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Home > Wellness Resources > 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.
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 (EFS) 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.[26,29,87,88] 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 EFS of 92%. While reports from single clinical trial groups have variably 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.[26,29,87,89,90,91]
Several 11q23/MLL-rearranged AML subgroups appear to be associated with poor outcome. For example, cases with the t(10;11) translocation are a group at high risk of relapse in bone marrow and the central nervous system (CNS).[26,30,92] 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.[93,94] 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, in the international retrospective study. A follow-up study by the international collaborative group demonstrated that additional cytogenetic abnormalities further influenced outcome of children with MLL translocations, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.
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.[42,43,52]
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.[52,53]
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.[Level of evidence: 3iiA]
The basis for current treatment programs for APL is the sensitivity of leukemia cells from patients with APL to the differentiation-inducing effects of ATRA. The dramatic efficacy of ATRA against APL results from the ability of pharmacologic doses of ATRA to overcome the repression of signaling caused by the PML/RARA fusion protein at physiologic ATRA 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 ATRA, though single-agent ATRA is generally not curative.[24,25] A series of randomized clinical trials has defined the benefit of combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy.[26,27,28] ATRA is also commonly used as a component of postinduction consolidation therapy, with treatment regimens that include several additional courses of ATRA given with an anthracycline with or without cytarabine.[10,13,14,29] Evidence for the benefit of giving ATRA with consolidation chemotherapy is derived from historical comparisons of results from adult APL clinical trials showing significant improvements in outcome for patients receiving ATRA given in conjunction with chemotherapy compared with chemotherapy alone.[13,14] For children with APL, survival rates exceeding 80% are now achievable using treatment programs that prescribe the rapid initiation of ATRA and appropriate supportive care measures.[1,8,9,10,13,14,29]
The standard approach to treating children with APL builds upon adult clinical trial results and begins with induction therapy using ATRA given in combination with an anthracycline administered with or without cytarabine. One regimen uses ATRA in conjunction with standard-dose cytarabine and daunorubicin,[8,30] while another utilizes idarubicin and ATRA without cytarabine for remission induction.[9,10] Almost all children with APL treated with one of these approaches achieves CR in the absence of coagulopathy-related mortality.[9,10,29,30] Assessment of response to induction therapy in the first month of treatment using morphologic and molecular criteria may provide misleading results as delayed persistence of differentiating leukemia cells can occur in patients who will ultimately achieve CR.[1,2] Alterations in planned treatment based on these early observations are not appropriate as resistance of APL to ATRA plus anthracycline-containing regimens is extremely rare.[14,31]
Consolidation therapy typically includes ATRA 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 ATRA regimen in adults with low-risk APL showed a benefit for the addition of cytarabine, regimens using high-dose anthracycline appear to produce as good or better results for low-risk patients. For high-risk patients (WBC ≥10 × 109 /L), a historical comparison of the LPA2005 trial to the preceding PETHEMA LPA99 trial suggested that the addition of cytarabine to anthracycline-ATRA combinations can lower the relapse rate. The results of the AIDA-2000 trial confirmed that the cumulative incidence of relapse for adult patients with high-risk disease can be reduced to approximately 10% with consolidation regimens containing ATRA, anthracyclines, and cytarabine.
Maintenance therapy includes ATRA plus 6-mercaptopurine and methotrexate; this combination showed an advantage over ATRA alone in randomized trials in adults with APL.[26,34] A randomized study in adults has reported that maintenance therapy does not improve event-free survival (EFS) for patients with APL who achieve a complete molecular remission at the end of consolidation. The utility of maintenance therapy in APL may be dependent on multiple factors (e.g., risk group, the anthracycline used during induction, the intensity of induction and consolidation therapy, etc.), and at this time maintenance therapy remains standard for children with APL. Because of the favorable outcomes observed with chemotherapy plus ATRA (EFS rates of 70%–80%), hematopoietic stem cell transplantation (HSCT) is not recommended in first CR.
Central nervous system (CNS) relapse is uncommon for patients with APL, particularly for those with WBC less than 10 × 109 /L.[36,37] In two clinical trials enrolling over 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 less than 10 × 109 /L, while it was approximately 5% for those with WBC of 10 × 109 /L or greater.[36,37] In addition to high WBC 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 less than 10 × 109 /L, CNS surveillance and prophylactic CNS therapy may not be needed for this group of patients, although there is not consensus on this topic.
Arsenic trioxide has also been identified as an active agent in patients with APL, and there are now data for its use as induction therapy, consolidation therapy, and in the treatment of patients with relapsed APL:
Because arsenic trioxide causes QT interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes), it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.
