IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia

Abstract

Background: Prognostic index for survival estimation by clinical-demographic variables were previously proposed in chronic lymphocytic leukemia (CLL) patients. Our objective was to test in a large retrospective cohort of CLL patients the prognostic power of biological and clinical-demographic variable in a comprehensive multivariate model. A new prognostic index was proposed.

Methods: Overall survival and time to treatment in 620 untreated CLL patients were analyzed retrospectively to evaluate the multivariate independence and predictive power of mutational status of immunoglobulin heavy chain variable gene segments (IGHV), high-risk chromosomal aberration such as 17p or 11q deletions, CD38 and ZAP-70 expression, age, gender, Binet stage, β2-microglobulin levels, absolute lymphocyte count and number of lymph node regions.

Results: IGHV mutational status and 17p deletion were the sole biological variables with independent prognostic relevance in a multivariate model for overall survival, which included easily measurable clinical parameters (Binet staging, β2-microglobulin levels) and demographics (age and gender). Analysis of time to treatment in Binet A patients below 70 years of age showed that IGHV was the most important predictor. A novel 6-variable clinical-biological prognostic index was developed and internally validated, which assigned 3 points for Binet C stage, 2 points/each for Binet B stage and for age > 65 years, 1 point/each for male gender, high β2-microglobulin levels, presence of an unmutated IGHV gene status or 17p deletion. Patients were classified at low-risk (score = 0-1; 21%), intermediate-risk (score 2-5; 63% of cases), high-risk (score 6-9; 16% of cases). Projected 5-year overall survival was 98%, 90% and 58% in low-, intermediate- and high-risk groups, respectively. A nomogram for individual patient survival estimation was also proposed.

Conclusions: Data indicate that IGHV mutational status and 17p deletion may be integrated with clinical-demographic variables in new prognostic tools to estimate overall survival.

Figure 1

Overall survival (OS) and time to treatment (TTT) in the whole cohort of 620 CLL patients.

Figure 2

Clinical-biological index. a) histogram of score points according to clinical-biological prognostic model. Vertical red lines show the positions of cut points splitting sample in 3 risk groups. b) Kaplan-Meyer plot showing prognostic stratification in 3 risk groups according to clinical-biological score. c) prognostic stratification in 3 risk groups according to Wierda et al prognostic score⁶.

Figure 3

Heatmap of individual patient clinical-biological scores. Columns refer to individual patient; rows refer to predictors. In heatmap, each dicotomic predictor is indicated in green or red if present in its favourable or unfavourable configuration, respectively. Binet stages A, B, C are indicated in green, red and black, respectively. Yellow bars show the splits between low, intermediate and high-risk groups. Number of patients in each score class are reported at the bottom of columns.

Figure 4

Nomogram for predicting overall survival according to the clinical-biological prognostic index. To read the nomogram, draw a vertical line from each tick marker indicating the status of a predictor to the top axis labeled Points. Sum the points and find the corresponding number on the axis labeled Total Points. Draw a vertical line down to the axes showing 5- and 10-year overall survival rates and median survival. Beta2M, ß2 microglobulin; ULN, upper limit of normal; OS, overall survival.

Figure 5

Kaplan-Meyer plots of overall survival (OS) for the 6 variable of the clinical-prognostic index.