Approximately 20% of childhood leukemias are of myeloid origin and represent a spectrum of hematopoietic malignancies.[1] Most myeloid leukemias in children are acute; the remainder include chronic and/or subacute myeloproliferative disorders, such as chronic myeloid leukemia and juvenile myelomonocytic leukemia. Myelodysplastic neoplasms (MDS) occur much less frequently in children than in adults and almost invariably represent clonal, preleukemic conditions that often evolve from congenital marrow failure syndromes, such as Fanconi anemia and Shwachman-Diamond syndrome.
The general characteristics of myeloid leukemias and other myeloid malignancies are described below:
For more information about TAM and MLDS, see Childhood Myeloid Proliferations Associated With Down Syndrome Treatment.
The presence of a karyotype abnormality in a hypocellular marrow is consistent with MDS, and transformation to AML should be expected. Patients with MDS are typically referred for stem cell transplant before transformation to AML.
If a patient with MDS has a common defining genetic variant that is seen in AML, the clinician should be aware that, despite the relatively low proportion of blasts, the child should be treated similarly to those with blast proportions of 20% or more.
In children with Down syndrome younger than 4 years, the finding of MDS likely represents an early presentation of typical AML, and patients should be treated with regimens used for AML in Down syndrome.
For more information, see Childhood Myelodysplastic Neoplasms Treatment.
JMML characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash, along with an elevated white blood cell (WBC) count and increased circulating monocytes.[7] In addition, patients often have elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte-macrophage colony-stimulating factor (GM-CSF), monosomy 7, and leukemia cell variants in a gene involved in RAS pathway signaling (e.g., NF1, KRAS, NRAS, PTPN11, or CBL).[7-9]
For more information, see Juvenile Myelomonocytic Leukemia Treatment.
CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the WBC count can be extremely elevated, the bone marrow does not show increased numbers of leukemic blasts during the chronic phase of this disease. CML is caused by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22 (i.e., t(9;22)) resulting in fusion of the BCR and ABL1 genes.
For more information, see Childhood Chronic Myeloid Leukemia Treatment.
Other chronic myeloproliferative neoplasms, such as polycythemia vera, primary myelofibrosis, and essential thrombocytosis, are extremely rare in children.
For more information, see Childhood Acute Promyelocytic Leukemia Treatment.
Genetic abnormalities (cancer predisposition syndromes) are associated with the development of AML and other myeloid malignancies. These inherited/familial syndromes are recognized as a unique category in the 5th edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors. There are also several acquired conditions that increase the risk of developing AML and other myeloid malignancies (categorized below). These inherited and acquired conditions can induce leukemogenesis through mechanisms that include chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, and altered protein synthesis.[1-3]
Inherited syndromes
Nonsyndromic genetic susceptibility to AML and other myeloid malignancies is also being studied. For example, homozygosity for a specific IKZF1 polymorphism has been associated with an increased risk of AML.[4-6]
The 5th edition of the WHO classification system has categorized the myeloid neoplasms with germline predisposition as follows:[3]
There is a high concordance rate of leukemia in identical twins. However, this finding is not believed to be related to genetic risk, but rather to shared circulation and the inability of one twin to reject leukemic cells from the other twin during fetal development.[7-9] There is an estimated twofold to fourfold increased risk of developing leukemia for the fraternal twin of a pediatric leukemia patient up to about age 6 years, after which the risk is not significantly greater than that of the general population.[10,11]
Over the past 40 years, myeloid malignancies have been categorized using several classification systems that have built upon ever-improving methods of diagnosis. Initially, the French-American-British (FAB) classification system was created primarily based on morphologically distinct subgroups that were defined histochemically and, eventually, immunologically. The World Health Organization's (WHO) classification system for acute myeloid leukemia (AML) was developed after the FAB system, and it is the primary system used now. The WHO classification was initially and primarily based on cytogenetics and morphology, and it now also uses molecular genetics. It has gone through several iterations, with the latest publication in 2022 (5th edition of the WHO Classification of Hematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms). A third classification system, the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias, has been published and is primarily used as a tool for clinical trial development instead of clinical use.
The first comprehensive morphological-histochemical classification system for AML was developed by the FAB Cooperative Group.[1-5] This classification system, which has been replaced by the WHO system, categorized AML into major subtypes primarily on the basis of morphology and immunohistochemical detection of lineage markers.
The major subtypes of AML include the following:
Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.
Although the FAB classification was superseded by the WHO classification described below, it remains relevant as the basis of the WHO's subcategory of AML, defined by differentiation. AML, defined by differentiation, is used for patients whose AML does not meet the criteria for classification within all the current and newly discovered cytogenetic-specific, molecular-specific, and myelodysplastic neoplasms (MDS) or treatment-related AML categories.
In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and that more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17), or KMT2A (MLL) translocations, which collectively made up nearly half of childhood AML cases, were classified as AML with recurrent cytogenetic abnormalities. This classification system also decreased the required bone marrow percentage of leukemic blasts for the diagnosis of AML from 30% to 20%. An additional clarification was made so that patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered an AML patient.[8-10]
In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific gene variants (CEBPA and NPM) in its classification system.[11]
In 2016, and again in 2022, the WHO classification underwent revisions to incorporate the expanding knowledge of leukemia biomarkers, which are important to the diagnosis, prognosis, and treatment of leukemia.[12,13] With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will continue to evolve and provide informative prognostic and biological guidelines to clinicians and researchers.
The inaugural WHO Classification of Pediatric Tumors was also published in 2022. It focuses on a multilayered approach to AML classification, encompassing multiple clinico-pathological parameters and seeking a genetic basis for disease classification wherever possible.[13,14] The recurrent translocations and other genomic alterations that are used to define specific pediatric AML entities in the pediatric WHO classification are listed in Table 1.
| Diagnostic Category | Approximate Prevalence in Pediatric AML |
|---|---|
| aAdapted from Pfister et al.[14] | |
| bCryptic chromosomal translocation. | |
| AML with t(8;21)(q22;q22); RUNX1::RUNX1T1 | 13%–14% |
| AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11 | 4%–9% |
| APL with t(15;17)(q24.1;q21.2); PML::RARA | 6%–11% |
| AML with KMT2A-rearrangement | 25% |
| AML with t(6;9)(p23;q34.1); DEK::NUP214 | 1.7% |
| AML with inv(3)(q21q26)/t(3;3)(q21;q26); GATA2, RPN1::MECOM | <1% |
| AML with ETV6 fusion | 0.8% |
| AML with t(8;16)(p11.2;p13.3); KAT6A::CREBBP | 0.5% |
| AML with t(1;22)(p13.3;q13.1); RBM15::MRTFA (MKL1) | 0.8% |
| AML with CBFA2T3::GLIS2 (inv(16)(p13q24))b | 3% |
| AML with NUP98 fusionb | 10% |
| AML with t(16;21)(p11;q22); FUS::ERG | 0.3%–0.5% |
| AML with NPM1 variants | 8% |
| AML with variants in the bZIP domain of CEBPA | 5% |
It is critical to distinguish AML from acute lymphoblastic leukemia (ALL) because the treatment for children with AML differs significantly from that for ALL. Special histochemical stains performed on bone marrow specimens of children with acute leukemia can be helpful to confirm their diagnosis. The stains most commonly used and variably positive in AML include myeloperoxidase, nonspecific esterases, and Sudan Black B, whereas periodic acid-Schiff is usually positive in ALL, M6 AML (AEL), and, occasionally, M4 and M5 FAB subtypes. In most cases, the pattern with these histochemical stains will distinguish AML from ALL. However, histochemical stains have been mostly replaced by flow cytometric immunophenotyping for diagnostic purposes.
The use of monoclonal antibodies via flow cytometry to determine cell-surface antigens of AML cells is now the primary tool used to diagnose AML. Various lineage-specific monoclonal antibodies that detect antigens on AML cells should be used at the time of initial diagnostic workup, along with a battery of lineage-specific T-lymphocyte and B-lymphocyte markers to help distinguish AML from ALL and acute leukemias of ambiguous lineage. The expression of various CD proteins that are relatively lineage-specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIb/IIIa), CD15, CD11B, CD36, and antiglycophorin A.
Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10% to 20% of AML cases, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent. Similarly, lineage-associated T-lymphocytic antigens CD2, CD3, CD5, and CD7 are present in 20% to 40% of AML cases.[15-17] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[15,16]
Immunophenotyping can also be helpful in distinguishing the following FAB classification subtypes of AML:
Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[21-23] These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies, although most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[13,24-26] In the WHO classification, the presence of MPO is required to establish myeloid lineage. This is not the case for the EGIL classification. The 5th edition of the WHO classification also denotes that in some cases, leukemia with otherwise classic B-cell ALL immunophenotype may also express low-intensity MPO without other myeloid features. The clinical significance of that finding is unclear, suggesting that caution should be used in designating these cases as mixed-phenotype acute leukemia (MPAL).[13]
For the group of acute leukemias that have characteristics of both AML and ALL, the acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 2.[27] The criteria for lineage assignment for a diagnosis of MPAL are provided in Table 3. Note that similar disease categories and diagnostic criteria are included in the International Consensus Classification of Leukemias of Ambiguous Origin.[28]
Leukemias of mixed phenotype may be seen in various presentations, including the following:
Biphenotypic cases represent the majority of mixed-phenotype leukemias.[21] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[22,23,29,30]; [31][Level of evidence C1]
A large retrospective study from the international Berlin-Frankfurt-Münster (BFM) group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplant (HSCT) in first CR was not beneficial, with the possible exception of cases with morphological evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.[30]
| aCredit: Khoury, J.D., Solary, E., Abla, O. et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36, 1703–1719 (2022). https://doi.org/10.1038/s41375-022-01613-1.[13] This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
| Acute leukemia of ambiguous lineage with defining genetic abnormalities | |
| Mixed-phenotype acute leukemia with BCR::ABL1 fusion | |
| Mixed-phenotype acute leukemia with KMT2A rearrangement | |
| Acute leukemia of ambiguous lineage with other defined genetic alterations: | |
| Mixed-phenotype acute leukemia with ZNF384 rearrangement | |
| Acute leukemia of ambiguous lineage with BCL11B rearrangement | |
| Acute leukemia of ambiguous lineage, immunophenotypically defined | |
| Mixed-phenotype acute leukemia, B/myeloid | |
| Mixed-phenotype acute leukemia, T/myeloid | |
| Mixed-phenotype acute leukemia, rare types | |
| Acute leukemia of ambiguous lineage, not otherwise specified | |
| Acute undifferentiated leukemia | |
| Lineage | Criterion |
|---|---|
| aCredit: Khoury, J.D., Solary, E., Abla, O. et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36, 1703–1719 (2022). https://doi.org/10.1038/s41375-022-01613-1.[13] This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
| bCD19 intensity in part exceeds 50% of normal B cell progenitor by flow cytometry. | |
| cCD19 intensity does not exceed 50% of normal B cell progenitor by flow cytometry. | |
| dProvided T lineage not under consideration, otherwise cannot use CD79a. | |
| eUsing anti-CD3 epsilon chain antibody. | |
| B lineage | |
| CD19 strongb, OR | 1 or more also strongly expressed: CD10, CD22, or CD79ad |
| CD19 weakc | 2 or more also strongly expressed: CD10, CD22, or CD79ad |
| T lineage | |
| CD3 (cytoplasmic or surface)e | Intensity in part exceeds 50% of mature T-cells level by flow cytometry or immunocytochemistry positive with non-zeta chain reagent |
| Myeloid lineage | |
| Myeloperoxidase, OR | Intensity in part exceeds 50% of mature neutrophil level |
| Monocytic differentiation | 2 or more expressed: Nonspecific esterase, CD11c, CD14, CD64, or lysozyme |
The ICC of Myeloid Neoplasms and Acute Leukemias was published in 2022 to further incorporate new discoveries in the biology of myeloid malignancies. The ICC seeks to integrate morphological, clinical, and genomic data into a new classification system.[32] The ICC has not replaced the WHO classification, but it is increasingly being used in the development of international clinical trials.
Genetic analysis of leukemia blast cells (using both conventional cytogenetic methods and molecular methods) is performed on children with AML because both chromosomal and molecular abnormalities are important diagnostic and prognostic markers.[33-37] Clonal chromosomal abnormalities are identified in the blasts of about 75% of children with AML and are useful in defining subtypes with both prognostic and therapeutic significance. Detection of molecular abnormalities can also aid in risk stratification and treatment allocation. For example, variants of NPM and CEBPA are associated with favorable outcomes, while certain variants of FLT3 portend a high risk of relapse. Identifying the latter variants may allow for targeted therapy.[38-41]
Comprehensive molecular profiling of pediatric and adult AML has shown that AML is a disease demonstrating both commonalities and differences across the age spectrum.[42,43]
The 5th edition (2022) of the World Health Organization (WHO) Classification of Hematolymphoid Tumors, as well as the Inaugural WHO Classification of Pediatric Tumors, emphasize a multilayered approach to AML classification. These classifications consider multiple clinico-pathological parameters and seek a genetic basis for disease classification wherever possible.[13,14] These karyotypic abnormalities and other genomic alterations are used to define specific pediatric AML entities and are outlined in Table 4.[13,14]
In addition to the cytogenetic/molecular abnormalities that aid AML diagnosis, as defined by the WHO, there are additional entities that, while not disease-defining, have prognostic significance in pediatric AML. All prognostic abnormalities, both those defined by the WHO and these additional abnormalities, have been clustered according to favorable or unfavorable prognosis, as defined by contemporary Children's Oncology Group (COG) clinical trials. These entities are summarized below. After these entities are described, information about additional cytogenetic/molecular and phenotypic features associated with pediatric AML will be described. However, these additional features may not, at present, be used to aid in risk stratification and treatment.
While the t(15;17) fusion that results in the PML::RARA gene product is defined as a pediatric AML risk-defining lesion, given its association with acute promyelocytic leukemia, it is discussed in Childhood Acute Promyelocytic Leukemia.
| Diagnostic Category | Approximate Prevalence in Pediatric AML |
|---|---|
| aAdapted from Pfister et al.[14] | |
| bCryptic chromosomal translocation. | |
| AML with t(8;21)(q22;q22); RUNX1::RUNX1T1 | 13%–14% |
| AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11 | 4%–9% |
| APL with t(15;17)(q24.1;q21.2); PML::RARA | 6%–11% |
| AML with KMT2A rearrangement | 25% |
| AML with t(6;9)(p23;q34.1); DEK::NUP214 | 1.7% |
| AML with inv(3)(q21q26)/t(3;3)(q21;q26); GATA2, RPN1::MECOM | <1% |
| AML with ETV6 fusion | 0.8% |
| AML with t(8;16)(p11.2;p13.3); KAT6A::CREBBP | 0.5% |
| AML with t(1;22)(p13.3;q13.1); RBM15::MRTFA (MKL1) | 0.8% |
| AML with CBFA2T3::GLIS2 (inv(16)(p13q24))b | 3% |
| AML with NUP98 fusionb | 10% |
| AML with t(16;21)(p11;q22); FUS::ERG | 0.3%–0.5% |
| AML with NPM1 variant | 8% |
| AML with variants in the bZIP domain of CEBPA | 5% |
Specific recurring cytogenetic and molecular abnormalities are briefly described below. The abnormalities are listed by those in clinical use that identify patients with favorable or unfavorable prognosis, followed by other abnormalities. The nomenclature of the 5th edition of the WHO classification is incorporated for disease entities where relevant.
