acute myelocytic leukemia

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Acute Myelocytic LeukemiaMark E Weinblatt, MD, Chief, Division of Pediatric Hematology/Oncology, Professor of Clinical Pediatrics, Department of Pediatrics, Winthrop University Hospital

Updated: Jun 22, 2010

Introduction

Background

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

Pathophysiology

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

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

Many of the leukemic cells no longer possess the normal property of apoptosis, or programmed cell death. As aresult, they have a prolonged life span and are capable of unrestricted clonal proliferation. Because transformedcells lack normal regulatory and growth constraints, they have favorable competitive advantage over normalhematopoietic cells. The result is the accumulation of abnormal cells with qualitative defects. A major cause ofmorbidity and mortality is the deficiency of normally functioning mature hematopoietic cells rather than the numberof malignant cells.

Splenomegaly due to leukemic infiltration further contributes to pancytopenia by sequestering and destroyingcirculating 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 CNSinvolvement, 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 childreneach year. Although 1 in every 3 newly diagnosed leukemias is acute myeloid leukemia, the ratio of acute myeloidleukemia to ALL rapidly decreases until adolescence.[1 ]During adolescence, the rate increases to account fornearly 50% of all new diagnoses of leukemia.

International

Although leukemia has been reported in children worldwide, the incidence rate widely varies. In the United Statesand other highly industrialized countries, acute myeloid leukemia accounts for about 15% of childhood leukemia. Inother 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 toALL is roughly 1:1. Likewise, the incidence of acute myeloid leukemia in Asia is significantly higher than more

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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 myeloidleukemia accounts for about 35% of childhood deaths from leukemia. Mortality is a consequence of resistantprogressive 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 allraces nearly equally. The incidence of one subtype, acute promyelocytic leukemia (APL), is slightly increased in theHispanic pediatric population. Areas of the world where rates of acute myeloid leukemia are higher than averageinclude 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 firstyear of life, acute myeloid leukemia accounts for nearly one third of all newly diagnosed leukemias. For the rest ofthe first decade of life, ALL is more common than acute myeloid leukemia by a ratio of 4:1. The incidence of thesediseases is roughly equal during adolescence, and the incidence of acute myeloid leukemia increases inadulthood.

Clinical

History

Symptoms of acute myeloid leukemia (AML) can be divided into those caused by a deficiency of normallyfunctioning cells, those due to the proliferation and infiltration of the abnormal leukemic cell population, andconstitutional symptoms.

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

Cytopenias

Anemia: This common finding is characterized by pallor, fatigue, tachycardia, and headache. The majorpathophysiologic 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 thebone 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 havesymptoms of hemorrhage or thrombosis, including painful swelling and sharp, colored demarcation of anextremity.

Fever: This is a common presenting complaint in patients with acute leukemia. In this context, fever shouldalways be attributed to infection. Depending on the site of infection, symptoms may vary. Symptoms may bepulmonary (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 andbowel function due to colitis or urinary tract infection).

Symptoms due to the proliferation and infiltration of the abnormal leukemic cell mass and infiltrative diseaseinclude 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.



In rare cases, a mediastinal mass may cause symptoms of respiratory insufficiency or superior vena cavasyndrome.

Abdominal masses may cause pain or obstruct the GI or urogenital tracts. Nodules of myeloblasts, calledchloromas, can be found in the skin, CNS or any other organ.

Monoblastic leukemia is often associated with gingival hyperplasia and CNS infiltration. See the imagebelow.

Gingival hyperplasia in a patient with monoblastic leukemia.



Constitutional and miscellaneous symptoms include the following:

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 canresult 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 patientswith acute lymphoblastic leukemia (ALL). Its cause may be periosteal elevation due to leukemic cell infiltratesor bone infarctions. On occasion, weakened bony cortex permits pathologic fractures of the extremity, whichresult in pain and decreased mobility, or vertebral compression fractures after minimal trauma. Suchcompression fractures cause back pain and dysfunction of the lower extremity (eg, weakness, loss of bladderand bowel function).

CNS: Although uncommon initially, it can appear during follow-up with various findings. The most commonsigns 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 (resultingin Bell palsy) and the abducens nerve (resulting in esotropia), may be isolated or may occur in combinationwith 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. Spinallesions are rare. In acute myeloid leukemia, blast cells periodically form large aggregates called chloromasor granulocytic sarcomas, leading to epidural compression. Extreme leukocytosis with WBC counts of morethan 200 X 109/L is often associated with hyperviscosity, intracerebral leukostasis, and intracerebralhemorrhage early in the course.

Ocular manifestations: In rare cases, leukemic cells infiltrate all parts of the eye. The retina and iris are thesites 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. Withsevere 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, purpuriclesions, and ecchymoses.

