Escolar Documentos
Profissional Documentos
Cultura Documentos
emedicine.medscape.com
Introduction
Background
Acute myeloid leukemia (AML) 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.
Pathophysiology
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. A major cause of
morbidity and mortality is the deficiency of normally functioning mature hematopoietic cells rather than the number
of malignant cells.
Splenomegaly due to leukemic infiltration further contributes to pancytopenia by sequestering and destroying
circulating erythrocytes and platelets. As the disease progresses, signs and symptoms of anemia,
thrombocytopenia, and neutropenia increase.
Leukemic cells may infiltrate other bodily tissues, causing many clinically significant complications including CNS
involvement, pulmonary dysfunction, or skin and gingival infiltration.
Frequency
United States
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
Although leukemia has been reported in children worldwide, the incidence rate widely varies. 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 more
…medscape.com/…/987228-print 1/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
developed parts of the world, nearly equal to that of ALL as reported by Bhatia and Neglia.[2 ]
Mortality/Morbidity
The long-term survival rate for pediatric patients with acute myeloid leukemia is nearly 55%. Acute myeloid
leukemia accounts for about 35% of childhood deaths from leukemia. Mortality is a consequence of resistant
progressive disease or treatment-related toxicity.
Race
Minor geographic variations are observed in the incidences of the different subtypes of acute myeloid leukemia.
However, ALL is more common in white children than in black children, whereas acute myeloid leukemia affects all
races nearly equally. The incidence of one subtype, acute promyelocytic leukemia (APL), is slightly increased in the
Hispanic pediatric population. Areas of the world where rates of acute myeloid leukemia are higher than average
include Shanghai, New Zealand, and parts of Japan.
Sex
Male and female distributions are nearly equal at all ages.
Age
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.
Clinical
History
Symptoms of acute myeloid leukemia (AML) 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.
Cytopenias
Anemia: This common finding is characterized by pallor, fatigue, tachycardia, and headache. The major
pathophysiologic mechanism is related to decreased production in the infiltrated bone marrow. Bleeding,
hemolysis, and sequestration and destruction in an enlarged spleen or liver may all contribute to anemia.
Hemorrhage due to thrombocytopenia: This is 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: This is a common presenting complaint in patients with acute leukemia. In this context, fever should
always be attributed to infection. Depending on the site of infection, symptoms may vary. Symptoms may be
pulmonary (eg, cough, dyspnea, hypoxia, chest pain), as in patients with pneumonias; neurologic (eg,
lethargy, emesis, headache), as in patients with meningitis; or other (eg, pain or changes in bladder and
bowel function due to colitis or urinary tract infection).
Symptoms due to the proliferation and infiltration of the abnormal leukemic cell mass and infiltrative disease
include the following:
The most common extramedullary infiltration due to leukemic cells occurs in the reticuloendothelial system.
This infiltration may manifest as adenopathy, hepatomegaly, or splenomegaly.
…medscape.com/…/987228-print 2/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
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 and CNS infiltration. See the image
below.
…medscape.com/…/987228-print 3/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Fever: Unexplained persistent fevers are sometimes the only presenting symptom of patients with leukemia.
Weight loss and cachexia are unusual findings in children with leukemia but not in adults. These effects can
result from increased catabolic nutritional state combined with decreased caloric intake from anorexia.
Orthopedic symptoms: Bone pain is less common in patients with acute myelocytic leukemia than in patients
with acute lymphoblastic leukemia (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: Although uncommon initially, it 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.
Ocular manifestations: In rare cases, leukemic cells infiltrate all parts of the eye. The retina and iris are the
sites most commonly affected. Iritis often causes photophobia, pain, and increased lacrimation, whereas,
retinal involvement is often accompanied by hemorrhage and can lead to a loss of vision.
Physical
Pancytopenia
Pallor with tachycardia is observed to different degrees proportional to the severity of anemia. With
severe anemia, patients may have lethargy, a heart murmur, and signs of congestive heart failure.
Bleeding manifestations are most commonly observed in the skin and include petechiae, purpuric
lesions, and ecchymoses.
GI bleeding may indicate erosions or perforation.
Signs of infection include fever, gingivitis, hypotension, or respiratory distress, depending on the site of
infection.
Causes
…medscape.com/…/987228-print 4/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
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 DNA repair mechanisms also contribute to the
development of acute myeloid leukemia.
