Acute myeloid leukemia: Children and adolescents

INTRODUCTION — Acute leukemia is the most common cancer in children, and it corresponds to one-third of all childhood malignancies. Acute myeloid leukemia (AML) accounts for approximately 15 percent of childhood leukemia, while acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) corresponds to 80 percent of pediatric acute leukemia.

Treatment in clinical trials, risk stratification, intensification of therapy, and improved supportive care have contributed to improved survival for children and adolescents with AML, but outcomes remain inferior to those with ALL/LBL.

This topic reviews AML in children and adolescents.

Treatment of childhood ALL/LBL is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

CLINICAL PRESENTATION — The most common presenting symptoms of AML in children and adolescents are findings associated with the leukemic burden, associated cytopenias, or disease complications. The clinical presentation of AML may be indistinguishable from that of acute lymphoblastic leukemia/lymphoblastic lymphoma.

Patients can present with fever, malaise, musculoskeletal pains, lymphadenopathy, or hepatosplenomegaly. They may have clinical manifestations of cytopenias, including anemia (eg, pallor, fatigue, dyspnea), thrombocytopenia (eg, unusual bleeding or bruising), and/or neutropenia (eg, infection).

In some children, AML is first suspected because of laboratory abnormalities, such as circulating myeloblasts, electrolyte derangements, or liver dysfunction.

Less often, children present with symptoms related to complications of AML, such as involvement of the central nervous system (eg, headache, lethargy, mental status changes, cranial nerve palsies) or other extramedullary sites. Some children have respiratory or neurologic distress due to leukostasis (extreme levels of circulating myeloblasts). Disseminated intravascular coagulation can be present, especially in patients with acute promyelocytic leukemia.

EVALUATION — Evaluation of AML in children and adolescents includes history and physical examination, laboratory tests, bone marrow examination, and other clinical studies.

Clinical/laboratory testing

●Clinical – History should evaluate the child for symptoms, described above, related to tumor burden, cytopenias, and extramedullary involvement. (See 'Clinical presentation' above.)

Family history should determine if relatives have conditions consistent with a familial/inherited basis for the leukemia. Examples include other leukemias, myelodysplastic syndromes/neoplasms (MDS), or multiple cancers; unexplained cytopenias; suspicious abnormalities of hair, skin, nails, or organ dysfunction (eg, lung or liver); deafness; and short stature, as discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

Physical examination should evaluate the child for hepatosplenomegaly, bleeding/bruising, findings that may reflect an inherited/familial condition, or involvement of the central nervous system (CNS) or other extramedullary sites.

●Laboratory

•Hematology – Blood counts and coagulation tests:

-Complete blood count with leukocyte differential count

-Prothrombin time, activated partial thromboplastin time, fibrinogen

•Chemistries – Electrolytes, glucose, kidney function, liver function tests, including lactate dehydrogenase, calcium, magnesium, phosphorus, uric acid, albumin

●Other clinical studies

•Lumbar puncture – All children with suspected AML should have a lumbar puncture (LP) soon after diagnosis to examine cerebrospinal fluid, which should be analyzed by cell count, protein, glucose, and cytology (examination of stained cytospin slides). (See "Lumbar puncture in children".)

Leukemic involvement of the CNS is generally defined as >5 x 10⁶ leukocytes/L cerebrospinal fluid including blasts, in a nonbloody specimen.

•Imaging – Imaging is performed, as clinically indicated, to assess leukemic involvement of extramedullary sites.

-Central nervous system – For children with unexplained neurologic abnormalities, computed tomography (CT) and/or magnetic resonance imaging (MRI) should be performed to assess the patient for mass lesions or meningeal involvement.

-Other extramedullary sites – Suspected extramedullary involvement by AML should be evaluated by CT, positron emission tomography, and/or MRI, as clinically indicated.

Pathology — Bone marrow, peripheral blood, and suspected sites of extramedullary involvement should be evaluated for blasts. Analysis includes morphology, immunophenotype, cytogenetics, and molecular features, which are essential for distinguishing AML from ALL and other disorders.

Characteristic pathologic findings in childhood AML include:

●Morphology – Myeloblasts are immature cells with large nuclei, usually with prominent nucleoli, and a variable amount of pale blue cytoplasm. Myeloid blasts typically have more abundant cytoplasm than lymphoid blasts and may have granules or Auer rods (picture 1).

●Immunophenotype – The immunophenotype of the blasts is determined by flow cytometry and/or immunohistochemistry.

AML blasts express myeloid markers, such as CD11b, CD34, CD33, CD45, CD64, CD65, CD117, myeloperoxidase (MPO), and lysozyme.

●Cytogenetics – Cytogenetic abnormalities are found in three-quarters of pediatric AML cases [1]. Many of these abnormalities have prognostic significance, as discussed below. (See 'Cytogenetics' below.)

Although many cytogenetic abnormalities associated with pediatric AML are detected by conventional karyotype analysis, some require fluorescence in situ hybridization (FISH) or molecular techniques for detection.

In addition to conventional karyotyping, FISH should evaluate the specimen for t(8;21), inv(16), t(15;17), and 11q23 translocations. (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 'Recurrent translocations'.)

●Mutation analysis – Pediatric AML is genetically heterogeneous, and the molecular profiles differ from those of adult AML. Certain mutations or genetic profiles have prognostic or therapeutic implications, as discussed below. (See 'Molecular features' below.)

Next generation sequencing (NGS) and/or polymerase chain reaction (PCR) should be used to identify mutations of NPM1, CEBPA, FLT3, KIT, WT1, and/or cryptic fusions that are not detected by conventional cytogenetics [2,3]. (See "Acute myeloid leukemia: Molecular genetics", section on 'Gene mutations'.)

DIAGNOSIS AND CLASSIFICATION — AML should be considered in a child or adolescent with unexplained cytopenias or associated symptoms, organomegaly, or blasts in peripheral blood. (See 'Clinical presentation' above.)

Diagnosis — Diagnosis of AML requires pathologic confirmation in bone marrow, with or without analysis of blood and/or sites of extramedullary involvement.

Diagnosis is based on morphology (microscopy) and immunophenotyping that reveal the myeloid lineage of blasts, along with cytogenetic and molecular analysis. Details of the diagnostic criteria for AML are presented separately. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis", section on 'Diagnosis'.)

One of the following systems should be used to diagnose and classify AML:

●International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias [4]

●The 5^th edition of the World Health Organization (WHO5) of hematolymphoid tumors: myeloid and histiocytic/dendritic neoplasms [5]

Both ICC and WHO5 classify hematopoietic neoplasms by integrating morphology (eg, cytology, histology, tissue architecture) and cellular lineage (by immunophenotype) with cytogenetic and molecular features. Use of either ICC or WHO5 is acceptable and should replace outdated classification systems, such as the FAB (French-American-British) classification system [6] or the revised 4^th edition of the WHO classification system [7]. Details of the ICC and WHO5 classification systems are presented separately. (See "Classification of hematopoietic neoplasms".)

Recognition of inherited/familial AML has important implications for management. Familial AML is demonstrated by personal and family history and genetic testing of the blasts and nonhematopoietic tissue to demonstrate the presence of an implicated gene variant/mutation in the germline. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

Differential diagnosis — AML must be distinguished from other types of leukemia and hematologic malignancies with blood/marrow involvement and from other conditions associated with cytopenias and/or circulating immature cells.

●Acute lymphoblastic leukemia – Acute lymphoblastic leukemia (ALL) manifests similar clinical findings, but it is considerably more common than AML in children.

