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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $59.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Cancer Research UK. Acute myeloid leukaemia (AML) incidence statistics. Cancer Research UK[online], (accessed Jan 2015).
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).
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).
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.
Lindsley, R. C. et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125, 1367–1376 (2015).
Swerdllow, S. H. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn (IARC Press, 2008).
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).
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.
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).
Latin American Leukemia Net. Acute myeloid leukemia. Latin American Leukemia Net (LALNET)[online], (2009).
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).
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).
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).
Puumala, S. E., Ross, J. A., Aplenc, R. & Spector, L. G. Epidemiology of childhood acute myeloid leukemia. Pediatr. Blood Cancer 60, 728–733 (2013).
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).
Matsuo, K. & Ito, H. Descriptive epidemiology of myeloid leukemia. Nihon Rinsho 67, 1847–1851 (in Japanese) (2009).
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).
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).
Douer, D. The epidemiology of acute promyelocytic leukaemia. Best Pract. Res. Clin. Haematol. 16, 357–367 (2003).
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).
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).
Carney, D. A. et al. Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy. Leukemia 24, 2056–2062 (2010).
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).
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).
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).
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.
Seif, A. E. Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis. Cancer Genet. 204, 227–244 (2011).
Burnett, A., Wetzler, M. & Löwenberg, B. Therapeutic advances in acute myeloid leukemia. J. Clin. Oncol. 29, 487–494 (2011).
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).
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).
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).
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.
Bower, H. et al. Assessing temporal trends in survival of acute myeloid leukemia patients using the loss in expectation of life. ANCR[online], (2014).
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).
Juliusson, G. et al. Attitude towards remission induction for elderly patients with acute myeloid leukemia influences survival. Leukemia 20, 42–47 (2006).
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).
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).
Grimwade, D. & Mrózek, K. Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia. Hematol. Oncol. Clin. North Am. 25, 1135–1161 (2011).
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).
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).
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).
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).
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).
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).
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).
Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).
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).
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).
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).
Figueroa, M. E. et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17, 13–27 (2010).
Abdel-Wahab, O. et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 22, 180–193 (2012).
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).
Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2011).
Patel, J. P. et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 366, 1079–1089 (2012).
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).
Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360, 2289–2301 (2009).
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).
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).
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).
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).
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).
Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).
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).
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).
Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Dick, J. E. Acute myeloid leukemia stem cells. Ann. NY Acad. Sci. 1044, 1–5 (2005).
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).
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).
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).
Shlush, L. I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).
Ugale, A. et al. Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation. Cell Rep. 9, 1246–1255 (2014).
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).
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).
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).
Bernt, K. M. et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78 (2011).
Jordan, C. T., Guzman, M. L. & Noble, M. Cancer stem cells. N. Engl. J. Med. 355, 1253–1261 (2006).
Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).
Score, J. et al. Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals. Leukemia 29, 1600–1602 (2015).
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).
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).
Röllig, C. & Ehninger, G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood 125, 3246–3252 (2015).
Kim, H. et al. Analysis of fatal intracranial hemorrhage in 792 acute leukemia patients. Haematologica 89, 622–624 (2004).
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).
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).
Estey, E. H. Acute myeloid leukemia: 2013 update on risk-stratification and management. Am. J. Hematol. 88, 318–327 (2013).
Walter, M. J. et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc. Natl Acad. Sci. USA 106, 12950–12955 (2009).
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).
Jaffe, E. S. et al. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues (IARC Press, 2001).
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).
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).
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).
Kayser, S. et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood 119, 551–558 (2012).
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).
Lindsley, R. C. & Ebert, B. L. The biology and clinical impact of genetic lesions in myeloid malignancies. Blood 122, 3741–3748 (2013).
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).
Falini, B. et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N. Engl. J. Med. 352, 254–266 (2005).
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).
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).
Löwenberg, B. & Pabst, T. Cytarabine dose for acute myeloid leukemia. N. Engl. J. Med. 17, 1027–1036 (2011).
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).
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).
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).
Cornely, O. A. et al. Posaconazole versus fluconazole or itraconazole prophylaxis in patients with neutropenia. N. Engl. J. Med. 356, 348–359 (2007).
Rolston, K. V. I. Neutropenic fever and sepsis: evaluation and management. Cancer Treat. Res. 161, 181–202 (2014).
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).
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).
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).
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).
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).
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.
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).
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.
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).
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).
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).
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).
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).