GI bleeding may indicate erosions or perforation.

Signs of infection include fever, gingivitis, hypotension, or respiratory distress, depending on the site ofinfection.

Signs of leukemic infiltration and proliferation

Adenopathy, at times generalized, is less common in acute myeloid leukemia than in ALL.

Splenomegaly is sometimes massive, particularly in young children.

Pronounced organomegaly occasionally result in respiratory embarrassment in infants due todecreased diaphragmatic excursion.

CNS findings include lethargy, cranial nerve dysfunction (particularly esotropia and facial palsy), andpapilledema.

Typhlitis can lead to acute pain in the lower quadrants that mimic signs of appendicitis.

Signs of perforation include hypotension, abdominal distension, and decreased bowel sounds. Clinicaldeterioration is rapid if the condition is not recognized.

Skin nodules are occasionally found in patients with acute myeloid leukemia. They are typically firm,raised, and often bluish-purple in color.

Causes



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

Radiation exposure

A great deal of evidence has implicated radiation in leukemogenesis in many patients, as evidenced inJapan after the atomic explosions at Hiroshima and Nagasaki. Although young children had the highrisk of developing ALL, teens and adults were most likely to contract acute myeloid leukemia. Most ofthe leukemias arose within the first 5 years after exposure, although some developed as much as 15years after exposure.

Reports of increased risk of leukemia among patients who live near nuclear plants are underinvestigation, but data are lacking. Likewise, early reports that exposure to strong electromagneticfields is a risk factor for acute leukemia have not been corroborated.

Exposure to toxins and drugs

Exposure to toxic chemicals that cause damage to bone marrow, such as benzene and toluene used inthe leather, shoe, and dry cleaning industries, is associated with leukemia in adults. Direct evidence ofthis effect in children has not been established. Exposure to pesticides has been noted to increase therisk of acute myeloid leukemia.

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

Genetic factors and syndromes

Children with Down syndrome (trisomy 21) have a 15-fold increased risk of developing leukemia, mostcommonly acute megakaryoblastic leukemia, compared with the general population. The risk ofmegakaryoblastic leukemia in Down syndrome is approximately 400 times greater than the rest of thepopulation. Children with Down syndrome who have transient myeloproliferative syndrome as neonates,a condition often indistinguishable from acute leukemia, also have a high risk of developing acuteleukemia in subsequent years.

Patients with inherited disorders, such as Shwachman-Diamond syndrome, Bloom syndrome, orDiamond-Blackfan anemia, Fanconi anemia, dyskeratosis congenita, Kostmann syndrome, also havean elevated risk of developing leukemia. Although statistics vary, about 10% of patients with Fanconianemia, 5-10% of patients with Shwachman-Diamond syndrome, and 1 in 6 patients with Bloomsyndrome develop leukemia. The risk of acute myeloid leukemia in patients with dyskeratosiscongenita is nearly 200 times the normal population. These syndromes share features of poor DNArepair that are believed to predispose affected individuals to leukemogenic stimuli. Children withneurofibromatosis type I also appear to be at increased risk for developing acute myeloid leukemia.

Although most cases are diagnosed after a relatively brief duration of symptoms, some patients maypresent with myelodysplasia. This relatively indolent disorder is characterized by slowly progressiveanemia or thrombocytopenia. This disorder can be present for many months or even years before itultimately converts to acute myeloid leukemia.

Differential Diagnoses

Acute Lymphoblastic Leukemia Lymphoproliferative Disorders

Anemia, Megaloblastic Myelodysplasia

Cytomegalovirus Infection Myelofibrosis

Gaucher Disease Neuroblastoma

Histiocytosis Rhabdomyosarcoma



Human Immunodeficiency Virus Infection Systemic Lupus Erythematosus

Other Problems to Be Considered

Aplastic anemiaDrug-induced pancytopeniaTransient myeloproliferative syndrome in Down syndrome

Workup

Laboratory Studies

Blood counts and blood smears

The hallmark of acute myeloid leukemia (AML) is a reduction or absence of normal hematopoieticelements. Anemia is usually normocytic, with a reticulocyte count lower than expected for the level of thehemoglobin. The decrease in hemoglobin levels can range from minimal to profound.

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

WBC counts may be decreased or elevated. Hyperleukocytosis with WBC counts of more than 100 X109/L (>100,000/µL) are occasionally observed; with high numbers, the blood specimen appears white.The WBC differential is usually the key to evaluating suspected leukemia; primitive granulocyte ormonocyte precursors are observed on peripheral smears. Numbers of mature neutrophils are usuallydiminished.

Upon careful examination of the blood smears, Auer rods (thin, needle-shaped eosinophiliccytoplasmic inclusions) are revealed in specimens of circulating blood obtained from many patientsacute myelocytic leukemia. They are particularly prominent in children with acute promyelocyticleukemia (APL).

