Flavopiridol, fludarabine and rituximab (FFR) is an active regimen in indolent B-cell lymphoproliferative disorders and mantle cell lymphoma (MCL)

Abstract

7599 Background: The cyclin-dependent kinase inhibitor flavopiridol is active in MCL and chronic lymphocytic leukemia (CLL) when given by 1-hr IV bolus dosing. Flavopiridol induces apoptosis independent of p53 and may eliminate tumor cells resistant to fludarabine and rituximab. Methods: We performed a phase I dose escalation study of flavopiridol, fludarabine and rituximab (FFR) in patients (pts) with MCL, CLL and indolent B-cell non-Hodgkin’s lymphoma (NHL). Pts received fludarabine 25 mg/m2 IV day 1–5 and rituximab 375 mg/m2 day 1 every 28 days for up to 6 cycles. Flavopiridol was given 50 mg/m2 by 1-hr IV bolus day 1 (cohort 1), day 1–2 (cohort 2), or day 1–3 (cohort 3) of each cycle. Growth factor support was prohibited. Results: Twenty-one pts were enrolled and are evaluable for toxicity and response. Median age was 62 years (range, 43–81); 8 pts had CLL, 5 MCL, 4 follicular NHL (FL), and 4 other low-grade NHL. Nine pts had received 1–2 prior therapies; 12 pts were previously untreated. CLL pts were Rai stage III/IV (5) or required treatment for stage I/II disease (3). NHL pts had stage III/IV (10) or progressive stage II disease (3). Dose limiting toxicity (DLT) was not observed in 3 pts in cohort 1. Two of 6 pts in cohort 2 developed DLT (grade 3 seizures; grade 3 renal failure due to nausea and diarrhea). Twelve additional pts were enrolled at the cohort 1 dose level, to define toxicity and efficacy. Pts received a median of 4 cycles (range 1–6), and 9 of 21 pts completed 6 cycles. Therapy was stopped early due to cytopenias (7), infection (2), DLT (2) or progressive disease (1). Response was graded by NCI 96 (CLL) or IWG (NHL) criteria. Overall response rate was 90%, and 14 pts achieved CR (67%). Six pts relapsed a median of 7.5 months (range 4–18) after finishing therapy; 13 pts remain in remission a median of 13.5 months (range 4–25) after therapy. All 9 MCL/FL pts responded (8 CR, 1 PR), and 8 pts remain in remission a median of 17 months (range 6–25) after therapy. Conclusions: FFR showed significant clinical activity in a small group of pts, but cytopenias limited therapy. We are currently studying a modified FFR regimen using a more active flavopiridol schedule (30-min IV bolus followed by 4-hr IV infusion) and allowing the use of prophylactic filgrastim. [Table: see text]