Identification of a 20-gene expression-based risk score as a predictor of clinical outcome in chronic lymphocytic leukemia patients

Abstract

Despite the improvement in treatment options, chronic lymphocytic leukemia (CLL) remains an incurable disease and patients show a heterogeneous clinical course requiring therapy for many of them. In the current work, we have built a 20-gene expression (GE)-based risk score predictive for patients overall survival and improving risk classification using microarray gene expression data. GE-based risk score allowed identifying a high-risk group associated with a significant shorter overall survival (OS) and time to treatment (TTT) (P ≤ .01), comprising 19.6% and 13.6% of the patients in two independent cohorts. GE-based risk score, and NRIP1 and TCF7 gene expression remained independent prognostic factors using multivariate Cox analyses and combination of GE-based risk score together with NRIP1 and TCF7 gene expression enabled the identification of three clinically distinct groups of CLL patients. Therefore, this GE-based risk score represents a powerful tool for risk stratification and outcome prediction of CLL patients and could thus be used to guide clinical and therapeutic decisions prospectively.

Figure 1

GE-based risk score in CLL patients. (a) Clustergram of genes ordered from best to worst prognosis. The level of the probe set signal is displayed from low (deep blue) to high (deep red) expression. (b) CLL patients (n = 107) were ordered by increasing GE-based risk score.

Figure 2

Prognostic value of GE-based risk score in CLL patients. (a) Patients of the training cohort (n = 107) were ranked according to increasing GE-based risk score and a maximum difference in OS was obtained with a score = −32.3, splitting patients into a high risk (19,6%) and a low risk (80,4%) groups. (b) The prognostic value of GE-based risk score was assayed on an independent cohort of 44 patients (validation cohort). The parameters to compute GE-based risk score of patients in the validation cohort and the proportions delineating the 2 prognostic groups were those defined with the training cohort.

Figure 3

High GE-based risk score is associated with a shorter time to the first treatment in CLL patients. The prognostic value of GE-based risk score was tested in two independent cohorts of CLL patients. A high GE-based risk score is associated with a shorter time to the first treatment in the two independent cohorts ((a) n = 70, P = 7.9E − 9 and (b) n = 130, P = 0.01) and in patients with cytogenetically defined good prognostic ((c) n = 52, P = 1E − 5).

Figure 4

Combination of the prognostic information of GE-based risk score and NRIP1 and TCF7 gene expression. (a) Kaplan-Meier analyses were performed to combine the prognostic information of GE-based risk score and NRIP1 and TCF7 gene expression. Patients were scored from 1 to 5 according to GE-based risk score in TCF7^{high  or  Low} and NRIP1^{high  or  low} groups. (b) After merging consecutive groups with no prognostic difference, 3 patient groups with different overall survival (OS) were obtained: I, II, and III (patients of the training cohort, n = 107).