The induction and consolidation therapies currently employed result in molecular remission as measured by reverse transcriptase–polymerase chain reaction (RT–PCR) for PML-RARA in the large majority of APL patients, with 1% or fewer showing molecular evidence of disease at the end of consolidation therapy.[14,31] While two negative RT-PCR assays after completion of therapy are associated with long-term remission, conversion from negative to RT-PCR positivity is highly predictive of subsequent hematologic relapse. Patients with persistent or relapsing disease based upon PML-RARA RT-PCR measurement may benefit from intervention with relapse therapies (refer to the Recurrent Acute Promyelocytic Leukemia (APL) subsection of the Recurrent Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies section of this summary for more information).
Molecular Variants of APL Other than PML-RARA
Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA. Recognition of these rare variants is important as they differ in their sensitivity to ATRA and to arsenic trioxide. The PLZF-RARA variant, characterized by t(11;17)(q23q21), represents about 0.8% of APL, expresses surface CD56, and has very fine granules compared with t(15;17) APL.[57,58,59] APL with PLZF-RARA has been associated with a poor prognosis and does not usually respond to ATRA or to arsenic trioxide.[56,57,58,59] The rare APL variants with NPM-RARA (t(5;17)(q35;q21)) or with NuMA-RARA (t(11;17)(q13;q21)) translocations are responsive to ATRA.[56,60,61,62,63]
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about clinical trials is available from the NCI Web site.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute promyelocytic leukemia (M3). The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Children with Down syndrome have a tenfold to twentyfold increased risk of leukemia compared to children without Down syndrome; the ratio of acute lymphoblastic leukemia to acute myeloid leukemia (AML) is nevertheless 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.[1,2,3,4,5,6,7,8,9] 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.
In addition to increased risk of AML during the first 3 years of life, about 10% of neonates with Down syndrome may also develop a transient myeloproliferative disorder (TMD) (also termed transient leukemia). This disorder mimics congenital AML, but typically improves spontaneously within the first 3 months of life, though TMD can remit as late as 20 months. Although TMD is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 20% of affected infants.[11,12,13] Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37-weeks gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), and very high white blood cell count are at particularly high risk for early mortality.[12,14] Death has been reported to occur in 21% of these patients with high-risk TMD. Three risk groups have been identified based on the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms: (1) low risk includes those with neither finding (38% of patients and 92% ± 8% OS); (2) intermediate risk with hepatomegaly alone (40% of patients and 77% ± 12% OS); and (3) high risk with both characteristics (21% of patients and 51% ± 19% OS). Therapeutic intervention is warranted in patients in whom severe hydrops or organ failure is apparent. Several treatment approaches have been used, including exchange transfusion, leukapheresis, and low-dose cytarabine.
The mean time for the development of AML in the 10% to 30% of children who have a spontaneous remission of TMD but then develop AML, has been reported to be approximately 16 months with a range of 1 to 30 months.[11,15,17] Thus, most infants with Down syndrome and TMD who later develop AML will do so within the first 3 years of life. Patients with Down syndrome who develop AML with an antecedent TMD have superior event-free survival (EFS) (91% ± 5%) compared with such children without TMD (70% ± 4%) at 5 years. While TMD is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk for developing subsequent AML.
For children with Down syndrome who develop AML, outcome is generally favorable. The prognosis is particularly good (EFS exceeding 80%) in children aged 4 years or younger at diagnosis, the age group that accounts for the vast majority of Down syndrome patients with AML. Appropriate therapy for these children is less intensive than current AML therapy, and hematopoietic stem cell transplant is not indicated in first remission.[3,17,19,20,21,22,23,24]
Children with mosaicism for trisomy 21 are recommended to be treated similarly to those children with clinically evident Down syndrome. Children with Down syndrome who are older than 4 years have a significantly worse prognosis. Although an optimal treatment for these children has not been defined, they are usually treated on AML regimens designed for children without Down syndrome.
The myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS), which represent between 5% and 10% of all myeloid malignancies in children, are a heterogeneous group of disorders with the former usually presenting with cytopenias and the latter with increased peripheral white blood cell (WBC), 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 stem cell transplantation.
