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Acute myeloid leukaemia

Nature Reviews Disease Primers volume 2, Article number: 16010 (2016) Cite this article

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Abstract

Acute myeloid leukaemia (AML) is a disorder characterized by a clonal proliferation derived from primitive haematopoietic stem cells or progenitor cells. Abnormal differentiation of myeloid cells results in a high level of immature malignant cells and fewer differentiated red blood cells, platelets and white blood cells. The disease occurs at all ages, but predominantly occurs in older people (>60 years of age). AML typically presents with a rapid onset of symptoms that are attributable to bone marrow failure and may be fatal within weeks or months when left untreated. The genomic landscape of AML has been determined and genetic instability is infrequent with a relatively small number of driver mutations. Mutations in genes involved in epigenetic regulation are common and are early events in leukaemogenesis. The subclassification of AML has been dependent on the morphology and cytogenetics of blood and bone marrow cells, but specific mutational analysis is now being incorporated. Improvements in treatment in younger patients over the past 35 years has largely been due to dose escalation and better supportive care. Allogeneic haematopoietic stem cell transplantation may be used to consolidate remission in those patients who are deemed to be at high risk of relapse. A plethora of new agents — including those targeted at specific biochemical pathways and immunotherapeutic approaches — are now in trial based on improved understanding of disease pathophysiology. These advances provide good grounds for optimism, although mortality remains high especially in older patients.

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Figure 1: Schematic overview of the main types of leukaemia.
Figure 2: UK incidence of AML by sex and age.
Figure 3: Age-related survival in England, Sweden and the United States.
Figure 4: Schematic representation of the epigenetic modifiers that are frequently mutated in AML.
Figure 5: Normal and leukaemic haematopoiesis.
Figure 6: Bone marrow smears in AML.
Figure 7: Schematic overview of disease-free survival.
Figure 8: Haematopoietic stem cell transplantation strategies in AML.
Figure 9: Targeting cell signalling to treat AML.

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References

  1. Cancer Research UK. Acute myeloid leukaemia (AML) incidence statistics. Cancer Research UK[online], (accessed Jan 2015).

  2. Derolf, A. R. et al. Improved patient survival for acute myeloid leukemia: a population-based study of 9729 patients diagnosed in Sweden between 1973 and 2005. Blood 113, 3666–3672 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Sant, M. et al. Survival for haematological malignancies in Europe between 1997 and 2008 by region and age: results of EUROCARE-5, a population-based study. Lancet Oncol. 15, 931–942 (2014).

    Article  PubMed  Google Scholar 

  4. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013). This study from the Cancer Genome Atlas Research Network details a comprehensive catalogue of genetic abnormalities (genomic, transcriptomic and epigenomic) identified in 200 adult patients with AML, demonstrates the molecular complexity and heterogeneity of the disease and provides a platform for future classification of patients and potential areas of research.

    Article  CAS  Google Scholar 

  5. Lindsley, R. C. et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125, 1367–1376 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Swerdllow, S. H. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn (IARC Press, 2008).

    Google Scholar 

  7. Bennett, J. M. et al. Proposals for the classification of the acute leukaemias. French–American–British (FAB) co-operative group. Br. J. Haematol. 33, 451–458 (1976).

    Article  CAS  PubMed  Google Scholar 

  8. Juliusson, G. et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 113, 4179–4187 (2009). This is a population-based study showing that the total survival of elderly patients with AML was better in the geographical regions where most of them were given standard intensive therapy.

    Article  CAS  PubMed  Google Scholar 

  9. Juliusson, G., Lazarevic, V., Hörstedt, A.-S., Hagberg, O. & Höglund, M. Acute myeloid leukemia in the real world: why population-based registries are needed. Blood 119, 3890–3899 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Latin American Leukemia Net. Acute myeloid leukemia. Latin American Leukemia Net (LALNET)[online], (2009).

  11. Dores, G. M., Devesa, S. S., Curtis, R. E., Linet, M. S. & Morton, L. M. Acute leukemia incidence and patient survival among children and adults in the United States, 2001–2007. Blood 119, 34–43 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Craig, B. M., Rollison, D. E., List, A. F. & Cogle, C. R. Underreporting of myeloid malignancies by United States cancer registries. Cancer Epidemiol. Biomarkers Prev. 21, 474–481 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Polednak, A. P. Recent improvement in completeness of incidence data on acute myeloid leukemia in US cancer registries. J. Registry Manag. 41, 77–84 (2014).

