AUTHOR INFORMATION

Section 1 of 11

Authored by 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 for Clinical Oncology, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Edited by Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	Mark E Weinblatt, MD
Editor's Email:	Kathleen Sakamoto, MD

eMedicine Journal, June 6 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 11

Background: Acute myelocytic leukemia (AML) is a group of malignant disorders characterized by the replacement of normal bone marrow with abnormal, primitive hematopoietic cells. If untreated, the disorder uniformly results in death, usually from infection or bleeding. In the recent past, children with this malignancy had an extremely poor prognosis; however, the cure rate has improved, although treatments are associated with significant morbidity and mortality.

Pathophysiology: Acute leukemia is believed to begin in a single somatic hematopoietic progenitor that transforms to a cell incapable of normal differentiation. Many of these cells no longer possess the normal property of apoptosis, or programmed cell death, thus resulting in a cell with a prolonged life span and unrestricted clonal proliferation.

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

Because the transformed cell lacks normal regulatory and growth constraints, it has a favorable competitive advantage at the expense of 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 normal functioning mature hematopoietic cells rather than the presence of numerous malignant cells.

Splenomegaly from leukemic infiltration further contributes to pancytopenia by sequestering and destroying circulating erythrocytes and platelets. As the disease progresses, there are increasing signs and symptoms resulting from anemia, thrombocytopenia, and neutropenia.

Leukemic cells may infiltrate other bodily tissues, causing many significant complications including central nervous system (CNS) involvement, pulmonary dysfunction, or skin and gingival infiltration.

Frequency:

• In the US: Out of approximately 3250 newly diagnosed cases of leukemia in children each year, nearly 20% are AML. While 1 of 3 newly diagnosed infants with leukemia has AML, the ratio of AML to acute lymphoblastic leukemia (ALL) falls rapidly until adolescence, when it increases to account for nearly 50% of all new leukemia diagnoses.

Mortality/Morbidity: The long-term survival rate for pediatric patients with AML is nearly 50%. AML accounts for about 35% of childhood deaths from leukemia, with mortality a consequence of either resistant progressive disease or treatment-related toxicity.

Race: Although there are some minor geographic variations in the incidence of different AML subtypes, this is a disorder that affects all races equally. As opposed to the incidence of ALL, which affects white children more commonly than black children, the incidence of AML is near equal for all races. One subtype, acute promyelocytic leukemia (APL), does exhibit a slightly greater incidence in the Hispanic population. Some areas of the world having higher than average rates of AML include Shanghai, New Zealand, and areas of Japan.

Sex: Distribution of affected males and females is nearly equal at all ages.

Age: AML is diagnosed in persons of all ages, from the newborns to persons advanced in age. In the first year of life, AML accounts for nearly one third of all newly diagnosed leukemias. For the remainder of the first decade of life, myeloblastic leukemia is much less frequent than ALL, with a 4:1 ratio of ALL to AML. The incidence of these is roughly equal for adolescence, and incidence of AML increases in adult years.

CLINICAL

Section 3 of 11

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

• Cytopenia



• Anemia


• • This common finding is characterized by pallor, fatigue, tachycardia, and headache.
  
  
  
  • The major pathophysiologic mechanism is related to decreased production in the infiltrated bone marrow.
  
  
  
  • Bleeding, hemolysis, and sequestration and destruction in an enlarged spleen or liver all may contribute to anemia.
  
  
  
• Hemorrhage from thrombocytopenia


• • This is due to decreased production of megakaryocytes in the bone marrow.
  
  
  
• The most common findings will be easy bruising, petechiae, epistaxis, gingival bleeding, and, less often, gastrointestinal or central nervous system hemorrhage.



• The patient with disseminated intravascular coagulation might also have symptoms of hemorrhage or thrombosis, including painful swelling and sharp color demarcation of an extremity.



• Fever


• • This is a common presenting complaint in acute leukemia.
  
  
  
  • It should always be attributed to infection.
  
  
  
  • Depending on the site of infection, symptoms may be pulmonary in nature, as in the case of pneumonias (cough, dyspnea, hypoxia, chest pain); neurologic, as in the case of meningitis (lethargy, emesis, headache); or may cause pain in other sites of involvement, eg, UTI or colitis (bladder and bowel function).
  
  
  
• Mass and infiltrative disease


• • The most common extramedullary infiltration by the leukemic cell will occur in the reticuloendothelial system. This may manifest itself as adenopathy, hepatomegaly, or splenomegaly.

  • Rarely, a mediastinal mass may cause symptoms of respiratory insufficiency or superior vena cava syndrome.

  • Abdominal masses may cause pain or obstruction of the gastrointestinal or urogenital tracts.

  • Nodules of myeloblasts, called chloromas, can be found in the skin or central nervous system.

  • Monoblastic leukemia often is associated with gingival hyperplasia and CNS infiltration.
  
  
  
• Constitutional and miscellaneous symptoms


• • Unexplained persistent fevers are sometimes the only presenting symptom of leukemia. Unlike in adults, weight loss and cachexia are unusual findings in children with leukemia. These effects can result from a combination of increased catabolic nutritional state and decreased caloric intake from anorexia.

  • Orthopedic symptoms
    • Bone pain, although less common than in patients with ALL, may be caused by periosteal elevation by leukemic cell infiltrates or bone infarctions.

    • Occasionally, the weakened bony cortex leads to pathologic fractures of the extremity, with resultant pain and decreased mobility, or vertebral compression fractures after minimal trauma, causing back pain and lower extremity dysfunction (weakness, loss of bladder and bowel function).