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).
de Thé, H. & Chen, Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat. Rev. Cancer 10, 775–783 (2010).
Lo-Coco, F. et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369, 111–121 (2013).
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).
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).
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).
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).
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).
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).
Hills, R. K. & Burnett, A. K. Applicability of a ‘Pick a Winner’ trial design to acute myeloid leukemia. Blood 118, 2389–2394 (2011).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Gratwohl, A. et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer 115, 4715–4726 (2009).
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).
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).
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).
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).
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).
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).
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).
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).
Vellenga, E. et al. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood 118, 6037–6042 (2011).
Scheinberg, D. A. et al. Monoclonal antibody M195: a diagnostic marker for acute myelogenous leukemia. Leukemia 3, 440–445 (1989).
Dao, T. et al. Targeting the intracellular WT1 oncogene product with a therapeutic human antibody. Sci. Transl. Med. 5, 176ra33 (2013).
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).
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).
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).
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).
Bross, P. F. et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin. Cancer Res. 7, 1490–1496 (2001).
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).
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).
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).
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).
McDevitt, M. R. et al. Tumor therapy with targeted atomic nanogenerators. Science 294, 1537–1540 (2001).
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).
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).
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).
Konig, H. & Levis, M. Targeting FLT3 to treat leukemia. Expert Opin. Ther. Targets 19, 37–54 (2015).
Sato, T. et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 117, 3286–3293 (2011).
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).
Burgess, M. R. et al. Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood 124, 3947–3955 (2014).
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).
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).
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.
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).
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).
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).
US National Library of Science. Pilot trial of sirolimus/MEC in high risk acute myelogenous leukemia (AML). ClinicalTrials.gov[online], (2010).
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).
US National Library of Science. Sirolimus, idarubicin, and cytarabine in treating patients with newly diagnosed acute myeloid leukemia. ClinicalTrials.gov[online], (2013).
Récher, C. et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 105, 2527–2534 (2005).
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).
Garcia, P. D. et al. Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin. Cancer Res. 20, 1834–1845 (2014).
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.
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).
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).
Puissant, A. et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 25, 226–242 (2014).
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).
Gjertsen, B. T. & Schöffski, P. Discovery and development of the polo-like kinase inhibitor volasertib in cancer therapy. Leukemia 29, 11–19 (2015).
Guzman, M. L. et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98, 2301–2307 (2001).
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).
Sujobert, P. et al. Co-activation of AMPK and mTORC1 induces cytotoxicity in acute myeloid leukemia. Cell Rep. 11, 1446–1457 (2015).
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).
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).
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).
Pickrell, W. O., Rees, M. I. & Chung, S.-K. Next generation sequencing methodologies — an overview. Adv. Protein Chem. Struct. Biol. 89, 1–26 (2012).
Iqbal, N. & Iqbal, N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother. Res. Pract. 2014, 357027 (2014).
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).
Srivastava, S. & Riddell, S. R. Engineering CAR-T cells: design concepts. Trends Immunol. 36, 494–502 (2015).
Ivey, A. et al. Assessment of minimal residual disease in standard-risk AML. N. Engl. J. Med. 374, 422–433 (2016).
Klco, J. M. et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA 314, 811–822 (2015).
Linch, D. C., Yates, A. P. & Watts, M. J. Haematology: Colour Guide (Churchill Livingstone, 1996).
US National Library of Science. Selumetinib in treating patients with recurrent or refractory acute myeloid leukemia. ClinicalTrials.gov[online], (2007).
US National Library of Science. BKM120 for patients with PI3K-activated tumors (SIGNATURE). ClinicalTrials.gov[online], (2013).
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.
About this article
Cite this article
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
The characteristics of circRNA as competing endogenous RNA in pathogenesis of acute myeloid leukemia
BMC Cancer (2021)
Journal of Experimental & Clinical Cancer Research (2021)
Profiling of somatic mutations and fusion genes in acute myeloid leukemia patients with FLT3-ITD or FLT3-TKD mutation at diagnosis reveals distinct evolutionary patterns
Experimental Hematology & Oncology (2021)
Arsenic trioxide synergistically promotes the antileukaemic activity of venetoclax by downregulating Mcl-1 in acute myeloid leukaemia cells
Experimental Hematology & Oncology (2021)
CRNDE enhances the expression of MCM5 and proliferation in acute myeloid leukemia KG-1a cells by sponging miR-136-5p
Scientific Reports (2021)