AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Acute myelocytic leukemia (AML) is a group of malignant disorders characterized by the replacement of normal bone marrow with abnormal, primitive hematopoietic cells. If untreated, the disorder uniformly results in death, usually from infection or bleeding. Although the cure rate has improved, treatments are associated with notable morbidity and mortality.

Pathophysiology

Acute leukemia is believed to begin in a single somatic hematopoietic progenitor that transforms to a cell incapable of normal differentiation. Many of these cells no longer possess the normal property of apoptosis, or programmed cell death. As a result, they have a prolonged life span and are capable of unrestricted clonal proliferation.

Leukemogenesis is frequently associated with chromosomal abnormalities and gene translocations. Many translocations are characteristic of a particular subtype of acute leukemia and often convey additional prognostic information to the clinician.

Because transformed cells lack normal regulatory and growth constraints, they have favorable competitive advantage over normal hematopoietic cells. The result is the accumulation of abnormal cells with qualitative defects. A major cause of morbidity and mortality is the deficiency of normally functioning mature hematopoietic cells rather than the number of malignant cells.

Splenomegaly due to leukemic infiltration further contributes to pancytopenia by sequestering and destroying circulating erythrocytes and platelets. As the disease progresses, signs and symptoms of anemia, thrombocytopenia, and neutropenia increase.

Leukemic cells may infiltrate other bodily tissues, causing many clinically significant complications including CNS involvement, pulmonary dysfunction, or skin and gingival infiltration.

Frequency

United States

AML accounts for nearly 20% of about 3250 newly diagnosed cases of leukemia in children each year. Among infants, although 1 in every 3 newly diagnosed leukemias is AML, the ratio of AML to acute lymphoblastic leukemia (ALL) decreases rapidly until adolescence. During adolescence, the rate increases to account for nearly 50% of all new diagnoses of leukemia.

International

Although leukemia has been reported in children worldwide, the incidence rate widely varies. In the United States and other highly industrialized countries, AML accounts for about 15% of childhood leukemia. In other areas, such as Turkey, nearly one half of children diagnosed with leukemia have AML. Childhood leukemia (other than Burkitt type) is less common in Africa, but the ratio of AML to ALL is roughly 1:1. Likewise, the incidence of AML in Asia is equal to that of ALL.

Mortality/Morbidity

The long-term survival rate for pediatric patients with AML is nearly 55%. AML accounts for about 35% of childhood deaths from leukemia. Mortality is a consequence of resistant progressive disease or treatment-related toxicity.

Race

Minor geographic variations are observed in the incidences of the different subtypes of AML. However, ALL is more common in Caucasian children than in African-American children, whereas AML affects all races nearly equally. The incidence of one subtype, acute promyelocytic leukemia (APL), is slightly increased in the Hispanic population. Areas of the world where rates of AML are higher than average include Shanghai, New Zealand, and parts of Japan.

Sex

Male and female distributions are nearly equal at all ages.

Age

AML is diagnosed in persons of all ages, ranging from the newborns to the elderly. In the first year of life, AML accounts for nearly one third of all newly diagnosed leukemias. For the rest of the first decade of life, ALL is more common than AML by a ratio of 4:1. The incidence of these diseases is roughly equal during adolescence, and the incidence of AML increases in adulthood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Symptoms can be divided into those caused by a deficiency of normally functioning cells, those due to the proliferation and infiltration of the abnormal leukemic cell population, and constitutional symptoms.

• Symptoms due to a deficiency of normally functioning cells
• • Cytopenia
  • Anemia: This common finding is characterized by pallor, fatigue, tachycardia, and headache. The major pathophysiologic mechanism is related to decreased production in the infiltrated bone marrow. Bleeding, hemolysis, and sequestration and destruction in an enlarged spleen or liver may all contribute to anemia.
  • Hemorrhage due to thrombocytopenia: This is due to decreased production of megakaryocytes in the bone marrow. The most common findings are easy bruising, petechiae, epistaxis, gingival bleeding, and, sometimes, GI or CNS hemorrhage. The patient with disseminated intravascular coagulation might also have symptoms of hemorrhage or thrombosis, including painful swelling and sharp, colored demarcation of an extremity.
  • Fever: This is a common presenting complaint in patients with acute leukemia. In this context, fever should always be attributed to infection. Depending on the site of infection, symptoms may vary. Symptoms may be pulmonary (eg, cough, dyspnea, hypoxia, chest pain), as in patients with pneumonias; neurologic (eg, lethargy, emesis, headache), as in patients with meningitis; or other (eg, pain or changes in bladder and bowel function due to colitis or urinary tract infection).

• Symptoms due to the proliferation and infiltration of the abnormal leukemic cell mass and infiltrative disease
• • The most common extramedullary infiltration due to leukemic cells occurs in the reticuloendothelial system. This infiltration may manifest as adenopathy, hepatomegaly, or splenomegaly.
  • In rare cases, a mediastinal mass may cause symptoms of respiratory insufficiency or superior vena cava syndrome.
  • Abdominal masses may cause pain or obstruct the GI or urogenital tracts. Nodules of myeloblasts, called chloromas, can be found in the skin or CNS.
  • Monoblastic leukemia is often associated with gingival hyperplasia and CNS infiltration.