Blood chemistries and other blood work

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

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

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

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

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

Imaging Studies

Imaging studies are not required for the diagnosis or extent of disease evaluation of children with acute myeloidleukemia. They can be helpful in managing complications that arise.

Radiography

Routine chest radiography should be performed to rule out mediastinal masses, particularly in patientswith respiratory symptoms or suspected superior vena cava syndrome.

If the patient has abdominal pain and distention, abdominal images often depict free air suggestive of aperforation.

Radiograph examination of the extremities may reveal findings such as metaphyseal bands at the distalfemurs (most commonly observed in young children with ALL), periosteal new bone formation, focal lyticlesions, or pathologic fractures.

CT and MRI

If the patient has abdominal pain and possible infection of the large bowel, CT may reveal thickeningand 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 ismandatory to rule out intracranial hemorrhage or infiltrative disease.



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 causeclinically significant cardiomyopathy.

Radionuclide imaging

Radionuclide imaging is often used to detect occult infection that cultures and other imaging modalitiesdo 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 withappropriate antibiotic management.

Other Tests

Tests of cytogenetic markers, histochemical staining, and immunophenotyping

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

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

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

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 differenttreatment strategies.

Another gene affecting prognosis is the nucleophosmin (NPM1) mutation. The presence of thismutation 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 completeremission.

Human leukocyte antigen (HLA) typing

HLA-matched family donors should be identified because bone marrow transplantation (orhematopoietic stem cell transplantation) may be considered in high-risk patients.

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



Procedures

Bone marrow examination

Bone marrow examination is necessary to establish the diagnosis of AML. The sample is examinedunder the microscope at which time the percentage of different cells are tabulated. The hallmark ofleukemia is the presence of a high proportion of primitive cells and a paucity of normal hematopoieticelements.

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

Acute myeloid leukemia can be divided into subtypes on the basis of marrow findings. Some of thesesubtypes have characteristic clinical pictures. The French-American-British classification systemrecognizes 7 primary types of AML (M1-M7), which can usually be established with additional marrowstudies. The World Health Organization has classified acute myeloid leukemias into groups, includingthe following: acute myeloid leukemia with recurrent cytogenetic translocations (eg, promyelocyticleukemia with typical t[15;17]), acute myeloid leukemia with multilineage dysplasia, acute myeloidleukemia and myelodysplasia syndromes secondary to therapy (eg, those following alkylating agents),and acute myeloid leukemia not otherwise categorized (eg, erythroid leukemias, monocytic leukemias).

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

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

Biopsy is necessary to gauge the cellularity of a marrow specimen and was the former standard duringfollow-up to aid subsequent therapeutic decisions. However, biopsy is now less commonly used as thedisease status can usually be evaluated with marrow aspirations and immunologic and cytogenetictesting.

Lumbar puncture and cerebrospinal fluid (CSF) examination

Lumbar puncture is necessary for diagnostic and therapeutic reasons.

Even if the marrow is not involved at the time of diagnosis, CNS seeding can occur later. Therefore,periodic surveillance lumbar puncture with the administration of intrathecal chemotherapy is necessary.

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

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

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

Placement of a central venous catheter

Because of the patient's need for intense chemotherapy and supportive care, guaranteed venousaccess is critical. An indwelling central venous catheter with at least 2 lumens is usually placed beforethe start of therapy. This catheter provides access for infusing chemotherapeutic drugs and forproviding intravenous nutritional support, transfusions, antibiotics, and other supportive medications. Inaddition, they allowing for blood withdrawal for required testing.

Subcutaneous ports and peripheral indwelling central catheters in the cubital area are sometimes used.These are sometimes added when patients require additional therapy, such as stem celltransplantation, or when a temporary access situation develops (as when an indwelling central line isremoved because of infection).

Histologic Findings



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

Patients with low blast count t(8;21) can also present a diagnostic challenge, sometimes considered amyelodysplastic syndrome, and often require multiple marrow examinations before the diagnosis of leukemiais 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 leukemiccell population as rapidly as possible and to prevent the emergence of a resistant clone. Patients aresimultaneously given supportive care until their bone marrow achieves hematologic remission and is againproducing normal hematopoietic cells.

Chemotherapy

Virtually all chemotherapeutic drug regimens include some combination of an anthracycline (most oftendaunomycin) 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 protocolsdeveloped by the Children’s Cancer Group and the Pediatric Oncology Group. These protocols, whichused different multiagent chemotherapies, were associated with improved results as therapy wasintensified. Although these treatments prolonged pancytopenia, they decreased induction failures andsubstantially improved disease-free survival.

