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  • Review Article
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Towards precision medicine for AML

Nature Reviews Clinical Oncology volume 18, pages 577–590 (2021)Cite this article

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Abstract

With rapid advances in sequencing technologies, tremendous progress has been made in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), thus revealing enormous genetic and clonal heterogeneity, and paving the way for precision medicine approaches. The successful development of precision medicine for patients with AML has been exemplified by the introduction of targeted FLT3, IDH1/IDH2 and BCL-2 inhibitors. When used as single agents, these inhibitors display moderate antileukaemic activity. However, augmented clinical activity has been demonstrated when they are administered in combination with drugs with broader mechanisms of action targeting epigenetic and/or other oncogenic signalling pathways or with conventional cytotoxic agents. The development of immunotherapies has been hampered by the expression of antigens that are expressed by both leukaemic and non-malignant haematopoietic progenitor cells; nonetheless, a diverse range of immunotherapies are now entering clinical development. This myriad of emerging agents also creates challenges, such as how to safely combine agents with different mechanisms of action, the need to circumvent primary and secondary resistance, and new challenges in future clinical trial design. In this Review, we discuss the current state of precision medicine for AML, including both the potential to improve patient outcomes and the related challenges.

Key points

  • Tremendous progress has been made in deciphering the molecular pathogenesis of acute myeloid leukaemia (AML), enabling the development of precision medicines.

  • Examples of the successful development of precision medicines include the introduction of small-molecule inhibitors of FLT3, IDH1/IDH2 and BCL-2.

  • When administered as single agents, these inhibitors exert substantial activity in patients with relapsed and/or refractory AML.

  • Combining these inhibitors with standard-of-care therapies or the use of combinations of novel agents augments clinical activity and can overcome both the primary resistance and the acquired resistance associated with use of the same agents as monotherapies.

  • The development of immunotherapies in AML has been impeded by the expression of antigens shared by leukaemic and non-malignant haematopoietic stem and progenitor cells, although novel approaches that bypass these obstacles are currently being actively pursued.

  • New trial designs and an increased level of international collaboration are being examined in an attempt to foster the more rapid development of new agents, in particular for smaller biologically defined subsets of patients with AML.

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Fig. 1: Cellular targets for precision medicine in AML.
Fig. 2: Diagnostic work-up for precision medicine in AML.

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Acknowledgements

The work of H.D is supported in part by the Deutsche Forschungsgemeinschaft (DFG; Collaborative Research Center 1074), DFG grant DO 436/7-1, and a grant by the Bundesministerium für Bildung und Forschung (BMBF; DRAMA 01KT1603).

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Authors and Affiliations

  1. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    Hartmut Döhner

  2. Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, VIC, Australia

    Andrew H. Wei

  3. Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands

    Bob Löwenberg

  4. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands

    Bob Löwenberg

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  1. Hartmut Döhner
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  2. Andrew H. Wei
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  3. Bob Löwenberg
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All authors made a substantial contribution to all aspects of the preparation of the manuscript.

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Correspondence to Hartmut Döhner.

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Competing interests

H.D. has acted as an advisor for AbbVie, Agios, Amgen, Astellas, Astex Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Celgene, GEMoaB, Helsinn, Janssen, Jazz Pharmaceuticals, Novartis, Oxford Biomedica and Roche, and has received research funding from Agios, Amgen, Astellas, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis and Pfizer. A.W. has acted as an advisor for AbbVie, Agios, Amgen, Bristol Myers Squibb, Gilead, Janssen, Macrogenics, Novartis, Pfizer, Roche and Servier, has received research funding from AbbVie, Amgen, Astra Zeneca, Bristol Myers Squibb, Novartis and Servier, serves on speakers bureaus for AbbVie, Celgene and Novartis, and receives royalty payments from the Walter and Eliza Hall Institute of Medical Research related to venetoclax. B.L. has acted as an advisor for AbbVie, AIMM Therapeutics, Astellas, Catamaran Bio Inc., Bristol Myers Squibb, Celgene, Clear Creek Bio, F. Hoffmann La Roche, GEMoaB, Kronos Bio Inc and Oxford Biomedica, and holds shares in Frame Pharmaceuticals.

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Nature Reviews Clinical Oncology thanks A. Venditti, A. Perl and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Döhner, H., Wei, A.H. & Löwenberg, B. Towards precision medicine for AML. Nat Rev Clin Oncol 18, 577–590 (2021). https://doi.org/10.1038/s41571-021-00509-w

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