Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Towards precision medicine for AML

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

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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

References

  1. Döhner, H., Weisdorf, D. & Bloomfield, C. D. Acute myeloid leukemia. N. Engl. J. Med. 373, 1136–1152 (2015).

    Article  PubMed  CAS  Google Scholar 

  2. Arber, D. A. et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 127, 2391–2405 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

    Article  CAS  Google Scholar 

  4. Papaemmanuil, E. et al. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 374, 2209–2221 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Figueroa, M. E. et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17, 13–27 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Döhner, H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129, 424–447 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Bullinger, L., Döhner, K. & Döhner, H. Genomics of acute myeloid leukemia diagnosis and pathways. J. Clin. Oncol. 35, 934–946 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Voso, M. T. et al. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a sub-analysis from the RATIFY trial. Blood Adv. 4, 4945–4954 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Smith, C. C. The growing landscape of FLT3 inhibition in AML. Hematol. Am. Soc. Hematol. Educ. Program. 2019, 539–547 (2019).

    Article  Google Scholar 

  10. Stone, R. M. et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl. J. Med. 377, 454–464 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schlenk, R. F. et al. Midostaurin added to chemotherapy and continued single agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood 133, 840–851 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Perl, A. E. et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 18, 1061–1075 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cortes, J. et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 19, 889–903 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cortes, J. E. et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 20, 984–997 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Perl, A. E. et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N. Engl. J. Med. 381, 1728–1740 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Burchert, A. et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN). J. Clin. Oncol. 38, 2993–3002 (2020).

    Article  PubMed  Google Scholar 

  17. Xuan, L. et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 21, 1201–1212 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Mathew, N. R. et al. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nat. Med. 24, 282–291 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Smith, C. C. et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485, 260–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Smith, C. C. et al. Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis. Blood 130, 48–58 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schmalbrock, L. K. et al. Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin. Blood https://doi.org/10.1182/blood.2020007626 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  22. McMahon, C. M. et al. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer Discov. 9, 1050–1063 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, H. et al. Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. Nat. Commun. 10, 244 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Yamaura, T. et al. A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations. Blood 131, 426–438 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Piloto, O. et al. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood 109, 1643–1652 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yen, K. et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 7, 478–493 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. DiNardo, C. D. et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N. Engl. J. Med. 378, 2386–2398 (2018).

    Article  CAS  PubMed  Google Scholar 

  31. Stein, E. M. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, 722–731 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stein, E. M. et al. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood 133, 676–687 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Amatangelo, M. D. et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130, 732–741 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fathi, A. T. et al. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol. 4, 1106–1110 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Roboz, G. J. et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 135, 463–471 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pollyea, D. A. et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia 33, 2575–2584 (2019).

    Article  CAS  PubMed  Google Scholar 

  37. Döhner, H. et al. Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care. Leukemia 32, 2546–2557 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Choe, S. et al. Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Adv. 4, 1894–1905 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Intlekofer, A. M. et al. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 559, 125–129 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Harding, J. J. et al. Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition. Cancer Discov. 8, 1540–1547 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. DiNardo, C. D. et al. Enasidenib plus azacitidine significantly improves complete remission and overall response compared with azacitidine alone in patients with newly diagnosed acute myeloid leukemia (AML) with isocitrate dehydrogenase 2 (IDH2) mutations: interim phase II results from an ongoing, randomized study. Blood 134 (Suppl. 1), 643 (2019).

    Article  Google Scholar 

  42. DiNardo, C. D. et al. Mutant IDH1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J. Clin. Oncol. 39, 57–65 (2021).

    Article  PubMed  Google Scholar 

  43. Stein, E. M. et al. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: A phase 1 study. Blood 137, 1792–1803 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chan, S. M. et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat. Med. 21, 178–184 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. DiNardo, C. D. et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N. Engl. J. Med. 383, 617–629 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Lachowiez, C. A. et al. Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax +/− azacitidine in IDH1-mutated hematologic malignancies [abstract]. J. Clin. Oncol. 38 (Suppl.), 7500 (2020).

