Acute Myeloid Leukemia

OVERVIEW: What every practitioner needs to know

Acute myeloid leukemia (AML) is a form of blood cancer characterized by clonal expansion of malignant myeloid blasts in the bone marrow, blood, or other tissues. The initial diagnosis and management of AML should be considered a medical emergency and is best provided in a specialized pediatric oncology treatment center.

Are you sure your patient has acute myeloid leukemia? What are the typical findings for this disease?

The majority of children with AML present with a constellation of symptoms that are attributable to bone marrow infiltration with leukemic blasts. Additional symptoms can be caused by infiltration of other tissues. Many symptoms are general and relatively nonspecific. Not all patients will have all symptoms but the following are typical:

Fever, fatigue, and/or bone pain are observed in the majority of patients.

Bone pain, arthralgia, and/or arthritis may manifest as decreased activity, general fussiness, irritability, or refusal to walk. Long bones, in which the marrow cavities are being replaced with myeloblasts, are often more affected; however generalized bone pain and discomfort are common.

Weight loss, if present, is usually relatively mild, but anorexia is frequent.

Bleeding manifestations due to thrombocytopenia are common. Bruising and petechiae are frequent. Often caregivers will note a "rash" or "red spots," which are actually petechiae. Central nervous system (CNS) bleeding, retroperitoneal bleeding, severe gastrointestinal bleeding, or hemorrhagic stroke are rare but life-threatening complications. The risk of serious bleeding complications is particularly high in patients with newly diagnosed acute promyelocytic leukemia (APL; M3 by the French-American-British [FAB] classification), in which thrombocytopenia is often accompanied by disseminated intravascular coagulopathy.

Anemia may manifest as pallor, headache, fatigue, dizziness, decreased energy or exercise tolerance, and sometimes syncope.

Hepatomegaly and/or splenomegaly resulting from leukemic infiltration are present in many patients at diagnosis but are often overlooked.

Lymphadenopathy is more common in acute lymphoblastic leukemia (ALL) than in AML but may occur in either.

A rare but important presentation of AML is spinal cord compression, which results from a chloroma (a solid tumor resulting from the localized proliferation of myeloblasts) in the paraspinal/epidural region. Chloromas occur in approximately 10% of patients with AML. They can occur anywhere in the body but most commonly in skin or bones. They are particularly common in cases with the t(8;21) translocation with FAB M2 morphologic subtype but are also common in patients with FAB M4 and M5 subtypes.

CNS involvement occurs in about 5% of patients with AML, with higher rates occurring in those with AML with monocytic differentiation (FAB M4 or M5 classification), particularly if the white blood cell (WBC) count is high. In most cases, CNS involvement is asymptomatic, but sometimes patients present with headaches, meningismus, or cranial nerve palsies.

Hyperleukocytosis becomes a potential clinical problem when the WBC count rises to greater than 100,000/µL. Circulating blood can become hyperviscous with markedly elevated WBCs, leading to sludging of blood in brain, lungs, kidneys, and other organs, manifested by respiratory distress/hypoxia, impaired consciousness/stroke, and renal insufficiency.

Not all patients with AML have high WBC counts. Even subtle abnormalities on the complete blood count (CBC) may suggest leukemia. These may include a mild increase or decrease in the WBC count or some suppression in any or all lineages of red cells, white cells, and platelets. Pancytopenia may be subtle or more profound. Almost all patients with AML have one or more abnormalities seen in the CBC.

Leukemic blasts may not be present on the peripheral blood smear, and only a bone marrow aspirate and/or biopsy can confirm the diagnosis in this situation. Light microscopy is not sufficient for specific diagnostic information, although it can delineate AML from ALL most of the time. In many circumstances, special stains and laboratory techniques are required to confirm the diagnosis and phenotype. Additional analyses with flow cytometry and cytogenetic techniques (both conventional and molecular) are required to further categorize different subsets of AML and to appropriately plan treatment.

Some children with a new diagnosis of AML present with tumor lysis syndrome, a metabolic derangement caused by the release of intracellular contents in the face of cell death caused by rapid cell turnover. The most common findings can be seen on routine chemistry panels, including elevations in potassium, phosphorus, and uric acid levels, which can lead to secondary hypocalcemia and renal injury with elevated blood urea nitrogen and creatinine levels. Transaminase levels may also be elevated.

