Acute myeloid leukemia (AML) is a genomically complex disease, with a molecular architecture that varies significantly, both between patients and within patients over time. Clonal evolution within each patient throughout the course of their disease means that genomic alterations can occur pre- and post-treatment. By capturing and assessing these genomic changes, clinicians and diagnosticians can obtain a more accurate disease profile and decide on the most suitable therapeutic approach.
Measurable residual disease (MRD) testing is well established as an essential tool to detect evidence of residual malignant cells in a patient’s blood or bone marrow post-treatment. This testing – traditionally via techniques like flow cytometry and polymerase chain reaction (PCR) – enables clinicians to evaluate the depth of treatment response, and to monitor for signs of relapse of blood cancers such as AML.
Broadening the focus
While traditional MRD testing methods can robustly and effectively detect and quantify residual disease burden, they are limited in their ability to detect all cases of disease refraction or relapse. This is due to a narrow focus on either phenotypic markers or a single genomic biomarker, which is unable to provide a full understanding of the potential causes of treatment failure.
To address these limitations, clinicians and diagnosticians are adopting more expansive genomic technologies – such as next-generation sequencing (NGS) – to capture the broader range of genomic biomarkers associated with blood cancer MRD. Here, “genomic biomarkers” really means changes in the genome of malignant cells – from small, single-base changes to large rearrangements. These changes within an individual mark cancerous cells as distinct from healthy cells, and from these biomarkers, the “driver mutations” of an individual’s blood cancer can be captured more comprehensively.
Accessing deeper insights
Using NGS-based MRD technologies to detect genomic biomarkers has an important advantage over previous generations of techniques. NGS can reach lower limits of detection while simultaneously providing deeper insights into the underlying genomic profile of the disease – enabling stronger clinical decision making. A benefit of NGS panels is the ability to tailor targeted content. This allows labs to focus on currently actionable mutations, or – if in a clinical research environment – to broaden their scope to a wider range of biomarkers.
By capturing this assortment of markers in each sample and combining it with optimized bioinformatic analysis, labs can – at scale – identify and assess variants that impact the disease course and therapeutic response. By also capturing deeper levels of information, such as the longitudinal dynamics of the disease, they ascertain genomic findings that have traditionally been difficult to capture and visualize.
Towards real-time observation
Let’s consider the example of FLT3-ITDs in AML. Data have shown that FLT3-ITD-positive AML patients have a higher risk of poorer disease outcomes than those in whom it is not detected (1). This even applies to patients who would otherwise meet the clinical criteria for complete remission.
Indeed, discoveries indicate that FLT3-ITD levels as low as 0.001 percent variant allele frequency are associated with an adverse prognosis (2). This means that evermore sensitive technologies like NGS are required to determine the presence of these mutations and provide as close to real-time observation as possible.
When we consider that FLT3-ITD is just a singular marker in a wide landscape of disease-associated biomarkers, there is an emerging need to be able to sensitively detect and track multiple residual or emerging variants post treatment. This would allow us to obtain a stronger profile of a patient’s disease status.
Quantifiable possibilities
It’s an exciting time for NGS-based MRD testing. Imagine the possibilities if we could establish the optimal performance standards for each indication, ensure compatibility with non-invasive sample types, like peripheral blood, and produce assays that are affordable enough to be used on a frequent basis.
Then, NGS-based MRD has the potential to act as a close-to-real-time molecular microscope. This would unlock the possibility to quantify patient disease progression and treatment success at each stage; and deliver unprecedented, high-resolution insights into the genomic determinants of therapeutic responses.
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References
- Chevallier P et al., Leukemia, 25,6 (2011). PMID: 21331073.
- S Loo et al., Blood, 140, 22 (2022). PMID: 35960851.
