Experimental drugs in clinical trials for acute myeloid leukemia: innovations, trends, and opportunities

ABSTRACT

Introduction

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by many cytogenetic and molecular alterations. Due to better knowledge of the molecular basis of AML, many targeted therapies have been introduced and registered, e.g. FMS-like tyrosine kinase 3 inhibitors, isocitrate dehydrogenase 1/2 mutation inhibitors, and Bcl-2 inhibitor. Despite that, the cure for AML remains an unmet clinical need in most patients.

Areas covered

The review aims to present new, not yet registered drugs for AML. We searched the English literature for articles concerning AML, targeted drugs, menin inhibitors, DOT1L, BET, IDH inhibitors, FLT3, hedgehog inhibitors, Polo-like kinase inhibitors, RNA splicing, and immune therapies via PubMed. Publications from January 2000 to August 2022 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles and Google search. Conference proceedings from the previous 5 years of The American Society of Hematology, the European Hematology Association, and the American Society of Clinical Oncology were searched manually. Additional relevant publications were obtained by reviewing the references.

Expert opinion

For several years, the therapeutic approach in AML has become more individualized. Novel groups of drugs give hope for greater curability. High response rates have agents that restore the activity of the p53 protein. In addition, agents that work independently of a particular mutation seem promising for AML without any known mutation.

KEYWORDS:

• Acute myeloid leukemia
• bromodomain
• DOT1L
• extraterminal domain
• FLT3
• hedgehog inhibitor
• IDH inhibitor
• immune therapy
• Polo-like kinase
• RNA splicing
• targeted drugs

Article highlights

• Along with a better understanding of the molecular basis of AML, it became possible to introduce targeted therapies

• New targeted therapies include menin inhibitors, DOT1L inhibitors, BET inhibitors

• A completely new strategy considers drugs targeting RA splicing that comprises splicing modulators and IRAK4 inhibitors

• Immune therapy in AML is not as effective as in lymphomas, mainly due to the heterogeneity of the disease and the lack of a specific antigen

• Future directions of the development of already registered drugs are assessing their role in new combinations and the development of next-generation molecules

This box summarizes the key points contained in the article.

Acknowledgments

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

Author contributions

A Golos, J Gora-Tybor, and T Robak wrote and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.