Pediatric Acute Myelocytic Leukemia

Acute myeloid leukemia consists of 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.

The long-term survival rate for pediatric patients with acute myeloid leukemia is nearly 60%. Acute myeloid leukemia accounts for about 35% of childhood deaths from leukemia. Mortality is a consequence of resistant progressive disease or treatment-related toxicity.

See Acute Myelogenous Leukemia and Pediatric Acute Lymphoblastic Leukemia for complete information on these topics.

Classification of acute myeloid leukemia

Acute myeloid 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 acute myeloid leukemia (M1-M7), which can usually be established by morphology and additional marrow studies.

The World Health Organization (WHO) has classified acute myeloid leukemias into groups, although this classification is rarely used in pediatrics. However, for general purposes, note the following:

• Acute myeloid leukemia with characteristic cytogenetic translocations (eg, promyelocytic leukemia with typical t[15;17])

• Acute myeloid leukemia with multilineage dysplasia

• Acute myeloid leukemia and myelodysplasia syndromes secondary to therapy (eg, those following alkylating agents)

• Acute myeloid leukemia not otherwise categorized (eg, erythroid leukemias, monocytic leukemias)

Complications

Immediate and short-term complications include the following:

• Serious infections

• Alopecia

• Emesis

• GI erosions and bleeding

• Hemorrhage

• Malnutrition

• Nausea

• Death

Long-term or delayed complications include the following:

• Congestive heart failure and arrhythmia (rare)

• Growth and other endocrine disorders

• Second malignancies

• Death

Infection

Infection is a major cause of morbidity and mortality in acute myeloid leukemia. Signs of serious infections in children with leukemia 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.

The predisposition to infection is a consequence of granulocytopenia and immunosuppression. The risk of sepsis is greatest when the absolute granulocyte count is less 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 most commonly secondary to gram-negative bacteria, Staphylococcus aureus, and group A Streptococcus bacteria and is 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 in acute myeloid leukemia.

Severe GI, pulmonary, or intracranial hemorrhage is frequently observed.

Disseminated intravascular coagulation is a serious potential problem in all patients with acute promyelocytic leukemia (APL) and, to some extent, in those with other acute myelocytic leukemia 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.

Mucositis and typhlitis in association with intestinal perforation, renal, and pulmonary complications are common problems patients and clinicians face.

Central nervous system complications

Central nervous system (CNS) involvement, with leukemic cell infiltration, hemorrhage, or infection, can cause devastating complications or death.

The risk is particularly high for patients with hyperleukocytosis and white blood cell (WBC) counts of more than 200 X 109/L (>200,000/μL). These patients are at greater risk of intracranial hemorrhage, and their conditions must be treated as true emergencies.

Although the cause of acute myeloid leukemia 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 deoxyribonucleic acid (DNA) repair mechanisms also contribute to the development of acute myeloid leukemia.

Acute leukemia is believed to begin in a single somatic hematopoietic progenitor that transforms to a cell incapable of normal differentiation. Acute myeloid leukemia is a very heterogeneous disease from a molecular standpoint; oncogenic transformation into a leukemic stem cell may occur at different stages of normal hematopoietic cellular maturation, from the most primitive hematopoietic stem cell to later stages, including myeloid/monocytoid progenitor cells and promyelocytes. This determines which subtype of acute myeloid leukemia results, often with very different behavior and growth characteristics.

As opposed to acute lymphoblastic leukemia (ALL), acute myeloid leukemia is most commonly associated with the development of fusion genes resulting from chromosome translocations. Many translocations are characteristic of a particular subtype of acute leukemia and often convey additional prognostic information to the clinician. Although many patients have only a single cytogenetic abnormality, multiple genetic mutations are often required for the complete leukemic transformation.

Many of the leukemic 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. 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. The 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 may further contribute 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.

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 acute myeloid leukemia. 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 acute myeloid leukemia.

A compelling association has been observed after treatment with antineoplastic cytotoxic agents, particularly alkylating agents such as procarbazine, the nitrosoureas, cyclophosphamide, melphalan, and the epipodophyllotoxins etoposide and teniposide. Patients receiving these agents to treat malignancies (eg, Hodgkin disease) have a significantly increased risk of developing a preleukemic syndrome that ultimately transforms into overt acute myeloid leukemia, especially if the agents are administered with radiation therapy.

