Molecular Profiling of Acute Myeloid Leukemia
Acute myeloid leukemia is a clinically and biologically heterogeneous disease and the most common cause of leukemia-related mortality in the United States, with an estimated 19,520 new cases and 10,670 deaths anticipated in 2018 (ACS 2018). In AML, somatic genetic changes are often thought to contribute to leukemogenesis through a “two-hit” process. In other words, for leukemogenesis to occur, two types of mutations, or “two hits,” are needed: 1) a mutation that improves hematopoietic cells’ ability to proliferate (class I, including FLT3 and KIT), and 2) a mutation that prevents the cells from maturing (class II, including CBFB-MYH11, CEBPA, DEK-NUP214, MLL-MLLT3, NPM1, PML-RARA, RUNX1-RUNX1T1; Naoe and Kiyoi 2013; Shih et al. 2012). As study of genetic variation in AML continues, this theory is being modified to accommodate new types of mutations, including mutations in epigenetic modifiers such as IDH1, IDH2, and DNMT3A (Naoe and Kiyoi 2013; Shih et al. 2012).
Genetic variation in AML is measured using cytogenetics (karyotype and FISH) and molecular diagnostics (gene mutations accessed by DNA analysis). Results of these tests are used for patient risk stratification and to guide patient management. Below, each of the common genetic variants is listed, grouped by risk category (Table 1; Dohner et al. 2010; Dohner and Gaidzik 2011; Estey 2012; Ferrara, Palmieri, and Leoni 2007; Grimwade et al. 2010; Grossman et al. 2012; Martelli et al. 2012; NCCN 2012; Patel et al. 2012).
Despite increasing knowledge of the effects of genetic variation on prognosis of AML, there are few options for tailoring treatment based on genetic characteristics. Standard treatment options include combination chemotherapy (cytarabine with either idarubicin or daunorubicin) or hematopoietic stem cell transplant (NCCN 2012). Survival rates remain low; novel therapies and treatment strategies are needed. Acute promyelocytic leukemia (APL), a subtype of AML defined by the presence of the t(15;17) translocation, is an exception. In addition to the standard treatments, APL may also be treated using all trans-retinoic acid or arsenic trioxide (NCI 2013a).
No kinase inhbitors, therapeutic antibodies, or immunotherapies are currently in routine clinical use in AML, although several are in preclinical or clinical development. DOT1L inhibitors; FLT3, JAK2, MEK, and mTOR kinase inhibitors; and multi-kinase inhibitors of FLT3, KIT, PDGFRB, RAF, RET, and VEGF are being investigated for use in AML (Cancer Discovery 2013; Daver and Cortes 2012; Stein and Tallman 2012).Table 1. Common Genetic Variants in AML, Grouped by Risk Category.
|Cytogenetic Variant||Single Gene Variant(s)||Frequency in AML|
|inv(16) or t(16;16)a,b||5%c|
|Normal karyotype||Biallelic CEBPA mutation positive; FLT3 ITD negativea,b,d||9%e (regardless of FLT3 ITD)|
|NPM1 mutation positive; FLT3 ITD negativeb,d,f||26–64%e,g (regardless of FLT3 ITD)|
|NPM1 mutation positive; IDH1 or IDH2 mutation positive; FLT3 negativeh||3.5%h|
|Isolated trisomy 8b||10%c|
|inv(16) or t(16;16)b||KIT mutation||~1.5%k|
|Other cytogenetic abnormalitiesc,d||N/A|
|inv(3) or t(3;3)a,d||1%c|
|Monosomy 5 or 5q-a||2%c|
|Monosomy 7 or 7q-a||5%c|
|11q23, other than t(9;11)b||3%c|
|Normal karyotype||FLT3 ITDb,d,h,m||27–34%h|
|Complex karyotype (≥3 clonal abnormalities)d||27%c|
|t(8;21)a,b||FLT3 mutation or FLT3 ITDp||< 1%p,q|
|inv(16) or t(16;16)a,b||FLT3 mutation or FLT3 ITDq||< 1%p,q|
|CALR mutation||< 1%s|
NOTE: Designations apply to specified variants or sets of variants. Risk categories may change when additional variants are present.
i In cases where the intermediate category was subdivided in a classification scheme, they are shown here in a single intermediate category. See cited references for more details.
j 35% of t(8;21) (Li, Sun, and Wu 2008).
k ~30% of inv(16)/t(16;16) (Paschka et al. 2006).
l Occurs in AMKL (NCI 2013c).
m Note that recent publications and the European Leukemia Net (Estey 2012) differ from NCCN guidelines in this categorization; NCCN guidelines include FLT3 ITD with normal karyotype in the poor risk category (NCCN 2012), while Estey (2012) and ELN include FLT3 ITD with normal karyotype in the intermediate risk category.
n Monosomal karyotype is any karyotype with two or more monosomies, or one monsomy and one or more additional structural abnormalities (Estey 2013).
Suggested Citation: Seegmiller, A., M. Jagasia, S. Wheeler, C. Vnencak-Jones. 2018. Molecular Profiling of Acute Myeloid Leukemia. My Cancer Genome https://www.mycancergenome.org/content/disease/acute-myeloid-leukemia/ (Updated March 30).
Last Updated: March 30, 2018