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.
Differential Diagnoses
Acute Lymphoblastic Leukemia Lymphoproliferative Disorders
Anemia, Megaloblastic Myelodysplasia
Cytomegalovirus Infection Myelofibrosis
Gaucher Disease Neuroblastoma
Histiocytosis Rhabdomyosarcoma
…medscape.com/…/987228-print 5/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Human Immunodeficiency Virus Infection Systemic Lupus Erythematosus
Other Problems to Be Considered
Aplastic anemia
Drug-induced pancytopenia
Transient myeloproliferative syndrome in Down syndrome
Workup
Laboratory Studies
Imaging Studies
Imaging studies are not required for the diagnosis or extent of disease evaluation of children with acute myeloid
leukemia. They can be helpful in managing complications that arise.
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.
Radiograph 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 and MRI
If the patient has abdominal pain and possible infection of the large bowel, CT may reveal thickening
and edema of the bowel wall suggestive of typhlitis.
If a patient has neurologic symptoms, CT or MRI of the head, spine, or other involved region is
mandatory to rule out intracranial hemorrhage or infiltrative disease.
…medscape.com/…/987228-print 6/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
CT scanning may also allow early detection of asymptomatic sinusitis that might cause persistent,
unexplained fevers.
Sonography
Because serious infections that affect heart function are routinely observed in this patient population,
periodic cardiac monitoring is important.
Perform echocardiography before chemotherapy.
Most treatment regimens include anthracyclines, such as daunomycin and idarubicin, which may cause
clinically significant cardiomyopathy.
Radionuclide imaging
Radionuclide imaging is often used to detect occult infection that cultures and other imaging modalities
do not reveal.
Technetium bone scans often help in localizing an occult osteomyelitis.
Whole-body gallium or indium scanning often reveals an occult deep tissue infection and can help with
appropriate antibiotic management.
Other Tests
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.
…medscape.com/…/987228-print 7/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Procedures
Histologic Findings
…medscape.com/…/987228-print 8/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
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).
Treatment
Medical Care
Treatment for patients with acute myeloid leukemia (AML) involves intensive chemotherapy to destroy the leukemic
cell population as rapidly as possible and to prevent the emergence of a resistant clone. Patients are
simultaneously given supportive care until their bone marrow achieves hematologic remission and is again
producing normal hematopoietic cells.
Chemotherapy
Virtually all chemotherapeutic drug regimens include some combination of an anthracycline (most often
daunomycin) with cytosine arabinoside. Other drugs that have been administered include etoposide,
amsacrine, dexamethasone, 6-thioguanine, cyclophosphamide, and mitoxantrone.
For many years, most children in the United States were treated with chemotherapy protocols
developed by the Children’s Cancer Group and the Pediatric Oncology Group. These protocols, which
used different multiagent chemotherapies, were associated with improved results as therapy was
intensified. Although these treatments prolonged pancytopenia, they decreased induction failures and
substantially improved disease-free survival.
After the 2 national groups merged to form the Children's Oncology Group (COG), the recommended
regimen,[3 ]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 US market), an anti-CD33
antibody linked to an antitumor antibiotic, is currently under investigation in a COG pediatric national
trial.
After remission is induced, postinduction treatment is necessary because more than 90% of patients
otherwise relapse without additional treatment. In patients without human leukocyte antigen (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 bone marrow
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 acute promyelocytic leukemia (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. See the section on stem cell transplant below.
…medscape.com/…/987228-print 9/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
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.[4,5 ]
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. 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 radiation.
…medscape.com/…/987228-print 10/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Transfusion support
Because treatment regimens are intensive, expeditious blood product transfusion support is critical.
Throughout long periods of pancytopenia, platelet and RBC transfusions are necessary to correct
anemia and thrombocytopenia until remission is achieved.
Fresh frozen plasma is occasionally required to correct coagulopathies, particularly in patients with
disseminated intravascular coagulation. All transfused products must be irradiated to prevent GVHD in
heavily immunosuppressed patients.
Support from the blood bank is mandatory when patients present with hyperleukocytosis and are at high
risk for stroke and heart failure due to hyperviscosity. These patients are best treated with
leukophoresis or double-volume exchange transfusion to rapidly and safely decrease the leukemic cell
burden without contributing to metabolic abnormalities. This procedure also facilitates rapid correction
of anemia, which viscosity constraints would otherwise have prohibited.