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. The risk of megakaryoblastic leukemia in Down syndrome is approximately 400 times greater than it is in the rest of the 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.

Patients with inherited disorders, such as Shwachman-Diamond syndrome, Bloom syndrome, Diamond-Blackfan anemia, Fanconi anemia, dyskeratosis congenita, and Kostmann syndrome, also have an elevated risk of developing leukemia. Although statistics vary, about 10% of patients with Fanconi anemia, 5-10% of patients with Shwachman-Diamond syndrome, and 1 in 6 patients with Bloom syndrome develop leukemia. The risk of acute myeloid leukemia in patients with dyskeratosis congenita is nearly 200 times that of the normal population. These syndromes share features of poor DNA repair that are believed to predispose affected individuals to leukemogenic stimuli.

Children with neurofibromatosis type I also appear to be at increased risk for developing acute myeloid leukemia.

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 acute myeloid leukemia.

United States statistics

Acute myeloid leukemia accounts for nearly 20% of about 3250 newly diagnosed cases of leukemia in children each year. Although 1 in every 3 newly diagnosed leukemias is acute myeloid leukemia, the ratio of acute myeloid leukemia to ALL rapidly decreases until adolescence.[2] During adolescence, the rate increases to account for nearly 50% of all new diagnoses of leukemia.

International statistics

Although leukemia has been reported in children worldwide, the incidence varies widely. In the United States and other highly industrialized countries, acute myeloid leukemia accounts for about 15% of childhood leukemia. In other areas, such as Turkey, nearly one half of children diagnosed with leukemia have acute myeloid leukemia. Childhood leukemia (other than Burkitt type) is less common in Africa, but the ratio of acute myeloid leukemia to ALL is roughly 1:1. Likewise, the incidence of acute myeloid leukemia in Asia is significantly higher than it is in more developed parts of the world, being nearly equal to that of ALL, as reported by Bhatia and Neglia.[3]

Geographic predilection

Minor geographic variations are observed in the incidences of the different subtypes of acute myeloid leukemia. Areas of the world where rates of acute myeloid leukemia are higher than average include Shanghai, New Zealand, and parts of Japan.

Race-, sex-, and age-related demographics

Although ALL is more common in White children than in Black children, acute myeloid leukemia affects all races nearly equally. The incidence of one subtype, APL, is slightly increased in the Hispanic pediatric population.[4]

Male and female distributions are nearly equal at all ages.

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

With an overall survival rate of 45-60%, the prognosis for children with acute myeloid leukemia has improved significantly since the late 20th century. A Dutch study found that the 5-year survival rate rose from 40% in the early 1990s to 74% in 2010-2015.[5]

A Japanese consortium reported an overall 5-year survival rate of 62%.[6] The long-term, disease-free survival rate is approximately 65% for patients receiving human leukocyte antigen (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.

A 2012 study from Japan confirmed the results of the AML99 trial for newly diagnosed pediatric patients with AML with a 5-year overall survival (OS) of 75.6% and event-free survival (EFS) of 61.6%. This group compared their results to another cohort of newly diagnosed AML patients and found their results to be the same as the original AML99 trial with 5-year OS of 77.7% and EFS of 66.7%. Interestingly, the 5-year EFS in patients with a normal karyotype was lower compared to the original AML99 trial.[7]

For children with Down syndrome, current outcomes favor younger children, with a survival rate of 84-86% for children younger than age 2 years, 79% for children aged 2-4 years, and only 33% for children older than age 4 years.[8]

Acute promyelocytic leukemia prognosis has an event-free survival rate of 70-80%, with overall survival close to 90%.[9]

A study by Klco et al looked to determine whether genomic approaches can provide novel prognostic information for adult patients with de novo AML. The study found that although comprehensive genomic data from the patients did not improve outcome assessment, the detection of persistent leukemia-associated mutations in at least 5% of bone marrow cells in day 30 remission samples was associated with a significantly increased risk of relapse, and reduced overall survival.[10]

Cytogenetic abnormalities

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]).

