is given at 200 mg PO twice daily for 14 consecutive days on a 21 day cycle. CT scanning and/or FDG-PET are performed after every three cycles, as is marrow biopsy for those with marrow involvement at time of entry into study. Patients may have received up to four prior chemotherapy regimens including tositumomab or ibritumomab; previous transplant is allowed.

Results: 37 patients (14 female, 23 male) were accrued (2 ineligible patient due to wrong histology are excluded from the analysis). The median age for evaluable patients at treatment was 65 (32–79) years. Histologies represented: follicular lymphoma (FL)-20, mantle cell (MC)-8, marginal zone (MZL)- 7. Treatment was well tolerated. Grade 3–4 toxicities possibly attributable to study drug were thrombocytopenia, neutropenia, anemia, diarrhea, anorexia, myalgia, hypokalemia, hypophosphatemia, thrombus (1 patient) and fatigue. 18 patients were taken off study due to progression. Three pts came off study due to toxicities (fatigue and diarrhea after 10 cycles, diarrhea and dizziness after 2 cycles, DVT after 5 cycles), 1 stopped therapy due to intercurrent illness, 1 came off for alternate therapy. By the current Cheson criteria, 6 patients achieved complete remission (CR), and 4 patients achieved partial remission (PR), for an overall response rate (CR+PR) of 29%. By histology, 10 formal responses were seen in patients with follicular (8) or marginal zone lymphoma (2), thus for patients with FL and MZL the response rate is 37%, whereas no responses were seen in mantle cell lymphoma. Two patients with PR as best response subsequently progressed (one at 6 months, one after 16 months), the other two remain on therapy. One CR was achieved after 2 years of stable disease on therapy. At a median follow up of 12 months, median progression-free survival for the 35 eligible patients is 7 months; 5 patients are progression-free for more than 18 months. Eleven patients remain on therapy.

Conclusions: The histone deacetylase inhibitor vorinostat is well tolerated over long durations of therapy, and shows promising activity (10 CR+PR out of 27 patients) against relapsed/refractory follicular and marginal zone lymphoma.