In rare cases, granulocyte transfusions are administered to treat serious infections that do not respond
to appropriate antibiotic therapy. This approach may be most appropriate for gram-negative sepsis,
serious intra-abdominal infections, and, sometimes, fungal infections, although the efficacy of this
approach as not been definitively proven.
Metabolic management
Patients who present with a large leukemic cell burden, either a high circulating WBC count or massive
organomegaly, are at risk for severe, often life-threatening metabolic derangements.
Before beginning cytoreduction, correct any existing abnormalities and take measures to prevent new
ones.
Hyperkalemia and hyperphosphatemia with associated hypocalcemia result from rapid cell turnover
and destruction.
Promptly treat elevated potassium levels by using measures such as sodium polystyrene sulfonate
(Kayexalate), an insulin and glucose combination, and, sometimes, hemodialysis.
…medscape.com/…/987228-print 11/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Calcium replacement is often necessary to correct severe hypocalcemia.
Prevention is key to avoiding most serious metabolic complications. The combination of vigorous
hydration, administration of allopurinol (a xanthine oxidase inhibitor to prevent the formation of uric
acid), and alkalinization of the urine with sodium bicarbonate is usually successful in preventing serious
tumor lysis syndromes. For patients at high risk for tumor lysis syndrome, those with renal dysfunction,
or those whose uric acid levels are already elevated, rasburicase directly lyses uric acid and can
rapidly reduce its levels.
Antibiotic therapy
Infection is a major cause of morbidity and mortality.
Patients with fever, particularly if they have severe neutropenia, are presumed to have serious infection
until proven otherwise.
Empiric broad-spectrum antibacterial antibiotics are administered when a patient is febrile and has an
absolute neutrophil count of less than 7.5-10 X 109/L (<750-1000/µL). The choice of antibiotics
depends on the typical pathogens found in the community and hospital. It is usually some combination
of an aminoglycoside and a cephalosporin or semisynthetic penicillin with beta-lactamase inhibitor until
culture results are available.
When tunnel infections around a central venous catheter are suspected, vancomycin should be
administered. At certain institutions, removal of the intravenous line is also recommended.
If a patient presents with abdominal or GI symptoms, the antibiotic chosen should cover anaerobes.
When neutropenia is prolonged, particularly after treatment with broad-spectrum antibacterial agents,
fungal disease becomes a great concern.
Empiric use of antifungal therapy is indicated in patients with persistent fever 3-5 days of initiation of
broad spectrum antibiotics and negative bacterial cultures. Although amphotericin has been the
standard treatment for many years, other agents, such as voriconazole, are increasingly used.
CT scanning is often necessary to detect subtle abscesses in the lungs, liver, spleen, kidneys, or brain.
Prophylactic antibiotics have helped to decrease the incidence of a number of infections.
Sulfamethoxazole-trimethoprim has dramatically reduced the incidence of Pneumocystis carinii
pneumonia. In some centers, prophylactic penicillin has decreased the incidence serious systemic
streptococcal sepsis in patients with severe mucositis. Acyclovir has been useful in preventing herpes
simplex infections, particularly in patients who have undergone bone marrow transplantation. Reports
have suggested that prophylactic levofloxacin decreases the incidence of sepsis and other life-
threatening infections. Patients who develop GVHD that requires significant immunosuppressive
therapy require more intense and more broadened infection prophylaxis.
Vigilance is most important in the patient with acute myeloid leukemia and persistent fever. Frequent
cultures of possible sites of infection should be performed.
To facilitate proper diagnosis, bronchoscopy, lung biopsy, and imaging studies are often necessary.
Surgical Care
Consultations
Urologist: Consider consulting a urologist when male teenagers are undergoing intense chemotherapy that
may cause oligospermia and fertility problems in the future. These conditions are usually temporary.
However, they are particularly problematic for patients who undergo high-dose chemotherapy in preparation
for blood or marrow transplantation, and they are major problems for patients who may be receiving total-
body irradiation. Encourage sperm banking, preferably before these patients begin any treatment that may
affect the quality of their sperm.
