Cell cycle inhibitors for the treatment of acute myeloid leukemia: a review of phase 2 & 3 clinical trials

ABSTRACT

Introduction: Acute myeloid leukemia (AML) is a clinically heterogeneous hematologic malignancy with poor long term outcomes. Cytotoxic chemotherapy remains the backbone of therapy especially among younger patients; however the effective incorporation of targeted therapies continues to be an area of active research in an effort to improve response durations and survival. Cell cycle inhibitors (CCI) are a novel class of agents which may be of particular interest for development in patients with AML.

Areas covered: We will review the concept of CCIs along with available pre-clinical and clinical data in the treatment of AML both in North America and abroad. Specific drug targets reviewed include cyclin D kinase, Aurora kinase, CHK1, and WEE1.

Expert opinion: Utilization of CCIs in patients with AML is an emerging approach that has shown promise in pre-clinical models. It has been challenging to translate this concept into clinical success thus far, due to marginal single-agent activity and significant toxicity profiles, however clinical evaluation is ongoing. Addition of these agents to cytotoxic chemotherapy and other targeted therapies provides a potential combinatorial path forward for this novel class of therapies. Developing optimal combinations while balancing toxicity are among the top clinical challenges that must be overcome before we can anticipate adoption of these agents into the armamentarium of AML therapy.

KEYWORDS:

• AML
• cell cycle inhibitors
• aurora kinase
• CDK
• CHK1
• WEE1

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

T Kadia: Consulting/honorarium: Pfizer; Novartis; Abbvie; Genentech, JAZZ, Agios; Daiichi-Sankyo; Research funding/clinical trials support: JAZZ; Genentech; BMS; Celgene; Amgen; Pfizer; AstraZeneca; Ascentage; AbbVie; Cellenkos. N Pemmaraju: Consulting/honorarium: Celgene; Stemline; Incyte; Novartis; MustangBio; Roche Diagnostics, LFB, Pacylex, AbbVie; Research funding/clinical trials support: Stemline; Novartis; AbbVie; Samus; Cellectis; Plexxikon; Daiichi-Sankyo; Affymetrix, SagerStrong Foundation. 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

This research is supported in part by the M. D. Anderson Cancer Center Support Grant P30 CA016672 and the SagerStrong Foundation.