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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.
Fortunately, 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 primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order 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/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 Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For acute myeloid leukemia, the 5-year survival rate has increased over the same time from less than 20% to 58% for children younger than 15 years and from less than 20% to approximately 40% for adolescents aged 15 to 19 years. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Myeloid Leukemias in Children
Approximately 20% of childhood leukemias are of myeloid origin and they represent a spectrum of hematopoietic malignancies. The majority of myeloid leukemias are acute and the remainder include chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia (CML) and juvenile myelomonocytic leukemia (JMML), as well as myelodysplastic syndromes.
Acute myeloid leukemia (AML) is defined as a clonal disorder caused by malignant transformation of a bone marrow-derived, self-renewing stem cell or progenitor, which demonstrates a decreased rate of self-destruction as well as aberrant differentiation. These events lead to increased accumulation in the bone marrow and other organs by these malignant myeloid cells. To be called acute, the bone marrow usually must include greater than 20% leukemic blasts, with some exceptions as noted in subsequent sections.
CML represents the most common of the chronic myeloproliferative disorders in childhood, although it accounts for only 10% to 15% of childhood myeloid leukemia. Although CML has been diagnosed in very young children, most patients are aged 6 years and older. CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the white blood cell (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 nearly always characterized 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 ABL genes. Other chronic myeloproliferative syndromes, such as polycythemia vera and essential thrombocytosis, are extremely rare in children.
JMML represents the most common myeloproliferative syndrome observed in young children. JMML occurs at a median age of 1.8 years and characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated 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).[4,5]
The transient myeloproliferative disorder (TMD) (also termed transient leukemia) observed in infants with Down syndrome represents a clonal expansion of myeloblasts that can be difficult to distinguish from AML. Most importantly, TMD spontaneously regresses in most cases within the first 3 months of life. TMD blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the GATA1 gene.[6,7] TMD may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TMD is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk for developing subsequent AML. Approximately 20% of infants with Down syndrome and TMD eventually develop AML, with most cases diagnosed within the first 3 years of life.[7,8] Early death from TMD-related complications occurs in 10% to 20% of affected children.[8,9] Infants with progressive organomegaly, visceral effusions, and laboratory evidence of progressive liver dysfunction are at a particularly high risk for early mortality.
The myelodysplastic syndromes in children represent a heterogeneous group of disorders characterized by ineffective hematopoiesis, impaired maturation of myeloid progenitors with dysplastic morphologic features, and cytopenias. Although the majority of patients have normocellular or hypercellular bone marrows without increased numbers of leukemic blasts, some patients may present with a very hypocellular bone marrow, making the distinction between severe aplastic anemia and low-blast count AML difficult.
There are genetic risks associated with the development of AML. There is a high concordance rate of AML in identical twins, which is believed to be in large part a result of shared circulation and the inability of one twin to reject leukemic cells from the other twin during fetal development.[10,11,12] There is an estimated twofold to fourfold risk of fraternal twins both developing leukemia up to about age 6 years, after which the risk is not significantly greater than that of the general population.[13,14] The development of AML has also been associated with a variety of predisposition syndromes that result from chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, as well as altered protein synthesis. (Refer to the following list of inherited and acquired genetic syndromes associated with myeloid malignancies.)
Inherited and Acquired Genetic Syndromes Associated with Myeloid Malignancies
French-American-British (FAB) Classification for Childhood Acute Myeloid Leukemia
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 categorizes AML into the following major subtypes primarily based on morphology and immunohistochemical detection of lineage markers:
Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.
Fifty percent to 60% of children with AML can be classified as having M1, M2, M3, M6, or M7 subtypes; approximately 40% have M4 or M5 subtypes. About 80% of children younger than 2 years with AML have an M4 or M5 subtype. The response to cytotoxic chemotherapy among children with the different subtypes of AML is relatively similar. One exception is FAB subtype M3, for which all-trans retinoic acid plus chemotherapy achieves remission and cure in approximately 70% to 80% of affected children.
World Health Organization (WHO) Classification System
In 2002, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17), and those with 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 AML.[9,10,11] In 2008, WHO expanded the number of cytogenetic abnormalities linked to AML classification, and for the first time included specific gene mutations (CEBPA and NPM mutations) in its classification system. (Refer to the WHO classification of myeloid leukemias section of this summary for more information.) Such a genetically based classification system links AML class with outcome and provides significant biologic and prognostic information. With new emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will likely evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.