  • Central nervous system involvement
    • Although uncommon at initial diagnosis, it can appear at any time during follow-up and is associated with a variety of symptoms.

    • The most common signs and symptoms are related to signs of elevated intracranial pressure, including headache, nausea and emesis, lethargy, irritability, and visual complaints.

    • Cranial nerve involvement, most often facial (Bell palsy) and abducens (esotropia), may appear as an isolated finding or in combination with other manifestations.

    • In addition to leukemic cell infiltration and proliferation with mass effect, intracranial hemorrhage and CNS infections can cause similar devastating CNS complications.

    • Spinal lesions are rare, although in AML blast cells periodically form large aggregates called chloromas or granulocytic sarcomas, leading to epidural compression.

    • Extreme leukocytosis with white blood cell counts greater than 200,000 cells/mm³ often is associated with hyperviscosity, intracerebral leukostasis, and intracerebral hemorrhage early in the course of the disease.

  • Ocular manifestations
    • In rare cases, leukemic cells infiltrate all parts of the eye. The retina and iris are the most common sites affected.

    • Iritis often will cause photophobia, pain, and increased lacrimation; whereas, retinal involvement, often accompanied by hemorrhage, can lead to loss of vision.
  
  
  
  • While most patients are diagnosed after a relatively brief duration of symptoms, a small group of patients may present with myelodysplasia, a more indolent disorder characterized by a slowly progressive anemia or thrombocytopenia. This disorder can exist for many months and even years before ultimately converting into AML.
  
  
  

Physical:

• Pancytopenia


• • Pallor with tachycardia is observed to different degrees, proportional to the severity of anemia. With more severe anemia, lethargy, heart murmur, and signs of congestive heart failure may appear.
  
  
  
  • Bleeding manifestations most commonly are observed in the skin and include petechiae, purpuric lesions, and ecchymoses.
  
  
  
  • Gastrointestinal bleeding may indicate erosions or perforation.
  
  
  
  • Signs of infection may 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 than in ALL.
  
  
  
  • Splenomegaly at times can be massive, particularly in the young child.
  
  
  
  • On occasion, pronounced organomegaly can result in respiratory embarrassment in infants due to decreased diaphragmatic excursion.
  
  
  
  • CNS findings may include lethargy, cranial nerve dysfunction (particularly esotropia and facial palsy), or papilledema.
  
  
  
  • Typhlitis can present with acute lower-quadrant pain mimicking appendicitis.
  
  
  
  • Signs of perforation include hypotension, abdominal distension, and decreased bowel sounds. Clinical deterioration is rapid if the condition is not recognized.
  
  
  
  • Skin nodules occasionally are found in patients with AML. They are typically firm, raised, and often purpuric.
    
  
  
  

Causes: Although the cause of AML in most patients is unknown, several factors are associated with its development. Despite these correlations, most people exposed to the same factors do not develop leukemia. This would suggest that these factors trigger a cell's malignant transformation, perhaps through the action of one or more oncogenes.

• Radiation exposure


• • A great deal of evidence has implicated radiation in leukemogenesis in many patients, as evidenced from Japan following the release of radiation from atomic explosions at Hiroshima and Nagasaki. While younger children had a higher risk of developing ALL, teens and adults were more likely to contract AML. The latent period was from 2-15 years after the exposure, depending on the proximity to the radiation.
  
  
  
• Reports of increased risk of leukemia in patients living close to nuclear plants are currently under investigation, but data are lacking. Likewise, early reports of strong electromagnetic fields as a risk factor for acute leukemia have not been corroborated.



• 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, has been associated with leukemia in adults. Direct evidence of this effect in children has not been established. Likewise, exposure to pesticides has been noted to increase the risk of AML in some studies.
  
  
  
  • A more compelling association has been seen after treatment with antineoplastic cytotoxic agents, particularly alkylating agents such as procarbazine, the nitrosoureas, cyclophosphamide, melphalan, and, most recently, epipodophyllotoxins etoposide and teniposide. Patients treated with these agents for malignancies such as Hodgkin lymphoma especially if the agents are administered in conjunction with radiation therapy, have a significantly greater risk of developing a preleukemic syndrome that ultimately transforms into overt AML.
  
  
  
• Genetics and syndromes


• • Children with Down syndrome (trisomy 21) have a greater than 15-fold risk of developing leukemia over the general population, most commonly acute megakaryoblastic leukemia. Children with Down syndrome who experience the transient myeloproliferative syndrome as neonates, a condition often indistinguishable from acute leukemia, also have a greater risk of developing acute leukemia in subsequent years.
  
  
  
  • Approximately 8% of children with Fanconi anemia develop AML in their adolescent years.
  
  
  
  • Patients with other inherited disorders, such as Shwachman, Bloom, and Diamond-Blackfan syndromes, also have a greater risk of leukemia. These syndromes share features of poor DNA repair that are believed to predispose affected individuals to leukemogenic stimuli. Children with neurofibromatosis and Kostmann neutropenia (severe congenital neutropenia) also appear to be at a higher risk of developing AML.
  
  
  

DIFFERENTIALS

Section 4 of 11

Acute Lymphoblastic Leukemia
Anemia, Megaloblastic
Cytomegalovirus Infection
Gaucher Disease
Histiocytosis
Human Immunodeficiency Virus Infection
Lymphoproliferative Disorders
Myelodysplasia
Myelofibrosis
Neuroblastoma
Rhabdomyosarcoma
Systemic Lupus Erythematosus

Other Problems to be Considered:

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

WORKUP

Section 5 of 11

Lab Studies:

• Blood count and blood smear


• • The hallmark of leukemia is the reduction or absence of normal hematopoietic elements.
  
