Precision medicine in acute myeloid leukemia: where are we now and what does the future hold?

ABSTRACT

Introduction

Precision medicine has revolutionized the diagnostic and therapeutic management of acute myeloid leukemia (AML), from standardized schemes based on chemotherapy to tailored approaches according to molecular and genetic profile and targeted therapy.

Areas covered

The main topics of precision medicine in AML were reviewed in MEDLINE, EMBASE, and Cochrane Central Register databases, and future directions in this therapeutic area were addressed. This review included targeted therapies, drug-sensitivity tests and predictive biomarkers, and genetic studies employing pharmacogenetic and deep sequencing strategies.

Expert opinion

Precision medicine has opened the door to personalized therapy for specific AML patient populations with promising results. Several targeted therapies have been approved or are being tested for specific mutations (i.e. FLT3, IDH, BCL-2, TP53), obtaining improvements in clinical outcomes and less toxicity as compared with intensive treatment, allowing potential combination therapy. Ongoing trials and real data will establish the role of these molecules in monotherapy or combined in different AML settings (front-line, relapsed/refractory, or post-transplant). Experience in drug-sensitivity predictors and pharmacogenetic biomarkers is encouraging and could be useful tools in the next years, but we need a better understanding of AML biology and pathogenesis as well as confirmatory studies to demonstrate the utility in clinical practice.

KEYWORDS:

• Acute myeloid leukemia
• targeted therapies
• molecular pathways
• ex-vivo sensitivity
• predictive factors
• pharmacogenetics

Article highlights

• Precision medicine in AML is focused on targeted therapies (i.e. FLT3, IDH, BCL-2, TP53, Hedgehog, CD33), reaching improvements in clinical outcomes and less toxicity as compared with intensive treatment.

• Ongoing clinical trials of targeted therapies combined with intensive schemes or HMA will establish the role of these drugs in different AML subsets (front-line, R/R AML, or maintenance).

• Ex vivo drug-sensitivity tests have improved their predictive power, testing a wide range of drugs in a relatively short time frame, but these platforms should be validated in larger cohorts.

• Pharmacogenetics and NGS showed promising results, but we need a better understanding of AML biology and pathogenesis to implement these tools in clinical practice.

Declaration of interest

P Montesinos reports these potential conflicts of interest, AbbVie: advisory board, speakers bureau, research support; Astellas: research support, consultant, speakers bureau, advisory board; Agios: consultant; Tolero Pharmaceutical: consultant; Glycomimetics: consultant; Forma Therapeutics: consultant; Celgene: research support, consultant, speakers bureau, advisory board; Daiichi Sankyo: research support, consultant, speakers bureau, advisory board; Incyte: speakers bureau, advisory board; Janssen: research support, speakers bureau, advisory board; Karyopharm: research support, advisory board; Novartis: research support, speakers bureau, advisory board; Pfizer: research support, speakers bureau, advisory board; Teva: research support, speakers bureau, advisory board. 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 supported in part by a grant from the ‘Instituto Carlos III’ [PI16/00665]; and the ‘Instituto Investigacion Sanitaria La Fe’ [2019/052-1] assigned to the Pharmacy and Hematology Departments.