• Constitutional and miscellaneous symptoms
• • Fever: Unexplained persistent fevers are sometimes the only presenting symptom of patients with leukemia. Weight loss and cachexia are unusual findings in children with leukemia but not in adults. These effects can result from increased catabolic nutritional state combined with decreased caloric intake from anorexia.
  • Orthopedic symptoms: Bone pain is less common in patients with acute myelocytic leukemia (AML) than in patients with ALL. Its cause may be periosteal elevation due to leukemic cell infiltrates or bone infarctions. On occasion, weakened bony cortex permits pathologic fractures of the extremity, which result in pain and decreased mobility, or vertebral compression fractures after minimal trauma. Such compression fractures cause back pain and dysfunction of the lower extremity (eg, weakness, loss of bladder and bowel function).
  • CNS involvement
  • • Although this is uncommon at initial diagnosis, it can appear at any time during follow-up and is associated with various findings.
    • The most common signs and symptoms are related to elevated intracranial pressure; they include headache, nausea and emesis, lethargy, irritability, and visual complaints.
    • Involvement of the cranial nerves, most often the facial nerve (resulting in Bell palsy) and the abducens nerve (resulting in esotropia), may appear as an isolated finding or in combination with other manifestations.
    • In addition to infiltration and proliferation of leukemic cells with mass effect, intracranial hemorrhage and CNS infections can cause similar devastating CNS complications.
    • Spinal lesions are rare. However, in AML, blast cells periodically form large aggregates called chloromas or granulocytic sarcomas that lead to epidural compression.
    • Extreme leukocytosis with WBC counts of more than 200 X 10⁹/L (>200,000 cells/μL) is often associated with hyperviscosity, intracerebral leukostasis, and intracerebral hemorrhage early in the course of the disease.
  • Ocular manifestations: In rare cases, leukemic cells infiltrate all parts of the eye. The retina and iris are the sites most commonly affected. Iritis often causes photophobia, pain, and increased lacrimation, whereas, retinal involvement is often accompanied by hemorrhage and can lead to a loss of vision.
  • Myelodysplasia: Although most cases are diagnosed after a relatively brief duration of symptoms, some patients may present with myelodysplasia. This relatively indolent disorder is characterized by slowly progressive anemia or thrombocytopenia. This disorder can be present for many months or even years before it ultimately converts to AML.

Physical

• Pancytopenia
• • Pallor with tachycardia is observed to different degrees proportional to the severity of anemia. With severe anemia, patients may have lethargy, a heart murmur, and signs of congestive heart failure.
  • Bleeding manifestations are most commonly observed in the skin and include petechiae, purpuric lesions, and ecchymoses.
  • GI bleeding may indicate erosions or perforation.
  • Signs of infection include fever, gingivitis, hypotension, or respiratory distress, depending on the site of infection.
• Signs of leukemic infiltration and proliferation
• • Adenopathy, at times generalized, is less common in AML than in ALL.
• • Splenomegaly is sometimes massive, particularly in young children.
• • Pronounced organomegaly occasionally result in respiratory embarrassment in infants due to decreased diaphragmatic excursion.
• • CNS findings include lethargy, cranial nerve dysfunction (particularly esotropia and facial palsy), and papilledema.
• • Typhlitis can lead to acute pain in the lower quadrants that mimic signs of appendicitis.
• • Signs of perforation include hypotension, abdominal distension, and decreased bowel sounds. Clinical deterioration is rapid if the condition is not recognized.
• • Skin nodules are occasionally found in patients with AML. They are typically firm, raised, and often bluish-purple in color.

Causes

Although the cause of AML is unknown in most patients, several factors are associated with its development. Despite these correlations, most people exposed to the same factors do not develop leukemia. This pattern suggests that these factors trigger the malignant transformation of cells, perhaps due to the action of one or more oncogenes or tumor suppressor genes. Defects in DNA repair mechanisms also contribute to the development of AML.

• Radiation exposure
• • A great deal of evidence has implicated radiation in leukemogenesis in many patients, as evidenced in Japan after the atomic explosions at Hiroshima and Nagasaki. Although young children had the high risk of developing ALL, teens and adults were most likely to contract AML. Most of the leukemias arose within the first 5 years after exposure, although some developed as much as 15 years after exposure. 
  • Reports of increased risk of leukemia among patients who live near nuclear plants are under investigation, but data are lacking. Likewise, early reports that exposure to strong electromagnetic fields is a risk factor for acute leukemia have not been corroborated.
• Exposure to toxins and drugs
• • Exposure to toxic chemicals that cause damage to bone marrow, such as benzene and toluene used in the leather, shoe, and dry cleaning industries, is associated with leukemia in adults. Direct evidence of this effect in children has not been established. Exposure to pesticides has been noted to increase the risk of AML.
• • A compelling association has been observed after treatment with antineoplastic cytotoxic agents, particularly alkylating agents such as procarbazine, the nitrosoureas, cyclophosphamide, melphalan, and, most recently, epipodophyllotoxins etoposide and teniposide. Patients receiving these agents to treat malignancies (eg, Hodgkin lymphoma), especially if the agents are administered with radiation therapy, have a significantly increased risk of developing a preleukemic syndrome that ultimately transforms into overt AML.
• Genetic factors and syndromes
• • Children with Down syndrome (trisomy 21) have a 15-fold increased risk of developing leukemia, most commonly acute megakaryoblastic leukemia, compared with the general population. Children with Down syndrome who have transient myeloproliferative syndrome as neonates, a condition often indistinguishable from acute leukemia, also have a high risk of developing acute leukemia in subsequent years.
• • Approximately 8% of children with Fanconi anemia develop AML in their adolescent years.
• • Patients with inherited disorders, such as Shwachman, Bloom, or Diamond-Blackfan syndromes, also have an elevated risk of developing leukemia. These syndromes share features of poor DNA repair that are believed to predispose affected individuals to leukemogenic stimuli. Children with neurofibromatosis type I and Kostmann neutropenia (severe congenital neutropenia) also appear to be at increased risk for developing AML.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Aplastic anemia
Drug-induced pancytopenia
Transient myeloproliferative syndrome in Down syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