WHO classification of AML
The treatment for children with AML differs significantly from that for ALL. As a consequence, it is crucial 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 (PAS), Sudan Black B, and esterase. In most cases the staining pattern with these histochemical stains will distinguish AML from AMML and ALL (see below). This approach is being replaced by immunophenotyping using flow cytometry.
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 bilineal (as defined above) or biphenotypic leukemias. 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 AMLs, 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 AMLs.[13,14,15] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[13,14]
Immunophenotyping can also be helpful in distinguishing some FAB subtypes of AML. Testing for the presence of HLA-DR can be helpful in identifying APL. Overall, HLA-DR is expressed on 75% to 80% of AMLs but rarely expressed on APL. In addition, APL cases with PML/RARA were noted to express CD34/CD15 and demonstrate a heterogenous pattern of CD13 expression. Testing for the presence of glycoprotein Ib, glycoprotein IIb/IIIa, or Factor VIII antigen expression is helpful in making the diagnosis of M7 (megakaryocytic leukemia). Glycophorin expression is helpful in making the diagnosis of M6 (erythroid leukemia).
Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[18,19,20] These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies, although most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[21,22,23] In the WHO classification, the presence of MPO is required to establish myeloid lineage. This is not the case for the EGIL classification.
The WHO classification system is summarized in Table 2.[23,24]
Leukemias of mixed phenotype comprise two groups of patients: (1) bilineal leukemias in which there are two distinct population of cells, usually one lymphoid and one myeloid, and (2) biphenotypic leukemias where individual blast cells display features of both lymphoid and myeloid lineage. 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 and a significantly worse event-free survival compared with patients with B-precursor ALL. Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen,[19,20,25] although the optimal treatment for patients remains unclear.
Cytogenetic Evaluation and Molecular Abnormalities
Chromosomal analyses of leukemia should be performed on children with AML because chromosomal abnormalities are important diagnostic and prognostic markers.[26,27,28,29,30,31] Clonal chromosomal abnormalities have been identified in the blasts of about 75% of children with AML and are useful in defining subtypes with particular characteristics (e.g., t(8;21) with M2, t(15;17) with M3, inv(16) with M4Eo, 11q23 abnormalities with M4 and M5, t(1;22) with M7). Leukemias with the chromosomal abnormalities t(8;21) and inv(16) are called core-binding factor leukemias; core-binding factor (a transcription factor involved in hematopoietic stem cell differentiation) is disrupted by each of these abnormalities.
Molecular probes and newer cytogenetic techniques (e.g., fluorescence in situ hybridization [FISH]) can detect cryptic abnormalities that were not evident by standard cytogenetic banding studies. This is clinically important when optimal therapy differs, as in APL. Use of these techniques can identify cases of APL when the diagnosis is suspected but the t(15;17) is not identified by routine cytogenetic evaluation. The presence of the Philadelphia (Ph) chromosome in patients with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML. Molecular methods are also being used to identify recurring gene mutations in adults and children with AML, and as described below, some of these recurring mutations have prognostic significance.
A unifying concept for the role of specific mutations in AML is that mutations that promote proliferation (Type I) and mutations that block normal myeloid development (Type II) are required for full conversion of hematopoietic stem/precursor cells to malignancy.[33,34] Support for this conceptual construct comes from the observation that there is generally mutual exclusivity within each type of mutation, such that a single Type I and a single Type II mutation are present within each case. Further support comes from genetically engineered models of AML for which cooperative events rather than single mutations are required for leukemia development. Type I mutations are commonly in genes involved in growth factor signal transduction and include mutations in FLT3, KIT, NRAS, KRAS, and PTNP11. Type II genomic alterations include the common translocations and mutations associated with favorable prognosis (t(8;21), inv(16), t(16;16), t(15;17), CEBPA, and NPM1). MLL rearrangements (translocations and partial tandem duplication) are also classified as Type II mutations.
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.