    PubMed  Google Scholar 

  14. Puumala, S. E., Ross, J. A., Aplenc, R. & Spector, L. G. Epidemiology of childhood acute myeloid leukemia. Pediatr. Blood Cancer 60, 728–733 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hjalgrim, L. L. et al. Age- and sex-specific incidence of childhood leukemia by immunophenotype in the Nordic countries. J. Natl Cancer Inst. 95, 1539–1544 (2003).

    Article  PubMed  Google Scholar 

  16. Matsuo, K. & Ito, H. Descriptive epidemiology of myeloid leukemia. Nihon Rinsho 67, 1847–1851 (in Japanese) (2009).

    PubMed  Google Scholar 

  17. Wang, Y.-C., Wei, L.-J., Liu, J.-T., Li, S.-X. & Wang, Q.-S. Comparison of cancer incidence between China and the USA. Cancer Biol. Med. 9, 128–132 (2012).

    PubMed  PubMed Central  Google Scholar 

  18. Pan, J. W. Y., Cook, L. S., Schwartz, S. M. & Weis, N. S. Incidence of leukemia in Asian migrants to the United States and their descendants. Cancer Causes Control 13, 791–795 (2002).

    Article  PubMed  Google Scholar 

  19. Douer, D. The epidemiology of acute promyelocytic leukaemia. Best Pract. Res. Clin. Haematol. 16, 357–367 (2003).

    Article  PubMed  Google Scholar 

  20. Shimizu, Y., Schull, W. J. & Kato, H. Cancer risk among atomic bomb survivors. The RERF Life Span study. Radiation Effects Research Foundation. JAMA 264, 601–604 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Bueso-Ramos, C. E., Kanagal-Shamanna, R., Routbort, M. J. & Hanson, C. A. Therapy-related myeloid neoplasms. Am. J. Clin. Pathol. 144, 207–218 (2015).

    Article  PubMed  Google Scholar 

  22. Carney, D. A. et al. Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy. Leukemia 24, 2056–2062 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Morrison, V. A. et al. Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J. Clin. Oncol. 15, 3878–3884 (2002).

    Article  Google Scholar 

  24. Niparuck, P. et al. Therapy-related myelodysplastic syndrome/acute myeloid leukemia following fludarabine therapy for non-Hodgkin lymphoma and chronic lymphocytic leukemia in Thai patients. Leuk. Lymphoma 51, 2120–2125 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Landgren, O. et al. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 first-degree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden. Blood 112, 2199–2204 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Goldin, L. R. et al. Familial aggregation of acute myeloid leukemia and myelodysplastic syndromes. J. Clin. Oncol. 30, 179–183 (2012). In adults, no evidence for familial aggregation of AML or MDS was observed, but an increased risk of all haematological malignancies and of solid tumours among relatives of patients with AML suggests that genes for malignancy in general and/or other environmental factors may be shared.

    Article  PubMed  Google Scholar 

  27. Seif, A. E. Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis. Cancer Genet. 204, 227–244 (2011).

    Article  PubMed  Google Scholar 

  28. Burnett, A., Wetzler, M. & Löwenberg, B. Therapeutic advances in acute myeloid leukemia. J. Clin. Oncol. 29, 487–494 (2011).

    Article  PubMed  Google Scholar 

  29. Lazarevic, V. et al. Incidence and prognostic significance of karyotypic subgroups in older patients with acute myeloid leukemia: the Swedish population-based experience. Blood Cancer J. 4, e188 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Luke, C. et al. Myeloid leukaemia treatment and survival — the South Australian experience, 1977 to 2002. Asian Pac. J. Cancer Prev. 7, 227–233 (2006).

    PubMed  Google Scholar 

  31. Pulte, D., Gondos, A. & Brenner, H. Improvements in survival of adults diagnosed with acute myeloblastic leukemia in the early 21st century. Haematologica 93, 594–600 (2008).

    Article  PubMed  Google Scholar 

  32. Shah, A., Andersson, T. M.-L., Rachet, B., Björkholm, M. & Lambert, P. C. Survival and cure of acute myeloid leukaemia in England, 1971–2006: a population-based study. Br. J. Haematol. 162, 509–516 (2013). In this paper, substantial differences in cure for patients <40 years of age between England and Sweden from 2000 were described, which may be explained by variations in time to diagnosis, prognostic factors, transplantation and treatment.