Psychologists, psychiatrists, or other mental health professional: Patients and their families may experience
majors stresses as a result of intense treatment and frequent, prolonged hospitalizations for chemotherapy
and its resulting complications (especially fin patients undergoing stem cell transplant). Another stressor is
the real possibility of life-threatening complications. Psychologic support, with educational information and
numerous meetings and updates, are important for the family's psychological well-being.
Diet
Careful attention must be directed toward adequate nutrition. Because of prolonged neutropenia with
infections that blunt a patient's appetite and recurrent episodes of chemotherapy-induced mucositis, high-
calorie oral supplements are often helpful for maintaining weight. They allow help the patient in tolerating
therapy. Most patients require intravenous total parenteral nutrition or, preferably, nasogastric alimental
nutrition.
Low-bacteria diets are often prescribed to patients receiving a blood or marrow transplant to decrease the
incidence of infections because of the profound immunosuppression after transplantation. This would
include avoiding uncooked fresh vegetables and fruits. These recommendations are probably not necessary
for patients with acute myeloid leukemia who are not undergoing transplant.
Activity
Minimal limits on activity are necessary. Patients should avoid crowds and exposure to potentially contagious
disorders when they have neutropenia or immunosuppression after transplantation.
During episodes of thrombocytopenia, patients should curtail their participation in potentially traumatic
physical sports activities to avoid serious hemorrhage. Medications that can potentiate bleeding, such as
antiplatelet agents (eg, aspirin, nonsteroidal anti-inflammatory drugs) should be avoided.
Medication
Treatment is directed toward 2 goals: destroying the leukemic cells and supporting the patient through long periods
of pancytopenia. Chemotherapy meets the first goal, but many classes of drugs must also be included in treatment.
Such classes include broad-spectrum antibacterial, antiviral, and antifungal antibiotics; biologic-response
modifiers; and other classes of supportive medications.
Chemotherapeutic agents
Although many chemotherapeutic agents are active, most current regimens include combinations of an
anthracycline and cytosine arabinoside. Chemotherapeutic agents destroy myeloblasts in various mechanisms.
Cytarabine (Cytosar-U)
Purine antimetabolite; inhibits DNA polymerase. Used in both induction and intensification phases of treatment.
Dosing
Adult
…medscape.com/…/987228-print 13/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Pediatric
Induction therapy: 100 mg/m2/dose IV bolus q12h for 10 d during cycle 1 (ie, 20 doses with cumulative dose of
2000 mg/m2) and for 8 d during cycle 2 (ie, 16 doses with cumulative dose of 1600 mg/m2)
Intensification:
First intensification dose: 1000 mg/m2/dose IV q12h infused over 1 h for a total of 10 doses (total of 10,000 mg/m2)
Second intensification for nontransplant patients: 1000 mg/m2/dose IV q12h infused over 2 h, for a total of 8 doses
(total of 8,000 mg/m2)
Final intensification for nontransplant patients: 3000 mg/m2/dose IV q12h infused over 3 h for 4 doses on days 1
and 2, then repeat on days 8 and 9 for a total of 8 doses (total of 24,000 mg/m2 over the 9 day period)
Interactions
Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase toxicity
Contraindications
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Only experienced oncologists should administer this drug; severe myelosuppression, mucositis, nausea, diarrhea,
alopecia, ocular toxicity, neurotoxicity, and other complications are expected
Anthracycline that binds to nucleic acids by intercalating between pairs of DNA, interfering with DNA synthesis.
Used in induction phase of treatment.
Dosing
Adult
Pediatric
Induction: 50 mg/m2/dose IV infusion over 6 h qod for 3 doses during each induction cycle (ie, 150 mg/m2/cycle,
cumulative dose of 300 mg/m2 for both induction cycles)
Interactions
Increased risk of cardiotoxicity when combined with heart irradiation; additive risks of cardiotoxicity with
trastuzumab
Contraindications
Documented hypersensitivity; cardiac failure; severe hepatic or renal dysfunction; cumulative anthracycline dose
>450 mg/m2 is relative contraindication
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Only experienced oncologists should administer this drug; severe myelosuppression, mucositis, nausea, diarrhea,
alopecia, tissue damage with extravasation, and other complications expected; fatal cardiac complications have
occurred
Dosing
Adult
Pediatric
Interactions
May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in
cytotoxicity of tumor cells
Contraindications
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Only experienced oncologists should administer this drug; severe myelosuppression, hypotension, mucositis, and
other complications expected; consider dosage reduction in patients with low serum albumin levels, bone marrow
suppression, or renal impairment
Mitoxantrone (Novantrone)
Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II. Used in consolidation phase of
treatment.