After the 2 national groups merged to form the Children's Oncology Group (COG), the recommendedregimen,[3 ]based on the Medical Research Council acute myeloid leukemia trials, was adapted; thisconsisted of 2 cycles of induction therapy with infusions of daunomycin, cytosine arabinoside,etoposide (ADE therapy). Gemtuzumab ozogamicin (withdrawn from US market), an anti-CD33antibody linked to an antitumor antibiotic, is currently under investigation in a COG pediatric nationaltrial.

After remission is induced, postinduction treatment is necessary because more than 90% of patientsotherwise relapse without additional treatment. In patients without human leukocyte antigen (HLA)-matched donors from their family, sequential cycles of chemotherapy are administered by usingcombinations 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 alwaysimprove overall survival because of treatment-related mortality. Autologous bone marrowtransplantation has also been shown to reduce relapse rates but does not improve overall survivalcompared with chemotherapy alone because of treatment-related mortality.

In the COG trials, transplants are not recommended for "low-risk acute myeloid leukemia," which ischaracterized by chromosome inv(16) and t(8;21) abnormalities; these patients receive additional"consolidation" chemotherapy and are only transplanted in second remission. Allogeneic bone marrowtransplantation from an HLA-matched sibling or parent is recommended during the first completeremission (ie, after 3 cycles of chemotherapy) for other patients (ie, those with standard-risk acutemyeloid [normal cytogenetics] who enter remission with 2 induction courses and those with high-riskacute myeloid leukemia [abnormal karyotypes, including monosomy 7, trisomy 3, 5q- or complexkaryotypes]). Transplantation is reserved for the second remission after a relapse for patients withDown syndrome and acute myeloid leukemia. Patients with acute promyelocytic leukemia (APL) shouldnot 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 haveshown promise. See the section on stem cell transplant below.



Other approaches have met with success in other parts of the world. Nordic and Japanese researcheshave reported promising results using multiple cycles of high-dose cytosine arabinoside.[4,5 ]

Treatment for APL[6 ]

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

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

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

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

Gemtuzumab ozogamicin (withdrawn from US market), or anti-CD33 calicheamicin, is also beingtested in patients with APL. The hope is that both arsenic and gemtuzumab ozogamicin may reduceexposure to anthracyclines without sacrificing efficacy. The COG is planning on piloting a trial that willreplace an anthracycline course of chemotherapy with arsenic trioxide plus ATRA in order to reduce theanthracycline exposure from an estimated 650 mg/m2 to 350 mg/m2 in standard-risk patients and to450 mg/m2 in high-risk patients.

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

Treatment for children with Down syndrome

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

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

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

Radiation therapy

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

Persistent CNS leukemia usually requires craniospinal irradiation.

Most pretransplantation myeloablative regimens given to children in their first complete remission havereplaced total body irradiation with busulfan to decrease the incidence of some long-term adverseeffects. Although busulfan is associated with significant potential short-term and long-term adverseeffects (including seizures and infertility), the incidence of second malignancies is lower than thatassociated with total body radiation.



Blood and marrow transplantation

A myeloablative combination of chemotherapy and irradiation followed by rescue with an infusion ofHLA-matched stem cells to reconstitute the patient's bone marrow is an effective approach to cureacute myeloid leukemia.[7 ]In several randomized studies, allogeneic transplantation raised overall anddisease-free survival rates.[8 ]However, this option is not available to most patients because HLA-matched donors are found for only approximately 25%. In addition, for good-risk patients,transplantation is reserved for a second remission because the salvage rate is quite high for suchpatients.

Options have substantially increased with the availability of international HLA registries that can help inlocating HLA-matched unrelated donors (MUD). Results with MUD are virtually equivalent to HLA-matched family donors and have become more available with the development of large internationalHLA registries. Umbilical cord blood, which is rich in stem cells, has further expanded the availability ofdonor stem cells because increased HLA mismatch appears to be better tolerated with such donorcells in terms of the development of high-grade graft versus host disease (GVHD).

In addition, the use of both purged or unpurged autologous stem cells, which offer the advantages ofavailability and avoidance of graft versus host disease, are under investigation in clinical trials.However, to date, randomized studies in pediatric patients have not shown an overall survivaladvantage for autologous stem cell transplantation compared with chemotherapy.

Success rates for stem cell transplants have also increased because of improved GVHD prophylaxisand treatment, using different combinations of methotrexate, cyclosporine, tacrolimus, mycophenolate,and corticosteroids to lower mortality rates.

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

The substitution of busulfan-cyclophosphamide for regimens involving total-body irradiation hasreduced long-term problems related to growth retardation and the increased risk of brain tumors.However, the risk of sterility, second malignancies, and neurocognitive abnormalities (especially inyoung children) remain a significant problem in survivors.

Transfusion support

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

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

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

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

In rare cases, granulocyte transfusions are administered to treat serious infections that do not respondto 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 thisapproach as not been definitively proven.