Blood counts and blood smears

The hallmark of leukemia is a reduction or absence of normal hematopoietic elements. Anemia is usually normocytic, with a reticulocyte count lower than expected for the level of the hemoglobin. The decrease in hemoglobin levels can range from minimal to profound.

Platelet counts are usually low and generally commensurate with the degree of bleeding. Patients with spontaneous petechiae usually have platelet counts of less than 20 X 10⁹/L (<20,000/μL).

WBC counts may be decreased or elevated. Hyperleukocytosis with WBC counts of more than 100 X 10⁹/L (>100,000/μL) are occasionally observed; with high numbers, the blood specimen appears white. The WBC differential is usually the key to evaluating suspected leukemia; primitive granulocyte or monocyte precursors are observed on peripheral smears. Numbers of mature neutrophils are usually diminished.

Upon careful examination of the blood smears, Auer rods (characteristic cytoplasmic inclusions) are revealed in specimens of circulating blood obtained from many patients acute myelocytic leukemia (AML). They are particularly prominent in children with APL.

Blood chemistries and other blood work

Both serum uric acid and lactic dehydrogenase levels are frequently elevated as a consequence of increased cell proliferation and destruction.

Serum muramidase (lysozyme) levels are usually increased in patients with monocytic leukemias.

Other signs of tumor lysis, including hyperkalemia, hypocalcemia, and lactic acidosis, may be present.

Blood and urine cultures should always be obtained in a child with fever and leukemia.

Coagulation tests should also be performed during initial diagnosis to look for evidence of disseminated intravascular coagulation that might suggest APL.

Bone marrow examination

Results of the bone marrow examination establish the definitive diagnosis.

Bone marrow aspirates and biopsy samples demonstrate the characteristic replacement of normal marrow elements with the monotonous sheets of leukemic blasts.

Acute myelogenous leukemia can be divided into subtypes on the basis of marrow findings. Some of these subtypes have characteristic clinical pictures.

The French-American-British classification system recognizes 7 primary types of AML (M1-M7), which can usually be established with additional marrow studies.

The World Health Organization recently classified acute myeloid leukemias into groups, including the following: AML with recurrent cytogenetic translocations (eg, promyelocytic leukemia with typical t[15;17]), AML with multilineage dysplasia, AML and myelodysplasia syndromes secondary to therapy (eg, those following alkylating agents), and AML not otherwise categorized (eg, erythroid leukemias, monocytic leukemias).

Tests of cytogenetic markers, histochemical staining, and immunophenotyping

Leukemia cells demonstrate clonal cytogenetic abnormalities in more than 85% of patients. These changes are often unique to the subtype. For example, the t(15;17) translocation is nearly always found in patients with APL, whereas t(8;21) is most commonly found in those with myeloblastic leukemia. Some of the cytogenetic abnormalities have now been shown to confer either greater risk of recurrent disease (eg, monosomy 7 and monosomy 5) or lower risk (eg, t[8;21] and inv[16]/t[16;16]).

In addition to standard Wright-Giemsa stains, histochemical stains help in differentiating the various acute leukemias. Positive periodic acid-Schiff stains indicate acute biphenotypic leukemia or undifferentiated leukemia with lymphoblastic features. Most AML cells have strong positive reactions to myeloperoxidase and Sudan black stains. Esterase stains findings usually help in differentiating myeloid (specific esterase positive) from monocytic (nonspecific esterase positive) leukemia.

Monoclonal antibodies specific for different cell lineages and stages of development are routinely used to further characterize the leukemic cells. The most common myeloid markers are CD13, CD14, CD15, and CD33, with more than 90% of leukemic cells demonstrating positivity to some of these antigens. CD34 is frequently found in AML blasts.

Lumbar puncture and CSF examination

Although the CSF is less frequently involved in AML than in ALL,  leukemic infiltration can occur.

CSF samples should be obtained before any therapy is begun. Fluid should be sent for cytologic evaluation in addition to the usual cell counts and chemical tests.

Intrathecal chemotherapy is administered simultaneously and repeated intermittently to treat or prevent CNS involvement.

Typing of human leukocyte antigen

Human leukocyte antigen (HLA)–matched family donors should be identified because bone marrow (or hematopoietic stem cell) transplantation may be considered in high-risk patients.

At the time of diagnosis, the donor screening process should be started by obtaining blood for HLA matching from the patient and immediate family members.