  
  
  • Anemia is usually normocytic, with a lower than expected reticulocyte count for the level of the hemoglobin. The decrease in hemoglobin levels can range from minimal to profound.
  
  
  
  • Platelet counts are usually low and are generally commensurate with the degree of bleeding. Patients with spontaneous petechiae usually have platelet counts less than 20,000/mm³.
  
  
  
  • White cell counts may be decreased or elevated. On occasion, hyperleukocytosis with white cell counts greater than 100,000 can be observed, with higher numbers conferring a white color to the blood specimen. The white cell differential is usually the key to suspected leukemia, with primitive granulocyte or monocyte precursors observed on peripheral smear.
  
  
  
  • Mature neutrophils are usually diminished.
  
  
  
  • Auer rods, characteristic cytoplasmic inclusions, can be found in specimens of circulating blood of many AML patients on careful examination of the blood smear. They are particularly prominent in children with acute promyelocytic leukemia.
  
  
  
• Chemistries and other blood work


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

  • Serum muramidase (lysozyme) levels are usually increased in patients with monocytic leukemias.
  
  
  
  • Other signs of tumor lysis, including hyperkalemia, hypocalcemia, and lactic acidosis, may be present.
  
  
  
  • Cultures of blood and urine should always be obtained in a child with fever and leukemia. Coagulation tests should also be obtained at the initial diagnosis to look for any evidence of disseminated intravascular coagulation that might suggest acute promyelocytic leukemia.
  
  
  
• Bone marrow examination


• • This establishes a definitive diagnosis.
  
  
  
  • Bone marrow aspirate and biopsy demonstrate the characteristic replacement of normal marrow elements with the monotonous sheets of leukemic blasts.
  
  
  
  • Acute myelogenous leukemia is subdivided into different subtypes, some having characteristic clinical pictures. The French-American-British classification system recognizes 7 primary AML types (M1-M7), which can usually be established with additional marrow studies. The World Health Organization recently has classified Acute Myeloid Leukemias into groups that include the following:
    • AML with recurrent cytogenetic translocations, eg, promyelocytic leukemia with typical t(15;17)

    • AML with multilineage dysplasia

    • AML and myelodysplasia syndromes secondary to therapy (eg, those following alkylating agents)

    • AML not otherwise categorized (including erythroid leukemias, monocytic leukemias and others)
  
  
  
• Cytogenetic markers, histochemical stains, and immunophenotyping


• • Leukemia cells demonstrate clonal cytogenetic abnormalities in more than 85% of patients. These are often unique to the subtype; for example, the t(15;17) translocation is nearly always found in patients with acute promyelocytic leukemia, while t(8;21) is more commonly found in myeloblastic leukemia.
  
  
  
  • In addition to the standard Wright-Giemsa stain, histochemical stains help differentiate the various acute leukemias. Periodic acid-Schiff positivity indicates acute biphenotypic leukemia or undifferentiated leukemia with lymphoblastic features. Most AML cells yield strongly positive reactions to myeloperoxidase and Sudan black stains. Esterase stains usually can help differentiate myeloid from monocytic leukemia.
  
  
  
  • Monoclonal antibodies specific for different cell lineages and stages of development are routinely used to further characterize the leukemic cell. The most common myeloid markers include CD13, CD14, CD15, and CD33, with more than 90% of leukemic cells demonstrating positivity to some of these antigens. CD34 marker is also frequently found in AML blasts.
  
  
  
• Lumbar puncture and cerebrospinal fluid examination
  • While less frequently involved than in patients with ALL, leukemic infiltration can occur in patients with AML.

  • CSF should be obtained prior to beginning any therapy.

  • Send fluid for cytology evaluation in addition to the usual cell count and chemistries.

  • Intrathecal chemotherapy is administered at the same time and repeated on an intermittent basis to treat or prevent CNS involvement.

• Human leukin antigen (HLA) typing: Following successful remission induction, patients with HLA-matched donors usually undergo high-dose myeloablative chemotherapy followed by bone marrow (or hematopoietic stem cell) rescue. At the time of diagnosis, it is important to begin the donor screening process by obtaining blood for HLA matching from the patient and immediate family members.

Imaging Studies:

• Radiographic studies


• • While not helpful in confirming the diagnosis, these can be important when there is suspicion of leukemic complications.
  
  
  
  • A routine chest radiograph should be done to rule out the presence of a mediastinal mass, particularly in the presence of respiratory symptoms or suspicion of a superior vena cava syndrome.
  
  
  
  • If the patient has abdominal pain and distention, an abdominal film can often detect free air suggestive of a perforation.
  
  
  
  • Radiograph examination of the extremities may show findings such as metaphyseal bands at the distal femurs (more commonly observed in young children with ALL), periosteal new bone formation, focal lytic lesions, or pathologic fractures.
  
  
  
• Computed tomography and magnetic resonance imaging


• • If the patient has abdominal pain and suspicion of possible large bowel infection, a computed tomography (CT) scan may reveal thickening and edema of the bowel wall suggestive of typhlitis.
  
  
  
  • If a patient has neurologic symptoms, a CT scan or magnetic resonance imaging (MRI) of the head, spine, or other involved region is mandatory to rule out intracranial hemorrhage of infiltrative disease.
  