Molecular abnormalities associated with favorable prognosis include the following:
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.[34,53,54,55]NPM1 mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[34,54,55] For the pediatric population, conflicting reports have been published regarding the prognostic significance of a NPM1 mutation when a FLT3-ITD mutation is also present, with one study reporting that a NPM1 mutation did not completely abrogate the poor prognosis associated with having a FLT3-ITD mutation,[54,56] but with other studies showing no impact of a FLT3-ITD mutation on the favorable prognosis associated with a NPM1 mutation.[34,55]
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 and similar to the effect observed in adult studies.[61,62] Although both double- 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 in toto), making a conclusion regarding the prognostic significance of single-allele CEBPA mutations in children premature.
Molecular abnormalities associated with an unfavorable prognosis include the following:
Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[73,79,80] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all-trans retinoic acid.[80,81,82,83]
Activating point mutations of FLT3 have also been identified in both adults and children with AML,[70,74,84] though the clinical significance of these mutations is not clearly defined. FLT3-ITD and point mutations occur in 30% to 40% of children and adults with APL.[73,79,81,82] The prognostic significance of this mutation in APL is unclear, although a mutant to wild type allelic ratio of greater than or equal to 0.5 may be associated with a worse outcome.
Other molecular abnormalities observed in pediatric AML include the following:
Outcome for patients with de novo AML and MLL gene rearrangement are generally reported as being similar to that for other patients with AML.[26,87,88] However, as the MLL 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 MLL-rearranged AML. For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/MLL-rearranged AML, showed a highly favorable outcome with 5-year event-free survival (EFS) of 92%. While several reports have described more favorable prognosis for cases with t(9;11), in which the MLL gene is fused with the AF9 gene, the international retrospective study did not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup.[26,87,89,90,91] A similarly inferior outcome for patients with t(9;11) AML was reported from the AML-BFM 98 study. A follow-up study demonstrated that additional cytogenetic abnormalities further influenced outcome, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.
Several 11q23/MLL-rearranged AML subgroups are associated with poor outcome. For example, cases with the t(10;11) translocation are a group at particularly high risk of relapse in bone marrow and the central nervous system (CNS).[26,30,93] Some cases with the t(10;11) translocation have fusion of the MLL gene with the AF10/MLLT10 at 10p12, while others have fusion of MLL with ABI1 at 10p11.2.[94,95] The international retrospective study found that these cases, which present at a median age of approximately 1 year, have a 5-year EFS in the 20% to 30% range. Patients with t(6;11)(q27;q23) and with t(4;11)(q21;q23) also show poor outcome, with a 5-year EFS of 11% and 29%, respectively. An international collaborative study of 733 children with de novo 11q23/MLL-rearranged AML showed prognostic significance after multivariate analysis with: (1) specific translocation partners (10p12, hazard ratio for EFS 1.36, OS 1.62, relapse 1.76; 6q27, EFS 2.29, OS 2.72, relapse 2.79; 1q21, EFS 0.12; 10p11.2, EFS 2.12, OS 2.56); (2) selected trisomies (trisomy 8, EFS 0.57, OS 0.54; trisomy 19, EFS 1.77, OS 2.11); and (3) additional structural chromosomal aberrations (EFS 1.39).
A subset of patients with 12p abnormalities have the t(7;12)(q36;p13) translocation involving ETV6 on chromosome 12p13 and HLXB9 on chromosome 7q36. This alteration occurs virtually exclusively in children younger than 2 years, is mutually exclusive with MLL rearrangement, and is associated with a high risk of treatment failure.[29,30,34,106,107]
Classification of Myelodysplastic Syndromes in Children
The FAB classification of myelodysplastic syndromes (MDS) is not completely applicable to children.[155,156] In adults, MDS is divided into several distinct categories based on the presence of myelodysplasia, types of cytopenia, specific chromosomal abnormalities, and the percentage of myeloblasts.[156,157,158,159]
A modified classification schema for MDS and myeloproliferative disorders (MPDs) was published by WHO in 2008. The primary WHO classification includes:
WHO classification of MDS
Refractory cytopenia of childhood is noted to be reserved for children with MDS who have less than 2% blasts in their peripheral blood and less than 5% blasts in their bone marrow along with persistent cytopenia(s) and dysplasia. It is also noted in the new WHO classification that refractory cytopenia of childhood, unlike MDS in adults, is usually characterized by bone marrow hypocellularity, making the distinction with aplastic anemia and bone marrow failure syndromes often difficult.
