Guest guest Posted December 12, 2008 Report Share Posted December 12, 2008 Immunochemotherapy with Fludarabine (F), Cyclophosphamide ©, and Rituximab ® (FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL) n = 817 pts with good physical fitness - median CIRS score was 1 (range 0-8), median age was 61 years (range 30 to 81), 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. http://ash.confex.com/ash/2008/webprogram/Paper9237.html Monday, December 8, 2008: 11:00 AM 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) ³ 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). [Comment: Suggesting that lower disease burden (Binet A and was associated with higher CR rate, overall response rate, and longer progression free survival. ] 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. Halls B and C (Moscone Center) Hallek, MD1, Guenter Fingerle-Rowson, MD, PhD1*, - Fink, MD1*, e Busch2*, Jiri Mayer, MD3*, Manfred Hensel, MD4*, Georg Hopfinger, MD5*, Georg Hess, MD6*, Ulrich von Gruenhagen, MD7*, a A. Bergmann, MD8, Catalano, MD9, Pier Luigi Zinzani, MD10*, Federico Caligaris Cappio, MD11*, Francis Seymour, MBBS12, Alain Berrebi, MD13*, Ulrich Jaeger, MD14, Bruno Cazin, MD15*, Marek Trneny, MD, PhD16, Anne Westermann1*, Clemens- Wendtner, MD1, Barbara F. Eichhorst, MD1, Staib, MD17*, Sebastian Boettcher, MD18*, Matthias Ritgen, MD19*, Stephan Stilgenbauer, MD20, Myriam Mendila, MD21*, Kneba, MD, PhD19, Hartmut Döhner, MD20* and Kirsten Fischer, MD1* 1Department I of Internal Medicine, University of Cologne, Cologne, Germany 2Technical University, Institute for Medical Statistic and Epidemiology, Munich, Germany 3Hematology/Oncology, Masaryk University Hospital, Brno, Czech Republic 4University of Heidelberg, Mannheim, Germany 5Department of Medicine III, Hanusch Hospital, Vienna, Austria 6Johannes Gutenberg-Universität, Mainz, Germany 7Praxis für Hämatologie/Onkologie, Cottbus, Germany 8Hem./Onc., Univ. Hosp. Munich, Muenchen, Germany 9Dorevitch Pathology Laboratory, ston Hospital, ston, VIC, Australia 10Department of Hematology/Oncology, University of Bologna, Bologna, Italy 11Ospedale San Raffaele, Milano, Italy 12 MacCallum Cancer Institute, Richmond, Australia 13Kaplan Medical Center, Rehovot, Israel 14Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria 15Service des Maladies du Sang, Hopital Claude Huriez, Lille, France 16First Dept. of Medicine, Univ. General Hosp., Prague, Czech Republic 17Klinik für Hämatologie und Onkologie, St.-Antonius Hospital, Eschweiler, Germany 18Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany 19Department of Internal Medicine II, University Hospital, Kiel, Germany 20Internal Medicine III, University of Ulm, Ulm, Germany 21Pharmaceuticals Division, F. 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