  
  
  • CT scanning also may allow early detection of asymptomatic sinusitis that might cause persistent unexplained fevers.
  
  
  
• Sonography


• • Since serious infections that affect heart function are routinely observed in this patient population, periodic cardiac monitoring is important.
  
  
  
  • Perform an echocardiogram prior to chemotherapy.
  
  
  
  • Most treatment regimens use anthracyclines, such as daunomycin and idarubicin, which may cause significant cardiomyopathy.
  
  
  
• Radionuclide imaging


• • This is often used to detect occult infection that cultures and other imaging modalities fail to identify.
  
  
  
  • Technetium bone scans often help localize an occult osteomyelitis.
  
  
  
  • Whole-body gallium or indium scanning often reveals an occult deep tissue infection and can help with appropriate antibiotic management.
  
  
  

Procedures:

• Bone marrow aspirate and biopsy


• • Bone marrow examination is necessary to establish the diagnosis of AML.
  
  
  
  • The preferred site is the iliac crest, either anterior or posterior. In infancy, the tibia may be a better source of marrow for diagnostic purposes, but the iliac crest is nearly always an adequate source of marrow, even in infants, and prevents the risk of tibial fracture. On rare occasion, a sternal biopsy is necessary.
  
  
  
  • While bone marrow aspirate is often sufficient to establish the diagnosis and follow disease progress, a core biopsy is often necessary for "packed" marrows or dry taps (usually heavily infiltrated marrows that do not yield enough diagnostic materials).
  
  
  
  • A biopsy is necessary to gauge the cellularity of a marrow specimen during follow-up for making subsequent therapeutic decisions.
  
  
  
• Lumbar puncture


• • This is necessary for diagnostic and therapeutic reasons.
  
  
  
  • Even if marrow is not involved at the time of diagnosis, CNS seeding can occur later; therefore, periodic surveillance lumbar punctures with the administration of intrathecal chemotherapy are necessary.
  
  
  
• Central venous catheter placement


• • Because of intense chemotherapy and supportive care needs, guaranteed venous access is critical. An indwelling central venous catheter with at least 2 lumens is usually placed prior to beginning therapy. This provides access for chemotherapy infusions, intravenous nutritional support, transfusions, antibiotics, and other supportive care medications, as well as allowing blood withdrawal for required testing.
  
  
  
  • Families are taught catheter care, including sterile technique and preventive maintenance to avoid catheter clotting and infection.
  
  
  
  • Subcutaneous ports and peripheral indwelling central catheters placed in the cubital area are less commonly used.
  
  
  

TREATMENT

Section 6 of 11

Medical Care: Treatment for patients with acute myelogenous leukemia involves intensive chemotherapy regimens used to destroy the leukemic cell population as rapidly as possible and prevent the emergence of a resistant clone and simultaneous supportive care to sustain the patient until the bone marrow has achieved a hematologic remission and is once again producing normal hematopoietic cells.

• Chemotherapy


• • Virtually all of the chemotherapeutic drug regimens use some combination of an anthracycline (most often daunomycin) with cytosine arabinoside. Additional 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 combinations of multiagent chemotherapy, resulted in improved results as therapy was intensified, which often meant beginning the next myelosuppressive cycle of treatment before recovery from the previous course of treatment. While prolonging the period of pancytopenia, induction failures have been fewer and disease-free survival has improved significantly.

  • Following the merger of the 2 national groups into the Children's Oncology Group, the regimen now being piloted is 2 cycles of ADE induction therapy (infusions of daunomycin, cytosine arabinoside, etoposide). Gemtuzumab, an anti-CD33 antibody drug that has shown great promise in adults and in the relapse setting, follows the first cycle.

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

  • Several studies have demonstrated a clear survival benefit for patients who are treated with allogeneic bone marrow transplant, with no advantage of autologous transplant over chemotherapy intensification. As a result, patients with HLA-matched family members are treated with busulfan/cyclophosphamide with marrow transplantation. Exceptions to performing an allogeneic transplant in first remission include acute myelocytic leukemia (AML) characterized by chromosome inv(16) and, possibly, t(8;21) abnormalities, acute promyelocytic leukemia (APL), and Down syndrome in young children.
  
  
  
• Acute promyelocytic leukemia
  • The discovery of effective maturation agents has altered the approach to treating APL.

  • All-trans-retinoic acid (ATRA) can effectively induce most newly diagnosed APL into remission, 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 high WBC count (>10K), concomitant ATRA and authrocycline are used.

  • Additional cycles of this combination are used as consolidation chemotherapy. Following recovery from this phase, patients are randomized to ATRA versus ATRA with 6-mercaptopurine and methotrexate. The randomized study has closed, and, although not fully evaluated yet, enough information is now available to recommend maintenance therapy with the combination of ATRA, 6-mercaptopurine, and methotrexate.

  • Another approach that is going through clinical trials is the use of arsenic trioxide, which has been shown to be very active in both newly diagnosed and relapsed APL. Although shown to be effective in inducing remissions in 85% of patients who relapse, arsenic is now being tested in newly diagnosed patients. Gemtuzumab ozogamicin (Mylotarg) or anti-CD33 calicheamicin is also being tested in patients with APL. Both arsenic and Mylotarg are hoped to reduce the level of exposure to anthracyclines without sacrificing efficacy.

  • Patients with APL and very high presenting WBC counts should not undergo phoresis because of 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.

Surgical Care: The role of surgery is limited.