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 eventually can lead to the development of acute myeloid leukemia (AML). The percentage of abnormal blasts is less than 20%. 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.[1,2]
Although the etiology of MDS has not been elucidated, clues have begun to be defined. For instance, approximately 20% of malignant myeloid disorders, including MDS, in adults have been shown to have mutations in the TET2 gene. Other genes shown to be mutated in MDS include EZH2, DNMT3A, ASXL1, IDH1/2, RUNX1, ETV6/TEL, and TP53. Most of these genes are key elements of epigenetic regulation of the genome and affect DNA methylation and/or histone modification.[3,4,5] Mutations in proteins involved in RNA splicing have been described in 45% to 85% of MDS. MDS in both adults and children has been shown to have aberrant DNA methylation patterns and approximately one-half of cases are characterized by hypermethylation of the promoters for the CDKN2B and CALC genes, both of which play roles in cell cycle regulation.[7,8] Inherited disorders, such as Fanconi anemia, due to germline mutations in DNA repair genes, or in dyskeratosis congenita, due to mutations in genes regulating telomere length, have significantly increased risk of developing MDS. Additional bone marrow failure syndromes may also evolve into MDS, including those due to mutations in genes encoding ribosome associated proteins, such as Shwachman-Diamond syndrome and Diamond-Blackfan anemia. The 15-year cumulative risk of MDS in patients with severe congenital neutropenia, also know as Kostmann syndrome, which is due to mutations in the gene encoding elastase, has been estimated to be 15% with an annual risk of MDS/AML of 2% to 3%; how mutations affecting this protein as well as what role the chronic exposure of granulocyte-colony stimulating factor (G-CSF) contribute to the development of MDS is unclear.[10,11] Inherited mutations in the RUNX1 or CEPBA genes have also been shown to be associated with familial MDS/AML.[12,13]
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 WHO system.[14,15,16,17,18] The WHO system  has been modified for pediatrics.
Diagnostic Categories for Myelodysplastic and Myeloproliferative Disease 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.[20,21] The relatively common abnormalities of -Y, 20q- and 5q- in adults with MDS are rare in childhood MDS. The presence of cytogenetic abnormalities found in AML defines disease that should be treated as AML and not MDS. 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, in part because children often have more high-risk characteristics compared with adults, especially in terms of cytopenias.[22,23] Nevertheless, the median survival for children with high-risk MDS remains substantially better than adults.
The optimal therapy for childhood MDS has not been established. A key issue in thinking about therapy for pediatric patients with MDS is that these disorders usually involve a primitive hematopoietic stem cell. Thus, allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be the optimal approach to treatment for pediatric patients with advanced MDS. Unresolved issues include determining the best transplant preparative regimen and source of donor cells.[25,26] However, some data are important to consider when making decisions. For example, disease-free survival has been estimated to be between 50% to 70% for pediatric patients with advanced MDS using myeloablative transplant preparative regimens.[27,28,29,30,31] While using 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.[32,33,34]
The question of whether chemotherapy should be used in high-risk MDS has been examined. The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS. There were 77 patients with refractory anemia (n = 2), refractory anemia with excess blasts (n = 33), refractory anemia with excess blasts in transformation (n = 26), or AML with antecedent MDS (n = 16) who were enrolled and randomly assigned to standard or intensively timed induction. Subsequently, patients were allocated to allogeneic HSCT if there was a suitable family donor, or randomly assigned to autologous HSCT or chemotherapy. Patients with refractory anemia/refractory anemia with excess blasts had a poor remission rate (45%), and those with refractory anemia with excess blasts in transformation (69%) or AML with history of MDS (81%) had similar remission rates compared with de novo AML (77%). Six-year survival was poor for those with refractory anemia/refractory anemia with excess blasts (28%) and refractory anemia with excess blasts in transformation (30%). Patients with AML and antecedent MDS had a similar outcome to those with de novo AML (50% survival compared with 45%). Allogeneic HSCT appeared to improve survival at a marginal level of significance (P = .08). Based on analysis of these data and the literature, the authors concluded that children with a history of MDS who present with AML and many of those with refractory anemia with excess blasts in transformation do as well with AML therapy at diagnosis as children with AML. An exception to this conclusion is children with AML with a precedent MDS and monosomy 7; these patients have a very poor prognosis and are usually treated with some type of allogeneic HSCT. An analysis of 37 children with MDS treated on Berlin-Frankfurt-Munster AML protocols 83, 87, and 93 confirmed the induction response of 74% for patients with refractory anemia with excess blasts in transformation and suggested that transplantation was beneficial. Another study by the same group showed that with current approaches to HSCT, survival occurred in more than 60% of children with advanced MDS, and outcomes for patients receiving unrelated donor cells were similar to those for patients who received matched-family donor (MFD) cells.
