Effect of the addition of oblimersen (Bcl-2 antisense) to fludarabine/cyclophosphamide for relapsed/refractory chronic lymphocytic leukemia (CLL) on survival in patients who achieve CR/nPR: Five-year follow-up from a randomized phase III study

Abstract

7008 Background: Bcl-2 upregulation is critical in the pathogenesis and progression of CLL. OBL enhances the cytotoxic activity of agents used for CLL, including fludarabine (F) and cyclophosphamide (C). In a recent Phase 3 trial, patients (pts) who received OBL+FC (N=120) versus FC (N=121) achieved a significantly greater rate of complete response (CR, defined as CR plus nPR; primary endpoint) (O'Brien et al, J Clin Oncol 2007). CR duration was also superior for OBL+FC-treated pts. We evaluated whether these benefits would translate into improved survival for CR pts. Methods: Pts received ≤ 6 cycles of FC with/without OBL (3 mg/kg/d x 7d by continuous IV infusion beginning 4 days before FC). NCI-WG response was determined by blinded expert review. Five-year follow-up data will be collected for CR pts, and landmark analyses of the probability of maintaining CR and surviving performed (ITT population). Results: OBL+FC significantly increased the CR rate (17%) versus FC (7%) (P=0.025). CR duration was also significantly greater for OBL+FC (median not reached [estimated 36+ mos] versus FC [22 mos]) (P=0.031). In both groups, CR was associated with relief from all predefined CLL symptoms for ≥180 days (P<0.0001). Among CR pts at 54 months, 12/20 OBL+FC pts and 3/8 FC pts were still alive. CR was continuing in 5/12 OBL+FC pts versus 0/3 FC pts. Median survival among OBL+FC CR pts had not been reached (estimated 55+ mos) versus 45 months in FC pts. Conclusions: The addition of OBL to FC significantly increased CR rate and CR duration. The OBL+FC group had a higher probability of CRs with long survival than the FC group. CR is a valuable primary endpoint in relapsed/refractory CLL trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genta Incorporated Genta Incorporated Genta Incorporated Bayer, Celgene, Genentech™ BioOncology Bayer, Berlex Oncology, BioGen IDEC, Bristol-Myers Squibb, Eli Lilly, GeminX, Genentech™ BioOncology, Genta, Novartis