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Review
. 2022 Mar 26;14(7):1689.
doi: 10.3390/cancers14071689.

Refining AML Treatment: The Role of Genetics in Response and Resistance Evaluation to New Agents

Adriane Halik  1   2 , Christopher Maximilian Arends  1   2 , Lars Bullinger  1   3 , Frederik Damm  1   3 , Mareike Frick  1   3
Affiliations
Review

Refining AML Treatment: The Role of Genetics in Response and Resistance Evaluation to New Agents

Adriane Halik et al. Cancers (Basel). .

Abstract

The number of treatment options for acute myeloid leukemia (AML) has greatly increased since 2017. This development is paralleled by the broad implantation of genetic profiling as an integral part of clinical studies, enabling us to characterize mutation-response, mutation-non-response, or mutation-relapse patterns. The aim of this review is to provide a concise overview of the current state of knowledge with respect to newly approved AML treatment options and the association of response, relapse and resistance with genetic alterations. Specifically, we will highlight current genetic data regarding FLT3 inhibitors, IDH inhibitors, hypomethylating agents (HMA), the BCL-2 inhibitor venetoclax (VEN), the anti-CD33 antibody conjugate gemtuzumab ozogamicin (GO) and the liposomal dual drug CPX-351.

Keywords: AML; CPX-351; FLT3; IDH1/2; gemtuzumabozogamicin; mutations; precision medicine; targeted therapy; venetoclax.

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Conflict of interest statement

L.B. received honoraria from Seattle Genetics, Sanofi, Astellas, Amgen, a consultancy fee from Gilead, Hexal, and Menarini, a consultancy fee and Honoraria Abbvie, BMS/Celgene, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, Novartis and Pfizer, and research funding from Bayer and Jazz Pharmaceuticals. F.D. reports personal fees from AbbVie, Astra Zeneca, Gilead, Novartis, and Roche outside the submitted work.

Figures

Figure 1
Figure 1
Schematic overview of the therapeutic agents discussed in this article and their mechanisms of action in acute myeloid leukemia. Abbreviations: BAK, Bcl-2 homologous antagonist/killer; BAX, Bcl-2 associated X protein; BCL-2, B-cell Lymphoma 2; DNMT, DNA methyltransferase; FLT3, FMS-like tyrosine kinase 3; 2-HG, 2-hydroxyglutarate; IDH, Isocitrate dehydrogenase; JAK, janus kinase; α-KG, α-ketoglutarate; MEK, mitogen-activated protein kinase; RAF, rapidly growing fibrosarcoma; RAS, rat sarcoma; STAT5, signal transducer and activator of transcription 5; TET, ten-eleven translocation methylcytosine dioxygenase. Created with BioRender.com (accessed on 10 March 2022).
Figure 2
Figure 2
Schematic illustration of FLT3 tyrosine kinase displaying activating FLT3 mutations according to the affected receptor domain localization. FLT3 kinase comprises an extracellular domain, a transmembrane domain, a juxtamembrane domain (JMD), two tyrosine kinase domains (TKD1 and TKD2) and a C-Terminus. Internal tandem duplications (ITD) are usually located in the JMD whereas deletions and point mutations are mostly found in the TKD domains. Created with BioRender.com (accessed on 10 March 2022).
See this image and copyright information in PMC

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