Clinical Implications of Novel Genomic Discoveries in Chronic Lymphocytic Leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy with a remarkably heterogeneous course, ranging from indolent disease with no need for immediate therapy to rapidly progressive disease associated with therapeutic resistance. The recent US Food and Drug Administration approvals of novel targeted therapies such as inhibitors of B-cell receptor signaling and B-cell lymphoma 2 have opened up new opportunities in the clinical management of patients with CLL and heralded a new era in the clinical treatment of this disease. In parallel, the implementation of novel sequencing technologies has provided new insights into CLL complexity, identifying a growing list of putative drivers that underlie inter- and intratumor heterogeneities in CLL affecting disease progression and resistance. The identification of these novel genomic features that can indicate future drug resistance or guide therapeutic management is now becoming a major goal in CLL so that patients can best benefit from the increasingly diverse available therapies, as discussed herein.

Fig 1.

Putative driver gene mutations and recurrent somatic copy number variations in chronic lymphocytic leukemia (CLL). (A) Frequency of somatic copy number alterations when combining cohorts from the Spanish International Cancer Genome Consortium (ICGC) trial (n = 452), German CLL Study Group CLL8 trial (n = 353), Scandinavian SCALE trial (n = 369), Ouillette et al study (n = 255), and Dana-Farber Cancer Institute (DFCI)/Brown et al study (n = 161), identified through single-nucleotide polymorphism array (except as identified by whole-exome sequencing [WES] for Spanish ICGC cohort). Also shown are the frequencies of somatic single-nucleotide variants (from DFCI/Broad Institute [n = 548] and from Spanish ICGC [n = 452]) identified through WES. Only the events over 1% in frequency in the combined cohorts are reported. IGLL5, MAP2K1, and SAMHD1 have been reported in DFCI cohort only, whereas ZNF292, KLH6, SETD2, and PAX5 enhancer have been reported in Spanish ICGC cohort only. All remaining genes were consistent among cohorts. Mutations in the 3′UTR of NOTCH1 were detected in four of 150 patient cases with whole-genome sequencing. (B) Summaries of the characteristics of frequently mutated genes in CLL. amp, amplification; ANK, ankyrin repeat; del, deletion; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; FAT, FRAP-ATM-transformation/transcription domain associated protein; HD, heterodimerization domain; MAPK, mitogen-activated protein kinase; PD, programmed death; PEST, proline, glutamic acid, serine, and threonine; PI3K, phosphatidylinositol 3-kinase; SCALE, Scandinavian Lymphoma Etiology; TAD, transaction activation domain; TET, ten-eleven translocation.

Fig 2.

A summary of the frequencies and most common coassociations of putative chronic lymphocytic leukemia (CLL) drivers, per analysis of the Dana-Farber Cancer Institute/Broad Institute cohort of 538 CLLs.

Fig 3.

Schema of clonal evolution of chronic lymphocytic leukemia (CLL) in relation to exposure to therapy. From the start, sequential acquisition of somatic alterations in CLL leads to its genomic diversification. Exposure to chemoimmunotherapy as first-line treatment commonly selects TP53-disrupted subclones. Each therapy proposed at relapse may differentially shape the CLL architecture and would be associated with preferential alterations: TP53 loss with chemotherapy-based treatment and BTK or PLCG2 mutation (mut) or 8p deletion (del) with ibrutinib therapy. ? indicates other mutations. FCR, fludarabine, cyclophosphamide, and rituximab.

Fig 4.

Summary of prognosis impact of somatic mutations evaluated in retrospective studies or clinical trials in chronic lymphocytic leukemia (CLL). The medians of time to first treatment (TTFT), overall survival (OS), and progression-free survival (PFS) in subgroups of patients with CLL with mutations are indicated in months and compared with subgroups of patients with wild type (in parentheses). When medians were not available in studies, the value of the hazard ratio in multivariable analyses is reported in square brackets. The UK Leukaemia Research Fund (LRF) CLL4 trial compared median months for the ATM biallelic inactivation subgroup with ATM wild type and ATM mutation subgroup. Data from the German CLL Study Group (GCLLSG) CLL3X trial were inferred from Kaplan-Meier curves. ERIC, European Research Initiative on CLL; FILO, French Intergroup on CLL; IPI, International Prognostic Index; MLL, Munich Leukemia Laboratory; NA, not available; NCRN, National Cancer Research Network; NR, not reached; ORR, overall response rate; R/R, relapsed/refractory; SCALE, Scandinavian Lymphoma Etiology. *5-year OS rate (%). †10-year rate (%).