• Initial central venous catheter insertion is necessary to initiate treatment and manage all aspects of chemotherapy and transfusion support.



• Biopsy or aspiration of tissue for culture is often necessary for the febrile patient with possible abscess.



• The acute abdomen in this patient population often presents the clinician with serious complications, such as typhlitis, that requires expeditious surgical intervention.

Consultations:

• Urology consultation: Consider this consultation for male teenagers who will be undergoing intense chemotherapy that may cause oligospermia and fertility problems in the future. While this condition is usually temporary, it is a more significant problem for patients who undergo high-dose chemotherapy as preparation for blood or marrow transplant. It is a major problem for patients who may be receiving total body radiation. Encourage sperm banking, preferably before beginning any treatment that will affect the quality of the sperm being banked.



• Psychologic support: The intense treatment and frequent prolonged hospitalizations for chemotherapy and resulting complications (especially for patients undergoing stem cell transplant), as well as the very real possibility of life-threatening complications, place major stresses on the patient and family. Psychologic support, with educational information and numerous meetings and updates, are very important for the psychologic well being of the family.

Diet:

• Careful attention must be directed towards adequate nutrition. Because of prolonged periods of neutropenia with infections that blunt a patient's appetite, along with recurrent episodes of chemotherapy-induced mucositis, high calorie oral supplements are often helpful for maintaining weight, allowing the patient to better tolerate therapy. Most patients require intravenous total parenteral nutrition.



• For patients receiving a blood or marrow transplant, low-bacteria diets are often instituted to decrease the incidence of posttransplant infections resulting from profound immunosuppression. Emphasis is to initially avoid uncooked fresh vegetables and fruits.

Activity:

• Minimal limits on activity are necessary. Patients should avoid crowds and exposure to potentially contagious disorders when neutropenic or immunosuppressed after transplant.



• When thrombocytopenic, potentially traumatic physical sports activities need to be curtailed to avoid serious hemorrhage. Medications that can potentiate bleeding, such as antiplatelet agents, including aspirin and other nonsteroidal anti-inflammatory drugs, should be avoided.

MEDICATION

Section 7 of 11

Treatment is directed towards 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 also must be included in treatment, including broad-spectrum antibacterial, antiviral, and antifungal antibiotics, biologic response modifiers, and other classes of supportive medications.

Drug Category: Chemotherapeutic agents -- While many chemotherapeutic agents are active, most current regimens use combinations of an anthracycline and cytosine arabinoside. All chemotherapy agents destroy myeloblasts using a variety of mechanisms.

Drug Name	Cytarabine (Cytosar-U) -- Synonyms include cytosine arabinoside and ARA-C. Purine antimetabolite; inhibits DNA polymerase. Used in both the induction and intensification phases of treatment.
Pediatric Dose	Induction therapy: 100 mg/m2/dose IV push 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 for patients not undergoing stem cell transplantation: 1000 mg/m2/d IV infusion qd for 10 d during cycle 1, and for 8 d during cycle 2 Consolidation therapy: 3000 mg/m2 IV infusion (infuse over 3 h) q12h for 4 doses/wk during the final course of consolidation therapy
Contraindications	Documented hypersensitivity; severe hepatic or renal compromise
Interactions	Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase cytarabine toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	This drug should only be administered by experienced oncologists; severe myelosuppression, mucositis, nausea, diarrhea, alopecia, ocular toxicity, neurotoxicity, and other complications are expected

Drug Name	Daunorubicin (Cerubidine) -- Synonyms include daunomycin. Anthracycline that binds to nucleic acids by intercalation between pairs of DNA, interfering with DNA synthesis. Used in the induction phase of treatment.
Pediatric Dose	Induction: 50 mg/m2/dose IV infusion over 6 h every other day for 3 doses during each induction cycle (ie, 150 mg/m2/cycle, cumulative dose of 300 mg/m2 for both induction cycles)
Contraindications	Documented hypersensitivity; cardiac failure; severe hepatic or renal dysfunction; cumulative anthracycline dose in excess of 450 mg/m2 is a relative contraindication
Interactions	Increased risk of cardiotoxicity when combined with heart irradiation; additive risks of cardiotoxicity with trastuzumab
Pregnancy	D - Unsafe in pregnancy
Precautions	Should only be administered by experienced oncologists; severe myelosuppression, mucositis, nausea, diarrhea, alopecia, tissue damage with extravasation, and other complications are expected; fatal cardiac complications have occurred

Drug Name	Etoposide (VePesid) -- Synonym is VP-16. Podophyllotoxin derivative. Used in the induction and consolidation phases of treatment.
Pediatric Dose	Induction: 100 mg/m2/d IV infusion qd for 5 d during each cycle Consolidation: 150 mg/m2/d IV infusion qd for 5 d during the first phase
Contraindications	Documented hypersensitivity to etoposide or Cremophor EL; significant hypotension; IT administration may cause death
Interactions	May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	Should only be administered by experienced oncologists; severe myelosuppression, hypotension, mucositis, and other complications are expected; dosage reduction should be considered in patients with low serum albumin, bone marrow suppression, and renal impairment

Drug Name	Mitoxantrone (Novantrone) -- Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II. Used in the consolidation phase of treatment.
Pediatric Dose	Induction: 12 mg/m2/d IV for 4 d during the second cycle of consolidation
Contraindications	Documented hypersensitivity; hepatic failure
Interactions	CYP 450 2E1 inducer (weak); valspodar increases AUC (decrease mitoxantrone dose)
Pregnancy	D - Unsafe in pregnancy
Precautions	Should only be administered by experienced oncologists; severe myelosuppression, anaphylaxis; cardiotoxicity; interstitial pneumonitis; hepatic dysfunction, nausea, mucositis, and other complications are expected

