Open access peer-reviewed chapter

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

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Katarzyna Derwich, Dorothy Mitkowski and Jolanta Skalska- Sadowska

Submitted: June 12th, 2017 Reviewed: September 12th, 2017 Published: May 16th, 2018

DOI: 10.5772/intechopen.70937

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Acute leukemia is the most common childhood malignancy, accounting for almost 35% of all childhood cancers. Acute myeloid leukemia (AML) represents 15–20% of pediatric acute leukemia. Majority of AML cases appear de novo, however a minority of cases can present as a secondary malignancy. AML is a highly heterogeneous disease and its diagnosis involves a combination of diagnostic analyses including morphology, immunophenotyping, cytochemistry, and leukemic blasts derived from peripheral blood or bone marrow demonstrating cytogenic and molecular characteristics. Through the identification of recurrent genetic mutations, it has been made possible to refine individual prognosis and guide therapeutic management. The current survival rate of children with AML is approximately 70%. The standard therapeutic regimen is a combination of cytarabine- and anthracycline-based regimens with allogenic stem cell transplantation in appropriate patients. Relapse in pediatric patients suffering from AML occurs in approximately 30% of cases, whereas death occurs in 5–10% of patients as a result of disease complications or chemotherapeutic side effects. In understanding the genetic basis of AML, targeted therapies will have the ability to reduce treatment-related morbidity and mortality. Here, we provide a comprehensive review of AML, its biology, diagnosis and therapeutic management in pediatric patients.


  • acute myeloid leukemia
  • pediatrics
  • diagnosis
  • immunophenotype
  • cytogenetics
  • classification
  • treatment
  • hematopoietic stem cell transplantation

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 [12]. 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].

1.2. Etiology and pathophysiology

The majority of AML cases appear as a de novomalignancy 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, 7, 8, 9, 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, 13, 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, 17, 18, 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, 21, 22, 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, 25, 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.


2. Therapeutic considerations

2.1. Classification

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

TypesGenetic abnormalities
AML with recurrent genetic abnormalitiesAML with t(8:21)(q22;q22); RUNX1-RUNX1T1
AML with inv.(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 APL with PML-RARA
AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A
ML with t(6;9)(p23;q34.1); DEK-NUP214
AML with inv.(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1 AML with BCR-ABL1 (provisional entity)
AML with mutated NPM1
AML with biallelic mutations of CEBPA
AML with mutated RUNX1 (provisional entity)
AML with myelodysplasia-related changes
Therapy-related myeloid neoplasms
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic/monocytic leukemia acute erythroid leukemia
Pure erythroid leukemia
Acute megakaryoblastic leukemia acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
Transient abnormal myelopoiesis
ML associated with Down Syndrome

Table 1.

WHO classification of AML and related neoplasms [29].

Abbreviations: WHO, World Health Organization; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; ML, myeloid leukemia.

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 without prior transient abnormal myelopoiesis [29].

In pediatric patients, specifically under the age of 2, it is important to search for translocations that are specific for pediatric AML, as WHO classification does not represent them as new disease categories due to their rarity. These translocations, mentioned above, include t(7;12)(q36;p13) and t(11;12)(p15;p13) [1, 29].

2.2. Diagnostic approach

AML is a highly heterogeneous disease in regards to its morphology, immunophenotyping, and its clinical manifestations [1]. The clinical presentation of AML commonly manifests with leukocytosis, anemia, and thrombocytopenia. Fatigue, anorexia, and weight loss are less commonly seen and symptoms such as lymphadenopathy and organomegaly are not usually present. If a patient is left untreated, death will most likely occur secondary to an infection or bleeding [11]. In order to establish a diagnosis of acute leukemia, 20% or more blasts must be found in the bone marrow or peripheral blood [30]. To further diagnose AML, a combination of analyses is required, including, morphology, immunophenotyping, cytochemistry, and leukemic blasts derived from peripheral blood or bone marrow demonstrating cytogenic and molecular characteristics [31]. Although there is some overlap between the diagnostic recommendations for AML in children and adults, there are important differences between these two age groups that need to be focused on.

Morphological examination is conducted from blood and bone marrow smears using a May-Grunwald-Giemsa or a Wright-Giemsa stain [30]. The FAB classification is used to define the morphological characteristics of AML, which are based on the lineage of associated phenotypes: undifferentiated, myeloid, monoblastic, erythroblastic, or megakaryoblastic [32]. By looking at the morphology of AML, it is possible to determine the percentage of undifferentiated, atypical, or granulated blasts, intracellular structures such as Auer Rods and the presence of myelodysplasia [31]. Auer Rods are comprised of needle-shaped, azurophilic, cytoplasmic inclusion bodies and are commonly seen in APL, acute myelomonocytic leukemia and in majority of cases of AML with t(8;21) [28]. Once the lineage has been established through morphology, cytochemistry is then used to confirm the affiliation as well as differentiate between myeloid (myeloperoxidase [MPO]-positive) and monoblastic (nonspecific esterase-positive) classification. In certain cases in which the morphology and cytochemistry provide an ambiguous picture, immunophenotyping is required to further support the appropriate diagnosis [31].

Immunophenotyping is necessary to distinguish between AML and ALL. It is also required to classify minimally differentiated AML (FAB M0) and acute megakaryoblastic leukemia (AMKL, FAB M7). In minimally differentiated AML, morphological and cytochemical evaluation do not reveal myeloid differentiation. Although cytochemistry is negative for MPO activity, immunophenotyping is positive for myeloid markers, such as MPO (proenzyme) and/or CD13, CD33, and CD117 [31, 32]. AMKL is a type of leukemia with 20% or more blasts but of this, 50% or more are of megakaryocytic lineage. Immunophenotyping in AMKL is positive for platelet markers, such as CD41 and/or CD61 [30, 31]. The current WHO 2016 classification has not changed significantly from the 2008 classification. Markers required to assign lineages and define otherwise not specified mixed phenotype acute leukemia (MPAL) include MPO, lysozyme, CD11c, CD14, CD64, nonspecific esterase cytochemistry, i(intracellular)CD3, CD19, iCD22, CD79, and CD10 [29]. Table 2 presents the suggested antigen panel for immunophenotypic analysis required for the diagnosis of AML in pediatric patients. It was modified specifically for pediatric patients by Creutzig et al. from the recommended panel for AML in adults [30, 31].

