mmunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with Advanced Chronic Ly

Introduction: Previous phase II studies have suggested that a combination of FCR may increase the outcome of both untreated and relapsed CLL pts. In order to validate this concept the German CLL study group (GCLLSG) initiated a multicentre, multinational phase III trial, CLL8, to evaluate the efficacy and tolerability of FCR versus FC for the first-line treatment of pts with advanced CLL. Methods and Patients: 817 pts with good physical fitness as defined by a cumulative illness rating scale (CIRS) score (Extermann et al., JCO 1998) of up to 6 and a creatinine clearance (cr cl) □d 70 ml/min were enrolled between July 2003 and March 2006. Pts were randomly assigned to receive 6 courses of either FC (N=409; F 25mg/m 2 i.v. d1–3 and C 250 mg/m 2 i.v. d1–3; q 28 days) or FC plus R (N=408; 375 mg/m 2 i.v. d 0 at first cycle and 500 mg/m 2 d1 all subsequent cycles; q 28 days). Both treatment arms were well balanced with regard to age, stage, genomic aberrations and VH status. 64% were Binet B, 32% Binet C and 5% Binet A. The median age was 61 years (range 30 to 81), the median CIRS score was 1 (range 0–8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively, with no statistically significant differences between treatment arms. A mean number of 5.2 courses was given in the FCR arm versus 4.8 courses in the FC arm (p=0.006). 74% (FCR) and 67% (FC) of pts received 6 cycles. Dose was reduced by more than 10% in at least one treatment course in 43% (FCR) and 30% (FC) of pts, and in 21% (FCR) and 17% (FC) of all treatment courses given. 17 pts did not receive any study medication, 10 due to violation of enrolment criteria (4 decreased renal function, 2 active secondary malignancies, 2 active infections, 1 autoimmune thrombocytopenia, 1 pt not requiring treatment), 3 due to withdrawal of consent, 2 due to worsened concomitant diseases. 2 pts were lost before start of treatment. 56 pts were not evaluable for response: 17 did not receive any study medication, 16 withdrew consent before interim staging, 7 due to violation of enrolment criteria, 4 discontinued treatment due to toxicity and 12 due to early death (caused by toxicity, progression or secondary malignancy). Prophylactic use of antibiotics or growth factors was not generally recommended in the protocol. Results: At the time of analysis, June 2008, the median observation time was 25.5 months (mo). 761 pts (FCR 390; FC 371) were evaluable for response, 787 pts (FCR 400; FC 387) for PFS and all for OS. The overall response rate (ORR) was significantly higher in the FCR arm (95%; 370/390) compared to FC (88%; 328/371 (p=0.001). The complete response rate of the FCR arm was 52% as compared to 27.0% in the FC arm (p Conclusion: Treatment with FCR chemoimmunotherapy improves response rates and PFS when compared to the FC chemotherapy. FCR caused more neutropenia/leukopenia without increasing the incidence of severe infections. These results suggest that FCR chemoimmunotherapy might become the new standard first-line treatment for physically fit CLL patients.