What other disease/condition shares some of these symptoms?

Many children who are eventually diagnosed with AML have been evaluated for other causes of their symptoms. Commonly, patients may have been evaluated for recurrent fevers, fatigue, adenopathy, splenomegaly, hepatomegaly, weight loss, and bone pain.

Most commonly, infectious diseases and rheumatologic conditions are considered in the differential diagnosis.

Infections, particularly viral disease, not only mimic the physical symptoms and findings but also may share an elevated WBC count or some element of pancytopenia as well as an elevated erythrocyte sedimentation rate elevated (ESR) or C-reactive protein (CRP) level as well.

Joint pain, fever, hepatosplenomegaly, and pallor are common presenting features in both systemic-onset juvenile rheumatoid arthritis (JRA) and leukemia. A bone marrow aspirate should be considered to rule out leukemia before treatment with steroids in suspected cases of systemic-onset JRA.

A smaller percentage of patients see orthopedic specialists because of recurrent fever and bone pain, and a subset of patients are actually treated for osteomyelitis because of these symptoms when radiologic imaging shows bony abnormalities, which are mistaken for infection but actually represent bone marrow or bony involvement of leukemic infiltration.

Patients may also have other malignancies. The subtype of leukemia cannot be diagnosed based on signs and symptoms because those of AML are quite similar to those of ALL and sometimes chronic myeloid leukemia. Sometimes the signs and symptoms of other "small round blue-cell tumors" of childhood, including Ewing sarcoma, lymphoma, rhabdomyosarcoma, or neuroblastoma can mimic those of AML. Each of these tumors shares a similar appearance under the microscope, and only further testing coupled with imaging and clinical information can distinguish them from each other.

Aplastic anemia or other syndromes of bone marrow failure may present with similar symptoms, physical findings, and blood counts, such as pancytopenia, anemia, headaches, infections, petechiae, or bleeding manifestations.

What caused this disease to develop at this time?

The vast majority of cases of childhood AML occur in patients with no known predisposition and can be considered sporadic.

The most common inherited predisposition for the development of AML (or ALL) is Down syndrome. Children with Down syndrome have an approximately 10- to 20-fold increased risk of leukemia compared with other children. During the first 3 years of life, children with Down syndrome have a particularly high risk of the megakaryoblastic subtype of AML (FAB M7) developing.

Overall, patients with Down syndrome compose approximately 10% of pediatric patients with AML. In addition, approximately 10% of neonates with Down syndrome manifest a transient myeloproliferative disorder (TMD). This disorder mimics congenital AML but usually improves spontaneously within 4-6 weeks. Retrospective surveys indicate that FAB M7 AML will develop in 20%-30% of infants with Down syndrome and TMD will develop before 3 years of age.

Inherited bone marrow failure syndromes predispose to AML. Some of these syndromes result in trilineage failure (e.g., Fanconi anemia, congenital dyskeratosis) whereas others primarily affect one or two hematopoietic lineages (e.g., Kostmann syndrome, Diamond-Blackfan anemia, Schwachman-Diamond syndrome, congenital amegakaryoctyic thrombocytopenia).

Other inherited disorders associated with an increased incidence of AML development but not typically characterized by bone marrow failure include Li-Fraumeni syndrome, Bloom syndrome, familial platelet disorder with a propensity to the development of AML, neurofibromatosis type 1, and Noonan syndrome.

There have been rare reports of kindreds with several cases of AML occurring over multiple generations in which no known predisposing syndrome or other condition is identified, but in which a common constitutional chromosomal abnormality has been detected. Monosomy 7 has been the most common abnormality noted.

There are several acquired conditions that have been associated with an increased risk of AML. Patients with severe aplastic anemia (SAA) treated with immunosuppressive regimens and recombinant human granulocyte colony-stimulating factor have been noted to have a significant risk (up to 20%) of myelodysplastic syndrome (MDS) or AML developing.

Paroxysmal nocturnal hemoglobinuria is also associated with an increased risk of the development of MDS and AML but occurs less frequently than SAA in the pediatric age group.

MDS is considered a predisposing condition for AML development in any age group, but AML arising from MDS is far more common in adults than in children.