Cytogenetic/molecular abnormalities associated with a favorable prognosis include the following:
Cases with CBFB::MYH11 or RUNX1::RUNX1T1 fusions have distinctive secondary variants, with CBFB::MYH11 secondary variants primarily restricted to genes that activate receptor tyrosine kinase signaling (NRAS, FLT3, and KIT).[50,51] The prognostic significance of activating KIT variants in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT variants appear to increase the risk of relapse without an impact on OS for adults with AML and RUNX1::RUNX1T1 fusions.[52] The prognostic significance of KIT variants in pediatric CBF AML remains unclear. Some studies have found no impact of KIT variants on outcomes,[53-55] although, in some instances, the treatment used was heterogenous, potentially confounding the analysis. Other studies have reported a higher risk of treatment failure when KIT variants are present.[56-61] An analysis of a subset of pediatric patients treated with a uniform chemotherapy backbone on the COG AAML0531 study demonstrated that the subset of patients with KIT exon 17 variants had inferior outcomes, compared with patients with CBF AML who did not have the variant. However, treatment with gemtuzumab ozogamicin abrogated this negative prognostic impact.[60] While there was a trend toward inferior outcomes for patients with CBF AML with co-occurring KIT exon 8 abnormalities, this finding was not statistically significant. A second study of 46 patients who were treated uniformly found that KIT exon 17 variants only had prognostic significance in AML with RUNX1::RUNX1T1 fusions but not CBFB::MYH11 fusions.[61]
While KIT variants are seen in both CBF AML subsets, other secondary variants tend to cluster with one of the two fusions. For example, patients with RUNX1::RUNX1T1 fusions also have frequent variants in genes regulating chromatin conformation (e.g., ASXL1 and ASXL2) (40% of cases) and genes encoding members of the cohesin complex (20% of cases). Variants in ASXL1 and ASXL2 and variants in members of the cohesin complex are rare in cases with leukemia and CBFB::MYH11 fusions.[50,51] Despite this correlation, a study of 204 adults with AML and RUNX1::RUNX1T1 fusions found that ASXL2 variants (present in 17% of cases) and ASXL1 or ASXL2 variants (present in 25% of cases) lacked prognostic significance.[62] Similar results, albeit with smaller numbers, were reported for children with the same abnormalities.[63]
Studies of children with AML suggest a lower rate of occurrence of NPM1 variants in children compared with adults with normal cytogenetics. NPM1 variants occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[38,39,70,71] NPM1 variants are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[38,39,71] For the pediatric population, conflicting reports have been published regarding the prognostic significance of an NPM1 variant when a FLT3 ITD variant is also present. One study reported that an NPM1 variant did not completely abrogate the poor prognosis associated with having a FLT3 ITD variant,[38,72] but other studies showed no impact of a FLT3 ITD variant on the favorable prognosis associated with an NPM1 variant.[39,43,71]
CEBPA variants occur in approximately 5% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2.
Given these findings in pediatric AML with CEBPA variants, the presence of a bZIP variant alone confers a favorable prognosis. Importantly, however, there is a small subset of patients with AML and CEBPA variants who have less-favorable outcomes. Specifically, CSF3R variants occur in 10% to 15% of patients with AML and CEBPA variants. CSF3R variants appear to be associated with an increased risk of relapse, but without an impact on OS.[74,83] At present, the occurrence of this secondary variant does not result in stratification to more intensified therapy in pediatric patients with AML.
While not common, a small percentage of children with AML and CEBPA variants may have an underlying germline variant. In newly diagnosed patients with double-variant CEBPA AML, germline screening should be considered in addition to usual family history queries because 5% to 10% of these patients have a germline CEBPA abnormality that confers an increased malignancy risk.[73,84]
The 5th edition (2022) of the WHO Classification of Hematolymphoid Tumors includes a diagnostic category of AML with KMT2A rearrangements. Specific translocation partners are not listed because there are more than 80 KMT2A fusion partners.[13]
Genetic abnormalities associated with an unfavorable prognosis are described below. Some of these are disease-defining alterations that are initiating events and maintained throughout a patient's disease course. Other entities described below are secondary alterations (e.g., FLT3 alterations). Although these secondary alterations do not induce disease on their own, they are able to promote the cell growth and survival of leukemias that are driven by primary genetic alterations.
Abnormalities involving MECOM can also be detected in some AML cases with other 3q abnormalities (e.g., t(3;21)(26.2;q22)). The RUNX1::MECOM fusion is also associated with poor prognosis.[97,98]
t(6;9) AML appears to be associated with a high risk of treatment failure in children, particularly for those not proceeding to allogeneic HSCT.[34,102,105,106]
In a study of approximately 2,000 children with AML, the CBFA2T3::GLIS2 fusion was identified in 39 cases (1.9%), with a median age at presentation of 1.5 years. All cases observed in children were younger than 3 years.[123] Approximately one-half of cases had M7 megakaryoblastic morphology, and 29% of patients were Black or African American (exceeding the 12.8% frequency in patients lacking the fusion). Children with the fusion were found to be MRD positive after induction 1 in 80% of cases. In an analysis of outcomes from serial COG trials of 37 identified patients, OS at 5 years from study entry was 22.0% for patients with CBFA2T3::GLIS2 fusions versus 63.0% for fusion-negative patients (n = 1,724). Even worse outcomes were demonstrated when the subset of patients with CBFA2T3::GLIS2 AMKL were compared with patients with AMKL without the abnormality. Analysis from the COG AAML0531 and AAML1031 trials revealed OS rates of 43% (± 37%) and 10% (± 19%), respectively, among children with AMKL and this fusion.[120] As CBFA2T3::GLIS2 leukemias express high levels of cell surface FOLR1, a targetable surface antigen by immunotherapeutic approaches, the roles of such agents are planned for study in this high-risk population.[124,125]
The NUP98::NSD1 gene fusion, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[102,128-130] This alteration occurs in approximately 4% to 7% of pediatric AML cases.[12,102,128,131,132] It is the most common NUP98 fusion seen. This disease phenotype is characterized by the following:
A cytogenetically cryptic translocation, t(11;12)(p15;p13), results in the NUP98::KDM5A gene fusion.[134] Approximately 2% of all pediatric AML patients have NUP98::KDM5A fusions, and these cases tend to present at a young age (median age, 3 years).[135] Additional clinical characteristics are as follows:
Increasing data show that the presence of monosomy 7 is associated with a higher risk of a patient having germline GATA2, SAMD9 or SAMD9L pathogenic variants. Cases associated with an underlying RUNX1-altered familial platelet disorder, telomere biology disorder, and germline ERCC6L2 pathogenic variants have also been reported.[149] Germline testing should be considered when monosomy 7 disease is identified.
In the past, patients with del(7q) were also considered to be at high risk of treatment failure, and data from adults with AML support a poor prognosis for both del(7q) and monosomy 7.[36] However, outcome for children with del(7q), but not monosomy 7, appears comparable to that of other children with AML.[35,146] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[33,146]
The prevalence of FLT3 ITD is increased in certain genomic subtypes of pediatric AML, including cases with the NUP98::NSD1 gene fusion, 80% to 90% of which have a co-occurring FLT3 ITD.[128,129]
The prognostic significance of FLT3 ITD is modified by the presence of other recurring genomic alterations.[128,129] For patients who have FLT3 ITD, the presence of either WT1 variants or NUP98::NSD1 fusions is associated with poorer outcomes (EFS rates below 25%) than for patients who have FLT3 ITD without these alterations.[43] Conversely, a co-occurring cryptic DEK::NUP214 fusion may be more favorable, particularly with the addition of a FLT3 inhibitor to standard front-line chemotherapy. When FLT3 ITD is accompanied by NPM1 variants, the outcome is relatively favorable and is similar to that of pediatric AML cases without FLT3 ITD.[43] The latter subset is the one scenario in which the presence of the FLT3 ITD variant does not necessarily upstage a patient to high risk, based on the favorable outcomes seen with the co-occurring variants.[43]
Activating single nucleotide variants of FLT3 have also been identified in both adults and children with AML, although the clinical significance of these variants is not clearly defined. Some of these single nucleotide variants appear to be specific to pediatric patients.[43]
This section includes cytogenetic/molecular abnormalities that are seen at diagnosis and do not impact disease risk stratification but may have prognostic significance.