    Article  PubMed  Google Scholar 

  33. Bower, H. et al. Assessing temporal trends in survival of acute myeloid leukemia patients using the loss in expectation of life. ANCR[online], (2014).

  34. Andersson, T. M.-L. et al. Temporal trends in the proportion cured among adults diagnosed with acute myeloid leukaemia in Sweden 1973–2001, a population-based study. Br. J. Haematol. 148, 918–924 (2010).

    Article  PubMed  Google Scholar 

  35. Juliusson, G. et al. Attitude towards remission induction for elderly patients with acute myeloid leukemia influences survival. Leukemia 20, 42–47 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Pulte, D., Redaniel, M. T., Jansen, L., Brenner, H. & Jeffreys, M. Recent trends in survival of adult patients with acute leukemia: overall improvements, but persistent and partly increasing disparity in survival of patients from minority groups. Haematologica 98, 222–229 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kristinsson, S. Y., Derolf, A. R., Edgren, G., Dickman, P. W. & Björkholm, M. Socioeconomic differences in patient survival are increasing for acute myeloid leukemia and multiple myeloma in Sweden. J. Clin. Oncol. 27, 2073–2080 (2009).

    Article  PubMed  Google Scholar 

  38. Grimwade, D. & Mrózek, K. Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia. Hematol. Oncol. Clin. North Am. 25, 1135–1161 (2011).

    Article  PubMed  Google Scholar 

  39. Mrózek, K. et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J. Clin. Oncol. 30, 4515–4523 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Grimwade, D. et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116, 354–365 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Grisolano, J. L., O'Neal, J., Cain, J. & Tomasson, M. H. An activated receptor tyrosine kinase, TEL/PDGFβR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. Proc. Natl Acad. Sci. USA 100, 9506–9511 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schessl, C. et al. The AML1–ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J. Clin. Invest. 115, 2159–2168 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Greif, P. A. et al. GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia. Blood 120, 395–403 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Kottaridis, P. D. et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United King. Blood 98, 1752–1759 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Marcucci, G. et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J. Clin. Oncol. 28, 2348–2355 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Thiede, C. et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99, 4326–4335 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Linch, D. C., Hills, R. K., Burnett, A. K., Khwaja, A. & Gale, R. E. Impact of FLT3ITD mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood 124, 273–276 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Sinha, S. et al. Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML and responds to EZH2 inhibition. Blood 125, 316–326 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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 

  51. Abdel-Wahab, O. et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 22, 180–193 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Holz-Schietinger, C., Matje, D. M. & Reich, N. O. Mutations in DNA methyltransferase (DNMT3A) observed in acute myeloid leukemia patients disrupt processive methylation. J. Biol. Chem. 287, 30941–30951 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Patel, J. P. et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 366, 1079–1089 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sehgal, A. R. et al. DNMT3A mutational status affects the results of dose-escalated induction therapy in acute myelogenous leukemia. Clin. Cancer Res. 21, 1614–1620 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360, 2289–2301 (2009).

    Article  PubMed  Google Scholar 

  57. Metzeler, K. H. et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J. Clin. Oncol. 29, 1373–1381 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  58. 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 

  59. Becker, H. et al. Mutations of the Wilms tumor 1 gene (WT1) in older patients with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood 116, 788–792 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Virappane, P. et al. Mutation of the Wilms' tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J. Clin. Oncol. 26, 5429–5435 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Rampal, R. et al. DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Rep. 9, 1841–1855 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gross, S. et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med. 207, 339–344 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dick, J. E. Acute myeloid leukemia stem cells. Ann. NY Acad. Sci. 1044, 1–5 (2005).