Exposure-related risk factors for AML include ionizing radiation and various chemotherapeutic drugs.

There are several rare inherited and acquired risk factors that have been shown to be associated with increased risk of AML in childhood.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

CBC and differential of the WBC count is abnormal in the overwhelming majority of children with AML and may show cytopenias of one, two, or three lineages.

The peripheral blood smear may show blasts and/or subtle changes that suggest an infiltrative process, including presence of "teardrop" red cells, relative thrombocytopenia (platelet count <100,000/µL), or lack of an appropriate reticulocyte count for the degree of anemia.

Lactate dehydrogenase levels are frequently elevated, as it is contained within WBCs, and "spills" out when these cells turn over.

Uric acid levels are often elevated because of rapid cell turnover and breakdown of intracellular contents, including DNA.

Serum chemistry panels may reflect mild to moderate renal insufficiency with an elevated creatinine level, hyperphosphatemia, hypocalcemia, and other metabolic markers of tumor lysis syndrome.

The ESR and CRP level are usually elevated and are not particularly helpful because they do not help delineate AML from other inflammatory or infectious processes. The converse is also true; a normal ESR or CRP level would not rule out AML.

Coagulation panels (prothrombin time, international normalized ratio, activated partial thromboplastin time) can demonstrate clinically significant coagulopathy, particularly in APL (FAB M3).

Would imaging studies be helpful? If so, which ones?

In general, imaging for pediatric AML is fairly limited, except when focal physical examination findings suggest that the patient may have a chloroma or internal bleeding due to coagulopathy.

Confirming the diagnosis

Once suspected based on a CBC, clinical history and physical examination, the definitive diagnosis of AML is made by bone marrow aspiration and biopsy. When the WBC count is high and there are peripheral blood blast cells, flow cytometry can be performed on the peripheral blood. Although this can give an accurate diagnostic picture, bone marrow aspiration and biopsy are still the gold standard and should be pursued unless the procedures are medically contraindicated.

Morphologic evaluation is performed by standard light microscopy of bone marrow aspirate smears stained with Wright-Giemsa or similar stains.

Flow cytometric assessment of surface antigen expression is the definitive approach to classifying leukemia.

Chromosomal analyses by both standard karyotyping and fluorescence in situ hybridization (FISH) should be performed in children with AML because they detect the presence of chromosomal abnormalities (e.g., translocations, deletions) that are diagnostic, prognostic, and in many cases guide therapeutic decisions. The FISH studies should, at a minimum, include probes to evaluate for inv(16)/t(16;16), t(8;21), t(15;17), 11q23, -7 and -5/5q-.

Polymerase chain reaction–based molecular testing should also be performed to detect the presence of mutations in certain genes (e.g., FLT3, NPM1, CEBPA) that are prognostic and may guide treatment.

A lumbar puncture is performed to assess the presence or absence of leukemic involvement in the CNS. Cytologic examination is the only means to assess this appropriately. This should be done by a pediatric hematology/oncology practitioner who has extensive experience in treating pediatric oncology patients. Imaging is not generally indicated unless there are focal neurologic signs.

If you are able to confirm that the patient has acute myeloid leukemia, what treatment should be initiated?

Patients suspected of having AML should be stabilized and transferred to the care of trained pediatric oncologists in a setting that can support intensive care of children. Expertise in pediatric surgery and anesthesia is helpful, as is a strong transfusion medicine service.

Aggressive blood product support with platelets and, if coagulopathy is present, fresh frozen plasma should be considered to reduce the risk of serious bleeding. In cases of suspected APL, early treatment with the differentiation-inducing agent all-trans retinoic acid (ATRA) has been shown to decrease the risk of serious bleeding.

Patients with newly diagnosed leukemia are at significant risk of harboring invasive bacterial and fungal infections because of prolonged absolute and functional neutropenia. Cultures from sterile sites should be performed in febrile patients and prompt use of empirical antimicrobial agents should be strongly considered.

Patients with a high WBC count (>100,000/µL) are at risk for complications of hyperleukocytosis. Symptomatic patients should undergo prompt exchange transfusion or leukopheresis. Data support the use of similar procedures for asymptomatic patients with hyperleukocytosis, but controversy exists regarding the optimum WBC level at which these procedures should be performed. Definitive leukemia-directed therapy should begin as soon as possible in a patient with hypderleukocytosis.

