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Home > Health Library > Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For acute myeloid leukemia (AML), the 5-year survival rate increased over the same time from less than 20% to 68% for children younger than 15 years and from less than 20% to 57% for adolescents aged 15 to 19 years.
Characteristics of Myeloid Leukemias and Other Myeloid Malignancies in Children
Approximately 20% of childhood leukemias are of myeloid origin and they represent a spectrum of hematopoietic malignancies. Most myeloid leukemias are acute, and the remainder include chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia and juvenile myelomonocytic leukemia. Myelodysplastic syndromes occur much less frequently in children than in adults and almost invariably represent clonal, preleukemic conditions that may 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:
TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the GATA1 gene in the presence of trisomy 21.[6,7] TAM may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk of developing subsequent AML. Approximately 20% of infants with TAM of Down syndrome eventually develop AML, with most cases diagnosed within the first 3 years of life.[7,8]
Early death from TAM-related complications occurs in 10% to 20% of affected infants.[8,9] Infants with progressive organomegaly, visceral effusions, high blast count (>100,000 cells/μL) and laboratory evidence of progressive liver dysfunction are at a particularly high risk of early mortality.[8,9] (Refer to the Myeloid Proliferations Associated with Down Syndrome section of this summary for more information.)
The presence of a karyotype abnormality in a hypocellular marrow is consistent with MDS and transformation to AML should be expected. Given the high association of MDS evolving into AML, patients with MDS are typically referred for stem cell transplantation before transformation to AML. (Refer to the Myelodysplastic Syndromes [MDS] section of this summary for more information.)
JMML characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated white blood cell (WBC) count and increased circulating monocytes. In addition, patients often have an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte-macrophage colony-stimulating factor (GM-CSF), monosomy 7, and leukemia cell mutations in a gene involved in RAS pathway signaling (e.g., NF1, KRAS/NRAS, PTPN11, or CBL).[12,13,14] (Refer to the Juvenile Myelomonocytic Leukemia [JMML] section of this summary for more information.)
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. (Refer to the Chronic Myelogenous Leukemia [CML] section of this summary for more information.)
Other chronic myeloproliferative syndromes, such as polycythemia vera and essential thrombocytosis, are extremely rare in children.
Conditions Associated With Myeloid Malignancies
Genetic abnormalities (cancer predisposition syndromes) are associated with the development of AML. There is a high concordance rate of AML in identical twins; however, this 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.[15,16,17] 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.[18,19]
The development of AML has also been associated with a variety of inherited/familial syndromes, which are recognized as a unique category within the 2016 World Health Organization (WHO) Classification of Myeloid Neoplasms and Acute Leukemia. There are also several acquired conditions that increase the risk of developing AML. 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.[20,21]
The 2016 WHO classification system has categorized the myeloid neoplasms with germline predisposition as follows:
Nonsyndromic genetic susceptibility to AML is also being studied. For example, homozygosity for a specific IKZF1 polymorphism has been associated with an increased risk of infant AML.
French-American-British (FAB) Classification System for Childhood AML
The first comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the FAB Cooperative Group.[1,2,3,4,5] This classification system, which has been replaced by the World Health Organization (WHO) system described below, 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.
The FAB classification was superseded by the WHO classification described below but remains relevant as it forms the basis of the WHO's subcategory of AML, not otherwise specified (AML, NOS).
World Health Organization (WHO) Classification System for Childhood AML
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 constituted nearly half of the cases of childhood AML, were classified as AML with recurrent cytogenetic abnormalities. This classification system also decreased the bone marrow percentage of leukemic blast requirement 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.[8,9,10]
In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific gene mutations (CEBPA and NPM) in its classification system. In 2016, the WHO classification underwent revisions to incorporate the expanding knowledge of leukemia biomarkers that are significantly important to the diagnosis, prognosis, and treatment of leukemia. With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will certainly continue to evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.
2016 WHO classification of AML and related neoplasms
2016 WHO classification of acute leukemias of ambiguous lineage
For the group of acute leukemias that have characteristics of both AML and acute lymphoblastic leukemia (ALL), the acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 1.[13,14] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.[12,15]
Leukemias of mixed phenotype may be seen in various presentations, including the following:
Biphenotypic cases represent the majority of mixed phenotype leukemias. B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have a lower rate of complete remission (CR) and a significantly worse event-free survival (EFS) compared with patients with precursor B-cell ALL. Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[17,18,19,20]; [Level of evidence: 3iiiA] 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 transplantation (HSCT) in first CR was not beneficial, with the possible exception of cases with morphologic evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.
WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes
The FAB classification of myelodysplastic syndromes (MDS) was not completely applicable to children.[22,23] Traditionally, MDS classification systems have been divided into several distinct categories on the basis of the presence of the following:[23,24,25,26]
A modified classification schema for MDS and myeloproliferative disorders (MPDs) was published by the WHO in 2008 and included subsections that focused on pediatric MDS and MPD. This pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was initially proposed in 2003. The 2016 revision to the WHO classification has removed focus on the specific lineage (anemia, thrombocytopenia, or neutropenia) and now distinguishes cases with dysplasia in single versus multiple lineages. The category of MDS with excess blasts (MDS-EB) now encompasses the pediatric cases previously classified as refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEB-T). The category of refractory cytopenia of childhood is retained as a provisional entity. The bone marrow and peripheral blood findings for MDS according to the 2008 WHO classification schema are summarized in Tables 3 and 4.[12,27] When MDS-EB is associated with the recurrent cytogenetic abnormalities that are usually associated with AML, a diagnosis of AML is made and patients are treated accordingly.
Distinguishing MDS from similar-appearing, reactive causes of dysplasia and/or cytopenias is noted to be difficult. In general, the finding of more than 10% dysplasia in a cell lineage is a diagnostic criteria for MDS; however, the 2016 WHO guidelines caution that reactive etiologies, rather than clonal, may have more than 10% dysplasia and should be excluded especially when dysplasia is subtle and/or restricted to a single lineage.
The International Prognostic Scoring System is used to determine the risk of progression to AML and the outcome in adult patients with MDS. When this system was applied to children with MDS or juvenile myelomonocytic leukemia (JMML), only a blast count of less than 5% and a platelet count of more than 100 × 109 /L were associated with a better survival in MDS, and a platelet count of more than 40 × 109 /L predicted a better outcome in JMML. These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS.
Pediatric MDS can be grouped into several general categories, each with distinctive clinical and biological characteristics, as follows:
Genomic characterization of pediatric primary MDS has identified specific subsets defined by alterations in selected genes (refer to the Molecular Abnormalities subsection of this summary for more information about MDS). For example, germline mutations in either GATA2 or SAMD9/SAMD9L[31,32,33] are especially common in children with deletions of all or part of chromosome 7. Genomic characterization has also shown that primary MDS in children differs from adult MDS at the molecular level.[32,34]
The treatment for children with acute myeloid leukemia (AML) differs significantly from that for acute lymphoblastic leukemia (ALL). As a consequence, it is critical to distinguish AML from 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 include myeloperoxidase, periodic acid-Schiff, Sudan Black B, and esterase. In most cases, the staining pattern with these histochemical stains will distinguish AML from acute myelomonocytic leukemia (AMML) and ALL (refer to Table 5). Histochemical stains have been mostly replaced by flow cytometric immunophenotyping.
The use of monoclonal antibodies to determine cell-surface antigens of AML cells is helpful to reinforce the histologic diagnosis. 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 cluster determinant (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, CD2, CD3, CD5, and CD7 lineage-associated T-lymphocytic antigens are present in 20% to 40% of AML cases.[1,2,3] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[1,2]
Immunophenotyping can also be helpful in distinguishing the following French-American-British (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.[7,8,9] 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 World Health Organization (WHO) criteria.[10,11,12] In the WHO classification, the presence of myeloperoxidase (MPO) is required to establish myeloid lineage. This is not the case for the EGIL classification. The 2016 revision to 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, and the clinical significance of that finding is unclear such that one should be cautious before designating these cases as mixed phenotype acute leukemia (MPAL).
Molecular features of acute myeloid leukemia
Comprehensive molecular profiling of pediatric and adult AML has shown that AML is a disease demonstrating both commonalities and differences across the age spectrum.[14,15]
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.[16,17,18,19,20] 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, mutations of NPM and CEBPA are associated with favorable outcomes while certain mutations of FLT3 portend a high risk of relapse, and identifying the latter mutations may allow for targeted therapy.[21,22,23,24]
The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia emphasizes that recurrent chromosomal translocations in pediatric AML may be unique or have a different prevalence than in adult AML. The pediatric AML chromosomal translocations that are found by conventional chromosome analysis and those that are cryptic (identified only with fluorescence in situ hybridization or molecular techniques) occur at higher rates than in adults. These recurrent translocations are summarized in Table 6.[13,15] Table 6 also shows, in the bottom three rows, additional relatively common recurrent translocations observed in children with AML.[15,18,19,25]
The genomic landscape of pediatric AML cases can change from diagnosis to relapse, with mutations detectable at diagnosis dropping out at relapse and, conversely, with new mutations appearing at relapse. In a study of 20 cases for which sequencing data were available at diagnosis and relapse, a key finding was that the variant allele frequency at diagnosis strongly correlated with persistence of mutations at relapse. Approximately 90% of the diagnostic variants with variant allele frequency greater than 0.4 persisted to relapse, compared with only 28% with variant allele frequency less than 0.2 (P < .001). This observation is consistent with previous results showing that presence of a mutation in the FLT3 gene resulting from internal tandem duplications (ITD) predicted for poor prognosis only when there was a high FLT3 ITD allelic ratio.
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 2016 revision to the WHO classification of myeloid neoplasms and acute leukemia is incorporated for disease entities where relevant.
