NCRI‐CLL 201

Methods	Randomisation: RCT with 2 arms: arm 1 FluCM‐R versus arm 2 FluCM Recruitment period: from July 2005 to January 2007 Median follow‐up time: median follow‐up of 29 months (range 24 to 46 months)
Participants	Eligibility criteria: diagnosis of CLL requiring therapy previously treated with ≥ 1 chemotherapeutic regimen WHO performance status 0 to 2 life expectancy ≥ 12 weeks Patients recruited (N = 52): FluCM‐R: N = 26 (1 withdrew consent to participate, 0 withdrew consent for follow‐up, 12 stopped treatment early) FluCM: N = 26 (2 withdrew consent to participate, 1 withdrew consent for follow‐up, 14 stopped treatment early) Mean age: FluCM‐R: 66 years (range 44 to 79 years) FluCM: 68 years (range 32 to 79 years) Gender (male, female): FluCM‐R: 85%, 15% FluCM: 73%, 27% Stage: FluCM‐R: Binet A 15.4%, Binet B 42.3%, Binet C 38.5% FluCM: Binet A 19.2%, Binet B 15.4%, Binet C 61.5% Country: participating centres not stated
Interventions	Arm 1: FluCM‐R, 6 cycles, every 28 days: fludarabine (24 mg/m2 PO, days 1 to 5) cyclophosphamide (150 mg/m2 PO, days 1 to 5) mitoxantrone (6 mg/m2 IV on day 1) rituximab (375 mg/m2 on day 0 of the first course, and 500 mg/m2 on day 1 of the second to sixth courses. NOTE: dose of rituximab was originally 375 mg/m2 for all cycles, but the protocol was amended to increase the dose of rituximab to 500 mg/m2 for cycles 2 to 6. Three patients were treated prior to this amendment and received all cycles at 375 mg/m2) Arm 2: FluCM, 6 cycles, every 28 days: fludarabine (24 mg/m2 PO, day 1 to 5) cyclophosphamide (150 mg/m2 PO, day 1 to 5) mitoxantrone (6 mg/m2 IV on day 1) Additional therapy: no recommended additional treatment was stated
Outcomes	Outcomes and time points from the study that are considered in the review: reported: OS PFS CRR ORR MRD TRM AEs number of patients discontinuing the study because of drug‐related AEs not reported: time to next treatment
Notes	Roche Pharmaceuticals provided rituximab for the trial as well as an unrestricted grant to support the running of the trial
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "patients were randomized" Comment: the authors did not describe the method used to generate the allocation sequence
Allocation concealment (selection bias)	Unclear risk	No information provided
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: "multi‐centre, randomized, controlled, open, two‐stage, parallel group, Phase II trial" Quote: 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. FluCM‐R: 1 withdrew consent to participate, 0 withdrew consent for follow‐up, 12 stopped treatment early; FluCM: 2 withdrew consent to participate, 1 withdrew consent for follow‐up, 14 stopped treatment early)
Selective reporting (reporting bias)	Low risk	Comment: protocol is registered (ClinicalTrials.gov: NCT00337246) Pre‐planned outcomes (relevant for the review) that were reported: OS PFS CRR ORR MRD AEs TRM number of patients discontinuing the study because of drug‐related AEs Pre‐planned outcomes (relevant for the review) that were not reported: none
Other bias	Unclear risk	No information provided