Precision diagnostics in chronic lymphocytic leukemia: Past, present and future

Abstract

Genetic diagnostics of hematological malignancies has evolved dramatically over the years, from chromosomal banding analysis to next-generation sequencing, with a corresponding increased capacity to detect clinically relevant prognostic and predictive biomarkers. In diagnostics of patients with chronic lymphocytic leukemia (CLL), we currently apply fluorescence in situ hybridization (FISH)-based analysis to detect recurrent chromosomal aberrations (del(11q), del(13q), del(17p) and trisomy 12) as well as targeted sequencing (IGHV and TP53 mutational status) for risk-stratifying purposes. These analyses are performed before start of any line of treatment and assist in clinical decision-making including selection of targeted therapy (BTK and BCL2 inhibitors). Here, we present the current view on the genomic landscape of CLL, including an update on recent advances with potential for clinical translation. We discuss different state-of-the-art technologies that are applied to enable precision diagnostics in CLL and highlight important genomic markers with current prognostic and/or predictive impact as well as those of prospective clinical relevance. In the coming years, it will be important to develop more comprehensive genomic analyses that can capture all types of relevant genetic aberrations, but also to develop highly sensitive assays to detect minor mutations that affect therapy response or confer resistance to targeted therapies. Finally, we will bring up the potential of new technologies and multi-omics analysis to further subclassify the disease and facilitate implementation of precision medicine approaches in this still incurable disease.

Keywords: chronic lymphocitic leukemia; genomic aberrations; next-generation sequencing; precision diagnostics; precision medicine.

Figure 1

TP53 abnormalities in CLL. In approximately 40-60% of cases with TP53 aberrations, del(17p) is found in combination with a TP53 mutation, another 20-30% of cases carry one or more TP53 mutations without del(17p), while in the remaining TP53 aberrant cases (10-20% of patients), only del(17p) is detected.

Figure 2

IGHV gene SHM status in CLL and its impact on BcR signaling. While the BcR in IGHV-unmutated CLL often displays polyreactive antigen affinity resulting in increased BcR signaling, the BcR of IGHV-mutated CLL demonstrates reduced BcR signaling and reduced NF-κB activation.

Figure 3

Mutational landscape and deregulated signaling pathways in CLL (, , , –37). A selection of recurrently mutated genes are included; genes in red indicate mutations emerging during or after targeted therapy.

Figure 4

Precision diagnostics in CLL, present status and future directions. SNV, single-nucleotide variants; CNV, copy-number variants; SV, structural variants; IGHV, immunoglobulin heavy variable.