Imaging Studies

• Radiography
• • Although radiographic studies are not helpful in confirming the diagnosis, they can be important when leukemic complications are suspected.
  • Routine chest radiography should be performed to rule out mediastinal masses, particularly in patients with respiratory symptoms or suspected superior vena cava syndrome.
  • If the patient has abdominal pain and distention, abdominal images often depict free air suggestive of a perforation.
  • Radiograph examination of the extremities may show findings such as metaphyseal bands at the distal femurs (most commonly observed in young children with ALL), periosteal new bone formation, focal lytic lesions, or pathologic fractures.
• CT and MRI
• • If the patient has abdominal pain and possible infection of the large bowel, CT may reveal thickening and edema of the bowel wall suggestive of typhlitis.
• • If a patient has neurologic symptoms, CT or MRI of the head, spine, or other involved region is mandatory to rule out intracranial hemorrhage or infiltrative disease.
• • CT scanning also may allow early detection of asymptomatic sinusitis that might cause persistent, unexplained fevers.
• Sonography
• • Because serious infections that affect heart function are routinely observed in this patient population, periodic cardiac monitoring is important.
• • Perform echocardiography before chemotherapy.
• • Most treatment regimens include anthracyclines, such as daunomycin and idarubicin, which may cause clinically significant cardiomyopathy.
• Radionuclide imaging
• • Radionuclide imaging is often used to detect occult infection that cultures and other imaging modalities do not reveal.
• • Technetium bone scans often help in localizing an occult osteomyelitis.
• • Whole-body gallium or indium scanning often reveals an occult deep tissue infection and can help with appropriate antibiotic management.

Procedures

• Bone marrow aspirate and biopsy
• • Bone marrow examination is necessary to establish the diagnosis of AML.
  • The preferred site is the iliac crest, either anterior or posterior. Although the posterior iliac crest is the preferred site for bone marrow aspiration, the tibia may be an alternative source of marrow for diagnostic purposes in infants. On rare occasion, sternal biopsy is necessary.
  • Although bone marrow aspiration is often sufficient to establish the diagnosis and to follow up the progress of the disease, core biopsy is often necessary if samples yield packed marrow or dry taps (which usually are heavily infiltrated marrows that do not yield enough diagnostic material).
  • Biopsy is necessary to gauge the cellularity of a marrow specimen during follow-up to aid subsequent therapeutic decisions.
• Lumbar puncture
• • Lumbar puncture is necessary for diagnostic and therapeutic reasons.
• • Even if the marrow is not involved at the time of diagnosis, CNS seeding can occur later. Therefore, periodic surveillance lumbar puncture with the administration of intrathecal chemotherapy is necessary.
• Placement of a central venous catheter
• • Because of the patient's need for intense chemotherapy and supportive care, guaranteed venous access is critical. An indwelling central venous catheter with at least 2 lumina is usually placed before the start of therapy. This catheter provides access for infusing chemotherapeutic drugs and for providing intravenous nutritional support, transfusions, antibiotics, and other supportive medications. In addition, they allowing for blood withdrawal for required testing.
• • Families are taught catheter care, including sterile technique and preventive maintenance to prevent clotting and infection.
• • Subcutaneous ports and peripheral indwelling central catheters in the cubital area are sometimes used.

Histologic Findings

Bone marrow examination usually reveals characteristic hyperplastic marrow with monotonous replacement with leukemia cells. Patients with myelodysplasia have less than 20% of blast cells, megaloblastic features, and a decrease in the normal hematopoietic cell population. Pronounced fibrosis is often observed, particularly in the acute megakaryoblastic subtype (M7).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment for patients with acute myelogenous leukemia involves intensive chemotherapy to destroy the leukemic cell population as rapidly as possible and to prevent the emergence of a resistant clone. Patients are simultaneously given supportive care until their bone marrow achieves hematologic remission and is again producing normal hematopoietic cells.

Chemotherapy

Virtually all chemotherapeutic drug regimens include some combination of an anthracycline (most often daunomycin) with cytosine arabinoside. Other drugs that have been administered are etoposide, amsacrine, dexamethasone, 6-thioguanine, cyclophosphamide, and mitoxantrone.

For many years, most children in the United States were treated with chemotherapy protocols developed by the Children's Cancer Group and the Pediatric Oncology Group. These protocols, which used different multiagent chemotherapies, were associated with improved results as therapy was intensified. Although these treatments prolonged pancytopenia, they decreased induction failures and substantially improved disease-free survival.

After the 2 national groups merged to form the Children's Oncology Group (COG), the recommended regimen, based on the Medical Research Council acute myelocytic leukemia (AML) trials, was adapted; this consisted of 2 cycles of induction therapy with infusions of daunomycin, cytosine arabinoside, etoposide (ADE therapy). Gemtuzumab ozogamicin, an anti-CD33 antibody linked to an anti-tumor antibiotic, is currently under investigation in a COG pediatric national trial.

After remission is induced, postinduction treatment is necessary because more than 90% of patients have a relapse without additional treatment. In patients without HLA-matched donors from their family, sequential cycles of chemotherapy are administered by using combinations of cytosine arabinoside and etoposide, mitoxantrone and cytosine arabinoside, and, finally, high-dose cytosine arabinoside with L-asparaginase.

