Acute myeloid leukemia (AML) comprises a heterogeneous group of disorders characterized by proliferation of clonal, abnormally differentiated hematopoietic progenitor cells of myeloid lineage that infiltrate the bone marrow, blood, and other tissues.1 In most cases, AML is rapidly fatal if left untreated. Over the past 2 decades, our understanding of the underlying disease biology responsible for the development of AML has improved substantially. We have learned that biological differences drive the various clinical, cytogenetic, and molecular subentities of AML; distinguishing among these subentities helps to identify optimal therapies, while offering improved clinical outcomes for select groups. After years of stagnation in therapeutic advances, 4 new drugs for treating AML were approved by the US Food and Drug Administration (FDA) in 2017. In this article, we review key features of AML diagnosis and management in the context of 2 case presentations.
Epidemiology and Risk Factors
An estimated 21,380 new cases of AML were diagnosed in the United States in 2017, constituting roughly 1.3% of all new cases of cancer.2 Approximately 10,590 patients died of AML in 2017. The median age of patients at the time of diagnosis is 68 years, and the incidence is approximately 4.2 per 100,000 persons per year. The 5-year survival for AML has steadily risen from a meager 6.3% in 1975 to 17.3% in 1995 and 28.1% in 2009.2 The cure rates for AML vary drastically with age. Long-term survival is achieved in approximately 35% to 40% of adults who present at age 60 years or younger, but only 5% to 15% of those older than 60 years at presentation will achieve long-term survival.3
Most cases of AML occur in the absence of any known risk factors. High-dose radiation exposure, chronic benzene exposure, chronic tobacco smoking, and certain chemotherapeutics are known to increase the risk for AML.4 Inconsistent correlations have also been made between exposure to organic solvents, petroleum products, radon, pesticides, and herbicides and the development of AML.4 Obesity may also increase AML risk.4
Two distinct subcategories of therapy-related AML (t-AML) are known. Patients who have been exposed to alkylating chemotherapeutics (eg, melphalan, cyclophosphamide, and nitrogen mustard) can develop t-AML with chromosomal 5 and/or 7 abnormalities after a latency period of approximately 4 to 8 years.5 In contrast, patients exposed to topoisomerase II inhibitors (notably etoposide) develop AML with abnormalities of 11q23 (leading to MLL gene rearrangement) or 21q22 (RUNX1) after a latency period of about 1 to 3 years.6 AML can also arise out of other myeloid disorders such as myelodysplastic syndrome and myeloproliferative neoplasms, and other bone marrow failure syndromes such as aplastic anemia.4 Various inherited or congenital conditions such as Down syndrome, Bloom syndrome, Fanconi anemia, neurofibromatosis 1, and dyskeratosis congenita can also predispose to the development of AML. A more detailed listing of conditions associated with AML can be found elsewhere.4
The first cancer genome sequence was reported in an AML patient in 2008.7 Since then, various elegantly conducted studies have expanded our understanding of the molecular abnormalities in AML. The Cancer Genome Atlas Research Network analyzed the genomes of 200 cases of de novo AML in adults.8 Only 13 mutations were found on average, much fewer than the number of mutations in most adult cancers. Twenty-three genes were commonly mutated, and another 237 were mutated in 2 or more cases. Essentially, all cases had at least 1 nonsynonymous mutation in 1 of 9 categories of genes: transcription-factor fusions (18%), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), spliceosome-complex genes (14%), and cohesin-complex genes (13%).