Clinical findings are like those of AML, but ALL is more likely to present with extramedullary disease, such as a mediastinal mass. ALL blasts are generally smaller, have less conspicuous nucleoli, less cytoplasm, and lack intracytoplasmic granules and Auer rods.

Immunophenotyping (eg, using flow cytometry) is essential for distinguishing the lymphoid blasts of ALL from the myeloid blasts of AML. Diagnosis of ALL in children is discussed separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

●Other acute leukemias – A variety of childhood leukemias share clinical or morphologic similarities with AML. Examples include:

•Mixed phenotype acute leukemia and acute undifferentiated leukemia are distinguished from AML by immunophenotype, as discussed separately. (See "Mixed phenotype acute leukemia".)

•Juvenile myelomonocytic leukemia can present with organomegaly, but the malignant cells are not as immature and exhibit features of the monocytic lineage. (See "Juvenile myelomonocytic leukemia".)

●Chronic myeloid leukemia – Accelerated phase or blast crisis of chronic myeloid leukemia (CML) typically manifests splenomegaly and/or constitutional symptoms, with an expanded population of circulating myeloid cells at various stages of differentiation. However, malignant cells of CML exhibit the characteristic t(9;22) chromosomal rearrangement (Philadelphia chromosome) and BCR::ABL1 rearrangement, which distinguish them from AML blasts. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

●Myelodysplastic syndromes/neoplasms – Myelodysplastic syndromes/neoplasms (MDS) and AML are considered by many experts to be components of a spectrum of myeloid malignancies with related clinical features and certain aspects of natural history. MDS may present with cytopenias with circulating myeloid cells with aberrant morphology, including myeloblasts. MDS is distinguished from AML by fewer blasts in blood and marrow and by genetic abnormalities that differ from, but may overlap with, findings of AML.

For cases with 10 to 20 percent myeloid blasts, the ICC does not distinguish between MDS and AML; such cases are labeled MDS/AML [4]. The WHO5 describes such cases as MDS with increased blasts [5]. Details of diagnosis and classification of MDS and AML are discussed separately. (See "Classification of hematopoietic neoplasms", section on 'Myeloid neoplasms'.)

●Leukemoid reaction – A leukemoid reaction describes a high leukocyte count (eg, ≥50,000/microL) with neutrophilia and prominent left shift, usually in response to infection. However, myeloblasts and other very immature cells are scant or absent, and a leukemoid reaction can be distinguished by morphology. Bone marrow examination and/or cytogenetic testing is rarely needed to distinguish a leukemoid reaction from AML.

●Aplastic anemia – Aplastic anemia is a bone marrow failure state that presents with variable levels of pancytopenia and related symptoms. Aplastic anemia can be caused by drugs, infections, inherited conditions, and acquired/autoimmune damage to hematopoietic stem and progenitor cells. Bone marrow examination demonstrates profound hypoplasia of hematopoietic elements, and the marrow space is composed primarily of fat cells and marrow stroma. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Evaluation and diagnosis of various forms of familial/inherited aplastic anemia are discussed separately. (See "Clinical manifestations and diagnosis of Fanconi anemia" and "Shwachman-Diamond syndrome" and "Dyskeratosis congenita and other telomere biology disorders".)

For children with Down syndrome (DS)/trisomy 21, it is important to distinguish transient abnormal myelopoiesis (TAM) and myeloid leukemia associated with DS (ML-DS) from AML. TAM and ML-DS have very different natural histories and require management that is distinct from that of AML. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)" and "Myeloid leukemia associated with Down syndrome (ML-DS)".)

Classification — Cases of pediatric AML should be classified using either the ICC or the WHO5 system. Both systems assign AML subtypes according to morphologic, cytogenetic, and molecular features.

●Defining genetic abnormalities – ICC and WHO5 apply similar diagnostic criteria and labels for cases of AML with defining cytogenetic and molecular findings.

Details of classification of AML subtypes with defining genetic abnormalities are presented separately. (See "Acute myeloid leukemia: Classification", section on 'AML with defining genetic abnormalities'.)

●Other cases of AML – For cases without AML-defining genetic abnormalities, ICC and WHO5 differ in the labels, diagnostic criteria, and assignment to disease categories. Differences between ICC and WHO5 that affect classification of pediatric AML include:

•AML without a defining genetic abnormality – ICC defines many cases without defining genetic abnormalities as AML, not otherwise specified [4], while WHO5 categorizes them according to the degree of blast differentiation [5].

•AML associated with germline or inherited gene variants – AML associated with germline or inherited gene variants is described differently:

-International Consensus Classification – Cases of AML in association with a germline predisposition constitute a separate category, Hematologic neoplasms with germline predisposition; cases are further defined according to association with abnormalities in multiple organ systems, a constitutional platelet disorder, or no abnormalities in multiple organ systems.

-The 5^th edition of the World Health Organization – Cases of AML in association with a germline predisposition are included in the category, Secondary myeloid neoplasms, which also includes therapy-related AML. Cases are assigned subtypes according to associated findings, as described with ICC classification above.

•Therapy-related AML – For AML that arises in a patient with prior exposure to cytotoxic agents, ionizing radiation, or immune interventions, "Therapy-related" is added as a qualifier following the diagnosis of AML in ICC. In WHO5, such cases are included in a category of Secondary myeloid neoplasms (which also includes AML in association with a germline predisposition).

•Myeloid sarcoma – This is a distinct subtype of AML in the ICC system, whereas it is described as a tissue-based manifestation of AML in WHO5.

Other details of differences between the ICC and WHO5 classification systems are presented separately. (See "Acute myeloid leukemia: Classification", section on 'Other subtypes'.)

PROGNOSTIC FACTORS — Prognosis in pediatric AML is informed by cytogenetic and molecular features of the blasts. For children whose AML has no prognostically important genetic features, outcomes are associated with the response to induction therapy. These prognostic features are important components of risk stratification for treatment of pediatric AML, as discussed below. (See 'Risk stratification' below.)

Cytogenetics

●Favorable – AML with favorable cytogenetics accounts for approximately 20 to 30 percent of pediatric AML. Favorable cytogenetic features are:

•t(8;21)(q22;q22); RUNX1::RUNX1T1

•Core-binding factor AML: inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11

Treatment on contemporary protocols with chemotherapy alone results in approximately 80 percent long-term overall survival (OS) and 70 percent relapse-free survival (RFS) [8-10].

●High risk – Children with adverse cytogenetic features account for approximately 15 percent of pediatric AML [8].

Patients with high-risk cytogenetic features include those that harbor any of the following cytogenetic abnormalities (and lack any of the favorable features described above) [3,11-13]:

•Monosomy 7

•Monosomy 5 or del(5q)

•Abnormalities of 3q: inv(3)(q21q26.2) and t(3;3)(q21;q26.2); RPN1::EVI1

•t(6;9)(p23;q34)

•Complex karyotype (≥3 cytogenetic abnormalities)

Children and adolescents harboring these unfavorable features have <50 percent long-term OS; some features are associated with <20 percent OS [3]. Trisomies are common events in pediatric AML (often involving chromosome 8, 19, or 21) and can occur alone or in conjunction with other karyotypic abnormalities.

Cytogenetic abnormalities associated with AML are discussed in more detail separately. (See "Acute myeloid leukemia: Cytogenetic abnormalities".)

Molecular features — Certain mutations are predictive of relapse and associated with prognosis in pediatric AML.

