The efficacy of oral fludarabine (FLU) does not differ from the intravenous formulation and its safety profile is similar in previously treated CLL. A synergistic effect of cyclophosphamide (CY) with FLU has been demonstrated in vitro and in vivo. Based on this scientific background, we are conducting a multicenter, uncontrolled, open-label phase II clinical trial to evaluate the efficacy and safety of the combination of oral FLU and CY, as front line therapy in CLL. Oral FLU is administered at 30mg/m2/d and oral CY at 200mg/m2/d, days 1 through 5, repeated every 28 days for 6 courses. Efficacy endpoints include overall response rate (according to NCI criteria), minimal residual disease assessment, duration of response, time to treatment failure and treatment free interval. Response evaluation is performed 2 months after the end of treatment and confirmed 3 months after. Enrollment is closed with 76 pts since Feb. 2001. We are presenting data from the fourth and last intermediate analysis on 75 pts, who received treatment. Pts characteristics included median age of 54 (37-66); 62 male, 13 female; 59 Binet stage B and 16 stage C, no previous treatment. A mean of 5.3 cycles (1-6) was administered. Response was assessed on 75pts: 37 CR (49.3%), 4 nodularPR (5.3%), 19 PR (25.3%), 6 SD (8%), 9 failure (12%) including 2 PD (2.6%) of which 1 Richter's syndrome, 1 unexplained early death after cycle 1, 1death in neutropenia after 5 cycles, 4 pts withdrawn for toxicity, before cycle 3, 1 unevaluable according to NCI criteria. 2 pts died during follow up (1SD of Richter's syndrome at months 21, 1 CR of neuroendocrine carcinoma of the liver at month 19). Safety data were evaluated on 401 cycles in 75 pts. The toxicity was mainly hematological: NCI gr 3/4 lymphopenia (79% of the cycles), neutropenia (52%), anemia (3%) and thrombocytopenia (6%). We observed 7 (9.3% of the pts) hemolytic anemia of which 5 considered as autoimmune. Peripheral thrombocytopenia was observed in 3 cases. 91% of cycles were administered without delay and 97% at full dose. Herpes zoster and PCP prophylaxis were recommended. Infection was not a major concern since only 3 gr 3/4 infections were registered. 13% of the cycles were complicated by gr 1/2 infection. However, 1 case of PCP occurred 4 months after the end of treatment and prophylaxis, 1 pulmonary aspergillosis was observed in the follow up. GI toxicity was mild : 75% of the pts experienced gr 1/2 nausea (7% gr 3/4), 37% gr 1/2 vomiting ( 3% gr 3/4). Only 1 pt stopped the treatment because of GI toxicity. In conclusion, this analysis suggests that this oral combination treatment is a promising front-line therapy in CLL, with 80% overall response rate. Centralized flow cytometry in blood and study of molecular response by clonal specific PCR are presently on evaluation.
Full conference title:
Amerian Society of Hematology Annual Meeting
- ASH 44th (2002)