Metabolic management

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

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

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

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



Calcium replacement is often necessary to correct severe hypocalcemia.

Prevention is key to avoiding most serious metabolic complications. The combination of vigoroushydration, administration of allopurinol (a xanthine oxidase inhibitor to prevent the formation of uricacid), and alkalinization of the urine with sodium bicarbonate is usually successful in preventing serioustumor 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 canrapidly 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 infectionuntil proven otherwise.

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

When tunnel infections around a central venous catheter are suspected, vancomycin should beadministered. 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 ofbroad spectrum antibiotics and negative bacterial cultures. Although amphotericin has been thestandard 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 systemicstreptococcal sepsis in patients with severe mucositis. Acyclovir has been useful in preventing herpessimplex infections, particularly in patients who have undergone bone marrow transplantation. Reportshave suggested that prophylactic levofloxacin decreases the incidence of sepsis and other life-threatening infections. Patients who develop GVHD that requires significant immunosuppressivetherapy require more intense and more broadened infection prophylaxis.

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

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

Treatment with biologic-response modifiers

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

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

Surgical Care

The role of surgery is limited.

Insertion of a central venous catheter is necessary to begin treatment and to manage all aspects ofchemotherapy and transfusion support.

Biopsy or aspiration of tissue for culture is often necessary for febrile patients with a possible abscess.

Acute abdomen often results in serious complications (eg, typhlitis) that require expeditious surgical



intervention.

Consultations

Urologist: Consider consulting a urologist when male teenagers are undergoing intense chemotherapy thatmay 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 preparationfor 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 mayaffect the quality of their sperm.

Psychologists, psychiatrists, or other mental health professional: Patients and their families may experiencemajors stresses as a result of intense treatment and frequent, prolonged hospitalizations for chemotherapyand its resulting complications (especially fin patients undergoing stem cell transplant). Another stressor isthe real possibility of life-threatening complications. Psychologic support, with educational information andnumerous 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 withinfections 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 toleratingtherapy. Most patients require intravenous total parenteral nutrition or, preferably, nasogastric alimentalnutrition.

Low-bacteria diets are often prescribed to patients receiving a blood or marrow transplant to decrease theincidence of infections because of the profound immunosuppression after transplantation. This wouldinclude avoiding uncooked fresh vegetables and fruits. These recommendations are probably not necessaryfor 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 contagiousdisorders when they have neutropenia or immunosuppression after transplantation.

During episodes of thrombocytopenia, patients should curtail their participation in potentially traumaticphysical sports activities to avoid serious hemorrhage. Medications that can potentiate bleeding, such asantiplatelet 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 periodsof 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-responsemodifiers; and other classes of supportive medications.

Chemotherapeutic agents

Although many chemotherapeutic agents are active, most current regimens include combinations of ananthracycline 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



Pediatric

Induction therapy: 100 mg/m2/dose IV bolus q12h for 10 d during cycle 1 (ie, 20 doses with cumulative dose of2000 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 1and 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

Documented hypersensitivity; severe hepatic or renal compromise

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

Daunorubicin, daunomycin (Cerubidine)

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 withtrastuzumab

Contraindications

Documented hypersensitivity; cardiac failure; severe hepatic or renal dysfunction; cumulative anthracycline dose>450 mg/m2 is relative contraindication

Precautions

Pregnancy


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 haveoccurred

Etoposide, VP-16 (VePesid)



Podophyllotoxin derivative. Used in induction and consolidation phases of treatment.

Dosing

Adult

Pediatric

Induction: 100 mg/m2/d IV infusion qd for 5 d during each cycleConsolidation: 150 mg/m2/d IV infusion qd for 5 d during first phase

Interactions

May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine incytotoxicity of tumor cells

Contraindications

Documented hypersensitivity to etoposide or Cremophor EL; clinically significant hypotension; IT administrationmay cause death

Precautions

Pregnancy


Precautions

Only experienced oncologists should administer this drug; severe myelosuppression, hypotension, mucositis, andother complications expected; consider dosage reduction in patients with low serum albumin levels, bone marrowsuppression, or renal impairment

Mitoxantrone (Novantrone)

Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II. Used in consolidation phase oftreatment.

Dosing

Adult

Pediatric

Intensification: 12 mg/m2/d IV for 4 d during second cycle of intensification for patients not undergoing stem celltransplant

Interactions

Cytochrome P450 (CYP) 2E1 inducer (weak); valspodar increases area under the concentration-time curve (AUC)(decrease dose)

Contraindications

Documented hypersensitivity; hepatic failure

Precautions

Pregnancy


Precautions

Only experienced oncologists should administer this drug; severe myelosuppression, anaphylaxis; cardiotoxicity;interstitial pneumonitis; hepatic dysfunction, nausea, mucositis, and other complications expected

Tretinoin, all-trans-retinoic acid, ATRA (Vesanoid)



Used in induction and maintenance phases in patients with APL.