Diagnosis of AMLMandatory Markers to fulfill WHO & EGIL CriteriaOther Markers
Precursor stageCD34, CD117CD133, HLA-DR
Myelomonocytic markersCD11b, CD11c, CD13, CD14, CD15, CD33, CD64, CD65, iMPO, i-lysozymeCD4, CD36, CD184 (CXCR4)
Megakaryocytic markersCD41, CD61CD42
Erythroid markerCD235a
Leukemia specific antigenNG2 homolog
Lineage aberrant antigensCD2, CD7, CD19, CD56
Pan-leukocyte markersCD11a, CD45

Table 2.

Immunophenotypic markers in Pediatric Patients for the diagnosis of AML.

The use of conventional cytogenetic analysis for the diagnosis of AML is a necessary component of the diagnostic evaluation. It allows for the detection of chromosomal abnormalities in 70–80% of pediatric patients with AML [31]. In the case of which cytogenetic analysis fails, fluorescence in situhybridization (FISH) is an option to detect gene rearrangement. FISH allows for the detection of fusion genes, such as RUNX1-RUNX1T1, CBFB-MYH11, MLL, and EVI1 as well as the loss of chromosome 5q and 7q material [33, 34]. As previously mentioned, the two most common cytogenetic abnormalities in children are t(8;21)(q22;q22) in CBF-AML and t(15;17)(q;22;q21) in APL, together making up approximately 50% of pediatric AML [16, 17, 18, 19].

Molecular genetics can be performed on bone marrow and/or blood specimens. Both DNA and RNA should be extracted, however if there is a small amount of specimen with a limited number of cells, RNA extraction is preferred. This is because RNA is more suitable for molecular screening for fusion genes and mutations specific to leukemia [30]. The frequency and nonrandom associations of type I and type II mutations (stated previously in Section 1.2) differ between pediatric and adult patients with AML [35]. Mutations in the RAS-RAF-ERK signal transduction pathway (PTPN11, NF-1, N-RAS, K-RAS) occur in 5–21% of pediatric AML cases and even more frequently in cases with CBF-AML and MLL-rearranged AML in young children. C-KIT mutations occur in 4% of all leukemia types, except CBF-AML, in which the incidence raises to approximately 25% in children [15, 30]. Despite the differences between children and adults in the expression of type I and type II mutations routine evaluation as suggested by Creutzig et al. should include FLT2-ITD, WTI, C-KIT, CEBPA, and NPM1 [31].

Gene expression profiling has the ability to contribute to the accurate diagnosis and risk-stratification of pediatric AML patients. However, its use remains limited as large cohorts are required for validation of the true prognostic significance of these genes [36]. Biobanking is strongly recommended for all patients, allowing for confirmation of initial diagnosis, or adding new data in the case of a relapse. Stored material should include AML blasts, DNA, and RNA. Buccal swabs are also recommended to be stored as they allow for discrimination between germ line and somatic genetic aberrations. This material can be used to identify new prognostic markers, monitoring for minimal residual disease (MRD) and contribute to research studies about the biological mechanism, subgroups and leukemogenesis of AML [30, 31].

2.3. Prognostic factors

The most relevant prognostic factors for the survival of pediatric AML are genetic and molecular abnormalities and the initial response to treatment. Both of these prognostic factors are independent and are both usually essential elements of the risk group classification [31, 37]. Presence of a very high blast count at the time of diagnosis is associated with a higher risk of early death and nonresponse [38]. Other favorable prognostic factors include, t(8;21)(q22;q22)/RUNX1-RUNX1T1, t(15;17)(q22;q21)/PML-RARA, NPM1-mutated AML and CEBPA double mutation - amongst a few [31]. A favorable prognostic group is CBF-AML [19, 39, 40]. MLL-translocations have variable outcomes and depend on the associated translocation. In MLL t(1;11)(q21;q23) has a very favorable outcome in pediatric AML. In comparison, those with t(6;11)(q27;q23) and t(10;11)(p12;q23) translocations have been reported to have poor survival rates [31, 41, 42]. Certain prognostic makers vary between children and adults. For example, deletion of 7q in adults is suggestive of an intermediate prognosis; however in pediatric patients it is associated with a poorer outcome. In these pediatric patients, the outcome has been found to be dependent on other cytogenetic abnormalities in the leukemia cell [19, 43]. Other poor prognostic abnormalities that have been described in adult AML, such as abnormalities of chromosomes 3q and 5q and the monsoonal karyotypes are very rare in children [44, 45, 46, 47].

The type I mutations of WT1 and FLT3-itd are indicative of a poor prognosis. FLT3-itd outcome depends on the allele ratio, whereas both of these mutations are described as events in clonal emulation towards relapse [48].

2.4. Pediatric AML treatment

The current survival rate of children with AML has increased to approximately 70%. This increase has been achieved by better risk stratification and intensification of chemotherapeutic regimens. The treatment of childhood AML should be risk adapted according to various biological factors in order to avoid over treatment in patients with a favorable prognosis and provide adequate chemotherapy to improve outcome in those with a less favorable prognosis [31]. This allows for the destruction of leukemia cells with the hope of avoiding side effects or as little late side effects as possible. With regards to infant AML, the most powerful prognostic factor for the outcome has been found to be favorable cytogenetics and a blast count of less than 5% after induction therapy [49].

