1. Gurney JG, Ross JA, Wall DA, Bleyer WA, Severson RK, Robison LL.

Infant cancer
in the U.S.: histology-specific incidence and trends, 1973 to 1992. J Pediatr Hematol
Oncol. 1997 Sep-Oct. 19(5):428-32. [Medline].
2. Bhatia S, Neglia JP. Epidemiology of childhood acute myelogenous leukemia. J
Pediatr Hematol Oncol. 1995 May. 17(2):94-100. [Medline].
3. Matasar MJ, Ritchie EK, Consedine N, Magai C, Neugut AI. Incidence rates of acute
promyelocytic leukemia among Hispanics, blacks, Asians, and non-Hispanic whites in
the United States. Eur J Cancer Prev. 2006 Aug. 15(4):367-70. [Medline].
4. [Guideline] Tomizawa D, Tabuchi K, Kinoshita A, Hanada R, Kigasawa H, Tsukimoto
I, 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.
2007 Aug. 49(2):127-32. [Medline].
5. Imamura T, Iwamoto S, Kanai R, Shimada A, Terui K, Osugi Y, et al. Outcome in 146
patients with paediatric acute myeloid leukaemia treated according to the AML99
protocol in the period 2003-06 from the Japan Association of Childhood Leukaemia
Study. Br J Haematol. 2012 Aug 28. [Medline].
6. Gamis AS, Woods WG, Alonzo TA, Buxton A, Lange B, Barnard DR, 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. 2003 Sep 15. 21(18):3415-22. [Medline].
7. Ortega JJ, Madero L, Martn G, Verdeguer A, Garca P, Parody R, et al. Treatment
with all-trans retinoic acid and anthracycline monochemotherapy for children with
acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin
Oncol. 2005 Oct 20. 23(30):7632-40. [Medline].
8. [Guideline] Children's Oncology Group. Chemotherapy. Long-term follow-up
guidelines for survivors of childhood, adolescent, and young adult cancers. Mar 2006.
9. Harding A. One-third cure rate in first-ever pediatric relapsed AML trial. Medscape
Medical News. January 18, 2013. Available at
http://www.medscape.com/viewarticle/777872. Accessed: January 28, 2013.
10. Kaspers GJ, Zimmermann M, Reinhardt D, et al. Improved Outcome in Pediatric
Relapsed Acute Myeloid Leukemia: Results of a Randomized Trial on Liposomal
Daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Jan 14.
[Medline].

11. Lie SO, Abrahamsson J, Clausen N, Forestier E, Hasle H, Hovi L, et al. Treatment
stratification based on initial in vivo response in acute myeloid leukaemia in children
without Down's syndrome: results of NOPHO-AML trials. Br J Haematol. 2003 Jul.
122(2):217-25. [Medline].
12. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al.
Management of acute promyelocytic leukemia: recommendations from an expert
panel on behalf of the European LeukemiaNet. Blood. 2009 Feb 26. 113(9):1875-91.
[Medline].
13. [Guideline] Children's Oncology Group. Hematopoetic cell transplant. Long-term
follow-up guidelines for survivors of childhood, adolescent, and young adult cancers.
Mar 2006.
14. Klingebiel T, Reinhardt D, Bader P. Place of HSCT in treatment of childhood AML.
Bone Marrow Transplant. 2008 Oct. 42 Suppl 2:S7-9. [Medline].
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Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N
Engl J Med. 2005 Sep 8. 353(10):977-87. [Medline].
16. Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, Fleischhack G, Graf N, et
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2013. [Full Text].

Practice Essentials
Acute myeloid (myelogenous, myelocytic, myeloblastic) leukemia (AML) consists of a group
of malignant disorders characterized by the replacement of normal bone marrow with
abnormal, primitive hematopoietic cells. Although the cure rate has improved, treatments are
associated with notable morbidity and mortality.