A significant issue to consider for these results is 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 represent MDS. The optimum therapy for patients with refractory anemia/refractory anemia with excess blasts without MFD is unknown. Some of these patients require no therapy for years and have indolent diseases. Because failure rates after HSCT are lower in this group, strong consideration should be given for such treatment, especially when a 5/6 or 6/6 HLA-MFD is available. However, alternative forms of HSCT, utilizing matched unrelated donor cord blood, should be considered when treatment is required, as is usually the case in patients with severe cytopenias.[28,31]
For patients with clinically significant cytopenias, supportive care, including transfusions and prophylactic antibiotics, can be considered, but have not been proven to be curative; however, it is important that supportive care be utilized in these patients awaiting transplant. In addition, the use of hematopoietic growth factors can improve the hematopoietic status, but there is some concern that such treatment could accelerate conversion to AML. Steroid therapy has also been used, including glucocorticoids and androgens, with mixed results. Treatments directed toward scavenging free oxygen radicals with amifostine [39,40] or the use of differentiation-promoting retinoids, DNA methylation inhibitors (e.g., azacytidine and decitabine), and histone deacetylase inhibitors, have all shown some positive responses. Azacytidine has been FDA-approved for the treatment of MDS in adults based on randomized studies. Agents, such as lenalidomide, an analog of thalidomide, have been tested based on findings that demonstrated increased activity in the bone marrow of patients with MDS. Lenalidomide has shown most efficacy in patients with 5q- syndrome and is now FDA-approved for use in this group. Immunosuppression with antithymocyte globulin and/or cyclosporine has also been reported.[43,44]
The following are examples of national and/or institutional clinical trials that are currently being conducted.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood myelodysplastic syndromes. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The development of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) following treatment with ionizing radiation or chemotherapy, particularly alkylating agents and topoisomerase inhibitors, is termed therapy-related (t-AML or t-MDS, respectively). 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/t-MDS is regimen-dependent and is related to the cumulative doses of chemotherapy agents received, as well as 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/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/t-MDS not greater than 1% to 2%. t-AML/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 following exposure to alkylating agents or ionizing radiation often occurs 5 to 7 years later and is commonly associated with monosomies or deletions of chromosomes 5 and 7.[1,7]
The goal of treatment is to achieve an initial complete remission (CR) using AML-directed regimens and then, usually, proceed directly to hematopoietic stem cell transplantation (HSCT) with the best available donor. However, treatment is challenging due to 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] Patients with t-MDS-refractory anemia usually have not needed induction chemotherapy prior to transplant; the role of induction therapy with refractory anemia with excess blasts-1 prior to transplant is controversial.
Only a few reports describe the outcome of children undergoing HSCT for t-AML. One study described outcomes of 27 children with t-AML who received related and unrelated donor HSCT. Three-year OS rates were 18.5% ± 7.5% and event-free survival rates were 18.7% ± 7.5%. Poor survival was mainly due to very high transplant-related mortality (59.6% ± 8.4%). Another study reported a second retrospective single-center experience of 14 patients transplanted for t-AML/t-MDS between 1975 and 2007. Survival was 29%, but in this review only 63% of patients diagnosed with t-AML/t-MDS underwent HSCT. A multicenter study (CCG-2891) looked at outcomes of 24 children with t-AML/t-MDS compared with other children enrolled on the study with de novo AML (n = 898) or MDS (n = 62). Children with t-AML/t-MDS were older and low-risk cytogenetics rarely occurred. Although rates of achieving CR and OS at 3 years were worse in the t-AML/t-MDS group (CR, 50% vs. 72%, P = .016; OS, 26% vs. 47%, P = .007), survival was similar (OS, 45% vs. 53%, P = .87) if patients achieved a CR. The importance of remission to survival in these patients is further illustrated by another single-center report of 21 children undergoing HSCT for t-AML/t-MDS between 1994 and 2009. Of the 21 children, 12 had t-AML (11 in CR at the time of transplant), seven had refractory anemia (for whom induction was not done), and two had refractory anemia with excess blasts. Survival of the entire cohort was 61%; those in remission or with refractory anemia had a disease-free survival of 66%, and for those with more than 5% blasts at the time of HSCT, survival was 0% (P = .015). 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 approaches should be adapted to give adequate intensity while minimizing transplant-related mortality.
Juvenile myelomonocytic leukemia (JMML), formerly termed juvenile chronic myeloid leukemia, is a rare hematopoietic malignancy of childhood accounting for less than 1% of all childhood leukemias. A number of clinical and laboratory features distinguish JMML from adult-type chronic myeloid leukemia. The diagnostic criteria that need to be met for JMML are included in Table 5.[2,3]
The pathogenesis of JMML has been closely linked to activation of the RAS oncogene pathway, along with related syndromes (see Figure 1).[2,3] 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.[4,5]
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 1 (NF1) and Noonan syndrome are at increased risk for developing JMML,[6,7] and up to 14% of cases of JMML occur in children with NF1. Approximately 75% of JMML cases harbor one of three mutually exclusive mutations leading to activated RAS signaling, including direct oncogenic RAS mutations (approximately 20%),[9,10] NF1 inactivating mutations (approximately 15%–25%), or protein tyrosine phosphatase, non-receptor type 11 (PTPN11) (SHP-2) mutations (approximately 35%).[12,13] Mutations of the E3 ubiquitin ligase CBL are observed in 10% to 15% of JMML cases,[14,15] with many of these cases occurring in children with germline CBL mutations.[16,17]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. Noonan syndrome, which is usually inherited as an autosomal dominant condition, but can also arise spontaneously, is characterized by facial dysmorphism, short stature, webbed neck, neurocognitive abnormalities, and cardiac abnormalities. 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.