    Article  PubMed  Google Scholar 

  69. Kelly, P. N., Dakic, A., Adams, J. M., Nutt, S. L. & Strasser, A. Tumor growth need not be driven by rare cancer stem cells. Science 317, 337 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Taussig, D. C. et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood 112, 568–575 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Sarry, J.-E. et al. Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice. J. Clin. Invest. 121, 384–395 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Shlush, L. I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ugale, A. et al. Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation. Cell Rep. 9, 1246–1255 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. 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 

  75. Jin, L. et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor α chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 5, 31–42 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Lagadinou, E. D. et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12, 329–341 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bernt, K. M. et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jordan, C. T., Guzman, M. L. & Noble, M. Cancer stem cells. N. Engl. J. Med. 355, 1253–1261 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Score, J. et al. Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals. Leukemia 29, 1600–1602 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Barabé, F., Kennedy, J. A., Hope, K. J. & Dick, J. E. Modeling the initiation and progression of human acute leukemia in mice. Science 316, 600–604 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Röllig, C. & Ehninger, G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood 125, 3246–3252 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Kim, H. et al. Analysis of fatal intracranial hemorrhage in 792 acute leukemia patients. Haematologica 89, 622–624 (2004).

    PubMed  Google Scholar 

  85. Cheson, B. D. et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J. Clin. Oncol. 21, 4642–4649 (2003).

    Article  PubMed  Google Scholar 

  86. Bene, M. C. et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 9, 1783–1786 (1995).

    CAS  PubMed  Google Scholar 

  87. Estey, E. H. Acute myeloid leukemia: 2013 update on risk-stratification and management. Am. J. Hematol. 88, 318–327 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Walter, M. J. et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc. Natl Acad. Sci. USA 106, 12950–12955 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Iacobucci, I., Lonetti, A., Papayannidis, C. & Martinelli, G. Use of single nucleotide polymorphism array technology to improve the identification of chromosomal lesions in leukemia. Curr. Cancer Drug Targets 13, 791–810 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jaffe, E. S. et al. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues (IARC Press, 2001).

    Google Scholar 

  91. Byrd, J. C. et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100, 4325–4336 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Slovak, M. L. et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 96, 4075–4083 (2000).

    CAS  PubMed  Google Scholar 

  93. Breems, D. A. & Löwenberg, B. Acute myeloid leukemia with monosomal karyotype at the far end of the unfavorable prognostic spectrum. Haematologica 96, 491–493 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Kayser, S. et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood 119, 551–558 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Medeiros, B. C., Othus, M., Fang, M., Appelbaum, F. R. & Erba, H. P. Cytogenetic heterogeneity negatively impacts outcomes in patients with acute myeloid leukemia. Haematologica 100, 331–335 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Lindsley, R. C. & Ebert, B. L. The biology and clinical impact of genetic lesions in myeloid malignancies. Blood 122, 3741–3748 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Gale, R. E. et al. Simpson's paradox and the impact of different DNMT3A mutations on outcome in younger adults with acute myeloid leukemia. J. Clin. Oncol. 33, 2072–2083 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Falini, B. et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N. Engl. J. Med. 352, 254–266 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Wouters, B. J. et al. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 113, 3088–3091 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Tomasetti, C. & Vogelstein, B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Löwenberg, B. & Pabst, T. Cytarabine dose for acute myeloid leukemia. N. Engl. J. Med. 17, 1027–1036 (2011).

    Article  Google Scholar 

  102. Döhner, H. et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115, 453–474 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Walter, R. B. et al. Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center study. J. Clin. Oncol. 28, 1766–1771 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Othus, M. et al. Declining rates of treatment-related mortality in patients with newly diagnosed AML given ‘intense’ induction regimens: a report from SWOG and MD Anderson. Leukemia 28, 289–292 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Cornely, O. A. et al. Posaconazole versus fluconazole or itraconazole prophylaxis in patients with neutropenia. N. Engl. J. Med. 356, 348–359 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Rolston, K. V. I. Neutropenic fever and sepsis: evaluation and management. Cancer Treat. Res. 161, 181–202 (2014).

    Article  PubMed  Google Scholar 

  107. Gardner, A. et al. Randomized comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J. Clin. Oncol. 26, 5684–5688 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Giles, F. J. et al. Leukapheresis reduces early mortality in patients with acute myeloid leukemia with high white cell counts but does not improve long- term survival. Leuk. Lymphoma 42, 67–73 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Al Ameri, A. et al. Acute pulmonary failure during remission induction chemotherapy in adults with acute myeloid leukemia or high-risk myelodysplastic syndrome. Cancer 116, 93–97 (2010).

    PubMed  Google Scholar 

  110. de Lima, M. et al. Implications of potential cure in acute myelogenous leukemia: development of subsequent cancer and return to work. Blood 90, 4719–4724 (1997).