Initially, patients should be hydrated with 1.5-2 times maintenance intravenous fluids (IVF) that are alkalinized to try to maintain urine pH of approximately 6.5-7. A typical IVF would be D5W1/4NS with 25-50 mEq NaHCO3 at 2 times maintenance. This is done to maintain good flow through the kidneys and prevent renal damage from tumor lysis and increase the solubility of uric acid that is excreted in the urine.

Patients should not be given any steroid medication if leukemia is suspected, as steroids can mask a complete diagnosis by temporarily decreasing the leukemic burden.

In emergent circumstances, any blood product that is transfused should be leukofiltered (to prevent cytomegalovirus (CMV) transmission) and irradiated. The preference is to use CMV-negative products initially, until definitive serologic results are available. It is wise to discuss any potential transfusions with the receiving pediatric oncologist to determine the best transfusion plan and product selection in advance.

Patients should be given medication to prevent and/or treat acute tumor lysis syndrome. In most cases, allopurinol, a xanthine oxidase inihibitor that decreases production of uric acid, is used. Typical dosing of allopurinol is 100 mg/m2/dose every 8 hours. For patients with significant hyperphosphatemia, a phosphate binder such as aluminum hydroxide is used.

Rasburicase, a recombinant form of urate oxidase that directly cleaves and breaks down uric acid, is indicated for patients with clinical manifestations of tumor lysis or those at high risk because of a very elevated WBC count (>50,000-100,000/µL) or substantial extramedullary tumor burden. Because rasburicase is quite expensive, it is usually not given to patients with low risk for tumor lysis, as the cost-benefit ratio is not favorable. Conversely, in patients at high risk for tumor lysis, the cost of sometimes a single dose of rasburicase and the clinical benefit manifested far outweigh the risk for and cost of renal dialysis that may be needed in these patients.

Once the definitive diagnosis is made, leukemia-directed treatment can begin.

What are the standard treatment approaches for childhood acute myeloid leukemia?

Treatment for AML is relatively standardized and the majority of children are treated on or according to a regimen derived from an ongoing or recently completed clinical trial.

Patients with Down syndrome–related AML and patients with APL are treated on protocols separate from those that other children with AML receive.

For newly diagnosed patients, the standard of care includes an attempt to induce remission with intensive combination chemotherapy. Induction therapy for AML typically includes a combination of the two most active agents, cytarabine (typically given at "low" doses by either continuous infusion or twice daily, for 7-10 days, and an anthracycline. Additional agents used during the first course of induction therapy include etoposide and/or 6-thioguanine.

With contemporary therapy, 80%-85% of children with AML will enter remission with one cycle of chemotherapy, with failures due to refractory leukemia and/or death from toxicity or complications such as fatal infection.

After induction therapy is completed, leukemia genetic risk factors are integrated with measures of early treatment response to determine postinduction therapy. Sensitive measures of end-induction minimal residual disease (MRD) that can detect a 0.1% or lower burden of remaining leukemia cells are used to measure treatment response and have been shown to be predictive of ultimate prognosis.

Patients predicted to be at high risk of relapse based on these factors are generally offered allogeneic hematopoietic stem cell transplantation (HSCT) in at first remission if a suitable donor (either related or unrelated) can be identified. Patients predicted to be at relatively low risk of relapse based on these factors are generally treated with three-four additional courses of chemotherapy, most of which include high-dose cytarabine as the backbone.

Each cycle of AML therapy is typically associated with 2-4 weeks of profound panycytopenia and a significant risk of invasive bacterial and/or fungal infection. Because of this, supportive care is a critical component of AML therapy. Patients are often hospitalized during this period of pancytopenia with a very low threshold to start empirical antibiotic therapy. Prophylactic treatment to prevent yeast/fungal infections is typically administered, but controversy exists regarding the choice of agents.

Unlike ALL, AML therapy does not include a prolonged, low-intensity "maintenance" phase, as randomized studies have shown that maintenance therapy does not improve outcomes in AML.

Targeted therapies directed at the genetic lesions that cause leukemia are now being developed and tested; in AML, the best example is inhibitors of the receptor tyrosine kinase FLT3 for patients with a certain type of mutation in the FLT3 gene.