Genetic abnormalities associated with a favorable prognosis
Genetic abnormalities associated with a favorable prognosis include the following:
Both RUNX1-RUNX1T1 and CBFB-MYH11 subtypes commonly show mutations in genes that activate receptor tyrosine kinase signaling (e.g., NRAS, FLT3, and KIT); NRAS and KIT are the most commonly mutated genes for both subtypes. The prognostic significance of activating KIT mutations in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT mutations appear to increase the risk of relapse without an impact on OS for adults with RUNX1-RUNX1T1 AML.KIT mutations are often subclonal in children and adults with CBF AML;[35,36] and in adults with RUNX1-RUNX1T1 AML, higher KIT-mutant allele ratio appears to be associated with higher risk of treatment failure.[31,35] The prognostic significance of KIT mutations in pediatric CBF AML remains unclear; some studies have found no impact of KIT mutations on outcome,[37,38,39] while other studies have reported a higher risk of treatment failure when KIT mutations are present.[36,40,41,42,43]
Although both RUNX1-RUNX1T1 and CBFB-MYH11 fusion genes disrupt the activity of CBF, cases with these genomic alterations have distinctive secondary mutations.[31,32]
Utilization of quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) for PML-RARA transcripts has become standard practice. Quantitative RT-PCR allows identification of the three common transcript variants and is used for monitoring response on treatment and early detection of molecular relapse. Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t(11;17)(q23;q21) involving the PLZF gene).[48,49] Identification of cases with the t(11;17)(q23;q21) is important because of their decreased sensitivity to tretinoin.
Studies of children with AML suggest a lower rate of occurrence of NPM1 mutations in children compared with adults with normal cytogenetics. NPM1 mutations occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[21,22,56,57]NPM1 mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[21,22,57] For the pediatric population, conflicting reports have been published regarding the prognostic significance of an NPM1 mutation when a FLT3 ITD mutation is also present. One study reported that an NPM1 mutation did not completely abrogate the poor prognosis associated with having a FLT3 ITD mutation,[21,58] but other studies showed no impact of a FLT3 ITD mutation on the favorable prognosis associated with an NPM1 mutation.[15,22,57]
CEBPA mutations occur in 5% to 8% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2; 70% to 80% of pediatric patients have double-mutant alleles, which is predictive of a significantly improved survival, similar to the effect observed in adult studies.[23,65] Although both double-mutant and single-mutant alleles of CEBPA were associated with a favorable prognosis in children with AML in one large study, a second study observed inferior outcome for patients with single CEBPA mutations. However, very low numbers of children with single-allele mutants were included in these two studies (only 13 total patients), which makes a conclusion regarding the prognostic significance of single-allele CEBPA mutations in children premature. In newly diagnosed patients with double-mutant CEBPA AML, germline screening should be considered in addition to usual family history queries, because 5% to 10% of these patients are reported to have a germline CEBPA mutation.CSF3R mutations commonly occur in a subset of patients with mutant CEBPA AML, and when present, may be associated with increased risk of treatment failure but without an impact on OS.
GATA1 mutations confer increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.
Genetic abnormalities associated with an unfavorable prognosis
Genetic abnormalities associated with an unfavorable prognosis include the following:
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. However, outcome for children with del(7q), but not monosomy 7, appears comparable to that of other children with AML.[19,76] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[17,76]
Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are aged 4 years and younger.
Abnormalities involving MECOM can be detected in some AML cases with other 3q abnormalities and are also associated with poor prognosis.
The prognostic significance of FLT3 ITD is modified by the presence of other recurring genomic alterations. The prevalence of FLT3 ITD is increased in certain genomic subtypes of pediatric AML, including those with the NUP98-NSD1 fusion gene, of which 80% to 90% have FLT3 ITD.[88,89] Approximately 15% of patients with FLT3 ITD have NUP98-NSD1, and patients with both FLT3 ITD and NUP98-NSD1 have a poorer prognosis than do patients who have FLT3 ITD without NUP98-NSD1. For patients who have FLT3 ITD, the presence of either WT1 mutations or NUP98-NSD1 fusions is associated with poorer outcome (EFS rates below 25%) than for patients who have FLT3 ITD without these alterations. Conversely, when FLT3 ITD is accompanied by NPM1 mutations, the outcome is relatively favorable and is similar to that of pediatric AML cases without FLT3 ITD.
For APL, FLT3 ITD and point mutations occur in 30% to 40% of children and adults.[84,86,90,91] Presence of the FLT3 ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[90,92,93,94] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes tretinoin and arsenic trioxide.[91,93,95,96,97,98]
Activating point mutations of FLT3 have also been identified in both adults and children with AML, although the clinical significance of these mutations is not clearly defined. Some of these point mutations appear to be specific to pediatric patients.
Other genetic abnormalities observed in pediatric AML
Other genetic abnormalities observed in pediatric AML include the following:
The most common translocation, representing approximately 50% of KMT2A-rearranged cases in the pediatric AML population, is t(9;11)(p22;q23), in which the KMT2A gene is fused with MLLT3 gene. The 2016 revision to the WHO classification defined AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A as a distinctive disease entity. However, more than 50 different fusion partners have been identified for the KMT2A gene in patients with AML.
The median age for 11q23/KMT2A-rearranged cases in children is approximately 2 years, and most translocation subgroups have a median age at presentation of younger than 5 years. However, significantly older median ages are seen at presentation of pediatric cases with t(6;11)(q27;q23) (12 years) and t(11;17)(q23;q21) (9 years).
Outcome for patients with de novo AML and KMT2A gene rearrangement is generally reported as being similar to that for other patients with AML.[17,18,101,102] However, as the KMT2A gene can participate in translocations with many different fusion partners, the specific fusion partner appears to influence prognosis, as demonstrated by a large international retrospective study evaluating outcome for 756 children with 11q23- or KMT2A-rearranged AML. For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/KMT2A-rearranged AML, showed a highly favorable outcome, with a 5-year event-free survival (EFS) rate of 92%.
While reports from single clinical trial groups have variably described more favorable prognosis for patients with AML who have t(9;11)(p21.3;q23.3)/MLLT3-KMT2A, the international retrospective study did not confirm the favorable prognosis for this subgroup.[17,18,101] An international collaboration evaluating pediatric AMKL patients observed that the presence of t(9;11), which was seen in approximately 5% of AMKL cases, was associated with an inferior outcome compared with other AMKL cases.
KMT2A-rearranged AML subgroups that appear to be associated with poor outcome include the following:
t(6;9) AML appears to be associated with a high risk of treatment failure in children, particularly for those not proceeding to allogeneic stem cell transplantation.[18,105,108,109]
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, and with all cases observed in children younger than 3 years. 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). The CBFA2T3-GLIS2 fusion was an independent prognostic factor for both OS and EFS. The OS rate at 5 years was 22% for patients with CBFA2T3-GLIS2 versus 63% for fusion-negative patients. CBFA2T3-GLIS2 leukemia cells have a distinctive immunophenotype (initially reported as the RAM phenotype),[118,119] with high CD56, dim or negative expression of CD45 and CD38, and a lack of HLA-DR expression.
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. 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 AMKL patients with other specific genetic abnormalities (CBFA2T3/GUS2, NUP98/KDM5A, KMT2A rearrangements, monosomy 7).
A substantial proportion of infants diagnosed with t(8;16) AML in the first month of life show spontaneous remission, although AML recurrence may occur months to years later.[126,127,128,129] These observations suggest that a watch and wait policy could be considered in cases of t(8;16) AML diagnosed in the neonatal period if close long-term monitoring can be ensured.
The NUP98-NSD1 fusion gene, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[88,89,105,135] This alteration occurs in approximately 4% to 7% of pediatric AML cases.[13,25,88,105,136]
The NUP98-KDM5A fusion gene results from the fusion of the NUP98 gene with the KDM5A gene, which results from a cytogenetically cryptic translocation, t(11;12)(p15;p13). Approximately 2% of pediatric AML patients have NUP98-KDM5A, and these cases tend to present at a young age (median age, 3 years).
The prognostic significance of activating KIT mutations in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT mutations appear to increase the risk of relapse without an impact on OS for adults with RUNX1-RUNX1T1 AML.KIT mutations are often subclonal in children and adults with CBF AML;[35,36] in adults with RUNX1-RUNX1T1 AML, higher KIT mutant–allele ratio appears to be associated with higher risk of treatment failure in adults with RUNX1-RUNX1T1 AML.[31,35] The prognostic significance of KIT mutations in pediatric CBF AML remains unclear; some studies found no impact of KIT mutations on outcome,[37,38,39] while other studies reported a higher risk of treatment failure when KIT mutations were present.[36,40,41,42,43]
In children with AML, WT1 mutations are observed in approximately 10% of cases.[147,148] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3 ITD, but are less common among children younger than 3 years.[147,148] AML cases with NUP98-NSD1 are enriched for both FLT3 ITD and WT1 mutations. In univariate analyses, WT1 mutations are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of WT1 mutation status is unclear because of its strong association with FLT3 ITD and its association with NUP98-NSD1.[88,147,148] The largest study of WT1 mutations in children with AML observed that children with WT1 mutations in the absence of FLT3 ITD had outcomes similar to that of children without WT1 mutations, while children with both WT1 mutation and FLT3 ITD had survival rates less than 20%.
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%).
Mutations in IDH1 and IDH2 are rare in pediatric AML, occurring in 0% to 4% of cases.[152,161,162,163,164,165] There is no indication of a negative prognostic effect for IDH1 and IDH2 mutations in children with AML.
Activating mutations in CSF3R are also observed in patients with severe congenital neutropenia. These mutations are not the cause of severe congenital neutropenia, but rather arise as somatic mutations and can represent an early step in the pathway to AML. In one study of patients with severe congenital neutropenia, 34% of patients who had not developed a myeloid malignancy had CSF3R mutations detectable in peripheral blood neutrophils and mononuclear cells, while 78% of patients who had developed a myeloid malignancy showed CSF3R mutations. A study of 31 patients with severe congenital neutropenia who developed AML or MDS observed CSF3R mutations in approximately 80% of patients, and also observed a high frequency of RUNX1 mutations (approximately 60%), suggesting cooperation between CSF3R and RUNX1 mutations for leukemia development within the context of severe congenital neutropenia.
Leukemia is considered to be disseminated in the hematopoietic system at diagnosis, even in children with acute myeloid leukemia (AML) who present with isolated chloromas (also called granulocytic or myeloid sarcomas). If these children do not receive systemic chemotherapy, they invariably develop AML in months or years. 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.
Childhood AML is diagnosed when bone marrow has 20% or greater blasts. The blasts have the morphologic and histochemical characteristics of one of the French-American-British (FAB) subtypes of AML. It can also be diagnosed by biopsy of a chloroma. For treatment purposes, patients with clonal cytogenetic abnormalities typically associated with AML, such as t(8;21)(RUNX1-RUNX1T1), inv(16)(CBFB-MYH11), t(9;11)(MLLT3-KMT2A) or t(15;17)(PML-RARA) and who have less than 20% bone marrow blasts, are considered to have AML rather than a myelodysplastic syndrome.