    CAS  PubMed  Google Scholar 

  111. Willemze, R. et al. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial. J. Clin. Oncol. 32, 219–228 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Löwenberg, B. Sense and nonsense of high-dose cytarabine for acute myeloid leukemia. Blood 121, 26–28 (2013). This is a good summary of the literature on high-dose cytarabine, showing that doses of 2–3 g per m2 often used are unnecessary.

    Article  PubMed  Google Scholar 

  113. Luskin, M. R. et al. Benefit of high dose daunorubicin in AML induction extends across cytogenetic and molecular groups: updated analysis of E1900. Bloodhttp://dx.doi.org/10.1182/blood-2015-07-657403 (2016).

  114. Burnett, A. K. et al. A randomized comparison of daunorubicin 90 mg/m2 versus 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 125, 3878–3885 (2015). Although doses of 90 mg per m2 of daunorubicin daily for 3 days have recently come into vogue (90 mg per m2 has been shown to be superior to 45 mg per m2), this paper shows general equivalence between 90 mg per m2 daily for 3 days and the commonly used 60 mg per m2 daily for 3 days.

  115. Burnett, A. K. et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J. Clin. Oncol. 31, 3360–3368 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Hills, R. K. et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 15, 986–996 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Stone, R. M. et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18–60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). American Society of Hematology Annual Meeting and Exposition[online], (2015).

  118. Walter, R. B. et al. Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center. Leukemia 29, 312–320 (2015).

    Article  CAS  PubMed  Google Scholar 

  119. Chen, X. et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J. Clin. Oncol. 33, 1258–1264 (2015).

    Article  PubMed  Google Scholar 

  120. Kayser, S., Schlenk, R. F., Grimwade, D., Yosuico, V. E. D. & Walter, R. B. Minimal residual disease-directed therapy in acute myeloid leukemia. Blood 125, 2331–2335 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. de Thé, H. & Chen, Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat. Rev. Cancer 10, 775–783 (2010).

    Article  CAS  PubMed  Google Scholar 

  122. Lo-Coco, F. et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369, 111–121 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Sanz, M. A. et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113, 1875–1891 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Burnett, A. K. et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 109, 1114–1124 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Fenaux, P. et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J. Clin. Oncol. 28, 562–569 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. 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, 2670–2677 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Dombret, H. et al. International Phase 3 study of azacitidine versus 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 

  128. Seymour, J. F. Azacitidine versus conventional care regimens in older patients with newly diagnosed acute myeloid leukemia (>30% bone marrow blasts) with myelodysplasia-related changes: a subgroup analysis of the AZA-AML-001 trial. Blood Abstr. 124, 10 (2014).

    Google Scholar 

  129. Hills, R. K. & Burnett, A. K. Applicability of a ‘Pick a Winner’ trial design to acute myeloid leukemia. Blood 118, 2389–2394 (2011).

    Article  CAS  PubMed  Google Scholar 

  130. Burnett, A. K. et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood 122, 1384–1394 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Burnett, A. K. et al. The addition of the farnesyl transferase inhibitor, tipifarnib, to low dose cytarabine does not improve outcome for older patients with AML. Br. J. Haematol. 158, 519–522 (2012).

    Article  CAS  PubMed  Google Scholar 

  132. Burnett, A. K. et al. The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 Pick-a-Winner comparison. Leukemia 27, 75–81 (2013).

    Article  CAS  PubMed  Google Scholar 

  133. Burnett, A. K. et al. A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia 29, 1312–1319 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Dennis, M. et al. Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) versus low-dose Ara-C alone in older patients with acute myeloid leukemia. Blood 125, 2923–2932 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Koreth, J. et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301, 2349–2361 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Cornelissen, J. J. et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat. Rev. Clin. Oncol. 9, 579–590 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Terwijn, M. et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J. Clin. Oncol. 31, 3889–3897 (2013).

    Article  PubMed  Google Scholar 

  138. Cornelissen, J. J. et al. Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories. J. Clin. Oncol. 30, 2140–2146 (2012).

