A Phase I/II Study Of Fludarabine, Cyclophosphamide, Rituximab and Vorinostat Followed By Rituximab and Vorinostat Maintenance Therapy In Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia (CLL) Or Small Lymphocytic Leukemia (SLL)

The limitations of current CLL/SLL treatments include suboptimal response rates, variable remission durations, toxicities, and few cures. Vorinostat is a histone deacetylase inhibitor that regulates gene transcription and possibly CD20 expression, leading to its investigative use in the treatment of B-cell malignancies. For this reason, we studied the addition of vorinostat to fludarabine, cyclophosphamide and rituximab (FCR+V) followed by maintenance therapy with rituximab and vorinostat.

Patients over age 18 with previously untreated Rai stage I-IV CLL or SLL and ECOG 0-2 were eligible. They received 4-6 cycles of FCR+V followed by up to eight cycles of maintenance with rituximab and vorinostat. Each cycle of FCR used cyclophosphamide 250 mg/m² IV on days 1-3 and fludarabine 25 mg/m² IV days 1-3 of each cycle given every 28 days; with rituximab 375 mg/m² IV once with cycle 1 followed by 500 mg/m²IV once per cycle for cycles 2-6. Rituximab 500 mg/m2 IV was given day 1 of each 3 month cycle of maintenance for up to 8 cycles. Vorinostat was given on days 1-5 and 8-12 of each treatment cycle and days 1-14 of each 3-month maintenance cycle. The Phase I vorinostat starting dose was 200 mg/day and escalated by 100 mg/day to a maximum pre-determined dose of 400 mg/day in a 3 x 3 design. Since no dose limiting toxicity was seen during Phase I, the previously designated maximum dose of 400 mg/day vorinostat was chosen for the Phase II portion of the trial.

Ten patients were treated on the Phase I portion of the study, and 26 patients have been enrolled in the Phase II portion at the maximum vorinostat dose of 400 mg/day combined with FCR and rituximab maintenance. The median age of patients on study was 58 (range, 36-72); with 6 patients enrolled with Stage I, 15 with Stage II, 5 with Stage III and 10 with Stage IV disease. Nine patients (25%) had >30% CD38 expression, 13 patients (36%) had >20% ZAP70 expression, and 4 patients (11%) had 17p deletions detected by FISH of marrow samples. Median follow-up on study is 15 months (range, 0.9-38.6). Of the 36 patients enrolled, 22 patients are evaluable after completing 4-6 cycles of FCR+V, 1 patient progressed after cycle 2 (del17p), 9 patients are currently receiving FCR+V and 4 patients are unevaluable. Of these 4 patients, one withdrew voluntarily, one was taken off study due to non-compliance, one went off study after cycle 3 due to cytopenias, and one patient with multiple co-morbidities died of sepsis after cycle 5. Of the 22 patients who have completed 4-6 cycles of FCR+V, 16 (73%) obtained a complete response (CR), 5 (22.5%) obtained a partial response (PR), and 1 (4.5%) has stable disease. Of these 22 patients, 4 (18%) have completed 8 cycles of maintenance with rituximab and vorinostat, 5 (23%) were taken off study due to cytopenias, 1 (4.5%) went off study due to insurance issues, 1 (4.5%) went off study due to recurrent infections, 2 (9%) voluntarily withdrew from study, and 9 (41%) are still receiving maintenance therapy. The most common grade 3-4 non-hematologic toxicities during FCR+V were gastrointestinal symptoms in 10 patients and fatigue in 3 patients. However, there were no grade 3-4 non-hematologic toxicities that resulted in patient withdrawal from study during treatment with FCR+V. No grade 3-4 non-hematologic toxicities have been observed in patients who have completed or are undergoing maintenance with rituximab and vorinostat.

Treatment of CLL/SLL with fludarabine, cyclophosphamide, rituximab and 400mg/day vorinostat (FCR +V) followed by maintenance with rituximab and vorinostat appears feasible and tolerable, and may warrant further study.

Gopal: Merck: Research Funding. Press:Roche/Genentech: Consultancy.