Drug Name	Tretinoin (Vesanoid) -- Synonym is all-trans-retinoic acid. Used in both induction and maintenance phases for patients with acute promyelocytic leukemia.
Pediatric Dose	45 mg/m2/d PO divided bid
Contraindications	Documented hypersensitivity (including sensitivity to retinoids, paraben); leukocytosis
Interactions	CYP450 substrate (caution with coadministration of CYP450 inhibitors or inducers); ketoconazole significantly increases AUC; coadministration with tetracylines may increase risk for pseudotumor cerebri and intracranial hypertension; coadministration with vitamin A may increase risk of hypervitaminosis A; fatal thrombotic complications have been reported when coadministered with antifibrinolytic agents (eg, tranexamic acid, aminocaproic acid, aprotinin)
Pregnancy	D - Unsafe in pregnancy
Precautions	Should only be administered by experienced oncologists; severe leukocytosis with pulmonary infiltrates and respiratory failure is expected; patients commonly experience headache, fever, weakness, and fatigue

Drug Name	Arsenic trioxide (Trisenox) -- May cause DNA fragmentation and damage or degrade the fusion protein PML-RAR alpha. Use only in patients that have relapsed or are refractory to retinoid or anthracycline chemotherapy.
Pediatric Dose	Consolidation: 0.15 mg/kg/d IV for 5 d/wk for 5 wk
Contraindications	Documented hypersensitivity
Interactions	Electrolyte abnormalities may occur if used concomitantly with diuretics or amphotericin B; concurrent use with QTc prolonging agents (type Ia and type II antiarrhythmic agents, cisapride, thioridazine, and selected quinolones) may increase risk of potentially fatal arrhythmias
Pregnancy	D - Unsafe in pregnancy
Precautions	Correct electrolyte abnormalities prior to treatment and monitor potassium and magnesium levels during therapy; may prolong QT interval; discontinue therapy and hospitalize patient if QTc >500 ms, syncope or irregular heartbeats develop during therapy; may lead to torsade de points or complete AV block (risk factors include congestive heart failure, history of torsade de pointes, preexisting QT interval prolongation, patients taking potassium-wasting diuretics, conditions that cause hypokalemia or hypomagnesemia)

Drug Name	L-asparaginase (Elspar) -- Used in consolidation phase of therapy
Pediatric Dose	6000 U/m2/dose IM administered 3 h following final high-dose cytosine arabinoside during the 2 weekly cycles of consolidation
Contraindications	Documented hypersensitivity
Interactions	Decreased effect if given prior to methotrexate; coadministration with vincristine increases toxicity; coadministration with prednisone increases risk of hyperglycemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Allergic reactions are 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

Drug Category: Antibiotics, prophylactic -- Infections remain the biggest problem. The use of prophylactic medications can help prevent several of these often life-threatening infections.

Drug Name	Sulfamethoxazole and trimethoprim (Bactrim, Septra) -- Sulfa medications can very effectively prevent Pneumocystis carinii pneumonia (PCP) in this immunocompromised group of patients.
Pediatric Dose	<2 months: Do not administer >2 months, PCP prophylaxis: 5 mg/kg/d or 150 mg/m2/d (based on trimethoprim component) PO 3 times/wk
Contraindications	Documented hypersensitivity; megaloblastic anemia caused by folate deficiency; infants <2 mo
Interactions	May increase warfarin effect; may decrease phenytoin hepatic clearance and prolong half-life; may displace methotrexate from plasma protein binding sites, thus increasing free concentrations and may potentiate its effects in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid use 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 G6PD deficiency, and it is frequently dose-related; exercise caution in patients with renal or hepatic impairment; maintain adequate fluid intake to prevent crystalluria and stone formation

Drug Name	Fluconazole (Diflucan) -- Effective in treating and decreasing the host colonization of candidiasis.
Pediatric Dose	Prophylaxis: 3-5 mg/kg/d PO or IV infusion qd
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Concomitant use with hydrochlorothiazide may increase fluconazole concentrations, perhaps because of a reduced renal clearance CYP3A4 inhibitor, may increase serum levels of 3A4 substrates (examples follow); increases phenytoin or cyclosporine concentrations when administered concurrently; similarly, it increases the half-life of theophylline; may increase serum concentration of tolbutamide, glyburide, and glipizide A single warfarin dose after 14 d of fluconazole administration can result in an increase in PT response
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Rare exfoliative skin disorders (monitor closely and discontinue drug if lesions progress); adjust dose for renal insufficiency; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) when taken with underlying medical conditions (eg, AIDS, malignancy) or while taking multiple concomitant medications

Drug Category: Antiemetic agents -- Antineoplastic induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters, dopamine in CTZ or acetylcholine in VC, appears to be a major mediator for inducing vomiting. Following administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3-receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.

