A Phase 2 Study of Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Plus Rituximab in Newly Diagnosed, Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma

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. An earlier study of single agent vorinostat showed promising activity in indolent lymphomas, thus a follow up study combining vorinostat with rituxan was performed.

We report the results of the planned interim analysis (first stage) of a two-stage phase II study of oral vorinostat combined with rituximab in patients with newly diagnosed, 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. Rituximab is given on day one of each 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. 17 eligible patients (8 female, 9 male) were accrued during the first stage of accrual. The median age at treatment was 60 years (range 44–71). Histologies represented: mantle cell (MC)-2, marginal zone (MZL)-1, and follicular lymphoma (FL)-14. Treatment was well tolerated. Grade 4 toxicities possibly attributable to study drug include neutropenia (n=1), thrombosis (n=3), and platelet (n=1). Grade 3 possibly related toxicities include fatigue (n=5), hyperglycemia (n=3), dehydration (n=2), and one each of platelets, hypophosphatemia, hypotension, infection, diarrhea, syncope, and thrombosis (nonclinical pulmonary embolism discovered incidentally on CT scan).

The overall formal response (CR+PR) rate thus far is 35% (6/17), with a response rate of 43% (6/14) for patients with FL, and no formal responses seen in mantle cell (0/2) or MZL (0/1). By the current Cheson criteria, 5 patients achieved complete remission (CR), and 1 patients achieved partial remission (PR). One patient (FL) with a CR relapsed 14 months after treatment initiation. The remaining 5 responders have not relapsed, at 4, 9, 13, 16 and 21 months. The median PFS has not been reached, and only 1 responder has progressed to date at 9 months (patient with FL).

The combination of the histone deacetylase inhibitor vorinostat with rituximab is well tolerated, and shows encouraging activity against relapsed/refractory indolent lymphoma The study has passed interim analysis and will proceed to full accrual of 33 patients.

Supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp.

Kirschbaum:Merck: Honoraria, Research Funding. Off Label Use: clinical trial of vorinostat in indolent lymphomas. Pullarkat:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau.