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The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous with some patients requiring early therapy whereas others will not be treated for years. The evaluation of an individual CLL patient's prognosis remains a problematic issue. The presence or absence of somatic mutations in the IgVH genes is currently the gold-standard prognostic factor, but this technique is labor intensive and costly. Genomic studies uncovered that 70 kDa zeta-associated protein (ZAP-70) expression was associated with unmutated IgVH genes and ZAP-70 protein expression was proposed as a surrogate for somatic mutational status. Among the available techniques for ZAP-70 detection, flow cytometry is most preferable as it allows the simultaneous quantification of ZAP-70 protein expression levels in CLL cells

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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/m2 i.v. d1–3 and C 250 mg/m2 i.v. d1–3; q 28 days) or FC plus R (N=408; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 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<0.0001). PFS was 76.6% at 2 years in the FCR arm and 62.3% in the FC arm (p<0.0001). There was a trend for an increased OS rate in the FCR arm (91% vs 88% at 2 years p=0.18). Hazard Ratio for PFS was 0.59, for OS 0.76. The largest benefit for FCR was observed in Binet stage A and B with regard to CR, ORR and PFS (A: p=0.01, B: p<0.0001). FCR treatment was more frequently associated with CTC grade 3 and 4 adverse events (47% of FC vs 62% of FCR treated pts). Severe hematologic toxicity occurred in 55% (FCR) versus 39% (FC) of all patients. Significant differences were observed for neutropenia (FCR 33,6%; FC 20,9% p=0.0001) and leukocytopenia (FCR 24%; FC 12,1% p<0.0001) but not for thrombocytopenia (FCR 7,4%; FC 10,8% p=0.09) and anemia (FCR: 5,4% FC 6,8% p=0.42). The incidence of CTC grade 3 or 4 infections was not significantly increased in the FCR arm (18,8% versus 14,8% in the FC arm, p=0.68). Tumor lysis syndrome (FCR 0,2% FC 0,5%) and cytokine release syndrome (FCR 0,2% FC 0,0%) were rarely observed in both arms. Treatment related mortality occurred in 2.0% in the FCR and 1.5% in the FC arm. Multivariate analyses were performed to evaluate factors predicting outcome. Amongst these variables age, sex, Binet stage, CIRS score, renal function (cr cl < 70 ml/min) were independent prognostic factors predicting OS or PFS. 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.

535 Introduction: In 2008, first results of a multicenter, international randomized phase III trial (CLL8) were presented, showing superiority of FCR chemoimmunotherapy for response rates and progression-free survival (PFS) when compared to FC chemotherapy. We now report updated results with a longer median observation time of 37.7 months (mo). Methods and Patients: 817 treatment-naïve patients (pts) with good physical fitness and CD20-positive CLL randomly (1:1) received treatment with 6 courses of either FCR or FC therapy. Both treatment arms were well balanced with regard to sex, age, stage, genomic aberrations and IGVH gene status. The median age was 61 years (range 30 to 81), 25.7% pts were female in both arms, 64.1% were Binet B, 31% Binet C and 4.9% Binet A. The median cumulative illness rating scale (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. A mean number of 5.2 treatment courses were delivered in the FCR arm vs 4.8 courses in the FC arm (p=0.006). Dose reductions by more than 10% in at least one treatment course were performed in 47% (FCR) and 27% (FC) of pts (p<0.001), respectively. 74% (FCR) and 67% (FC) of pts received 6 cycles (p=0.02). The total median cumulative dose applied per pt was 775 mg for F and 7712 mg for C, with no statistically significant difference among the two treatment arms. Pts in Binet stages A and B received more treatment cycles (5.31) than Binet C pts (4.52; p<0.001). Only 57.1% (FC) and 60.3% (FCR) Binet C pts received 6 cycles. Dose reductions by more than 10% were observed in 49% of FCR pts (vs 28% FC (p=0.001). Results: As of June 2009, the median observation time was 37.7 (mo). 