Dosing
Adult
Pediatric
Intensification: 12 mg/m2/d IV for 4 d during second cycle of intensification for patients not undergoing stem cell
transplant
Interactions
Cytochrome P450 (CYP) 2E1 inducer (weak); valspodar increases area under the concentration-time curve (AUC)
(decrease dose)
Contraindications
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Only experienced oncologists should administer this drug; severe myelosuppression, anaphylaxis; cardiotoxicity;
interstitial pneumonitis; hepatic dysfunction, nausea, mucositis, and other complications expected
Dosing
Adult
Pediatric
Interactions
CYP substrate (caution with coadministration of CYP inhibitors or inducers); ketoconazole significantly increases
AUC; coadministration with tetracyclines may increase risk of pseudotumor cerebri and intracranial hypertension;
coadministration with vitamin A may increase risk of hypervitaminosis A; fatal thrombotic complications reported
when coadministered with antifibrinolytic agents (eg, tranexamic acid, aminocaproic acid, aprotinin)
Contraindications
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Only experienced oncologists should administer this drug; severe leukocytosis with pulmonary infiltrates and
respiratory failure expected; headache, fever, weakness, and fatigue common
May cause DNA fragmentation and damage or degrade fusion protein promyelocytic leukemia protein–retinoic
acid receptor alpha (PML-RAR alpha). Use only in patients who have relapse or whose disease is refractory to
retinoid or anthracycline chemotherapy.
Dosing
Adult
Pediatric
Interactions
Concomitant use with diuretics or amphotericin B may cause electrolyte abnormalities; concurrent use with QTc-
prolonging agents (type Ia or II antiarrhythmic agents, cisapride, thioridazine, and selected quinolones) may
increase risk of potentially fatal arrhythmias
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Correct electrolyte abnormalities before treatment and monitor potassium and magnesium levels during therapy;
may prolong QT interval; discontinue t and hospitalize patient if QTc >500 ms or if syncope or irregular heartbeats
develop; may lead to torsade de points or complete atrioventricular (AV) block (risk factors include congestive
heart failure, history of torsade de pointes, preexisting prolongation of QT interval, use of potassium-wasting
…medscape.com/…/987228-print 16/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
diuretics, conditions that cause hypokalemia or hypomagnesemia)
L-asparaginase (Elspar)
Dosing
Adult
Pediatric
6000 U/m2/dose IM 3 h after final high-dose cytosine arabinoside during 2 weekly cycles of consolidation
Interactions
Decreased effect if given prior to methotrexate; coadministration with vincristine increases toxicity;
coadministration with prednisone increases risk of hyperglycemia
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits
outweigh risk to fetus
Precautions
Allergic reactions common (symptoms range from localized urticaria to angioedema or anaphylaxis); bone marrow
depression, hyperglycemia, hepatotoxicity, and bleeding may occur; known to cause fevers, nausea, abdominal
pain, coagulopathy, thrombosis, and pancreatitis
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.
Monoclonal antibody against CD33 antigen, which is expressed on leukemic blasts in >80% of patients with acute
myeloid leukemia and normal myeloid cells. Antibody-antigen complex is then internalized and the calicheamicin
derivative is released inside the myeloid cell where binds to DNA resulting in double strand breaks and cell death.
Nonhematopoietic and pluripotent cells are not affected.
For administration to patients >60 years (CD33 positive) in first relapse who are not considered candidates for
cytotoxic chemotherapy.