WHO classification of myelodysplastic/myeloproliferative neoplasms
Refractory anemia with ring sideroblasts and thrombocytosis is notable in that 50% to 60% of cases have JAK2 V617F mutations.
WHO classification of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1
The peripheral blood and bone marrow findings for the myelodysplastic syndromes according to the 2008 WHO classification schema  are summarized in Table 3.
Refractory anemia with ring sideroblasts is rare in children. Refractory anemia and refractory anemia with excess blasts are more common. The WHO classification schema has a subgroup that includes JMML (formerly juvenile chronic myeloid leukemia), CMML, and Ph chromosome–negative CML. This group can show mixed myeloproliferative and sometimes myelodysplastic features. JMML shares some characteristics with adult CMML [162,163,164] but is a distinct syndrome (see below). A subgroup of children younger than 4 years at diagnosis with myelodysplasia will have monosomy 7. For this subset of children, their disease is best classified as a subtype of JMML. 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 JMML, only a blast count of less than 5% and a platelet count of more than 100 x 109 /L were associated with a better survival in MDS, and a platelet count of more than 40 x 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. Older children with monosomy 7 and high-grade MDS, however, behave more like adults with MDS and are best classified that way and treated with allogeneic hematopoietic stem cell transplantation.[166,167] The risk group or grade of MDS is defined according to International Prognostic Scoring System guidelines. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was published in 2003; however, the usefulness of this classification has yet to be evaluated prospectively in clinical practice. A retrospective comparison of the WHO classification with the category, cytology, and cytogenetics system and a Pediatric WHO adaptation for MDS/MPD, has shown that the latter two systems are better able to effectively classify childhood MDS than the more general WHO system. A prospective study should be done to definitively determine the optimal classification scheme for childhood MDS/MPD.
Diagnostic Classification of Juvenile Myelomonocytic Leukemia
JMML is a rare leukemia that occurs approximately ten times less frequently than AML in children. JMML typically presents in young children (a median age of approximately 1.8 years) and occurs more commonly in boys (male to female ratio approximately 2.5:1). Common clinical features at diagnosis include hepatosplenomegaly (97%), lymphadenopathy (76%), pallor (64%), fever (54%), and skin rash (36%). In children presenting with clinical features suggestive of JMML, current criteria used for a definitive diagnosis are as follows:
Characteristics of JMML cells include in vitro hypersensitivity to granulocyte-macrophage colony-stimulating factor and activated RAS signaling secondary to mutations in various components of this pathway including NF1, KRAS,NRAS, and PTPN11.[174,175,176] Mutations of the E3 ubiquitin ligase CBL are observed in 10% to 15% of JMML cases,[177,178] with many of these cases occurring in children with germline CBL mutations.[179,180]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 mutually exclusive with RAS/PTPN11 mutations. While the majority of children with JMML have no detectable cytogenetic abnormalities, a minority (20%–25%) show loss of chromosome 7 in bone marrow cells.[163,170,179,181,182]
There is presently no therapeutically or prognostically meaningful staging system for these disorders. 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 sarcomas). If these children do not receive systemic chemotherapy, they invariably develop AML in months or years. AML may invade nonhematopoietic 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 greater than 20% blasts. The blasts have the morphologic and histochemical characteristics of one of the French-American-British subtypes of AML. It can also be diagnosed by biopsy of a chloroma. For treatment purposes, children with a t(8;21) and less than 20% marrow blasts should be considered to have AML rather than myelodysplastic syndrome.
Remission is defined in the United States as peripheral blood counts (white blood cell count, differential, and platelet count) rising toward normal, a mildly hypocellular to normal cellular marrow with fewer than 5% blasts, and no clinical signs or symptoms of the disease, including in the central nervous system or at other extramedullary sites. Achieving a hypoplastic bone marrow is usually the first step in obtaining remission in AML with the exception of the M3 (acute promyelocytic leukemia [APL]); a hypoplastic marrow phase is often not necessary prior to 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; correlation with blood cell counts, clinical status, and cytogenetic/molecular testing 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 about 1 week.