The standard chemotherapeutic regimen consists of a combination of 4–5 cycles of cytarabine and anthracycline-based regimens with allogenic stem cell transplantation in appropriate patients [1]. Induction therapy typically includes 1 or 2 cycles of chemotherapy in both children and adults. Standard induction therapy involves 3 days of an anthracycline and 7–10 days of cytarabine (“3 + 7” or “3 + 10”). This induction regimen achieves complete remission in greater than 85% of children and adolescence. A third drug, such as etoposide or 6-thioguanine, can be included in induction, but their benefits have not yet been proven [50]. There are a number of various anthracyclines that have been evaluated through randomized controlled pediatric trials. Daunorubicin and mitoxantrone resulted in similar overall survival; however treatments with a mitoxantrone base resulted in lower relapse rates [51]. In comparison, iadrubicin and liposomal daunorubicin had similar survival rates, but liposomal daunorubicin was more effective in cases with a RUNX1/RUNX1T1 translocation and caused less treatment-related mortality [52]. Studies have shown that higher doses of anthracyclines improve the outcome in children and adults [53, 54]. However, at higher doses there is an increased risk for toxicity, especially acute and late cardiotoxicity. A cumulative dose of >300 mg/m2 has been associated with significant later cardiac toxicity and should take into consideration factors such as the patients age and sex [55, 56]. To avoid reaching peak serum concentrations, suggestions of splitting the dose, or using prolonged drug infusions have been proposed, however there have been conflicting benefits of dose scheduling and no conclusion on the best regimen has yet been reached [57, 58]. Dexrazozane is another option to reduce cardiotoxicity during anthracycline exposure and has been proven to be beneficial [59]. Failure of induction therapy is seen in 10–15% of pediatric patients. The subsequent outcomes for a patient with induction failure are similar to the patient with AML who relapsed early (<12 months after remission) [60, 61]. These patients, similar to patients that have relapsed, have been shown to have the highest end free survival after stem cell transplantation in comparison to after chemotherapy (31.2 vs. 5%, p < 0.0001) [62].

A considerable challenge in the treatment of children with AML is to prolong the initial remission. This is done with additional chemotherapy, similar to that in induction, but with the addition of non-cross-resistant drugs and high dose (HD) cytarabine [63, 64]. The ideal number of post remission cycles of therapy remains unclear, but appears to require at least two courses of intensive therapy, with the addition of the induction course. A study done by the United Kingdom Medical Research Council randomly assigned adult and pediatric patients to four or five courses of intensive therapy. There was no advantage seen in relapse free and overall survival in patients treated with five courses [51, 65].

The benefits of the intensification of cytarabine have been studied by a number of trials. In most studies, intensification of cytarabine from 12 to 36 g/m2 did not improve survival in adult AML patients [66]. However, a study by the Cancer and Leukemia Group B (CALGB) in adults showed that four courses of HD cytarabine (3 g/m2 per every 12 h on days 1, 3, and 5) were superior to four courses of lower dose cytarabine (100 mg/m2 continuous intravenously on days 1–5) but only in patients with CBF-AML and CN-AML [63, 67]. Several pediatric trials (NOPHO AML 93, AML-BFM 2004, AML 10, and AML99 of the JPLSG) showed that the use of intensive chemotherapy courses that include HD cytarabine reduced relapse rates [67, 68, 69, 70, 71, 72].

Hematopoietic stem cell transplantation (HSCT) is used as post remission consolidation therapy. Allogenic HSCT (allo-HSCT) has been found to have a greater benefit than autologous HSCT (auto-HSCT). Several trials have found no benefit of auto-HSCT compared with nonmyeloablative chemotherapy during the first complete remission [69, 73, 74, 75, 76]. In addition, the degree of toxicity associated with the conditioning regimen greatly out ways the benefits/use of auto-HSCT [77]. In comparison, prospective trials of transplantation in children with AML suggest that 60–70% of children with HLA-matched donors will experience long-term remissions when treat with an allo-HSCT during their first remission [69, 74]. Although there is a significantly lower relapse risk associated with allo-HSCT as compared with post-remission chemotherapy, the improvement in overall survival is controversial [78, 79, 80]. The current utilization of allo-HSCT involves incorporation of risk classification to determine whether transplantation should occur during the first remission. There is consensus that favorable-risk patients should not be transplanted in first complete remission but only after the first relapse and achievement of a second complete remission [73, 78, 79, 81]. Some benefit has been shown in allo-HSCT during first complete remission in intermediate- and high-risk patients. A meta-analysis combining the results of the POG-8821, CCG-2891, COG-2961, and MRC-Leuk-AML-10 showed benefit for allo-HSCT in intermediate-risk patients only [78]. Weakness in this analysis was due to a large percentage of patients not assigned to a risk group resulting in potential selection bias. If transplantation is chosen in pediatric AML, myeloablative chemotherapy is preferred over total body irradiation as the latter is associated with an increased risk of secondary malignancies and more late effects [82, 83, 84]. A large prospective CIBMTR cohort study of children and adults with AML, MDS, and CML, showed superior survival of patients in the early stages of the disease and less toxicity with busulfan-based regimens as compared to total body irradiation [85]. Despite these results, the optimal preparative regimen remains undetermined [86, 87, 88]. In summary, the role of HSCT in pediatric patients with AML in the first complete remission should continue to be assessed, particularly within specific risk groups. However, there is a consensus that HSCT should be offered to all children with relapsed AML once second remission has been achieved and that favorable-risk patients should not be offered HSCT [79].

The presence of CNS involvement at diagnosis and at relapse is seen in 5–10% of childhood AML cases. An increased risk of CNS involvement is seen in patients with hyperleukocytosis, monocytic leukemia (FAB M4 and M5, especially those with inv(16) or 11q23 chromosomal abnormalities), MLL gene rearrangement, and younger age [89]. All pediatric patients receive CNS treatment, even if no CNS involvement is detected. This is done with the presumption that systemic chemotherapy has little efficacy in penetrating the blood–brain-barrier to eradicate any potential AML blasts in the CNS. The most common regimen used for CNS treatment involves intrathecal chemotherapy-single agent cytarabine or methotrexate, or triple cytarabine, methotrexate and hydrocortisone. Other treatments such as cranial irradiation have also proven to be effective in the treatment of CNS involvement in pediatric AML. According to European protocols, prophylactic cranial radiotherapy is used in pediatric patients with AML. This is based on German pediatric AML studies, BFM-78 and BFM-83 where the use of cranial irradiation suggested to prevent both CNS and systemic relapse [89, 90]. However, due to its high side effect profile (including late toxicities and secondary malignancies), prophylactic cranial irradiation still remains controversial and is used less frequently in other countries [90].

