An overview of novel therapies in advanced clinical testing for acute myeloid leukemia

ABSTRACT

Introduction

The past decade has seen a sea change in the AML landscape with vastly improved cognizance of molecular pathogenesis, clonal evolution, and importance of measurable residual disease. Since 2017, the therapeutic armamentarium of AML has considerably expanded with the approval of midostaurin, enasidenib, ivosidenib, gilteritinib, and venetoclax in combination with hypomethylating agents and others. Nevertheless, relapse and treatment refractoriness remain the insurmountable challenges in AML therapy. This has galvanized the leukemic research community leading to the discovery and development of agents that specifically target gene mutations, molecularly agnostic therapies that exploit immune environment, apoptotic pathways, leukemic cell surface antigens and so forth.

Areas covered

This article provides an overview of the pathophysiology of AML in the context of non-cellular immune and molecularly targeted and agnostic therapies that are in clinical trial development in AML.

Expert opinion

Ever growing understanding of the molecular pathogenesis and metabolomics in AML has allowed the researchers to identify targets directed at specific genes and metabolic pathways. As a result, AML therapy is constantly evolving and so are the escape mechanisms leading to disease relapse. Therefore, it is of paramount importance to sequentially evaluate the patient during AML treatment and intervene at the right time.

KEYWORDS:

• AML
• uproleselan
• magrolimab
• menin
• quizartinib

Article highlights

• Routine assessment of Measurable Residual Disease (molecular and/or multiparameter flow cytometry-based) at set time points must be considered for AML prognostication.

• In the current era of epigenetic therapies, slower response kinetics must be considered before labeling it as lack of response to therapy.

• Menin inhibitors may prove to be an effective targeted therapy for patients with KMT2A rearranged or NPM1 mutated AML.

• Immunotherapy is a promising treatment strategy in AML that still needs further investigation regarding the biomarkers of response and ideal setting, i.e. newly diagnosed vs relapsed/refractory AML.

• There are no effective therapies for TP53 ^mut AML; therefore, patients with TP53 ^mut AML must be referred for clinical trial enrollment, when feasible.

• Hypomethylating agents with Venetoclax based triplet combinations in AML therapy must not be attempted outside of clinical trial setting.

Acknowledgments

All figures were created with BioRender.com.

Declaration of Interest

AM Zeidan has received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AM Zeidan has also participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, Mendus, Foran, Syros, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene. AM Zeidan is a Leukemia and Lymphoma Society Scholar in Clinical Research. None of these relationships were related to this work.

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.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.