Mutation testing is an essential component of the diagnostic/classification workup and subsequent risk stratification. Next generation sequencing (NGS) and other emerging technologies can detect cryptic fusion genes, copy number alternations (focal gains or losses of genomic regions), loss of heterozygosity, and AML subtypes [14-16].

Molecular features that are associated with prognosis in pediatric AML include:

●Low risk

•CEBPA – Mutations involving CEBPA occur in approximately 5 percent of pediatric AML. Children with CEBPA mutations affecting the bZip domain have a more favorable prognosis, with approximately 70 percent long-term OS following treatment with chemotherapy alone [17,18].

•NPM1 – Mutations involving NPM1 are present in approximately 8 to 10 percent of pediatric AML [19]. Only cases of AML with mutated NPM1 without associated FLT3-ITD (internal tandem repeat) are associated with a favorable prognosis; in such patients, long-term OS is approximately 70 percent with chemotherapy alone. (See "Acute myeloid leukemia: Molecular genetics", section on 'NPM1 mutations' and "Acute myeloid leukemia: Risk factors and prognosis".)

●High risk

•FLT3 mutation – Activating mutations in the FLT3 gene are among the most common recurring somatic mutations in AML. Of these, FLT3-ITD is the most common, and it occurs in 10 to 15 percent of pediatric AML [20,21]. The prevalence of FLT3-ITD increases with age, occurring in 15 to 25 percent of adolescents and young adults. Point mutations of FLT3 (ie, activating loop mutations) occur in 5 to 7 percent of childhood AML and have no clear prognostic impact [22]. (See "Acute myeloid leukemia: Molecular genetics", section on 'FLT3'.)

Patients with mutations involving FLT3-ITD with a high allelic ratio (HAR; of mutant to wild-type FLT3) have a poor prognosis. Cooperative groups use different thresholds, but it is generally accepted that an allelic ratio greater than 0.4 to 0.5 is a marker of poor prognosis [22,23]. Patients with HAR FLT3-ITD are more likely to be refractory to induction chemotherapy and are at a greater risk for relapse [20]. Children with HAR FLT3-ITD mutations have a 20 to 30 percent OS with contemporary chemotherapy regimens alone, but the OS is 50 to 60 percent when FLT3 inhibitors and/or consolidation allogeneic hematopoietic cell transplantation (HCT) are employed [22,23]. (See 'Postremission management' below.)

•KMT2A rearrangements – Translocations involving KMT2A (previously called MLL) at the 11q23 locus are present in 15 to 20 percent of pediatric AML cases. Rearrangements involving KMT2A are most prevalent in young children, especially those <2 years [24].

There are many fusion partners of KMT2A, and prognosis may vary according to the fusion partner. Chromosomal rearrangements, including t(6;11)(q27;q23), t(10;11)(p11.2;q23.3), t(10;11)(p12;q23.3), and t(11;19)(q23;p13.3) have been associated with a poor prognosis [13,25].

The most common rearrangement in pediatric AML involving KMT2A is t(9;11)(p22;q23), which accounts for one-half of cases with KMT2A abnormalities, but it is not associated with adverse outcomes [25]. The t(1;11)(q21;23) rearrangement has been associated with a more favorable outcome relative to other KMT2A fusions [13,25].

•NUP abnormalities

-t(6;9)(p23;q34)/DEK::NUP214.

-NUP98 fusions – NUP98::NSD1 fusions, which commonly occur with FLT3-ITD mutations, are associated with a poor prognosis in children and adults [13,26-28].

•CBFA2T3A::GLIS2

Other recurring mutations have been identified in pediatric AML (eg, WT1, KIT, NRAS, and KRAS), but prognostic significance has not been confirmed. Their association of these mutations with additional cytogenetic and molecular aberrations suggests they may serve as cooperating mutations in leukemogenesis [29-32]. (See "Acute myeloid leukemia: Molecular genetics", section on 'Gene mutations'.)

Treatment response — Children with AML that does not harbor prognostically significant cytogenetic or molecular abnormalities are classified as intermediate risk. For these patients, the most important prognostic factor is the response to induction therapy, including the assessment of measurable residual disease (MRD) [33-35]:

●Measurable residual disease negative – Children with intermediate-risk AML with negative MRD (eg, <0.1 percent by flow cytometry) experience approximately 65 percent RFS [34].

●Measurable residual disease positive – Children with detectable MRD following induction therapy have an inferior prognosis. In one study, children with detectable MRD at the end of first induction had twice the three-year relapse rate compared with MRD-negative patients (60 versus 29 percent) [34].

The prognostic significance of persistent MRD for children with favorable or unfavorable cytogenetic or molecular features is less certain [34,36].

Detection of MRD by the expression of leukemia-associated genes or disease-specific mutations is not routinely used but can provide sensitive detection of a low level of residual leukemia and may inform prognostic and therapeutic decisions [37,38]. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Remission criteria'.)

RISK STRATIFICATION — Risk in cases of pediatric AML is based on prognostic factors, including cytogenetic/molecular features and/or response to induction chemotherapy, as described above. (See 'Prognostic factors' above.)

There is general agreement about what constitutes low-risk genetic features in pediatric AML. However, cooperative groups assign cases to high-risk disease using different genetic features and/or definitions for treatment response.

●Favorable

•t(8;21)(q22;q22); RUNX1::RUNX1T1

•inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11

•Mutated NPM1 without FLT3-ITD (internal tandem duplication; normal karyotype)

•Mutated bZip CEBPA (normal karyotype)

●Intermediate – Cases that do not harbor cytogenetic or molecular abnormalities that classify them as favorable or adverse risk are categorized as intermediate risk.

For cases of intermediate risk, prognosis is primarily driven by response to induction therapy. (See 'Treatment response' above.)

●Adverse

•Cytogenetic features (see 'Cytogenetics' above)

-t(6;9)(p23;q34)/DEK::NUP214

-Abnormalities of 3q

-Monosomy 5 or del(5q)

-Monosomy 7

-Complex karyotype

•Molecular features (see 'Molecular features' above)

-FLT3-ITD

-NUP98 fusions

-Certain KMT2A rearrangements

-CBFA2T3A::GLIS2

•Immunophenotype – RAM immunophenotype (CD56 high, dim or negative CD45 and CD38, and negative HLA-DR expression) [15]

TREATMENT — Children and adolescents with AML should be treated in the context of a current clinical protocol, whenever possible. When that is not possible, treatment should adhere to a contemporary pediatric AML protocol in consultation with experts in the management of pediatric leukemia.

Our approach to the treatment of pediatric AML is consistent with recommendations from international expert panels [39-41].

Information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health.

Induction therapy — Induction therapy with an anthracycline (or mitoxantrone) plus cytarabine is standard therapy in children and adolescents with AML. The doses and schedule of administration and the decision to add a third agent should be guided by the chosen protocol.

Induction therapy is intensive chemotherapy that seeks to achieve a complete remission (CR). Although achieving CR represents the reduction of the leukemic burden by orders of magnitude, it is generally not sufficient to cure AML in children and adolescents. For most patients, the achievement of CR is followed by consolidation therapy, as described below. (See 'Postremission management' below.)

●Administration – Standard induction chemotherapy comprises an anthracycline (eg, daunorubicin, idarubicin) or mitoxantrone plus extended exposure to cytarabine. This generally involves two courses of induction chemotherapy. In some protocols, a third drug is included in induction therapy; examples of third agents include etoposide, 6-thioguanine, gemtuzumab ozogamicin (CD33-directed immunoconjugate), or a kinase inhibitor.