The mainstay of the therapeutic approach is systemically administered combination chemotherapy. Future approaches involving risk-group stratification and biologically targeted therapies are being tested to improve antileukemic treatment while sparing normal tissues. Optimal treatment of acute myeloid leukemia (AML) requires control of bone marrow and systemic disease. Treatment of the central nervous system (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 two phases: (1) induction (to attain remission), and (2) postremission consolidation/intensification. 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) utilize similar chemotherapy regimens consisting of two courses of induction chemotherapy followed by two additional courses of intensification chemotherapy.[3,4]
Maintenance therapy is not part of most pediatric AML protocols as two randomized clinical trials failed to show a benefit for maintenance chemotherapy.[5,6] The exception to this generalization is acute promyelocytic leukemia (APL), for which maintenance therapy has been shown to improve event-free survival and overall survival (OS).
Treatment of AML is usually associated with severe and protracted myelosuppression along with other associated complications. Treatment with hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF] and granulocyte colony-stimulating factor [G-CSF]) has been used in an attempt to reduce the toxicity associated with severe myelosuppression but does not influence ultimate outcome. Virtually all adult randomized trials of hematopoietic growth factors (GM-CSF and G-CSF) have demonstrated significant reduction in the time to neutrophil recovery,[9,10,11,12] but varying degrees of reduction in morbidity and little, if any, effect on mortality. The BFM 98 study confirmed a lack of benefit for the use of G-CSF in a randomized pediatric AML trial.
Because of the intensity of therapy utilized to treat AML, children with this disease must have their care coordinated by specialists in pediatric oncology, and they must be treated in cancer centers or hospitals with the necessary supportive care facilities (e.g., to administer specialized blood products; to manage infectious complications; to provide pediatric intensive care; and to provide emotional and developmental support). Approximately one-half of the remission induction failures are due to resistant disease and the other half are due to toxic deaths. For example, in the MRC 10 and 12 AML trials, there was a 4% resistant disease rate in addition to a 4% induction death rate. With increasing rates of survival for children treated for AML comes an increased awareness of long-term sequelae of various treatments. For children who receive intensive chemotherapy, including anthracyclines, continued monitoring of cardiac function is critical. Periodic renal and auditory examinations are also suggested. In addition, total-body irradiation before HSCT increases the risk of growth failure, gonadal and thyroid dysfunction, and cataract formation.
Prognostic Factors in Childhood AML
Prognostic factors in childhood AML have been identified and can be categorized as follows:
Infants have been reported to have a 5-year survival of about 50%, although with increased treatment-associated toxicity when treated with standard AML regimens.
CNS2 disease has been observed in approximately 13% of children with AML and CNS3 disease in 11% to 17% of children with AML.[34,35]
The presence of CNS disease (CNS2 and/or CNS3) at diagnosis has not been shown to affect overall survival; however, it may be associated with an increased risk of isolated CNS relapse.
Molecular approaches to assessing MRD in AML (e.g., using quantitative reverse transcriptase–polymerase chain reaction [RT–PCR]) have been challenging to apply because of the genomic heterogeneity of pediatric AML and the instability of some genomic alterations. However, there has been success with these approaches as evidenced by the demonstration that the persistence of the PML-RARA fusion product in APL is significantly associated with a high risk of relapse, and that early therapeutic intervention prior to morphologic relapse may improve outcome.[44,45] Similarly, quantitative RT–PCR detection of AML1-ETO fusion transcripts can effectively predict higher risk of relapse for patients in clinical remission.[46,47,48] 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, and 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, it can be useful in detecting residual leukemia.
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.[42,43]
Risk classification systems under clinical evaluation
Risk classification for treatment assignment on the COG-AAML1031 study is based on cytogenetics, molecular markers, and MRD postinduction I, with patients being divided into a low-risk or high-risk group as follows:
The low-risk group represents about 73% of patients, has a predicted OS of approximately 75%, and is defined by the following:
The high-risk group represents the remaining 27% of patients, has a predicted OS less than 35%, and is defined by the following:
The high-risk group of patients will be offered transplantation in first remission with the most appropriate available donor. Patients in the low-risk group will only be offered transplantation in second complete remission.
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 acute promyelocytic leukemia (APL) and Down syndrome.
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.[1,2,3,4,5] 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 Cytogenetic Evaluation and Molecular Abnormalities section 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.
Because of the intensity of therapy used to treat children with AML, patients should have their care coordinated by specialists in pediatric oncology, and should be treated in cancer centers or hospitals with the necessary supportive care facilities (e.g., to administer specialized blood products; to manage infectious complications; to provide pediatric intensive care; and to provide emotional and developmental support).