AML therapy generally includes preventve, presymptomatic CNS-directed treatment with intrathecally administered chemotherapy.

What are the adverse effects associated with each treatment option?

The most common serious acute side effect from chemotherapy is myelosuppression, resulting in anemia, neutropenia, and thrombocytopenia. Other common acute chemotherapy side effects include nausea, vomiting, mucositis, alopecia, and fatigue. Rare but serious late effects of chemotherapy include infertility and a second cancer (most commonly treatment-related AML).

Individual chemotherapy drugs have their own unique side effect profile.

Anthracyclines and related drugs (doxorubicin, daunorubicin, mitoxantrone): Risk of acute and long-term cardiotoxicity

Cytarabine: Acute fever, hand-foot syndrome, capillary leak syndrome

Etoposide: Acute anaphylaxis/allergic reactions

HSCT is associated with myriad adverse effects related both to the intensive chemotherapy given before the stem cell infusion (e.g., infection, severe hepatotoxicity)and to the allogeneic immunologic effects that occur (graft versus host disease).

What are the possible outcomes of childhood acute myelogenous leukemia?

With proper treatment, the majority of children diagnosed with AML today will be cured. Overall, approximately 60% of children diagnosed with AML will be long-term survivors, with some subsets (APL, Down syndrome–related AML, core binding factor AML) having an approximate 80% chance for cure. Other patient subsets have a much poorer prognosis. Recent work has focused on identifying new agents with novel mechanisms of action and improving the effectiveness and tolerability of HSCT.

Without treatment, AML is fatal. Families should be told gently that with modern treatment, cure is possible but will not occur in a significant proportion of patients.

The majority of individuals successfully treated for AML in childhood can expect to have an excellent quality of life after treatment, attaining an academic, employment, and social status in adulthood that is similar to their siblings or age- and socioeconomically matched peers. However, long-term side effects and late complications are quite possible.

What causes childhood acute myelogenous leukemia and how frequent is it?

In the United States, the incidence of AML in children younger than 20 years old is approximately 7/million/year, or approximately 600 new cases/year. This accounts for 19% of leukemia in childhood, with the remainder being ALL (76%) and the rare chronic leukemias of childhood (5%). The incidence of AML in children aged 0 to 19 years in the United States increased at a rate of 1.3%/year from 1975-2004.

Unlike ALL, the incidence of AML in children does not have an obvious age peak, although there are subtle increases in incidence in the neonatal and adolescent age periods. After the age of 20 years, the incidence of AML increases steadily with age so that in adults, AML is approximately four times as common as ALL. The incidence of AML is not significantly different in boys and girls.

There is evidence of variation in childhood AML incidence with race, ethnicity and geography. In the United States, Hispanic children have a significantly higher incidence of AML (9 per million), which is primarily due to an increased incidence of the APL subtype.

The incidence of secondary AML after treatment for other malignancies is increasing in pediatric patients, likely as a result of increased survivorship and increased use of epipodophyllotoxins (such as etoposide) for the treatment of many solid tumors of childhood. Risk of secondary AML has been linked not only to epipodophyllotoxins but also to anthracyclines (which, like epipodophyllotoxins, inhibit topoisomerase II), alkylating chemotherapy agents, and irradiation.

How do these pathogens/genes/exposures cause the disease?

Several lines of evidence suggest that childhood AML is a disease that results from an accumulation of two or more perturbations in the function of certain oncogenes and/or tumor suppressor genes.

The most common recurrent cytogenetic abnormality in children and adults with AML is the t(8;21) translocation, which results in expression of the AML1-ETO fusion protein. Greaves et al examined DNA isolated from the archived neonatal screening blood spot cards (Guthrie cards) of children in whom t(8;21)/AML1-ETO AML developed up to 10 years later and found that the t(8;21)/AML1-ETO was detectable at birth in most of these children.

This study provided evidence that a significant proportion of childhood AML cases originate in utero, with the appearance of a myeloid precursor that becomes “preleukemic” as the result of a first, “permissive” mutation. Only later, sometimes years, does one of these preleukemic precursors acquire the second, “promotional” mutation that results in a full-blown case of leukemia.