    Article  Google Scholar 

  47. Molenaar, R. J. et al. IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors. Clin. Cancer Res. 24, 1705–1715 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Maifrede, S. et al. Tyrosine kinase inhibitor-induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors. Blood 132, 67–77 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Brien, G. L., Stegmaier, K. & Armstrong, S. A. Targeting chromatin complexes in fusion protein-driven malignancies. Nat. Rev. Cancer 19, 255–269 (2019).

    Article  CAS  PubMed  Google Scholar 

  50. Uckelmann, H. J. & Armstrong, S. A. Chromatin complexes maintain self-renewal of myeloid progenitors in AML: opportunities for therapeutic interventions. Stem Cell Rep. 15, 6–12 (2020).

    Article  CAS  Google Scholar 

  51. Stein, E. M. et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood 131, 2661–2669 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Borkin, D. et al. Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell 27, 589–602 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Krivtsov, A. V. et al. A menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia. Cancer Cell 36, 660–673 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kühn, M. W. et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 6, 1166–1181 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Uckelmann, H. J. et al. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science 367, 586–590 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Klossowski, S. et al. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J. Clin. Invest. 130, 981–997 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mohr, S. et al. Hoxa9 and Meis1 cooperatively induce addiction to Syk signaling by suppressing miR-146a in acute myeloid leukemia. Cancer Cell 31, 549–562 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Walker, A. R. et al. Entospletinib in combination with induction chemotherapy in previously untreated acute myeloid leukemia: response and predictive significance of HOXA9 and MEIS1 expression. Clin. Cancer Res. 26, 5852–5859 (2020).

    Article  CAS  PubMed  Google Scholar 

  59. Rücker, F. G. et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 119, 2114–2121 (2012).

    Article  PubMed  CAS  Google Scholar 

  60. Boettcher, S. et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science 365, 599–604 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bykov, V. J. N., Eriksson, S. E., Bianchi, J. & Wiman, K. G. Targeting mutant p53 for efficient cancer therapy. Nat. Rev. Cancer 18, 89–102 (2018).

    Article  CAS  PubMed  Google Scholar 

  62. Lehmann, S. et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J. Clin. Oncol. 30, 3633–9 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Zhang, Q., Bykov, V. J. N., Wiman, K. G. & Zawacka-Pankau, J. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis. 9, 439 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Sallman, D. A. et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J. Clin. Oncol. https://doi.org/10.1200/JCO.20.02341 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Cluzeau, T. et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myélodysplasies (GFM). J. Clin. Oncol. https://doi.org/10.1200/JCO.20.02342 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Aprea Therapeutics. Aprea Therapeutics announces results of primary endpoint from phase 3 trial of eprenetapopt in TP53 mutant myelodysplastic syndromes (MDS). Aprea https://ir.aprea.com/news-releases/news-release-details/aprea-therapeutics-announces-results-primary-endpoint-phase-3 (2020).

  67. Sallman D. A. et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in AML patients: phase 1b results. Blood https://doi.org/10.1182/blood-2019-126271 (2019).

  68. Wei, A. H. et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood 135, 2137–2145 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Adams, J. M. & Cory, S. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. 25, 27–36 (2018).

    Article  CAS  PubMed  Google Scholar 

  70. Sattler, M. et al. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275, 983–986 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. Vaux, D. L., Cory, S. & Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442 (1988).

    Article  CAS  PubMed  Google Scholar 

  72. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Mason, K. D. et al. Programmed anuclear cell death delimits platelet life span. Cell 128, 1173–1186 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Van Delft, M. F. et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10, 389–399 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Konopleva, M. et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10, 375–388 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Vo, T. T. et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell 151, 344–355 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Konopleva, M. et al. Efficacy and biological correlates of response in a phase 2 study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 6, 1106–1117 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. DiNardo, C. D. et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 19, 216–228 (2018).