Contemporary pediatric AML protocols result in 85% to 90% complete remission rates. Of those patients who do not go into remission, about one-half have resistant leukemia and one-half die from the complications of the disease or its treatment. To achieve a complete remission (CR), inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant.
The two most effective 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.[3,6,7] The United Kingdom Medical Research Council (MRC) 10 Trial compared induction with cytarabine, daunorubicin, and etoposide (ADE) versus cytarabine and daunorubicin administered with thioguanine (DAT); the results showed no difference between the thioguanine and etoposide arms in remission rate or disease-free survival.
The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[3,6,7] though idarubicin and the anthracenedione mitoxantrone have also been used.[9,10] 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. The German Berlin-Frankfurt-Munster (BFM) Group AML-BFM 93 study evaluated cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE) and observed similar EFS and OS for both induction treatments.[7,9] The MRC-LEUK-AML12 clinical trial studied induction with cytarabine, mitoxantrone, and etoposide (MAE) in children and adults with AML compared to a similar regimen using daunorubicin (ADE).[10,11] For all patients, MAE showed a reduction in relapse risk, but the increased rate of treatment-related mortality observed for patients receiving MAE led to no significant difference in disease-free survival or OS in comparison to ADE. Similar results were noted when analyses were restricted to pediatric patients. In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome to 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.
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. Another way of intensifying induction therapy is by the use of 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,[12,13] a benefit for the use of high-dose cytarabine compared with standard-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.
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.[16,17] These studies have generally shown a reduction of several days in the duration of neutropenia with the use of either G-CSF or GM-CSF  but have not shown significant effects on treatment-related mortality or OS. A randomized study in children with AML evaluating G-CSF administered following induction chemotherapy showed a reduction in duration of neutropenia, but no difference in infectious complications or mortality. A higher relapse rate has been reported for children with AML expressing the differentiation defective G-CSF receptor isoform IV. Thus, routine prophylactic use of hematopoietic growth factors is not recommended for children with AML.
Treatment options under clinical evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
Central Nervous System (CNS) Prophylaxis for AML
Although the presence of CNS leukemia at diagnosis (i.e., clinical neurologic features and/or leukemic cells in cerebral spinal fluid on cytocentrifuge preparation) is more common in childhood AML than in childhood acute lymphoblastic leukemia (ALL), survival is not adversely affected. This finding is perhaps related to both the higher doses of chemotherapy used in AML (with potential crossover to the CNS) and the fact that marrow disease has not yet been as effectively brought under long-term control in AML as in ALL. Children with M4 and M5 AML have the highest incidence of CNS leukemia (especially those with inv(16) or 11q23 chromosomal abnormalities). The use of some form of intrathecal chemotherapy as CNS-directed treatment is now incorporated into most protocols for the treatment of childhood AML and is considered a standard part of the treatment for AML. Cranial radiation is no longer routinely employed in the treatment of children with AML.
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 CCG, fewer than 1% of patients had isolated granulocytic sarcoma, and 11% had granulocytic sarcoma along with marrow disease at the time of diagnosis. 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.