Molecular studies

In addition to the established prognostic cytogenetic abnormalities, increasing evidence has revealed various molecular abnormalities that have an impact on outcome. The presence of the FLT3/ITD mutation, a receptor tyrosine kinase mutation, has been established as a predictor of worse outcome. These findings on the blast cells are now used to further stratify patients into risk groups with different treatment strategies.

Another gene affecting prognosis is the nucleophosmin (NPM1) mutation. The presence of this mutation has been shown to confer a favorable prognosis for event-free survival, although the combination of NPM1 and FLT3 mutations found in many patients is not favorable.

The presence of MLL gene is usually an unfavorable prognostic marker. The presence of the Wilms tumor gene (WT1) is also an adverse prognostic marker, with patients often failing to achieve complete remission.

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 patient education information, see Leukemia.

Symptoms of acute myeloid leukemia 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

Cytopenias can result from a deficiency of normally functioning cells.

Anemia, a 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.

Another symptom, hemorrhage due to thrombocytopenia, is in part due to decreased production of megakaryocytes in the bone marrow. The most common findings are easy bruising, petechiae, epistaxis, gingival bleeding, and, sometimes, gastrointestinal (GI) or central nervous system (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 is a common presenting complaint in patients with acute leukemia. In this context, fever should initially 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, CNS or any other organ.

Monoblastic leukemia is often associated with gingival hyperplasia (seen in the image below) and CNS infiltration.

Gingival hyperplasia in a patient with monoblastic leukemia.

Constitutional and miscellaneous symptoms

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 an increased catabolic nutritional state combined with decreased caloric intake from anorexia.

Bone pain is less common in patients with acute myelocytic leukemia 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 symptoms, although uncommon initially, can appear during follow-up with various findings. The most common signs and symptoms are related to elevated intracranial pressure, including headache, nausea and emesis, lethargy, irritability, and visual complaints.

Involvement of cranial nerves, most often the facial nerve (resulting in Bell palsy) and the abducens nerve (resulting in esotropia), may be isolated or may occur 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.

In acute myeloid leukemia, blast cells periodically form large aggregates called chloromas or granulocytic sarcomas, leading to epidural compression. Extreme leukocytosis with WBC counts of more than 200 X 109/L is often associated with hyperviscosity, intracerebral leukostasis, and intracerebral hemorrhage early in the course.

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.

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 acute myeloid leukemia than in ALL.

Splenomegaly is sometimes massive, particularly in young children.

Pronounced organomegaly occasionally results 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 acute myeloid leukemia. They are typically firm, raised, and often bluish-purple in color. (See the image below.)

Leukemia cutis (a skin nodule) in a patient with leukemia.

The hallmark of acute myeloid 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).

White blood cell (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 (thin, needle-shaped, eosinophilic cytoplasmic inclusions) are revealed in specimens of circulating blood obtained from many patients with acute myelocytic leukemia. They are particularly prominent in children with acute promyelocytic leukemia (APL).

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.

Imaging studies are not required for the diagnosis of acute myeloid leukemia in children or evaluation of the disease’s extent in these patients. Such studies, however, can be helpful in managing complications that arise.

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.

Radiographic examination of the extremities may reveal 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.

If the patient has abdominal pain and possible infection of the large bowel, computed tomography (CT) scanning may reveal thickening and edema of the bowel wall suggestive of typhlitis.

If a patient has neurologic symptoms, CT scanning or magnetic resonance imaging (MRI) of the head, spine, or other involved region is mandatory to rule out intracranial hemorrhage or infiltrative disease.

CT scanning may also allow early detection of asymptomatic sinusitis that might cause persistent, unexplained fevers.

Because serious infections that affect heart function are routinely observed in this patient population, periodic cardiac monitoring is important.

Perform echocardiography before chemotherapy and periodically when high cumulative doses of anthracyclines are administered.

Most treatment regimens include anthracyclines, such as daunomycin and idarubicin, which may cause clinically significant cardiomyopathy.

Radionuclide imaging is often used to detect occult infection that cultures and other imaging modalities do not reveal. For example, technetium-99m (99m Tc) 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.

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 acute myeloid leukemia cells have strong positive reactions to myeloperoxidase and Sudan black stains. Esterase stain 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 acute myeloid leukemia blasts.

