Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents

Frontiers in Oncology
Lenka SedlarikovaEva Kriegova

Abstract

Inhibitors of B-cell receptor signaling, ibrutinib and idelalisib, and BCL-2 antagonist, venetoclax, have become the mainstay of treatment for chronic lymphocytic leukemia (CLL). Despite significant efficacy in most CLL patients, some patients develop resistance to these agents and progress on these drugs. We provide a state-of-the-art overview of the acquired resistance to novel agents. In 80% of patients with ibrutinib failure, acquired mutations in BTK and PLCG2 genes were detected. No distinct unifying resistance-associated mutations or deregulated signaling pathways have been reported in idelalisib failure. Acquired mutations in the BCL2 gene were detected in patients who had failed on venetoclax. In most cases, patients who have progressed on ibrutinib and venetoclax experience resistance-associated mutations, often present at low allelic frequencies. Resistance-associated mutations tend to occur between the second and fourth years of treatment and may already be detected several months before clinical relapse. We also discuss the development of next-generation agents for CLL patients who have acquired resistant mutations to current inhibitors.

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Citations

Dec 5, 2020·Hematology·Andrew Lipsky, Nicole Lamanna
Feb 20, 2021·Cancer Management and Research·Paulina StefaniukMonika Podhorecka
Mar 30, 2021·Blood Reviews·Anna PetrackovaEva Kriegova
May 1, 2021·Cancers·Isabel González-Gascón-Y-MarínJosé-Ángel Hernández-Rivas
Apr 20, 2021·Frontiers in Oncology·Ilenia SanaMarta Muzio
Jun 3, 2021·International Journal of Molecular Sciences·Max Von SuskilManoj K Pandey
Jun 3, 2021·Diagnostics·Claudia Pérez-CarreteroJesús María Hernández-Rivas
Jun 28, 2021·Hematology/oncology Clinics of North America·Shanmugapriya Thangavadivel, Jennifer A Woyach

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Methods Mentioned

BETA
ubiquitination

Software Mentioned

Ensembl

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