Thalidomide (T) in Combination with Fludarabine (F) as Initial Therapy for Patients (pts) with Treatment Naïve Chronic Lymphocytic Leukemia (CLL): Preliminary Results of a Phase I/II Clinical Trial.

Introduction: The importance of VEGF and TNF-a and their interaction with other cytokines in the pathogenesis of CLL has recently been identified. These cytokines in the tumor microenvironment (ME) form a network of growth promoting signal(s) that regulate the CLL cell survival and progression. T is an immunomodulatory agent, reported to exert antitumor activity through down regulation of VEGF, TNF-a and IL-6. We hypothesized that targeting the tumor ME with T will interrupt the growth promoting signals and predispose CLL cells to enhanced proapoptotic activity of F with resultant improvement of clinical responses. In this abstract we report our findings to date of this phase I/II clinical trial.

Patients and Methods: Treatment naïve pts requiring therapy for CLL were eligible for this study. T was started at D1 and continued for 6 months while F (25mg/m² x 5 D every 4 wks) was given for 6 cycles starting on D7. Three doses of T (100,200,300 mg) were studied in phase I and as no dose response curve or DLT was noted, 200mg of T was selected for the phase II evaluation for concerns of cumulative toxicity of T. Low-dose coumadin (1 or 2 mg) was used for prophylaxis of venous thromboembolism (VTE).

Results: To date 20 pts (15M, 5F; median age 66, range 38–76 yrs) have been enrolled. Of these 11 pts had limited (0-II) stage and 9 pts had advance Rai stage (III/IV) disease. Pts who completed the intended 6 months of T were evaluable for response. Six pts were removed from study for toxicity (2VTE - 1 in the 1st week of therapy prior to F infusion, 2^nd during the 4^th cyc; 1 Hep C reactivation presumably secondary to F, 1 secondary to early death from advance disease, 1 non-compliance, and 1 early termination for poor tolerance to therapy), without evidence of disease progression. Thirteen pts completed 6 months of therapy and are available for response. Among the evaluable pts 9 (69.2 %) achieved a complete response (CR) and 4(30.7%) were noted to have a partial remission (PR). While all pts who completed 6 months of T achieved a major response, the ORR in the intent-to-treat population was 65% with median duration of response 12+ (range 3 – 18+) months. Fatigue, thrombocytopenia, and anemia were the most common side effects, noted in 75%, 65%, and 55% of the 20 patients, respectively.

Conclusion: T when combined with F results in a higher ORR when compared to F alone based on historical data. The combination FT was well tolerated with manageable toxicity. Completion of this ongoing phase II study will identify the role of this new combination in pts with CLL.