Allogeneic bone marrow transplantation has been shown to reduce relapse rates but does not always improve overall survival because of treatment-related mortality. Autologous bone marrow transplantation has also been shown to reduce relapse rates but does not improve overall survival compared with chemotherapy alone because of treatment-related mortality.  Allogeneic bone marrow transplantation is recommended in patients with low-risk AML, which is characterized by chromosome inv(16) and t(8;21) abnormalities. These patients enter remission rapidly only in second reemission. 

In the COG trials, allogeneic bone marrow transplantation is recommended during the first complete remission for other patients (ie, those with standard risk AML [normal cytogenetics] who enter remission with 2 induction courses and those with high risk AML [abnormal karyotypes, including monosomy 7, trisomy 3, 5q- or complex karyotypes]. Transplantation is reserved for the second remission after a relapse for patients with Down syndrome and AML. Patients with APL should not receive a transplant during the first remission. 

Upon relapse and the achievement of a molecular remission, autologous bone marrow transplantation has shown promising results and should be considered when an HLA-matched family donor is not available. The use of unrelated matched family donors remains experimental in patients with AML. 

Other approaches have met with success in other parts of the world. Recently, Japanese researches have reported promising results using multiple cycles of high-dose cytosine arabinoside.¹

Treatment for APL

The discovery of effective maturation agents has altered the approach to treating APL.

All-trans retinoic acid (ATRA) can effectively induce remission in most newly diagnosed APLs with the myelosuppressive effects of chemotherapy. The current treatment approach is to begin therapy with ATRA, followed with several days with an anthracycline to induce remission. For patients with a WBC count of more than 10 X 10⁹ (>10 X 10³/>µL), concomitant ATRA and anthracycline are used.

Additional cycles of this combination are used as consolidation chemotherapy. Randomized trials have shown an advantage of maintenance therapy for all patients with ATRA and, particularly, high-risk patients with ATRA in combination with 6-mercaptopurine and methotrexate.

Another approach that is being investigated in clinical trials is the use of arsenic trioxide, which is highly active in both newly diagnosed and relapsing APL. It effectively induces remissions in 85% of patients who have a relapse. In a North American Intergroup Study, the introduction of arsenic in consolidation was shown to significantly improve overall outcomes in adults with APL.   

Gemtuzumab ozogamicin (Mylotarg), or anti-CD33 calicheamicin, is also being tested in patients with APL. The hope is that both arsenic and gemtuzumab ozogamicin may reduce exposure to anthracyclines without sacrificing efficacy. The COG is planning on piloting a trial that will replace an anthracycline course of chemotherapy with arsenic trioxide plus ATRA in order to reduce the anthracycline exposure from an estimated 650 mg/m² to 350 mg/m² in standard-risk patients and to 450 mg/m² in high-risk patients. 

Patients with APL and high WBC counts at presentation should not undergo leukopheresis because of an increased risk of bleeding due to activation and degranulation of promyelocytes. Instead, hydration and hydroxyurea can be used, followed by rapid initiation of induction chemotherapy.

Treatment for children with Down syndrome

Unlike most children with AML who should receive intense therapy, young children (<4 y) with Down syndrome fare best with reduced-intensity therapy, which results in an improved likelihood of long-term, disease-free remission. Many children with trisomy 21 have had transient myeloproliferative disease as infants. This picture resembles AML in many ways, but it usually disappears with only supportive care. About 20-30% of the children who had this syndrome as neonates develop true AML requiring chemotherapy.

Children with Down syndrome also seem to have marked complications of intense therapy. As a result, treatment for children with trisomy 21 involves lowered doses of induction chemotherapy (daunomycin, cytosine arabinoside, and 6-thioguanine) with prolonged periods between treatments. These children receive intensified chemotherapy high-dose cytosine arabinoside rather than bone marrow transplantation. Consolidation and intensification courses of therapy with high-dose cytosine arabinoside do not cause increased toxicity or mortality in patients with Down syndrome.

Radiation therapy

Radiation treatment is primarily used to treat chloromas and other masses that are pressing on a vital structure and that may imminently cause irreversible damage. Examples include spinal cord compression and superior vena cava syndrome or airway compromise due to mediastinal masses. Corticosteroids and early administration of chemotherapy can effectively relieve most of these complications.

Persistent CNS leukemia usually requires craniospinal irradiation.

Most pretransplantation myeloablative regimens given to children in their first complete remission have replaced irradiation with busulfan to decrease the incidence of some long-term adverse effects.

Blood and marrow transplantation

A myeloablative combination of chemotherapy and irradiation followed by rescue with an infusion of HLA-matched stem cells to reconstitute the patient's bone marrow is an effective approach to cure AML. In several randomized studies, allogeneic transplantation raised overall and disease-free survival rates. However, this option is not available to most patients because HLA-matched donors are found for only approximately 25%. In addition, for good-risk patients, transplantation is reserved for a second remission because the salvage rate is quite high for such patients. 

Options have substantially increased with the availability of international HLA registries that can help in locating unrelated HLA-matched donors. In addition, the use of both purged or unpurged autologous stem cells, which offer the advantages of availability and avoidance of graft versus host disease (GVHD), are being studied in clinical trials. However, to date, randomized studies in pediatric patients have not shown an overall survival advantage for autologous stem cell transplantation compared with chemotherapy.