An international collaborative retrospective study of 51 t(1;22) cases reported that patients with this abnormality had a 5-year EFS rate of 54.5% and an OS rate of 58.2%, similar to the rates for other children with AMKL.[86] In another international retrospective analysis of 153 cases with non–Down syndrome AMKL who had samples available for molecular analysis, the 4-year EFS rate for patients with t(1;22) was 59% and the OS rate was 70%, significantly better than for AMKL patients with other specific genetic abnormalities (CBFA2T3::GUS2 fusions, NUP98::KDM5A fusions, KMT2A rearrangements, monosomy 7).[118] Similar outcomes were seen in the COG AAML0531 and AAML1031 phase III trials (5-year OS rates, 86% ± 26% [n = 7] and 54% ± 14% [n = 14] for AAML0531 and AAML1031, respectively).[120]
In a study of children with AML, RUNX1 variants were observed in 11 of 503 patients (approximately 2%). Six of 11 patients with AML and RUNX1 variants failed to achieve remission, and their 5-year EFS rate was 9%, suggesting that the RUNX1 variant confers a poor prognosis in both children and adults.[169] However, a second study in which 23 children were found to have RUNX1 variants among 488 children with AML found no significant impact of RUNX1 variants on response or outcome. Additionally, analysis identified that children with RUNX1 variants were more frequently male, adolescents, and had a greater incidence of co-occurring FLT3 ITD and other variants. However, in each of these groups, univariable and multivariable analyses found no survival differences based on the presence of RUNX1 variants.[170] Genetic variants of RUNX1 result in a familial platelet disorder with associated myeloid malignancy (FPD-MM).[13]
In children with AML, WT1 variants are observed in approximately 10% of cases.[175,176] Cases with WT1 variants are enriched among children with normal cytogenetics and FLT3 ITD but are less common among children younger than 3 years.[175,176] AML cases with NUP98::NSD1 fusions are enriched for both FLT3 ITD and WT1 variants.[128] In univariate analyses, WT1 variants are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of WT1 variant status is unclear because of its strong association with FLT3 ITD and its association with NUP98::NSD1 fusions.[128,175,176] The largest study of WT1 variants in children with AML observed that children with WT1 variants in the absence of FLT3 ITD had outcomes similar to that of children without WT1 variants, while children with both WT1 variants and FLT3 ITD had survival rates less than 20%.[175]
In a study of children with refractory AML, WT1 was overrepresented, compared with a cohort who did achieve remission (54% [15 of 28 patients] vs. 15%).[133]
Variants in IDH1 and IDH2 are rare in pediatric AML, occurring in 0% to 4% of cases.[44,180,189-193] There is no indication of a negative prognostic effect for IDH1 and IDH2 variants in children with AML.[44,189]
Activating variants in CSF3R are also observed in patients with severe congenital neutropenia. These variants are not the cause of severe congenital neutropenia, but rather arise as somatic variants and can represent an early step in the pathway to AML.[195] In one study of patients with severe congenital neutropenia, 34% of patients who had not developed a myeloid malignancy had CSF3R variants detectable in peripheral blood neutrophils and mononuclear cells, while 78% of patients who had developed a myeloid malignancy showed CSF3R variants.[195] A study of 31 patients with severe congenital neutropenia who developed AML or MDS observed CSF3R variants in approximately 80% of patients. The study also observed a high frequency of RUNX1 variants (approximately 60%), suggesting cooperation between CSF3R and RUNX1 variants for leukemia development within the context of severe congenital neutropenia.[196]
Childhood acute myeloid leukemia (AML) is diagnosed when the bone marrow has 20% or greater blasts or when a lower blast percentage is present but molecular evaluation reveals an AML-defining genetic abnormality.[1] For information about the defining abnormalities, see the World Health Organization (WHO) Classification System for Childhood AML section.
Leukemia is considered to be disseminated in the hematopoietic system at diagnosis, even in children with AML who present with isolated chloromas (also called granulocytic or myeloid sarcomas). These children invariably develop AML in months to years if they do not receive systemic chemotherapy. AML may invade nonhematopoietic (extramedullary) tissue such as meninges, brain parenchyma, testes or ovaries, or skin (leukemia cutis). Extramedullary leukemia is more common in infants than in older children with AML.[2] In one retrospective analysis, leukemia cutis did not have an adverse impact on outcomes of infants when they were treated with traditional chemotherapy.[3]
Granulocytic sarcoma (chloroma) describes extramedullary collections of leukemia cells. These collections can occur, albeit rarely, as the sole evidence of leukemia. In a review of three AML studies conducted by the former Children's Cancer Group, fewer than 1% of patients had isolated granulocytic sarcoma, and 11% had granulocytic sarcoma along with marrow disease at the time of diagnosis.[4] This incidence was also seen in the NOPHO-AML 2004 (NCT00476541) trial.[5]
Patients with isolated granulocytic sarcoma have a good prognosis if treated with current AML therapy.[4]
In a study of 1,459 children with newly diagnosed AML, patients with orbital granulocytic sarcoma and central nervous system (CNS) granulocytic sarcoma had better survival than patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease.[5,6] Most patients with orbital granulocytic sarcoma have a t(8;21) abnormality, which has been associated with a favorable prognosis. The use of radiation therapy does not improve survival in patients with granulocytic sarcoma who have a complete response to chemotherapy. However, radiation therapy may be necessary if the site(s) of granulocytic sarcoma do not show complete response to chemotherapy or for disease that recurs locally.[4]
CNS involvement is often described as extramedullary disease and included in overall summaries of extramedullary disease. However, it has a distinct prognostic impact and requires therapeutic alterations. It is therefore discussed in detail in sections for both prognosis and treatment.
The first goal in the treatment of AML is to eradicate all identifiable evidence of leukemia, also known as complete remission (CR).
CR has traditionally been defined in the United States using morphological criteria such as the following:
Alternative definitions of remission using morphology are used in AML because of the prolonged myelosuppression caused by intensive chemotherapy. These definitions include CR with incomplete platelet recovery (CRp) and CR with incomplete marrow recovery (typically absolute neutrophil count) (CRi). Whereas the use of CRp provides a clinically meaningful response in studies of adults with AML, the traditional CR definition remains the gold standard because patients in CR were more likely to survive longer than those in CRp.[8]
Achieving a hypoplastic bone marrow (using morphology) is usually the first step in obtaining remission in AML, with the exception of the M3 subtype (acute promyelocytic leukemia [APL]). In APL, a hypoplastic marrow phase is often not necessary before the achievement of remission. Additionally, early recovery marrows in any of the subtypes of AML may be difficult to distinguish from persistent leukemia, although the application of flow cytometric immunophenotyping and cytogenetic/molecular testing have made this less problematic. Correlation with blood cell counts and clinical status is imperative in passing final judgment on the results of early bone marrow findings in AML.[9] If the findings are in doubt, a bone marrow aspirate should be repeated in 1 to 2 weeks.[2]
In addition to morphology, more precise methodology (e.g., multiparameter flow cytometry or quantitative reverse transcriptase–polymerase chain reaction [RT-PCR]) is used to assess response. These methods have proven to be of greater prognostic significance than morphology. For more information about these methodologies, see the Prognosis and Prognostic Factors section.
The mainstay of the therapeutic approach is systemically administered combination chemotherapy. Approaches involving risk-group stratification and biologically targeted therapies are being tested to improve antileukemic treatment while sparing normal tissue. Optimal treatment of AML requires control of bone marrow and systemic disease.
Treatment of the CNS, usually with intrathecal medication, is a component of most pediatric AML protocols but has not yet been shown to contribute directly to an improvement in survival. CNS irradiation is not necessary in patients, either as prophylaxis or for those presenting with cerebrospinal fluid leukemia that clears with intrathecal and systemic chemotherapy.
Treatment is ordinarily divided into the following two phases:
Induction therapy typically involves several (usually 2–4) cycles of intensive chemotherapy. Past approaches often had four cycles of chemotherapy comprising the entire induction course. Contemporary protocols have combined the first two and the last two cycles into two more intensified cycles of overall induction, which has improved event-free survival (EFS) and overall survival (OS).
Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplant (HSCT). For example, the Children’s Oncology Group (COG) and the United Kingdom Medical Research Council (MRC) use similar chemotherapy regimens consisting of two courses of induction chemotherapy, followed by two to three additional courses of intensification chemotherapy.[10-12]
Maintenance chemotherapy is no longer part of pediatric AML protocols because two randomized clinical trials failed to show a benefit for maintenance therapy when given after modern intensive chemotherapy.[13,14] Contemporary APL therapy also does not use maintenance chemotherapy. A tretinoin- and arsenic trioxide–based treatment is used instead.[15] Maintenance therapy with targeted therapies is gaining interest. Treatment of patients with AML and FLT3 internal tandem duplication (ITD) using sorafenib (a FLT3 inhibitor) during chemotherapy cycles and maintenance (following completion of chemotherapy or HSCT) significantly improved survival.[16]
Attention to both acute and long-term complications is critical in children with AML. Modern AML treatment approaches are usually associated with severe, protracted myelosuppression with related complications. Children with AML should receive care under the direction of pediatric oncologists in cancer centers or hospitals with appropriate supportive care facilities (e.g., specialized blood products; pediatric intensive care; provision of emotional and developmental support). With improved supportive care, toxic death constitutes a smaller proportion of initial therapy failures than in the past.[10] Two COG trials reported an 11% to 13% incidence of remission failure, mainly because of resistant disease. Only 2% to 3% resulted from toxic death during the two induction courses.[12,17]
Children treated for AML are living longer and require close monitoring for cancer therapy side effects that may persist or develop months or years after treatment. The high cumulative doses of anthracyclines require long-term monitoring of cardiac function. The use of some modalities, including total-body irradiation with HSCT, have declined because of increased risk of growth failure, gonadal and thyroid dysfunction, cataract formation, and second malignancies.[18] For more information, see the Survivorship and Adverse Late Sequelae of Treatment for AML section and Late Effects of Treatment for Childhood Cancer.
Dramatic improvements in survival have been achieved for children and adolescents with cancer.[19] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[19-21] For AML, the 5-year survival rate increased over the same time, from less than 20% to 69% for children younger than 15 years and from less than 20% to 72% for adolescents aged 15 to 19 years.[19,21]
Most contemporary comparisons also show that OS rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 70% range.[21-25] Overall remission-induction rates are approximately 85% to 90%, and EFS rates from the time of diagnosis are in the 45% to 55% range.[23-26] There is, however, a wide range in outcomes for different biological subtypes of AML. After taking specific biological factors of their leukemia into account, the predicted outcome for any individual patient may be much better or much worse than the overall outcome for the general population of children with AML. For more information, see the sections on Genomics of AML and Risk Classification Systems.
Prognostic factors in childhood AML can be categorized as follows:
While outcome for infants with acute lymphoblastic leukemia (ALL) remains inferior to that of older children, outcome for infants (<12 months) with AML is similar to that of older children when they are treated with standard AML regimens.[27,32-34] Infants have been reported to have a 5-year survival rate of 60% to 70%, but with increased treatment-associated toxicity, particularly during induction.[27,32-35]
In a retrospective study of non–Down syndrome M7 patients with samples available for molecular analysis, the presence of specific genetic abnormalities (CBFA2T3::GLIS2 [cryptic inv(16)(p13q24)], NUP98::KDM5A, t(11;12)(p15;p13), KMT2A [MLL] rearrangements, monosomy 7) was associated with a significantly worse outcome than for other M7 patients.[55,56] By contrast, the 10% of patients with AMKL and GATA1 variants without Down syndrome appeared to have a favorable outcome if there were no prognostically unfavorable fusion genes also present, as did patients with HOX rearrangement.[56]
COG trials (including AAML03P1 [NCT00070174], AAML0531 [NCT00372593], and AAML1031 [NCT01371981]) used a modified version of the CNS disease definitions, in which patients were dichotomously classified for treatment purposes as CNS positive or negative. The CNS-positive group included all patients with blasts on cytospin (regardless of CSF WBC) unless there were more than 100 RBC/μL in the CSF. Patients with 100 RBC/μL in the CSF were CNS positive only if the WBC/RBC ratio in the CSF was greater than or equal to twice the ratio in the peripheral blood. CNS outcomes on COG studies were analyzed using the more traditional CNS1/2/3 definitions.[57]
In children with AML, CNS2 disease has been observed in approximately 13% to 16% of cases, and CNS3 disease has been observed in approximately 11% to 17% of cases.[57,58] Studies have variably shown that patients with CNS2/CNS3 disease were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).[57,58]
While CNS involvement (CNS2 or CNS3) at diagnosis has not been shown to be correlated with OS in most studies, a COG analysis of children with AML enrolled from 2003 to 2010 on two consecutive and identical backbone trials found that CNS disease was associated with inferior outcomes, including decreased CR rate, EFS, and disease-free survival (DFS), and an increased risk of relapse involving the CNS.[57] Another trial showed it to be associated with an increased risk of isolated CNS relapse.[59] The COG study did not find traumatic lumbar punctures at diagnosis to have an adverse impact on OS.[57] From an analysis of patients enrolled in the AAML0531 and AAML1031 trials, using the COG definition of CNS involvement, peripheral blood contamination increased the number of patients who were classified as CNS positive and guided to additional intrathecal therapy.[60] In these trials, following past precedence, diagnostic CSF examinations and initial intrathecal administration were done on or before day 1 of induction therapy. Beginning with the COG AAML1831 (NCT04293562) trial, to minimize the contamination risk, the newer guidance is to delay the diagnostic lumbar puncture to day 8, when most patients have cleared their peripheral blood of leukemic blasts. Additionally, a definition of CNS involvement that is more similar to the ALL definition is now in use.
| Favorable | Unfavorable | |
|---|---|---|
| aAdapted from the COG AAML1831 (NCT04293562) trial. | ||
| t(8;21)(q22;q22); RUNX1::RUNX1T1 | inv(3)(q21.3q26.2)/t(3;3)(q21.3q26.2); RPN1::MECOM and t(3;21)(26.2;q22); RUNX1::MECOM | |
| AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11 | t(3;5)(q25;q34.1); NPM1::MLF1 | |
| NPM1 variants | t(6;9)(p22.3;q34.1); DEK::NUP214 | |
| Variants in the bZIP domain of CEBPA | t(8;16)(p11.2;p13.3); KAT6A::CREBBP (if 90 days or older at diagnosis) | |
| t(16;21)(p11.2;q22.2); FUS::ERG | ||
| inv(16)(p13.3q24.3); CBFA2T3::GLIS2 | ||
| KMT2A rearrangement with high-risk partners: | ||
| t(4;11)(q21;q23.3) KMT2A::AFF1 | ||
| t(6;11)(q27;q23.3) KMT2A::AFDN | ||
| t(10;11)(p12.3;q23.3) KMT2A::MLLT10 | ||
| t(10;11)(p12.1;q23.3) KMT2A::ABI1 | ||
| t(11;19)(q23.3;p13.3) KMT2A::MLLT1 | ||
| 11p15; NUP98 rearrangement with any partner gene | ||
| 12p13.2; ETV6 rearrangement with any partner gene | ||
| Deletion 12p to include 12p13.2 loss of ETV6 | ||
| Monosomy 5/Del(5q) to include 5q31 loss of EGR1 | ||
| Monosomy 7 | ||
| 10p12.3; MLLT10 rearrangement with any partner gene | ||
| FLT3 ITD+ with allelic ratio >0.1% | ||
Molecular approaches to assessing MRD in AML: Molecular approaches (e.g., using quantitative RT-PCR) have been challenging to apply because of the genomic heterogeneity of pediatric AML and the instability of some genomic alterations. Results have shown the following:
Flow cytometric methods: Flow cytometry has been used for MRD detection and can detect leukemic blasts based on the expression of aberrant surface antigens that differ from the pattern observed in normal progenitors.
Risk classification for treatment assignment has been used by several cooperative groups performing clinical trials in children with AML. In the COG, stratifying therapeutic choices on the basis of risk factors is a relatively recent approach for the non-APL, non–Down syndrome patient.