Signs and symptoms

Signs and symptoms of pediatric acute myelocytic leukemia (AML) can be divided into the
following: (1) those caused by a deficiency of normally functioning cells, (2) those due to the
proliferation and infiltration of the abnormal leukemic cell population, and (3) constitutional
symptoms.

Symptoms due to a deficiency of normally functioning cells include the following:

Cytopenias: Can result from a deficiency of normally functioning cells

Anemia: Characterized by pallor, fatigue, tachycardia, and headache

Hemorrhage: Most commonly, easy bruising, petechiae, epistaxis, gingival bleeding

Fever: Should initially always be attributed to infection

Symptoms due to the proliferation and infiltration of the abnormal leukemic cell mass and
infiltrative disease include the following:

Extramedullary infiltration: Most commonly in the reticuloendothelial system

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

Gingival hyperplasia, CNS infiltration: Often associated with monoblastic leukemia

(see the image below)

Gingival hyperplasia in a
patient with monoblastic leukemia.
See Clinical Presentation for more detail.

Diagnosis
Classification of AML

AML can be divided into subtypes on the basis of marrow findings. The French-AmericanBritish classification system recognizes 7 primary types of AML (M1-M7), which can usually
be established by morphology and additional marrow studies.
The World Health Organization (WHO) classifies AML into groups as follows (rarely used in
pediatrics):

AML with characteristic cytogenetic translocations

AML with multilineage dysplasia

AML and myelodysplasia syndromes secondary to therapy

AML not otherwise categorized

Testing
The hallmark of AML is the reduction or absence of normal hematopoietic elements. Anemia
is usually normocytic, with a lower-than-expected reticulocyte count for the hemoglobin
level. The decrease in hemoglobin levels can range from minimal to profound.
Laboratory tests used in patients with AML include the following:

Blood counts with differential: WBC counts may be decreased or elevated; platelet
counts usually low

Blood smears: Primitive granulocyte/monocyte precursors observed; Auer rods

present in specimens of circulating blood from many AML patients but particularly
prominent in pediatric APL

Blood chemistries: Frequently elevated serum uric acid, serum muramidase

(lysozyme), LDH levels

Blood and urine cultures: Always obtain in a child with fever and leukemia

Coagulation tests: Perform with initial diagnosis for evidence of DIC indicating APL

Histochemical staining: Standard Wright-Giemsa stains and histochemical stains to

differentiate the various acute leukemias

Immunophenotyping: To further characterize leukemic cells for different cell lineages and
stages of development

Cytogenetic testing: To confirm the diagnosis and for prognostic purposes

HLA typing: To identify HLAmatched family donors for possible BMT or HSCT in
high-risk patients

Imaging studies
Imaging studies are not required for the diagnosis of AML in children, but the following
radiologic studies can be helpful in managing complications that arise:

Radiography: Routine CXR to rule out mediastinal masses; abdominal images in

patients with abdominal pain and distention to rule out perforation; extremity images
in patients to rule out metaphyseal bands at the distal femurs (mostly in pediatric
ALL), periosteal new bone formation, focal lytic lesions, or pathologic fractures

MRI or CT scanning of the head, spine, or other affected areas: For patients with
neurologic symptoms to rule out intracranial hemorrhage or infiltrative disease

CT scanning of abdomen or sinuses: For abdominal pain or suspected infection of the

large bowel; for early detection of asymptomatic sinusitis as cause of persistent,
unexplained fevers

Echocardiography: To exclude serious infections that affect heart function; also,

perform before chemotherapy and periodically with administration of high cumulative
doses of anthracyclines (eg, daunomycin, idarubicin)

Radionuclide imaging: To detect occult infection that cultures and other imaging
modalities do not reveal (eg, occult osteomyelitis, occult deep-tissue infection)

Procedures

Bone marrow examination: To establish the diagnosis of AML

Lumbar puncture and CSF examination: For diagnostic and therapeutic purposes

See Workup for more detail.