For patients with FLT3-ITD (internal tandem repeat) or other FLT3 mutations, a kinase inhibitor, such as sorafenib, may be added to induction therapy [42,43]. Midostaurin, sorafenib, quizartinib, and gilteritinib are approved by the US Food and Drug Administration (FDA) for the treatment of adults with FLT3-mutated AML. Although various kinase inhibitors are undergoing evaluation in children, none is currently approved for treatment in children. Treatment with a kinase inhibitor is typically continued through postremission management.

●Adverse effects – Toxicity of induction therapy is substantial. Prolonged and profound cytopenias are experienced by all patients and may be complicated by infections from neutropenia, bleeding from thrombocytopenia, and anemia that requires transfusion support.

Monitoring of the child during induction therapy and supportive/adjunctive care for treatment-related adverse effects (AEs) are discussed below. (See 'Adjunctive/supportive care' below.)

●Response assessment – Bone marrow examination is repeated as blood counts recover (typically ≥4 weeks) to assess treatment response and detection of measurable residual disease (MRD).

Remission criteria and response to therapy are described separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Remission status'.)

Patients with CR proceed to postremission management, as described below. (See 'Postremission management' below.)

Patients who do not achieve CR are managed as refractory AML. (See 'Relapsed/refractory AML' below.)

●Outcomes – Most contemporary pediatric AML induction regimens are associated with CR in approximately three-quarters of children and adolescents, but the rate may be affected by cytogenetic and molecular features.

•Anthracycline – No specific anthracycline/anthracenedione is clearly superior in this setting [44].

Daunorubicin, idarubicin, and mitoxantrone have been used for induction therapy for pediatric AML. No specific agent has emerged as clearly superior, based on studies by the Berlin-Frankfurt-Munster (BFM) group, Medical Research Council (MRC), EORTC (European Organisation for Research and Treatment of Cancer), and LAME (Leucemie Aique Myeloide Enfant) [8,45-47].

Children are generally at greater risk for anthracycline-induced cardiotoxicity than adults [48], but the risk of cardiac toxicity at increasing cumulative doses of anthracyclines in children is not well defined.

•Cytarabine – No specific cytarabine regimen is proven superior in children.

Studies that used various cytarabine regimens have provided mixed results [49-51], but it is not possible to draw a firm conclusion about the benefit of high-dose versus low-dose cytarabine because of other protocol differences.

•Third agent – There is no conclusive evidence of a survival benefit from the addition of a third agent to induction therapy for pediatric AML.

-A trial that randomly assigned 149 children (1 to 18 years) to two cycles of daunorubicin plus cytarabine, with or without etoposide, reported no difference in five-year overall survival (OS), five-year event-free survival, or toxicity [52].

-In a phase 3 trial for pediatric AML, the addition of gemtuzumab ozogamicin was associated with a lower rate of relapse, but there was no difference in OS compared with chemotherapy only [9].

Gemtuzumab ozogamicin is approved by the FDA for the treatment of newly diagnosed AML in children.

Central nervous system management — For all children and adolescents with AML, we suggest the administration of intrathecal (IT) chemotherapy as either prophylaxis or treatment based on neurologic evaluation that includes an initial diagnostic lumbar puncture (LP). Central nervous system (CNS)-directed therapy is generally continued through postremission management.

All patients should undergo an initial diagnostic LP to identify leukemic involvement of the CNS. It is acceptable to delay the initial LP for several days after initiation of therapy to reduce potential leukemic contamination of the CNS and to lessen the risk of bleeding, especially in patients with a coagulopathy at diagnosis. Children with unexplained neurologic abnormalities should also undergo imaging, as discussed above. (See 'Clinical/laboratory testing' above.)

CNS involvement is defined by cytologic confirmation of leukemia cells in the cerebrospinal fluid, clinical signs of CNS leukemia (eg, facial nerve palsy, brain/eye involvement), or a tumor mass/meningeal involvement detected by imaging.

All children and adolescents with AML receive CNS-directed therapy, as follows.

●Prophylaxis – Patients with no evidence of CNS involvement receive CNS prophylaxis, but the method varies between protocols.

Prophylaxis reduces the risk of CNS relapse. In general, either single-agent IT cytarabine or triple IT therapy (cytarabine, methotrexate, hydrocortisone) is given. Most regimens provide at least one dose of prophylaxis with each course of therapy, but the optimal number of prophylactic IT treatments is uncertain.

When CNS prophylaxis is not used, CNS involvement at relapse may be as high as 20 percent [1] compared with <10 percent of patients who received prophylaxis [53].

Cranial radiation therapy (RT) should not be used for CNS prophylaxis in children and adolescents because of an increased risk for late AEs, including cognitive deficits, endocrine deficits, and secondary malignancies [54-56], as described below. (See 'Late effects' below.)

●Treatment of central nervous system involvement – Patients with CNS involvement require augmented CNS-directed therapy, but no studies have defined an optimal method or established a consensus.

Management of CNS disease should be guided by the chosen treatment regimen. Most approaches deliver frequent IT chemotherapy combined with intensive systemic chemotherapy (eg, high-dose cytarabine [HiDAC]) [57,58]. Avoidance of cranial RT should be considered to lessen late AEs.

CNS involvement is generally found in 5 to 10 percent of children with AML at diagnosis [57], but some studies have estimated the risk in newly diagnosed pediatric AML to be as high as 30 percent [59]. Risk factors associated with CNS involvement include age <2 years; high white blood cell (WBC) count at presentation; hepatosplenomegaly; and t(8;21), inv(16), or t(16;16) [57,58].

CNS involvement at diagnosis is not an adverse prognostic factor for children with AML, and it is not associated with inferior OS when it is treated with intensified CNS-directed therapy [57].

Postremission management — For patients who achieve CR with induction therapy, postremission management is given to deepen the remission, reduce relapses, and achieve long-term survival and cure.

Consolidation therapy is the mainstay of postremission care; there is only limited evidence to support a role for maintenance therapy in childhood AML.

Consolidation therapy — The choice of consolidation varies with prognostic features and details of the chosen protocol. Risk stratification for children with AML is discussed above. (See 'Risk stratification' above.)

●Favorable risk – For children with favorable prognosis AML, we suggest HiDAC-based consolidation chemotherapy rather than allogeneic hematopoietic cell transplantation (HCT) or observation. There is no role for autologous HCT in children with AML.

At least one-third of children who achieve first CR (CR1) will relapse without consolidation therapy, and there is no proven benefit for autologous HCT. Most experts agree that children with favorable features should receive consolidation chemotherapy rather than HCT in CR1 because transplant-associated AEs outweigh the good prognosis for these children.

●Intermediate/higher risk – HiDAC or allogeneic HCT are reasonable options for children with intermediate-risk or high-risk features.

There is no consensus about which children should receive consolidation chemotherapy versus allogeneic HCT [60,61]. The choice is individualized and is informed by prognostic risk factors (ie, genetic features of the blasts and/or response to induction therapy), comorbidities, and donor availability. The decision to choose allogeneic HCT must weigh the reduced rate of relapse against the increased morbidity and mortality associated with transplantation.

No trials have randomly assigned children in CR1 to allogeneic HCT versus HiDAC-based consolidation. Most studies that compared approaches used biological randomization (ie, children who had a matched sibling donor [MSD] received transplantation, while those without an MSD received consolidation chemotherapy). Because of evolving transplantation techniques and different criteria for selecting consolidation therapy, it is difficult to compare outcomes across studies.