As a result of AML being a highly heterogeneous disease and its ability to present in different ways, management may vary based on age group or the type of AML. One special group is children with DS, as they have a 14–20-fold risk of developing leukemia. In addition to the increased risk of AML during the first 3 years of life, about 10% of neonates with DS also develop a TMD, which usually disappears spontaneously [91]. Despite TMD self-resolving within 4–10 weeks, it can cause severe and life threatening complications such as hydrops fetalis, pleural effusions, liver cirrhosis with hyperbilirubinemia, organomegaly, or hyperleukocytosis [92]. Approximately, 10–20% of these patients will develop myeloid leukemia with megakaryoblastic features (ML-DS) within the first 3 years. Treatment of ML-DS involves intensity reduced chemotherapy and no HSCT in the first complete remission. As children with DS are susceptible to chemotherapy, the event free survival and survival rates are >85% [92, 93, 94, 95].

APL is a distinct subtype of AML and is characterized by t(15;17). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) fusion protein [96]. Treatment is usually begun immediately with all-trans retinoid acid (ATRA) as APL is associated with an increased risk of a life threatening hemorrhage. In children, a dose of 25 mg/m2 per day of ATRA should be started and has shown to produce equivalent outcomes to the higher dose of 45 mg/m2 per day that is commonly used in adults [97, 98, 99]. Arsenic trioxide has proven to be an effective agent in combination with ATRA in the treatment of newly diagnosed, refractory, or relapsed APL [77]. In patients with hyperleukocytosis treated with ATRA or arsenic trioxide, approximately 10% of children can develop APL differentiation syndrome. This syndrome is characterized by fever, weight gain, respiratory distress, pleural, and pericardial effusions. The incidence of APL differentiation syndrome can be reduced by combining ATRA with chemotherapy. Pseudotumor cerebri occurs in 11% of children during initial ATRA administration and can be treated with steroids [97, 100].

Although there have been major improvements in treatment outcomes, AML remains a life-threatening malignancy. Approximately, 30% of pediatric patients relapse, with only 30–40% of these relapsed patients surviving, indicating a poor outcome [101, 102]. AML is a highly heterogeneous disease and through gaining knowledge on its molecular and genetic background it will allow new targeted and patient-specific therapies to become available to children.

2.5. Supportive treatment

The estimated incidence in children with high-risk AML of severe bacterial infections is 50–60% and the estimated incidence of invasive fungal infections is 7.0–12.5% [103, 104, 105]. The improved outcome in children with AML over the last 10 years may be associated to better supportive care strategies.

Hyperleukocytosis (WBC greater than 100,000/μL) at initial diagnosis is associated with an increased risk of CNS hemorrhage and leukostasis. Patients with monocytic or myelomonocytic (FAB M4 and M5) as well as APL and hyperleukocytosis are at an increased risk of early death [106, 107]. Treatment involves emergency care with intensive monitoring and careful hydration with the addition of rasburicase [108]. In more severe cases involving symptomatic coagulopathy, exchange transfusion or leukapheresis may be required. Controlled and effective reduction in cells with enforced diuresis or hemodialysis, may prevent the occurrence of tumor lysis syndrome [106, 107, 108].

Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy are not recommended in the pediatric population. Although a randomized study in children with AML evaluated G-CSF administered after induction chemotherapy showed a reduction in duration of neutropenia there was no difference in infectious complications or mortality [109]. In addition, a higher relapse rate has been recently demonstrated for children who over express the differentiation defective G-CSF receptor isoform IV [110]. Therefore, the routine prophylactic use of G-CSF or GM-CSF is not recommended for children with AML but remains an option in shortening neutropenia in critically ill patients.

Bacterial infections occur in up to 70% of children during AML therapy [111]. A retrospective study from St. Jude Children’s Research Hospital (SJCRH) in patients with AML found that the use of intravenous cefepime or vancomycin in conjunction with oral ciprofloxacin or a cephalosporin significantly reduced the incidence of bacterial infection and sepsis compared with patients receiving only oral or no antibiotic prophylaxis [112]. Another retrospective study reported a significant reduction in Gram positive, sterile-site infections with antibiotic prophylaxis [113]. While it is suggested that antibiotic prophylaxis is beneficial, prospective randomized trials are required in pediatric patients with AML.

The incidence of invasive fungal infections is up to 15% in children with AML, which is similar to that in adults. They are most commonly caused by Candidaand Aspergillusspecies [114]. Prophylaxis should be administered to all children with agents such as voriconazole, itraconazole, micafungin, or caspofungin. Due to drug interactions (e.g., itraconazole and voriconazole) and variable pharmacokinetics, voriconazole should be held during courses of chemotherapy and levels should be monitored periodically. Prophylaxis for Pneumocystis jiroveciiwith trimethoprim-sulfamethoxazole should also be administered [114, 115].


3. Conclusion

The diagnosis and treatment of AML has significantly improved over the past decades. Risk stratification has allowed for more targeted and specific therapy while avoiding, over treatment in low-risk patients and allowing for more intensive therapy in others. AML is a highly heterogeneous disease and through gaining knowledge on its molecular and genetic background as well as international collaboration, it will allow new targeted and patient-specific therapies to become available, particularly in pediatric patients.


