The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment

Abstract

The typical genome of chronic lymphocytic leukemia (CLL) carries ∼2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction. Prognostic biomarkers do not affect treatment choice, and can be integrated into prognostic scores that are based on both clinical and biological variables. Molecular predictive biomarkers affect treatment choice, and currently include TP53 disruption by mutation and/or deletion and IGHV mutation status. TP53 disruption by gene mutation and/or deletion associates with chemoimmunotherapy failure and mandates treatment with innovative drugs, including ibrutinib, idelalisib, or venetoclax. The mutation status of IGHV genes represents a predictive biomarker for identifying patients that may benefit the most from chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. Assessment of these biomarkers at the time of treatment requirement is recommended by most current guidelines for CLL management. Other molecular predictors are under investigation, but their application in clinical practice is premature.

Figure 1.

Genes and chromosomal regions affected by molecular lesions in CLL. The word cloud shows the genes that are reported as mutated in CLL by the Catalogue of Somatic Mutations in Cancer (COSMIC; v77) and the gross chromosomal abnormalities that are recurrent in CLL. The size of the font is proportional to the frequency of the molecular lesion.

Figure 2.

Mutated pathways in CLL. Cellular programs that are affected by the most recurrent molecular lesions are represented. Boxes show the genes that are recurrently mutated in each cellular program.

Figure 3.

Biomarker-informed decision nodes in the management of newly presented CLL. At the time of treatment requirement, the presence of TP53 mutation/deletion represents an indication for treatment with kinase inhibitors, for example, ibrutinib or, alternatively, idelalisib. Patients who require first-line treatment and carry a wild-type TP53 gene may be candidate to chemoimmunotherapy with one of the available combinations, especially in the presence of mutated IGHV genes. In patients with wild-type, a TP53 gene, and unmutated IGHV genes, the role of chemoimmunotherapy is under debate, and kinase inhibitors may represent a valuable option. CIRS, Cumulative Illness Rating Scale.