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. 2012 Nov 14;2012(11):CD008079. doi: 10.1002/14651858.CD008079.pub2

Wierda 2011

Methods Randomisation:

  • RCT with 2 arms: arm 1 FCO500: (fludarabine plus cyclophosphamide plus ofatumumab) (500 mg) versus arm 2 FCO1000 (fludarabine plus cyclophosphamide plus ofatumumab) (1000 mg)


Recruitment period:

  • not provided


Median follow‐up time:

  • 8 months (range: not reported)
Participants Eligibility criteria:

  • previously untreated patients

  • active CLL


Patients recruited (N = 67 screened, N = 61 assigned):

  • FCO500: 31 patients (9 discontinued treatment: cytopenias (N = 3), autoimmune haemolytic anaemia requiring treatment (N = 2), myocardial infarction (N = 1), non‐response (N = 2) or patient request (N = 1))

  • FCO1000: 30 patients (13 discontinued treatment: cytopenias (N = 7), autoimmune haemolytic anaemia requiring treatment (N = 1), non‐response (N = 1), chest discomfort (N = 1), patient request (N = 1), death (N = 1) or investigator's decision (N = 1))


 Mean age:

  • FCO500: 56 years (range: 38 to 73 years)

  • FCO1000: 56 years (range: 38 to 72 years)


 Gender (male, female):

  • FCO500: gender not provided

  • FCO1000: gender not provided


 Stage:

  • FCO500: Binet A or B 74%, Binet C 26%

  • FCO1000: Binet A or B 60%, Binet C 40%


Country:

  • Czech Republic, Germany, Lithuania, UK, US
Interventions Arm 1: FCO500, 6 cycles, every 4 weeks:

  • fludarabine (25 mg/m2 PO, days 1 to 3)

  • cyclophosphamide (250 mg/m2 PO, days 1 to 3)

  • ofatumumab (300 mg/m2 on day 1 of the first course, and 500 mg/m2 on day 1 of the second to sixth courses)


Arm 2: FCO1000, 6 cycles, every 28 days:

  • fludarabine (24 mg/m2 PO, days 1 to 5)

  • cyclophosphamide (150 mg/m2 PO, days 1 to 5)

  • ofatumumab (300 mg/m2 on day 1 of the first course, and 1000 mg/m2 on day 1 of the second to sixth courses)


Additional therapy:

  • pre‐medication was paracetamol (acetaminophen) 1000 mg and cetirizine 10 mg prior to each infusion

  • glucocorticoid (prednisolone 100 mg) prior to infusions 1 and 2

  • allopurinol, neutrophil growth factor and anti‐infective prophylaxis were permitted at the discretion of the investigator
Outcomes Outcomes and time points from the study that are considered in the review:

  • reported:

    • OS

    • time to next treatment

    • PFS

    • CRR

    • ORR

    • TRM

    • AEs


  • not reported:

    • MRD

    • number of patients discontinuing the study because of drug‐related AEs
Notes The trial was funded by GlaxoSmithKline
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Quote: "patients (...) were randomized to"
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 Unclear risk The study did report results regarding this outcome owing to the short time period of median follow‐up
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 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. FCO500: 9 discontinued treatment; FCO1000: 13 discontinued treatment)
Selective reporting (reporting bias) High risk Comment: protocol is registered (ClinicalTrials.gov: NCT00410163)
Pre‐planned outcomes (relevant for the review) that were reported:

  • PFS

  • CRR

  • ORR

  • AEs

  • time to next treatment


Pre‐planned outcomes (relevant for the review) that were not reported:

  • OS

  • MRD
Other bias Unclear risk No information provided

CALGB: Cancer and Leukemia Group B; Cam: alemtuzumab; CIRS: cumulative illness rating scale; CLL; chronic lymphocytic leukaemia: CRR: complete response rate; ECOG: Eastern Cooperative Oncology Group; FluC: fludarabine plus cyclophosphamide; FluCM: fludarabine plus cyclophosphamide plus mitoxantrone; FluCM‐R: fludarabine plus cyclophosphamide plus mitoxantrone plus rituximab; FluC‐R: fludarabine plus cyclophosphamide plus rituximab; Flu‐Cam: fludarabine plus alemtuzumab; FluC‐Cam: fludarabine plus cyclophosphamide plus alemtuzumab; FluC‐R: fludarabine plus cyclophosphamide plus rituximab; Flu‐R: fludarabine plus rituximab; IV: intravenous; MRD: minimal residual disease; NCI: National Cancer Institute; ORR: overall response rate; OS: overall survival; PFS: progression‐free survival; PO: per os; RCT: randomised controlled trial; SC: subcutaneous; TRM: treatment‐related mortality; WHO: World Health Organization.