Complete remission (CR) has traditionally been defined in the United States using morphologic criteria such as the following:
Alternative definitions of remission using morphology are used in AML because of the prolonged myelosuppression caused by intensive chemotherapy and 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, the traditional CR definition remains the gold standard because patients in CR were found to be more likely to survive longer than those in CRp.
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]); a hypoplastic marrow phase is often not necessary before the achievement of remission in APL. 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. If the findings are in doubt, the bone marrow aspirate should be repeated in 1 to 2 weeks.
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 and has been shown to be of greater prognostic significance than morphology. (Refer to the Prognostic Factors in Childhood AML section of this summary for more information about these methodologies.)
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:
Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). For example, ongoing trials of 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.[6,7,8]
Maintenance therapy is not part of most pediatric AML protocols because two randomized clinical trials failed to show a benefit for maintenance therapy when given after modern intensive chemotherapy.[9,10] The exception to this generalization is made for APL, because maintenance therapy was shown to improve event-free survival (EFS) and overall survival (OS) when tretinoin was combined with chemotherapy. Some studies of adult APL patients, including studies incorporating arsenic trioxide treatment, have shown no benefit to maintenance.[12,13]
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. The most recent COG trials reported an 11% to 13% incidence of remission failure because of resistant disease and only 2% to 3% resulted from toxic death during the two induction courses.[8,14]
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 have declined, including total-body irradiation with HSCT because of its increased risk of growth failure, gonadal and thyroid dysfunction, cataract formation, and second malignancies. (Refer to the Survivorship and Adverse Late Sequelae section of this summary or to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Prognostic Factors in Childhood AML
Prognostic factors in childhood AML can be categorized as follows:
Host risk factors
While outcome for infants with ALL remains inferior to that of older children, outcome for infants with AML is similar to that of older children when they are treated with standard AML regimens.[16,23,24,25] Infants have been reported to have a 5-year survival rate of 60% to 70%, although with increased treatment-associated toxicity, particularly during induction.[16,23,24,25,26]
Leukemia risk factors
In patients with APL, WBC at initial diagnosis alone is used to distinguish standard-risk and high-risk APL. A WBC count of 10,000 cells/μL or more denotes high risk, and these patients have an increased risk of both early death and relapse. However, more recent regimens that include arsenic trioxide result in low relapse rates that are not significantly different between the high-risk and low-risk groups.
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.[47,48] By contrast, the 10% of non–Down syndrome AMKL patients with GATA1 mutations appeared to have a favorable outcome if there were no prognostically unfavorable fusion genes also present, as did patients with HOX-rearrangement.
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 utilizing the more traditional CNS1/2/3 definitions.
CNS2 disease has been observed in approximately 13% to 16% of children with AML, and CNS3 disease has been observed in approximately 11% to 17% of children with AML.[50,51] Studies have variably shown that patients with CNS2/CNS3 were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).[50,51]
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 involvement, especially CNS3 status, was associated with inferior outcomes, including complete remission rate, EFS, disease-free survival, and an increased risk of relapse involving the CNS. Another trial showed it to be associated with an increased risk of isolated CNS relapse. Finally, the COG study did not find an adverse impact of traumatic lumbar punctures at diagnosis upon eventual outcome.
Therapeutic response risk factors
Molecular approaches to assessing MRD in AML (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. Quantitative RT-PCR detection of RUNX1-RUNX1T1 fusion transcripts can effectively predict higher risk of relapse for patients in clinical remission.[65,66,67] Other molecular alterations such as NPM1 mutations  and CBFB-MYH11 fusion transcripts  have also been successfully employed as leukemia-specific molecular markers in MRD assays; for these alterations, the level of MRD has shown prognostic significance. The presence of FLT3 ITD has been shown to be discordant between diagnosis and relapse, although when its presence persists (usually associated with a high-allelic ratio at diagnosis), it can be useful in detecting residual leukemia.
For APL, MRD detection at the end of induction therapy lacks prognostic significance, likely related to the delayed clearance of differentiating leukemic cells destined to eventually die.[71,72] However, the kinetics of molecular remission after completion of induction therapy is prognostic, with the persistence of minimal disease after three courses of therapy portending increased risk of relapse.[72,73,74]
Flow cytometric methods have 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. A CCG study of 252 pediatric patients with AML in morphologic remission demonstrated that MRD as assessed by flow cytometry was the strongest prognostic factor predicting outcome in a multivariate analysis. Other reports have confirmed both the utility of flow cytometric methods for MRD detection in the pediatric AML setting and the prognostic significance of MRD at various time points after treatment initiation.[60,61,63]
Risk Classification Systems
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  and further applied based on the ability of the pediatric patient to undergo reinduction and obtain a second complete remission and their subsequent OS after first relapse.
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 (refer to Table 7).
The high-risk group of patients was guided to transplantation in first remission with the most appropriate available donor. Patients in the low-risk group were instructed to pursue transplantation if they relapsed.[61,77]
Risk factors used for stratification vary by pediatric and adult cooperative clinical trial groups and 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.
The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below, followed by a more specific discussion of the treatment of children with Down syndrome and acute promyelocytic leukemia (APL).
Overall survival (OS) rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 65% range.[1,2,3,4] Overall remission-induction rates are approximately 85% to 90%, and event-free survival (EFS) rates from the time of diagnosis are in the 45% to 55% range.[2,3,4,5] There is, however, a wide range in outcome for different biological subtypes of AML (refer to the Molecular Evaluation and Risk Classification Systems sections of this summary for more information); 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.
Contemporary pediatric AML protocols result in 85% to 90% complete remission (CR) rates.[6,7,8] Approximately 2% to 3% of patients die during the induction phase, most often caused by treatment-related complications.[6,7,8,9] 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.
Treatment options for children with AML during the induction phase may include the following:
The two most effective and essential drugs used to induce remission in children with AML are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[3,10,11]
Evidence (induction chemotherapy regimen):
The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[3,10,11] although idarubicin and the anthracenedione mitoxantrone have also been used.[6,14,15] 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 (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). The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.
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, 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. A second pediatric study also failed to detect a benefit for high-dose cytarabine over standard-dose cytarabine when used during induction therapy.
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.
Antibody-drug conjugate therapy (gemtuzumab ozogamicin)
Gemtuzumab ozogamicin is a CD33-directed monoclonal antibody linked to a calicheamicin, a cytotoxic agent.
Evidence (gemtuzumab ozogamicin during induction):
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 mutations and/or their abnormal present or missing byproducts. As opposed to adult AML (except in APL as described in a later section), randomized clinical trials have not yet demonstrated that targeted therapies improve outcomes in children with newly diagnosed AML; therefore, targeted therapies have not been incorporated into the standard therapeutic induction regimens outside of clinical trials. 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.
FLT3 inhibitors in de novo AML
Because of the high prevalence of FLT3 mutations in adult AML and adverse impact in AML patients 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.
Evidence (midostaurin for adults with de novo AML):
Midostaurin has been studied in children with relapsed/refractory AML, but there is no experience with midostaurin in children with newly diagnosed AML. (Refer to the Targeted therapy subsection in the Recurrent or Refractory Childhood AML and Other Myeloid Malignancies section of this summary for more information.)
Sorafenib, another multikinase inhibitor, has been approved for the treatment of other malignancies but not AML, and has been evaluated for use in patients with de novo FLT3-mutated AML including children.
Sorafenib was evaluated in the COG AAML1031 (NCT01371981) study of pediatric patients with de novo high-allelic ratio FLT3 ITD AML. Patients received sorafenib with intensive chemotherapy, followed by allogeneic SCT and subsequent maintenance therapy with sorafenib alone. Eighty patients were evaluable and compared with historical controls from the COG AAML0531 trial. The CR rate after induction cycle II significantly improved (91% vs. 70%; P = .007), as did the 3-year EFS rate (57.5% vs. 34.3%; P = .007) and relapse risk after CR (18.2% vs. 52.5%; P = .006); however, the OS rate did not improve (63.9% vs. 54.1%; P = .375). Sorafenib was well tolerated in this young cohort, with no excess adverse events compared with the non-FLT3 ITD patients who received the same backbone therapy without 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%.[35,36,37] Several approaches have been examined to reduce the morbidity and mortality from infection in children with AML.
Hematopoietic growth factors
Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (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. 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  but have not shown significant effects on treatment-related mortality or OS. (Refer to the Treatment Option Overview for AML section in the PDQ summary on Acute Myeloid Leukemia Treatment for more information.)
Routine prophylactic use of hematopoietic growth factors is not recommended for children with AML.
Evidence (against the use of hematopoietic growth factors):
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):
Bacteremia or sepsis and anthracycline use have been identified as significant risk factors in the development of cardiotoxicity, manifested as reduced left ventricular function.[55,56] 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 be an effective method of reducing the risk of cardiac dysfunction during therapy.
Evidence (cardiac monitoring/dexrazoxane impact):
Hospitalization until adequate granulocyte (absolute neutrophil or phagocyte count) recovery has been used to reduce treatment-related mortality. The COG-2961 (NCT00002798) trial was the first to note a significant reduction in treatment-related mortality (19% before mandatory hospitalization was instituted in the trial along with other supportive care changes vs. 12% afterward); OS was also improved in this trial (P <.001). Another analysis of the impact of hospitalization using a survey of institutional routine practice found that those who mandated hospitalization had nonsignificant reduction in patients' treatment-related mortality (adjusted HR, 0.60 [0.26–1.36, P = .22]) compared with institutions who had no set policy. Although there was no significant benefit seen in this study, the authors noted the limitations, including its methodology (survey), an inability to validate cases, and limited power to detect differences in treatment-related mortality. To avoid prolonged hospitalizations until count recovery, some institutions have used outpatient IV antibiotic prophylaxis effectively.
Induction failure (refractory AML)
Induction failure (the morphologic 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).[58,59]
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. This incidence was also seen in the NOPHO-AML 2004 (NCT00476541) trial.
Importantly, the patient who presents with an isolated tumor, without evidence of marrow involvement, must be treated as if there is systemic disease. Patients with isolated granulocytic sarcoma have a good prognosis if treated with current AML therapy.
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 did patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease.[61,62] 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, but may be necessary if the site(s) of granulocytic sarcoma do not show complete response to chemotherapy or for disease that recurs locally.