In AML99, 240 children with AML were stratified for postremission management based on age, WBC count at diagnosis, cytogenetics, and treatment response [62]. CR was achieved in 95 percent of children and the five-year OS was 75 percent. Children in CR1 were stratified into low-risk (112 children), intermediate-risk (92 children), and high-risk (23 children) groups. Those with low-risk AML or intermediate-risk AML without an MSD received consolidation chemotherapy, while children with intermediate-risk disease with an MSD and all children with high-risk disease were offered allogeneic HCT. There was no difference in OS for children with intermediate-risk AML who received consolidation chemotherapy versus transplantation. At five years, the OS for low-, intermediate-, and high-risk groups were 86, 72, and 57 percent, respectively.

Consolidation chemotherapy — Consolidation chemotherapy is generally based on HiDAC, with or without other agents, but the preferred dose and number of cycles of HiDAC differs between cooperative trial groups.

In AML99, for children with low-risk and intermediate-risk AML who received consolidation chemotherapy, rates of five-year OS were 86 and 72 percent, respectively [62]. The corresponding rates of five-year disease-free survival (DFS) were 71 and 60 percent. There was no difference in outcomes for children with intermediate-risk disease who received chemotherapy versus transplantation, according to the availability of an MSD. (See 'Consolidation therapy' above.)

Other studies have also shown that HiDAC consolidation therapy is associated with good outcomes for most children with AML [40,63].

No benefit was associated with autologous HCT compared with consolidation chemotherapy for children with AML who achieved remission [64-66].

Allogeneic hematopoietic cell transplantation — Allogeneic HCT is primarily offered for children who have AML with adverse pathologic features or limited treatment response. (See 'Risk stratification' above.)

There is broad support for allogeneic HCT for children with high-risk features and positive MRD after induction, but the benefit in specific genetic subsets of AML is not known. A survival benefit with allogeneic HCT must be balanced against transplantation-related mortality (TRM) and long-term AEs, including graft-versus-host disease (GVHD) [60]. There is no benefit for autologous HCT in children with AML [64-66].

Some studies suggested that allogeneic HCT in CR1 for patients with high-risk AML was associated with improved outcomes [45,60,67], while others reported no benefit compared with induction therapy alone [68,69]. Historical comparisons of outcomes are difficult because of evolving transplantation techniques and decreasing TRM.

●Several studies indicated that allogeneic HCT in CR1 was associated with improved survival in children with high allelic ratio (HAR) FLT3/ITD [23,70,71].

●A meta-analysis reported that allocation to HCT was associated with a reduced risk of relapse and an improved DFS and OS [72]. The graft-versus-leukemia effect is more evident in AML than in acute lymphoblastic leukemia [73].

MSDs are a preferred donor source, but matched unrelated donor grafts are currently associated with similar outcomes [61,74]. Donor selection is discussed separately. (See "Donor selection for hematopoietic cell transplantation".)

Maintenance therapy — We suggest not administering maintenance therapy, based on the absence of a proven benefit.

Results of studies that evaluated maintenance therapy have been mixed.

●A trial (LAME 89/91) that randomly assigned children to 18 months of maintenance therapy (6-mercaptopurine and subcutaneous cytarabine) reported no benefit from maintenance therapy [75]. Maintenance therapy was associated with inferior OS (58 versus 81 percent) and did not reduce relapses. Furthermore, children who did not receive maintenance therapy had a higher likelihood of achieving a second CR than those who received maintenance therapy [76].

●In another trial, among 215 children who were randomly assigned to 18 months of maintenance therapy (thioguanine, vincristine, cytarabine, azacitidine, and cyclophosphamide) versus no maintenance therapy, there was a trend toward inferior five-year OS in children who received maintenance therapy (46 versus 68 percent) and a lower rate of salvage from relapse if maintenance therapy had been given [77].

●Maintenance therapy with sorafenib was associated with improved outcomes for children with HAR FLT3-mutated AML in a phase 1/2 study (AAML1031), but the interpretation of outcomes was confounded by a higher rate of allogeneic HCT in children who received sorafenib [42]. Multivariable analysis that accounted for rates of HCT and favorable co-occurring mutations reported that those who did not receive sorafenib had a higher rate of relapse (hazard ratio [HR] 3.03 [95% CI 1.31-7.04]).

●Maintenance therapy using interleukin 2 failed to show a benefit in DFS [78].

●Results from a series of studies by the BFM-AML group, which routinely administered one year of maintenance therapy to children with AML, were not better than results from other groups [8,44,46,62,79,80].

ADJUNCTIVE/SUPPORTIVE CARE — Children and adolescents with AML are at risk for complications of the underlying AML and its treatment. Supportive/adjunctive care is an essential aspect of management.

Monitoring — The child should be examined at least daily during induction therapy and consolidation therapy for infusion reactions, tumor lysis syndrome (TLS; especially those with high blast counts), nausea/vomiting, mucositis, diarrhea, infections, and other complications of therapy. Careful attention is paid to fluid balance and daily weights, and diuretics may be necessary.

It is especially important to be vigilant for complications in children. Depending on age and development, children may have a limited ability to describe their symptoms, and clinical findings of infection may be blunted or absent during periods of profound neutropenia.

●Laboratory studies

•Hematology – Monitor blood counts daily until recovery of white blood cell (WBC) count to ≥500/microL and platelet transfusion independence is achieved. The frequency of complete blood counts can then be reduced (eg, to every other day), as clinically appropriate.

•Coagulation – Prothrombin time and partial thromboplastin time should be monitored at least weekly or more frequently, if clinically indicated. Fibrinogen should be measured early in remission induction because disseminated intravascular coagulation (DIC) can be triggered by chemotherapy. In patients with clinical or laboratory evidence of DIC, serum fibrinogen, fibrin degradation products (FDPs), and/or other tests should be monitored at least daily until DIC has resolved.

•Chemistries – Chemistry profile, including electrolytes, blood urea nitrogen (BUN), creatinine, uric acid, calcium, phosphorus, and liver function tests, including lactate dehydrogenase, should be performed at least daily until the risk of TLS has passed. The frequency of testing can then be adjusted as clinically appropriate.

Close monitoring of BUN and creatinine may be required throughout the hospitalization for patients who are receiving nephrotoxic agents, such as certain antibiotics. Elevated serum lysozyme levels may lead to renal tubule damage/dysfunction in patients with monocytic/monoblastic leukemia.

Symptom management

●Nausea and vomiting – Effective management of nausea and vomiting enhances patient comfort, improves oral hydration and nutritional status, and can reduce the risk of gastrointestinal (GI) bleeding or a Mallory-Weiss tear from forceful vomiting. Management of severe nausea and vomiting is described separately. (See "Approach to the infant or child with nausea and vomiting".)

●Mucositis – Induction chemotherapy can damage GI epithelia and cause painful oral mucositis and diarrhea. Pain may also limit the ability to take oral fluids and nutrition, exacerbating fluid imbalances and impaired nutrition.

Breakdown of the mucosal barrier predisposes to viral, bacterial, and fungal (mostly Candida albicans) superinfection, particularly as the hematologic nadir is reached. Management of chemotherapy-induced mucositis and diarrhea is presented separately. (See "Oral toxicity associated with systemic anticancer therapy", section on 'Treatment of established mucositis'.)

Cytopenias — Profound and prolonged cytopenias are universal with intensive remission induction therapy, and transfusion of red blood cells (RBCs) and platelets should be provided as needed. Granulocyte colony-stimulating factor (G-CSF; filgrastim) and other myeloid growth factors are not routinely administered.