Patients with marrow disease and extramedullary disease limited to the skin do worse than those without granulocytic sarcoma. In one study, AML patients with orbital granulocytic sarcoma and CNS granulocytic sarcoma appeared to have a better survival than patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease. The majority of 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.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood acute myeloid leukemia and other myeloid malignancies. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
A major challenge in the treatment of children with acute myeloid leukemia (AML) is to prolong the duration of the initial remission with additional chemotherapy or hematopoietic stem cell transplantation (HSCT). In practice, most patients are treated with intensive chemotherapy after remission is achieved, as only a small subset have a matched-family donor (MFD). Such therapy 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 to consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes.[1,2] 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.[3,4,5]
The optimal number of postremission courses of therapy remains unclear, but appears to require at least three courses of intensive therapy, including the induction course. A United Kingdom Medical Research Council (MRC) study randomly assigned adult and pediatric patients to four versus five courses of intensive therapy. Five courses did not show an advantage in relapse-free and overall survival (OS).[7,8][Level of evidence: 1iiA]
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.[10,11] In prospective trials of allogeneic HSCT compared with chemotherapy and/or autologous HSCT, a superior disease-free survival (DFS) has been observed for patients who were assigned to allogeneic transplantation based on availability of a family 6/6 or 5/6 HLA-matched donor in adults and children.[10,11,12,13,14,15,16] 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.[10,11,12,14]
Because of the improved outcome in patients with favorable prognostic features receiving contemporary regimens, it is now recommended that this group of patients receive an MFD HSCT only after first relapse and the achievement of a second complete remission (CR).[9,18,19]
While there is a clear movement away from transplantation in first remission using matched family donors in pediatric patients with AML that has favorable prognostic features, there is evidence suggesting an advantage for allogeneic HSCT in patients with intermediate-risk characteristics. A large intent-to-treat analysis of 472 young adults treated on Bordeaux Grenoble Marseille Toulouse (BGMT) studies showed a survival benefit from allogeneic HSCT in intermediate-risk patients (all patients not favorable or unfavorable), while patients with favorable-risk disease (t(15;17), t(8:21), or inv(16)) did not appear to benefit. Of note, there were insufficient numbers in the study to determine whether patients with unfavorable-risk disease (complex karyotype (≥5 cytogenetic findings), del(5q), monosomy 5 or 7, 3q rearrangements, t(9;22), t(6;9), or 11q23 rearrangements, except t(9;11)) benefit from this approach. A second study combining the results of the POG-8821, CCG-2891, COG-2961, and MRC-Leuk-AML-10-Child studies confirmed an advantage for allogeneic HSCT in patients with intermediate-risk AML but not favorable-risk as defined above or poor-risk as defined below. However, again, there were insufficient numbers in this study to assess the role of matched family member transplantation in patients with poor-risk AML, defined by del(5q), monosomy 5 or 7, or more than 15% blasts after first induction for POG/CCG studies as well as including 3q abnormalities and complex cytogenetics in the MRC study.
Many, but not all, pediatric clinical trial groups prescribe allogeneic HSCT for high-risk patients in first remission. For example, the Children's Oncology Group (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 2004 clinical trial restricts allogeneic HSCT to patients in second CR and to refractory AML based on results from their AML-BFM 98 study showing no improvement in DFS or OS for high-risk patients receiving allogeneic HSCT in first CR. 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 due to the ongoing association of molecular characteristics of the tumor with outcome (e.g., FLT-3 internal tandem duplications, WT1 mutations, and NPM1 mutations) as well as 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.
Maintenance chemotherapy has been shown to be effective in the treatment of acute promyelocytic leukemia (APL). In other subtypes, 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,[3,23] and maintenance therapy with interleukin-2 also proved ineffective.
Treatment Options Under Clinical Evaluation
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute myeloid leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) and is treated differently than other types of AML. Optimal treatment requires rapid initiation of treatment with all-trans retinoic acid (ATRA) and supportive care measures.[1,2] 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 (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 a severe coagulopathy that is often present at the time of diagnosis. Mortality during induction (particularly with cytotoxic agents used alone) due to bleeding complications is more common in this subtype than in other French-American-British classifications. A lumbar puncture at diagnosis should not be performed until evidence of coagulopathy has resolved.
APL in children is generally similar to APL in adults, though children have a higher incidence of hyperleukocytosis (defined as white blood cell [WBC] count higher than 10 × 109 /L) and a higher incidence of the microgranular morphologic subtype.[8,9,10,11] Similar to adults, children with WBC counts less than 10 × 109 /L at diagnosis have significantly better outcome than patients with higher WBC counts.[9,10,12] The prognostic significance of WBC count is used in defining high-risk and low-risk patient populations for assigning postinduction treatment, with high-risk patients most commonly defined by WBC of 10 × 109 /L or greater.[13,14]FLT3 mutations (either internal tandem duplications or kinase domain 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.[15,16,17,18,19]FLT3 mutation has been associated with an increased risk of induction death, and in some reports, an increased risk of treatment failure.[15,16,17,18,19,20,21] Data from a combined analysis of two European trials demonstrated that children younger than 4 years with APL presented with higher WBC counts, had an increased incidence of the M3v subtype, and had a higher cumulative incidence of relapse and fatal cardiac toxicity during remission than did adolescents and adults; however, overall survival (OS) was similar.[