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CLL7

Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia

Phase 3N = 800NCT00275054

Population
Untreated Binet stage A CLL with two or more of four risk features (randomised high-risk patients, n=201)
Design
Randomised prospective phase 3 study, conducted collaboratively by the German CLL Study Group and the French Cooperative Group on CLL. 800 patients with untreated Binet stage A CLL were enrolled as the intention-to-treat population and assessed for four prognostic markers (lymphocyte doubling time under 12 months, serum thymidine kinase above 10 U/L, unmutated IGHV, unfavourable cytogenetics). The 201 patients with two or more risk features (high risk) were randomised 1:1 to immediate 6xFCR or observation. Primary endpoint event-free survival, with progression, treatment or death counted as events (full text). The ClinicalTrials.gov record lists 825 enrolled.
Primary endpoint
EFS
Arms
  • Early FCR (Hi-FCR) (experimental, n = 100): Six cycles of fludarabine, cyclophosphamide and rituximab
  • Watch and wait (Hi-W&W) (control, n = 101): Observation according to standard of care
People
Herling CD, German CLL Study Group and French Cooperative Group on CLL
EFSHR 0.22 (95% CI 0.15–0.33)Δ 60-month OS+3 points
Show the numbers
Results reported for CLL7
EndpointAnalysisEarly FCR (Hi-FCR)Watch and wait (Hi-W&W)Effect
EFSHigh-risk randomised patients (n=201)primarymedian follow-up 55.6 monthsHerling 2020—median 18.5 monthsHR 0.22 (95% CI 0.15–0.33)P<0.001Primary endpoint. Events were progression, treatment or death. Median EFS not reached in the early-FCR arm; 36 of 100 (36.0%) early-FCR and 83 of 101 (82.2%) observation patients had an event. Hazard ratio is for early FCR vs observation (stratified and non-stratified log-rank P<0.001). Median observation time 55.6 months (range 0-99.2). Overall response rate after early FCR 92.7%.
OSHigh-risk randomised patients (n=201)primarymedian follow-up 55.6 monthsHerling 202082.9% at 5 y79.9% at 5 yP=0.8645-year overall survival; no significant overall survival benefit.
Results reported for CLL7
EndpointAnalysisEarly FCR (Hi-FCR)Watch and wait (Hi-W&W)Effect
EFSHigh-risk randomised patients (n=201)primarymedian follow-up 55.6 monthsHerling 2020—median 18.5 monthsHR 0.22 (95% CI 0.15–0.33)P<0.001Primary endpoint. Events were progression, treatment or death. Median EFS not reached in the early-FCR arm; 36 of 100 (36.0%) early-FCR and 83 of 101 (82.2%) observation patients had an event. Hazard ratio is for early FCR vs observation (stratified and non-stratified log-rank P<0.001). Median observation time 55.6 months (range 0-99.2). Overall response rate after early FCR 92.7%.
OSHigh-risk randomised patients (n=201)primarymedian follow-up 55.6 monthsHerling 202082.9% at 5 y79.9% at 5 yP=0.8645-year overall survival; no significant overall survival benefit.
Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.
EFS0.512◀ experimentalcontrol ▶
Data table
EndpointHR95% CI
EFS0.220.15–0.33
Illustrative — modelled from reported values, not trial data. EFS, primary.
0%25%50%75%100%010203040Months (modelled)
  • Watch and wait (Hi-W&W) (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsWatch and wait (Hi-W&W)
0100.0%
1263.8%
2342.2%
3526.9%
4617.8%
Primary publication: Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P, et al. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020;34(8):2038-2050. PubMedDOI

Appears in

Sources

  1. Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P, et al. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020;34(8):2038-2050.

    PubMedDOI