Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia

ABSTRACT

Introduction: Over the last few years, several new synthetic drugs, particularly Bruton’s tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL).

Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL. A literature review of the MEDLINE database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed. Publications from 2000 through July 2017 were scrutinized. The search terms used were acalabrutinib, ACP-196, BGB-3111, ONO-4059, GS-4059, duvelisib, IPI-145, TGR-1202, copanlisib, Bay 80–6946, buparlisib, BKM-120, BCL-2 inhibitors, venetoclax, ABT-263, navitoclax, CDK inhibitors, alvocidib, flavopiridol, dinaciclib, SCH 727,965, palbociclib, PD-0332991, in conjunction with CLL. Conference proceedings from the previous five years of the ASH and EHA Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles.

Expert opinion: The use of new synthetic drugs is a promising strategy for the treatment of CLL. Data from ongoing and future clinical trials will aid in better defining the status of new drugs in the treatment of CLL.

KEYWORDS:

• CLL
• B-cell receptor
• BCL-2 antagonist
• BTK inhibitor
• ibrutinib
• idelalisib
• PI3K inhibitor
• venetoclax

Article highlights

• Oral targeted drugs, including the BTK inhibitor ibrutinib, PI3K inhibitor idelalisib and BCL-2 antagonist venetoclax, have been recently approved for the treatment of patients with CLL

• New drugs improved the prognosis of most treated CLL patients, particularly those with high-risk disease (del(17p)/TP53 mutated), elderly/unfit patients, and those refractory for previous therapies

• More specific BTK inhibitors, such as acalabrutinib, ONO- 4059, CC-292, BGB-3111 and spebrutinib, are now in development and some should be available in clinical practice soon

• Second-generation PI3K inhibitors currently in development, including duvelisib, TGR-1202, copanlisib, Bay 80-6946, buparlisib and BKM-120, have shown preliminary activity in CLL

• Several small molecule inhibitors of BCL-2 are in active clinical trials in CLL and offer promising therapeutic potential

This box summarizes key points contained in the article.

Acknowledgment

We thank Edward Lowczowski from the Medical University of Lodz for editorial assistance.

Declaration of interest

T. Robak has received research grants and personal fees from Hoffmann-La Roche, GlaxoSmithKline, Gilead, Pharmacyclix, Abbvie, and Janssen 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.

Additional information

Funding

The study was supported in part by grant funding from the Medical University of Lodz, Poland: No. 503/1-093-01/503-11-004 and by the Foundation for the Development of Diagnostics and Therapy, Warsaw, Poland.