Classification is most directly derived from the observations of the MRC AML 10 trial for EFS and OS.[65] Classification is further applied based on the ability of the pediatric patient to undergo reinduction to obtain a second complete remission and their subsequent OS after first relapse.[79]
The following COG trials have used a risk classification system to stratify treatment choices:
Where risk factors contradicted each other, the following evidence-based table was used (see Table 6).
| Risk Assignment: | Low Risk | High Risk | |||
|---|---|---|---|---|---|
| Low-Risk Group 1 | Low-Risk Group 2 | High-Risk Group 1 | High-Risk Group 2 | High-Risk Group 3 | |
| ITD = internal tandem duplications. | |||||
| aGroups are based on combinations of risk factors, which may be found in any individual patient. | |||||
| bBold indicates the overriding risk factor in risk-group assignment. | |||||
| cNPM1, CEBPA, t(8;21), inv(16). | |||||
| d"Any" indicates any status and thus the marker's presence/absence or minimal residual disease status does not impact risk classification in the particular Risk Group. | |||||
| eMonosomy 7, monosomy 5, del(5q). | |||||
| FLT3 ITD allelic ratio | Low/negative | Low/negative | High | Low/negative | Low/negative |
| Good-risk molecular markersc | Present | Absent | Anyd | Absent | Absent |
| Poor-risk cytogenetic markerse | Anyd | Absent | Anyd | Present | Absent |
| Minimal residual disease | Anyd | Negative | Anyd | Anyd | Positive |
The high-risk group of patients was guided to transplant in first remission with the most appropriate available donor. Patients in the low-risk group were instructed to pursue transplant if they relapsed.[67,81]
The COG AAML1831 (NCT04293562) trial for patients with newly diagnosed AML uses a more complex risk-stratification system. This system incorporates more genetic lesions into the high-risk group and builds on the use of MRD as a strong prognostic marker.[82]
Risk factors used for stratification vary by pediatric and adult cooperative clinical trial groups. The prognostic impact of a given risk factor may vary in their significance depending on the backbone of therapy used. Other pediatric cooperative groups use some or all of these same factors, generally choosing risk factors that have been reproducible across numerous trials and sometimes including additional risk factors previously used in their risk group stratification approach.
Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence.[2] This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:
For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[3] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below. For information about the treatment of children with Down syndrome, see Childhood Myeloid Proliferations Associated With Down Syndrome Treatment. For information about the treatment of children with acute promyelocytic leukemia (APL), see Childhood Acute Promyelocytic Leukemia Treatment.
Contemporary pediatric AML protocols result in 85% to 90% complete remission (CR) rates.[1-3] To achieve a CR, inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary with currently used combination-chemotherapy regimens. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant. Approximately 2% to 3% of patients die during the induction phase, most often caused by treatment-related complications.[1-4]
Treatment options for children with AML during the induction phase may include the following:
Common induction therapy regimens in children with AML use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[5-7]
Evidence (induction chemotherapy regimen):
The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[5-7] although idarubicin and the anthracenedione mitoxantrone have also been used.[1,10,11] Randomized trials have attempted to determine whether any other anthracycline or anthracenedione is superior to daunorubicin as a component of induction therapy for children with AML. In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome over daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML in the United States.
Evidence (daunorubicin vs. other anthracyclines):
Although the combination of an anthracycline and cytarabine is the basis of initial standard induction therapy for adults and children, there is evidence that alternative drugs can be used to reduce the use of anthracyclines when necessary.
Evidence (reduced-anthracycline induction regimen):
The intensity of induction therapy influences the overall outcome of therapy. The CCG-2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better EFS than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer).[16] The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.[5]
In adults, another method of intensifying induction therapy is to use high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2–3 g/m2/dose) compared with standard-dose cytarabine,[17] a benefit for the use of high-dose cytarabine in children was not observed using a cytarabine dose of 1 g/m2 given twice daily for 7 days with daunorubicin and thioguanine.[18] A second pediatric study also failed to detect a benefit for high-dose cytarabine over standard-dose cytarabine when used during induction therapy.[19]
Because further intensification of induction regimens has increased toxicity with little improvement in EFS or OS, alternative approaches, such as the use of gemtuzumab ozogamicin, have been examined.
Gemtuzumab ozogamicin is a CD33-directed monoclonal antibody linked to a calicheamicin, a cytotoxic agent.
Evidence (gemtuzumab ozogamicin during induction):
Fractionated gemtuzumab ozogamicin dosing (3 mg/m2 per dose on days 1, 4, and 7; maximum dose, 5 mg), which has been shown to be safe and effective in adult patients with de novo AML, is an alternative option to single-dose administration during induction.[24] Because this is the recommended dosing method for adults, this schedule is now being evaluated in the MyeChild 01 (NCT02724163) phase III study for pediatric patients with de novo AML in the United Kingdom.
The characteristics of CD33, the target of gemtuzumab ozogamicin, have been examined to further identify the patients who will benefit most from this agent.
Similar to immunotherapeutic approaches, the use of targeted therapy attempts to circumvent the severe toxicity of traditional chemotherapy by employing agents that target leukemia-specific variants and/or their abnormal present or missing byproducts. While randomized clinical trials have not yet demonstrated that targeted therapies improve outcomes in children with newly diagnosed AML, single-arm trials have demonstrated a survival benefit, such as the sorafenib trial described below. Because most data on the use of targeted agents are from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience in children.
Because of the high prevalence of FLT3 variants in adult AML and the adverse impact in patients with AML of all ages, the FLT3 target has received the greatest attention for target-specific drug development in AML. Among the various FLT3 inhibitors developed and clinically studied, midostaurin, a multikinase inhibitor, is the only one with U.S. Food and Drug Administration (FDA) approval for adult de novo AML. It was approved in 2017 for use with conventional backbone chemotherapy but not as a single agent.[27]
Evidence (midostaurin for adults with de novo AML):
Midostaurin has been studied in children with relapsed/refractory AML,[30] but there is no experience with midostaurin in children with newly diagnosed AML. For more information, see the Targeted therapy (FLT3 inhibitors) section.
Sorafenib, another multikinase inhibitor, has been approved for the treatment of other malignancies, but it has not been approved for use in patients with AML. This agent has been evaluated for use in adult and pediatric patients with de novo AML and FLT3 variants.
Evidence (sorafenib):
In children with AML receiving modern intensive therapy, the estimated incidence of severe bacterial infections is 50% to 60%, and the estimated incidence of invasive fungal infections is 7.0% to 12.5%.[32-34] Several approaches have been examined to reduce the morbidity and mortality from infection in children with AML.
The use of antibacterial prophylaxis in children undergoing treatment for AML has been supported by several studies. Studies, including one prospective randomized trial, suggest a benefit to the use of antibiotic prophylaxis.
Evidence (antimicrobial prophylaxis):
Antifungal prophylaxis is important in the management of patients with AML.
Evidence (antifungal prophylaxis):
Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF during AML induction therapy have been evaluated in multiple placebo-controlled studies in adults with AML in attempts to reduce the toxicity associated with prolonged myelosuppression.[2] These studies have generally shown a reduction in the duration of neutropenia of several days with the use of either G-CSF or GM-CSF [49] but have not shown significant effects on treatment-related mortality or OS.[49] For more information, see the Treatment Option Overview for AML section in Acute Myeloid Leukemia Treatment.
Routine prophylactic use of hematopoietic growth factors is not recommended for children with AML.
Evidence (against the use of hematopoietic growth factors):
Bacteremia or sepsis and anthracycline use have been identified as significant risk factors in the development of cardiotoxicity, manifested as reduced left ventricular function.[52,53] Monitoring of cardiac function through the use of serial exams during therapy is an effective method for detecting cardiotoxicity and adjusting therapy as indicated. The use of dexrazoxane in conjunction with bolus dosing of anthracyclines can effectively reduce the risk of cardiac dysfunction during therapy.[54]
Evidence (cardiac monitoring/dexrazoxane impact):
Hospitalization until adequate granulocyte (absolute neutrophil or phagocyte count) recovery has been used to reduce treatment-related mortality.
To avoid prolonged hospitalizations until count recovery, some institutions have used outpatient IV antibiotic prophylaxis effectively.[36]
Therapy with either radiation or intrathecal chemotherapy has been used to treat CNS leukemia present at diagnosis. However, the use of radiation has essentially been abandoned as a means of prophylaxis because of the lack of documented benefit and long-term sequelae.[55] Intrathecal chemotherapy is used to prevent later development of CNS leukemia. The COG has historically used single-agent cytarabine for both CNS prophylaxis and therapy. Other groups have attempted to prevent CNS relapse by using additional intrathecal agents. Similarly, the ongoing COG AAML1831 (NCT04293562) trial incorporates the use of intrathecal triples (methotrexate, cytarabine, and hydrocortisone).
