Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence is increasing as the population ages. Unfortunately, currently used “one-size-fits-all” chemotherapy regimens result in cure for only a minority of patients. Although progress has been made in identifying subsets of patients who require chemotherapy alone—as compared with those who require initial chemotherapy followed by allogeneic stem cell transplantation to maximize the chance for cure—clinical and cytogenetic prognosticators are not sufficiently accurate for such a risk-adapted stratification approach. New molecular technologies have allowed for in-depth molecular analyses of AML patients. These studies have revealed novel mutations, epigenetic changes, and/or aberrant expression levels of protein-coding and noncoding genes involved in leukemogenesis. These molecular aberrations are now being increasingly used not only to select risk-adapted treatment strategies, but also to incorporate newer molecularly targeted agents into conventional chemotherapy and/or transplant treatments. The hope is that this approach will lead to a better selection of “personalized” treatments for individual patients at diagnosis, the ability to assess these treatments in real time, and the ability, if necessary, to modify these therapies utilizing molecular endpoints for guidance regarding their antileukemia activity. We review here the state of the art of diagnosis and treatment of AML and provide insights into the emerging novel biomarkers and therapeutic agents that are anticipated to be useful for the implementation of personalized medicine in AML.
In 2015, approximately 20,000 new cases of acute myeloid leukemia (AML) and 10,000 AML-related deaths occurred in the United States alone. The median age at diagnosis is 67 years, and the incidence of the disease increases with age. While recurrent acquired genetic abnormalities have been found in leukemia blasts, the direct causes of AML are unknown for the majority of patients. However, for some patients, risk factors are readily identifiable. Hereditary or congenital conditions (eg, Down syndrome, ataxia telangiectasia, Bloom syndrome, Fanconi anemia, congenital neutropenia) and germline mutations (eg, CEBPA, RUNX1, TP53, ANKRD26, DDX41, ETV6, GATA2, SRP72, TERC, and TERT) have been linked to a higher predisposition to AML.[3,4] Patients with prior exposure to chemotherapeutics are at risk for developing therapy-associated AML.[5,6] Similarly, patients with clonal hematologic disorders, including myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs), may progress to “secondary” AML. In general, patients with therapy-associated AML and secondary AML have worse outcomes than those with primary (de novo) AML.
The World Health Organization (WHO) classification has established a blast cutoff of 20% to distinguish AML from MDS—except for certain genetic abnormalities pathognomonic for AML, which require < 20% blasts, ie, t(8;21), inv(16), t(15;17). The WHO classification also recognizes a variety of categories that reflect the disease’s clinical and biologic heterogenetity, including AML with certain genetic abnormalities, AML with myelodysplasia-related changes, AML related to previous chemotherapy or radiation, and AML not otherwise specified. The revised 2016 WHO classification is expected to incorporate additional emerging biologic and molecular information. While the WHO classification does not provide prognostic information, other classifications utilize cytogenetic and molecular features for treatment guidance (eg, to decide between chemotherapy and allogeneic hematopoietic stem cell transplantation [alloHSCT]), according to the risk of relapse.[7-9]
Cytogenetic and Molecular Risk
The mainstream approach to defining prognostic risk in AML patients is to conduct cytogenetic and molecular analyses at diagnosis. Generally, patients with recurrent cytogenetic aberrations (~45%) have been grouped into favorable-, intermediate-, and poor-risk categories.[10,11] The favorable cytogenetic groups include patients with t(15;17), t(8;21), or inv(16)/t(16;16). Individuals are classified as poor risk if aberrations constitute a complex karyotype (CK; defined here as at least three chromosomal abnormalities that are not included in the WHO category of “AML with recurrent abnormalities”); if they have t(6;9), inv(3)/t(3;3), 11q23 translocations, or –7; or if they have a monosomal karyotype (defined as the occurrence of at least two autosomal monosomies [loss of chromosomes besides Y or X] or a single autosomal monosomy with additional structural abnormalities in the absence of t(15;17), t(8;21), or inv(16)/t(16;16)). Patients with cytogenetic abnormalities that are not classifiable as belonging in any of the aforementioned groups, those who have t(9;11), and those who are cytogenetically normal (CN; ie, lacking a cytogenetic abnormality [~55%]) are considered to be intermediate risk.