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

Drug Name	Ondansetron (Zofran) -- Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy.
Pediatric Dose	<3 years: Not established >3 years: 0.15 mg/kg/dose PO or IV rapid infusion; may repeat q4h for 2 doses
Contraindications	Documented hypersensitivity
Interactions	Although there is potential for CYP450 inducers (barbiturates, rifampin, carbamazepine, phenytoin) to change half-life and clearance of ondansetron, dosage adjustment usually is not required
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Headache is one of the more common adverse drug reactions; medication is to be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting

Drug Name	Granisetron (Kytril) -- At chemoreceptor trigger zone, blocks serotonin peripherally on vagal nerve terminals and centrally.
Pediatric Dose	<2 years: Not established >2 years: 10 mcg/kg/dose PO or IV push qd
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Hospitalizations are necessary for chemotherapy and treating complications related to the disease and its treatment, usually infections or febrile neutropenic episodes. Some hospitalizations can be quite lengthy, with numerous antibiotic changes necessary until the infections and the patient's neutropenia resolve.



• Following transplant, most febrile episodes require in-patient treatment and observation until the profound neutropenia is clear and there is no significant infection.

Further Outpatient Care:

• Since early intervention prevents cytopenic complications, blood counts must be monitored carefully during and between phases of treatment.



• Following all planned therapy, careful physical examinations and blood work are important to ensure continued hematologic remission.

In/Out Patient Meds:

• Most supportive medications can be discontinued when chemotherapy is completed, including prophylactic antibiotics, nutritional support (eg, appetite stimulants), and antiemetics.



• Patients usually require prolonged immunosuppressive therapy with prednisone and cyclosporine following transplant. 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, association of AML 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; this should certainly be a priority for physicians caring for pregnant women. Until there is more evidence, general avoidance of chemicals and toxins should also be a priority. No dietary changes are known to affect the risk of developing AML.

Complications:

• Immediate and short-term


• • Serious infections

  • Alopecia

  • Emesis

  • Gastrointestinal erosions and bleeding

  • Hemorrhage

  • Malnutrition

  • Nausea

  • Death
  
  
  
• Long-term or delayed


• • Congestive heart failure and arrhythmia (rare)

  • Growth and other endocrine disorders

  • Second malignancies

  • Death
  
  
  
• Infection


• • This is a major cause of morbidity and mortality.

  • Predisposition to infection is a consequence of granulocytopenia, with the greatest risk for sepsis present when the absolute granulocyte count is less than 200 cells/mm³.

  • Sepsis and pneumonia are particularly common, with the entire gamut of bacterial, fungal, viral, and other pathogens as agents.

  • Septic shock, usually secondary to gram-negative bacteria, is often lethal.

  • Due to prolonged periods of neutropenia, immunosuppression, and treatment with broad-spectrum antibiotics, fungal, antibiotic-resistant bacterial, and other opportunistic infections are common causes of death.
  
  
  
• Bleeding


• • This is the second most common cause of death.

  • Severe gastrointestinal, pulmonary, and intracranial hemorrhage is observed frequently.

  • Disseminated intravascular coagulation is a serious potential problem in all patients with acute promyelocytic leukemia, and to some extent in other AML subtypes. It can exhibit coexisting thrombosis and hemorrhage.
  
  
  
• Tumor lysis syndrome
  • Patients with high leukemic cell counts or massive organomegaly are at significant risk.

  • This condition is often characterized by pronounced metabolic abnormalities, including hyperkalemia, hypocalcemia, hyperuricemia, and renal failure.

• Chemotherapy
  • The aggressive chemotherapy treatment necessary to cure the patient also entails a great deal of morbidity.

  • Profound myelosuppression from high-dose, intensive treatment regimens contribute to the high risk of infection and bleeding.

• Gastrointestinal
  • Mucositis and typhlitis with intestinal perforation, renal, and pulmonary complications are common problems facing the patient and clinician.



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

  • The risk is particularly significant for the patient who presents with hyperleukocytosis, having white cell counts above 200,000/mm³. These patients have a high risk of intracranial hemorrhage, and these cases must be treated as true emergencies.

Prognosis:

• With an overall survival rate of 45-50%, the prognosis for children with AML has improved significantly over the past 2 decades. Long-term, disease-free survival is approximately 65% for patients receiving HLA-matched stem cell transplants from family donors. Death during treatment and after relapse is most commonly secondary to infection, bleeding, or refractory disease.



• Disease-free survival of patients with acute promyelocytic leukemia is approximately 75%.

Patient Education:

• Family members should be familiar with signs of infection other than fever. Dermatologic clues to bleeding risk (especially petechiae and purpura) should be recognized and acted upon.



• Discuss the adverse effects of chemotherapy and transplant at length with family members.



• Psychosocial intervention is often necessary for the patient, parents, and siblings. A diagnosis of leukemia will have profound effects on all family members, with a dramatic change in the patient's lifestyle until the completion of all treatment. Home tutoring is often necessary during the entire period of treatment.



• For excellent patient education resources, visit eMedicine’s Blood and Lymphatic System Center. Also, see eMedicine’s patient education article Leukemia.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to recognize associated complications such as infections, hemorrhage, metabolic complications, or early organ dysfunction



• Failure to inform patient and family of treatment complications

Special Concerns:

• Children may not demonstrate classic symptoms of the disease or its complications. Symptoms, such as fatigue, irritability, fever, or bruising, are common in childhood and might not be recognized as symptoms of leukemia.



• Signs of serious infection are often subtle, and fever at any time must be taken seriously, using appropriate cultures and investigation to diagnose and treat early.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A patient with newly diagnosed acute myelocytic leukemia (AML) and neutropenia has persistent high fevers despite several days of broad-spectrum antibiotics. There is no respiratory distress or hypotension. Which of the following would be the most likely pathogen causing this clinical picture?