CNS involvement in patients with AML and its impact on prognosis has been discussed in the Prognosis and Prognostic Factors section.
Evidence (CNS prophylaxis):
A major challenge in the treatment of children with AML is to prolong the duration of the initial remission with additional chemotherapy or HSCT.
Treatment options for children with AML in postremission may include the following:
Postremission chemotherapy includes some of the drugs used in induction while introducing non–cross-resistant drugs and, commonly, high-dose cytarabine. Studies in adults with AML have demonstrated that consolidation with a high-dose cytarabine regimen improves outcome, compared with consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes.[60] For more information about the treatment of adults with AML, see the Treatment of AML in Remission section in Acute Myeloid Leukemia Treatment. Randomized studies evaluating the contribution of high-dose cytarabine to postremission therapy have not been conducted in children, but studies employing historical controls suggest that consolidation with a high-dose cytarabine regimen improves outcome compared with less-intensive consolidation therapies.[6,61,62]
The optimal number of postremission courses of therapy remains unclear, but it appears that at least two to three courses of intensive therapy are required after induction.[7]
Evidence (number of postremission courses of chemotherapy):
Additional study of the number of intensification courses and specific agents used will better address this issue. However, these data suggest that four chemotherapy courses should only be administered to the favorable group described above, and that all other patients who do not undergo HSCT should receive five chemotherapy courses.
The use of HSCT in first remission has been under evaluation since the late 1970s, and evidence-based appraisals concerning indications for autologous and allogeneic HSCT have been published. Prospective trials of transplants in children with AML suggest that overall, 60% to 70% of children with HLA-matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions,[5,64] with the caveat that outcome after allogeneic HSCT is dependent on risk-classification status.[65]
In prospective trials that compared allogeneic HSCT with chemotherapy and/or autologous HSCT, superior DFS rates were observed for patients who were assigned to allogeneic HSCT on the basis of family 6/6 or 5/6 HLA-matched donors in adults and children.[5,64,66-70] However, the superiority of allogeneic HSCT over chemotherapy has not always been observed.[71] Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.[5,64,66,68]
Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplant should be pursued in first remission. An analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) examined pretransplant variables to create a model for predicting leukemia-free survival (LFS) posttransplant in pediatric patients (aged <18 years). All patients were first transplant recipients who had myeloablative conditioning, and all stem cells sources were included. For patients with AML, the predictors associated with lower LFS included age younger than 3 years, intermediate-risk or poor-risk cytogenetics, and second CR or higher with MRD positivity or not in CR. A scale was established to stratify patients on the basis of risk factors to predict survival. The 5-year LFS rate was 78% for the low-risk group, 53% for the intermediate-risk group, 40% for the high-risk group, and 25% for the very high-risk group.[72]
Patients receiving contemporary chemotherapy regimens have improved outcome if they have favorable prognostic features (low-risk cytogenetic or molecular variants). This finding and the lack of demonstrable superiority for HSCT in this patient population means that such patients typically receive matched-family donor (MFD) HSCT only after first relapse and the achievement of a second CR.[65,73-75]
There is conflicting evidence regarding the role of allogeneic HSCT in first remission for patients with intermediate-risk characteristics (neither low-risk or high-risk cytogenetics or molecular variants).
Evidence (allogeneic HSCT in first remission for patients with intermediate-risk AML):
Given the improved outcome for patients with intermediate-risk AML in recent clinical trials and the burden of acute and chronic toxicities associated with allogeneic transplant, many childhood AML treatment groups (including the COG) employ chemotherapy for intermediate-risk patients in first remission and reserve allogeneic HSCT for use after potential relapses.[1,76,77]
There are conflicting data regarding the role of allogeneic HSCT in first remission for patients with high-risk disease, complicated by the varying definitions of high risk used by different study groups.
Many, but not all, pediatric clinical trial groups prescribe allogeneic HSCT for high-risk patients in first remission.[75] For example, the COG frontline AML clinical trial (COG-AAML1031) prescribes allogeneic HSCT in first remission only for patients with predicted high risk of treatment failure based on unfavorable cytogenetic and molecular characteristics and elevated end-of-induction MRD levels. On the other hand, the AML-BFM trials restrict allogeneic HSCT to patients in second CR or patients with refractory AML. This was based on results from their AML-BFM 98 study, which found no improvement in DFS or OS for high-risk patients receiving allogeneic HSCT in first CR, as well as the successful treatment using HSCT for a substantial proportion of patients who achieved a second CR.[71,78] Additionally, late sequelae (e.g., cardiomyopathy, skeletal anomalies, and liver dysfunction or cirrhosis) were increased for children undergoing allogeneic HSCT in first remission on the AML-BFM 98 study.[71]
Evidence (allogeneic HSCT in first remission for patients with high-risk AML):
Further analysis of subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials because of the evolving definitions of high-, intermediate-, and low-risk AML, the ongoing association of molecular characteristics of the tumor with outcome (e.g., FLT3 ITD, WT1 variants, and NPM1 variants), and response to therapy (e.g., MRD assessments postinduction therapy).
If transplant is chosen in first CR, the optimal preparative regimen and source of donor cells has not been determined, although alternative donor sources, including haploidentical donors, are being studied.[70,85,86] There are no data that suggest total-body irradiation (TBI) is superior to busulfan-based myeloablative regimens.[71,73] Additionally, outstanding outcomes have been noted for patients who were treated with treosulfan-based regimens. However, trials comparing treosulfan with busulfan or TBI are lacking.[87]
Evidence (myeloablative regimen):
There are no data that demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration. Maintenance chemotherapy failed to show benefit in two randomized studies that used modern intensive consolidation therapy.[61,91] Maintenance therapy with interleukin-2 also proved ineffective.[7]
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The diagnosis of recurrent acute myeloid leukemia (AML) is made when patients who were in previous remission after therapy develop more than 5% bone marrow blasts. The diagnosis of refractory AML is made when complete remission is not achieved by the end of induction therapy.
Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most relapses occurring by 4 years after diagnosis.[1] The vast majority of relapses occur in the bone marrow, and central nervous system (CNS) relapse is very uncommon.[1]
Factors associated with survival include the following:
Additional prognostic factors were identified in the following studies:
Patients with subsequent relapses and those with refractory first relapses have declining outcomes with each event. In the TACL analysis, remission outcomes, primarily in patients with early relapses, declined with each attempt to reinduce remission (56% ± 5%, 25% ± 8%, and 17% ± 7% for each consecutive attempt).[6] An analysis by the NOPHO group found a 5-year OS rate of 17% in children who had a second relapse or in children who had a refractory first relapse and were subsequently treated with curative intent.[11]
Treatment options for children with recurrent AML may include the following:
Regimens that have been successfully used to induce remission in children with recurrent AML have commonly included high-dose cytarabine given in combination with the following agents:
The standard-dose cytarabine regimens used in the United Kingdom Medical Research Council (MRC) AML10 study for newly diagnosed children with AML (cytarabine and daunorubicin plus either etoposide or thioguanine) have, when used in the setting of relapse, produced remission rates similar to those achieved with high-dose cytarabine regimens.[3] In a COG phase II study, the addition of bortezomib to idarubicin plus low-dose cytarabine resulted in an overall CR rate of 57%. The addition of bortezomib to etoposide and high-dose cytarabine resulted in an overall CR rate of 48%.[22]
Before its U.S. Food and Drug Administration (FDA) approval for use in children with de novo AML in 2020, gemtuzumab ozogamicin was approved for children with relapsed or refractory AML who are aged 2 years and older.
Evidence (gemtuzumab ozogamicin with or without chemotherapy):
There is limited experience with midostaurin in pediatric patients with AML.
A phase II trial is under way in Europe, beginning with the 30 mg/m2 twice-daily dosing (NCT03591510).