●Transfusions – All patients should receive leukoreduced blood products to decrease febrile nonhemolytic transfusion reactions, alloimmunization, and other complications. Irradiated blood products are required for individuals who may be candidates for hematopoietic cell transplantation (HCT) to prevent transfusion-associated graft-versus-host disease (ta-GVHD). For cytomegalovirus (CMV)-negative patients who are candidates for HCT, blood products should be leukoreduced or from CMV-negative donors.

There is no consensus threshold for transfusion of RBCs or platelets. We generally transfuse RBCs when the child has anemia-associated symptoms (eg, profound fatigue, dyspnea) and aim to maintain the hemoglobin ≥7 g/dL, but this may vary with age, symptoms, comorbid conditions, and institutional approach.

We transfuse platelets prophylactically for patients with platelet counts <10,000/microL or for overt bleeding (eg, oral purpura).

●Cytokines – There is no demonstrated role for prophylactic administration of G-CSF or other cytokines in this setting [81-83].

Infections/fever — Bacteremia is a leading cause of morbidity and mortality in children who are treated with intensive chemotherapy for AML. Prevention and effective management of bacterial, viral, and fungal infections is critical for optimizing outcomes in these patients.

The infectious risks are due, in part, to alterations in mucosal barriers and the prolonged absence of neutrophils. Adolescents and young adults may be at a higher risk for treatment-related toxicity compared with younger children [84,85].

●Fever – Fever or other infectious findings in a neutropenic child require prompt evaluation and administration of empiric, broad-spectrum parenteral antibiotics. The choice of antibiotics should be tailored to the most likely organisms and institutional drug resistance patterns.

Initial evaluation of new or prolonged fevers in the setting of neutropenia should include CT of the chest, abdomen, pelvis, and sinuses [86]. If a patient has additional symptoms that involve extremities or the central nervous system (CNS), appropriate imaging and diagnostic testing, including examination of the cerebrospinal fluid, should be obtained. Among patients with radiographic lung findings suspicious for fungal infection, additional diagnostic testing may include bronchial alveolar lavage or biopsy of suspicious lesions [87].

Management of febrile neutropenia in children is discussed separately. (See "Fever in children with chemotherapy-induced neutropenia".)

●Bacterial infections – Viridans group streptococci and gram-negative bacteria are common pathogens in this setting. Viridans group streptococci can cause sepsis and viridans streptococcal shock syndrome (SVS), resulting in hemodynamic instability and acute respiratory distress syndrome. The risk of infection with viridans group streptococci is more pronounced in patients treated with high-dose cytarabine (HiDAC) and in those with prolonged neutropenia [88]. Among children treated for AML, as many as 25 percent develop SVS [89]. Prompt recognition of the potential for SVS is critical as rapid progression can be fatal, and appropriate intravenous antibiotics should be started immediately [90].

●Fungal infections – Severe fungal infections, including those caused by yeasts (eg, Candida spp) and invasive molds (eg, Aspergillus spp), pose a significant risk throughout AML therapy and for those undergoing allogeneic HCT [91]. New or prolonged fevers in the setting of neutropenia should prompt suspicion of fungal infection, and empiric antifungal therapy should be administered immediately for presumed or documented fungal infections; treatment should not be delayed for the completion of the diagnostic workup [87,92,93]. (See "Fever in children with chemotherapy-induced neutropenia".)

●Prophylactic antimicrobials – Antibiotic prophylaxis can reduce the risk of bacteremia during intensive chemotherapy treatment, but there is no consensus for use and/or choice of prophylactic antibiotics, antifungals, and antiviral agents during remission induction therapy.

Some institutions administer prophylactic fluoroquinolones and/or antifungals, but the potential benefit varies according to the local flora and results of surveillance cultures and must be weighed against the risk of selecting for drug-resistant organisms.

●Antibacterial prophylaxis – Quinolone prophylaxis has not been shown to reduce severe infectious complications (eg, sepsis) or improve survival; thus, the benefits must be balanced against potential toxicity and institutional resistance patterns to avoid the emergence of antibiotic resistance.

A phase 3 trial that evaluated levofloxacin prophylaxis versus no prophylaxis was terminated early based on efficacy of levofloxacin [81]. Among 195 children (age 6 months to 21 years) with AML or relapsed acute lymphoblastic leukemia (ALL) who were receiving two cycles of intensive chemotherapy, levofloxacin reduced bacteremia (21.9 versus 43.4 percent; risk difference, 21.6 percent [95% CI 8.8-34.4 percent]). However, for children with AML, the reduction of bacteremia was modest (23.4 versus 29.7 percent), and there was no benefit in a cohort of children undergoing allogeneic HCT. Levofloxacin was also associated with fewer episodes of fever and neutropenia (71.2 versus 82.1 percent), but there was no difference in severe infections, invasive fungal disease, Clostridioides difficile-associated diarrhea, or musculoskeletal toxic effects between trial arms.

●Antifungal prophylaxis – Antifungal prophylaxis is effective at reducing invasive fungal infections and should be incorporated into the management of children and adolescents receiving therapy for AML [83,94].

Antifungals used for prophylaxis include fluconazole, which has activity against Candida spp, [95] and voriconazole, posaconazole, and itraconazole, which have activity against both Candida spp and molds, such as Aspergillus spp [96-99]. The choice of regimen depends upon the most likely pathogen, and prophylaxis regimens vary among centers.

Consultation with Infectious Disease specialists should be considered in cases of presumed or documented infections. (See "Treatment and prevention of invasive aspergillosis".)

●Other infection prevention measures – Even though most infections during induction therapy are due to endogenous flora, precautions should be taken to limit exposure to exogenous pathogens.

Careful hand hygiene, prohibition against sick visitors, and other precautions are used to limit infections. Most methods to reduce the risk of infection have not been rigorously tested, but they are applied because they are relatively simple and may reduce exposure to potential pathogens.

Other complications

●Hyperleukocytosis/leukostasis – WBC count >100,000/microL (>100 x 10⁹/L) is described as hyperleukocytosis. Although the threshold is arbitrary, there is an increased risk for complications including leukostasis, DIC, and TLS.

The risk of morbidity and mortality from these complications is highest at the time of diagnosis and within days of initiating therapy [100]. In pediatric AML, higher WBC counts are more common in patients presenting with FLT3-ITD (internal tandem repeat), MLL rearrangements, myelomonocytic phenotypes, and core-binding factor-associated AML [22,100,101]. Hyperleukocytosis is more common with AML compared with acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL), and complications can occur with lower WBC counts in AML [102].

•Leukostasis – Hyperleukocytosis may lead to tissue damage from blast infiltration and leukostasis, resulting in hemorrhagic and thromboembolic events. Leukostasis is an oncologic emergency and can be life threatening, especially the pulmonary and neurologic complications.

The clinical presentation of leukostasis varies according to the affected organs. As an example, lung involvement may manifest as dyspnea, hypoxemia, or respiratory failure, while neurologic involvement may manifest as somnolence, coma, or focal neurologic deficits.

The most effective means of reducing the WBC count is prompt diagnosis and initiation of chemotherapy [103,104]. Leukapheresis or exchange transfusion can lower the WBC count temporarily, but these procedures pose significant risk, are temporary, and can exacerbate thrombocytopenia and the risk of DIC [105].

Diagnosis and management of leukostasis is discussed separately. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

•Tumor lysis syndrome – Supportive management should include vigorous hydration to reduce the risk of tumor lysis and decrease blood viscosity.