A: Disseminated candidiasis
B: Staphylococcus aureus
C: Resistant enteric gram-negative rods
D: Pneumocystis pneumoniae
E: Varicella zoster

The correct answer is A: Persistent fevers in children with persistent neutropenia on broad-spectrum antibiotics should make the physician suspicious of an underlying fungal infection, even for those patients who have been treated with antifungal prophylaxis. Resistant gram-negative rods and Staphylococcus infections are unlikely to appear early into treatment and usually cause a more toxic appearance. Pneumocystis infection is uncommon in patients with AML, especially if they are on prophylactic therapy. Varicella zoster usually would show a characteristic rash or pain.

CME Question 2: A new patient presents with a white count of 250,000/mm³ with 98% blasts, a hematocrit of 11%, pulmonary infiltrates, and mild hypoxia. Which of the following is the safest and preferred method of correcting these abnormalities?

A: Immediately administer chemotherapy that includes high-dose Cytosine Arabinoside, etoposide, 6-Thioguanine, and Daunomycin.
B: Transfuse 2 units of irradiated packed red blood cells to correct the anemia.
C: Begin daily injections of erythropoietin and granulocyte colony stimulating factor.
D: Perform a double volume exchange transfusion.
E: Give no blood products until after performing a bone marrow biopsy to confirm the diagnosis and type of leukemia.

The correct answer is D: If intense chemotherapy were begun immediately, the patient would have serious metabolic complications that would probably result in renal failure and further deterioration of the clinical situation. However, exchange transfusion would solve multiple problems simultaneously (correcting anemia, improving oxygen carrying capacity, decreasing the leukemia cell burden, reducing metabolic complications) without causing new problems such as hyperviscosity from ordinary red cell transfusions or metabolic complications from tumor lysis syndrome.

Pearl Question 1 (T/F): A patient who presents with clinical and laboratory evidence of disseminated intravascular coagulation at diagnosis would most likely have acute promyelocytic leukemia (APL).

The correct answer is True: Most patients with APL present with evidence of disseminated intravascular coagulation.

Pearl Question 2 (T/F): A patient who presents with fever and neutropenia with no obvious source of infection should be started on broad-spectrum antibacterial antibiotics.

The correct answer is True: Broad-spectrum antibacterial antibiotics containing an aminoglycoside and either a semisynthetic penicillin or cephalosporin are appropriate. Monotherapy with either ceftazidime or ciprofloxacin (for teenaged patients) could also be considered.

Pearl Question 3 (T/F): A patient who presents with gingival hypertrophy and no history of phenytoin ingestion has chronic monoblastic leukemia.

The correct answer is False: Acute monoblastic leukemia would be the correct diagnosis.

Pearl Question 4 (T/F): Causes of acute myelocytic leukemia (AML) include radiation exposure, toxins and drugs, and genetic syndromes.

The correct answer is True: Although the cause of AML in most patients is unknown, several factors are associated with its development. Despite these correlations, most people exposed to the same factors do not develop leukemia. This would suggest that these factors trigger a cell’s malignant transformation, perhaps through the action of one or more oncogenes.

A great deal of evidence has implicated radiation in leukemogenesis in many patients, as evidenced from Japan following the release of radiation from atomic explosions at Hiroshima and Nagasaki. While younger children had a higher risk of developing acute lymphoblastic leukemia (ALL), teens and adults were more likely to contract AML. The latent period was 2-15 years after exposure, depending on the proximity to the radiation. Reports of increased risk of leukemia in patients living close to nuclear plants are currently under investigation, but data are lacking. Likewise, early reports of strong electromagnetic fields as a risk factor for acute leukemia have not been corroborated.

Exposure to toxic chemicals that cause damage to bone marrow, such as benzene and toluene used in the leather, shoe, and dry cleaning industries, has been associated with leukemia in adults. Direct evidence of this effect in children has not been established. Likewise, exposure to pesticides has been noted to increase the risk of AML in some studies. A more compelling association has been seen after treatment with antineoplastic cytotoxic agents, particularly alkylating agents such as procarbazine, the nitrosoureas, cyclophosphamide, melphalan, and, most recently, epipodophyllotoxins etoposide and teniposide. Patients treated with these agents for malignancies such as Hodgkin lymphoma, especially if the agents are administered in conjunction with radiation therapy, have a significantly greater risk of developing a preleukemic syndrome that ultimately transforms into overt AML.

Children with Down syndrome (trisomy 21) have a greater than 15-fold risk of developing leukemia over thegeneral population, most commonly acute megakaryoblastic leukemia. Children with Down syndrome who experience the transient myeloproliferative syndrome as neonates, a condition often indistinguishable from acute leukemia, also have a greater risk of developing acute leukemia in subsequent years. Approximately 8% of children with Fanconi anemia develop AML in their adolescent years. Patients with other inherited disorders, such as Shwachman, Bloom, and Diamond-Blackfan syndromes, also have a greater risk of leukemia. These syndromes share features of poor DNA repair that are believed to predispose affected individuals to leukemogenic stimuli. Children with neurofibromatosis and Kostmann neutropenia also appear to be at higher risk for AML.

BIBLIOGRAPHY

Section 11 of 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 2005; 106: 1183-1188[Medline].
• Bucaneve G, Micozzi A, Menichetti F, et al: Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Eng J Med 2005; 353: 977-987[Medline].
• 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 1998; 339: 1649-1656[Medline].
• Kersey JH: Fifty years of studies of the biology and therapy of childhood leukemia. Blood 1997; 90: 4243-4251[Medline].
• 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. Br J Haematol 1998; 101: 130-140[Medline].

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