Targeting Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML): Moving beyond Prognostication

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Abstract

Measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) has an established role in disease prognostication, particularly in guiding decisions for hematopoietic cell transplantation in first remission. Serial MRD assessment is now routinely recommended in the evaluation of treatment response and monitoring in AML by the European LeukemiaNet. The key question remains, however, if MRD in AML is clinically actionable or “does MRD merely portend fate”? With a series of new drug approvals since 2017, we now have more targeted and less toxic therapeutic options for the potential application of MRD-directed therapy. Recent approval of NPM1 MRD as a regulatory endpoint is also foreseen to drastically transform the clinical trial landscape such as biomarker-driven adaptive design. In this article, we will review (1) the emerging molecular MRD markers (such as non-DTA mutations, IDH1/2, and FLT3-ITD); (2) the impact of novel therapeutics on MRD endpoints; and (3) how MRD might be used as a predictive biomarker to guide therapy in AML beyond its prognostic role, which is the focus of two large collaborative trials: AMLM26 INTERCEPT (ACTRN12621000439842) and MyeloMATCH (NCT05564390).

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Most cited references 118

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Genomic Classification and Prognosis in Acute Myeloid Leukemia

Elli Papaemmanuil, Moritz Gerstung, Lars Bullinger … (2016)

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Age-related clonal hematopoiesis associated with adverse outcomes.

Siddhartha Jaiswal, Pierre Fontanillas, Jason Flannick … (2014)

The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).

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Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

Timothy Ley, Christopher Miller, Li Ding … (2013)

Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).