Management
The treatment of AML is directed toward 2 goals: (1) destroying the leukemic cells as rapidly
as possible and preventing the emergence of a resistant clone, and (2) supporting the patient
through long periods of pancytopenia until their bone marrow achieves hematologic
remission and is again producing normal hematopoietic cells.
Pharmacotherapy
Pharmacotherapy used in managing AML includes the following medications:

Chemotherapeutic drugs: Cytarabine (cytosine arabinoside), fludarabine,

daunorubicin (daunomycin), etoposide, amsacrine, 6-thioguanine, cyclophosphamide,
mitoxantrone, tretinoin, arsenic trioxide, L-asparaginase, gemtuzumab ozogamicin

Antiemetic drugs: Ondansetron, granisetron

Prophylactic broad-spectrum antimicrobials: Trimethoprim-sulfamethoxazole

Prophylactic antifungals: Fluconazole, nystatin

Nonpharmacologic therapy
AML may also be managed with nonpharmacologic treatments such as the following:

Allogeneic or autologous BMT following chemotherapy and irradiation: May reduce

relapse rates but doesnt always improve overall survival

Radiation treatment: Primarily to treat chloromas and other masses pressing on a vital
structure and that may imminently cause irreversible damage; craniospinal irradiation
for persistent CNS leukemia

Transfusion support: To correct anemia and thrombocytopenia until remission is

achieved (eg, RBC transfusions); to correct coagulopathies (FFP)

Surgical options
The role of surgery in AML is limited and may include the following:

Placement of a central venous catheter: To begin treatment and to manage all aspects
of chemotherapy and transfusion support

Biopsy or aspiration of tissue for culture: To detect possible abscess in febrile patients

Intervention for an acute abdomen (eg, typhlitis)

See Treatment and Medication for more detail.

Background
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/L.
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/L). These patients are at greater risk of
intracranial hemorrhage, and their conditions must be treated as true emergencies.

Etiology
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.

Epidemiology
Incidence in the United States
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.[1] During adolescence, the rate increases to account for nearly 50% of all new
diagnoses of leukemia.

International incidence
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.[2]

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 predilection
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.[3]

Sex predilection
Male and female distributions are nearly equal at all ages.

Age predilection
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.

Prognosis
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 Japanese consortium reported an overall 5-year survival rate of 62%.[4] 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.[5]
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.[6]
Acute promyelocytic leukemia prognosis has an event-free survival rate of 70-80%, with
overall survival close to 90%.[7]

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.

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.

History
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, 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 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.

Physical Examination
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.

Diagnostic Considerations
Children may not have well-known symptoms of leukemia, such as adenopathy, overt
bleeding, and serious infections. Nonspecific symptoms, such as fatigue, irritability, fevers,
and bruising, are common in childhood and might not be recognized as symptoms of
leukemia, thus delaying a diagnosis of leukemia. Persistence of these symptoms should
prompt further investigation.
Differentials in the diagnosis of acute myeloid leukemia, aside from those listed in the next
section, include the following:

Aplastic anemia

Drug-induced pancytopenia

Viral-induced pancytopenia

Systemic lupus erythematosus

Neuroblastoma

Transient myeloproliferative syndrome in Down syndrome

Differential Diagnoses

Epstein-Barr Virus Infection

Gaucher Disease

Histiocytosis

Lymphoproliferative Disorders

Parvovirus B19 Infection

Pediatric Acute Lymphoblastic Leukemia

Pediatric Cytomegalovirus Infection

Pediatric HIV Infection

Pediatric Megaloblastic Anemia

Pediatric Myelodysplasia

Pediatric Myelofibrosis

Approach Considerations

Imaging studies are not required for the diagnosis of acute myeloid leukemia in children or
evaluation of the diseases extent in these patients. Such studies, however, can be helpful in
managing complications that arise.
Blood Counts and Blood Smears

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/L).