TLS may manifest as hyperphosphatemia, hypocalcemia (caused by precipitation of calcium phosphate), hyperuricemia, hyperkalemia, and acute renal failure. Rapid leukemic cell lysis after chemotherapy can cause overproduction and overexcretion of uric acid. Precipitation of uric acid in renal tubules can lead to oliguric or anuric renal failure. Administration of prophylactic medications to prevent complications of TLS (eg, allopurinol, rasburicase) and careful monitoring of renal function is essential. (See "Tumor lysis syndrome: Prevention and treatment".)

•Disseminated intravascular coagulation – Acute DIC occurs most commonly in patients presenting with acute promyelocytic leukemia (APL), but it may also occur with AML with monoblastic differentiation or other subtypes.

If APL is suspected, all-trans retinoic acid should be started immediately (ie, even before confirmation of the diagnosis of APL). Supportive care of patients with AML-associated DIC should include standard management with appropriate blood products (eg, platelets and coagulation factors), which is essential to minimize bleeding risk. (See "Disseminated intravascular coagulation in infants and children".)

SPECIAL POPULATIONS

Down syndrome and AML — Children with Down syndrome (DS; trisomy 21) have a 10 to 20 times greater risk of developing AML compared with children without DS.

Children with myeloid leukemia associated with DS (ML-DS) cannot tolerate the toxic effects of the intensive pediatric AML regimens and must receive distinctive treatment that should be given in a center with specialized expertise. Children with DS have high rates of infection and cardiotoxicity as complications of intensive chemotherapy [106,107].

Children with DS also have specific myeloid cell disorders that must be distinguished from AML:

●Transient abnormal myelopoiesis – Approximately 10 percent of infants with DS (or trisomy 21) manifest transient abnormal myelopoiesis (TAM), which presents with peripheral leukocytosis and circulating cells that resemble megakaryoblasts. Complications of TAM include pericardial and pleural effusions, coagulopathy, hydrops fetalis, hepatic dysfunction, and hepatic fibrosis [108-110].

In most affected children, TAM resolves spontaneously without any treatment [110]. Approximately one-quarter of infants with TAM require chemotherapy to ameliorate respiratory compromise, liver dysfunction, or hyperviscosity associated with hyperleukocytosis [110]. Diagnosis, management, and monitoring of infants with TAM are discussed separately. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)

●Myeloid leukemia of Down syndrome – Some children with DS later develop ML-DS, which resembles acute megakaryoblastic leukemia. ML-DS has a good prognosis, unique biologic characteristics (eg, trisomy 21 plus mutated GATA1), and requires distinctive treatment that should be administered in a center with specialized expertise.

Children with ML-DS have superior outcomes compared with children without DS who develop AML. ML-DS blasts are extremely sensitive to cytarabine and daunorubicin [111,112], and children with DS-AML can experience excellent outcomes without the intensive therapy that is used to cure pediatric AML in other children [113-117].

Diagnosis and management of ML-DS is discussed separately. (See "Myeloid leukemia associated with Down syndrome (ML-DS)".)

Other inherited/germline disorders — Children with suspected inherited or germline causes of AML require distinctive evaluation, diagnostic procedures, management, and counseling.

Children and/or family members who have hematologic malignancies or multiple cancers; unexplained cytopenias; suspicious abnormalities of hair, skin, nails, or organ dysfunction (eg, lung or liver); deafness; short stature; and other clinical findings should be evaluated for a potential underlying inherited or germline cause for AML.

Evaluation of inherited or germline causes of AML is discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

Myeloid sarcoma — Myeloid sarcoma (chloroma) refers to deposits of myeloid blasts outside the bone marrow that may cause destruction or compression in normal tissue. Management of myeloid sarcoma is like that for other cases of AML.

Myeloid sarcoma most often affects the central nervous system (CNS), skin, orbit, and bone. The incidence of myeloid sarcoma in pediatric AML is approximately 10 percent and is more common in patients with the following features [118,119]:

●Younger age

●High white blood cell (WBC) count at diagnosis

●t(8;21)

●Myelomonocytic morphology

In children, the prognostic impact of myeloid sarcoma appears to depend upon the site of involvement [57,118,119]. Children with myeloid sarcoma involving the CNS or orbit have improved outcomes compared with those without CNS/orbit involvement and compared with patients without chloroma. By contrast, children with chloromatous skin involvement have higher rates of relapse.

Extramedullary relapses are more common among children with extramedullary disease at diagnosis. Focal radiation may provide symptomatic benefit, but it does not appear to offer any additional survival benefit compared with chemotherapy in patients with myeloid sarcoma [118,120].

Acute promyelocytic leukemia — Acute promyelocytic leukemia (APL) is a rare subtype of AML that is characterized by maturation arrest at the promyelocyte stage, t(15;17)(q22;q21) chromosomal translocation, and PML::RARA rearrangement. Rare cases are associated with other genetic rearrangements.

Many patients with APL present with disseminated intravascular coagulation (DIC), which requires urgent and aggressive management. All-trans retinoic acid should be started quickly when APL is suspected [121].

Treatment of APL is risk stratified based on the presenting WBC count [122]:

●Standard risk – WBC <10 x 10⁹/L (<10,000/microL) at presentation

●High risk – WBC ≥10 x 10⁹/L

Patients with a high WBC count at presentation experience higher rates of relapse and are especially susceptible to early mortality due to DIC.

All-trans retinoic acid, which targets the PML::RARA fusion protein and induces differentiation of APL blasts, is a critical component of APL management [123]. Treatment using an anthracycline, all-trans retinoic acid, and arsenic trioxide is associated with excellent outcomes [124-127]. A prospective study reported that for children with standard-risk APL who were treated with all-trans retinoic acid and arsenic trioxide, outcomes were similar to those using chemotherapy-containing regimens [128]. Patients with high-risk APL treated with an anthracycline, all-trans retinoic acid, and arsenic trioxide for induction therapy, followed by consolidation therapy using all-trans retinoic acid and arsenic trioxide, had outcomes comparable with regimens that used more anthracycline and other conventional chemotherapies.

Management of APL in children is like that in adults, as discussed separately. (See "Initial treatment of acute promyelocytic leukemia in adults".)

LATE EFFECTS — Potential late treatment-related adverse effects include late onset cardiotoxicity, central nervous system (CNS) impairment, decreased linear growth, infertility, cataracts, secondary cancers, and impaired health status due to such factors as neurocognitive dysfunction, depression, fatigue, and anxiety. (See "Assuring quality of care for cancer survivors: The survivorship care plan" and "Overview of cancer survivorship in adolescents and young adults".)

The occurrence of specific complications depends on the patient's age and the type and intensity of therapy with which they were treated. Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group.

●Cardiac – Anthracyclines carry a risk of both early and late onset cardiotoxicity, which in severe cases results in heart failure. The cumulative anthracycline dose is the most important risk factor for late cardiac effects.

Late cardiac effects are seen in 3 to 5 percent of patients who receive 300 to 440 mg/m² cumulative anthracycline dosing with contemporary treatment protocols for pediatric AML [129,130]. There is no dose that is recognized to be safe, but cumulative doses of >300 mg/m² are associated with higher rates of late cardiac compromise; this risk rises even more steeply with >400 mg/m² [131,132].

Children and adolescents treated for AML should receive long-term follow-up with routine cardiac monitoring.

●Second cancers – Survivors of childhood AML are at risk for secondary neoplasms, mainly solid tumors.