Dosing

Adult

Pediatric

45 mg/m2/d PO divided bid

Interactions

CYP substrate (caution with coadministration of CYP inhibitors or inducers); ketoconazole significantly increasesAUC; 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 reportedwhen coadministered with antifibrinolytic agents (eg, tranexamic acid, aminocaproic acid, aprotinin)

Contraindications

Documented hypersensitivity (including sensitivity to retinoids, paraben); leukocytosis

Precautions

Pregnancy


Precautions

Only experienced oncologists should administer this drug; severe leukocytosis with pulmonary infiltrates andrespiratory failure expected; headache, fever, weakness, and fatigue common

Arsenic trioxide (Trisenox)

May cause DNA fragmentation and damage or degrade fusion protein promyelocytic leukemia protein–retinoicacid receptor alpha (PML-RAR alpha). Use only in patients who have relapse or whose disease is refractory toretinoid or anthracycline chemotherapy.

Dosing

Adult

Pediatric

Consolidation: 0.15 mg/kg/d IV for 5 d/wk for 5 wk

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) mayincrease risk of potentially fatal arrhythmias

Contraindications

Documented hypersensitivity

Precautions

Pregnancy


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 heartbeatsdevelop; may lead to torsade de points or complete atrioventricular (AV) block (risk factors include congestiveheart failure, history of torsade de pointes, preexisting prolongation of QT interval, use of potassium-wasting



diuretics, conditions that cause hypokalemia or hypomagnesemia)

L-asparaginase (Elspar)

Used in consolidation phase of therapy.

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


Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefitsoutweigh risk to fetus

Precautions

Allergic reactions common (symptoms range from localized urticaria to angioedema or anaphylaxis); bone marrowdepression, hyperglycemia, hepatotoxicity, and bleeding may occur; known to cause fevers, nausea, abdominalpain, coagulopathy, thrombosis, and pancreatitis

Gemtuzumab ozogamicin (Mylotarg)

Withdrawn from United States market (June 21, 2010). A confirmatory, postapproval clinical trial was begun in2004. The trial was designed to determine whether adding gemtuzumab to standard chemotherapy demonstratedan improvement in clinical benefit (survival time) to patients with AML. The trial was stopped early when noimprovement in clinical benefit was observed and after a greater number of deaths occurred in the group ofpatients who received gemtuzumab compared with those receiving chemotherapy alone. At initial approval in2000, gemtuzumab was associated with a serious liver condition called veno-occlusive disease, which can befatal. This rate has increased in the postmarket setting.Monoclonal antibody against CD33 antigen, which is expressed on leukemic blasts in >80% of patients with acutemyeloid leukemia and normal myeloid cells. Antibody-antigen complex is then internalized and the calicheamicinderivative 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 forcytotoxic 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 ofsecond dose; administer 50 mg diphenhydramine PO and 650-1000 mg acetaminophen PO 1 h prior toadministration of each dose

Pediatric

3 mg/m2 IV over 2 h; administer 1 mg/kg diphenhydramine PO and 15 mg/kg acetaminophen PO 1 h prior toadministration of each dose



Interactions

None reported

Contraindications

Documented hypersensitivity to drug, calicheamicin derivatives, or patients with anti-CD33 antibody

Precautions

Pregnancy


Precautions

Postinfusion reactions including hypotension, fever, chills, or dyspnea (acetaminophen, intravenous fluids, anddiphenhydramine may be administered to reduce incidence); severe myelosuppression occurs in all patients atrecommended dosages; caution in renal and hepatic impairment; tumor lysis may occur (risk may be reduced byadministering allopurinol prophylactically and adequate hydration)

Antiemetic agents

Antineoplastic-induced vomiting is stimulated by actions on the chemoreceptor trigger zone. This zone thenstimulates the vomiting center in the brain. Increased activity of central neurotransmitters, dopamine in thechemoreceptor trigger zone or acetylcholine in the vomiting center, appears to be a major mediator in inducingvomiting. After antineoplastic agents are given, serotonin (5-HT) is released from enterochromaffin cells in the GItract. With this release and with the subsequent of 5-HT binding to 5-HT3-receptors, vagal neurons are stimulatedand 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 isimportant to use these drugs prophylactically.

Ondansetron (Zofran)

Selective 5-HT3 receptor antagonist that blocks serotonin peripherally and centrally. Prevents nausea and vomitingassociated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and whole-body radiotherapy.

