GCLLSG CLL 8

Methods	Randomisation: RCT with 2 arms: FluC‐R versus FluC Recruitment period: from July 2003 to March 2006. Median follow‐up time: not provided (assessment at 3 years after randomisation)
Participants	Eligibility criteria: ≥ 18 years diagnosed B‐cell CLL defined by the NCI Working Group criteria ECOG performance status 0 to 1 CIRS score > 6 life expectancy > 6 months Binet stage C disease or Binet stage B disease (plus symptoms) Patients recruited (N = 817): FluC‐R: N = 408 (4 did not receive study drugs, 20 without response assessment, 7 lost to follow‐up) FluC: N = 409 (13 did not receive study drugs, 38 without response assessment, 20 lost to follow‐up) Mean age: FluC‐R: 61 years (range: 30 to 80 years) FluC: 61 years (range: 36 to 81 years) Gender (male, female): FluC‐R: N = 303, N = 105 FluC: N = 304, N = 105 Stages of disease: FluC‐R: Binet A 4%, Binet B 64%, Binet C 31% FluC: Binet A 5%, Binet B 63%, Binet C 31% Country: 190 centres in 11 countries
Interventions	Arm 1: FluC‐R, 6 cycles, every 28 days: fludarabine (25 mg/m2 IV daily, 1 to 5 cycles) cyclophosphamide (250 mg/m2 per day, for the first 3 days) rituximab (375 mg/m2 on day 0 of the first course, and 500 mg/m2 on day 1 of the second to sixth courses) Arm 2: FluC, 6 cycles, every 28 days: fludarabine (25 mg/m2 IV daily, 1 to 5 cycles) cyclophosphamide (250 mg/m2 per day, for the first 3 days) Additional therapy: prophylaxis of pneumonia caused by Pneumocystis was recommended for severe leukocytopenia that lasted for more than 7 days prophylaxis with antiviral drugs or granulocyte‐colony stimulating factor were not recommended in this study
Outcomes	Outcomes and time points from the study that are considered in the review: reported: OS PFS time to next treatment CRR ORR TRM AEs number of patients discontinuing the study because of drug‐related AEs not reported: MRD
Notes	The trial was funded by Hoffmann‐La Roche
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomly assigned" Quote: "using a randomisation list that was computer generated"
Allocation concealment (selection bias)	Low risk	Quote: "assignment to treatment was done centrally at the Institute for Medical Statistics and Epidemiology, Technical University of Munich"
Blinding (performance bias and detection bias) Overall survival	Low risk	Comment: the review authors judge that the outcome OS in this unblinded trial is unlikely to be influenced by lack of blinding
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Quote: "investigators and patients were not masked to the treatment assignment" Comment: patient and physician unblinded. No information about blinding of outcome assessor provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: all patients were assessed in the analyses. The small number of missing outcome data were balanced in numbers across intervention groups, with similar reasons for missing data across groups (i.e. FluC‐R, 4 did not receive study drugs, 20 without response assessment, 7 lost to follow‐up; FluC: 13 did not receive study drugs, 38 without response assessment, 20 lost to follow‐up)
Selective reporting (reporting bias)	Low risk	Comment: protocol is registered (ClinicalTrials.gov: NCT00281918) Pre‐planned outcomes (relevant for the review) that were reported: OS PFS time to next treatment CRR ORR Pre‐planned outcomes (relevant for the review) that were not reported: none Reported outcomes that were not predefined in the protocol: TRM AEs number of patients discontinuing the study because of drug‐related AEs
Other bias	Unclear risk	No information provided