WBC counts may be decreased or elevated. Hyperleukocytosis with WBC counts of more
than 100 X 109/L (>100,000/L) 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 acute myelocytic leukemia. They are particularly prominent in children with APL.
Blood Chemistries and Other Blood Work

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.
Radiography

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.
CT Scanning and MRI

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.
Ultrasonography

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

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.
Histochemical Staining

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.
Immunophenotyping

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.
Cytogenetics

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.
HLA Typing

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

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.
Histologic Findings

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 and Cerebrospinal Fluid Examination

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.

Approach Considerations

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).
Chemotherapy

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, 6thioguanine, cyclophosphamide, and mitoxantrone.
For many years, most children in the United States were treated with chemotherapy protocols
developed by the Childrens 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,[8] 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). Gemtuzumab ozogamicin
(withdrawn from the US market), an anti-CD33 antibody linked to an antitumor antibiotic, is
currently under investigation in a COG pediatric national trial.

The International Berlin-Frankfurt-Mnster (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.[9, 10] 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.[9, 10]
Postinduction Therapy

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 HLAmatched 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.[4, 11]
Treatment of Acute Promyelocytic Leukemia

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.[12]
Treatment in Children With Down Syndrome

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 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 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.
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 acute myeloid leukemia.[13]
In several randomized studies, allogeneic transplantation raised overall and disease-free
survival rates.[14]
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.
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.
Transfusion Support

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 gramnegative 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 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/L) (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, 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.[15]
Many centers routinely administer fluconazole or nystatin prophylaxis to reduce the risk of
fungal infections.
Patients who develop GVHD that requires significant immunosuppressive therapy require
more intense and more broadened infection prophylaxis.
Treatment With Biologic-Response Modifiers

Granulocyte colony-stimulating factor (G-CSF) and granulocyte monocyte colonystimulating 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.
Surgical Care

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.
Dietary Modification

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.
Activity Restrictions

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.
Deterrence/Prevention of Acute Myelocytic Leukemia

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, 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 acute myelocytic
leukemia.
Monitoring and Follow-Up Care

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.
Consultations

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.

Medication Summary
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; biologicresponse modifiers; and other classes of supportive medications.

Chemotherapeutic agents
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.
View full drug information

Cytarabine

Cytarabine is a purine antimetabolite; it inhibits deoxyribonucleic acid (DNA) polymerase.

The drug is used in the induction and intensification phases of treatment.
View full drug information

Daunorubicin, daunomycin (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.
View full drug information

Etoposide (Toposar)

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

of treatment.
View full drug information

Mitoxantrone (Novantrone)

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

Tretinoin, all-trans-retinoic acid

This is used in the induction and maintenance phases in patients with APL.
View full drug information

Arsenic trioxide (Trisenox)

Arsenic trioxide may cause DNA fragmentation and damage or degrade fusion protein
promyelocytic leukemia proteinretinoic acid receptor alpha (PML-RAR alpha).
View full drug information

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 ozogamicin (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.
The drug is for administration to patients over age 60 years (CD33 positive) in first relapse
who are not considered candidates for cytotoxic chemotherapy.
Gemtuzumab ozogamicin was withdrawn from United States market (June 21, 2010). A
confirmatory, postapproval clinical trial was begun in 2004. The trial was designed to
determine whether adding gemtuzumab to standard chemotherapy demonstrated an
improvement in clinical benefit (survival time) to patients with AML. The trial was stopped
early when no improvement in clinical benefit was observed and after a greater number of
deaths occurred in the group of patients who received gemtuzumab compared with those
receiving chemotherapy alone. At initial approval in 2000, gemtuzumab was associated with
a serious liver condition called veno-occlusive disease, which can be fatal. This rate has
increased in the postmarket setting.

Antiemetic agents
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.
View full drug information

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.
View full drug information

Granisetron (Kytril, Granisol, Sancuso)

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

Antimicrobials, prophylactic
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.
View full drug information

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

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

Antifungals
Class Summary
These agents may change the permeability of the fungal cell, resulting in a fungicidal effect.
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Fluconazole (Diflucan)

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

http://emedicine.medscape.com/article/987228-overview