Historically, more than 90% of patients with JMML died despite the use of chemotherapy, but with the application of hematopoietic stem cell transplant (HSCT), survival rates of approximately 50% are now reported. Patients appeared to follow three distinct clinical courses: (1) rapidly progressive disease and early demise; (2) transiently stable disease followed by progression and death; and (3) clinical improvement that lasted up to 9 years before progression or, rarely, long-term survival. Favorable prognostic factors for survival after any therapy include being younger than 3 years, having a platelet count of greater than 33 × 109 /L, and low age-adjusted fetal hemoglobin levels.[8,20] In contrast, being older than 3 years and having high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[8,20] It remains controversial whether specific mutations are predictive of outcome.
The role of conventional antileukemia therapy in the treatment of JMML is not defined. The absence of consensus response criteria for JMML complicates determination of the role of specific agents in the treatment of JMML. Some of the agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and 6-mercaptopurine), and isotretinoin, but none of these have been shown to improve outcome.[21,22,23,24,25]
HSCT offers the best chance of cure for JMML.[19,26,27,28] A report from the European Working Group on Childhood myelodysplastic syndrome notes a 55% and 49% 5-year event-free survival for a large group of children with JMML transplanted with HLA-identical matched family donors or unrelated donors, respectively. The trial included 100 recipients at multiple centers using a common preparative regimen of busulfan, cyclophosphamide, and melphalan, with or without antithymocyte globulin. Recipients had been treated with varying degrees of pretransplant chemotherapy or differentiating agents and some patients had splenectomy performed. Multivariate analysis showed no effect on survival of prior AML-like chemotherapy versus low-dose chemotherapy or none; no effect on survival was observed for the presence or absence of a spleen, difference in spleen size, or related versus unrelated donors. Only gender and age older than 4 years were shown to be poor prognostic factors for outcome (relative risk [RR] 2.24 [1.07–4.69], P = .032, RR 2.22 [1.09–4.50], P = .028 for older age and female gender, respectively). The use of reduced-intensity preparative regimens in order to reduce the adverse side effects of transplantation have also been reported in small numbers of patients, with variable success.[29,30]
Disease recurrence is the primary cause of treatment failure for children with JMML following HSCT and occurs in 30% to 40% of cases.[19,26,27] While the role of donor lymphocyte infusions is uncertain, it has been reported that approximately 50% of patients with relapsed JMML can be successfully treated with a second HSCT.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with juvenile myelomonocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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-ABL 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 three clinical phases: chronic, accelerated, and blast crisis. Chronic phase, which lasts for approximately 3 years if untreated, usually presents with side effects secondary to hyperleukocytosis such as weakness, fever, night sweats, bone pain, respiratory distress, priapism, left upper quadrant pain (splenomegaly), and, rarely, hearing loss and visual disturbances. The accelerated phase is characterized by progressive splenomegaly, thrombocytopenia, and increased percentage of peripheral and bone marrow blasts, along with accumulation of karyotypic abnormalities in addition to the Ph chromosome. Blast crisis is notable for the bone marrow, showing greater than 30% blasts and a clinical picture that is indistinguishable from acute leukemia. Approximately two-thirds of blast crisis is myeloid and the remainder lymphoid, usually of B lineage. Patients in blast crisis will die within a few months.
In the pre-imatinib era, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary treatment with curative intent 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. As compared with transplant in chronic phase, transplantation in accelerated or blast crisis, as well as a 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, supporting the contribution of a graft-versus-leukemia effect to favorable outcome following allogeneic HSCT.
The introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec) as a therapeutic drug targeted at inhibiting the BCR-ABL fusion kinase revolutionized the treatment of patients with CML for both children and adults. As most data for 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 for children.
Treatment of CML in Adults with TKIs
Imatinib mesylate is a potent inhibitor of the ABL tyrosine kinase, and also of PDGF receptors (alpha and beta) and KIT. Imatinib mesylate treatment achieves clinical, cytogenetic, and molecular remissions (as defined by the absence of BCR-ABL fusion transcripts) in a high proportion of CML patients treated in chronic phase. Imatinib mesylate replaced the use of alpha-interferon in the initial treatment of CML based on the results of a large phase III trial comparing imatinib mesylate with interferon plus cytarabine (IRIS).[11,12] Patients receiving imatinib mesylate had higher complete cytogenetic response rates (76% vs. 14% at 18 months)  and the rate of treatment failure diminished over time, from 3.3% and 7.5% in the first and second years of imatinib mesylate treatment, respectively, to less than 1% by the fifth year of treatment. After censoring for patients who died from causes unrelated to CML or transplantation, the overall estimated survival rate for patients randomly assigned to imatinib mesylate was 95% at 60 months.