761 pts (FCR 388; FC 371) were evaluable for response, 790 pts (FCR 401; FC 389) for PFS and all for OS. FCR induced a higher overall response rate than FC (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p<0.001). Median PFS was 32.8 mo for FC and 51.8 mo for FCR pts (p<0.001, Hazard Ratio (HR) 0.56, CI 95% 0.460-0.689). The largest benefit for FCR was observed in Binet stage A and B for CR, ORR and PFS (Binet A: p=0.08, HR 0.423 CI 95%, 0.157-1.135, Binet B: p<0.001 HR: 0.504 CI 95%, 0.390-0.651, Binet C: p=0.08, HR 0.732 CI 95%, 0.514-1.041). In Binet C, the median PFS was 14 mo for pts treated with up to 3 courses FC, but 44 mo for pts that received 4 courses or more (p<0.001). Median PFS for pts treated with up to 3 cycles FCR was 12.5 mo, while for pts with 4 cycles or more, median PFS has not been reached (p<0.001). Statistically significant differences were observed in OS between the two treatment arms. The OS rate at 37.7 mo was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01). In both arms, the median OS has not been reached. Only patients in Binet stages A and B showed a superior OS after FCR treatment (Binet A: HR 0.19, CI 95%, 0.023-1.613 p=0.09; Binet B: HR 0.45, CI 95%, 0.296-0.689, p<0.001; Binet C HR1.4, CI 95%, 0.843-2.620, p=0.168). As previously reported more hematologic adverse events, particularly neutropenia, were observed with FCR treatment, but this did not result in an increased infection rate. More deaths have occurred in the FC arm (86/396, 21.7%) than in the FCR arm (65/404, 16.1%). In the majority of cases, the underlying cause of death was progressive disease (FC 48/86, FCR 33/65), secondary malignancies (FC 13/86, FCR 5/65) or unrelated causes of death such as myocardial infarction (FC 15/86, FCR 17/65). Treatment related mortality occurred in 8 (2.0%) of pts in each arm. Of these, 7 FC-treated pts and 5 FCR-treated pts died from infections related to treatment. In 7 pts (3 FC vs. 4 FCR), treatment was discontinued before the third treatment course due to fatal toxicity. Multivariate analysis was performed to evaluate factors predicting outcome. Age, sex, FCR-treatment, response, number of cycles (0-3), 17p-deletion, increased serum levels of thymidine kinase and β2-microglobulin and unmutated IGVH genes were independent prognostic factors predicting OS or PFS. Conclusion: Treatment with FCR chemoimmunotherapy is more effective than FC chemotherapy. The partial failure to demonstrate a benefit for FCR in Binet stage C patients may be related to an insufficient treatment intensity in these patients with higher tumor load. To our knowledge, this is the first time that a randomized trial is able to demonstrate that a specific first-line treatment for CLL results in an improved overall survival. The results corroborate the recommendation to use FCR as standard therapy in physically fit pts with CLL requiring therapy. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding. Fingerle-Rowson:Roche: Honoraria, travel grants. Fink:Roche: Travel grants. Mayer:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy; Fresenius: Consultancy; Roche: Research Funding; Pfizer: Research Funding. Hensel:Roche: Honoraria, Travel Grants; Bayer: Honoraria. Hopfinger:Roche: Membership on an entity's Board of Directors or advisory committees. Hess:Roche: Honoraria. Bergmann:Roche: Honoraria for monitoring and CRFs. Catalano:Roche: Honoraria, Research Funding, Travel grants. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Berrebi:Roche: travel grants. Jaeger:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants. Trneny:Roche: Honoraria, Research Funding. Westermann:Roche: Travel Grants. Wendtner:Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Eichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Staib:Roche: Research Funding. Boettcher:Roche: Honoraria, Research Funding, Travel grants. Ritgen:Roche: Research Funding. Mendila:Roche: Employment. Kneba:Roche: Honoraria, Research Funding. Doehner:Roche: Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding, travel grants. Fischer:Mundipharma: Research Funding; Roche: travel grants.