    Article  PubMed  Google Scholar 

  139. Gratwohl, A. et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer 115, 4715–4726 (2009).

    Article  PubMed  Google Scholar 

  140. Sorror, M. L. et al. Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood 110, 4606–4613 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Barba, P. et al. Combination of the Hematopoietic Cell Transplantation Comorbidity Index and the European Group for Blood and Marrow Transplantation score allows a better stratification of high-risk patients undergoing reduced-toxicity allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 20, 66–72 (2014).

    Article  PubMed  Google Scholar 

  142. Versluis, J. et al. Prediction of non-relapse mortality in recipients of reduced intensity conditioning allogeneic stem cell transplantation with AML in first complete remission. Leukemia 29, 51–57 (2015).

    Article  CAS  PubMed  Google Scholar 

  143. Sorror, M. L. et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J. Clin. Oncol. 32, 3249–3256 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Russell, N. H. et al. A comparative assessment of the curative potential of reduced intensity allografts in acute myeloid leukaemia. Leukemia 29, 1478–1484 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Cornelissen, J. J. et al. Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40–60 years. Leukemia 29, 1041–1050 (2015).

    Article  CAS  PubMed  Google Scholar 

  146. Stelljes, M. et al. Allogeneic transplantation versus chemotherapy as postremission therapy for acute myeloid leukemia: a prospective matched pairs analysis. J. Clin. Oncol. 32, 288–296 (2014).

    Article  PubMed  Google Scholar 

  147. Burnett, A. K. et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties. Lancet 351, 700–708 (1998).

    Article  CAS  PubMed  Google Scholar 

  148. Vellenga, E. et al. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood 118, 6037–6042 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. Scheinberg, D. A. et al. Monoclonal antibody M195: a diagnostic marker for acute myelogenous leukemia. Leukemia 3, 440–445 (1989).

    CAS  PubMed  Google Scholar 

  150. Dao, T. et al. Targeting the intracellular WT1 oncogene product with a therapeutic human antibody. Sci. Transl. Med. 5, 176ra33 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Greiner, J., Bullinger, L., Guinn, B., Döhner, H. & Schmitt, M. Leukemia-associated antigens are critical for the proliferation of acute myeloid leukemia cells. Clin. Cancer Res. 14, 7161–7166 (2008).

    Article  CAS  PubMed  Google Scholar 

  152. Dubrovsky, L. et al. A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR–ABL+ leukemias. Blood 123, 3296–3304 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Sergeeva, A. et al. An anti-PR1/HLA-A2 T-cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells. Blood 117, 4262–4272 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Jurcic, J. G., DeBlasio, T., Dumont, L., Yao, T. J. & Scheinberg, D. A. Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clin. Cancer Res. 6, 372–380 (2000).

    CAS  PubMed  Google Scholar 

  155. Bross, P. F. et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin. Cancer Res. 7, 1490–1496 (2001).

    CAS  PubMed  Google Scholar 

  156. Giles, F. J. et al. Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer 92, 406–413 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Gamis, A. S. et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized Phase III children's oncology group trial AAML0531. J. Clin. Oncol. 32, 3021–3032 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Shenoi, J., Gopal, A. K., Press, O. W. & Pagel, J. M. Recent advances in novel radioimmunotherapeutic approaches for allogeneic hematopoietic cell transplantation. Curr. Opin. Oncol. 22, 143–149 (2010).

    Article  PubMed  Google Scholar 

  159. Rosenblat, T. L. et al. Sequential cytarabine and α-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin. Cancer Res. 16, 5303–5311 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. McDevitt, M. R. et al. Tumor therapy with targeted atomic nanogenerators. Science 294, 1537–1540 (2001).

    Article  CAS  PubMed  Google Scholar 

  161. Wang, Q. et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol. Ther. 23, 184–191 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Friedrich, M. et al. Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia. Mol. Cancer Ther. 13, 1549–1557 (2014).

    Article  CAS  PubMed  Google Scholar 

  163. Levis, M. J. et al. Final results of a Phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. American Society of Hematology Annual Meeting and Exposition[online], (2012).