Guidelines for imatinib mesylate treatment have been developed for adults with CML based on 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-ABL/control gene ratio).[13,14,15] The identification of BCR-ABL kinase domain mutations at the time of failure or of suboptimal response to imatinib mesylate treatment also has clinical implications, as there are alternative BCR-ABL kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib mesylate.[13,17,18] Poor adherence is a major reason for loss of complete cytogenetic response and imatinib mesylate failure for adult CML patients on long-term therapy.
Two additional TKIs have received regulatory approval for the frontline chronic phase CML indication, nilotinib and dasatinib. Dasatinib was approved on the basis of a phase III trial comparing dasatinib (100 mg daily) with imatinib mesylate (400 mg daily). Similarly, nilotinib (at a dose of either 300 mg or 400 mg twice daily) was compared in a phase III trial with imatinib mesylate (400 mg daily). For both agents, superiority over imatinib mesylate was demonstrated for complete cytogenetic response rate and for major molecular response rate, which has led to the use of these agents as first-line therapy in adults with CML. These agents have not been extensively tested in children yet. Additional follow-up will be required to demonstrate the impact of these agents on clinical endpoints such as progression to accelerated/blast phase and overall survival.
Although imatinib mesylate is an active treatment for CML, there is limited evidence that it is curative. Most adults with CML treated with imatinib mesylate continue to have BCR-ABL transcripts detectable by highly sensitive molecular methods, although the rate of molecular complete remission does increase with duration of therapy.[22,23] Six of 12 adults with molecularly undetectable disease who stopped imatinib mesylate lost their molecular remission within 18 months of treatment cessation.[24,25,26] In the STIM (Stop Imatinib) trial, 100 patients older than 18 years and in complete molecular remission for at least 2 years had imatinib mesylate stopped. Of these patients, 41% maintained a complete molecular remission at 24 months. Further research is required before cessation of imatinib mesylate or other BCR-ABL targeted therapy for selected patients with CML in molecular remission can be recommended as a standard clinical practice.
Treatment of CML in Children
Imatinib mesylate has shown a high level of activity in children with CML that is comparable to that observed in adults, with approximately 75% achieving a complete cytogenetic response and with approximately 20% showing an unsatisfactory response to imatinib.[28,29,30,30,30,31] The pharmacokinetics of imatinib mesylate in children appears consistent with prior results in adults. Doses of imatinib mesylate used in phase II trials for children with CML have been 260 mg/m2 to 340 mg/m2, which provide comparable drug exposures as the adult flat doses of 400 mg to 600 mg.[30,31] Because there are no pediatric-specific data regarding optimal timing of monitoring for BCR-ABL transcript levels and for the presence of BCR-ABL kinase domain mutations, the monitoring guidelines described above for adults with CML are reasonable to utilize.
Imatinib mesylate is generally well tolerated in children, with adverse effects usually being mild to moderate and quickly reversible with treatment discontinuation or dose reduction.[30,31] Growth retardation occurs in some children receiving imatinib mesylate. The growth inhibitory effects of imatinib mesylate appear to be most pronounced in prepubertal children compared to pubertal children, and children receiving imatinib mesylate and experiencing growth impairment may show a return to normal growth rates when they reach puberty.
In children who develop a hematologic or cytogenetic relapse on imatinib mesylate or who have an inadequate initial response to imatinib mesylate, determination of BCR-ABL kinase domain mutation status should be considered to help guide subsequent therapy. Depending upon the patient's mutation status, alternative kinase inhibitors such as dasatinib or nilotinib can be considered based on adult experience with these agents.[20,21,34,35,36] A pediatric phase I study of dasatinib showed good tolerance for dasatinib in children at doses used to treat adults with CML, and nilotinib is under investigation in children with CML or Ph chromosome–positive ALL (NCT01077544 [CAMN107A2120]). In the presence of the T315I mutation, which is resistant to all FDA-approved kinase inhibitors, strong consideration should be given to performing an allogeneic transplant.