    Article  CAS  PubMed  Google Scholar 

  80. DiNardo, C. D. et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133, 7–17 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wei, A. H. et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J. Clin. Oncol. 37, 1277–1284 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Teh, T.-C. et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia 32, 303–312 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Pollyea, D. A. et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia cells in patients with acute myeloid leukemia. Nat. Med. 24, 1859–1866 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jones, C. L. et al. Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell 34, 724–740.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chyla, B. et al. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am. J. Hematol. 93, E202–205 (2018).

    Article  PubMed Central  Google Scholar 

  86. Chua, C. C. et al. Chemotherapy and venetoclax in elderly acute myeloid leukemia trial (CAVEAT): a phase Ib dose-escalation study of venetoclax combined with modified intensive chemotherapy. J. Clin. Oncol. 38, 3506–3517 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. DiNardo, C. D. et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood 135, 791–803 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Nechiporuk, T. et al. The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov. 9, 910–925 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chen, X. et al. Targeting mitochondrial structure sensitizes acute myeloid leukemia to venetoclax treatment. Cancer Discov. 9, 890–909 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lachowiez, C. et al. Interim analysis of the phase 1b/2 study of the BCL-2 inhibitor venetoclax in combination with standard intensive AML induction/consolidation therapy with FLAG-IDA in patients with newly diagnosed or relapsed/refractory AML. Blood https://doi.org/10.1182/blood-2020-134300 (2020).

  91. Perl, A. E. et al. Venetoclax in combination with gilteritinib in patients with relapsed/refractory acute myeloid leukemia: A Phase 1b Study. Blood 134 (Suppl. 1), 3910 (2019).

    Article  Google Scholar 

  92. Han, L. et al. Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models. Haematologica 105, 697–707 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Daver, N. et al. Preliminary results from a phase Ib study evaluating BCL-2 inhibitor venetoclax in combination with MEK inhibitor cobimetinib or MDM2 inhibitor idasanutlin in patients with relapsed or refractory (R/R) AML. Blood 130, 813–813 (2017).

    Article  Google Scholar 

  94. Glaser, S. P. et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 26, 120–125 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kaufmann, S. H. et al. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood 91, 991–1000 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Pei, S. et al. Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia. Cancer Discov. 10, 536–551 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Moujalled, D. M. et al. Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. Leukemia 33, 905–917 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Caenepeel, S. et al. AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. Cancer Discov. 8, 1582–1597 (2018).

    CAS  PubMed  Google Scholar 

  99. Tron, A. E. et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat. Commun. 9, 5341 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Luedtke, D. A. et al. Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia. Signal. Transduct. Target. Ther. 5, 17 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, X. et al. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev. 27, 1351–1364 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dombret, H. et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126, 291–299 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kantarjian, H. M. et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J. Clin. Oncol. 30, 2670–7 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wei, A. H. et al. Maintenance therapy with CC-486 for patients with acute myeloid leukemia in first remission after chemotherapy. N. Engl. J. Med. 383, 2526–2537 (2020).

    Article  CAS  PubMed  Google Scholar 

  105. Garcia-Manero, G. et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood 136, 674–683 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Garcia-Manero, G. et al. A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. Leukemia 31, 2799–2806 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Craddock, C. F. et al. Outcome of azacitidine therapy in acute myeloid leukemia is not improved by concurrent vorinostat therapy but is predicted by a diagnostic molecular signature. Clin. Cancer Res. 23, 6430–6440 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Garcia-Manero, G. et al. Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study. Blood Adv. 3, 508–518 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Patel, M. R. et al. Phase 1 dose escalation and expansion study to determine safety, tolerability, pharmacokinetics, and pharmacodynamics of the BET inhibitor FT-1101 as a single agent in patients with relapsed or refractory hematologic malignancies. Blood 134 (Suppl. 1), 3907 (2019).