As in de novo AML, most of the focus and published experience with FLT3 inhibitors is in adults with AML and this applies to the relapsed and refractory setting as well. Gilteritinib is a type 1 selective FLT3 inhibitor with activity against both FLT3 variants (ITD and D835/I836 tyrosine kinase domain [TKD]). In relapsed or refractory AML, gilteritinib is the first and only FLT3 inhibitor that has received FDA approval for single-agent use in adults. The approval was based on the ADMIRAL (NCT02421939) trial.[31]
Gilteritinib is now being studied in children with FLT3-positive de novo AML in the COG AAML1831 (NCT04293562) trial.
Sorafenib has been evaluated in pediatric patients with relapsed and refractory AML.
The selection of additional treatment after the achievement of a second CR depends on previous treatment and individual considerations. Consolidation chemotherapy followed by HSCT is conventionally recommended, although there are no controlled prospective data regarding the contribution of additional courses of therapy once a second CR is obtained.[1]
Evidence (HSCT after second CR):
There is evidence that long-term survival can be achieved in a portion of pediatric patients who undergo a second transplant subsequent to relapse after a first myeloablative transplant. Improved survival was associated with late relapse (>6–12 months from first transplant), achievement of complete response before the second procedure, and use of a second myeloablative regimen if possible.[46-49]
Isolated CNS relapse occurs in 3% to 6% of pediatric patients with AML.[50-52] Factors associated with an increased risk of isolated CNS relapse include the following:[50]
The risk of CNS relapse increases with more CNS leukemic involvement at initial AML diagnosis (CNS1: 0.6%, CNS2: 2.6%, CNS3: 5.8% incidence of isolated CNS relapse, P < .001; multivariate HR for CNS3: 7.82, P = .0003).[52] The outcome of isolated CNS relapse when treated as a systemic relapse is similar to that of bone marrow relapse. In one study, the 8-year OS rate for a cohort of children with an isolated CNS relapse was 26% (± 16%).[50] Concurrent bone marrow and CNS relapses can occur, and the incidence increases with CNS involvement at diagnosis (CNS1: 2.7%, CNS2: 8.5%, CNS3: 9.2%, P < .001).[52]
Induction failure (the morphological presence of 5% or greater marrow blasts at the end of all induction courses) is seen in 10% to 15% of children with AML. Subsequent outcomes for patients with induction failure are similar to those for patients with AML who relapse early (<12 months after remission).[4,23]
Treatment options for children with refractory AML may include the following:
Like patients with relapsed AML, patients with induction failure are typically directed toward HSCT once they attain a remission. Studies suggest a better EFS rate in patients treated with HSCT than in patients treated with chemotherapy only (31.2% vs. 5%; P < .0001). Attainment of morphological CR for these patients is a significant prognostic factor for disease-free survival (DFS) after HSCT (46% vs. 0%; P = .02). Failure primarily resulted from relapse (relapse risk, 53.9% vs. 88.9%; P = .02).[53]
For more information about chemotherapy to induce remission, see the Chemotherapy section in the Treatment of Recurrent AML section.
Evidence (treatment of refractory childhood AML with gemtuzumab ozogamicin):
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The development of acute myeloid leukemia (AML) or myelodysplastic neoplasms (MDS) after treatment with ionizing radiation or chemotherapy, particularly alkylating agents and topoisomerase inhibitors, is termed therapy-related AML (t-AML) or therapy-related MDS (t-MDS). In addition to genotoxic exposures, genetic predisposition susceptibilities (such as polymorphisms in drug detoxification and DNA repair pathway components) may contribute to the occurrence of secondary AML/MDS.[1-4]
The risk of t-AML or t-MDS depends on the treatment regimen. It is often related to the cumulative doses of chemotherapy agents received and the dose and field of radiation administered.[5] Regimens previously used that employed high cumulative doses of either epipodophyllotoxins (e.g., etoposide or teniposide) or alkylating agents (e.g., mechlorethamine, melphalan, busulfan, and cyclophosphamide) induced excessively high rates of t-AML or t-MDS that exceeded 10% in some cases.[5,6] However, most current chemotherapy regimens that are used to treat childhood cancers have a cumulative incidence of t-AML or t-MDS no greater than 1% to 2%.
t-AML or t-MDS resulting from exposures to epipodophyllotoxins and other topoisomerase II inhibitors (e.g., anthracyclines) usually occur within 2 years of treatment and are commonly associated with chromosome 11q23 abnormalities.[7] Other subtypes of AML (e.g., acute promyelocytic leukemia) have also been reported.[8,9] t-AML that occurs after exposure to alkylating agents or ionizing radiation often presents 5 to 7 years later and is commonly associated with monosomies or deletions of chromosomes 5 and 7.[1,7]
Treatment options for t-AML or t-MDS include the following:
The goal of treatment is to achieve an initial complete remission (CR) using AML-directed regimens and then, usually, to proceed directly to HSCT with the best available donor. However, treatment is challenging because of the following:[10]
Accordingly, CR rates and overall survival (OS) rates are usually lower for patients with t-AML than for patients with de novo AML.[10-12] Also, pediatric patients with t-MDS have worse survival rates than pediatric patients with MDS not related to previous therapy.[13]
Patients with t-MDS-refractory anemia usually have not needed induction chemotherapy before transplant. The role of induction therapy before transplant is controversial in patients with refractory anemia with excess blasts-1.
Only a few reports describe the outcome of children undergoing HSCT for t-AML.
Evidence (HSCT for t-AML or t-MDS):
Because t-AML is rare in children, it is not known whether the significant decrease in transplant-related mortality after unrelated-donor HSCT noted over the past several years will translate to improved survival in this population. Patients should be carefully assessed for pre-HSCT morbidities caused by earlier therapies, and treatment approaches should be adapted to give adequate intensity while minimizing transplant-related mortality.
While the issues of long-term complications of cancer and its treatment cross many disease categories, several important issues related to the treatment of myeloid malignancies are worth emphasizing. For more information, see Late Effects of Treatment for Childhood Cancer.
Selected studies of the late effects of acute myeloid leukemia (AML) therapy in adult survivors who were not treated with hematopoietic stem cell transplant (HSCT) include the following:
Renal, gastrointestinal, and hepatic late adverse effects were rare for children who received chemotherapy only for treatment of AML.[9]
Selected studies of the late effects of AML therapy in adult survivors who were treated with HSCT include the following:
New therapeutic approaches to reduce long-term adverse sequelae are needed, especially for reducing the late sequelae associated with myeloablative HSCT.
Important resources for details on follow-up and risks for survivors of cancer have been developed, including the COG’s Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers and the National Comprehensive Cancer Network's Guidelines for Acute Myeloid Leukemia. Furthermore, having access to past medical history that can be shared with subsequent medical providers has become increasingly recognized as important for cancer survivors.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Classification of Pediatric Myeloid Malignancies
Added text to state that increasing data show that the presence of monosomy 7 is associated with a higher risk of a patient having germline GATA2, SAMD9 or SAMD9L pathogenic variants. Cases associated with an underlying RUNX1-altered familial platelet disorder, telomere biology disorder, and germline ERCC6L2 pathogenic variants have also been reported (cited Wlodarski et al. as reference 149). Germline testing should be considered when monosomy 7 disease is identified.
Treatment Option Overview for Childhood AML
Added text to state that in one retrospective analysis, leukemia cutis did not have an adverse impact on outcomes of infants when they were treated with traditional chemotherapy (cited Renaud et al. as reference 3).
Added text to state that from an analysis of patients enrolled in the AAML0531 and AAML1031 trials, using the Children's Oncology Group (COG) definition of central nervous system (CNS) involvement, peripheral blood contamination increased the number of patients who were classified as CNS positive and guided to additional intrathecal therapy. In these trials, following past precedence, diagnostic cerebrospinal fluid examinations and initial intrathecal administration were done on or before day 1 of induction therapy (cited Kutny et al. as reference 60). Beginning with the COG AAML1831 trial, to minimize the risk of contamination, the newer guidance is to delay the diagnostic lumbar puncture to day 8, when most patients have cleared their peripheral blood of leukemic blasts. Additionally, a definition of CNS involvement that is more similar to the ALL definition is now in use.
Added Table 5 showing favorable and unfavorable cytogenetic and molecular prognostic findings.
Added text about the results of the NOPHO-DBH-AML2012 study (cited Tierens et al. as reference 81).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Acute Myeloid Leukemia Treatment are:
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389454]
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