  1. 1. de Rooij J, Zwaan C, van den Heuvel-Eibrink M. Pediatric AML: From biology to clinical management. Journal of Clinical Medicine. 2015;4(1):127-149
  2. 2. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, et al. SEER Cancer Statistics Review, 1975-2011. Bethesda, MD: National Cancer Institute; Based on November 2013 SEER data submission, posted to the SEER web site, April 2014.
  3. 3. Puumala S, Ross J, Aplenc R, Spector L. Epidemiology of childhood acute myeloid leukemia. Pediatric Blood & Cancer. 2013;60(5):728-733
  4. 4. Linabery A, Ross J. Trends in childhood cancer incidence in the U.S. (1992-2004). Cancer. 2008;112(2):416-432
  5. 5. Zwaan C, Reinhardt D, Hitzler J, Vyas P. Acute leukemias in children with down syndrome. Pediatric Clinics of North America. 2008;55(1):53-70
  6. 6. Hahn C, Chong C, Carmichael C, Wilkins E, Brautigan P, Li X, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nature Genetics. 2011;43(10):1012-1017
  7. 7. Ganly P, Walker L, Morris C. Familial mutations of the transcription factor RUNX1 (AML1, CBFA2) predispose to acute myeloid leukemia. Leukemia & Lymphoma. 2004;45(1):1-10
  8. 8. Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukaemia—A review. British Journal of Haematology. 2007;140(2):123-132
  9. 9. Smith M, Cavenagh J, Lister T, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. New England Journal of Medicine. 2004;351(23):2403-2407
  10. 10. Link D, Schuettpelz L, Shen D, Wang J, Walter M, Kulkarni S, et al. Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML. Journal of the American Medical Association. 2011;305:1568-1576
  11. 11. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: A comprehensive review and 2016 update. Blood Cancer Journal. 2016;6(7):e441
  12. 12. Kelly L, Gilliland D. Genetics of myeloid leukemias. Annual Review of Genomics and Human Genetics. 2002;3:179-198
  13. 13. Takahashi S. Current findings for recurring mutations in acute myeloid leukemia. Journal of Hematology & Oncology. 2011;4(1):36
  14. 14. Kihara R, Nagata Y, Kiyoi H, Kato T, Yamamoto E, Suzuki K, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia. 2014;28(8):1586-1595
  15. 15. The Cancer Genome Atlas Research Network. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. The New England Journal of Medicine. 2013;368(22):2059-2074
  16. 16. Grimwade D. The clinical significance of cytogenetic abnormalities in acute myeloid leukaemia. Best Practice & Research Clinical Haematology. 2001;14(3):497-529
  17. 17. Harrison C, Hills R, Moorman A, Grimwade D, Hann I, Webb D, et al. Cytogenetics of childhood acute myeloid leukemia: United Kingdom medical research council treatment trials AML 10 and 12. Journal of Clinical Oncology. 2010;28(16):2674-2681
  18. 18. Betts D, Ammann R, Hirt A, Hengartner H, Beck-Popovic M, Kuhne T, et al. The prognostic significance of cytogenetic aberrations in childhood acute myeloid leukaemia. A study of the Swiss Paediatric oncology group (SPOG). European Journal of Haematology. 2007;78(6):468-476
  19. 19. von Neuhoff C, Reinhardt D, Sander A, Zimmermann M, Bradtke J, Betts D, et al. Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. Journal of Clinical Oncology. 2010;28(16):2682-2689
  20. 20. Mercher T, Busson-Le Coniat M, Khac F, Ballerini P, Mauchauffé M, Bui H, et al. Recurrence of OTT-MAL fusion in t(1;22) of infant AML-M7. Genes, Chromosomes and Cancer. 2001;33(1):22-28
  21. 21. von Bergh A, van Drunen E, van Wering E, van Zutven L, Hainmann I, Lönnerholm G, et al. High incidence of t(7;12)(q36;p13) in infant AML but not in infant ALL, with a dismal outcome and ectopic expression ofHLXB9. Genes, Chromosomes and Cancer. 2006;45(8):731-739
  22. 22. Slater R, Drunen E, Kroes W, Olde Weghuis D, van den Berg E, Smit E, et al. T(7;12)(q36;p13) and t(7;12)(q32;p13)—Translocations involving ETV6 in children 18 months of age or younger with myeloid disorders. Leukemia. 2001;15(6):915-920
  23. 23. Hollink I, von den Heuvel-Eibrink M, Arentsen-Peters S, Pratcorona M, Abbas S, Kuipers J, et al. NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood. 2011;118(13):3645-3656
  24. 24. Cook A, Li L, Ho Y, Lin A, Li L, Stein A, et al. Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells. Blood. 2014;123:2826-2837
  25. 25. Spiekermann K, Bagrintseva K, Schwab R, Schmieja K, Hiddemann W. Over expression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells. Clinical Cancer Research. 2003;9:2140-2150
  26. 26. Steensma D, McClure R, Karp J, Tefferi A, Lasho T, Powell H, et al. JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia. 2006;20(6):971-978
  27. 27. Patel J, Gonen M, Figueroa M, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. New England Journal of Medicine. 2012;366:1079-1089
  28. 28. Vardiman J, Thiele J, Arber D, Brunning R, Borowitz M, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood. 2009;114(5):937-951
  29. 29. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. Blood. 2016;128(3):462-463
  30. 30. Dohner H, Estey E, Amadori S, Appelbaum F, Buchner T, Burnett A, et al. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2009;115(3):453-474
  31. 31. Creutzig U, van den Heuvel-Eibrink M, Gibson B, Dworzak M, Adachi S, de Bont E, et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: Recommendations from an international expert panel. Blood. 2012;120(16):3187-3205
  32. 32. Bennett J, Catovsky D, Daniel M, Flandrin G, Galton D, Gralnick H, et al. Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-MO). British Journal of Haematology. 1991;78(3):325-329
  33. 33. Fröhling S, Skelin S, Liebisch C, Scholl C, Schlenk R, Döhner H, et al. Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia. Journal of Clinical Oncology. 2002;20(10):2480-2485
