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MINIMAL RESIDUAL DISEASE

Perspective on measurable residual disease testing in acute myeloid leukemia

Leukemia volume 38, pages 10–13 (2024)Cite this article

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Half a century ago, the common occurrence of relapses in patients with acute myeloid leukemia (AML) after achieving a morphologic remission, together with the inverse linear relationship between the number of transplanted leukemia cells and survival of experimental animals, sparked interest in quantifying residual neoplastic cells that survive seemingly successful chemotherapy and cause disease recurrence [1]. The genetic heterogeneity of leukemic cells within and between individual patients has complicated the development of assays to assess measurable (“minimal”) residual disease (MRD) in AML, a disease in which only a subset of entities, e.g., acute promyelocytic leukemia or core-binding factor leukemias, are characterized by single, canonical genetic abnormalities. Therefore, several methodologies that rely on the detection of either immunophenotypic abnormalities, specifically leukemia-associated immunophenotypes and/or cell population(s) showing deviation(s) from antigen-expression patterns typical of normal or regenerating cells of similar lineage and maturation stage, or genetic/molecular changes of the neoplastic cells have been developed to test for MRD (Table 1) [2]. The technologies—most common are multiparameter flow cytometry, quantitative polymerase chain reaction (PCR), and next-generation sequencing (NGS)—have advanced over time. The primary focus is the analyses of marrow, although peripheral blood and, for molecular testing, circulating cell-free DNA can also be used and may yield similar findings. Single-cell MRD assays are a new development [3]. Addressing a key current limitation, efforts are underway to reduce methodological differences between laboratories by developing more detailed guidelines for assay standardization or, at the minimum, harmonization [2, 4]. There are many additional areas for further improvement of the various MRD assay technologies. For multiparameter flow cytometry, these involve automated approaches to data analysis and interpretation [5] and determination of the value of including evaluations of less mature (“leukemia stem cell”) populations; despite intrinsic challenges regarding definition and isolation of such cell populations, emerging data indicate leukemia stem cell-based MRD testing might surpass and/or complement the performance of conventional flow cytometric MRD testing assays and refine risk assessment [6, 7]. For quantitative PCR-based testing, digital PCR provides an absolute quantification of molecules, affording easier standardization across laboratories, independence from fluctuations in the normalization target, and more direct data interpretability [8]. For NGS-based testing, improvements focus on laboratory and bioinformatic error-suppression/correction techniques (e.g., duplex sequencing) to reduce error rates and increase mutation detection sensitivities [8]. Still, for reasons not only related to assay methodologies but also biospecimen sampling, statistics, and, foremost, AML biology, the perfect MRD test for AML may never exist (Table 2) [9, 10].

Table 1 Methodologies for MRD testing in AML.
Full size table
Table 2 Limitations of MRD testing.
Full size table

Nonetheless, even with current MRD assays, numerous studies have shown MRD testing allows risk-stratification of patients in morphologic remission in the context of intensive first-line therapy: those with MRD face a higher likelihood (but not certainty) of relapse and shorter survival than similarly treated individuals without MRD; not all of the latter will remain in remission, however [11, 12]. Increasing evidence indicates similar principles apply for patients receiving lower intensity therapies and those receiving treatment for relapsed/refractory AML [13,14,15]. The strong association between MRD and inferior outcomes has been confirmed at several time-points throughout the course of intensive AML therapy: as early as several days after the start of induction chemotherapy; after completion of 1 or 2 courses of induction chemotherapy; after post-remission therapy; both before and after hematopoietic cell transplantation (HCT); and after salvage chemotherapy for relapsed/refractory disease. Furthermore, the negative prognostic impact of a positive MRD test on outcome has been demonstrated irrespective of the MRD testing methodology. MRD data were routinely found to be the most important adverse factor in univariate analyses and, often, the only significant one remaining as an independent factor in multivariable models [1, 2, 11, 12].

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Acknowledgements

RBW acknowledges support from the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research.

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  1. Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Roland B. Walter

  2. Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA

    Roland B. Walter

  3. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

    Roland B. Walter

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Correspondence to Roland B. Walter.

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RBW received laboratory research grants and/or clinical trial support from Aptevo, Celgene, ImmunoGen, Janssen, Jazz, Kite, Kura, and Pfizer; has ownership interests in Amphivena; and is (or has been) a consultant to Abbvie, Adicet, Amphivena, BerGenBio, Bristol Myers Squibb, GlaxoSmithKline, ImmunoGen, Kura, and Orum.

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Walter, R.B. Perspective on measurable residual disease testing in acute myeloid leukemia. Leukemia 38, 10–13 (2024). https://doi.org/10.1038/s41375-023-02084-8

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