Dosing
Adult
9 mg/m2 IV over 2 h; give total of 2 doses 14 d apart; full hematologic recovery not necessary for administration of
second dose; administer 50 mg diphenhydramine PO and 650-1000 mg acetaminophen PO 1 h prior to
administration of each dose
Pediatric
…medscape.com/…/987228-print 17/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Interactions
None reported
Contraindications
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Postinfusion reactions including hypotension, fever, chills, or dyspnea (acetaminophen, intravenous fluids, and
diphenhydramine may be administered to reduce incidence); severe myelosuppression occurs in all patients at
recommended dosages; caution in renal and hepatic impairment; tumor lysis may occur (risk may be reduced by
administering allopurinol prophylactically and adequate hydration)
Antiemetic agents
Antineoplastic-induced vomiting is stimulated by actions on the chemoreceptor trigger zone. This zone then
stimulates the vomiting center in the brain. Increased activity of central neurotransmitters, dopamine in the
chemoreceptor trigger zone or acetylcholine in the vomiting center, appears to be a major mediator in inducing
vomiting. After antineoplastic agents are given, serotonin (5-HT) is released from enterochromaffin cells in the GI
tract. With this release and with the subsequent of 5-HT binding to 5-HT3-receptors, vagal neurons are stimulated
and transmit signals to the vomiting center, resulting in nausea and vomiting.
Emesis is a notable problem in patients receiving high-dose chemotherapy. The resultant nutritional, metabolic,
and fluid derangements can be unpleasant enough that patients may refuse further life-saving therapy. It is
important to use these drugs prophylactically.
Ondansetron (Zofran)
Selective 5-HT3 receptor antagonist that blocks serotonin peripherally and centrally. Prevents nausea and vomiting
associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and whole-body radiotherapy.
Dosing
Adult
Pediatric
Interactions
Although there is potential for CYP450 inducers (barbiturates, rifampin, carbamazepine, phenytoin) canto change
half-life and clearance of ondansetron, dosage adjustment usually is not required
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Headache is one of most common adverse drug reactions; administered to prevent and not for rescue of nausea
and vomiting
…medscape.com/…/987228-print 18/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Granisetron (Kytril)
At chemoreceptor trigger zone, blocks serotonin centrally and peripherally on vagal nerve terminals.
Dosing
Adult
Pediatric
Interactions
None reported
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Antimicrobials, prophylactic
Infections remain the biggest problem. Use of prophylactic drugs can help prevent several of these often life-
threatening infections.
Sulfa drugs can effectively prevent P carinii pneumonia in this immunocompromised group of patients.
Dosing
Adult
Pediatric
Interactions
May increase effect of warfarin; may decrease phenytoin hepatic clearance and prolong half-life; may displace
methotrexate from plasma protein-binding sites, increasing free concentrations; may potentiate its effects in bone
marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase
zidovudine levels
Contraindications
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits
outweigh risk to fetus
Precautions
…medscape.com/…/987228-print 19/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Avoid during pregnancy when near term (increases risk of jaundice in newborn); discontinue at first appearance of
rash or any sign of adverse reaction; rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura,
or jaundice may be early indications of serious reactions; hepatic necrosis; aplastic anemia; agranulocytosis;
hemolysis may occur in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (frequently dose
related); caution in patients with renal or hepatic impairment; maintain adequate fluid intake to prevent crystalluria
and stone formation
Fluconazole (Diflucan)
Dosing
Adult
Pediatric
Interactions
Concomitant use with hydrochlorothiazide may increase fluconazole concentrations, perhaps because of reduced
renal clearance
CYP3A4 inhibitor and may increase serum levels of 3A4 substrates; increases phenytoin or cyclosporine
concentrations when administered concurrently; increases half-life of theophylline; may increase serum
concentration of tolbutamide, glyburide, and glipizide
Single dose of warfarin after administration of fluconazole for 14 d can increase prothrombin time (PT) response
Contraindications
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits
outweigh risk to fetus
Precautions
Rare exfoliative skin disorders (monitor closely and discontinue if lesions progress); adjust dose in renal
insufficiency; may cause clinical hepatitis, cholestasis, or fulminant hepatic failure (including death) if patient has
underlying medical conditions (eg, AIDS, malignancy) or is taking several concomitant medications
Follow-up
Further Inpatient Care
Hospitalization is necessary in patients with acute myeloid leukemia (AML) 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.
Because early intervention can often cytopenic complications, blood counts must carefully be monitored
during and between phases of treatment.
After all planned therapy, careful physical examinations and blood work are important to ensure continued
hematologic remission.
…medscape.com/…/987228-print 20/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Inpatient & Outpatient Medications
Most supportive medications can be discontinued when chemotherapy is completed. Such medications
include prophylactic antibiotics, agents for nutritional support (eg, appetite stimulants), and antiemetics.