Central Nervous System (CNS) Prophylaxis for AML
CNS involvement in patients with AML and its impact on prognosis has been discussed above in the Prognostic Factors in Childhood AML section of this summary. Therapy with either radiation or intrathecal chemotherapy has been used to treat CNS leukemia present at diagnosis and to prevent later development of CNS leukemia. The use of radiation has essentially been abandoned as a means of prophylaxis because of the lack of documented benefit and long-term sequelae. The COG has used single-agent cytarabine for both CNS prophylaxis and therapy. Other groups have attempted to prevent CNS relapse by using additional intrathecal agents.
Evidence (CNS prophylaxis):
Postremission Therapy for AML
A major challenge in the treatment of children with AML is to prolong the duration of the initial remission with additional chemotherapy or hematopoietic stem cell transplantation (HSCT).
Treatment options for children with AML in postremission may include the following:
Postremission chemotherapy includes some of the drugs used in induction while also 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. (Refer to the Treatment of AML in Remission section of the PDQ summary on Acute Myeloid Leukemia Treatment for more information.) 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.[11,67,68]
The optimal number of postremission courses of therapy remains unclear, but appears to require at least two to three courses of intensive therapy after induction.
Evidence (number of postremission courses of chemotherapy):
Additional study of the number of intensification courses and specific agents used will better address this issue, but 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 transplantation 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,[10,70] with the caveat that outcome after allogeneic HSCT is dependent on risk-classification status.
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.[10,70,72,73,74,75,76] However, the superiority of allogeneic HSCT over chemotherapy has not always been observed. Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.[10,70,72,74]
Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplantation should be pursued in first remission. Because of the improved outcome in patients with favorable prognostic features (low-risk cytogenetic or molecular mutations) receiving contemporary chemotherapy regimens and the lack of demonstrable superiority for HSCT in this patient population, this group of patients typically receives matched-family donor (MFD) HSCT only after first relapse and the achievement of a second CR.[71,78,79,80]
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 mutations):
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 transplantation, 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 relapse.[6,81,82]
There are conflicting data regarding the role of allogeneic HSCT in first remission for patients with high-risk disease, complicated by the differing definitions of high risk used by different study groups.
Evidence (allogeneic HSCT in first remission for patients with high-risk AML):
Many, but not all, pediatric clinical trial groups prescribe allogeneic HSCT for high-risk patients in first remission. 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 and to 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.[77,88] 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.
Because definitions of high-, intermediate-, and low-risk AML are evolving because of the ongoing association of molecular characteristics of the tumor with outcome (e.g., FLT3 ITD, WT1 mutations, and NPM1 mutations) and response to therapy (e.g., MRD assessments postinduction therapy), further analysis of subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials.
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.[76,89,90] There are no data that suggest total-body irradiation (TBI) is superior to busulfan-based myeloablative regimens.[77,78] 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.
Evidence (myeloablative regimen):
Other than the APL subtype, 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,[67,94] and maintenance therapy with interleukin-2 also proved ineffective.
Current Clinical Trials
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.
Recurrent or Refractory Childhood AML and Other Myeloid Malignancies
The diagnosis of recurrent or relapsed AML according to COG criteria is essentially the same as the criteria for making the diagnosis of AML. Usually this is defined as patients having more than 5% bone marrow blasts who were in previous remission after therapy for a diagnosis of AML according to WHO classification criteria.[95,96]
Despite second remission induction in over one-half of children with AML treated with drugs similar to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive AML is generally poor.[58,97]
Recurrent childhood AML
Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most relapses occurring by 4 years from diagnosis. The vast majority of relapses occur in the bone marrow, and CNS relapse is very uncommon.
Prognosis and prognostic factors
Factors affecting the ability to attain a second remission include the following:
Additional prognostic factors were identified in the following studies:
Treatment of recurrent AML
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:
Regimens built upon clofarabine and [110,111,112][Level of evidence: 2Div] 2-chloroadenosine have been used. The COG AAML0523 (NCT00372619) trial evaluated the combination of clofarabine plus high-dose cytarabine in patients with relapsed AML; the response rate was 48% and the OS rate, with 21 of 23 responders undergoing HSCT, was 46%. MRD before HSCT was a strong predictor of survival.[Level of evidence: 2Di]
The standard-dose cytarabine regimens used in the United Kingdom 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. In a COG phase II study, the addition of bortezomib to idarubicin plus low-dose cytarabine resulted in an overall CR rate of 57%, and the addition of bortezomib to etoposide and high-dose cytarabine resulted in an overall CR rate of 48%.
Before its FDA approval for use in children with de novo AML in 2020, gemtuzumab ozogamicin was approved for children with relapsed or refractory AML in patients aged 2 years and older.
Targeted therapy (FLT3 inhibitors)
Midostaurin. There is limited experience with midostaurin in pediatric patients with AML.
Gilteritinib. 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. In relapsed or refractory AML, gilteritinib, a type 1 selective FLT3 inhibitor with activity against both FLT3 mutations (ITD and D835/I836 tyrosine kinase domain [TKD]), is the first and only FLT3 inhibitor that has received FDA approval for single-agent use in adults based on the ADMIRAL (NCT02421939) trial.
Gilteritinib is now being studied in children with FLT3-positive de novo AML in the COG AAML1831 (NCT04293562) trial.
Sorafenib. Sorafenib has been evaluated in pediatric patients with relapsed and refractory AML.
The selection of additional treatment after the achievement of a second complete remission 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 complete remission is obtained.
Evidence (HSCT after second complete remission):
Second transplant after relapse following a first transplant
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. 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.[134,135,136,137]
Isolated CNS relapse occurs in 3% to 6% of pediatric AML patients.[64,138,139] Factors associated with an increased risk of isolated CNS relapse include the following:
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). 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%). CNS relapse may also occur in the setting of bone marrow relapse and its likelihood increases with CNS involvement at diagnosis (CNS1: 2.7%, CNS2: 8.5%, CNS3: 9.2% incidence of concurrent CNS relapse, P < .001).
Refractory childhood AML (induction failure)
Treatment options for children with refractory AML may include the following:
Like patients with relapsed AML, induction failure patients are typically directed towards HSCT once they attain a remission, because studies suggest a better EFS than in patients treated with chemotherapy only (31.2% vs. 5%, P < .0001). Attainment of morphologic CR for these patients is a significant prognostic factor for DFS after HSCT (46% vs. 0%; P = .02), with failure primarily resulting from relapse (relapse risk, 53.9% vs. 88.9%; P = .02).
Evidence (treatment of refractory childhood AML with gemtuzumab ozogamicin):
Treatment options under clinical evaluation
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, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) because of several factors, including the following:
These unique features of APL mandate a high index of suspicion at diagnosis so as to initiate proper supportive care measures to avoid coagulopathic complications during the first days of therapy. It is also critical to institute a different induction regimen of therapy to minimize the risk of coagulopathic complications and to provide a much improved long-term relapse-free survival and overall survival (OS) than with past approaches to treating APL and compared with outcomes for patients with the other forms of AML.[2,3]
The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the promyelocytic leukemia (PML)–retinoic acid receptor alpha (RARA) fusion protein.
Patients with a suspected diagnosis of APL can have their diagnosis confirmed by detection of the PML-RARA fusion protein (e.g., through fluorescence in situ hybridization [FISH], reverse transcriptase–polymerase chain reaction [RT-PCR], or conventional cytogenetics). An immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML-RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein.[4,5,6]
Clinically, APL is characterized by severe coagulopathy that is often present at the time of diagnosis. This is typically manifested with thrombocytopenia, prolonged prothrombin time, partial thromboplastin time, elevated d-dimers, and hypofibrinogenemia. Mortality during induction (particularly with cytotoxic agents used alone) caused by bleeding complications is more common in this subtype than in other FAB or World Health Organization (WHO) classifications.[9,10] A multicooperative group analysis of children with APL who were treated with tretinoin and chemotherapy reported that early induction coagulopathic deaths occurred in 25 of 683 children (3.7%); 23 deaths resulted from hemorrhage (19 CNS, 4 pulmonary), and 2 resulted from CNS thrombosis. A lumbar puncture at diagnosis should not be performed until evidence of coagulopathy has resolved.
Tretinoin therapy is initiated as soon as APL is suspected on the basis of morphological and clinical presentation,[2,12] because tretinoin has been shown to ameliorate bleeding risk for patients with APL. A retrospective analysis identified an increase in early death resulting from hemorrhage in patients with APL in whom tretinoin introduction was delayed. Additionally, initiation of supportive measures such as replacement transfusions directed at correction of the coagulopathy is critical during these initial days of diagnosis and therapy. Patients at greatest risk of coagulopathic complications are those presenting with high white blood cell (WBC) counts, high body mass index, hypofibrinogenemia, molecular variants of APL, and the presence of FLT3 internal tandem duplication (ITD) mutations.[8,11]
APL in children is generally similar to APL in adults, although children have a higher incidence of hyperleukocytosis (defined as WBC count higher than 10 × 109 /L) and a higher incidence of the microgranular morphologic subtype.[14,15,16,17] As in adults, children with WBC counts less than 10 × 109 /L at diagnosis have significantly better outcomes than do patients with higher WBC counts.[15,16,18]
Risk Classification for Treatment Stratification
The prognostic significance of WBC count is used to define high-risk and low-risk patient populations and to assign postinduction treatment, with high-risk patients most commonly defined by WBC count of 10 × 109 /L or greater.[19,20]FLT3 mutations (either ITD or tyrosine kinase domain [TKD] mutations) are observed in 40% to 50% of APL cases, with the presence of FLT3 mutations correlating with higher WBC counts and the microgranular variant (M3v) subtype.[21,22,23,24,25] The FLT3 mutation has been associated with an increased risk of induction death and, in some reports, an increased risk of treatment failure.[21,22,23,24,25,26,27]
In the COG AAML0631 (NCT00866918) trial, which included treatment with chemotherapy, tretinoin, and arsenic trioxide, risk classification primarily defined early death risk rather than relapse risk (standard risk, 0 of 66 patients vs. high risk, 4 of 35 patients). Relapse risk after remission induction was 4% overall, with one relapse in a standard-risk child and two relapses in high-risk children. High-risk patients on this trial had earlier initiation of idarubicin, with first dose on day 1 rather than day 3 to reduce leukemic burden more rapidly, and one additional consolidation chemotherapy (high-dose cytarabine and idarubicin) and tretinoin cycle.
