Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia

Abstract

Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant treatment advancement in chronic lymphocytic leukemia (CLL). In the new scenario of targeted agents, there is an increasing interest in identifying patients who gain the maximum benefit from FCR. In this observational multicenter retrospective analysis of 404 CLL patients receiving frontline FCR, the combination of three biomarkers that are widely tested before treatment (IGHV mutation status, 11q deletion and 17p deletion; available in 80% of the study cohort) allowed to identify a very low-risk category of patients carrying mutated IGHV genes but neither 11q or 17p deletion that accounted for 28% of all cases. The majority of very low-risk patients (71%) remained free of progression after treatment and their hazard of relapse decreased after 4 years from FCR. The life expectancy of very low-risk patients (91% at 5 years) was superimposable to that observed in the matched normal general population, indicating that neither the disease nor complications of its treatment affected survival in this favorable CLL group. These findings need a prospective validation and may be helpful for the design of clinical trials aimed at comparing FCR to new targeted treatments of CLL, and, possibly, for optimized disease management.

Figure 1

Estimates of PFS, hazard of progression, OS, and prevalence of second tumors according to the model based on 17p deletion, 11q deletion, and IGHV mutation status. High-risk cases harboring 17p deletion independent of co-occurring 11q deletion or unmutated IGHV genes are color-coded in red. Intermediate-risk cases harboring unmutated IGHV genes and/or 11q deletion in the absence of 17p deletion are color-coded in yellow. Low-risk cases harboring mutated IGHV genes in the absence of 11q and 17p deletion are color-coded in blue. (A) PFS. (B) Estimate of the hazard of progression in relation to the time elapsed from FCR treatment start. (C) OS. The black line represents the expected OS in the age, sex, and calendar year of treatment-matched general population. P values according to Log-rank statistics. (D) Prevalence of second tumors among assessable cases of the three risk subgroups. Whiskers represent the 95% confidence interval (CI) of the proportion. P value according to Fisher’s exact test. na, not applicable; nr, not reached.