Long-term follow-up data report a prevalence of approximately 1.7 percent [133]. This risk is increased in patients who receive radiation, which may be used in hematopoietic cell transplantation (HCT) conditioning [134].

●Endocrine – The intensity of therapy for AML, especially radiation therapy for HCT, puts survivors at risk for thyroid, gonadal, and other endocrine dysfunction [133-135].

●Other – Children who receive total body irradiation or cranial irradiation are at risk for growth defects and neurocognitive dysfunction; this is more pronounced in very young children who receive radiation [136].

Further details of late effects of treatment of pediatric leukemia are described separately. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents".)

RELAPSED/REFRACTORY AML — Approximately one-third of children with AML experience relapse. The prognosis for these children is generally poor and is especially grave for those patients with high-risk disease features or who previously received allogeneic hematopoietic cell transplantation (HCT).

We strongly encourage enrollment in a clinical trial.

Time to relapse is an important prognostic factor, with survival <20 percent for patients relapsing within one year of achieving first complete remission (CR) [137].

●Salvage therapy – There is no consensus regimen for relapsed or refractory (r/r) pediatric AML. Reinduction regimens vary but commonly include cytarabine, with or without an anthracycline. Use of an anthracycline depends on cardiac function at relapse and the cumulative anthracycline dose with initial therapy.

•High-dose cytarabine – Regimens have combined high-dose cytarabine (HiDAC) with other agents, such as fludarabine and clofarabine, and anthracyclines when appropriate [53,138,139].

•CPX-351 – Treatment of 32 children with CPX-351 (liposomal daunorubicin-cytarabine) was associated with 54 percent CR and 26 percent with CR with incomplete hematologic recovery, most of whom had no detectable measurable residual disease (MRD) by flow cytometry [140]. Treatment was associated with grade ≥3 fever/neutropenia, infection, and rash in 45, 47, and 40 percent, respectively.

CPX-351 is approved by the US Food and Drug Administration (FDA) for children ≥1 year with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes [141-144].

•Gemtuzumab ozogamicin – This CD33-directed immunoconjugate has shown responses in relapsed CD33-positive AML [145,146].

Gemtuzumab ozogamicin is approved by the FDA for treatment of r/r CD33-positive AML in patients ≥2 years.

•Venetoclax – The BCL-2 inhibitor, venetoclax, has activity in children with r/r AML. A study of venetoclax combined with cytarabine (with or without idarubicin) reported a 70 percent overall response rate, with many patients being MRD negative [147].

Achievement of a second CR (CR2) is the most important prognostic factor in long-term survival, and patients who have no evidence of MRD following second-line therapy have the best outcomes [138].

●Consolidation – Consolidation with allogeneic HCT is the only approach that offers children with r/r AML who achieve CR2 a chance for long-term survival.

Most study groups advocate HCT in CR2 for patients who were not previously transplanted [53,148-150]. Investigational approaches with a clinical trial should be considered for patients who relapse after having previously undergone HCT.

There are special considerations regarding allogeneic HCT for children with an inherited or germline cause of AML, as discussed separately. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)".)

●Central nervous system relapse – Central nervous system (CNS) relapse can occur either as an isolated relapse or as part of a combined relapse that usually involves the bone marrow. In one study, nearly 10 percent of patients had CNS involvement at relapse [53].

CNS relapse is managed as discussed above. (See 'Central nervous system management' above.)

Other treatments that are under investigation for r/r AML include epigenetic modifiers, targeted inhibitors, monoclonal antibody-based agents, chimeric antigen receptor T cells, novel T cell engagers (eg, dual affinity targeting receptors), and natural killer cell strategies [151-158].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute myeloid leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Leukemia in children (The Basics)" and "Patient education: Acute myeloid leukemia (AML) (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Description – Acute myeloid leukemia (AML) accounts for 15 percent of childhood acute leukemia. Pediatric AML is less common and has an inferior prognosis compared with childhood acute lymphoblastic leukemia (ALL).

●Clinical presentation – Fever, malaise, musculoskeletal pains, lymphadenopathy, hepatosplenomegaly, bleeding, and/or cytopenias are common. Some present with disseminated intravascular coagulation, neurologic abnormalities, hyperleukocytosis, or tumor lysis syndrome. (See 'Clinical presentation' above.)

●Evaluation – Clinical, laboratory, and pathologic evaluation is described above. (See 'Evaluation' above.)

All children and adolescents should have a lumbar puncture (LP) at diagnosis to assess central nervous system (CNS) involvement.

●Diagnosis – AML should be considered in children with unexplained cytopenias or associated symptoms, organomegaly, or circulating blasts.

•Diagnosis – Based on morphology and immunophenotype of myeloid blasts in bone marrow, blood, and/or extramedullary sites. (See 'Diagnosis' above.)

•Differential diagnosis – ALL and other leukemias and other causes of cytopenias (eg, aplastic anemia) or circulating immature cells should be excluded. (See 'Differential diagnosis' above.)

•Classification – Classified according to the International Consensus Classification (ICC) or World Health Organization 5^th edition (WHO5) as a subtype within one of the following large categories (see 'Classification' above):

-AML with defining genetic features

-Other subtypes (defined by ICC and WHO5 criteria)

●Prognosis – Informed by cytogenetic/molecular features and treatment response. (See 'Prognostic factors' above.)

●Risk stratification – Stratified as low, intermediate, or high risk, based on genetic features and initial treatment response. (See 'Risk stratification' above.)

●Treatment – Participation in a clinical trial is encouraged. Care should adhere to a contemporary pediatric treatment protocol. Treatment comprises:

•Induction therapy – Induction therapy with an anthracycline (or mitoxantrone) plus cytarabine is standard therapy; choice of agents, protocol for administration, and addition of a third agent is guided by the chosen protocol. (See 'Induction therapy' above.)

•Central nervous system management – All patients should have an initial diagnostic LP. (See 'Clinical/laboratory testing' above.)

-No central nervous system disease – We suggest intrathecal (IT) cytarabine or triple IT therapy (cytarabine, methotrexate, hydrocortisone) prophylaxis (Grade 2C). (See 'Central nervous system management' above.)

-Central nervous system involvement – There is no established consensus. Patients are generally treated with more intensive IT and systemic chemotherapy, with or without cranial radiation therapy, as guided by the chosen treatment protocol.

•Consolidation – Varies with prognostic features and protocol:

-Favorable risk – We suggest high-dose cytarabine (HiDAC)-based consolidation chemotherapy rather than allogeneic hematopoietic cell transplantation (HCT) or observation (Grade 2C). (See 'Consolidation therapy' above.)

-Intermediate/higher risk – HiDAC or allogeneic HCT are reasonable options.

•Maintenance – We suggest not administering maintenance therapy (Grade 2C). (See 'Maintenance therapy' above.)

●Adjunctive/supportive care – Monitoring and management of symptoms, cytopenias, and complications are essential aspects of care, as described above. (See 'Adjunctive/supportive care' above.)

●Special populations – Children with Down syndrome, germline conditions, myeloid sarcoma, and acute promyelocytic leukemia require distinctive management. (See 'Special populations' above.)

●Late toxicity – Treatment may be associated with late cardiotoxicity, second cancers, and other late effects. (See 'Late effects' above.)

●Relapsed/refractory AML – Prognosis of relapsed or refractory AML is poor. There is no consensus for salvage induction therapy.

For patients with complete remission after salvage therapy, allogeneic HCT (if eligible) or a clinical trial should be considered. (See 'Relapsed/refractory AML' above.)