Dosing

Adult

Pediatric

<3 years: Not established>3 years: 0.15 mg/kg/dose PO or IV rapid infusion; may repeat q4h for 2 doses

Interactions

Although there is potential for CYP450 inducers (barbiturates, rifampin, carbamazepine, phenytoin) canto changehalf-life and clearance of ondansetron, dosage adjustment usually is not required

Contraindications


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 nauseaand vomiting



Granisetron (Kytril)

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

Dosing

Adult

Pediatric

<2 years: Not established>2 years: 10 mcg/kg/dose PO or IV push qd

Interactions

None reported

Contraindications


Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in liver disease

Antimicrobials, prophylactic

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

Sulfamethoxazole and trimethoprim (Bactrim, Septra)

Sulfa drugs can effectively prevent P carinii pneumonia in this immunocompromised group of patients.

Dosing

Adult

Pediatric

<2 months: Contraindicated>2 months, PCP prophylaxis: 5 mg/kg/d or 150 mg/m2/d (based on trimethoprim component) PO 3 times/wk

Interactions

May increase effect of warfarin; may decrease phenytoin hepatic clearance and prolong half-life; may displacemethotrexate from plasma protein-binding sites, increasing free concentrations; may potentiate its effects in bonemarrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increasezidovudine levels

Contraindications

Documented hypersensitivity; megaloblastic anemia caused by folate deficiency; infants <2 mo

Precautions

Pregnancy


Precautions



Avoid during pregnancy when near term (increases risk of jaundice in newborn); discontinue at first appearance ofrash 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 doserelated); caution in patients with renal or hepatic impairment; maintain adequate fluid intake to prevent crystalluriaand stone formation

Fluconazole (Diflucan)

Effective in treating and decreasing host colonization of candidiasis.

Dosing

Adult

Pediatric

Prophylaxis: 3-5 mg/kg/d PO or IV infusion qd

Interactions

Concomitant use with hydrochlorothiazide may increase fluconazole concentrations, perhaps because of reducedrenal clearanceCYP3A4 inhibitor and may increase serum levels of 3A4 substrates; increases phenytoin or cyclosporineconcentrations when administered concurrently; increases half-life of theophylline; may increase serumconcentration of tolbutamide, glyburide, and glipizideSingle dose of warfarin after administration of fluconazole for 14 d can increase prothrombin time (PT) response

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy


Precautions

Rare exfoliative skin disorders (monitor closely and discontinue if lesions progress); adjust dose in renalinsufficiency; may cause clinical hepatitis, cholestasis, or fulminant hepatic failure (including death) if patient hasunderlying 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 andfor treating complications related to the disease and its treatment, usually infections or febrile neutropenicepisodes. Some hospitalizations can be lengthy. Numerous changes in antibiotics may be necessary untilinfections and neutropenia resolve.

After transplantation, most febrile episodes require in-patient treatment and observation until profoundneutropenia and clinically significant infection resolves.

Further Outpatient Care

Because early intervention can often cytopenic complications, blood counts must carefully be monitoredduring and between phases of treatment.

After all planned therapy, careful physical examinations and blood work are important to ensure continuedhematologic remission.



Inpatient & Outpatient Medications

Most supportive medications can be discontinued when chemotherapy is completed. Such medicationsinclude prophylactic antibiotics, agents for nutritional support (eg, appetite stimulants), and antiemetics.

Patients usually require prolonged immunosuppressive therapy with prednisone and cyclosporine aftertransplantation. Penicillin, antifungal medications, acyclovir, and trimethoprim-sulfamethoxazole are continueduntil all immunosuppressive medications are discontinued.

Transfer

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

For patients with suitable donors, transfer to a center capable of performing blood and marrow transplants isusually necessary.

Deterrence/Prevention

As detailed in Causes, the association of acute myelocytic leukemia with radiation, toxins, and drugs is welldocumented. Reduced exposure to ionizing radiation should be an important maxim for every physician whoorders 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

Immediate and short-term complications

Serious infections

Alopecia

Emesis

GI erosions and bleeding

Hemorrhage

Malnutrition

Nausea

Death

Long-term or delayed complications

Congestive heart failure and arrhythmia (rare)

Growth and other endocrine disorders

Second malignancies

Death

Infection

Infection is a major cause of morbidity and mortality.

The predisposition to infection is a consequence of granulocytopenia. The risk of sepsis is greatestwhen 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-spectrumantibiotics, common causes of death are fungal, antibiotic-resistant bacterial, and other opportunistic



infections.

Bleeding

Bleeding is the second most common cause of death.

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

Disseminated intravascular coagulation is a serious potential problem in all patients with acutepromyelocytic leukemia (APL) and, to some extent, in those with other acute myelocytic leukemiasubtypes. It can occur in association with thrombosis and hemorrhage.

Tumor lysis syndrome

Patients with high leukemic cell counts or massive organomegaly are at significant risk for tumor lysissyndrome.

