REACH

Methods	Randomisation: RCT with 2 arms: arm 1: FluC‐R versus arm 2 FluCM Recruitment period: from July 2003 to August 2007 Median follow‐up time: 25 month (range: not reported)
Participants	Eligibility criteria: B‐CLL confirmed according to NCI Working Group criteria  minimum 1 lone treatment of the CLL age ≥ 18 expected survival > 6 months  Patients recruited (N = 571 screened, N = 552 assigned): FluC‐R: 276 patients (2 did not receive treatment, 87 discontinued treatment, 6 did not enter follow‐up phase, 131 withdrew from follow‐up) FluCM: 276 patients (4 did not receive treatment, 91 discontinued treatment, 14 did not enter follow up phase, 162 withdrew from follow up)  Mean age: FluC‐R: 63 years (range: 35 to 83 years) FluCM: 62 years (range: 36 to 81 years)  Gender (male, female): FluC‐R: 68%, 32% FluCM: 66%, 34%  Stage: Binet A: FluC‐R 24 (9%); FluCM 31 (11%) Binet B: FluC‐R 166 (60%); FluCM 160 (58%) Binet C: FluC‐R 86 (31%); FluCM 85 (31%) Country 87 centres in Australia, Canada, Europe , New Zealand and US
Interventions	Arm 1: FluC‐R, 6 cycles, every 28 days: fludarabine (25 mg/m2 PO, days 1 to 3) cyclophosphamide (250 mg/m2 PO, days 1 to 3) rituximab (375 mg/m2 on day 1 of the first course, and 500 mg/m2 on day 1 of the second to sixth courses) Arm 2: FluCM, 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) Additional therapy: pre‐medication (oral paracetamol (acetaminophen) and an antihistamine) supportive care as needed, including antibiotics, blood transfusions and haematopoietic growth factors prophylaxis for tumour lysis syndrome (including allopurinol or rasburicase) prophylactic antimicrobials (cotrimoxazole and acyclovir/valacyclovir)
Outcomes	Outcomes and time points from the study that are considered in the review: reported: OS PFS time to next treatment CRR ORR MRD TRM AEs number of patients discontinuing the study because of drug‐related AEs
Notes	The trial was funded by Hoffmann‐La Roche, Genentech, and Biogen Idec
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "phase III trial randomly assigned patients" 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: "multicenter, open‐label, phase III trial" 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: 2 did not receive treatment, 87 discontinued treatment, 6 did not enter follow‐up phase, 131 withdrew from follow‐up; FluCM: 4 did not receive treatment, 91 discontinued treatment, 14 did not enter follow‐up phase, 162 withdrew from follow‐up)
Selective reporting (reporting bias)	Low risk	Comment: protocol is registered (ClinicalTrials.gov: NCT00090051) Pre‐planned outcomes (relevant for the review) that were reported: OS PFS CRR ORR AEs number of patients discontinuing the study because of drug‐related AEs Pre‐planned outcomes (relevant for the review) that were not reported: none Not pre‐planned outcomes (relevant for the review) that were reported: MRD time to next treatment
Other bias	Unclear risk	No information provided