  34. 34. Lugthart S, van Drunen E, van Norden Y, van Hoven A, Erpelinck C, Valk P, et al. High EVI1 levels predict adverse outcome in acute myeloid leukemia: Prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood. 2008;111(8):4329-4337
  35. 35. Bos J, Toksoz D, Marshall C, Verlaan-de Vries M, Veeneman G, van der Eb A, et al. Amino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia. Nature. 1985;315(6022):726-730
  36. 36. Ross M. Gene expression profiling of pediatric acute myelogenous leukemia. Blood. 2004;104(12):3679-3687
  37. 37. Dluzniewska A, Balwierz W, Armata J, Balcerska A, Chybicka A, Kowalczyk J, et al. Twenty years of polish experience with three consecutive protocols for treatment of childhood acute myelogenous leukemia. Leukemia. 2005;19(12):2117-2124
  38. 38. Creutzig U, Zimmermann M, Ritter J, Henze G, Graf N, Loffler H, et al. Definition of a standard-risk group in children with AML. British Journal of Haematology. 1999;104(3):630-639
  39. 39. Balgobind B, Hollink I, Arentsen-Peters S, Zimmermann M, Harbott J, Beverloo H, et al. Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia. Haematologica. 2011;96(10):1478-1487
  40. 40. Rubnitz J, Raimondi S, Halbert A, Tong X, Srivastava D, Razzouk B, et al. Characteristics and outcome of t(8;21)-positive childhood acute myeloid leukemia: A single institution’s experience. Leukemia. 2002;16(10):2072-2077
  41. 41. Balgobind B, Raimondi S, Harbott J, Zimmermann M, Alonzo T, Auvrignon A, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: Results of an international retrospective study. Blood. 2009;114(12):2489-2496
  42. 42. Coenen E, Raimondi S, Harbott J, Zimmermann M, Alonzo T, Auvrignon A, et al. Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: Results of an international study. Blood. 2011;117(26):7102-7111
  43. 43. Hasle H, Alonzo T, Auvrignon A, Behar C, Chang M, Creutzig U, et al. Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: An international retrospective study. Blood. 2007;109(11):4641-4647
  44. 44. Pession A, Masetti R, Rizzari C, Putti M, Casale F, Fagioli F, et al. Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia. Blood. 2013;122(2):170-178
  45. 45. Kelly M, Horan J, Alonzo T, Eapen M, Gerbing R, He W, et al. Comparable survival for pediatric acute myeloid leukemia with poor-risk cytogenetics following chemotherapy, matched related donor, or unrelated donor transplantation. Pediatric Blood & Cancer. 2013;61(2):269-275
  46. 46. Johnston D, Alonzo T, Gerbing R, Hirsch B, Heerema N, Ravindranath Y, et al. Outcome of pediatric patients with acute myeloid leukemia (AML) and −5/5q− abnormalities from five pediatric AML treatment protocols: A report from the Children’s oncology group. Pediatric Blood & Cancer. 2013;60(12):2073-2078
  47. 47. Manola K, Panitsas F, Polychronopoulou S, Daraki A, Karakosta M, Stavropoulou C, et al. Cytogenetic abnormalities and monosomal karyotypes in children and adolescents with acute myeloid leukemia: Correlations with clinical characteristics and outcome. Cancer Genetics. 2013;206(3):63-72
  48. 48. Bachas C, Schuurhuis G, Hollink I, Kwidama Z, Goemans B, Zwaan C, et al. High-frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: Implications for personalized medicine. Blood. 2010;116(15):2752-2758
  49. 49. Masetti R, Vendemini F, Zama D, Biagi C, Pession A, Locatelli F. Acute myeloid leukemia in infants: Biology and treatment. Frontiers in Pediatrics. 2015;3:37. DOI: 10.3389/fped.2015.00037
  50. 50. Kaspers GJ. Pediatric acute myeloid leukemia. Expert Review of Anticancer Therapy. 2012;12(3):405-413
  51. 51. Gibson B, Webb D, Howman A, De Graaf S, Harrison C, Wheatley K. Results of a randomized trial in children with acute myeloid leukaemia: Medical Research Council AML12 trial. British Journal of Haematology. 2011;155(3):366-376
  52. 52. Creutzig U, Zimmermann M, Bourquin J, Dworzak M, Fleischhack G, Graf N, et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: Results from study AML-BFM 2004. Blood. 2013;122(1):37-43
  53. 53. Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. New England Journal of Medicine 2009;361(13):1235-1248
  54. 54. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. New England Journal of Medicine. 2009;361(13):1249-1259
  55. 55. Grenier M, Lipshultz S. Epidemiology of anthracycline cardiotoxicity in children and adults. Seminars in Oncology. 1998;25(4 Suppl 10):72-85
  56. 56. Kremer L, van der Pal H, Offringa M, van Dalen E, Voute P. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: A systematic review. Annals of Oncology. 2002;13(6):819-829
  57. 57. Lipshultz S, Giantris A, Lipsitz S, Dalton V, Asselin B, Barr R, et al. Doxorubicin administration by continuous infusion is not cardioprotective: The Dana-Farber 91-01 acute lymphoblastic leukemia protocol. Journal of Clinical Oncology. 2002;20(6):1677-1682
  58. 58. Bielack S, Erttmann R, Kempf-Bielack B, Winkler K. Impact of scheduling on toxicity and clinical efficacy of doxorubicin: What do we know in the mid-nineties? European Journal of Cancer. 1996;32(10):1652-1660
  59. 59. Lipshultz S, Alvarez J, Scully R. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart. 2007;94(4):525-533
  60. 60. Wells R, Adams M, Alonzo T, Arceci R, Buckley J, Buxton A, et al. Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children’s cancer group study 2951. Journal of Clinical Oncology. 2003;21(15):2940-2947
  61. 61. Aplenc R, Alonzo T, Gerbing R, Lange B, Hurwitz C, Wells R, et al. Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: A report from the Children’s oncology group. Journal of Clinical Oncology. 2008;26(14):2390-2395