A similar phenomenon has been demonstrated in children with ALL with the t(12;21)/TEL-AML1 and the t(4;11)/MLL-AF4 cytogenetic abnormalities. A model of myeloid leukemogenesis has emerged in which mutations that primarily cause impaired differentiation, such as AML1-ETO and PML–retinoic acid receptor-alpha (RAR-a), cooperate with mutations that confer a proliferative/survival advantage, such as FLT3 or RAS mutations, to cause AML.

The specific recurring cytogenetic and molecular abnormalities that have been associated with AML can be broadly classified as chimeric transcription factors, mutationally activated oncogenes, or other miscellaneous abnormalities.

The chimeric transcription factors are generally produced as a result of chromosomal translocations that fuse a DNA-binding domain of a transcriptional activator to a transcriptional repressor. The transcriptional repressor is thereby redirected to target genes of the transcriptional activator, many of which have been shown to play important roles in myeloid differentiation. Functionally, this is thought to produce the block in differentiation that characterizes acute leukemia. The presence of one of these translocations in an individual case of AML may have significant prognostic and therapeutic implications.

AML with t(8;21) and AML1-ETO fusion: The t(8;21) translocation is associated with characteristic clinical, morphologic, and immunophenotypic features. Chloromas (extramedullary collections of leukemia cells, also known as granulocytic sarcoma) occur in approximately 20% of cases. More than 80% of t(8;21) cases are classified as FAB type M2; conversely, of all cases classified as FAB M2, approximately 40% will be found to harbor t(8;21). The immunophenotype of cases with t(8;21) often includes expression of the B-cell antigen CD19 and the natural killer cell antigen CD56. In both adults and children, t(8;21) is associated with a favorable prognosis.

AML with inv(16) or t(16;16) and CBFB-MYH11 fusion: The inv(16) and t(16;16) abnormalities are essentially pathognomonic for the FAB M4Eo subtype, and both confer a favorable prognosis for both adults and children with AML.

AML with (15;17) and PML-RARA fusion (and variants): AML with t(15;17) is invariably associated with APL, a distinct subtype of AML that is treated differently from other types of AML because of its marked sensitivity to the differentiating effects of ATRA and arsenic trioxide. The t(15;17) translocation leads to the production of a fusion protein involving RAR-α and PML. Other much less common translocations involving RAR-α can also result in APL [e.g., t(11;17) involving the PLZF gene]. Identification of patients with t(11;17) is important because of their decreased sensitivity to ATRA.

AML with MLL gene rearrangements: Translocations of chromosomal band 11q23 involving the MLL gene, including most cases of AML secondary to epipodophyllotoxin, are associated with monocytic differentiation (FAB M4 and M5). Prognosis is intermediate for de novo AML with MLL rearrangement but is poor for treatment-related cases.

AML with t(1;22) and OTT-MAL fusion: The t(1;22)(p13;q13) translocation is restricted to acute megakaryoblastic leukemia (AMKL) and occurs in as many as one third of AMKL cases in children. In the small number of children reported, the presence of t(1;22) appears to be associated with poor prognosis, although long-term survivors have been noted after intensive therapy.

Mutationally Activated Oncogenes

AML with FLT3 mutations: Internal tandem duplication (ITD) mutations of FLT3 occur in approximately 15% of children with AML and are associated with poor prognosis, particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele. Mutations in the kinase domain (KD) of FLT3 have also been identified in about 7% of children with AML. FLT3-KD mutations do not have the same negative prognostic significance as FLT3-ITD mutations. FLT3 mutations occur in 30%-40% of children and adults with APL, and FLT3-ITD mutations are strongly associated with the microgranular variant (M3v) and with hyperleukocytosis. The prognostic influence of FLT3-ITD in APL is unclear.

AML with RAS or c-KIT mutations:RAS (N-RAS or KRAS) mutations occur in approximately 20% and c-KIT mutations in approximately 5% of pediatric cases of AML. However, activating c-KIT mutations occur in 20%-40% of cases of AML with t(8;21) and inv(16), and are associated with a relatively poor prognosis when compared with similar patients without c-KIT mutations.

Miscellaneous Abnormalities

Chromosomal abnormalities associated with poorer prognosis in adults with AML include those involving chromosome 7 [monosomy 7 and del(7q)], chromosome 5 [monosomy 5 and del(5q)] and the long arm of chromosome 3 or t(3;3)(q21;q26)). These cytogenetic subgroups are also associated with poor prognosis in children with AML.

