A Pilot Study 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(GNS) enhances apoptosis induced by fludarabine (F), dexamethasone, and rituximab (R) in vitro, and has limited single-agent activity in heavily pre-treated CLL pts. Down-regulation of Bcl-2 may further sensitize CLL cells to apoptosis induced by F and R without exposing subjects to the toxicity of alkylating agents. CLL and NHL pts occasionally exhibit a “cytokine release syndrome” (spiking fever, back pain, and occasional hypotension) with GNS treatment. We hypothesized that a “step dosing” approach with GNS, similar to that sometimes used for R, could ameliorate these effects and allow safe and effective combination of this agent with F and R. We are currently evaluating this combination 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, GNS is given by continuous intravenous infusion at 1.5 mg/kg/d days 1 to 7. R is given on a dose-escalating schema (day 4, 125 mg/m²; day 6, 250 mg/m²). F (25 mg/m²/d) is given on days 6 to 8. In subsequent 28-day cycles (up to 6), the dose of GNS is escalated to 3 mg/kg/d days 1 to7 days, with R 375 mg/m² on day 5 and F days 5 to7. To date, 20 pts have been enrolled (17 PT and 3 UT). Characteristics included: median age, 62 yrs (range 39 to 82 yrs); Rai stage III (2 pts) and IV (6 pts).

Prior to administration of either F or R, single-agent GNS treatment at the initial reduced dose in Cycle 1 resulted in a median decrease in lymphocytes of 15% (among all patients regardless of decline in lymphocyte count) (Baseline: 48.3 cells x 10³/ml; day 4: 40.1 cells x 10³/ml). For the 13 pts who experienced a decline in lymphocyte count in cycle 1 prior to F and R, the median percentage change was 17%, with 4 pts having a > 25% decrease. Three PT pts discontinued from study treatment prior to completing 6 cycles, 2 due to disease progression, and 1 with Grade 3 thrombocytopenia that was unresolved after 4 weeks. Among the 20 pts treated to date (9 ongoing), the most common grade 3 or higher adverse events have been neutropenia, pyrexia and thrombocytopenia. Serious adverse events have been noted in only 6 of 20 pts (all PT pts) and have included 2 pts with fever (1 neutropenic), 2 R infusion reactions, 1 lymph node abscess and 1 tumor lysis syndrome (with sepsis).

Conclusions: 20 pts have been treated with combination GNS, F and R. Single-agent activity with GNS has been observed at a reduced dose of 1.5 mg/kg/d in cycle 1. The “step dosing” approach appears to be a well-tolerated, alternative approach to the administration of GNS. Further details of safety and efficacy will be presented.