  164. Konig, H. & Levis, M. Targeting FLT3 to treat leukemia. Expert Opin. Ther. Targets 19, 37–54 (2015).

    Article  CAS  PubMed  Google Scholar 

  165. Sato, T. et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 117, 3286–3293 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Johnson, D. B., Smalley, K. S. M. & Sosman, J. A. Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia. Clin. Cancer Res. 20, 4186–4192 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Burgess, M. R. et al. Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood 124, 3947–3955 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Jain, N. et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago Phase II consortium trial. Clin. Cancer Res. 20, 490–498 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. Eghtedar, A. et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood 119, 4614–4618 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Sujobert, P. et al. Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106, 1063–1066 (2005). Constitutive activation of mTORC1 sensitizes leukaemic cells to cell death induced by specific GSK621-induced 5′ AMP-activated protein kinase (AMPK) activation. GSK621 generates cytotoxicity by activating autophagy that is independent of mTORC1 inhibition, and the eukaryotic initiation factor 2α–activating transcription factor 4 signalling pathway is crucial for this lethal interaction between activated mTORC1 and AMPK.

  171. Chapuis, N. et al. Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia. Clin. Cancer Res. 16, 5424–5435 (2010).

    Article  CAS  PubMed  Google Scholar 

  172. US National Library of Science. Study to assess safety, tolerability and preliminary efficacy of BKM120, PI3K kinase inhibitor, with advanced leukemias. ClinicalTrials.gov[online], (2011).

  173. US National Library of Science. Phase I, dose-finding study of BEZ235 in adult patients with relapsed or refractory acute leukemia. ClinicalTrials.gov[online], (2012).

  174. US National Library of Science. Pilot trial of sirolimus/MEC in high risk acute myelogenous leukemia (AML). ClinicalTrials.gov[online], (2010).

  175. US National Library of Science. PF-05212384 (PKI-587) for t-AML/MDS or de novo relapsed or refractory acute myeloid leukemia (AML) (LAM-PIK). ClinicalTrials.gov[online], (2015).

  176. US National Library of Science. Sirolimus, idarubicin, and cytarabine in treating patients with newly diagnosed acute myeloid leukemia. ClinicalTrials.gov[online], (2013).

  177. Récher, C. et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 105, 2527–2534 (2005).

    Article  CAS  PubMed  Google Scholar 

  178. Park, S. et al. A Phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse. Leukemia 27, 1479–1486 (2013).

    Article  CAS  PubMed  Google Scholar 

  179. Garcia, P. D. et al. Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin. Cancer Res. 20, 1834–1845 (2014).

    Article  CAS  PubMed  Google Scholar 

  180. Keeton, E. K. et al. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood 123, 905–913 (2014). AZD1208 inhibits the three isoforms of the PIM kinases and induces cell cycle arrest and apoptosis in AML cell lines through regulating the activity of PIM1 and the activation of signal transducer and activator of transcription 5. AZD1208 has significant anti-leukaemic activity in primary AML cells and in vivo in xenograft tumours.

  181. Rushworth, S. A., Murray, M. Y., Zaitseva, L., Bowles, K. M. & MacEwan, D. J. Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia. Blood 123, 1229–1238 (2014).

    Article  CAS  PubMed  Google Scholar 

  182. Fialin, C. et al. The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors. Leukemia 27, 325–335 (2013).

    Article  CAS  PubMed  Google Scholar 

  183. Puissant, A. et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 25, 226–242 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Moore, A. S., Blagg, J., Linardopoulos, S. & Pearson, A. D. J. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia 24, 671–678 (2010).

    Article  CAS  PubMed  Google Scholar 

  185. Gjertsen, B. T. & Schöffski, P. Discovery and development of the polo-like kinase inhibitor volasertib in cancer therapy. Leukemia 29, 11–19 (2015).

    Article  CAS  PubMed  Google Scholar 

  186. Guzman, M. L. et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98, 2301–2307 (2001).

    Article  CAS  PubMed  Google Scholar 

  187. Guzman, M. L. et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105, 4163–4169 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Sujobert, P. et al. Co-activation of AMPK and mTORC1 induces cytotoxicity in acute myeloid leukemia. Cell Rep. 11, 1446–1457 (2015).

    Article  CAS  PubMed  Google Scholar 

  189. Mohty, M. & Apperley, J. F. Long-term physiological side effects after allogeneic bone marrow transplantation. Hematol. Am. Soc. Hematol. Educ. Program 2010, 229–236 (2010).

    Article  Google Scholar 

  190. Alibhai, S. M. H. et al. Quality of life beyond 6 months after diagnosis in older adults with acute myeloid leukemia. Crit. Rev. Oncol. Hematol. 69, 168–174 (2009).

