CALBG 9712

Methods	Randomisation: RCT with 2 arms: arm 1 (sequential): 6 monthly courses of fludarabine alone followed 2 months later by rituximab consolidation therapy versus arm 2 (concurrent): 6 monthly courses of Flu‐R followed 2 months later by 4 weekly doses of rituximab for consolidation therapy Recruitment period: from January 1998 to January 2000 Median follow‐up time: 23 months (range not provided)
Participants	Eligibility: Inclusion criteria: histologically and immunophenotypically documented CLL either Rai stage III/IV disease or required therapy for Rai stage I/II disease no prior therapy for CLL age: older than 17 years CALGB performance status of ≤ 3 Exclusion criteria: patients with bright expression of surface immunoglobulin Patients recruited (N = 104): sequential (N = 53): all patients were analysed concurrent (N = 51): all patients were analysed Mean age: sequential: 63 years (range: 36‐79 years) concurrent: 63 years (range 36‐86 years) Gender (male, female): sequential: 34%, 19% concurrent: 24%, 27% Stage of disease (Rai stage group): stage I‐II (intermediate risk): sequential: 58%; concurrent: 61% stage III‐IV (high risk): sequential: 42%; concurrent: 39% Country: US, multicentre trial with 26 principal investigators
Interventions	Arm 1: sequential, 6 cycles, every 28 days: fludarabine (25 mg/m2 IV daily, 1 to 5 cycles) after 2 months of observation patients with stable disease or better were then treated with 4 weekly doses of rituximab (375 mg/m2) Arm 2: concurrent, 6 cycles, every 28 days: fludarabine (25 mg/m2 IV daily, 1 to 5 cycles) rituximab (375 mg/m2, on days 1 and 4 of cycle 1 of fludarabine therapy ‐ 2 doses of rituximab were administered to the first 44 patients with the first cycle to ensure adequate saturation of CD20‐binding sites; a single dose of rituximab was then administered on day 1 of cycles 2, 3, 4, 5 and 6. Modification: the stepped‐up dosing improved tolerability of rituximab, so the schedule of administration was modified for the last 7 patients: day 1 of the first cycle rituximab (50 mg/m2) IV without rate escalation, day 3: rituximab (325 mg/m2) IV at 50 mg/h, and then infusion rate was escalated in 50 mg/h to a maximum of 400 mg/h; day 5 and during all subsequent cycles of fludarabine: rituximab (375 mg/m2) started at 100 mg/h and the rate was increased to entire dose, rituximab with this same 1‐hour dosing on day 1 of cycles 2 to 6) after 2 months of observation patients with stable disease or better were then treated with 4 weekly doses of rituximab (375 mg/m2) Additional therapy: all patients received allopurinol (300 mg orally) for the first 14 days and antiemetics (not specified, but could not include corticosteroids) at 30 minutes prior to all rituximab doses, paracetamol (acetaminophen) (650 mg) and diphenhydramine (50 mg IV) were administered
Outcomes	Outcomes and time points from the study that are considered in the review: reported: OS PFS CRR ORR AEs not reported: time to next treatment TRM MRD Number of patients discontinuing the study because of drug‐related AEs
Notes	The research for CALGB 9712 was supported, in part, by grants from the NCI (CA31946) to the CALGB. A table of these grants is provided in the article
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "patients were randomly assigned" 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	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 for analyses
Selective reporting (reporting bias)	Unclear risk	Comment: protocol is registered (ClinicalTrials.gov: NCT00003248), but outcomes for assessment were not stated
Other bias	Unclear risk	Not reported