An important question is the impact of imatinib mesylate treatment on outcome for patients who subsequently proceed to allogeneic HSCT. A retrospective comparison of 145 patients who received imatinib mesylate prior to transplant compared with a historical cohort of 231 patients who did not, showed no difference in early hepatotoxicity or engraftment delay. In addition, overall survival, disease-free survival, relapse, and nonrelapse mortality were similar between the two cohorts. The only factor associated with poor outcome in the cohort that received imatinib mesylate was a poor initial response to imatinib mesylate. Further evidence for a lack of effect of pretransplant imatinib mesylate on posttransplant outcomes was supplied by a report from the Center for International Blood and Marrow Transplant Research comparing outcomes for 181 pediatric and adult subjects with CML in first chronic phase treated with imatinib mesylate before HSCT with that for 657 subjects who did not receive the agent before HSCT. Among the patients in first chronic phase, imatinib mesylate therapy before HSCT was associated with better overall survival. A third report of allogeneic HSCT following imatinib supports the efficacy of the strategy of transplantation of patients with imatinib mesylate failure in first chronic phase; 3-year overall survival was 94% for this group (n = 37) with approximately 90% achieving a complete molecular remission following HSCT. The available data suggest that imatinib mesylate prior to transplant does not have a deleterious effect on outcome.
The following are examples of national and/or institutional clinical trials that are currently being conducted for patients with refractory CML.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Despite second remission induction in over one-half of children with acute myeloid leukemia (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.[1,2] Approximately 50% to 60% of relapses occur within the first year following diagnosis, with most relapses occurring by 4 years from diagnosis. The vast majority of relapses occur in the bone marrow, with central nervous system (CNS) relapse being very uncommon. Length of first remission is an important factor affecting the ability to attain a second remission; children with a first remission of less than 1 year have substantially lower rates of remission than children whose first remission is greater than 1 year (50%–60% vs. 70%–90%, respectively).[2,3,4] Survival for children with shorter first remissions is also substantially lower (approximately 10%) than that for children with first remissions exceeding 1 year (approximately 40%).[2,3,4]
Regimens that have been successfully used to induce remission in children with recurrent AML have commonly included high-dose cytarabine given in combination with other agents, such as mitoxantrone, fludarabine and idarubicin,[5,6,7], L-asparaginase, etoposide, and clofarabine.[9,10,11] The standard-dose cytarabine regimens used in the United Kingdom Medical Research Council AML 10 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 report of 379 children with AML who relapsed after initial treatment on BFM protocols, a second complete remission (CR2) rate was 63% and overall survival was 23%.[Level of evidence: 3iiiA] The most significant prognostic factors associated with a favorable outcome after relapse included achieving CR2, a relapse greater than 12 months from initial diagnosis, no allogeneic bone marrow transplant in first remission, and favorable cytogenetics (t(8;21), t(15;17), and inv(16)). The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium also identified duration of previous remission as a powerful prognostic factor, with 5-year OS rates of 54% ± 10% for patients with greater than 12 months first remission duration compared with 19% ± 6% for patients with shorter periods of first remission.
The selection of further treatment following the achievement of a second remission depends on prior treatment as well as individual considerations. Consolidation chemotherapy followed by HSCT is conventionally recommended, though there are no controlled prospective data regarding the contribution of additional courses of therapy once CR2 is obtained. Unrelated donor HSCT has been reported to result in 5-year probabilities of leukemia-free survival of 45%, 20%, and 12% for patients with AML transplanted in second complete remission, overt relapse, and primary induction failure, respectively.[Level of evidence: 3iiA] The optimum type of preparative transplant regimen and source of donor cells has not been determined, although alternative donor sources, including haploidentical donors, are being studied. Importantly, however, there are no data that suggest total-body irradiation (TBI) is superior compared with busulfan-based myeloablative regimens.[16,17]
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 months from first transplant), achievement of complete response prior to the second procedure, and use of a TBI-based regimen (after receiving a non-TBI regimen for the first procedure).
Clinical trials, including new chemotherapy and/or biologic agents and/or novel bone marrow transplant (autologous, matched or mismatched unrelated donor, cord blood) programs, are also considerations. Information about ongoing clinical trials is available from the NCI Web site
Isolated CNS Relapse
Isolated CNS relapse occurs in 3% to 5% of pediatric AML patients.[19,20] Factors associated with an increased risk of isolated CNS relapse include the following:
The outcome of isolated CNS relapse is similar to bone marrow relapse; in one study, the 8-year overall survival for a cohort of children with an isolated CNS relapse was 26% ± 16%.
Recurrent Acute Promyelocytic Leukemia (APL)
Despite the improvement in outcomes for patients with newly diagnosed APL, approximately 10% to 20% of patients relapse.
An important issue in children is the prior 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. For children with recurrent APL, the use of arsenic trioxide as a single agent or regimens including all-trans retinoic acid 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 following treatment with this agent.[22,23,24,25] Data are limited on the use of arsenic trioxide in children, though published reports suggest that children with relapsed APL have a response to arsenic trioxide similar to that of adults.[22,24,26] 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 anti-CD33/calicheamicin monoclonal antibody as a single agent resulted in 91% (9 of 11 patients) molecular remission after two doses and in 100% of patients (13 of 13) after three doses, thus demonstrating excellent activity of this agent in relapsed APL.