Umbilical cord blood, which is rich in stem cells, has further expanded the availability of donor stem cells because increased HLA mismatch appears to be better tolerated with such donor cells in terms of the development of high-grade GVHD. Success rates for stem cell transplants have also increased because of improved GVHD prophylaxis and treatment, using different combinations of methotrexate, cyclosporine, tacrolimus, mycophenolate, and corticosteroids to lower mortality rates.

Veno-occlusive disease (also termed sinusoidal obstructive syndrome) of the liver, a complication that can be fatal, has shown excellent responses to defibrotide in early phase clinical trials.

The substitution of busulfan-cyclophosphamide for regimens involving total-body irradiation has reduced long-term problems related to growth retardation. However, the risk of sterility, second malignancies, and neurocognitive abnormalities (especially in young children) remain a real problem in survivors.

Transfusion support

Because treatment regimens are intensive, expeditious blood product transfusion support is critical.

Throughout long periods of pancytopenia, platelet and RBC transfusions are necessary to correct anemia and thrombocytopenia until remission is achieved.

Fresh frozen plasma is occasionally required to correct coagulopathies, particularly in patients with disseminated intravascular coagulation. All transfused products must be irradiated to prevent GVHD in heavily immunosuppressed patients.

Support from the blood bank is mandatory when patients present with hyperleukocytosis and are at high risk for stroke and heart failure due to hyperviscosity. These patients are best treated with leukophoresis or double-volume exchange transfusion to rapidly and safely decrease the leukemic cell burden without contributing to metabolic abnormalities. This procedure also facilitates rapid correction of anemia, which viscosity constraints would otherwise have prohibited.

In rare cases, granulocyte transfusions are administered to treat serious infections that do not respond to appropriate antibiotic therapy. This approach may be most appropriate for gram-negative sepsis, serious intra-abdominal infections, and, sometimes, fungal infections, although the efficacy of this approach as not been definitively proven.  

Metabolic management

Patients who present with a large leukemic cell burden, either a high circulating WBC count or massive organomegaly, are at risk for severe, often life-threatening metabolic derangements.

Before beginning cytoreduction, correct any existing abnormalities and take measures to prevent new ones.

Hyperkalemia and hyperphosphatemia with associated hypocalcemia result from rapid cell turnover and destruction.

Promptly treat elevated potassium levels by using measures such as sodium polystyrene sulfonate (Kayexalate), an insulin and glucose combination, and, sometimes, hemodialysis.

Calcium replacement is often necessary to correct severe hypocalcemia.

Prevention is key to avoiding most serious metabolic complications. The combination of vigorous hydration, administration of allopurinol (a xanthine oxidase inhibitor to prevent the formation of uric acid), and alkalinization of the urine with sodium bicarbonate is usually successful in preventing serious tumor lysis syndromes. For patients at high risk for tumor lysis syndrome, those with renal dysfunction, or those whose uric acid levels are already elevated, rasburicase directly lyses uric acid and can rapidly reduce its levels.

Antibiotic therapy

Infection is a major cause of morbidity and mortality.

Patients with fever, particularly if they have severe neutropenia, are presumed to have serious infection until proven otherwise.

Empiric broad-spectrum antibacterial antibiotics are administered when a patient is febrile and has an absolute neutrophil count of less than 7.5-10 X 10⁹/L  (<750-1000/μL). The choice of antibiotics depends on the typical pathogens found in the community and hospital. It is usually some combination of an aminoglycoside and a cephalosporin or semisynthetic penicillin with beta-lactamase inhibitor until culture results are available.

When tunnel infections around a central venous catheter are suspected, vancomycin should be administered. At certain institutions, removal of the intravenous line is also recommended.

If a patient presents with abdominal or GI symptoms, the antibiotic chosen should cover anaerobes.

When neutropenia is prolonged, particularly after treatment with broad-spectrum antibacterial agents, fungal disease becomes a great concern.

Empiric use of antifungal therapy is indicated in patients with persistent fever 3-5 days of initiation of broad spectrum antibiotics and negative bacterial cultures. Although amphotericin has been the standard treatment for many years, other agents, such as voriconazole, are increasingly used.

CT scanning is often necessary to detect subtle abscesses in the lungs, liver, spleen, kidneys, or brain.

Prophylactic antibiotics have helped to decrease the incidence of a number of infections. Sulfamethoxazole-trimethoprim has dramatically reduced the incidence of Pneumocystis carinii pneumonia. In some centers, prophylactic penicillin has decreased the incidence serious systemic streptococcal sepsis in patients with severe mucositis. Acyclovir has been useful in preventing herpes simplex infections, particularly in patients who have undergone bone marrow transplantation. Reports have suggested that prophylactic levofloxacin decreases the incidence of sepsis and other life-threatening infections. Patients who develop GVHD that requires significant immunosuppressive therapy will require more intense and more broadened infection prophylaxis.

Vigilance is most important in the patient with AML and persistent fever. Frequent cultures of possible sites of infection should be performed.

To facilitate proper diagnosis, bronchoscopy, lung biopsy, and imaging studies are often necessary.

Treatment with biologic-response modifiers

Granulocyte colony-stimulating factor (G-CSF) and granulocyte monocyte colony-stimulating factor (GM-CSF) shorten the period of chemotherapy-induced neutropenia. However, their role in the treatment of leukemia has not been definitively established because no improvement in survival has been demonstrated. Their use is not recommended in patients with AML.

The role of synthetic erythropoietin is yet to be elucidated, and its use is not recommended.

