Pharmacodynamic considerations of small molecule targeted therapy for treating B-cell malignancies in the elderly

Abstract

Introduction: Small molecule inhibitors are currently in various stages of preclinical and clinical trials and are expected to revolutionize the treatment of many neoplastic diseases, including B-cell lymphoid malignancies.

Areas covered: This article reviews the chemical structure, mechanisms of action, pharmacodynamic and pharmacokinetic properties, as well as clinical applications of small molecules in the treatment of elderly patients with B-cell hematological malignancies. Bibliographic research covering mainly the period from 2010 until February 2015 was conducted on the MEDLINE database for articles in English. Proceedings of the American Society of Hematology, European Hematology Association and American Society of Clinical Oncology conferences held during the last 5 years were also included.

Expert opinion: In the last few years, several preclinical and clinical trials have evaluated many small weight organic molecules which downregulate B-cell receptor (BCR) signaling and act via inhibition of either BCR-associated kinases or cyclin-dependent kinases, or which are antagonists of members of the B-cell lymphoma 2 protein family. Pharmacokinetic profiles of these agents as well as dosage used and adverse events in patients with lymphoid malignancies have been established. Some of these inhibitors satisfy therapeutic modalities as suitable for the elderly patients, including those with chronic lymphocytic leukemia and non-Hodgkin’s lymphoma.

Keywords:

• B-cell malignancies
• clinical efficacy
• dinaciclib
• fostamatinib
• ibrutinib
• idelalisib
• navitoclax
• pharmacokinetics
• small molecules
• venetoclax

Declaration of interest

This work was supported in part by the grants from the Medical University of Lodz (No 503/1-093-01/503-01) and by the Foundation for the Development of Diagnostics and Therapy, Warsaw, Poland. D Wolowiec was a member of Advisory Board of Roche, Poland and Janssen-Cilag, and has received a travel grant from Gilead. T Robak has received research grants from Hoffmann-La Roche, GlaxoSmithKline, Trubion Pharmaceuticals Inc., Janssen, Pharmacyclics and Gilead, and travel grants from Hoffmann-La Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

This box summarizes key points contained in the article.