Ibrutinib in CLL: a focus on adverse events, resistance, and novel approaches beyond ibrutinib.
Bruton's tyrosine kinase (BTK), a mediator in B cell receptor signaling has been successfully exploited as a therapeutic target in treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a BTK inhibitor that has shown excellent efficacy in treatment-naïve, heavily pre-treated, and high-risk CLL/SLL. With remarkable efficacy, good oral bioavailability, and modest adverse events profile, ibrutinib use is likely to continue to increase. As data with ibrutinib use in CLL matures, concerns regarding adverse events and drug resistance have emerged. New insights into mechanisms of ibrutinib resistance in CLL have uncovered potential therapeutic targets. Several promising novel agents are currently in early phases of development for overcoming ibrutinib resistance in CLL/SLL. We provide a comprehensive analysis of emerging adverse events profile of ibrutinib, summarize our current understanding of ibrutinib resistance in CLL, and review promising novel therapeutic tools to overcome this challenge.
Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, USA. varinderdhaliwal@gmail.com.
Varinder
http://orcid.org/0000-0002-6480-7204
V
Kaur
Departement of Medicine, Govt. Medical College, Chandigarh, India.
Arjun
A
Swami
D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D001549:Benzamides / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D003967:Diarrhea / Q000139:chemically induced; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D009325:Nausea / Q000139:chemically induced; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010880:Piperidines; D011719:Pyrazines; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000604908:acalabrutinib; D000225:Adenine; C579720:venetoclax
Bruton’s tyrosine kinase inhibition; CLL; Ibrutinib resistance; Novel therapeutic agents; Resistance; SLL