The Central Nervous System (CNS) and APL
CNS involvement at the time of diagnosis is not ascertained in most patients with APL because of the presence of disseminated intravascular coagulation. The COG AAML0631 (NCT00866918) trial identified 28 patients out of 101 enrolled children who had cerebrospinal fluid (CSF) exams at diagnosis, and in 7 of these children, blasts were identified in atraumatic taps. None of the patients experienced a CNS relapse with intrathecal treatment during induction and prophylactic doses during therapy.
Overall, CNS relapse is uncommon for patients with APL, particularly for those with WBC counts of less than 10 × 109 /L.[29,30] In two clinical trials enrolling more than 1,400 adults with APL in which CNS prophylaxis was not administered, the cumulative incidence of CNS relapse was less than 1% for patients with WBC counts of less than 10 × 109 /L, while it was approximately 5% for those with WBC counts of 10 × 109 /L or greater.[29,30] In addition to high WBC counts at diagnosis, CNS hemorrhage during induction is also a risk factor for CNS relapse. A review of published cases of pediatric APL also observed low rates of CNS relapse. Because of the low incidence of CNS relapse among children with APL presenting with WBC counts of less than 10 × 109 /L, CNS surveillance and prophylactic CNS therapy may not be needed for this group of patients, although there is no consensus on this topic.
Treatment of APL
Modern treatment programs for APL are based on the sensitivity of leukemia cells from APL patients to the differentiation-inducing and apoptotic effects of tretinoin and arsenic trioxide. APL therapy first diverged from the therapy of other non-APL subtypes of AML with the addition of tretinoin to chemotherapy. With the incorporation of arsenic trioxide into modern treatment regimens, the use of traditional chemotherapy in adults is increasingly restricted to the induction phase for high-risk patients.[33,34]
Treatment options for children with APL may include the following:
Given the very high level of activity for the combination of arsenic trioxide and tretinoin for adults with APL,[33,34] and given data indicating that children with APL have a similar response to these agents,[35,36,37,38,39,40] children with APL are often treated using the adult treatment regimens.
For patients with high-risk disease, the approach begins with induction therapy using tretinoin given in combination with an anthracycline, administered with or without arsenic trioxide. For patients with standard-risk disease, induction can include tretinoin and arsenic trioxide without cytotoxic chemotherapy. Results from a completed cooperative group trial (COG AAML1331 [NCT02339740]) are pending and will provide additional data about the efficacy and toxicity of arsenic trioxide and tretinoin for children with newly diagnosed APL. The dramatic efficacy of tretinoin against APL results from the ability of pharmacologic doses of tretinoin to overcome the repression of signaling caused by the PML-RARA fusion protein at physiologic tretinoin concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis. Most patients with APL achieve a complete remission (CR) when treated with tretinoin, although single-agent tretinoin is generally not curative.[42,43]
A series of randomized clinical trials defined the benefit of combining tretinoin with chemotherapy during induction therapy and the utility of using tretinoin as maintenance therapy.[44,45,46] One regimen uses tretinoin in conjunction with standard-dose cytarabine and daunorubicin,[14,47] while another uses idarubicin and tretinoin without cytarabine for remission induction.[15,16] Almost all children with APL treated with one of these approaches achieves CR in the absence of coagulopathy-related mortality.[15,16,47,48,49]
Assessment of response to induction therapy in the first month of treatment using morphologic and molecular criteria may provide misleading results because delayed persistence of differentiating leukemia cells can occur in patients who will ultimately achieve CR.[2,3] Alterations in planned treatment based on these early observations are not appropriate because resistance of APL to tretinoin plus anthracycline-containing regimens is extremely rare.[20,50]
For patients with standard-risk APL, consolidation may include repeated cycles of tretinoin and arsenic trioxide without further chemotherapy, based on the adult experience.[33,34] However, for high-risk APL, consolidation therapy has typically included tretinoin given with an anthracycline with or without cytarabine. The role of cytarabine in consolidation therapy regimens is controversial. While a randomized study addressing the contribution of cytarabine to a daunorubicin-plus-tretinoin regimen in adults with low-risk APL showed a benefit for the addition of cytarabine, regimens using a high-dose anthracycline appear to produce as good as or better results in low-risk patients. For high-risk patients (WBC ≥10 × 109 /L), a historical comparison of the Programa para el Tratamiento de Hemopatías Malignas (PETHEMA) LPA 2005 (NCT00408278) trial with the preceding LPA 99 (NCT00465933) trial suggested that the addition of cytarabine to anthracycline-tretinoin combinations can lower the relapse rate. The results of the AIDA 2000 (NCT00180128) trial confirmed that the cumulative incidence of relapse for adult patients with high-risk disease can be reduced to approximately 10% with consolidation regimens that contain tretinoin, anthracyclines, and cytarabine. Studies using arsenic trioxide–based consolidation have demonstrated excellent survival without cytarabine consolidation.[26,33,53]
Maintenance therapy includes tretinoin plus mercaptopurine and methotrexate; this combination has shown conflicting benefit, with some randomized trials in adults with APL showing an advantage over tretinoin alone [44,54] and other studies showing no benefit.[33,55,56] However, the utility of maintenance therapy in APL may be dependent on multiple factors (e.g., risk group, the anthracycline used during induction, the use of arsenic trioxide, and the intensity of induction and consolidation therapy).
At this time, maintenance therapy remains standard for children with high-risk APL. Maintenance therapy is likely unnecessary for patients with standard-risk APL who are treated with tretinoin and arsenic trioxide, based on data from adult trials. Because of the favorable outcomes observed with chemotherapy plus tretinoin and arsenic trioxide (event-free survival [EFS] rates of 70%–90%), hematopoietic stem cell transplantation is not recommended in first CR.
Arsenic trioxide is the most active agent in the treatment of APL, and while initially used in relapsed APL, it is now incorporated into the treatment of newly diagnosed patients. Data supporting the use of arsenic trioxide initially came from trials that included adult patients only, but more recently, its efficacy has been seen in trials that included both pediatric and adult patients and pediatric patients alone.
Evidence (arsenic trioxide therapy):
Numerous trials showed that for children with APL, survival rates exceeding 80% are now achievable using treatment programs that prescribe the rapid initiation of tretinoin with appropriate supportive care measures;[2,14,15,16,19,20,48,49] a rate exceeding 90% was demonstrated in a single trial that added arsenic trioxide to the treatment regimen. For patients in CR for more than 5 years, relapse is extremely rare.[Level of evidence: 1iiDi]
Complications unique to APL therapy
In addition to the previously mentioned universal presence of coagulopathy in patients newly diagnosed with APL (further described below), several other unique complications occur in patients with APL for which the clinician should be aware. These include two tretinoin-related conditions, pseudotumor cerebri and differentiation syndrome (also called retinoic acid syndrome), and an arsenic trioxide–related complication, QT interval prolongation.
The incidence of pseudotumor cerebri has been reported to be as low as 1.7% with very strict definitions of the complication and as high as 6% to 16% in three pediatric trials.[14,15,28,63] Pseudotumor cerebri is thought to be more prevalent in children receiving tretinoin, leading to lower dosing in contemporary pediatric APL clinical trials. Pseudotumor cerebri most typically occurs during induction at a median of 15 days (range, 1–35 days) after starting tretinoin, but is known to occur in other phases of therapy as well. Pseudotumor cerebri incidence and severity may be exacerbated with the concurrent use of azoles via inhibition of cytochrome P450 metabolism of tretinoin.
When a diagnosis of pseudotumor cerebri is suspected, tretinoin is held until symptoms abate and then is slowly escalated to full dose as tolerated.
Because of the increased incidence in high-risk patients, dexamethasone is given with tretinoin and/or arsenic therapy to prevent this complication in this subset of patients. Prophylaxis with dexamethasone and hydroxyurea (for cytoreduction) is also administered to standard-risk patients if their WBC count rises to greater than 10,000/uL after the start of tretinoin or arsenic. If differentiation syndrome occurs, the dexamethasone dose may be escalated with temporary holding of tretinoin and arsenic trioxide and, similar to pseudotumor cerebri, restarted at a lower dose with plans to escalate as tolerated.
Minimal disease monitoring
The induction and consolidation therapies currently employed result in molecular remission, as measured by RT-PCR for PML-RARA, in most APL patients, with 1% or fewer showing molecular evidence of disease at the end of consolidation therapy.[20,50] While two negative RT-PCR assays after completion of therapy are associated with long-term remission, conversion from negative to positive RT-PCR is highly predictive of subsequent hematologic relapse.
Patients with persistent or relapsing disease on the basis of PML-RARA RT-PCR measurement may benefit from intervention with relapse therapies [72,73] (refer to the Treatment of Recurrent Acute Promyelocytic Leukemia [APL] subsection of the Recurrent or Refractory Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies section of this summary for more information).
Molecular Variants of APL Other Than PML-RARA and Therapeutic Impact
Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA.[74,75] Recognition of these rare variants is important because they differ in their sensitivity to tretinoin and to arsenic trioxide.
Treatment of Recurrent APL
Historically, 10% to 20% of patients with APL relapse; however, more current studies that incorporated arsenic trioxide therapy showed cumulative incidence of relapse of less than 5%.[28,34]
In patients who initially received chemotherapy-based treatments, the duration of first remission is prognostic in APL, with patients who relapse within 12 to 18 months of initial diagnosis having a worse outcome.[84,85,86]
An important issue in children who relapse is the previous exposure to anthracyclines, which can range from 400 mg/m2 to 750 mg/m2. Thus, regimens containing anthracyclines are often not optimal for children with APL who suffer relapse.
Treatment options for children with recurrent APL may include the following:
For children with recurrent APL, the use of arsenic trioxide as a single agent or in regimens including tretinoin should be considered, depending on the therapy given during first remission. Arsenic trioxide is an active agent in patients with recurrent APL, with approximately 85% of patients achieving remission after treatment with this agent.[55,57,87,88,89] Arsenic trioxide is even capable of inducing remissions in patients who relapse after having received arsenic trioxide during initial therapy. APL cells, however, may become resistant to arsenic trioxide through mechanisms including mutation of the PML domain of the PML-RARA fusion oncogene.
For adults with relapsed APL, approximately 85% achieve morphologic remission after treatment with arsenic trioxide.[88,89,92] Data are limited on the use of arsenic trioxide in children, although published reports suggest that children with relapsed APL have a response to arsenic trioxide similar to that of adults.[87,89,93] Arsenic trioxide is well tolerated in children with relapsed APL. The toxicity profile and response rates in children are similar to that observed in adults.