    Article  PubMed  Google Scholar 

  191. Sekeres, M. A. et al. Decision-making and quality of life in older adults with acute myeloid leukemia or advanced myelodysplastic syndrome. Leukemia 18, 809–816 (2004).

    Article  CAS  PubMed  Google Scholar 

  192. Pickrell, W. O., Rees, M. I. & Chung, S.-K. Next generation sequencing methodologies — an overview. Adv. Protein Chem. Struct. Biol. 89, 1–26 (2012).

    Article  CAS  PubMed  Google Scholar 

  193. Iqbal, N. & Iqbal, N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother. Res. Pract. 2014, 357027 (2014).

    PubMed  PubMed Central  Google Scholar 

  194. DiNardo, C. et al. Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promotes differentiation of myeloid cells in patients with advanced hematologic malignancies: results of a Phase 1/2 trial. American Society of Hematology Annual Meeting and Exposition[online], (2015).

  195. Srivastava, S. & Riddell, S. R. Engineering CAR-T cells: design concepts. Trends Immunol. 36, 494–502 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Ivey, A. et al. Assessment of minimal residual disease in standard-risk AML. N. Engl. J. Med. 374, 422–433 (2016).

    Article  CAS  PubMed  Google Scholar 

  197. Klco, J. M. et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA 314, 811–822 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Linch, D. C., Yates, A. P. & Watts, M. J. Haematology: Colour Guide (Churchill Livingstone, 1996).

    Google Scholar 

  199. US National Library of Science. Selumetinib in treating patients with recurrent or refractory acute myeloid leukemia. ClinicalTrials.gov[online], (2007).

  200. US National Library of Science. BKM120 for patients with PI3K-activated tumors (SIGNATURE). ClinicalTrials.gov[online], (2013).

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Authors and Affiliations

  1. Department of Haematology, University College London, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK

    Asim Khwaja, Rosemary E. Gale & David C. Linch

  2. Department of Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden

    Magnus Bjorkholm

  3. Department of Medicine, Human Oncology and Pathogenesis Program, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Ross L. Levine

  4. Division of Hematology, University of Colorado Denver, Denver, Colorado, USA

    Craig T. Jordan

  5. Department of Internal Medicine, Technical University Dresden, Dresden, Germany

    Gerhard Ehninger

  6. Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA

    Clara D. Bloomfield

  7. Division of Hematology, University of Washington and Clinical Research Division Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Eli Estey

  8. CTI Life Sciences Ltd., Uxbridge, UK

    Alan Burnett

  9. Erasmus University Medical Center, Rotterdam, The Netherlands

    Jan J. Cornelissen

  10. Molecular Pharmacology Program, Experimental Therapeutics Center, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    David A. Scheinberg

  11. Département Développement Reproduction Cancer, Institut Cochin, CNRS UMR8104, Paris, INSERM U1016, France

    Didier Bouscary

  12. Service d'Hématologie, Hôpital Cochin, AP-HP, Paris, France

    Didier Bouscary

  13. Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France

    Didier Bouscary

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  1. Asim Khwaja
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Contributions

Introduction (A.K. and D.C.L.); Epidemiology (M.B.); Mechanisms/pathophysiology (A.K., D.C.L., R.E.G., R.L.L. and C.T.J.); Diagnosis, screening and prevention (G.E., C.D.B., R.E.G., D.C.L. and A.K.); Management (E.E., A.B., J.J.C., D.A.S. and D.B.); Quality of life (A.K. and D.C.L.); Outlook (D.C.L. and A.K.); Overview of Primer (A.K. and D.C.L.).

Corresponding author

Correspondence to David C. Linch.

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Competing interests

A.K. has received consulting fees from Celgene, Bergen Bio and research funding from AstraZeneca. G.E. has received research grants from Novartis and Celgene and has ownership in GEMoaB Monoclonals. A.B. receives salary from CTI Life Sciences Ltd. D.A.S. is the inventor of antibodies for AML owned by the Sloan Kettering Institute that are licensed to ‘for-profit companies’. D.C.L. has stock and receives salary from Autolus. All other authors declare no conflict of interests.

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Khwaja, A., Bjorkholm, M., Gale, R. et al. Acute myeloid leukaemia. Nat Rev Dis Primers 2, 16010 (2016). https://doi.org/10.1038/nrdp.2016.10

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