Analysis of the chromosome changes in the leukemic cell is often performed to confirm the diagnosis and for prognostic purposes. If patients have the 9;22 translocation, this would indicate an underlying chronic myelogenous leukemia that would necessitate treatment with tyrosine kinase inhibitors and possibly stem cell transplantation. FLT3 would likewise be an important prognostic marker.

Human leukocyte antigen (HLA)–matched family donors should be identified because bone marrow transplantation (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.

Bone marrow examination is necessary to establish the diagnosis of acute myeloid leukemia. The sample is examined under the microscope, at which time the percentage of different cells is tabulated. The hallmark of leukemia is the presence of a high proportion of primitive cells and a paucity of normal hematopoietic elements.

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

The preferred site for retrieving marrow is the iliac crest, either anterior or posterior. The tibia may be an alternative source of marrow for diagnostic purposes in infants, although it is rarely required as a preferred site. In rare cases, a sternal biopsy is necessary; this can sometimes be required in children with extensive marrow fibrosis. The sternal site is generally more painful and entails the risk of heart damage if the needle penetrates deeply beyond the sternal bone.

Although bone marrow aspiration is usually sufficient to establish the diagnosis and to follow up on the progress of the disease, a core biopsy may be necessary if one encounters a "dry tap." This can happen when a marrow is heavily infiltrated or when significant fibrosis of the bone marrow is present.

Biopsy is necessary to gauge the cellularity of a marrow specimen and was the former standard during follow-up to aid subsequent therapeutic decisions. However, biopsy is now less commonly used, since the disease status can usually be evaluated with marrow aspirations and immunologic and cytogenetic testing.

Bone marrow examination usually reveals characteristic hyperplastic marrow with monotonous replacement with leukemia cells.

Patients with low blast count t(8;21) can also present a diagnostic challenge, sometimes considered a myelodysplastic syndrome, and often require multiple marrow examinations before the diagnosis of leukemia is confirmed. Other 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).

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.

Although the cerebrospinal fluid (CSF) is less frequently involved in acute myeloid leukemia than in ALL, leukemic infiltration has been reported in 5-20% of patients with acute myeloid leukemia, depending on the study. The greatest risk is seen in patients with monocytic subtypes, in infants, and in children with hyperleukocytosis on presentation.

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.

Treatment for patients with acute myeloid 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.

The role of surgery is limited.

Be vigilant to recognize associated complications, such as infections, hemorrhage, metabolic complications, or early organ dysfunction.

Hospitalization is necessary in patients with acute myeloid leukemia 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.

Transfer considerations

Transfer to a pediatric cancer center is usually necessary for initial diagnostic studies and is mandatory for management of chemotherapy and treatment-related complications.

For patients with suitable donors, transfer to a center capable of performing stem cell transplantations is usually 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 or port with at least 2 lumens 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.

Peripheral indwelling central catheters in the cubital area are sometimes used. These are sometimes added when patients require additional therapy, such as stem cell transplantation, or when a temporary access situation develops (as when an indwelling central line is removed because of infection).

Virtually all chemotherapeutic drug regimens include some combination of an anthracycline (most often daunorubicin [daunomycin]) with cytosine arabinoside (cytarabine). Other drugs that have been administered include fludarabine, 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 all of the pediatric national groups merged to form the Children's Oncology Group (COG), the recommended regimen,[11] based on the Medical Research Council acute myeloid leukemia trials, was adapted; this consisted of 2 cycles of induction therapy with infusions of daunomycin, cytosine arabinoside, etoposide (ADE therapy). 

In September 2017, the FDA approved gemtuzumab ozogamicin (Mylotarg) for the treatment of relapsed or refractory CD33-positive AML in patients aged 2 years and older.

Gemtuzumab ozogamicin originally received accelerated approval in May 2000 as a stand-alone treatment for relapsed CD33-positive AML in older patients, but was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit and demonstrated safety concerns, including a high number of early deaths. The September 2017 approval includes a lower recommended dose, a different treatment schedule and a new patient population.[12]

The International Berlin-Frankfurt-Münster (BFM) Study Group reported that children with relapsed AML who received liposomal daunorubicin (DNX) in conjunction with the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF]) had improved early treatment response.[13, 14] Although overall long-term survival was similar in the 2 treatment groups, children with core-binding factor (CBF) AML who received FLAG/DNX had a 24% higher 4-year probability of survival than those who received the FLAG regimen alone.[13, 14]

Patients who are FLT3 positive can benefit from targeted agents, such as sorafenib.

