**1. Introduction**

#### **1.1. Epidemiology**

Acute leukemia is the most common childhood malignancy, accounting for almost 35% of all childhood cancers. It can be further divided into two main subtypes such as acute lymphoblastic leukemia (ALL), composing 80% of acute leukemia and acute myeloid leukemia (AML) which makes up 15–20% of acute leukemia in pediatric patients [1]. The incidence of AML is greatest in infants at 1.5 per 100,000 individuals per year and decreases to 0.4 per 100,000 individuals aged 5–9 years. After this, the incidence of AML begins to gradually increase reaching its highest point in individuals greater than 65 years of age at 16.2 per 100,000 individuals [1, 2]. A report using data from the surveillance, epidemiology, and end results (SEER) program identified Asian and Pacific Islanders to have the highest rate of childhood AML (0.84 per 100,000) followed by Hispanics (0.81 per 100,000), Caucasians (0.75 per 100,000), and African-Americans (0.66 per 100,000) [3, 4].

found in adults and these include t(1;22)(p13;q13), t(7;12)(q36;p13), and t(11;12)(p15;p13) [20–23]. The NPM1 and CEBPA, type II mutations, are found in approximately 27 and 6% of cases, respectively, and indicate a better prognosis [15]. Moreover, enhanced tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), involved in the stimulation of cellular proliferation and survival, is seen in almost 50% of AML cases and signifies a worse prognosis [24–26]. As stated by the two hit model of leukemogenesis, the pathogenesis of AML is dependent on two classes of cooperating genetic events. A study done by Patel et al. found that the c-KIT mutation has been associated with t(8,21) or inv. (16). Furthermore, they found that NMP1, which is a type II mutation, frequently occurs with FLT3-ITD (a type I mutation) or with mutations in epigenetic genes such as DNMT3A and IDH-1 or IDH-2 [27]. Despite these advancements in the pathogenesis of AML, there still remains much to be discovered on the exact implications that these individual mutations

Acute Myeloid Leukemia in Pediatric Patients: A Review About Current Diagnostic and…

http://dx.doi.org/10.5772/intechopen.70937

23

The first classification system used to distinguish between the different subtypes of AML was the French-American-British (FAB) classification system established in 1976. It identifies eight subtypes of AML (M0-M7) based on the morphological and cytochemical characteristics of the leukemic cells. The FAB classification was replaced by WHO in 2001 which was then revised in 2008 [28]. The WHO classification of AML was once again revised in 2016, this time integrating genetic information such as, karyotypes and molecular aberrations, with morphology, immunophenotype, and clinical presentation. It defines six major disease entities: AML with recurrent genetic abnormalities; AML with myelodysplasia-related features; therapy-related AML; AML not otherwise specified; myeloid sarcoma; and myeloid prolifera-

In **Table 1**, the subtypes of AML with recurrent genetic abnormalities are listed in accordance to their distinct chromosomal translocation. The newly incorporated provisional category of AML with mutated RUNX1 appears to represent a biologically distinct group with a worse prognosis in comparison to other AML subtypes. The category of AML with myelodysplasia-related changes remains to include a history of MDS as an inclusion criteria, however has been re-structured to better include subtypes with features suggesting a poor prognosis. Lastly, the myeloid proliferations of Down syndrome include transient abnormal myelopoiesis and myeloid leukemia associated with Down syndrome. As mentioned previously, both subtypes involve megakaryoblastic proliferations and are characterized by GATA1 mutations and mutations of the JAK-STAT pathway. Transient abnormal myelopoiesis typically occurs at birth or within the first few days of birth and resolves within 1–2 months. Myeloid leukemia associated with Down syndrome occurs later, but within the first 3 years of life, with or

have on the development of AML, particularly in pediatric patients.

**2. Therapeutic considerations**

tion related to Down syndrome (**Table 1**) [29].

without prior transient abnormal myelopoiesis [29].

**2.1. Classification**

#### **1.2. Etiology and pathophysiology**

The majority of AML cases appear as a *de novo* malignancy in previously healthy individuals, but there have been cases reported in which AML presents as a secondary malignancy. This has been witnessed in individuals with underlying hematological and genetic disorders such as Fanconi Anemia, Bloom Syndrome, Ataxia Telangiectasia, Shwachman-Diamond syndrome, Noonan syndrome, and Dyskeratosis Congenita. The most common genetic factor for the development of AML is trisomy 21 [3]. Children with Down syndrome have a 500-fold increased risk of developing a unique megakaryoblastic subtype of AML. This classically follows a transient myeloproliferative disorder in the neonatal period, which is characterized by somatic mutations in the GATA1 gene [3, 5]. Recently, a familial predisposition to AML has been suggested, as a number of germ-line mutations, such as GATA2, CEBPA, TP53, and RUNX1 have been found in families with an unexplained high risk of AML [3, 6–10]. In addition, exposure to prior therapy involving topoisomerases II, alkylating agents and radiation therapy have also been associated with an increased risk of developing AML as a secondary malignancy [1, 3].

The pathogenesis of AML involves the abnormal proliferation and differentiation of a clonal population of myeloid stem cells [11]. It is thought to arise from at least two classes of cooperating genetic events, known as a two-hit model of leukemogenesis [12–14]. Type I mutations result in increased and uncontrolled activation of pro-proliferative pathways of the leukemic cell and often involve activating genes that are part of signal transduction pathways, such as FLT3 (28% of cases), K/NRAS, TP53, and c-KIT (12, 8, and 4%, respectively) [15]. Type II mutations occur as a result of genetic aberrations in hematopoietic transcription factors leading to the impairment of normal hematopoietic differentiation. The most common type II cytogenic abnormalities in children, accounting for almost half of all pediatric AML cases are, t(8;21) (q22;q22) in the core-binding factor AML (CBF-AML) and t(15;17)(q;22;q21) in acute promyelocytic leukemia (APL) [16–19]. Other translocations are specific only to children and rarely found in adults and these include t(1;22)(p13;q13), t(7;12)(q36;p13), and t(11;12)(p15;p13) [20–23]. The NPM1 and CEBPA, type II mutations, are found in approximately 27 and 6% of cases, respectively, and indicate a better prognosis [15]. Moreover, enhanced tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), involved in the stimulation of cellular proliferation and survival, is seen in almost 50% of AML cases and signifies a worse prognosis [24–26]. As stated by the two hit model of leukemogenesis, the pathogenesis of AML is dependent on two classes of cooperating genetic events. A study done by Patel et al. found that the c-KIT mutation has been associated with t(8,21) or inv. (16). Furthermore, they found that NMP1, which is a type II mutation, frequently occurs with FLT3-ITD (a type I mutation) or with mutations in epigenetic genes such as DNMT3A and IDH-1 or IDH-2 [27]. Despite these advancements in the pathogenesis of AML, there still remains much to be discovered on the exact implications that these individual mutations have on the development of AML, particularly in pediatric patients.