Patients usually require prolonged immunosuppressive therapy with prednisone and cyclosporine after
transplantation. Penicillin, antifungal medications, acyclovir, and trimethoprim-sulfamethoxazole are continued
until all immunosuppressive medications are discontinued.
Transfer
Transfer to a pediatric cancer center is usually necessary for initial diagnostic studies and management of
both chemotherapy and treatment-related complications.
For patients with suitable donors, transfer to a center capable of performing blood and marrow transplants is
usually necessary.
Deterrence/Prevention
As detailed in Causes, the association of acute myelocytic leukemia with radiation, toxins, and drugs is well
documented. Reduced exposure to ionizing radiation should be an important maxim for every physician who
orders diagnostic testing for patients, certainly pregnant women.
Until more evidence is available, general avoidance of chemicals and toxins should be a priority.
No dietary changes are known to affect a person's risk of developing acute myelocytic leukemia.
Complications
Infection
Infection is a major cause of morbidity and mortality.
The predisposition to infection is a consequence of granulocytopenia. The risk of sepsis is greatest
when the absolute granulocyte count is more than 200 cells/µL.
Sepsis and pneumonia are particularly common. Causative agents cover the entire gamut of bacterial,
fungal, viral, and other pathogens.
Septic shock is usually secondary to gram-negative bacteria and often lethal.
Because of prolonged neutropenia, immunosuppression, and treatment with broad-spectrum
antibiotics, common causes of death are fungal, antibiotic-resistant bacterial, and other opportunistic
…medscape.com/…/987228-print 21/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
infections.
Bleeding
Bleeding is the second most common cause of death.
Severe GI, pulmonary, or intracranial hemorrhage is frequently observed.
Disseminated intravascular coagulation is a serious potential problem in all patients with 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.
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.
CNS complications
CNS involvement, with leukemic cell infiltration, hemorrhage, or infection, often cause devastating
complications or death.
The risk is particularly high for patients with hyperleukocytosis and WBC counts of more than 200 X
109/L (>200,000/µL). These patients are at high risk of intracranial hemorrhage, and their conditions
must be treated as true emergencies.
Prognosis
With an overall survival rate of 45-55%, the prognosis for children with acute myeloid leukemia has improved
significantly over the past 2 decades. A Japanese consortium has recently reported 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.
For children with Down syndrome, current outcomes favor younger children, with a survival rate of 84-86% for
children younger than 2 years, 79% for children aged 2-4 years, and only 33% for children older than 4
years.[9 ]
Acute promyelocytic leukemia prognosis has an event-free survival rate of 70-80%, with overall survival close
to 90%.[10 ]
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.
…medscape.com/…/987228-print 22/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see
eMedicine's patient education article Leukemia.
Miscellaneous
Medicolegal Pitfalls
Special Concerns
Children may not have well-known symptoms of leukemia, such as adenopathy, overt bleeding, and serious
infections. Nonspecific symptoms such as fatigue, irritability, fevers, or 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.
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 because
this still remains one of the most frequent causes of hospitalizations, morbidity, and mortality in children with
leukemia.
Multimedia
…medscape.com/…/987228-print 23/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
…medscape.com/…/987228-print 24/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
References
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. Sep-Oct 1997;19(5):428-
32. [Medline].
2. Bhatia S, Neglia JP. Epidemiology of childhood acute myelogenous leukemia. J Pediatr Hematol
Oncol. May 1995;17(2):94-100. [Medline].
3. [Guideline] Children's Oncology Group. Chemotherapy. Long-term follow-up guidelines for survivors of
childhood, adolescent, and young adult cancers. Mar 2006;[Full Text].
4. [Guideline] Tomizawa D, Tabuchi K, Kinoshita A, et al. Repetitive cycles of high-dose cytarabine are effective
for childhood acute myeloid leukemia: long-term outcome of the children with AML treated on two consecutive
trials of Tokyo Children's Cancer Study Group. Pediatr Blood Cancer. Aug 2007;49(2):127-32. [Medline].
5. Lie SO, Abrahamsson J, Clausen N, 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. Jul 2003;122(2):217-25. [Medline].
6. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations
from an expert panel on behalf of the European LeukemiaNet. Blood. Feb 26 2009;113(9):1875-
91. [Medline].