  62. 62. Quarello P, Fagioli F, Basso G, Putti M, Berger M, Luciani M, et al. Outcome of children with acute myeloid leukaemia (AML) experiencing primary induction failure in the AIEOP AML 2002/01 clinical trial. British Journal of Haematology. 2015;171(4):566-573
  63. 63. Mayer R, Davis R, Schiffer C, Berg D, Powell B, Schulman P, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. New England Journal of Medicine. 1994;331(14):896-903
  64. 64. Cassileth P, Lynch E, Hines J, et al. Varying intensity of postremission therapy in acute myeloid leukemia. Blood. 1992;79(8):1924-1930
  65. 65. Burnett A, Hills R, Milligan D, Goldstone A, Prentice A, McMullin M, et al. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: Results of the MRC AML12 trial. Journal of Clinical Oncology. 2010;28(4):586-595
  66. 66. Schaich M, Röllig C, Soucek S, Kramer M, Thiede C, Mohr B, et al. Cytarabine dose of 36 g/m2 compared with 12 g/m2 within first consolidation in acute myeloid leukemia: Results of patients enrolled onto the prospective randomized AML96 study. Journal of Clinical Oncology. 2011;29(19):2696-2702
  67. 67. Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Research. 1998;58(18):4173-4179
  68. 68. Lie S, Abrahamsson J, Clausen N, Forestier E, Hasle H, Hovi L, et al. Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down’s syndrome: Results of NOPHO-AML trials. British Journal of Haematology. 2003;122(2):217-225
  69. 69. Stevens R, Hann I, Wheatley K, Gray R. Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukaemia: Results of the United Kingdom Medical Research Council’s 10th AML trial. British Journal of Haematology. 1998;101(1):130-140
  70. 70. Creutzig U, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Lehrnbecher T. Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: Analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98. Journal of Clinical Oncology. 2004;22(21):4384-4393
  71. 71. Gibson B, Wheatley K, Hann I, Stevens R, Webb D, Hills R, et al. Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia. 2005;19(12):2130-2138
  72. 72. Tsukimoto I, Tawa A, Horibe K, Tabuchi K, Kigasawa H, Tsuchida M, et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: The AML99 trial from the Japanese childhood AML cooperative study group. Journal of Clinical Oncology. 2009;27(24):4007-4013
  73. 73. Oliansky D, Rizzo J, Aplan P, Arceci R, Leone L, Ravindranath Y, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: An evidence-based review. Biology of Blood and Marrow Transplantation. 2007;13(1):1-25
  74. 74. Woods W, Neudorf S, Gold S, et al. A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission: A report from the Children’s cancer group. Blood. 2001;97(1):56-62
  75. 75. Ravindranath Y, Yeager A, Chang M, Steuber C, Krischer J, Graham-Pole J, et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. New England Journal of Medicine. 1996;334(22):1428-1434
  76. 76. Alonzo T, Wells R, Woods W, Lange B, Gerbing R, Buxton A, et al. Postremission therapy for children with acute myeloid leukemia: The children’s cancer group experience in the transplant era. Leukemia. 2005;19(6):965-970
  77. 77. Sanz M, Grimwade D, Tallman M, Lowenberg B, Fenaux P, Estey E, et al. Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2008;113(9):1875-1891
  78. 78. Horan J, Alonzo T, Lyman G, Gerbing R, Lange B, Ravindranath Y, et al. Impact of disease risk on efficacy of matched related bone marrow transplantation for pediatric acute myeloid leukemia: The Children’s oncology group. Journal of Clinical Oncology. 2008;26(35):5797-5801
  79. 79. Niewerth D, Creutzig U, Bierings M, Kaspers G. A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia. Blood. 2010;116(13):2205-2214
  80. 80. Klingebiel T, Reinhardt D, Bader P. Place of HSCT in treatment of childhood AML. Bone Marrow Transplantation. 2008;42:S7-S9
  81. 81. Creutzig U, Reinhardt D. Current controversies: Which patients with acute myeloid leukaemia should receive a bone marrow transplantation?—A European view. British Journal of Haematology. 2002;118(2):365-377
  82. 82. Bhatia S. Long-term health impacts of hematopoietic stem cell transplantation inform recommendations for follow-up. Expert Review of Hematology. 2011;4(4):437-454
  83. 83. Gupta T, Kannan S, Dantkale V, Laskar S. Cyclophosphamide plus total body irradiation compared with busulfan plus cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation in patients with leukemia: A systematic review and meta-analysis. Hematology/Oncology and Stem Cell Therapy. 2011;4(1):17-29
  84. 84. Bresters D, van Gils I, Kollen W, Ball L, Oostdijk W, van der Bom J, et al. High burden of late effects after haematopoietic stem cell transplantation in childhood: A single-centre study. Bone Marrow Transplantation. 2009;45(1):79-85
  85. 85. Bredeson C, LeRademacher J, Kato K, DiPersio J, Agura E, Devine S, et al. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood. 2013;122(24):3871-3878
  86. 86. Koreth J, Schlenk R, Kopecky K, Honda S, Sierra J, Djulbegovic B, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission. Journal of the American Medical Association. 2009;301(22):2349
  87. 87. Liu D, Xu L, Liu K, Wang Y, Chen H, Han W, et al. Long-term outcomes of unmanipulated haploidentical HSCT for paediatric patients with acute leukaemia. Bone Marrow Transplantation. 2013;48(12):1519-1524
  88. 88. Locatelli F, Masetti R, Rondelli R, Zecca M, Fagioli F, Rovelli A, et al. Outcome of children with high-risk acute myeloid leukemia given autologous or allogeneic hematopoietic cell transplantation in the AIEOP AML-2002/01 study. Bone Marrow Transplantation. 2015;50(2):320-320
  89. 89. Creutzig U, Zimmermann M, Bourquin J, Dworzasungk M, Fleischhack G, von Neuhoff C, et al. CNS irradiation in pediatric acute myleoid leukemia: Equal results by 12 or 18 Gy in studies AML-BFM98 and 2004. Pediatric Blood & Cancer. 2011;57(6):986-992