Cytogenetics alone cannot accurately predict outcome for any of these prognostic groups. However, burgeoning technological developments have recently allowed for extended assessment of molecular biomarkers useful for outcome prediction; these new biomarkers include gene mutations, gene and noncoding RNA expression signatures, and DNA methylation profiles associated with distinct cytogenetic groups.[13-15] Still, to date only a few of these biomarkers have been incorporated into outcome-risk classifications. The European LeukemiaNet (ELN) classification, for example, incorporates NPM1 and CEBPA mutations and FLT3 internal tandem duplication (ITD) in an integrated cytogenetic-molecular classification that separates AML patients into four genetic groups: favorable, intermediate I, intermediate II, and adverse.[7,8] The favorable group includes patients with the NPM1 mutation in the absence of FLT3-ITD, and those with CEBPA mutations. The intermediate I group is composed of CN patients with FLT3-ITD. The intermediate II and adverse groups comprise those with intermediate and poor cytogenetic risk, respectively. The National Comprehensive Cancer Network (NCCN) treatment guidelines also use KIT mutations. As new molecular aberrations are discovered, these biomarkers may be grouped according to biologic and/or functional criteria useful for the selection of corresponding molecularly targeted drugs.[14,15]
Receptor tyrosine kinase mutations
Mutations occurring in the Fms-related tyrosine kinase 3 gene (FLT3), a gene that encodes a member of the class III receptor tyrosine kinase family, often lead to aberrant tyrosine kinase activation and, in turn, to rapid blast proliferation.[16-18] These mutations either appear within the juxtamembrane domain of the gene as an ITD or within the tyrosine kinase domain (TKD). FLT3-ITD mutations occur in 25% to 35% of patients with CN-AML, and they are linked to an increased risk of relapse and mortality. The ratio of mutant−to−wild-type alleles influences the prognostic effect of the ITD mutation, since the absence of the FLT3 wild-type allele is associated with a more dismal prognosis. The prognostic significance of FLT3 TKD mutations (seen in ~7% of AML) is unknown, although a recent large study has shown a potentially favorable prognostic effect. FLT3 mutations may also occur in the favorable genetic risk subgroups, including in patients with core binding factor (CBF) AML—ie, AML harboring t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)—and in acute promyelocytic leukemia (not reviewed here), but the prognostic impact of these mutations in distinct subsets remains to be fully elucidated.[20,21] KIT, like FLT3, encodes a member of the class III receptor tyrosine kinase family. KIT mutations are present in ~20% of CBF AML patients and have been tied to relapse and worse outcomes, especially in patients with t(8;21).[8,22]
Nucleophosmin (NPM) is a nucleolar phosphoprotein that normally shuttles between the nucleus and the cytoplasm to maintain cellular processes. Frameshift mutations at the C-terminus of the protein are relatively common in CN-AML patients (occurring in 45% to 60%). A significant prognostic interaction has been reported between the NPM1 mutation and FLT3-ITD.[8,25] Patients who had the combination NPM1-mutated/FLT3 wild-type AML were found to have high remission rates and better outcomes compared with patients who had NPM1 wild-type or NPM1-mutated/FLT3-ITD disease. In older CN-AML patients treated with intensive induction chemotherapy, NPM1 mutations predict for excellent disease response and better survival.
CCAAT/enhancer binding protein α (CEBPA) is a Basic Leucine Zipper (bZIP) transcription factor that is required for myeloid differentiation. Frameshift mutations within the N-terminus affect the transactivating domain, and insertions or deletions within the C-terminus affect the DNA-binding domain. CEBPA mutations occur in 10% to 15% of patients with CN-AML, and it is accepted now that only patients with CEBPA mutations that are biallelic (ie, each allele carries mutations) have a favorable prognosis.
The runt-related transcription factor 1 (RUNX1) is a transcription factor that regulates the expression of genes that are essential for hematopoietic growth and differentiation. Point mutations result in a loss of normal hematopoietic transcription factor activity, resulting in impaired cellular differentiation and altered mechanisms of apoptosis, thereby promoting leukemogenesis. Acquired RUNX1 mutations have been identified in ~13% of AML patients; the frequency of the mutations in younger patients is less than that in older patients. These mutations have been associated with lower complete remission (CR) rates and shorter median disease-free survival (DFS) and overall survival (OS). RUNX1 mutations and favorable mutations (such as those of NPM1 and CEBPA) appear to be mutually exclusive.
A loss of normal function in the tumor suppressor gene TP53—as a result of mutations, deletions, or both—results in genetic instability and in general promotes tumorigenesis. In AML, TP53 mutations are often associated with CK-AML and are correlated with worse outcomes.