…medscape.com/…/987228-print 25/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
7. [Guideline] Children's Oncology Group. Hematopoetic cell transplant. Long-term follow-up guidelines for
survivors of childhood, adolescent, and young adult cancers. Mar 2006;[Full Text].
8. Klingebiel T, Reinhardt D, Bader P. Place of HSCT in treatment of childhood AML. Bone Marrow
Transplant. Oct 2008;42 Suppl 2:S7-9. [Medline].
9. Gamis AS, Woods WG, Alonzo TA, et al. Increased age at diagnosis has a significantly negative effect on
outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer
Group Study 2891. J Clin Oncol. Sep 15 2003;21(18):3415-22. [Medline].
10. Ortega JJ, Madero L, Martin G, 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. Oct 20 2005;23(30):7632-40. [Medline].
11. Arceci RJ, Sande J, Lange B, et al. Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with
advanced CD33+ acute myeloid leukemia. Blood. Aug 15 2005;106(4):1183-8. [Medline].
12. [Best Evidence] Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in
patients with cancer and neutropenia. N Engl J Med. Sep 8 2005;353(10):977-87. [Medline].
13. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic
bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J
Med. Dec 3 1998;339(23):1649-56. [Medline].
14. Chen AR, Alonzo TA, Woods WG, Arceci RJ. Current controversies: which patients with acute myeloid
leukaemia should receive a bone marrow transplantation?--an American view. Br J
Haematol. Aug 2002;118(2):378-84. [Medline].
15. Kersey JH. Fifty years of studies of the biology and therapy of childhood leukemia. Blood. Dec
1 1997;90(11):4243-51. [Medline].
16. 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. Aug 2006;15(4):367-70. [Medline].
17. Meshinchi S, Woods WG, Stirewalt DL, et al. Prevalence and prognostic significance of Flt3 internal tandem
duplication in pediatric acute myeloid leukemia. Blood. Jan 1 2001;97(1):89-94. [Medline].
18. Stapnes C, Gjertsen BT, Reikvam H, Bruserud O. Targeted therapy in acute myeloid leukaemia: current
status and future directions. Expert Opin Investig Drugs. Apr 2009;18(4):433-55. [Medline].
19. Stevens RF, Hann IM, Wheatley K, Gray RG. Marked improvements in outcome with chemotherapy alone in
paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial.
MRC Childhood Leukaemia Working Party. Br J Haematol. Apr 1998;101(1):130-40. [Medline].
Keywords
acute myeloid leukemia, AML, acute myeloblastic leukemia, acute myelogenous leukemia, acute nonlymphoblastic
leukemia, leukemia, malignancy, cancer, acute promyelocytic leukemia, childhood leukemia, childhood cancer,
treatment, symptoms
Author
Mark E Weinblatt, MD, Chief, Division of Pediatric Hematology/Oncology, Professor of Clinical Pediatrics,
Department of Pediatrics, Winthrop University Hospital
Mark E Weinblatt, MD is a member of the following medical societies: American Society of Clinical Oncology,
American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.
…medscape.com/…/987228-print 26/27
1/4/2011 Acute Myelocytic Leukemia: [Print…
Medical Editor
Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of
Research, Mattel Children's Hospital at UCLA; Co-Associate Program Director of the Signal Transduction
Program Area, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California
Nanosystems Institute and Molecular Biology Institute, UCLA
Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology,
American Society of Pediatric Hematology/Oncology, International Society for Experimental Hematology, Society
for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.
Pharmacy Editor
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of
Pharmacy; Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.
Managing Editor
Timothy P Cripe, MD, PhD, Professor of Pediatrics, Division of Hematology/Oncology, Cincinnati Children's
Hospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-Medical Director, Office for
Clinical and Translational Research, Cincinnati Children's Hospital Medical Center; Director of Pilot and
Collaborative Clinical and Translational Studies Core, Center for Clinical and Translational Science and Training,
University of Cincinnati College of Medicine
Timothy P Cripe, MD, PhD is a member of the following medical societies: American Association for the
Advancement of Science, American Pediatric Society, American Society of Hematology, American Society of
Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.
CME Editor
Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor,
Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke
University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research,
American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society
of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.
Chief Editor
Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and
the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins
University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer
Research, American Association for the Advancement of Science, American Pediatric Society, American Society
of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.
Further Reading
© 1994-2011 by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)
…medscape.com/…/987228-print 27/27