GATA-1: GATA-1 mutations are present in most, if not all, children with Down syndrome with either transient myeloproliferative disease (TMD) or AMKL. GATA-1 mutations are not observed in children with AMKL who do not have Down syndrome nor in children with Down syndrome and other types of leukemia. GATA-1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells. GATA-1 mutations confer increased sensitivity to cytarabine, possibly by decreasing cytidine deaminase expression and thus providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.

CEBPA and NPM1: Mutations in CEBPA and NPM1 genes each occur in about 5%-10% of childhood AML cases and generally correlate with favorable outcome in patients with normal karyotype without FLT3/ITD.

How can childhood AML be prevented?

To date, there are no data to suggest that childhood AML is a preventable disease.

What is the evidence?

Creutzig, U, Zimmermann, M, Ritter, J. "Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials". Leukemia. vol. 19. 2005. pp. 2030-42.

(The German experience with childhood AML)

Kaspers, GJ, Zwaan, CM. "Pediatric acute myeloid leukemia: towards high-quality cure of all patients". Haematologica. vol. 92. 2007. pp. 1519-32.

(Nice overview of childhood AML treatment and prognosis)

Malinge, S, Izraeli, S, Crispino, JD. "Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome". Blood. vol. 113. 2009. pp. 2619-28.

(Clinical and biologic review of Down syndrome–related transient myeloproliferative disease and acute leukemia.)

Mulrooney, DA, Dover, DC, Li, S. "Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: a report from the Childhood Cancer Survivor Study". Cancer. vol. 112. 2008. pp. 2071-9.

(Late effects and survivorship in childhood AML)

Niewerth, D, Creutzig, U, Bierings, MB. "A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia". Blood. vol. 116. 2010. pp. 2205-14.

(Comprehensive discussion of the role of allogeneic HSCT in childhood AML)

Radhi, M, Meshinchi, S, Gamis, A. "Prognostic factors in pediatric acute myeloid leukemia". Curr Hematol Malig Rep. vol. 5. 2010. pp. 200-6.

(Review of prognostic factors and the basis for risk stratification in childhood AML)

Sanz, MA, Grimwade, D, Tallman, MS. "Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet". Blood. vol. 113. 2009. pp. 1875-91.

(Definitive guide to the treatment of acute promyelocytic leukemia)

Smith, FO, Alonzo, TA, Gerbing, RB. "Long-term results of children with acute myeloid leukemia: a report of three consecutive phase III trials by the Children's Cancer Group: CCG 251, CCG 213 and CCG 2891". Leukemia. vol. 19. 2005. pp. 2054-62.

(The North American experience with the treatment of childhood AML)

Vardiman, JW, Thiele, J, Arber, DA. "The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes". Blood. vol. 114. 2009. pp. 937-51.

(The current diagnostic approach and classification scheme for AML)

Ongoing controversies regarding etiology, diagnosis, treatment

The most important controversy in childhood AML is the most appropriate use of allogeneic HSCT in first remission. In the most recently completed Childrens Oncology Group (COG) protocol, patients with intermediate cytogenetic risk were allocated to HSCT based on the availability of an HLA-identical family donor. Patients with poor cytogenetic risk and those in whom primary induction had failed were allocated to HSCT with the best available donor. No patients with favorable cytogenetic risk were allocated to HSCT.

In the current ongoing COG protocol, patients with intermediate cytogenetic risk are allocated to HSCT with the best available donor based on the presence of detectable MRD at the end of the first induction course. All patients with a high allelic ratio of FLT3–ITD-positive are also allocated to HSCT with the best available donor.

There is significant disagreement between different groups regarding whether the COG approach to HSCT in AML is optimal. Randomized trials to address this controversy are lacking, so the controversy is likely to persist for the foreseeable future.

The cytotoxic chemotherapy regimens used to treat AML have significant toxicity, and it is unlikely that significant treatment improvements will be made by further intensifying chemotherapy. Thus there is great interest in developing "molecularly targeted" therapies directed at the underlying mutations that cause AML. Substantial improvements in outcome have been achieved using this approach in APML with ATRA and arsenic trioxide, but little progress has been made with targeted therapies to date in other subtypes of AML.

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