Surgical Care

• The role of surgery is limited.
• Insertion of a central venous catheter is necessary to begin treatment and to manage all aspects of chemotherapy and transfusion support.
• Biopsy or aspiration of tissue for culture is often necessary for febrile patients with a possible abscess.
• Acute abdomen often results in serious complications (eg, typhlitis) that require expeditious surgical intervention.

Consultations

• Urologist: Consider consulting a urologist when male teenagers are undergoing intense chemotherapy that may cause oligospermia and fertility problems in the future. These conditions are usually temporary. However, they are particularly problematic for patients who undergo high-dose chemotherapy in preparation for blood or marrow transplantation, and they are major problems for patients who may be receiving total-body irradiation. Encourage sperm banking, preferably before these patients begin any treatment that may affect the quality of their sperm.
• Psychologists, psychiatrists, or other mental health professional: Patients and their families may experience majors stresses as a result of intense treatment and frequent, prolonged hospitalizations for chemotherapy and its resulting complications (especially fin patients undergoing stem cell transplant). Another stressor is the real possibility of life-threatening complications. Psychologic support, with educational information and numerous meetings and updates, are important for the family's psychological well-being.

Diet

• Careful attention must be directed toward adequate nutrition. Because of prolonged neutropenia with infections that blunt a patient's appetite and recurrent episodes of chemotherapy-induced mucositis, high-calorie oral supplements are often helpful for maintaining weight. They allow help the patient in tolerating therapy. Most patients require intravenous total parenteral nutrition or, preferably, nasogastric alimental nutrition.
• Low-bacteria diets are often prescribed to patients receiving a blood or marrow transplant to decrease the incidence of infections because of the profound immunosuppression after transplantation. This would include avoiding uncooked fresh vegetables and fruits. These recommendations are probably not necessary for patients with AML who are not undergoing transplant.

Activity

• Minimal limits on activity are necessary. Patients should avoid crowds and exposure to potentially contagious disorders when they have neutropenia or immunosuppression after transplantation.
• During episodes of thrombocytopenia, patients should curtail their participation in potentially traumatic physical sports activities to avoid serious hemorrhage. Medications that can potentiate bleeding, such as antiplatelet agents (eg, aspirin, nonsteroidal anti-inflammatory drugs) should be avoided.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treatment is directed toward 2 goals: destroying the leukemic cells and supporting the patient through long periods of pancytopenia. Chemotherapy meets the first goal, but many classes of drugs must also be included in treatment. Such classes include broad-spectrum antibacterial, antiviral, and antifungal antibiotics; biologic-response modifiers; and other classes of supportive medications.

Drug Category: Chemotherapeutic agents

Although many chemotherapeutic agents are active, most current regimens include combinations of an anthracycline and cytosine arabinoside. Chemotherapeutic agents destroy myeloblasts in various mechanisms.

Drug Category: Antiemetic agents

Antineoplastic-induced vomiting is stimulated by actions on the chemoreceptor trigger zone. This zone then stimulates the vomiting center in the brain. Increased activity of central neurotransmitters, dopamine in the chemoreceptor trigger zone or acetylcholine in the vomiting center, appears to be a major mediator in inducing vomiting. After antineoplastic agents are given, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With this release and with the subsequent of 5-HT binding to 5-HT3-receptors, vagal neurons are stimulated and transmit signals to the vomiting center, resulting in nausea and vomiting.

Emesis is a notable problem in patients receiving high-dose chemotherapy. The resultant nutritional, metabolic, and fluid derangements can be unpleasant enough that patients may refuse further life-saving therapy. It is important to use these drugs prophylactically.

Drug Category: Antimicrobials, prophylactic

Infections remain the biggest problem. Use of prophylactic drugs can help prevent several of these often life-threatening infections.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Hospitalization is necessary for managing chemotherapy and for treating complications related to the disease and its treatment, usually infections or febrile neutropenic episodes. Some hospitalizations can be lengthy. Numerous changes in antibiotics may be necessary until infections and neutropenia resolve.
• After transplantation, most febrile episodes require in-patient treatment and observation until profound neutropenia and clinically significant infection resolves.

Further Outpatient Care

• Because early intervention prevents cytopenic complications, blood counts must carefully be monitored during and between phases of treatment.
• After all planned therapy, careful physical examinations and blood work are important to ensure continued hematologic remission.

In/Out Patient Meds

• Most supportive medications can be discontinued when chemotherapy is completed. Such medications include prophylactic antibiotics, agents for nutritional support (eg, appetite stimulants), and antiemetics.
• Patients usually require prolonged immunosuppressive therapy with prednisone and cyclosporine after transplantation. Penicillin, antifungal medications, acyclovir, and trimethoprim-sulfamethoxazole are continued until all immunosuppressive medications are discontinued.

Transfer

• Transfer to a pediatric cancer center is usually necessary for initial diagnostic studies and management of both chemotherapy and treatment-related complications.
• For patients with suitable donors, transfer to a center capable of performing blood and marrow transplants is usually necessary.

Deterrence/Prevention

• As detailed in Causes, the association of acute myelocytic leukemia (AML) with radiation, toxins, and drugs is well documented. Reduced exposure to ionizing radiation should be an important maxim for every physician who orders diagnostic testing for patients, certainly pregnant women.
• Until more evidence is available, general avoidance of chemicals and toxins should be a priority.
• No dietary changes are known to affect a person's risk of developing AML.