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

Effects of chemotherapy

The aggressive chemotherapy necessary to cure the patient also results in a great deal of morbidity.

Profound myelosuppression due to high-dose, intensive treatment regimens contribute to a high risk ofinfection and bleeding.

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

CNS complications

CNS involvement, with leukemic cell infiltration, hemorrhage, or infection, often cause devastatingcomplications or death.

The risk is particularly high for patients with hyperleukocytosis and WBC counts of more than 200 X109/L (>200,000/µL). These patients are at high risk of intracranial hemorrhage, and their conditionsmust be treated as true emergencies.

Prognosis

With an overall survival rate of 45-55%, the prognosis for children with acute myeloid leukemia has improvedsignificantly over the past 2 decades. A Japanese consortium has recently reported overall 5-year survivalrate of 62%.[4 ]The long-term, disease-free survival rate is approximately 65% for patients receiving humanleukocyte 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 mostcommonly infection, bleeding, or refractory disease.

For children with Down syndrome, current outcomes favor younger children, with a survival rate of 84-86% forchildren younger than 2 years, 79% for children aged 2-4 years, and only 33% for children older than 4years.[9 ]

Acute promyelocytic leukemia prognosis has an event-free survival rate of 70-80%, with overall survival closeto 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 diagnosisof leukemia has profound effects on all family members, with a dramatic change in the patient's lifestyle untilall treatment is completed.

Home tutoring is often necessary during the entire period of treatment.



For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, seeeMedicine's patient education article Leukemia.

Miscellaneous

Medicolegal Pitfalls

Failure to recognize associated complications, such as infections, hemorrhage, metabolic complications, orearly organ dysfunction

Failure to inform the patient and family about potential treatment complications

Special Concerns

Children may not have well-known symptoms of leukemia, such as adenopathy, overt bleeding, and seriousinfections. Nonspecific symptoms such as fatigue, irritability, fevers, or bruising are common in childhood andmight not be recognized as symptoms of leukemia, thus delaying a diagnosis of leukemia. Persistence ofthese symptoms should prompt further investigation.

Signs of serious infections in children with leukemia are often subtle. Fever at any time must be takenseriously, and appropriate cultures and investigations must be ordered to diagnose and treat it early becausethis still remains one of the most frequent causes of hospitalizations, morbidity, and mortality in children withleukemia.

Multimedia



Media file 1: Gingival hyperplasia in a patient with monoblastic leukemia.



Media file 2: Leukemia cutis (a skin nodule) in a patient with leukemia.

References

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bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J

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leukaemia should receive a bone marrow transplantation?--an American view. Br J

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15. Kersey JH. Fifty years of studies of the biology and therapy of childhood leukemia. Blood. Dec1 1997;90(11):4243-51. [Medline].

16. Matasar MJ, Ritchie EK, Consedine N, Magai C, Neugut AI. Incidence rates of acute promyelocytic leukemia

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Keywords

acute myeloid leukemia, AML, acute myeloblastic leukemia, acute myelogenous leukemia, acute nonlymphoblasticleukemia, leukemia, malignancy, cancer, acute promyelocytic leukemia, childhood leukemia, childhood cancer,treatment, symptoms

Contributor Information and Disclosures

Author

Mark E Weinblatt, MD, Chief, Division of Pediatric Hematology/Oncology, Professor of Clinical Pediatrics,Department of Pediatrics, Winthrop University HospitalMark 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.



Medical Editor

Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair ofResearch, Mattel Children's Hospital at UCLA; Co-Associate Program Director of the Signal TransductionProgram Area, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and CaliforniaNanosystems Institute and Molecular Biology Institute, UCLAKathleen 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, Societyfor 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 ofPharmacy; Pharmacy Editor, eMedicineDisclosure: Nothing to disclose.

Managing Editor

Timothy P Cripe, MD, PhD, Professor of Pediatrics, Division of Hematology/Oncology, Cincinnati Children'sHospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-Medical Director, Office forClinical and Translational Research, Cincinnati Children's Hospital Medical Center; Director of Pilot andCollaborative Clinical and Translational Studies Core, Center for Clinical and Translational Science and Training,University of Cincinnati College of MedicineTimothy P Cripe, MD, PhD is a member of the following medical societies: American Association for theAdvancement of Science, American Pediatric Society, American Society of Hematology, American Society ofPediatric 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, DukeUniversitySamuel 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 Societyof 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 andthe Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns HopkinsUniversity School of MedicineRobert J Arceci, MD, PhD is a member of the following medical societies: American Association for CancerResearch, American Association for the Advancement of Science, American Pediatric Society, American Societyof Hematology, and American Society of Pediatric Hematology/Oncology Disclosure: Nothing to disclose.

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