A Randomized, Multicenter Study (PALG CLL4/ ML 21283) Of Maintenance Treatment With Rituximab Versus Observation After Induction Treatment With Rituximab, Cladribine, and Cyclophosphamide (RCC) Regimen In Patients With Progressive Chronic Lymphocytic Leukemia: Interim Analysis

RFC (rituximab, fludarabine, cyclophosphamide) regimen showed extraordinary clinical activity in untreated CLL patients, with high rates of overall response (ORR), complete remission (CR), progression-free survival (PFS) and prolonged overall survival (OS). Recent reports suggest also high activity of rituximab combination with cladribine, and cyclophosphamide (RCC regimen) in previously treated CLL patients. The use of rituximab maintenance after induction treatment may prolong response duration in patients with CLL. The aim of current multicenter, open-label, randomized, two arm phase III b PALG CLL4/ ML 21283 study was to assess the effect of maintenance treatment with rituximab vs. no further treatment, after induction therapy with RCC regimen in previously untreated patients with progressive CLL. The initial induction treatment included rituximab 500mg/m² on day 1 (375 mg/m² the first cycle), cladribine (2-CdA) 0,12 mg/kg/day i.v.- days 2-4, cyclophosphamide 250mg/m² on days 2 to 4, for six cycles. After response assessment was performed 8 weeks after last induction cycle, patients who obtained a CR or a PR were randomized 1:1 to either rituximab maintenance or observation. Rituximab maintenance was started 12 weeks after the last induction cycle and included 8 doses of rituximab at 375 mg/m² i.v., given in 12 weeks intervals. Six centers entered a total of 128 patients to the study. Baseline demographics, disease characteristics, and prognostic factors were balanced between the two arms. Median patient age was 58 (range 31-74) years, and 37% of patients had advanced CLL stage (3 or 4 according to Rai classification). Following induction phase 22.6% of patients obtained CR, 51.6% of patients had PR while the remainder did not respond to RCC therapy rates. Median PFS in the total study population reached 36 months. In terms of safety and tolerability during induction with RCC regimen grade 3-4 neutropenia developed in 64.8% of patients and major infections were reported in 7.8%. Grade 3-4 thrombocytopenia in 10.94% and anemia 10.16% of patients were noted. During second maintenance/observation phase of the study in grade 3-4 adverse events were observed in 16 (48.5%) patients receiving maintenance with rituximab and in 9 (27.3%) patients in observation arm, p= 0.076. Grade 3-4 neutropenia and febrile neutropenia was significantly more common in maintenance arm (36%) than in observation arm (9%) (p=0.017). However, there was no significant difference regarding the rate of major grade 3-4 infections that were reported in 3% of patients in the maintenance arm as compared to 12% of patients in observation arm (p=0.36). Grade 3-4 thrombocytopenia or anemia were observed in 6% vs 0% (p=0.49) and 0% vs 3% (p=1.0) of patients, in maintenance and observation arm, respectively. In conclusion, early analysis of this study shows moderate toxicity of maintenance with rituximab in patients who achieved response after rituximab-based immunochemotherapy. Although severe neutropenia is more common in patients receiving rituximab immunotherapy as maintenance treatment in CLL this seems not to be followed by increased rate of major infections.