What is the role of genetics in treatment selection for acute myeloid leukemia (AML)?

Updated: Dec 17, 2018
  • Author: Ari VanderWalde, MD, MPH, MA, FACP; Chief Editor: Karl S Roth, MD  more...
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Testing for key genetic markers in patients with AML is important for both prognostic and treatment purposes. Generally, the relatively slow turnaround time for cytogenetic and molecular testing makes it difficult to tailor the initial induction based on these factors. However, the choice of consolidation and/or maintenance therapy can often benefit from risk stratification using genetic information. Treatment decisions have been made using this information in one of two ways: in deciding on the aggressiveness of treatment, and in determining whether targeted therapy may influence the genetic or genomic aberration and specifically treat the individual’s tumor.

A classic example of the latter is seen in patients with APL. Its characteristic t(15:17) translocation leads to production of an abnormal fusion protein known as PML-RAR alpha. In normal leukocytes, the RAR protein interacts with retinoic acid to promote cellular differentiation. However, the fusion gene product between the chromosomes in patients with APL causes the retinoic acid receptor to bind more tightly to the nuclear corepressor factor. This prevents the gene from being activated with physiologic doses of retinoic acid, and differentiation from promyelocytes into leukocytes does not occur, leading to a clonal overgrowth of promyelocytes. [4]

The discovery that supraphysiologic doses of all-trans retinoic acid (ATRA) can overcome PML-RAR alpha blockade of the retinoic acid receptor led to the use of ATRA in combination with chemotherapy in patients with APL, which yields very high rates of long-term survival. [4]

Agents targeted toward other molecular abnormalities in AML are in development, but are not currently available in a clinical setting outside of a clinical trial.

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