After remission is induced, postinduction treatment is necessary, because more than 90% of patients otherwise 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.

In the COG trials, transplants are not recommended for "low-risk acute myeloid leukemia," which is characterized by chromosome inv(16) and t(8;21) abnormalities; these patients receive additional "consolidation" chemotherapy and are only transplanted in second remission. Allogeneic stem cell transplantation from an HLA-matched sibling or parent is recommended during the first complete remission (ie, after 3 cycles of chemotherapy) for other patients (ie, those with standard-risk acute myeloid [normal cytogenetics] who enter remission with 2 induction courses and those with high-risk acute myeloid leukemia [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 acute myeloid leukemia. Patients with APL should not receive a transplant during the first remission.

Upon relapse and the achievement of a molecular remission in a child treated with chemotherapy only, stem cell transplantation offers the best chance of cure. If an HLA-matched family donor is not available, the use of unrelated matched donors and autologous bone marrow transplant are options that have shown promise.

Other approaches have met with success in other parts of the world. Nordic and Japanese researches have reported promising results using multiple cycles of high-dose cytosine arabinoside.[6, 15]

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/microliter), 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 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 (withdrawn from US market), or anti-CD33 calicheamicin, is also being tested in patients with APL. The hope is that 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 leukophoresis 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.[16]

Unlike most children with acute myeloid leukemia 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 acute myeloid leukemia 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 acute myeloid leukemia 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.

Age has been shown to be an important prognostic factor for children with Down syndrome; children younger than 2 years have the best outlook. A COG study (A2971) has shown that the 2-year-old to 4-year-old age group does as well as those younger than 2 years. Older children with Down syndrome continue to have a worse outlook than children younger than 4 years.

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 total body irradiation with busulfan to decrease the incidence of some long-term adverse effects (ie, growth retardation, brain tumors). Although busulfan is associated with significant, potential, short-term and long-term adverse effects (including seizures and infertility), the incidence of second malignancies is lower than that associated with total body irradiation.

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 acute myeloid leukemia.[17]

In several randomized studies, allogeneic transplantation raised overall and disease-free survival rates.[18]

However, this option is often not available, because HLA-matched donors are found for only approximately 25% of patients. 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 nonetheless substantially increased with the availability of international HLA registries that can help in locating HLA-matched unrelated donors (MUD). Results with MUD are virtually equivalent to HLA-matched family donors.

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 graft versus host disease (GVHD).

In addition, the use of purged or unpurged autologous stem cells, which offer the advantages of availability and avoidance of graft versus host disease, are under investigation 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.

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.

Hepatic veno-occlusive disease (also termed sinusoidal obstructive syndrome), a complication that can be fatal, has shown excellent responses to defibrotide. Defibrotide is a single-stranded polydeoxyribonucleotide derived from porcine tissue that possesses antithrombotic, thrombolytic, anti-inflammatory, and anti-ischemic properties.

In March 2016, the FDA approved defibrotide (Defitelio) for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). Approval was based on findings of a phase 3 trial (n = 102) which observed significant improvement in survival and complete response with defibrotide 6.25 mg IV q6h compared to 32 historical controls. Survival at Day+100 post-HSCT was 38.2% in the defibrotide group and 25% in the control group (estimated difference of 230%; 95.1% confidence interval [CI] 5.2%-40.8%; P=.0109, using a propensity-adjusted analysis based on 4 prognostic factors of survival). Observed Day+100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% in the controls (19% difference using similar methodology; 95.1% CI 3.5-34.6; P=.0160).[19]

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

Throughout long periods of pancytopenia, platelet and red blood cell (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 extreme 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.

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.

Infection is a major cause of morbidity and mortality in acute myeloid leukemia.

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) (see the Absolute Neutrophil Count calculator). 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 after initiation of broad-spectrum antibiotics and negative bacterial cultures. Although amphotericin has been the standard treatment for many years, other agents, such as voriconazole, caspofungin, and micafungin are increasingly used.

(To facilitate proper diagnosis of infection, bronchoscopy, lung biopsy, and imaging studies are often necessary. CT scanning is often required to detect subtle abscesses in the lungs, liver, spleen, kidneys, or brain.)