Because arsenic trioxide causes QT-interval prolongation that can lead to life-threatening arrhythmias, it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.
The use of gemtuzumab ozogamicin, an anti-CD33/calicheamicin monoclonal antibody, as a single agent resulted in a 91% (9 of 11 patients) molecular remission after two doses and a 100% (13 of 13 patients) molecular remission after three doses, thus, demonstrating excellent activity of this agent in patients with relapsed APL.
Retrospective pediatric studies have reported 5-year EFS rates after either autologous or allogeneic transplantation approaches to be similar, at approximately 70%.[95,96]
Evidence (autologous HSCT):
Such data support the use of autologous transplantation in patients who are MRD negative in second CR who have poorly matched allogeneic donors.
Because of the rarity of APL in children and the favorable outcome for this disease, clinical trials in relapsed APL to compare treatment approaches are likely not feasible. However, an international expert panel provided recommendations for the treatment of relapsed APL on the basis of the reported pediatric and adult experience.
Myeloid leukemias that arise in children with Down syndrome, particularly in patients younger than 4 years, are a distinct subset of AML characterized by the co-existence of trisomy 21 and GATA1 mutations within the leukemic blasts that are often, but not always, megakaryoblastic. This distinct leukemia is further subdivided into two versions: a transient newborn and young-infant version called transient abnormal myelopoiesis (TAM), which spontaneously remits over time; and an unremitting but chemosensitive version that appears later, between the ages of 90 days and 3 years. It is important to recognize the possibility of these versions in both children with Down syndrome phenotypes and in those who have mosaic trisomy 21, which can be solely present in the leukemic blasts. If possible, newborns with apparent AML should not have therapy initiated until genetic testing results have been returned. In older children with megakaryocytic AML, it is important to rule out the presence of co-existing trisomy 21 and GATA1 mutations; these children may be successfully treated on the lower-intensity chemotherapy regimens that are used for children with myeloid leukemia associated with Down syndrome.
Transient Abnormal Myelopoiesis (TAM) Associated With Down Syndrome
Approximately 10% of neonates with Down syndrome develop a TAM (also termed transient myeloproliferative disorder [TMD]). This disorder mimics congenital AML but typically improves spontaneously within the first 3 months of life (median, 49 days), although TAM has been reported to remit as late as 20 months. The late remissions likely reflect a persistent hepatomegaly from TAM-associated hepatic fibrosis rather than active disease.
Although TAM is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 17% of affected infants.[4,5,6,7,8] Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37 weeks of gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), renal failure, and very high white blood cell (WBC) count are at particularly high risk of early mortality.[5,6,8] Death has been reported to occur in 21% of these patients with high-risk TAM, although only 10% were attributable to TAM and the remaining deaths were caused by coexisting conditions known to be more prominent in neonates with Down syndrome.
The following three risk groups have been identified on the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms:
Therapeutic intervention is warranted in patients with apparent severe hydrops or organ failure. Because TAM eventually spontaneously remits, treatment is short in duration and primarily aimed at the reduction of leukemic burden and resolution of immediate symptoms. Several treatment approaches have been used, including the following:
Subsequent development of myeloid leukemia associated with Down syndrome is seen in 10% to 30% of children who have a spontaneous remission of TAM and has been reported at a mean age of 16 months (range, 1–30 months).[4,5,10] While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk of developing subsequent myeloid leukemia associated with Down syndrome. An additional risk factor reported in two studies is the late resolution of TAM, measured by either time to complete resolution of signs of TAM (defined as resolution beyond the median, 47 days from diagnosis) or by persistence of minimal residual disease (MRD) in the peripheral blood at week 12 of follow-up.; [Level of evidence: 2Di] The use of cytarabine for TAM symptoms or persistent MRD in TAM has failed to show a reduction in later myeloid leukemia associated with Down syndrome, as reported in large observational cohort studies.[5,8] In a prospective single-arm trial designed to assess whether cytarabine treatment for TAM could prevent the development of later myeloid leukemia associated with Down syndrome, no benefit was found when compared with historical controls (19% ± 4% vs. 22% ± 4%, respectively; P = .88).[Level of evidence: 2Di]
Myeloid Leukemia Associated With Down Syndrome
Children with Down syndrome have a tenfold to twentyfold increased risk of leukemia compared with children without Down syndrome; however, the ratio of acute lymphoblastic leukemia to acute myeloid leukemia (AML) is typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML, particularly the megakaryoblastic subtype, predominates and exhibits a distinctive biology characterized by GATA1 mutations and increased sensitivity to cytarabine.[11,12,13,14,15,16] Importantly, these risks appear to be similar whether a child has phenotypic characteristics of Down syndrome or whether a child has only genetic bone marrow mosaicism.
Prognosis and Treatment of Children With Down Syndrome and AML
Outcome is generally favorable for children with Down syndrome who develop AML (called myeloid leukemia associated with Down syndrome in the World Health Organization classification).[18,19,20]
Prognostic factors for children with Down syndrome and AML include the following:
Approximately 29% to 47% of Down syndrome patients present with myelodysplastic syndromes (MDS) (<20% blasts) but their outcomes are similar to those with AML.[19,20,22]
Treatment options for newly diagnosed children with Down syndrome and AML include the following:
Appropriate therapy for younger children (aged ≤4 years) with Down syndrome and AML is less intensive than current standard childhood AML therapy. Hematopoietic stem cell transplant is not indicated in first remission.[10,13,18,19,20,21,22,23,25]
The following two prognostic factors were identified:
Children with mosaicism for trisomy 21 are treated similarly to those children with clinically evident Down syndrome.[5,17,19] Although an optimal treatment for these children has not been defined, they are usually treated on AML regimens designed for children without Down syndrome.
Refractory Disease or Relapse in Children With Down Syndrome
A small number of publications address outcomes in children with Down syndrome who relapse after initial therapy or who have refractory AML. All of these retrospective analyses with varying approaches to therapy found that for these children who relapse or have refractory outcomes, the outlook is poor. Thus, these children are treated similarly to children without Down syndrome, with an intensive reinduction chemotherapy regimen, and if a remission is achieved, therapy is followed by an allogeneic hematopoietic stem cell transplantation (HSCT).
Treatment options for children with Down syndrome with refractory or relapsed AML include the following:
Evidence (treatment of children with Down syndrome with refractory or relapsed AML):
The myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) represent between 5% and 10% of all myeloid malignancies in children. They are a heterogeneous group of disorders, with MDS usually presenting with cytopenias and MPS presenting with increased peripheral white blood cell, red blood cell, or platelet counts. MDS is characterized by ineffective hematopoiesis and increased cell death, while MPS is associated with increased progenitor proliferation and survival. Because they both represent disorders of very primitive, multipotential hematopoietic stem cells, curative therapeutic approaches nearly always require allogeneic hematopoietic stem cell transplantation (HSCT).
Patients with the following germline mutations or inherited disorders have a significantly increased risk of developing MDS:
A retrospective analysis that used a capture assay to target mutations known to predispose to marrow failure and MDS was performed on genomic DNA from peripheral blood mononuclear cell samples from patients undergoing HSCT for MDS and aplastic anemia. Among the 46 children aged 18 years and younger with MDS, 10 patients (22%) harbored constitutional predisposition genetic mutations (5 GATA2, 1 each of MPL, RTEL1, SBDS, TINF2, and TP53), of which only 2 were suspected before transplant. This is considered a high incidence of genetic mutations compared with only 8% (4 of 64) in patients aged 18 to 40 years.
Patients usually present with signs of cytopenias, including pallor, infection, or bruising.
The bone marrow is usually characterized by hypercellularity and dysplastic changes in myeloid precursors. Clonal evolution can eventually lead to the development of AML. The percentage of abnormal blasts is less than 20% and lack common AML recurrent cytogenetic abnormalities (t(8;21), inv(16), t(15;17), or KMT2A translocations).
The less common hypocellular MDS can be distinguished from aplastic anemia in part by its marked dysplasia, clonal nature, and higher percentage of CD34-positive precursors.[18,19]
Molecular features of myelodysplastic syndromes (MDS)
Pediatric MDS are associated with a distinctive constellation of genetic alterations compared with MDS arising in adults. In adults, MDS often evolves from clonal hematopoiesis and is characterized by mutations in TET2, DNMT3A, and TP53. In contrast, mutations in these genes are rare in pediatric MDS, while mutations in GATA2, SAMD9/SAMD9L, SETBP1, ASXL1, and RAS/MAPK pathway genes are observed in subsets of pediatric MDS cases.[11,20]
A report of the genomic landscape of pediatric MDS described the results of whole-exome sequencing for 32 pediatric patients with primary MDS and targeted sequencing for another 14 cases. These 46 cases were equally divided between refractory cytopenia of childhood and MDS with excess blasts (MDS-EB). The results from the report include the following:
A second report described the application of a targeted sequencing panel of 105 genes to 50 pediatric patients with MDS (refractory cytopenia of childhood = 31 and MDS-EB = 19) and was enriched for cases with monosomy 7 (48%).[11,20]SAMD9 and SAMD9L were not included in the gene panel. The second report described the following results:
Patients with germline GATA2 mutations, in addition to MDS, show a wide range of hematopoietic and immune defects as well as nonhematopoietic manifestations. The former defects include monocytopenia with susceptibility to atypical mycobacterial infection and DCML deficiency (loss of dendritic cells, monocytes, and B and natural killer lymphoid cells). The resulting immunodeficiency leads to increased susceptibility to warts, severe viral infections, mycobacterial infections, fungal infections, and human papillomavirus–related cancers. The nonhematopoietic manifestations include deafness and lymphedema. Germline GATA2 mutations were studied in 426 pediatric patients with primary MDS and 82 cases with secondary MDS who were enrolled in consecutive studies of the European Working Group of MDS in Childhood (EWOG-MDS). The study had the following results:
SAMD9 and SAMD9L germline mutations are both associated with pediatric MDS cases in which there is an additional loss of all or part of chromosome 7.[12,13] In 2016, SAMD9 was identified as the cause of the MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy), which is associated with early-onset MDS with monosomy 7. Subsequently, mutations in SAMD9L were identified in patients with ataxia pancytopenia syndrome (ATXPC; OMIM 159550). SAMD9 and SAMD9L mutations were also identified as the cause of myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270), a syndrome first identified in phenotypically normal siblings who developed MDS or AML associated with monosomy 7 during childhood.
(Refer to the WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes section of this summary for more information about the WHO classification of MDS.)
