A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma

Abstract

This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1-14 along with 375 mg/m(2) of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876.

Trial registration: ClinicalTrials.gov NCT00720876.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Kaplan-Meier estimation of progression-free survival (PFS) defined as time from initial protocol treatment to progression, relapse, or death from any cause, whichever occurred first. Median follow up for surviving patients was 26.8 months. PFS is shown: (A) for all patients (n=28), (B) for all patients stratified by response, and (C) for patients with follicular lymphoma (n=22) stratified by response.

Figure 2.

Treatment time course in responding patients. Timing of treatment is shown for the 13 responding patients with duration of first response: stable disease (SD) (blue); duration of partial response (PR) (light green); duration of complete response (CR) (dark green). Duration of re-treatment after progressive disease (PD) (is shown in orange). Patients’ previous treatment status is indicated on the right and an arrow indicates that the patient was on treatment at the time of data analysis.

Figure 3.

Changes in cytokine levels in 14 days of treatment. Systemic levels of 16 cytokines (IL-1RA, IL-2R, IL-8, IL-12p40/p70, IL-15, IFN-α, MIP-1α, MIP-1β, IP-10, MIG, Eotaxin, MCP-1, G-CSF, EGF, FGF-basic, and HGF). were compared between day 1 pre-treatment and day 14 post-treatment and results are depicted graphically for each cytokine assay (x-axis) with each patient plotted as percent difference between day 1 and day 14 cytokine levels (y-axis). Individual patients are plotted with disease response indicated by the symbols depicted in the legend. Median for each assay is indicated by the red diamond.