Targeted therapy in chronic lymphocytic leukemia: past, present, and future.
BACKGROUND
Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world. Recent advances in understanding the biology of B-cell malignancies have resulted in the development of novel agents targeting key prosurvival pathways in the neoplastic B cell.


OBJECTIVE
The goal of this article was to summarize current literature on the emerging therapeutic approaches in CLL and B-cell malignancies.


METHODS
A literature review was performed, identifying pathways and key clinical trials involving novel therapies in CLL, with special emphasis on B-cell receptor (BCR)-targeting agents.


RESULTS
Understanding the biology of the BCR-signaling pathway has led to identification of novel molecular targets. Most notably, inhibitors of Bruton tyrosine kinase and phosphatidylinositide 3-kinase-δ have entered clinical trials and demonstrated high response rates in CLL, including high-risk disease. Cyclin-dependent kinase inhibitors may evolve into an alternative therapeutic approach in CLL. New drugs that target molecules within and outside of the BCR-signaling pathway have shown promise in preclinical studies.


CONCLUSIONS
Both preclinical and early clinical trial results involving novel targeted therapies suggest that the standard treatment paradigm in CLL and B-cell malignancies will soon change. Particular attention should be paid to the BCR-targeting agents, whose favorable adverse effect profile may improve the lives of elderly patients with CLL.
Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Electronic address: alexey.v.danilov@hitchcock.org.
Alexey V
AV
Danilov
D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000378:metabolism; D002986:Clinical Trials as Topic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use*; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine; C552946:idelalisib
B-cell receptor; NF-κB; chronic lymphocytic leukemia; ibrutinib