Identifying prognostic gene panels in acute myeloid leukemia

ABSTRACT

Introduction

Acute myeloid leukemia (AML) is a heterogeneous disease currently including 12 entities defined by genetic findings with remarkable differences in prognosis and targeted therapies availability. Therefore, identification of genetic abnormalities by efficient techniques has become a necessary tool in routine clinical practice for AML patients.

Areas covered

In the present review, we will focus on our current knowledge of relevant prognosis gene mutations in AML, as recently updated by European Leukemia Net Leukemia risk classification.

Expert opinion

About 25% of newly diagnosed younger AML patients will be promptly classified as favorable prognosis by demonstrating the presence of NPM1 mutations or CBF rearrangements by qRTPCR, allowing for implementing molecular measurable residual disease-guided chemotherapy-based protocols. In fit AML patients, rapid detection of FLT3ITD is mandatory to associate midostaurin or quizartinib to treatment and assignment to intermediate prognosis. Conventional cytogenetics and FISH still have a role for detection adverse prognosis karyotypes and KMT2A, MECOM, or NUP98 gene rearrangements. Further genetic characterization is performed with NGS panels including favorable prognosis gene CEBPA bZIP and adverse prognosis genes, such as TP53 and myelodysplasia associated genes.

KEYWORDS:

• AML
• prognosis
• targeted therapy
• NPM1
• FLT3
• TP53
• splicesosome

Article highlights

• Acute myeloid leukemia (AML) is a highly heterogenous disease.

• Genetic findings are mandatory to define AML diagnostic entities according to recent 5^th edition of WHO classification of myeloid neoplasms (2022).

• Risk classification based on updated European Leukemia Net (ELN2022) recommendations is based in cytogenetic and molecular abnormalities, with increased relevance of NGS findings.

• Favorable risk patients are those younger fit subjects displaying NPM1 or CEBPA b-Zip mutations as well as those with CBF rearrangements.

• Favorable risk fit patients can be treated with specific chemotherapy MRD-based protocols.

• In the current FLT3 inhibitors era, the presence of FLT3 Internal tandem duplication (ITD), regardless allelic ratio, confer intermediate prognosis according to ELN2022 .

• Adverse risk AML is a heterogenous group including patients with complex-monosomal karyotypes, TP53 mutations or Splicing-Factor Mutations, and remains a high unmet clinical need subset.

Declaration of interests

J Sanchez-Garcia discloses: Abbvie: speaker bureau; Janssen: speaker bureau, research support. P Montesinos discloses: 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; Sanofi: speakers bureau, advisory board; Teva: research support, speakers bureau, advisory board. J Serrano discloses: Abbvie: speaker bureau; Incyte: speaker bureau; Pfizer: speaker bureau; Astellas: speaker bureau. 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 study is partially supported by grants Instituto de Salud Carlos III, Spain: PI18/01340, PI19/00730.