Complications

• Immediate and short-term complications
• • Serious infections
  • Alopecia
  • Emesis
  • GI erosions and bleeding
  • Hemorrhage
  • Malnutrition
  • Nausea
  • Death
• Long-term or delayed complications
• • Congestive heart failure and arrhythmia (rare)
  • Growth and other endocrine disorders
  • Second malignancies
  • Death
• Infection
• • Infection is a major cause of morbidity and mortality.
  • The predisposition to infection is a consequence of granulocytopenia. The risk of sepsis is greatest when the absolute granulocyte count is more than 200 cells/μL.
  • Sepsis and pneumonia are particularly common. Causative agents cover the entire gamut of bacterial, fungal, viral, and other pathogens.
  • Septic shock is usually secondary to gram-negative bacteria and often lethal.
  • Because of prolonged neutropenia, immunosuppression, and treatment with broad-spectrum antibiotics, common causes of death are fungal, antibiotic-resistant bacterial, and other opportunistic infections.
• Bleeding
• • Bleeding is the second most common cause of death.
  • Severe GI, pulmonary, or intracranial hemorrhage is frequently observed.
  • Disseminated intravascular coagulation is a serious potential problem in all patients with  APL and, to some extent, in those with other AML subtypes. It can occur in association with thrombosis and hemorrhage.
• Tumor lysis syndrome
• • Patients with high leukemic cell counts or massive organomegaly are at significant risk for tumor lysis syndrome.
  • This condition is often characterized by pronounced metabolic abnormalities, including hyperkalemia, hypocalcemia, hyperuricemia, and renal failure.
• Effects of chemotherapy
• • The aggressive chemotherapy  necessary to cure the patient also results in a great deal of morbidity.
  • Profound myelosuppression due to high-dose, intensive treatment regimens contribute to a high risk of infection and bleeding.
  • GI complications: Mucositis and typhlitis in association with intestinal perforation, renal, and pulmonary complications are common problems patients and clinicians face.
• CNS complications
• • CNS involvement, with leukemic cell infiltration, hemorrhage, or infection, often cause devastating complications or death.
  • The risk is particularly high for patients with hyperleukocytosis and WBC counts of more than 200 X 10⁹/L (>200,000/μL). These patients are at high risk of intracranial hemorrhage, and their conditions must be treated as true emergencies.

Prognosis

• With an overall survival rate of 45-55%, the prognosis for children with AML has improved significantly over the past 2 decades. A Japanese consortium has recently reported overall 5-year survival rate of 62%.¹ The long-term, disease-free survival rate is approximately 65% for patients receiving HLA-matched stem cell transplants from family donors, but, as with chemotherapy, this rate is lower in high-risk patients. When patients die during treatment or after relapse, the cause is most commonly infection, bleeding, or refractory disease.
• The disease-free survival rate of patients with APL is approximately 75%.

Patient Education

• Family members should be familiar with signs of infection other than fever. Dermatologic clues of bleeding, especially petechiae and purpura, should be recognized and investigated.
• Discuss the adverse effects of chemotherapy and transplantation at length with family members.
• Psychosocial intervention is often necessary for the patient and his or her parents and siblings. A diagnosis of leukemia has profound effects on all family members, with a dramatic change in the patient's lifestyle until all treatment is completed.
• Home tutoring is often necessary during the entire period of treatment.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Leukemia.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize associated complications, such as infections, hemorrhage, metabolic complications, or early organ dysfunction
• Failure to inform the patient and family about potential treatment complications

Special Concerns

• Children may not have classic symptoms of the disease or its complications. Nonspecific symptoms such as fatigue, irritability, fever, or bruising are common in childhood and might not be recognized as symptoms of leukemia.
• Signs of serious infection are often subtle. Fever at any time must be taken seriously, and appropriate cultures and investigations must be ordered to diagnose and treat it early.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Tomizawa D, Tabuchi K, Kinoshita A, et al. Repetitive cycles of high-dose cytarabine are effective for childhood acute myeloid leukemia: long-term outcome of the children with AML treated on two consecutive trials of Tokyo Children's Cancer Study Group. Pediatr Blood Cancer. Aug 2007;49(2):127-32. [Medline].
2. Arceci RJ, Sande J, Lange B, et al. Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia. Blood. Aug 15 2005;106(4):1183-8. [Medline].
3. Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. Sep 8 2005;353(10):977-87. [Medline].
4. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. Dec 3 1998;339(23):1649-56. [Medline].
5. Chen AR, Alonzo TA, Woods WG, Arceci RJ. Current controversies: which patients with acute myeloid leukaemia should receive a bone marrow transplantation?--an American view. Br J Haematol. Aug 2002;118(2):378-84. [Medline].
6. Gamis AS, Woods WG, Alonzo TA, et al. Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. J Clin Oncol. Sep 15 2003;21(18):3415-22. [Medline].
7. Kersey JH. Fifty years of studies of the biology and therapy of childhood leukemia. Blood. Dec 1 1997;90(11):4243-51. [Medline].
8. Stevens RF, Hann IM, Wheatley K, Gray RG. Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol. Apr 1998;101(1):130-40. [Medline].

Article Last Updated: Aug 16, 2007