New Orleans—Combination fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy offers better event-free survival (EFS) to patients with high-risk, early-stage chronic lymphocytic leukemia (CLL), according to a first report from a randomized phase 3 trial end point and safety analysis presented at the 55th American Society of Hematology Annual Meeting and Exposition. 

“This is the first randomized phase 3 trial investigating the efficacy of FCR chemoimmunotherapy in early stage CLL,” reported a team of researchers led by Carmen D. Schweighofer, MD, of the Center of Integrated Oncology at Cologne-Bonn, University of Cologne, Cologne, Germany, and coauthors.

“So far, the study has revealed two major results: A combination of clinical and biological factors can be used to identify [patients with] early-stage CLL who experience a rapid disease progression with unfavorable outcome, [and] FCR chemoimmunotherapy substantially improves EFS in early-stage high-risk CLL.”

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No overall survival (OS) benefit was found.

FCR is already recognized to improve outcomes among patients with advanced CLL, the coauthors reported. But because monochemotherapies have not been shown to benefit patients with asymptomatic early-stage CLL, a “watch-and-wait” approach has long been the norm for these patients.

To compare FCR to watch-and-wait (deferred treatment), the researchers stratified 800 enrolled patients in Germany and France by risk status (25% were stratified as high-risk) between the years of 2005 and 2010. All enrolled patients had been diagnosed with CLL within 12 months, presenting with previously untreated stage Binet A CLL.

“Risk assessment was performed using four prognostic markers: lymphocyte doubling time [less than] 12 months, serum thymidine kinase [greater than] 10 U/L, unmutated immunoglobulin heavy chain variable region gene (IGHV) status, and presence of unfavorable cytogenetics (del11q, del17p, trisomy 12) by fluorescence-in-situ hybridization,” the coauthors reported. “Presence of at least two versus less than two of these factors defined ‘high-risk’ versus ‘low-risk’ CLL.”

High-risk patients with CLL were randomly assigned to receive six cycles FCR (n=100) or watch-and-wait (n=101). A total of 82 treated patients in the FCR arm completed four or more cycles of treatment; 18 patients had withdrawn from the study prior to treatment initiation.

“The most common of 228 [Common Toxicity Criteria] grade 3/4 adverse events reported within 12 months after treatment initiation were hematotoxicity (73.2% of patients) and infections (19.5% of patients),” the team reported.

Three patients died; two died of septic bacteremia (one of whom had pulmonary aspergillosis), and one patient died of encephalitis.

“Out of 79 patients available for response assessment until month 12 after treatment start, 76 showed a complete or partial remission (overall response rate [ORR], 96.2%), two patients had stable disease (2.5%) and one patient had progressed (1.3%).”

At a median follow-up of 49 months, patients receiving FCR “demonstrated a significantly improved EFS compared to watch-and-wait patients (median EFS not reached vs. 24.5 months, respectively, P < 0.0001),” the coauthors reported. Overall survival (OS) was not significantly different, however, and high-risk patients receiving FCR had significantly shorter EFS and OS than low-risk patients for whom treatment was deferred. The authors reported that this demonstrates “an efficient prognostic segregation of patients by risk assessment.”


  1. Schweighofer CD et al. Abstract #523. Presented at: American Society of Hematology Meeting 2013. Dec. 7-10, 2013; New Orleans.