Retrospective pediatric studies have reported 5-year event-free survival (EFS) rates after either autologous or allogeneic transplantation approaches to be similar at approximately 70%.[30,31] When considering autologous transplantation, a study in adult patients demonstrated improved 7-year EFS (77% vs. 50%) when both the patient and the stem cell product had negative promyelocytic leukemia/retinoic acid receptor alpha fusion transcript by polymerase chain reaction (molecular remission) prior to transplant. Another study demonstrated that among seven patients undergoing autologous HSCT and whose cells were minimal residual disease (MRD)-positive, all relapsed in less than 9 months after transplantation; however, only one of eight patients whose autologous donor cells were MRD-negative relapsed. Another report demonstrated that the 5-year EFS for patients who underwent autologous HSCT in second molecular remission was 83.3% compared with 34.5% for patients who received only maintenance therapy. Such data support the use of autologous transplantation in patients in a MRD-negative CR2 who have poorly matched allogeneic donors.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
While the issues of long-term complications of cancer and its treatment cross many disease categories, there are several important issues that relate to the treatment of myeloid malignancies that are worth stressing. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
The Children's Cancer Survivor Study examined 272 survivors of childhood acute myeloid leukemia (AML) who did not undergo a hematopoietic stem cell transplant (HSCT). This study identified second malignancies (cumulative incidence, 1.7%) and cardiotoxicity (cumulative incidence, 4.7%) as significant long-term risks. Cardiomyopathy has been reported in 4.3% of survivors of AML based on Berlin-Frankfurt-Munster studies. Of these, 2.5% showed clinical symptoms. Retrospective analysis of a single study suggests cardiac risk may be increased in children with Down syndrome, but prospective studies are required to confirm this finding.
In a review from one institution, the highest frequency of adverse long-term sequelae for children treated for AML included the following incidence rates: growth abnormalities (51%), neurocognitive abnormalities (30%), transfusion-acquired hepatitis (28%), infertility (25%), endocrinopathies (16%), restrictive lung disease (20%), chronic graft-versus-host disease (20%), secondary malignancies (14%), and cataracts (12%). It is noted that most of these adverse sequelae are the consequence of myeloablative, allogeneic HSCT. Although cardiac abnormalities were reported in 8% of patients, this is an issue that may be particularly relevant with the current use of increased anthracyclines in clinical trials for children with newly diagnosed AML. Another study examined outcomes for children younger than 3 years with AML or acute lymphoblastic leukemia (ALL) who underwent HSCT. The toxicities reported include growth hormone deficiency (59%), dyslipidemias (59%), hypothyroidism (35%), osteochondromas (24%), and decreased bone mineral density (24%). Two of the 33 patients developed secondary malignancies. Of note, survivors had average intelligence but frequent attention-deficit problems and fine-movement abnormalities compared with population controls. In contrast, The Bone Marrow Transplant Survivor Study compared childhood AML or ALL survivors with siblings using a self-reporting questionnaire. The median follow-up was 8.4 years and 86% of patients received total-body irradiation (TBI) as part of their preparative transplant regimen. Compared with siblings, survivors of leukemia who received an HSCT had significantly higher frequencies of several adverse effects, including diabetes, hypothyroidism, osteoporosis, cataracts, osteonecrosis, exercise-induced shortness of breath, neurosensory impairments and problems with balance, tremor, and weakness. The overall assessment of health was significantly decreased in survivors compared with siblings (odds ratio = 2.2; P = .03). Significant differences were not observed between regimens using TBI compared with chemotherapy only, which mostly included busulfan. The outcomes were similar for patients with AML and ALL, suggesting that the primary cause underlying the adverse late effects was undergoing an HSCT.
A population-based study of survivors of childhood AML who had not undergone an HSCT reported equivalent rates of educational achievement, employment, and marital status compared with siblings. AML survivors were, however, significantly more likely to be receiving prescription drugs, especially for asthma, compared with siblings (23% vs. 9%; P = .03). Chronic fatigue has also been demonstrated to be a significantly more likely adverse late effect in survivors of childhood AML than in survivors of other malignancies.
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 by the Children Oncology Group's Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers and the National Comprehensive Cancer Network (NCCN) 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. Different templates that address this issue are available, such as those from the Cancer Survivor's Treatment Record and the Cancer Survivor's Medical Treatment Summary.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Classification of Pediatric Myeloid Malignancies
Added text to state that a follow-up study by the international collaborative group demonstrated that additional cytogenetic abnormalities further influenced outcome of children with MLL translocations, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.
Treatment Overview for Acute Myeloid Leukemia (AML)
Added Loken et al. as reference 52.
Children with Down Syndrome
Added Sorrell et al. as reference 24.
Therapy-Related AML/Myelodysplastic Syndromes
Added this new section.
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
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childAML/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-04-04
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