Treatment Approaches to Chronic Lymphocytic Leukemia With High-Risk Molecular Features

Abstract

The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. Over the past decades, several cytogenetic, immunogenetic and molecular features have emerged that identify patients suffering from CLL with high-risk molecular features. These biomarkers can clearly aid prognostication, but may also be capable of predicting the efficacy of various treatment strategies in subgroups of patients. In this narrative review, we discuss treatment approaches to CLL with high-risk molecular features. Specifically, we review and provide a comprehensive overview of clinical trials evaluating the efficacy of chemotherapy, chemoimmunotherapy and novel agent-based treatments in CLL patients with TP53 aberrations, deletion of the long arm of chromosome 11, complex karyotype, unmutated IGHV, B cell receptor stereotypy, and mutations in NOTCH1 or BIRC3. Furthermore, we discuss future pharmaceutical and immunotherapeutic perspectives for CLL with high-risk molecular features, focusing on agents currently under investigation in clinical trials.

Cost Effectiveness of Molecular Diagnostic Testing Algorithms for the Treatment Selection of Frontline Ibrutinib for Patients with Chronic Lymphocytic Leukemia in Australia

“…This study utilized the best available public literature sources to inform a range of plausible clinical parameters in the model, but further effectiveness evidence may be required to improve the long-term clinical outcome estimates. Yet, such data will remain scarce unless clinical trials are designed to directly investigate the clinical benefit of treatment for predictive groups categorized by TP53 wildtype/aberrations and IGHV- U/ IGHV -M. These clinical trials are costly to conduct, and it is unlikely future patients with TP53 aberrations and/or IGHV- U enrolled in clinical trials will receive FCR with the shift away from this treatment for these patients [ 50 ]. Nonetheless, the trials included in the ITC analysis were comparable based on the study design, patient population and outcome measures (Table S2 in the ESM).…”

Reliable one-step assessment of IGHV mutational status and gene mutations in Chronic Lymphocytic Leukemia by capture-based high throughput sequencing

“…Indeed, IGHV and TP53 mutational status are currently the major theranostic markers in CLL, orienting treatment towards immunochemotherapy or chemo-free (BTKi, iBCL2) schedules (2,27,28). It would moreover be very easy to include other targets such as ATM, NOTCH1, SF3B1, BIRC3 (29) or others, should they become significant indicators of response or prognosis.…”

Dysregulation of Small Nucleolar RNAs in B-Cell Malignancies

“…It is characterized by the clonal expansion of CD5+ B-cells and mainly elderly people are affected [ 88 ]. CLL is a heterogeneous disease and most patients survive decades, while others have a rapid disease progression with poor outcome [ 89 ]. In a study of Ronchetti et al, snoRNA expression was profiled in CLL patients and different snoRNAs were identified as potential biomarkers [ 74 ].…”