Efficacy and Safety of the Combination of Genasense™ (Oblimersen Sodium, Bcl-2 Antisense Oligonucleotide), Fludarabine and Rituximab in Previously Treated and Untreated Subjects with Chronic Lymphocytic Leukemia.

Bcl-2 is an anti-apoptotic protein closely linked to chemotherapy resistance and inferior survival in patients (pts) with CLL. Genasense (G) enhances apoptosis induced by fludarabine (F), dexamethasone, and rituximab (R) in vitro. Despite limited single-agent activity in heavily pre-treated CLL pts, G significantly increased the rate of durable complete responses (CR) in combination with fludarabine (F) and cyclophosphamide in relapsed or refractory CLL (Rai, ASH 2004). Down-regulation of Bcl-2 sensitizes CLL cells to apoptosis induced by F and R. In order to examine the impact of G on the FR combination, we initiated a phase II study of the combination of FRG in pts with either previously untreated (UT) or relapsed, previously treated (PT) CLL who require systemic treatment. Eligibility includes: plts ≥ 50,000/mm3; serum Cr ≤ 1.5 mg/dL; adequate organ function; negative Coombs; no history of autoimmune hemolytic anemia. In cycle 1, G is given by continuous intravenous infusion at 1.5 mg/kg/d days 1 to 7. R is given in a dose-escalating schema: 125 mg/m² on day 4 and 250mg/m² on day 6, with F (25 mg/m²/d) on days 6 to 8. In subsequent 28-day cycles (up to 6), the dose of G is escalated to 3 mg/kg/d days 1 to 7, with R 375 mg/m² on day 5 and F days 5 to 7.

Results: To date, 24 pts have been enrolled (19 PT and 5 UT). Characteristics included: median age, 56.5 yrs (range 25–82 yrs); Rai stage III, 6 pts (4 PT and 2 UT) and IV, 6 pts (6 PT and 0 UT). Median prior regimens (PT pts), 2; 13/19 (68%) had received F and R previously. Median # cycles administered: 6 (both UT and PT). Four PT pts discontinued treatment before completing 6 cycles, 2 due to disease progression, and 2 with prolonged (> 4 week) Grade 3 thrombocytopenia/neutropenia. One PT pt completed only 3 cycles of R due to an R-related infusion reaction, but completed 6 cycles of G and F. Among the 5 UT pts, there was 1 case of grade 4 neutropenia. Among the 19 PT pts, there were 2 cases each of grade 4 thrombocytopenia and neutropenia. One of 5 UT pts had an SAE of reversible acute renal insufficiency. Seven of 19 PT pts (8 events total) experienced an SAE. These included R-related infusion reactions (2 pts), bacteremia (2 pts) and 1 pt each with fever, lymph node abscess, pneumonia, and thrombocytopenia/neutropenia. Responses have been observed in 5/5 UT pts (1 molecular CR (mCR), 1 nPR and 3 PR) and 10/19 PT pts (1 mCR, 2 nPR and 7 PR).

Conclusions: 24 pts have been treated with the combination of FRG. Employing a three-day regimen of F, good tolerability and efficacy have been noted in relapsed/refractory patients. Based on these results, an additional cohort receiving a full 5-day regimen of F is ongoing with measurement of Genasense PK and bcl-2 intracellular levels (mRNA and protein).