Gene Signature to Identify Benefit of Front-Line Fludarabine, Cyclophosphamide, and Rituximab in IGHV-Unmutated CLL

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In a retrospective cohort study reported in The Lancet Oncology, Herling et al identified a 17-gene signature that distinguished patients with IGHV-unmutated chronic lymphocytic leukemia (CLL) more likely to achieve long-term remission after front-line chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR).

Study Details

The study included a discovery and training cohort of samples from 101 patients treated at The University of Texas MD Anderson Cancer Center who had received at least three cycles of FCR and had been treated between October 2000 and October 2006. Transcriptional profiling was performed to identify genes associated with time to progression. Significant genes were used to categorize patients into intermediate-prognosis and unfavorable-prognosis groups, and a minimum gene signature was identified. The signature was tested in a validation cohort of 109 treatment-naive patients with IGHV-unmutated disease from the CLL8 trial of the German Chronic Lymphocytic Leukaemia Study Group treated between July 2003 and April 2006.


  • A 17-gene signature was identified that distinguished lower and higher risk of progression after front-line FCR.
  • The cause-specific hazard ratio for progression was 1.90 for high- vs low-risk in the validation cohort.

Performance of Gene Signature

Investigation in the MD Anderson cohort resulted in identification of a 17-gene expression signature that distinguished IGHV-unmutated patients with intermediate risk vs unfavorable risk of disease progression following front-line FCR, with a cause-specific hazard ratio for progression of 3.83 (P < .0001). The 5-year cumulative incidence of progression was 25% in the intermediate-risk group vs 65% in the unfavorable-risk group.

Use of the 17-gene signature in the CLL8 validation cohort distinguished low-risk (intermediate-prognosis) from high-risk (unfavorable-prognosis) cases with a cause-specific hazard ratio of 1.90 (P = .008). The median time to progression was 59 months in the low-risk group vs 39 months in the high-risk group. The 5-year cumulative incidence of progression was 51% vs 69%.

The investigators concluded, “We have developed a robust, reproducible 17-gene signature that identifies a subset of treatment-naive patients with IGHV-unmutated CLL who might substantially benefit from treatment with FCR chemoimmunotherapy. We recommend testing the value of this gene signature in a prospective study that compares FCR treatment with newer alternative therapies as part of a randomized clinical trial.”

Lynne V. Abruzzo, MD, of the Department of Pathology, The Ohio State University, Columbus, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute. For full disclosures of the study authors, visit

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