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

Prophylaxis

Prophylactic antibiotics have helped to decrease the incidence of a number of infections. Trimethoprim-sulfamethoxazole dramatically reduced the incidence of Pneumocystis (carinii) jiroveci 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.[20]

Many centers routinely administer fluconazole or nystatin prophylaxis to reduce the risk of fungal infections. Because of the significant incidence of life-threatening Enterococcal infections in this patient population, prophylaxis with penicillin or cephalosporins have also been advised.

Patients who develop GVHD that requires significant immunosuppressive therapy require more intense and more broadened infection prophylaxis.

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 routinely recommended in patients with acute myeloid leukemia.

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

The role of surgery is limited in acute myeloid leukemia.

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 often requires expeditious surgical intervention.

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 help the patient to tolerate therapy. Most transplantation 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 acute myeloid leukemia who are not undergoing transplantation.

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.

The association of acute myelocytic leukemia with radiation, toxins, and drugs has been well documented. Reduced exposure to ionizing radiation should be an important maxim for every physician who orders diagnostic testing for patients, particularly 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 acute myelocytic leukemia.

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.

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.

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.

Patients and their families may experience major stresses as a result of intense treatment and frequent, prolonged hospitalizations for chemotherapy and its resulting complications (especially in patients undergoing stem cell transplant). Another stressor is the real possibility of life-threatening complications. Psychological support, with educational information and numerous meetings and updates, are important for the family's psychological well-being.

The treatment of acute myeloid leukemia 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 other 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.

Class Summary

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

Cytarabine

Cytarabine is a purine antimetabolite; it inhibits deoxyribonucleic acid (DNA) polymerase. The drug is used in the induction and intensification phases of treatment.

Daunorubicin (Cerubidine)

This is an anthracycline that binds to nucleic acids by intercalating between pairs of DNA, interfering with DNA synthesis. It is used in the induction phase of treatment.

Etoposide

Etoposide is a podophyllotoxin derivative. It is used in the induction and consolidation phases of treatment.

Mitoxantrone

Mitoxantrone inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II. It is used in the consolidation phase of treatment.

Tretinoin

This is used in the induction and maintenance phases in patients with APL.

Arsenic trioxide (Trisenox)

Arsenic trioxide may cause DNA fragmentation and damage or degrade fusion protein promyelocytic leukemia protein–retinoic acid receptor alpha (PML-RAR alpha).

L-asparaginase (Elspar)

This is used in the consolidation phase of therapy. It inhibits protein synthesis by hydrolyzing asparagines to aspartic acid and ammonia.

Gemtuzumab (Mylotarg)

Gemtuzumab ozogamicin is a monoclonal antibody against CD33 antigen, which is expressed on leukemic blasts in more than 80% of patients with acute myeloid leukemia and normal myeloid cells. The antibody-antigen complex is then internalized and the calicheamicin derivative is released inside the myeloid cell, where it binds to DNA, resulting in double strand breaks and cell death. Nonhematopoietic and pluripotent cells are not affected.

Class Summary

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 binding of 5-HT 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.

Ondansetron (Zofran, Zuplenz)

Ondansetron is a selective 5-HT3 receptor antagonist that blocks serotonin peripherally and centrally. It prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and whole-body radiotherapy.

Granisetron (Sancuso)

At the chemoreceptor trigger zone, granisetron blocks serotonin centrally and peripherally on vagal nerve terminals.

Aprepitant (Emend, Fosaprepitant)

Aprepitant (Emend) is a human substance P/neurokinin 1 receptor antagonist

Palonosetron (Aloxi)

Palonosetron (Aloxi) is a long acting 5-HT3 receptor antagonist.

Class Summary

Infections remain the biggest problem in acute myeloid leukemia. The use of prophylactic drugs can help to prevent several infections that are often life threatening.

Sulfamethoxazole and trimethoprim (Bactrim, Bactrim DS, Septra DS)

Sulfa drugs can effectively prevent Pneumocystis (carinii) jiroveci pneumonia in this immunocompromised group of patients.

Class Summary

These agents may change the permeability of the fungal cell, resulting in a fungicidal effect.

Fluconazole (Diflucan)

Fluconazole is effective in treating and decreasing host colonization of candidiasis.