The Combination of 2-CDA and Rituximab in Patients with Chronic Lymphocytic Leukemia (CLL): A Prospective Multicenter Phase II Trial (SAKK 34/02).

Introduction: This trial aimed to determine the efficacy and toxicity of an induction immunochemotherapy consisting of rituximab and cladribine (2-chlorodeoxyadenosine, 2-CDA) in patients (pts) suffering from chronic lymphocytic leukemia (CLL).

Methods: Inclusion criteria were CLL at first diagnosis or after one treatment with alkylating agents. The regimen consisted of four remission induction cycles. In cycle 1, 2-CDA (0.1 mg/kg/day) was administered for 5 days. In cycles 2-4, Rituximab (375 mg/m^2) was given on day 1 followed by 2-CDA (0.1 mg/kg body weight), in intervals of 28 days. Responding pts (complete remission (CR), very good partial remission (VGPR) or nodular partial remission (NPR)) underwent stem cell mobilization chemotherapy with Cyclophosphamide (4g/m^2 on day 2) G-CSF (10 microgram/kg s.c. daily, from day 4 on), and Rituximab (375 mg/m^2) on day 1 and 8 as in vivo purging. If no CR, VGPR or NPR was achieved, up to 4 cycles CHOP were administered. Primary endpoint was CR, secondary endpoints were VGPR, NPR and toxicity after induction and feasibility of stem cell mobilization. For response evaluation, staging procedures included clinical examination as well as bone marrow biopsies and CT-scans. A total of 41 pts was planned using Simon’s two-stage design with 5% significance and 80% power for the null hypothesis of CR rate < 25% and the alternative hypothesis of CR rate > 45%.

Results: 42 pts were included, median age 53.8 y (range 38 – 65), WHO performance status 0 in 33 pts and 1 in 9 pts, stage Binet B in 20 pts, Binet C in 8 pts and progressive A in 14 pts. 2 pts were not evaluable for response. 9 pts reached CR (22.5%, 95% CI: 11–38%). Overall response rate including 15 VGPR and 2 NPR was 65% (CI: 48–79%). Of the 14 non-responders, 8 underwent CHOP treatment of which 2 achieved VGPR. 20 patients underwent mobilization and 8 pts refused further protocol treatment. 14 pts had leucapheresis. Stem cell harvest was feasible in 7 pts, all with &#8805; 2×10^6 cells/kg. Fever and infection were reported respectively in 13 and 9 pts. Infusion related adverse events of Rituximab were moderate and occurred mainly after the first infusion. 42 of 158 cycles (27%) were associated with grade 3 or 4 neutropenia and 6 of 158 cycles (4%) with grade 3 thrombocytopenia.

Conclusions: Although the expected CR rate was not achieved, a combination of Rituximab and 2-CDA is an effective and well tolerated treatment.