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Addition of Oblimersen (Bcl-2 Antisense) to Fludarabine/Cyclophosphamide for Relapsed/Refractory Chronic Lymphocytic Leukemia Extends Survival in Patients Who Achieve CR/nPR: Results from a Randomized Phase 3 Study.

Background: Up-regulation of Bcl-2 protein plays a critical role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). Oblimersen (OBL [Genasense®]) decreases Bcl-2 protein in a concentration- and time- dependent manner and enhances the cytotoxic activity of agents commonly used for CLL, including fludarabine (F) and cyclophosphamide (C). A recent randomized, controlled, Phase 3 study of FC ± OBL showed that patients (pts) who received OBL achieved a significantly greater rate of complete response (CR, defined as CR plus nPR), which was the trial’s primary endpoint (O’Brien et al, J Clin Oncol 2007). Since duration of CR was also superior for OBL-treated pts, we evaluated whether extended followup would indicate that these benefits would translate into improved survival for pts who achieved CR. Methods: Pts with relapsed/refractory CLL received up to six 28-day cycles of FC (25 mg/m 2 /d and 250 mg/m 2 /d x 3d, respectively) with or without OBL (3 mg/kg/d x 7d by continuous IV infusion beginning 4 days before FC). NCI-WG response was determined by a clinical expert blinded to treatment assignment and independent blinded review of bone marrow. CT was required to confirm CR in pts with baseline abnormalities. All pts were followed for at least 3 years from randomization, or until death or withdrawal of consent. Survival data were collected through May 2007 and landmark analysis (at yearly time points) of the probability of achieving a CR and surviving was performed for up to 4 years for the intent-to-treat (ITT) population. Results: OBL combined with FC significantly increased the CR rate (17% [20 of 120 pts] compared with pts treated with FC alone (7% [8 of 121 pts]) (P = 0.025). CR duration was also significantly greater for OBL-treated pts (median not reached [estimated 36+ mos] compared with pts treated with FC alone (22 mos) (P=0.031). In both treatment groups, achievement of CR was associated with relief from all predefined CLL symptoms for ≥ 180 days (Pearson chi-square test, P Exploratory analysis showed that OBL-treated pts survived significantly longer (see table). Twelve of the 20 pts in CR in the OBL group and 4 of the 8 pts in CR in the FC-only group were alive. Median survival time among pts in CR on this trial had not been reached in the OBL group (estimated to exceed 49 months), compared with 35 months in the FC-only group. Survival durations ranged from 48 to 64 months among the 12 surviving pts in the OBL group, and from 47 to 65 months among the 4 surviving pts in the FC-only group. Conclusions: The addition of OBL to FC significantly increased percent CR and CR duration. Pts who achieved CR with OBL also achieved significantly longer survival compared with pts treated with FC chemotherapy alone. These data strongly confirm that CR is a valuable primary endpoint for therapeutic trials in relapsed/refractory CLL and supports the clinical benefit associated with durable CR in this setting.