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Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is the gold-standard regimen for physically fit patients with chronic lymphocytic leukemia (CLL). The regimen is brief and inexpensive and patients younger than 65 years, without comorbidities and with mutations in IGHV, usually achieve long-term durable remissions. On the contrary, patients older than 65 years, or with comorbidities, often cannot tolerate a full treatment course.
In this paper, Carmen D Herling, Department I of Internal Medicine, Center for Integrated Oncology, Aachen-Bonn-Cologne-Duesseldorf, Cologne, DE, and colleagues hypothesized that the duration of response to FCR chemoimmunotherapy depends on differences in the expression of protein-coding genes. Therefore, they developed and validated a 17-gene expression signature to identify patients that might achieve durable remissions following front-line FCR chemoimmunotherapy.
After the gene expression data analysis for the MDACC cohort, the authors identified 1,136 probes associated with time to progression. Using these probes, patients with similar gene expression patterns were divided into favorable, intermediate, and unfavorable prognosis subsets. The intermediate prognosis and unfavorable prognosis subset had a shorter time to progression compared with patients in the favorable subset.
Genes highly expressed in unfavorable cases (n= 424) were associated with metabolic pathways, including oxidative phosphorylation and ribonucleoside metabolism. Genes highly expressed in favorable or intermediate cases (n= 401) encoded products involved in ATP binding, purine ribonucleoside triphosphate binding, nucleic acid binding, and DNA-template transcription.
The authors developed a prognostic model with 17 genes to distinguish IGHV-unmutated patients that had an intermediate outcome from those with an unfavorable outcome after front-line FCR therapy. The development process included:
These 17 genes were validated in 109 patients with an IGHV-unmutated status from the CLL8 cohort. In this cohort, patients classified as high risk (unfavorable prognosis; median time to progression of 39 months [IQR, 22–69]) had a hazard ratio of 1.90 (95% CI, 1.18–3.06; p = 0.008) compared with low-risk (intermediate prognosis; median time to progression of 59 months [IQR 28–84]) patients. Of the 17 genes, 13 came from the cluster of genes highly expressed in unfavorable cases with shorter time to progression, and increased expression corresponds to increased risk of progression. Three of the 17 genes came from the cluster of genes highly expressed in favorable or intermediate cases with longer time to progression and increased expression corresponds to decreased risk.
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