Classification of MDS
The French-American-British (FAB) and World Health Organization (WHO) classification systems of MDS and MPS have been difficult to apply to pediatric patients. Alternative classification systems for children have been proposed, but none have been uniformly adopted, with the exception of the modified 2008 WHO classification system.[24,25,26,27,28] The WHO system  has been modified for pediatrics. Refer to Table 3 and Table 4 for the WHO classification schema and diagnostic criteria. The 2016 revision to the WHO MDS classification did not affect classification in children.
The refractory cytopenia subtype represents approximately 50% of all childhood cases of MDS. The presence of an isolated monosomy 7 is the most common cytogenetic abnormality, although it does not appear to portend a poor prognosis compared with its presence in overt AML. However, the presence of monosomy 7 in combination with other cytogenetic abnormalities is associated with a poor prognosis.[31,32] The relatively common abnormalities of -Y, 20q-, and 5q- in adults with MDS are rare in childhood MDS. The presence of cytogenetic abnormalities that are found in AML (t(8;21)(q22;q22.1), inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), and APL with PML-RARA) defines disease that should be treated as AML and not MDS, regardless of blast percentage. The WHO notes that whether this should also apply to other recurring genetic abnormalities remains controversial.
The International Prognostic Scoring System can help to distinguish low-risk from high-risk MDS, although its utility in children with MDS is more limited than in adults because many characteristics differ between children and adults.[34,35] The median survival for children with high-risk MDS remains substantially better than adults, and the presence of monosomy 7 in children has not had the same adverse prognostic impact as does the presence in adults with MDS.
Treatment of Childhood MDS
Treatment options for children with MDS include the following:
MDS and associated disorders usually involve a primitive hematopoietic stem cell. Thus, allogeneic HSCT is considered to be the optimal approach to treatment for pediatric patients with MDS. Although matched sibling transplantation is preferred, similar survival has been noted with well-matched, unrelated cord blood and haploidentical approaches.[37,38,39,40,41]
When making treatment decisions, some data should be considered. For example, survival as high as 80% has been reported for patients with early-stage MDS who proceeded to transplant within a few months of diagnosis. Additionally, early transplant and not receiving pretransplant chemotherapy have been associated with improved survival in children with MDS.[Level of evidence: 3iiA] Disease-free survival (DFS) rates have been estimated to be between 50% to 70% for pediatric patients with advanced MDS using myeloablative transplant preparative regimens.[40,43,44,45,46] While nonmyeloablative preparative transplant regimens are being tested in patients with MDS and AML, such regimens are still investigational for children with these disorders, but may be reasonable in the setting of a clinical trial or when a patient's organ function is compromised in such a way that they would not tolerate a myeloablative regimen.[47,48,49,50]; [Level of evidence: 3iiiA]
The question of whether chemotherapy should be used in high-risk MDS has been examined.
When analyzing these results, it is important to consider that the subtype refractory anemia with excess blasts in transformation is likely to represent patients with overt AML, while refractory anemia and refractory anemia with excess blasts represents MDS. The WHO classification has now omitted the category of refractory anemia with excess blasts in transformation, concluding that this entity was essentially AML.
Because survival after HSCT is improved in children with early forms of MDS (refractory anemia), transplantation before progression to late MDS or AML should be considered. HSCT should especially be considered when transfusions or other treatment are required, as is usually the case in patients with severe symptomatic cytopenias.[40,46] The 8-year disease-free survival (DFS) rates for children with various stages of MDS has been reported to be 65% for those treated with HLA matched donor transplants and 40% for those treated with mismatched unrelated donor transplants.[Level of evidence: 3iiiDii] A 3-year DFS rate of 50% was reported with the use of unrelated cord blood donor transplants for children with MDS, when the transplants were done after the year 2001.[Level of evidence: 3iiiDiii]
Because MDS in children is often associated with inherited predisposition syndromes, reports of transplantation in small numbers of patients with these disorders have been documented. For example, in patients with Fanconi anemia and AML or advanced MDS, the 5-year overall survival (OS) rate has been reported to be 33% to 55%.[55,56][Level of evidence: 3iiiA] Second transplants have also been used in pediatric patients with MDS/MPD who relapse or suffer graft failure. The 3-year OS rates were 33% for those retransplanted after relapse and 57% for those transplanted after initial graft failure.[Level of evidence: 3iiiA]
For patients with clinically significant cytopenias, supportive care that includes transfusions and prophylactic antibiotics are considered standard of care. The use of hematopoietic growth factors can improve the hematopoietic status, but concerns remain that such treatment could accelerate conversion to AML.
Other supportive therapies that have been studied include the following:
Treatment Options Under Clinical Evaluation
The development of acute myeloid leukemia (AML) or myelodysplastic syndromes (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.[1,2,3,4]
The risk of t-AML or t-MDS is regimen-dependent and often related to the cumulative doses of chemotherapy agents received and the dose and field of radiation administered. 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 epipodophyllotoxins and other topoisomerase II inhibitors (e.g., anthracyclines) usually occur within 2 years of exposure and are commonly associated with chromosome 11q23 abnormalities, although other subtypes of AML (e.g., acute promyelocytic leukemia) have 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 of t-AML or t-MDS
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:
Accordingly, CR rates and overall survival (OS) rates are usually lower for patients with t-AML compared with patients with de novo AML.[10,11,12] Also, survival for pediatric patients with t-MDS is worse than survival for pediatric patients with MDS not related to previous therapy.
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.
Juvenile myelomonocytic leukemia (JMML) is a rare leukemia that occurs approximately ten times less frequently than acute myeloid leukemia (AML) in children, with an annual incidence of about 1 to 2 cases per 1 million people. JMML typically presents in young children (median age, approximately 1.8 years) and occurs more commonly in boys (male to female ratio, approximately 2.5:1).
Clinical Presentation and Diagnostic Criteria
Common clinical features at diagnosis include the following:
In children presenting with clinical features suggestive of JMML, current criteria used for a definitive diagnosis are described in Table 8.
Pathogenesis and Related Syndromes
The pathogenesis of JMML has been closely linked to activation of the RAS oncogene pathway, along with related syndromes (refer to Figure 1).[4,5] In addition, distinctive RNA expression and DNA methylation patterns have been reported; they are correlated with clinical factors such as age and appear to be associated with prognosis.[6,7]
Figure 1. Schematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and the gene mutations found to date contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML. NL/MGCL: Noonan-like/multiple giant cell lesion; CFC: cardia-facio-cutaneous; JMML: juvenile myelomonocytic leukemia. Reprinted from Leukemia Research, 33 (3), Rebecca J. Chan, Todd Cooper, Christian P. Kratz, Brian Weiss, Mignon L. Loh, Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium, Pages 355-62, Copyright 2009, with permission from Elsevier.
Children with neurofibromatosis type 1 (NF1) and Noonan syndrome are at increased risk of developing JMML:[8,9]
Importantly, some children with Noonan syndrome have a hematologic picture indistinguishable from JMML that self-resolves during infancy, similar to what happens in children with Down syndrome and transient myeloproliferative disorder.[5,12]
Within a large prospective cohort of 641 patients with Noonan syndrome and a germline PTPN11 mutation, 36 patients (approximately 6%) showed myeloproliferative features, with 20 patients (approximately 3%) meeting the consensus diagnostic criteria for JMML. Of the 20 patients meeting the criteria for JMML, 12 patients had severe neonatal manifestations (e.g., life-threatening complications related to congenital heart defects, pleural effusion, leukemia infiltrates, and/or thrombocytopenia), and 10 of 20 patients died during the first month of life. Among the remaining eight patients, none required intensive therapy at diagnosis or during follow-up. All 16 patients with myeloproliferative features not meeting JMML criteria were alive, with a median follow-up of 3 years, and none of the patients received chemotherapy.
Mutations in the CBL gene, an E3 ubiquitin-protein ligase that is involved in targeting proteins, particularly tyrosine kinases, for proteasomal degradation occur in 10% to 15% of JMML cases,[13,14] with many of these cases occurring in children with germline CBL mutations.[15,16]CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML. Some individuals with CBL germline mutations experience spontaneous regression of their JMML but develop vasculitis later in life.CBL mutations are nearly always mutually exclusive of RAS and PTPN11 mutations.
Genomics of JMML
Molecular features of JMML
The genomic landscape of JMML is characterized by mutations in one of five genes of the RAS pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[17,18,19] In a series of 118 consecutively diagnosed JMML cases with RAS pathway–activating mutations, PTPN11 was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 2). Patients with mutated NRAS accounted for 19% of cases, and patients with mutated KRAS accounted for 15% of cases. NF1 mutations accounted for 8% of cases, and CBL mutations accounted for 11% of cases. Although mutations among these five genes are generally mutually exclusive, 4% to 17% of cases have mutations in two of these RAS pathway genes,[17,18,19] a finding that is associated with poorer prognosis.[17,19]
The mutation rate in JMML leukemia cells is very low, but additional mutations beyond those of the five RAS pathway genes described above are observed.[17,18,19] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was mutated in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also mutated at low rates in JMML (e.g., SETBP1 was mutated in 6%–9% of cases).[17,18,19,20]JAK3 mutations are also observed in a small percentage (4%–12%) of JMML cases.[17,18,19,20] Cases with germline PTPN11 and germline CBL mutations showed low rates of additional mutations (refer to Figure 2). The presence of mutations beyond disease-defining RAS pathway mutations is associated with an inferior prognosis.[17,18]
A report describing the genomic landscape of JMML found that 16 of 150 patients (11%) lacked canonical RAS pathway mutations. Among these 16 patients, 3 were observed to have in-frame fusions involving receptor tyrosine kinases (DCTN1-ALK, RANBP2-ALK, and TBL1XR1-ROS1). These patients all had monosomy 7 and were aged 56 months or older. One patient with an ALK fusion was treated with crizotinib plus conventional chemotherapy and achieved a complete molecular remission and proceeded to allogeneic bone marrow transplantation.
Figure 2. Alteration profiles in individual JMML cases. Germline and somatically acquired alterations with recurring hits in the RAS pathway and PRC2 network are shown for 118 patients with JMML who underwent detailed genetic analysis. Blast excess was defined as a blast count ≥10% but <20% of nucleated cells in the bone marrow at diagnosis. Blast crisis was defined as a blast count ≥20% of nucleated cells in the bone marrow. NS, Noonan syndrome. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 : 1334-40, 2015), copyright (2015).