DNA cytosine methylation silences gene expression by epigenetically modifying structurally normal DNA. At least three isoforms of the DNA methyltransferase (DNMT) enzyme—DNMT1, DNMT3A, and DNMT3B—are recognized as responsible for establishing or maintaining DNA methylation. Aberrant DNA methylation can result in the silencing of tumor suppressor genes and thus in leukemia growth. In AML, mutations are relatively frequent in DNMT3A.[30-35] Approximately 60% of these mutations are identified as missense mutations at codon R882, whereas the remaining are nonsense or frameshift mutations that result in premature truncation of the protein; the latter mutations have been found across different domains of the gene. In an AML Study Group report, DNMT3A mutations were identified in 17.8% of younger AML patients. The majority of these mutations occurred in CN-AML patients (27.2%) and were linked with a lower CR rate and shorter OS. Within the NPM1 wild-type/FLT3-ITD subset, patients who also harbored the DNMT3A mutation had a lower CR rate, shorter OS (0.85 vs 4.41 years; P < .001), and shorter relapse-free survival than patients without the mutation. Additionally, Alliance reported a differential effect of DNMT3A mutations on different age groups. In younger patients, DNMT3A R882 mutations had no impact on outcome, whereas non-R882 mutations predicted for worse outcome compared with patients without the mutation. Among older patients, on the other hand, those with R882 mutations had both a shorter OS and DFS, whereas non-R882 mutations did not influence outcomes. The predictive effect of DNMT3A mutations with regard to the therapeutic response has also been evaluated. Patients with DNMT3A mutations who were randomly assigned to receive dose-intensified daunorubicin as part of induction therapy seemed to have a better OS.[34-36] In a more restricted analysis, patients with DNMT3A mutations appeared to have a better chance of achieving CR when treated with the hypomethylating agent (HMA) decitabine than did patients with wild-type DNMT3A, but this finding requires confirmation.
Isocitrate dehydrogenase (IDH), a member of the β-decarboxylating dehydrogenase family of enzymes, normally catalyzes the oxidative decarboxylation of 2,3-isocitrate during the Krebs cycle, generating 2-oxoglutarate and carbon dioxide.[38,39] In AML, missense mutations occur in the two isoforms, IDH1 (ie, R132 mutations) and IDH2 (ie, R140 or R172 mutations).[40-42] Mutant IDHs reduce α-ketoglutarate to 2-hydroxyglutarate via nicotinamide adenine dinucleotide phosphate (NADPH) oxidation, promoting tumorigenesis via a mechanism that has yet to be clarified but that likely includes epigenetic changes (eg, DNA hypermethylation) through inhibition of TET2 demethylase activity. Although the prognostic value of IDH mutations in AML remains unknown because of differences in reported studies, the clinical utility of detecting these mutations lies more in their ability to predict response to treatment with IDH inhibitors.
TET proteins are iron- and α-ketoglutarate-dependent proteins that lead to the demethylation of DNA via the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine. Mutations in the TET2 isoform lead to impaired hydroxylation of 5mC; consequently, genes necessary for normal cellular function remain hypermethylated and silenced. These mutations have been identified in AML, as well as in MDS and MPNs. CN-AML patients with TET2 mutations who have ELN favorable genetic risk (but not in those with ELN intermediate-I risk) have been reported to have a worse CR rate and shorter event-free survival (EFS) and OS. Similarly, Patel et al reported an association of TET2 mutations with poorer outcomes in patients with NPM1 wild-type/FLT3 wild-type AML, while other studies have failed to demonstrate a prognostic impact for TET2 mutations.[40,44]
The additional sex combs-like 1 gene (ASXL1) encodes a potential tumor suppressor that regulates gene transcription. ASXL1 mutations have been identified in approximately 15% of older patients with AML, MDS, and MPNs. Similar to TET2 mutations, the negative prognostic impact of ASXL1 mutations seems to be restricted to patients in the ELN favorable group.
The mixed-lineage leukemia gene (MLL) encodes a histone methyltransferase considered to be a positive global regulator of gene transcription. Chromosomal translocations involve the MLL gene, located at chromosomal band 11q23, in both AML and acute lymphoblastic leukemia; the prognostic significance of these translocations depends on the fusion partner. In AML, patients with t(9;11) have an improved outcome compared with patients who have other 11q23 translocations, and the former are usually classified in the intermediate cytogenetic risk group. An internal rearrangement (partial tandem duplication [PTD]) of the MLL gene without any contributing partner was one of the first molecular markers described in CN-AML patients and was initially associated with worse outcomes, although the negative prognostic impact may be overcome with more intensive consolidation treatments (eg, autologous stem cell transplantation).
The Wilms tumor 1 gene (WT1) encodes a transcription factor that plays a significant role in normal cellular growth and development. A functional epigenetic interplay between WT1 and TET2 has been recently recognized. Although the prognostic impact of WT1 mutations in patients with AML is not universally agreed upon, most studies report an inferior outcome.[47,48]
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