  90. 90. Dahl G, Simone J, Hustu H, Mason C. Preventive central nervous system irradiation in children with acute nonlymphocytic leukemia. Cancer. 1978;42(5):2187-2192
  91. 91. Gamis A, Alonzo T, Gerbing R, Hilden J, Sorrell A, Sharma M, et al. Natural history of transient myeloproliferative disorder clinically diagnosed in down syndrome neonates: A report from the Children’s oncology group study A2971. Blood. 2011;118(26):6752-6759
  92. 92. Klusmann J, Creutzig U, Zimmermann M, Dworzak M, Jorch N, Langebrake C, et al. Treatment and prognostic impact of transient leukemia in neonates with down syndrome. Blood. 2008;111(6):2991-2998
  93. 93. Creutzig U, Reinhardt D, Diekamp S, Dworzak M, Stary J, Zimmermann M. AML patients with down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia. 2005;19(8):1355-1360
  94. 94. Kudo K, Kojima S, Tabuchi K, Yabe H, Tawa A, Imaizumi M, et al. Prospective study of a pirarubicin, intermediate-dose cytarabine, and etoposide regimen in children with down syndrome and acute myeloid leukemia: The Japanese childhood AML cooperative study group. Journal of Clinical Oncology. 2007;25(34):5442-5447
  95. 95. Kudo K, Hama A, Kojima S, Ishii R, Morimoto A, Bessho F, et al. Mosaic down syndrome-associated acute myeloid leukemia does not require high-dose cytarabine treatment for induction and consolidation therapy. International Journal of Hematology. 2010;91(4):630-635
  96. 96. Melnick A, Licht J. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999;93(10):3167-3215
  97. 97. Mann G, Reinhardt D, Ritter J, Hermann J, Schmitt K, Gadner H, et al. Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children. Annals of Hematology. 2001;80(7):417-422
  98. 98. de Botton S, Coiteux V, Chevret S, et al. Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. Journal of Clinical Oncology. 2004;22(8):1404-1412
  99. 99. Ortega J, Madero L, Martín G, Verdeguer A, García P, Parody R, et al. Treatment with all-transretinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: A multicenter study by the PETHEMA group. Journal of Clinical Oncology. 2005;23(30):7632-7640
  100. 100. Gregory J, Feusner J. Acute promyelocytic leukemia in childhood. Current Oncology Reports. 2009;11(6):439-445
  101. 101. Sander A, Zimmermann M, Dworzak M, Fleischhack G, von Neuhoff C, Reinhardt D, et al. Consequent and intensified relapse therapy improved survival in pediatric AML: Results of relapse treatment in 379 patients of three consecutive AML-BFM trials. Leukemia. 2010;24(8):1422-1428
  102. 102. Kaspers G, Zimmermann M, Reinhardt D, Gibson B, Tamminga R, Aleinikova O, et al. Improved outcome in pediatric relapsed acute myeloid leukemia: Results of a randomized trial on liposomal daunorubicin by the international BFM study group. Journal of Clinical Oncology. 2013;31(5):599-607
  103. 103. Sung L, Gamis A, Alonzo T, Buxton A, Britton K, DeSwarte-Wallace J, et al. Infections and association with different intensity of chemotherapy in children with acute myeloid leukemia. Cancer. 2009;115(5):1100-1108
  104. 104. Kaya Z, Gursel T, Kocak U, Aral Y, Kalkanci A, Albayrak M. Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis. Pediatric Blood & Cancer. 2009;52(4):470-475
  105. 105. Kobayashi R, Kaneda M, Sato T, Ichikawa M, Suzuki D, Ariga T. The clinical feature of invasive fungal infection in pediatric patients with hematologic and malignant diseases. Journal of Pediatric Hematology/Oncology. 2008;30(12):886-890
  106. 106. Inaba H, Fan Y, Pounds S, Geiger T, Rubnitz J, Ribeiro R, et al. Clinical and biologic features and treatment outcome of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis. Cancer. 2008;113(3):522-529
  107. 107. Creutzig U, Ritter J, Budde M, Sutor A, Schellong G. Early deaths due to hemorrhage and leukostasis in childhood acute myelogenous leukemia. Associations with hyperleukocytosis and acute monocytic leukemia. Cancer. 1987;60(12):3071-3079
  108. 108. Malaguarnera G, Giordano M, Malaguarnera M. Rasburicase for the treatment of tumor lysis in hematological malignancies. Expert Review of Hematology. 2012;5(1):27-38
  109. 109. Lehrnbecher T, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Creutzig U. Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia. Blood. 2006;109(3):936-943
  110. 110. Ehlers S, Herbst C, Zimmermann M, Scharn N, Germeshausen M, von Neuhoff N, et al. Granulocyte colony-stimulating factor (G-CSF) treatment of childhood acute myeloid leukemias that overexpress the differentiation-DefectiveG-CSFReceptor isoform IV is associated with a higher incidence of relapse. Journal of Clinical Oncology. 2010;28(15):2591-2597
  111. 111. Sung L, Nathan P, Alibhai S, Tomlinson G, Beyene J. Meta-analysis: Effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection. Annals of Internal Medicine. 2007;147(6):400-411
  112. 112. Kurt B, Flynn P, Shenep J, Pounds S, Lensing S, Ribeiro R, et al. Prophylactic antibiotics reduce morbidity due to septicemia during intensive treatment for pediatric acute myeloid leukemia. Cancer. 2008;113(2):376-382
  113. 113. Yeh T, Liu H, Hou J, Chen K, Huang T, Chang C, et al. Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis. Cancer. 2014;120(8):1255-1262
  114. 114. Rubnitz J. How I treat pediatric acute myeloid leukemia. Blood. 2012;119(25):5980-5988
  115. 115. Lehrnbecher T, Groll A. Invasive fungal infections in the pediatric population. Expert Review of Anti-Infective Therapy. 2011;9(3):275-278

Written By

Katarzyna Derwich, Dorothy Mitkowski and Jolanta Skalska- Sadowska

Submitted: June 12th, 2017 Reviewed: September 12th, 2017 Published: May 16th, 2018