Prognosis (genomic and molecular factors)
Several genomic factors affect the prognosis of patients with JMML, including the following:
Prognosis (Clinical Factors)
Age, platelet count, and fetal hemoglobin level after any treatment. Historically, more than 90% of patients with JMML died despite the use of chemotherapy; however, with the application of hematopoietic stem cell transplantation (HSCT), survival rates of approximately 50% are now observed. Patients appeared to follow three distinct clinical courses:
Favorable prognostic factors for survival after any therapy include age younger than 2 years, platelet count greater than 33 × 109 /L, and low age-adjusted fetal hemoglobin levels.[1,2] In contrast, being older than 2 years and having high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[1,2]
Treatment of JMML
Treatment options for JMML include the following:
The role of conventional antileukemia therapy in the treatment of JMML is not defined. Determining the role of specific agents in the treatment of JMML is complicated because of the absence of consensus response criteria. Some agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and mercaptopurine), isotretinoin, and farnesyl inhibitors, but none of these have been shown to improve outcome.[25,26,27,28,29]; [Level of evidence: 2B]
HSCT currently offers the best chance of cure for JMML.[24,31,32,33,34]
Disease recurrence is the primary cause of treatment failure for children with JMML after HSCT and occurs in 30% to 40% of cases.[24,31,32] While the role of donor lymphocyte infusions is uncertain, reports indicate that approximately 50% of patients with relapsed JMML can be successfully treated with a second HSCT.
Chronic myelogenous leukemia (CML) accounts for less than 5% of all childhood leukemia, and in the pediatric age range, occurs most commonly in older adolescents.
The cytogenetic abnormality most characteristic of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t(9;22)) resulting in a BCR-ABL1 fusion protein.
CML is characterized by a marked leukocytosis and is often associated with thrombocytosis, sometimes with abnormal platelet function. Bone marrow aspiration or biopsy reveals hypercellularity with relatively normal granulocytic maturation and no significant increase in leukemic blasts. Although reduced leukocyte alkaline phosphatase activity is seen in CML, this is not a specific finding.
CML has the following three clinical phases:
Treatment of CML: Historical Perspective
Before the tyrosine kinase inhibitor (TKI) era, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary treatment for children with CML. Published reports from this period described survival rates of 70% to 80% when an HLA–matched-family donor (MFD) was used in the treatment of children in early chronic phase, with lower survival rates when HLA–matched-unrelated donors were used.[4,5,6]
Relapse rates were low (less than 20%) when transplant was performed in chronic phase.[4,5] The primary cause of death was treatment-related mortality, which was increased with HLA–matched-unrelated donors compared with HLA-MFDs in most reports.[4,5] High-resolution DNA matching for HLA alleles appeared to reduce rates of treatment-related mortality, leading to improved outcome for HSCT using unrelated donors.
Compared with transplantation in chronic phase, transplantation in accelerated phase or blast crisis and in second-chronic phase resulted in significantly reduced survival.[4,5,6] The use of T-lymphocyte depletion to avoid graft-versus-host disease resulted in a higher relapse rate and decreased overall survival (OS), supporting the contribution of a graft-versus-leukemia effect to favorable outcome after allogeneic HSCT.
The introduction of the TKI imatinib as a therapeutic drug targeted at inhibiting the BCR-ABL1 fusion kinase revolutionized the treatment of patients with CML, for both children and adults. As most data on the use of TKIs for CML is from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience in children.
Treatment of Adult CML With TKIs
Imatinib is a potent inhibitor of the ABL1 tyrosine kinase, platelet-derived growth factor (PDGF) receptors (alpha and beta), and KIT. Imatinib treatment achieves clinical, cytogenetic, and molecular remissions (as defined by the absence of BCR-ABL1 fusion transcripts) in a high proportion of CML patients treated in chronic phase.
Evidence (imatinib for adults):
Guidelines for imatinib treatment have been developed for adults with CML on the basis of patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in BCR-ABL1/control gene ratio).[13,14,15,16]
Poor adherence is a major reason for loss of complete cytogenetic response and imatinib failure for adult patients with CML on long-term therapy. The identification of BCR-ABL1 kinase domain mutations at the time of failure or of suboptimal response to imatinib treatment also has clinical implications, because there are alternative BCR-ABL1 kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib.[13,19,20]
Two TKIs, dasatinib and nilotinib, have been shown to be effective in patients who have an inadequate response to imatinib, although not in patients with the T315I mutation. Both dasatinib and nilotinib have also received regulatory approval for the treatment of newly diagnosed chronic-phase CML in adults, on the basis of the following studies:
Because of the superiority over imatinib in terms of complete cytogenetic response rate and major molecular response rate, both dasatinib and nilotinib are extensively used as first-line therapy in adults with CML. However, despite more rapid responses with dasatinib and nilotinib than with imatinib when used as frontline therapy, PFS and OS appear to be similar for all three agents.[23,24] Additional follow-up will be required to better define the impact of these agents on long-term PFS and OS.
Bosutinib is another TKI that targets the BCR-ABL1 fusion and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of all phases of CML in adults who show intolerance to or whose disease shows resistance to previous therapy with another TKI. Bosutinib has not been studied in the pediatric population.
Ponatinib is a BCR-ABL1 inhibitor that is effective against the T315I mutation. Ponatinib induced objective responses in approximately 70% of heavily pretreated adults with chronic-phase CML, with responses observed regardless of the baseline BCR-ABL1 kinase domain mutation. Development of ponatinib has been complicated by the high rate of vascular occlusion observed in patients receiving the agent, with arterial and venous thrombosis and occlusions (including myocardial infarction and stroke) occurring in more than 20% of treated patients. Ponatinib has not been prospectively studied in the pediatric population.
For adult patients with CML who proceed to allogeneic HSCT, there is no evidence that pretransplant imatinib adversely impacts outcome.
Evidence (imatinib followed by HSCT in adults):
For adult patients treated with a TKI alone (without HSCT), the optimal duration of therapy remains unknown and most patients continue TKI treatment indefinitely. Studies are ongoing to determine the safety of discontinuing TKI therapy and the criteria most prognostic of sustained remissions after ending TKI therapy.
Evidence (length of imatinib therapy in adults):
Additional research is required before cessation of imatinib or other BCR-ABL1 targeted therapy for selected patients with CML in molecular remission can be recommended as a standard clinical practice.
Treatment of Childhood CML
Treatment options for children with CML may include the following:
Imatinib has shown a high level of activity in children with CML that is comparable with the activity observed in adults.[32,33,34,35,36]
Evidence (imatinib in children):
As a result of this high level of activity, it is common to initiate imatinib treatment in children with CML rather than proceeding immediately to allogeneic stem cell transplantation. The pharmacokinetics of imatinib in children appears consistent with previous results in adults.
Doses of imatinib used in phase II trials for children with CML have ranged from 260 mg/m2 to 340 mg/m2, which provide comparable drug exposures as the adult flat-doses of 400 mg to 600 mg.[34,35,36]
Evidence (imatinib dose in children):
Thus, it appears that starting with the higher dose of 340 mg/m2 has superior efficacy and is typically tolerable, with dose adjustment as needed for toxicity.[35,36]
The monitoring guidelines described above for adults with CML are reasonable to use in children.
Imatinib is generally well tolerated in children, with adverse effects generally being mild to moderate and reversible with treatment discontinuation or dose reduction.[34,35] Growth retardation occurs in most prepubertal children receiving imatinib. Children receiving imatinib and experiencing growth impairment may show some catch-up growth during their pubertal growth spurts, but they are at risk of having lower-than-expected adult height, as most patients do not achieve midparental height.[40,41]
There are fewer published data regarding the efficacy and toxicities of the two other TKIs approved by the FDA for use in children with CML—dasatinib and nilotinib.
Evidence (dasatinib in children):
Evidence (nilotinib in children):
An initial study (NCT01077544 [CAMN107A2120]) of 11 patients evaluated pharmacokinetic, safety, and preliminary efficacy data; a second study (NCT01844765 [CAMN107A2203; AAML1321]) of 58 patients evaluated efficacy and safety. Data from both studies were combined for a pooled-data analysis of 69 patients, which included 25 patients with newly diagnosed CML and 44 patients with resistant or intolerant CML. Both studies utilized a dose of 230 mg/m2 given twice daily (rounded to the nearest 50 mg; maximum dose, 400 mg).
A safe pediatric dose has not yet been established for other TKIs (e.g., bosutinib and ponatinib).
Treatment Options under Clinical Evaluation
Treatment of Recurrent or Refractory Childhood CML
Treatment options for children with recurrent or refractory CML may include the following:
In children who develop a hematologic or cytogenetic relapse during treatment with imatinib or who have an inadequate initial response to imatinib, determination of BCR-ABL1 kinase domain mutation status should be considered to help guide subsequent therapy. Depending on the patient's mutation status, alternative kinase inhibitors such as dasatinib or nilotinib can be considered on the basis of the adult and pediatric experience with these agents.[21,22,44,47,48,49]
Evidence (dasatinib in children with resistant or intolerant CML):
Evidence (nilotinib in children with resistant or intolerant CML):
Dasatinib and nilotinib are active against many BCR-ABL1 mutations that confer resistance to imatinib, although the agents are ineffective in patients with the T315I mutation. In the presence of the T315I mutation, which is resistant to all FDA-approved kinase inhibitors, an allogeneic transplant should be considered. Ponatinib, the BCR-ABL1 inhibitor effective against the T315I mutation in adults, has not been prospectively studied in the pediatric population.
The question of whether a pediatric patient with CML should receive an allogeneic transplant when multiple TKIs are available remains unanswered; however, reports suggest that PFS does not improve when using HSCT, compared with the sustained use of imatinib. The potential advantages and disadvantages need to be discussed with the patient and family. While HSCT is currently the only known definitive curative therapy for CML, patients discontinuing treatment with TKIs after sustained molecular remissions, who remained in molecular remission, have been reported.
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
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. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Selected studies of the late effects of 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 have been reported to be rare for children undergoing chemotherapy only for treatment of AML.
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.
Treatment of Childhood Acute Myeloid Leukemia (AML)
Revised text to state that in the Children's Oncology Group AAML0531 trial, 8.6% of enrolled patients experienced left ventricular systolic dysfunction (LVSD) during protocol therapy, with a cumulative incidence of LVSD of 12% within 5 years of completing therapy.
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® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia and other myeloid malignancies. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
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Levels of Evidence
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies 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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