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Measurable residual disease testing in acute myeloid leukaemia

Leukemia volume 31, pages 1482–1490 (2017)Cite this article

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Abstract

There is considerable interest in developing techniques to detect and/or quantify remaining leukaemia cells termed measurable or, less precisely, minimal residual disease (MRD) in persons with acute myeloid leukaemia (AML) in complete remission defined by cytomorphological criteria. An important reason for AML MRD-testing is the possibility of estimating the likelihood (and timing) of leukaemia relapse. A perfect MRD-test would precisely quantify leukaemia cells biologically able and likely to cause leukaemia relapse within a defined interval. AML is genetically diverse and there is currently no uniform approach to detecting such cells. Several technologies focused on immune phenotype or cytogenetic and/or molecular abnormalities have been developed, each with advantages and disadvantages. Many studies report a positive MRD-test at diverse time points during AML therapy identifies persons with a higher risk of leukaemia relapse compared with those with a negative MRD-test even after adjusting for other prognostic and predictive variables. No MRD-test in AML has perfect sensitivity and specificity for relapse prediction at the cohort- or subject levels and there are substantial rates of false-positive and -negative tests. Despite these limitations, correlations between MRD-test results and relapse risk have generated interest in MRD-test result-directed therapy interventions. However, convincing proof that a specific intervention will reduce relapse risk in persons with a positive MRD-test is lacking and needs testing in randomized trials. Routine clinical use of MRD-testing requires further refinements and standardization/harmonization of assay platforms and results reporting. Such data are needed to determine whether results of MRD-testing can be used as a surrogate end point in AML therapy trials. This could make drug-testing more efficient and accelerate regulatory approvals. Although MRD-testing in AML has advanced substantially, much remains to be done.

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Acknowledgements

Frederick R Appelbaum (Fred Hutchinson Cancer Research Center), Anton Hagenbeek (University of Utrecht), Jacob M Rowe (Sharee Zedek Medical Centre), Charles A Schiffer (Wayne State University), Jerald P Radich (Fred Hutchinson Cancer Research Center), Paresh Vyas (University of Oxford) and Donna Przepiorka (US Food and Drug Administration) kindly reviewed the typescript. This work was supported in part by the Intramural Research Programs of the National Heart, Lung, and Blood Institute of the National Institutes of Health. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. RBW is a Leukemia & Lymphoma Society Scholar in Clinical Research. The opinions expressed here are ours and do not represent the official position of the National Institutes of Health, US Food and Drug Administration, or the United States Government.

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Authors and Affiliations

  1. Myeloid Malignancies Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    C S Hourigan

  2. Division of Experimental Medicine, Department of Medicine, Haematology Research Centre, Imperial College London, London, UK

    R P Gale

  3. Division of Hematology Products, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    N J Gormley

  4. Division of Hematology, VU University Medical Center, Amsterdam, The Netherlands

    G J Ossenkoppele

  5. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    R B Walter

  6. Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA

    R B Walter

  7. Department of Epidemiology, University of Washington, Seattle, WA, USA

    R B Walter

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  1. C S Hourigan
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Correspondence to C S Hourigan or R B Walter.

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CSH receives research funding from Merck Sharpe and Dohme and SELLAS Life Sciences Group AG. RPG is a part-time employee of Celgene Corp. The remaining authors declare no conflict of interest.

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Hourigan, C., Gale, R., Gormley, N. et al. Measurable residual disease testing in acute myeloid leukaemia. Leukemia 31, 1482–1490 (2017). https://doi.org/10.1038/leu.2017.113

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