    Article  Google Scholar 

  110. Irvine, D. A. & Copland, M. Targeting hedgehog in hematologic malignancy. Blood 119, 2196–204 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Fukushima, N. et al. Small-molecule hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci. 107, 1422–1429 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cortes, J. E. et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 33, 379–389 (2019).

    Article  CAS  PubMed  Google Scholar 

  113. Castaigne, S. et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 379, 1508–1516 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Lambert, J. et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica 104, 113–119 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ravandi, F. et al. Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML) [abstract]. J. Clin. Oncol. 38 (Suppl.), 7508 (2020).

    Article  Google Scholar 

  116. Uy, G. L. et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood 137, 751–762 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Riether, C. et al. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. J. Exp. Med. 214, 359–380 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Riether, C. et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat. Med. 26, 1459–1467 (2020).

    Article  CAS  PubMed  Google Scholar 

  119. Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138, 286–299 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chao, M. P. et al. Therapeutic targeting of the macrophage immune checkpoint CD47 in myeloid malignancies. Front. Oncol. 9, 1380 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  122. van Rhenen, A. et al. Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. Leukemia 21, 1700–1707 (2007).

    Article  PubMed  CAS  Google Scholar 

  123. Bakker, A. B. et al. C-type lectin-likemolecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. Cancer Res. 64, 8443–8450 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Zhao, X. et al. Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia. Haematologica 95, 71–78 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. van Rhenen, A. et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood 110, 2659–2666 (2007).

    Article  PubMed  CAS  Google Scholar 

  126. Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat. Med. 12, 1167–1174 (2006).

    Article  PubMed  CAS  Google Scholar 

  127. Legras, S. et al. A strong expression of CD44-6v correlates with shorter survival of patients with acute myeloid leukemia. Blood 91, 3401–3413 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. Casucci, M. et al. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood 122, 3461–3472 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Jan, M. et al. Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc. Natl Acad. Sci. USA 108, 5009–5014 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kikushige, Y. et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 7, 708–717 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Vadakekolathu, J. et al. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci. Transl Med. 12, eaaz0463 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kapp-Schwoerer, S. et al. Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial. Blood 136, 3041–3050 (2020).

    Article  CAS  PubMed  Google Scholar 

  133. Fournier, E. et al. Mutational profile and benefit of gemtuzumab ozogamicin in acute myeloid leukemia. Blood 135, 542–546 (2020).

    Article  PubMed  Google Scholar 

  134. Bewersdorf, J. P. & Zeidan, A. M. Randomized trials with checkpoint inhibitors in acute myeloid leukaemia and myelodysplastic syndromes: What have we learned so far and where are we heading? Best Pract. Res. Clin. Haematol. 33, 101222 (2020).

    Article  PubMed  Google Scholar 

  135. Kim, M. Y. et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell 173, 1439–1453 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Cartellieri, M. et al. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J. 6, e458 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Loff, S. et al. Rapidly switchable universal CAR-T cells for treatment of CD123-positive leukemia. Mol. Ther. Oncolytics 17, 408–420 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Miles, L. A. et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 587, 477–482 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Morita, K. et al. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics. Nat. Commun. 11, 5327 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Burd, A. et al. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial. Nat. Med. 26, 1852–1858 (2020).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  141. Schuurhuis, G. J. et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood 131, 1275–1291 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Yates, J. W. et al. Cytosine arabinoside and daunorubicin therapy in acute nonlymphocytic leukemia. Cancer Chemother. Rep. 52, 485–488 (1973).

    Google Scholar 

Download references

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).

Author information

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

Authors
  1. Hartmut Döhner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew H. Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bob Löwenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors made a substantial contribution to all aspects of the preparation of the manuscript.

Corresponding author

Correspondence to Hartmut Döhner.

Ethics declarations

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.

Additional information

Peer review information

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.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-021-00509-w

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer