Pediatric Medscape Lla

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http://emedicine.medscape.com/article/990113-overview#showall

Updated: Feb 5, 2013

Pediatric Acute Lymphoblastic Leukemia

Author: Vikramjit S Kanwar, MD, MBA, MRCP(UK), FAAP; Chief Editor: Robert J Arceci, MD,PhD more..

Practice Essentials

Signs and symptoms

Children with acute lymphoblastic leukemia (ALL) often present with signs and symptoms that reflect

bone marrow infiltration and/or extramedullary disease. When leukemic blasts replace the bone

marrow, patients present with signs of bone marrow failure, including anemia, thrombocytopenia,

and neutropenia.

Other presenting signs and symptoms of pediatric ALL include the following:

Patients with B-precursor ALL: Bone pain, arthritis, limping; fevers (low or high);neutropenia; fatigue, pallor, petechiae, and bleeding; lymphadenopathy and

hepatosplenomegaly

Patients with mature-B ALL: Extramedullary masses in the abdomen or head/neck; CNSinvolvement (eg, headache, vomiting, lethargy, nuchal rigidity)

Patients with T-lineage ALL: Respiratory distress/stridor due to a mediastinal mass

Symptoms of CNS involvement are rarely noted at initial diagnosis but are more common in T-

lineage and mature B cell ALL.[1]

Testicular involvement at diagnosis is also rare; if present, it appears

as unilateral painless testicular enlargement.

SeeClinical Presentationfor more detail.

Diagnosis

Testing

Complete morphologic, immunologic, and genetic examination of the leukemic cells is necessary to

establish the diagnosis of ALL.

Routine laboratory studies in pediatric ALL include the following:

CBC count Peripheral blood smear Serum chemistries (eg, potassium, phosphorus, calcium) Uric acid level
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LDH level Coagulation studies (helpful in T-lineage ALL), such as PT, aPTT, levels of fibrinogen and D-

dimer

Laboratory tests that help classify the type of ALL include the following:

Immunophenotyping: To detect surface immunoglobulin on leukemic blasts (diagnosis ofmature B-cell leukemia) or the expression of T-cellassociated surface antigens (diagnosis of

T-lineage ALL)

Cytogenetic studies: To identify specific genetic alterations in leukemic blasts Molecular studies (eg, FISH, RT-PCR, Southern blot analysis): to identify translocations not

detected on routine karyotype analysis; to distinguish lesions that appear cytogenetically

identical but are molecularly different

Minimal residual disease studies[2] : To detect chimeric transcripts generated by fusiongenes, detect clonal TCR or immunoglobulin heavy-chain (IgH) gene rearrangements, or

identify a phenotype specific to the leukemic blasts

Imaging studies

No other imaging studies than chest radiography to evaluate for a mediastinal mass should be

required in pediatric ALL. However, the following radiologic studies can be helpful:

Ultrasonography: To evaluate for testicular infiltration in boys with enlarged testes; toevaluate for leukemic kidney involvement as a risk assessment for tumor lysis syndrome

ECG, echocardiogram: To identify any preexisting cardiac dysfunction before administrationof anthracyclines (baseline studies); to monitor heart function during treatment with

anthracyclines

Procedures

Lumbar puncture with cytospin morphologic analysis: To assess for CNS involvement beforeadministration of systemic chemotherapy; to administer intrathecal chemotherapy

Bone marrow aspiration and biopsy: To confirm the diagnosis of ALLCNS disease is divided into the following groups:

CNS 1: Absence of blasts on CSF cytospin preparation, regardless of the WBC count CNS 2: WBC count of less than 5/mL and blasts on cytospin findings, or WBC count of more

than 5/mL but negative by Steinherz-Bleyer algorithm findings (if traumatic tap)

CNS 3: WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs ofCNS leukemia (eg, facial nerve palsy, brain/eye involvement, hypothalamic syndrome)

SeeWorkupfor more detail.
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Management

Leukemia is a systemic disease, and treatment is primarily based on chemotherapy. However, the

different forms of ALL require different approaches for optimal results. Treatment of subclinical CNS

leukemia is an essential component of ALL therapy.

Treatment for ALL typically consists of the following phases:

Remission-induction phase (eg, dexamethasone or prednisone, vincristine, asparaginase,daunorubicin)

Intensification/consolidation phase: Intensification (cytarabine, cyclophosphamide,etoposide, dexamethasone, asparaginase, doxorubicin, MTX, 6-MP, vincristine);

consolidation (MTX, 6-MP, cytarabine, cyclophosphamide)

Continuation therapy targeted at eliminating residual disease (eg, MTX, 6-MP, vincristinepulses, glucocorticoid)

Intrathecal chemotherapy includes primarily MTX, which may also be combined with hydrocortisone

and cytarabine (triple-intrathecal therapy).

Pharmacotherapy

Medications used in the treatment of pediatric ALL include the following:

Antineoplastics (eg, vincristine, asparaginase, asparaginase Erwinia chrysanthemi,daunorubicin, MTX, 6-MP, cytarabine, etoposide, cyclophosphamide, nelarabine,

clofarabine)

Corticosteroids (eg, prednisone, dexamethasone) Antimicrobials (eg, TMX/SMP, pentamidine) Antifungals (eg, fluconazole)

Treatment of T-cell ALL may benefit from the addition of cyclophosphamide and intensive treatment

with asparaginase. Mature B-cell ALL needs to be treated in the same way as disseminated Burkitt

lymphoma, with short-term intensive chemotherapy, including high-dose MTX, cytarabine, and

cyclophosphamide over a 6-month period.

Blood transfusions or antibiotics may be required to deal with complications of ALL therapy. Do not

administer folate supplementation owing to interactions with MTX.

On January 25, 2013, the FDA approved imatinib in conjunction with chemotherapy in children

with newly diagnosed Philadelphia chromosome (Ph)positive ALL in children.[3, 4]

This approval

expanded the use of imatinib and chemotherapy in children with leukemia; in 2011, imatinib plus

chemotherapy was approved for treatment of newly diagnosed pediatric Ph-positive CML.

The agencys current approval was based on trial results by the Childrens Oncology Group, which

showed, among other findings, that the combination of imatinib and chemotherapy in pediatric


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ALL doubled cure rates.[3]

The most common adverse effects observed with imatinib plus

chemotherapy were decreased levels of neutrophils and platelets, as well as liver toxicity and

infection.[3, 4]

Nonpharmacologic therapy

Other treatments involved in managing pediatric ALL may include the following:

Administration of IV fluids: Without potassium, with or without sodium bicarbonate Cranial irradiation: Effectively prevents overt CNS relapse but potentially causes

neurotoxicity and brain tumors; largely replaced by intensive intrathecal and systemic

chemotherapy

Allogeneic SCT soon after first remission: Potentially prevents relapse and/or mortality vschemotherapy alone

Surgical options

In generally, surgical care is not required in the treatment of ALL. However, placement of a central

venous catheter is needed for administering chemotherapy, blood products, and antibiotics, as well

as for obtaining blood samples.

SeeTreatmentandMedicationfor more detail.

Image library

Bone marrow aspirate from a child with B-precursor acute

lymphoblastic leukemia. The marrow is replaced primarily with small, immature lymphoblasts that

show open chromatin, scant cytoplasm, and a high nuclear-cytoplasmic ratio.

Background

Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children,

representing nearly one third of all pediatric cancers. The annual incidence of acute lymphoblastic

leukemia within the United States is 3.7-4.9 cases per 100,000 children age 0-14 years,[5]

with a peak

incidence in children aged 2-5 years.

Although a few cases are associated with inherited genetic syndromes (eg,Down syndrome) or

congenital immunodeficiencies (eg,Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause

remains largely unknown.[6]

With improvements in diagnosis and treatment, overall cure rates for children with acutelymphoblastic leukemia have reached 90%.

[7]The use of risk-adapted treatment protocols has
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improved cure rates while limiting the toxicity of therapy. This article summarizes the current

diagnosis and treatment of childhood acute lymphoblastic leukemia.

Pathophysiology

In acute lymphoblastic leukemia (ALL), a lymphoid progenitor cell becomes genetically altered andsubsequently undergoes dysregulated proliferation, with clonal expansion. In ALL, the transformed

lymphoid cells reflect the altered expression of genes usually involved in the normal development of

B cells and T cells. Several studies indicate that leukemic stem cells are present in certain types of

acute lymphoblastic leukemia.

Epidemiology

Annually, around 3000 children in the United States are diagnosed with ALL. The annual incidence of

ALL within the United States is 3.7-4.9 cases per 100,000 children 0-14 years of age.[5]

with a similar

estimated worldwide incidence, although it has been questioned whether the incidence may be less

in low-income countries.[8]

White children are more frequently affected than black children, and

there is a slight male preponderance, which is most pronounced for T-cell acute lymphoblastic

leukemia. The incidence of acute lymphoblastic leukemia peaks in children aged 2-5 years and

subsequently decreases with age.

Although a few cases are associated with inherited genetic syndromes (eg,Down syndrome) or

congenital immunodeficiencies (eg,Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause

remains largely unknown.[6]

Environmental risk factors such as exposure to ionizing radiation and

electromagnetic fields and parental use of alcohol and tobacco have not been shown to cause

pediatric acute lymphoblastic leukemia. In addition, no direct link has been established between

viral exposure and the development of childhood leukemia.

Prognosis

The likelihood of long-term cure in ALL depends on the clinical and laboratory features and the

treatment. Prognostic risk assessment includes clinical features (age and white blood cell [WBC]

count at diagnosis), biologic characteristics of the leukemic blasts, response to the induction

chemotherapy, and minimal residual disease (MRD) burden. Based on these criteria, patients can be

effectively stratified into low risk, average or standard risk, high risk, and very high risk.[9]

Standard-risk patients are aged 1-9.9 years with WBC of less than 50,000 at presentation, lackunfavorable cytogenetic features, and show a good response to initial chemotherapy, with less than

5% bone marrow blasts by 14 days and less than 0.01% blasts by 28 days (rapid early response). Low-

risk patients meet all these criteria and have favorable cytogenetics (eg, trisomy 4, 10, 17). High-risk

patients do not meet these criteria or have extramedullary involvement that makes it inappropriate

for them to be treated as standard risk. Very-high-risk patients have unfavorable cytogenetic

features (Philadelphia chromosome, hypodiploidy (n < 44, MLL gene rearrangement) or very poor

response to initial chemotherapy (induction failure with MRD >1%).

Patients younger than 1 year with acute leukemia have disease that is biologically distinct with a

poor outcome.[10]
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The 5-year event-free survival (EFS) varies considerably depending on risk category, from 95% (low

risk) to 30% (very high risk), with infant leukemia having the worst outcomes: 20% for patients

younger than 90 days. Overall, the cure rate for childhood acute lymphoblastic leukemia (ALL) is

more than 80%.

Five-year survival rates for children diagnosed with acute lymphoblastic leukemia, the most common

type in this group, rose to 90% from 2000-2005, which was up from 84% in 1990-

1994.[7]

Improvement in survival was observed for all age groups of children, except for infants

younger than 1 year. In low-income countries (LIC), therapy results for pediatric ALL have been less

encouraging due to delayed diagnosis, abandonment of therapy, and death from toxicity due to

suboptimal supportive care. Nevertheless, improved supportive care with intensive therapy

protocols has increased current 4-year event-free survival rates to 61% in India[11]

, and over 78% in

Lebanon[12]

, demonstrating that pediatric ALL is potentially highly curable in LIC.

An analysis of long-term survival among 21,626 people who were treated for leukemia as children in

Clinical Oncology Group trials from 1990-2005 found that 10-year survival rose to almost 84% in

1995-1999 from 80% in 1990-1994. The analysis also found that survival improved for almost all

groups, including older children and black children.[7]

Acute complications may involve all organ systems and include the following:

Tumor lysis syndrome Renal failure Sepsis Bleeding Thrombosis Typhlitis Neuropathy Encephalopathy Seizures

In addition, lifelong follow-up is necessary,[1]

because survivors may experience late effects from

treatment for this condition, such as the following:

Secondary malignancy Short stature (if craniospinal radiation) Growth hormone deficiency Learning disability Cognitive defects


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Patient Education

Ensure that the patient's parents and guardians understand that ALL usually does not have a known

cause, that accurate stratification helps guide therapy, and that participating in institutional or

consortium-based protocol therapy may help lead to better outcomes in the future. In addition,

parents and guardians must know the expected adverse effects of each medication and be able to

recognize signs and symptoms that require immediate medical attention, such as those for anemia,

thrombocytopenia, and infection. Furthermore, parents and patients must know how to quickly

access medical help from the oncology team.

For patient education information, seeCancer and Tumors Center, as well asLeukemia.

History

Children with acute lymphoblastic leukemia (ALL) often present with signs and symptoms that reflect

bone marrow infiltration and/or extramedullary disease. When leukemic blasts replace the bone

marrow, patients present with signs of bone marrow failure, including anemia, thrombocytopenia,

and neutropenia.

In patients with B-precursor ALL, bone pain, arthritis, and limping may be presenting symptoms and

in 5% of patients are the only symptoms, leading to delays in diagnosis.[13]

Fevers, whether low- or

high-grade, are common at presentation, but despite neutropenia, sepsis is rarely seen. Other

common clinical manifestations include fatigue, pallor, petechiae, and bleeding. In addition,

leukemic spread may manifest as lymphadenopathy and hepatosplenomegaly.

Mature-B ALL may be associated with extramedullary masses in the abdomen or head and neck and

central nervous system (CNS) involvement.

In patients with T-lineage ALL, respiratory distress and stridor secondary to a mediastinal mass may

be a presenting symptom.

Symptoms of CNS involvement, such as headache, vomiting, lethargy, and nuchal rigidity are rarely

noted at initial diagnosis but are more common in T-lineage and mature B cell ALL.[1]

Testicular

involvement at diagnosis is also rare; if present, it appears as unilateral painless testicular

enlargement.

Physical Examination

Physical findings in children with acute lymphoblastic leukemia (ALL) reflect bone marrow

infiltration, as well as extramedullary disease. Patients commonly present with pallor caused by

anemia and petechiae and bruising secondary to thrombocytopenia. Leukemic infiltration may

manifest as lymphadenopathy and hepatosplenomegaly. If it involves the central nervous system

(CNS), papilledema, nuchal rigidity, and cranial nerve palsy is sometimes found. Testicular

examination in males is critical; leukemic infiltration usually manifests as unilateral painless

testicular enlargement.

The presence of stridor is cause for concern and may signify a mediastinal mass, found in half of

patients with T-lineage ALL, with a risk of imminent respiratory arrest. Attempts to lay the patient
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flat or perform intubation should be avoided, and the patient should commence steroid therapy and

be transferred to the PICU for close observation.

Diagnostic Considerations

Complete morphologic, immunologic, and genetic examination of the leukemic cells is necessary toestablish the diagnosis of acute lymphoblastic leukemia.

The following are other conditions to consider when evaluating a child with suspected acute

lymphoblastic leukemia (ALL):

Acute anemia Aplastic anemia Idiopathic thrombocytopenic purpura (ITP)

Differential Diagnoses

Aplastic Anemia Fanconi Anemia Imaging in Arrhythmogenic Right Ventricular Dysplasia (ARVD) Juvenile Rheumatoid Arthritis Leukocytosis Parvovirus B19 Infection Pediatric Acute Myelocytic Leukemia Pediatric Mononucleosis and Epstein-Barr Virus Infection Pediatric Neuroblastoma Pediatric Non-Hodgkin Lymphoma Pediatric Osteomyelitis Pediatric Rhabdomyosarcoma

Approach Considerations

Upon initial evaluation, obtain a complete blood cell (CBC) count. A hematologist or

hematopathologist must evaluate the peripheral smear for the presence and morphology of

lymphoblasts. An elevated leukocyte count of more than 10 109/L (>10 103/L) occurs in one

half of patients with acute lymphoblastic leukemia (ALL). Neutropenia, anemia, and

thrombocytopenia are often observed secondary to inhibition of normal hematopoiesis by leukemic

infiltration. It is important to recognize that 20% of patients with ALL initially present with

pancytopenia and no evidence of peripheral blasts.[14]
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Various metabolic abnormalities may include increased serum levels of uric acid, potassium,

phosphorus, calcium, and lactate dehydrogenase (LDH). The degree of abnormality reflects the

leukemic cell burden and destruction (lysis). Although not universally performed, coagulation studies

can be helpful in patients with T-lineage ALL and should include tests of the prothrombin time (PT),

activated partial thromboplastin time (aPTT), fibrinogen level, and D-dimer level to assess for

disseminated intravascular coagulation (DIC).

No other imaging studies than chest radiography to evaluate for a mediastinal mass should be

required. However, if the physical examination reveals enlarged testes, perform ultrasonography to

evaluate for testicular infiltration. In addition, if anthracyclines are to be administered, obtain a

baseline echocardiogram and an electrocardiogram (ECG).

To assess for central nervous system (CNS) involvement and to administer intrathecal

chemotherapy, lumbar puncture with cytospin morphologic analysis is performed before systemic

chemotherapy is administered.

Immunophenotyping

Acute lymphoblastic leukemia (ALL) cells rearrange their immunoglobulin and T-cell receptor (TCR)

genes and express antigen receptor molecules in ways that correspond to such processes in normal

developing B and T lymphocytes, so that acute lymphoblastic leukemia can be classified as B-lineage

or T-lineage ALL.

The diagnosis of mature B-cell leukemia, which accounts for only 1-3% of childhood ALL, depends on

the detection of surface immunoglobulin on leukemic blasts. Lymphoblasts with this phenotype have

a distinctive morphology, with deeply basophilic cytoplasm containing prominent vacuoles,

designated L3 in the French-American-British (FAB) system (see Histologic Features). Mature B-cell

ALL should be differentiated from other B-lineage ALL.

B-lineage ALL accounts for 80% of childhood ALL and involves lymphoblasts that have cell-surface

expression of 2 or more B-lineageassociated antigens (ie, CD19, CD20, CD24, CD22, CD21, or

CD79).[6] CD10 is commonly expressed, which makes it a useful diagnostic marker, and the presence

of aberrant myeloid markers (eg, CD7) is occasionally noted but has little prognostic impact. B-cell

precursors of ALL can be further subclassified as early preB-cell, preB-cell, or transitional preB-

cell, but distinguishing these subtypes is usually not clinically relevant.


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T-lineage ALL is identified by the expression of T-cellassociated surface antigens, of which

cytoplasmic CD3 is specific. T-cell acute lymphoblastic leukemia cases can be classified by early, mid,

or late thymocytes. The prognosis of patients with T-cell ALL has historically been worse than that of

patients with B-lineage ALL. However, the outlook for patients with T-cell leukemia is comparable to

that of precursor B-cell ALL when intensive chemotherapy is used.

Cytogenetic and Molecular Studies

In more than 90% of pediatric acute lymphoblastic leukemia (ALL) cases, specific genetic alterations

can be found in the leukemic blasts, which have important diagnostic, therapeutic, and prognostic

implications. In addition, molecular techniques, including fluorescence in situ hybridization (FISH),

reverse transcriptase-polymerase chain reaction (RT-PCR), and Southern blot analysis help identify

translocations not detected on routine karyotype analysis and to distinguish lesions that appear

cytogenetically identical but are molecularly different.

Of the many abnormalities described, t(12;21)(p13;q22) or ETV6-RUNX1 (formerly known as TEL-

AML1) and hyperdiploidy (>50 chromosomes/cell) account for 50% of chromosomal abnormalities

found and confer a favorable prognosis. Trisomy 4, trisomy 10, and trisomy 17 (triple trisomy) may

be seen in some hyperdiploid cells and share the favorable outcome. Hypodiploidy (< 44

chromosomes/cell), t(4;11)(q21;q23) MLL-AF4 or MLL gene rearrangement, and t(9;22)(q34;q11), or

Philadelphia chromosome positivity confer a poor prognosis.

Minimal Residual Disease Studies

Traditionally, the response to leukemia treatment has been assessed morphologically, which can be

challenging when looking for small numbers of leukemic cells, especially in bone marrow specimens

recovering from chemotherapy or after transplantation.

Molecular analysis plays a promising role in the diagnosis and treatment of acute lymphoblastic

leukemia (ALL) and in monitoring patients' responses to therapy.

Studies of minimal residual disease (MRD) may be based on the detection of chimeric transcripts

generated by fusion genes, the detection of clonal TCR or immunoglobulin heavy-chain (IgH) gene

rearrangements, or the identification of a phenotype specific to the leukemic blasts.[2]

The methods for detecting MRD have been shown to have a much higher sensitivity than that of

morphology. All studies using MRD techniques have shown significant correlations between end-of-


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induction leukemia burden and outcome.[15] As a result, current treatment protocols use MRD

measurements for acute lymphoblastic leukemia risk assignment.[16]

Ultrasonography

Perform testicular ultrasonography if the testes are enlarged upon physical examination.

Some clinicians use renal ultrasonography to evaluate for leukemic kidney involvement as an

assessment of risk for tumor lysis syndrome.

Bone Marrow Aspiration and Biopsy

Bone marrow aspirate and biopsy results confirm the diagnosis of acute lymphoblastic leukemia

(ALL). In addition, special stains (immunohistochemistry), immunophenotyping, cytogenetic analysis,

and molecular analysis help in classifying each case. See the images below for examples of bone

marrow aspirate findings.

Bone marrow aspirate from a child with B-precursor acute lymphoblastic leukemia. The marrow is

replaced primarily with small, immature lymphoblasts that show open chromatin, scant cytoplasm,

and a high nuclear-cytoplasmic ratio.

Bone marrow aspirate from a child with T-cell acute lymphoblastic leukemia. The marrow is replaced

with lymphoblasts of various sizes. No myeloid or erythroid precursors are seen. Megakaryocytes are

absent.

Bone marrow aspirate from a child with B-cell acute lymphoblastic leukemia. The lymphoblasts are

large and have basophilic cytoplasm with prominent vacuoles.

Histologic Features

According to the French-American-British (FAB) classification system, acute lymphoblastic leukemia

(ALL) is classified into 3 groups based on morphology, as follows:

L1: The lymphoblast cells are usually small, with scant cytoplasm and inconspicuous nucleoli. L1

accounts for 85% of all cases of childhood acute lymphoblastic leukemia.


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L2: The lymphoblast cells are larger than in L1. The cells demonstrate considerable heterogeneity in

size, with prominent nucleoli, and abundant cytoplasm. L2 accounts for 14% of all childhood acute

lymphoblastic leukemia.

L3: The lymphoblast cells are large and notable for their deep cytoplasmic basophilia. They

frequently have prominent cytoplasmic vacuolation and are morphologically identical to Burkitt

lymphoma cells. L3 accounts for 1% of childhood acute lymphoblastic leukemia cases.

Although the FAB system was used in the past, it is no longer useful (except for L3), because current

standard diagnosis is based on immunophenotype and molecular techniques.

pproach Considerations

Leukemia is a systemic disease, and treatment is primarily based on chemotherapy. Thus, surgical

care is generally not required in the treatment of acute lymphoblastic leukemia, except for the

placement of a central venous catheter. Such catheters are used for administering chemotherapy,

blood products, and antibiotics, and for obtaining blood samples.

Different forms of acute lymphoblastic leukemia (ALL) require different approaches for optimal

results. Acute lymphoblastic leukemia treatment typically consists of a remission-induction phase,

intensification (consolidation) phase, and continuation therapy targeted at eliminating residual

disease. The addition of cyclophosphamide and intensive treatment with asparaginase is also

beneficial in the treatment of T-cell acute lymphoblastic leukemia. Mature B-cell ALL needs to be

treated like disseminated Burkitt lymphoma, with short-term intensive chemotherapy, including

high-dose methotrexate (MTX), cytarabine, and cyclophosphamide over a 6-month period.

Initially transfer children to a facility in which they can be in the care of a pediatric oncologist,

preferably a center that participates in multi-institutional clinical trials. Immediately admit any

patient who is neutropenic and who develops chills or fever to administer intravenous (IV) broad-

spectrum antibiotics. Frequent hospitalizations may be required to deal with complications of acute

lymphoblastic leukemia therapy, including the need for blood transfusions or antibiotics.

Because of the use of MTX, avoid folate supplementation.

Tumor Lysis Syndrome

Before and during the initial induction phase of chemotherapy, patients may developtumor lysis

syndrome, which refers to the metabolic derangements caused by the systemic and rapid release of

intracellular contents as chemotherapy destroys leukemic blasts. Because some cells can die before

therapy, such metabolic changes can occur even before therapy begins.

Primary features of tumor lysis syndrome include hyperuricemia (due to metabolism of purines),

hyperphosphatemia, hypocalcemia, and hyperkalemia. Hyperuricemia can lead to crystal formation

with tubular obstruction and acute renal failure requiring dialysis. Therefore, electrolyte and uric

acid levels should be closely monitored throughout initial therapy.

To prevent complications of tumor lysis syndrome, patients should initially receive intravenous (IV)

fluids at twice the maintenance rates, without potassium.
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Sodium bicarbonate may be added to the IV fluid to achieve moderate alkalinization of the urine (pH

level, 7.5-8) to enhance the excretion of uric acid. A urine pH level higher than this should be

avoided to prevent crystallization of hypoxanthine or calcium phosphate.

The standard prophylactic treatment for malignancy-associated hyperuricemia includes allopurinol.

By blocking the enzyme xanthine oxidase, allopurinol blocks uric acid formation. Patients at high risk

for tumor lysis still need to excrete preexisting uric acid, which is unaffected by the use of

allopurinol.

Rasburicase, a recombinant urate oxidase, has demonstrated increased efficacy in pediatric patients

at high risk for tumor lysis by catalyzing the enzymatic oxidation of uric acid to a much more urine

soluble product, allantoin. Its expense means that use is usually limited to patients at high risk of

tumor lysis syndrome (eg, T-cell leukemia with hyperleukocytosis).

Chemotherapy

The phases and duration of chemotherapy for acute lymphoblastic leukemia (ALL) are briefly

discussed in this section.

Phases of therapy

The treatment of childhood acute lymphoblastic leukemia, with the exception of mature B-cell acute

lymphoblastic leukemia, has 5 components: induction, consolidation, interim maintenance, delayed

intensification, and maintenance.

The goal of induction is to achieve remission, previously defined as less than 5% blasts in the bone

marrow. Induction therapy generally consists of 3 or 4 drugs, which includes a glucocorticoid,vincristine, asparaginase, and possibly an anthracycline. This type of therapy induces complete

remission based on morphology in more than 98% of patients. However, the measurement of

minimal residual disease (MRD) by flow cytometry or polymerase chain reaction (PCR) has been

shown to be much more specific and sensitive than the morphologic examination of blast cells, and

the goal is to have less than 0.1% and preferably less than 0.01% at the end of induction.

Current childhood acute lymphoblastic leukemia clinical trials incorporate MRD as a criterion for

determining rapid early responder versus slow early responder status during induction

chemotherapy. Based on MRD measurements, treatment may be intensified in patients with high

amounts of residual blasts at the end of induction therapy (>1%).

Consolidation therapy is given soon after remission is achieved to further reduce the leukemic cell

burden before the emergence of drug resistance and relapse in sanctuary sites (ie, testes, central

nervous system [CNS]). In this phase of therapy, the patient is given different drugs (eg

cyclophosphamide, cytarabine and/or 6-mercaptopurine [6-MP]). Consolidation therapy appears to

improve the long-term survival of patients with standard-risk disease.

In interim maintenance, nonmyelosuppressive chemotherapy (eg, vincristine and intravenous MTX)

are administered to maintain remission and allow the bone marrow to recover. This occurs for 4-8

weeks and is followed by delayed intensification, which is aimed at treating any remaining resistant


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leukemia cells. The addition of intensive reinduction and reconsolidation therapy (collectively known

as delayed intensification) is beneficial for patients in all risk groups.

The last (and longest) phase of treatment is maintenance. This consists of intrathecal MTX every 3

months, monthly vincristine and steroid pulses, daily 6-MP, and weekly MTX.

Duration of therapy

Whereas mature B-cell acute lymphoblastic leukemia (ALL) is treated with a 6- to 8-month course of

intensive therapy, achieving acceptable cure rates for patients with B-lineage and T-lineage ALL

requires approximately 2-2.5 years of continuation therapy. Attempts to reduce this time resulted in

high relapse rates after therapy was stopped. In the United States, in current ALL clinical trials, the

total duration of therapy for girls is 2 years from the start of interim maintenance; for boys, it is 3

years from the start of interim maintenance.

Most contemporary protocols include a continuation phase based on weekly orally administered

MTX given with daily, orally administered 6-MP, and monthly pulses of vincristine and a

glucocorticoid. Although these pulses improve outcomes, they are associated with avascular necrosis

of the bone and vincristine neuropathy, and the current Children's Oncology Group standard risk ALL

trial is evaluating whether these last 2 agents can be given every 3 months. A single-institution trial

has shown that patients with high-risk ALL may benefit from intensified continuation therapy that

includes the rotational use of drug pairs.

The use of continuous dexamethasone in adolescents has been associated with an unacceptably high

rate of osteonecrosis of the hips of around 40%,[17]

and this medication is therefore omitted from

induction and continuation therapy in older children.

Management of CNS Disease

Central nervous system (CNS) disease is divided into the following:

CNS 1 - Absence of blasts on cytospin preparation of cerebrospinal fluid (CSF), regardless ofthe number of white blood cells (WBCs)

CNS 2 - WBC count of less than 5/mL and blasts on cytospin findings, or WBC count of morethan 5/mL but negative by Steinherz-Bleyer algorithm findings* (if traumatic tap)

CNS 3 - WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs ofCNS leukemia, such as facial nerve palsy, brain/eye involvement, and hypothalamic

syndrome (Additional intrathecal therapy is only given for CNS 3 disease.)

*If the patient has blasts in the peripheral blood and thelumbar punctureis traumatic (containing

5/mL WBCs and blasts), treat as CNS 3 if the CSF WBC count divided by the CSF red blood cell (RBC)

count is greater than 2 times the blood WBC count divided by the blood RBC count.

Treatment of subclinical CNS leukemia is an essential component of acute lymphoblastic leukemia

therapy.

Cranial irradiation
http://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/80773-overviewhttp://emedicine.medscape.com/article/80773-overview


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Although cranial irradiation effectively prevents overt CNS relapse, concern about subsequent

neurotoxicity and brain tumors has led irradiation to be replaced with intensive intrathecal and

systemic chemotherapy for most patients. This strategy has produced excellent survival outcomes,

with CNS relapse rates of less than 2%.

Whether cranial irradiation is necessary for patients with very high-risk acute lymphoblastic

leukemia (patients with BCR-ABL or MLL gene rearrangements) is unclear. Pui et al conducted a

clinical trial in children with newly diagnosed acute lymphoblastic leukemia and determined that

prophylactic cranial irradiation can be safely omitted from treatment to avoid irradiation

consequences with effective risk-adjusted chemotherapy.[18]

The investigators reported that patients

who did not receive prophylactic cranial irradiation had significantly longer continuous complete

remission relative to historical controls. In addition, patients with CNS leukemia or traumatic lumbar

puncture with blast cells at diagnosis or those with a high level of minimal residual disease after 6

weeks of remission induction were significantly associated with poorer event-free survival.[18]

Risk

factors for CNS relapse included genetic abnormality, CNS involvement at diagnosis, and T-cell

immunophenotype.

Management of High-Risk Patients

Optimal treatment for patients with very high-risk acute lymphoblastic leukemia (ALL) has not been

determined; however, some centers recommend allogeneic stem cell transplantation (SCT) soon

after first remission is achieved. It is important to know that for the subset of patients with BCR-

ABL gene rearrangement, the addition of imatinib to intensified chemotherapy produced survival

results equivalent to allogeneic SCT.[19]

A review of 1041 patients with ALL and induction failure showed this population to be highlyheterogeneous in their clinical features. Those patients with T-cell ALL appeared to have a better

outcome with allogeneic stem-cell transplantation, whereas for patients with precursor B-cell ALL

and either an age of less than 6 years or high hyperdiploidy, the value of transplantation was less

certain.[20]

For patients without a matched family donor, transplantation of marrow from an unrelated donor

would therefore no longer be a reasonable treatment option for that subset, although it may be so

for other very-high-risk patients. Results of SCT, often reported from single institutions, have been

inconsistent and sometimes disappointing. Large, multi-institutional, controlled trials are clearly

needed to determine the effectiveness of this therapy for patients without a matched donor.

Treatment of Relapse

In general, relapsed acute lymphoblastic leukemia (ALL) cells acquire resistance to exposed

chemotherapy drugs. However, patients who relapse late (ie, 6 mo or longer after completion of

therapy) can often be re-treated with more intensive chemotherapy. Patients who relapse early

(ie, either during or just after completing therapy) may benefit from (SCT). It is very important that

patients who go for SCT have MRD of less than 0.1%; otherwise, they inevitably relapse. Overall, the

outcome of patients with relapse is poor.

Molecular Targeted Therapy


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A drug targeted at the underlying molecular defect that is unique to certain leukemias can have

potent and specific antileukemic activity while producing minimal toxicity to normal cells.[21]

The best example of molecular targeted therapy is imatinib mesylate, a selectiveBCR-ABL tyrosine

kinase inhibitor, that is standard front-line treatment for Ph-positive chronic myeloid leukemia

(CML). Combination regimens with imatinib and conventional chemotherapy have shown efficacy in

Ph-positive acute lymphoblastic leukemia, justifying its use as front-line therapy for Ph-positive

acute lymphoblastic leukemia[22, 19]

Imatinib is approved for children newly diagnosed with Ph+ ALL. Its approval was based on a trial

involving 92 patients in which children (1 year or older) and young adults were divided into 5 groups

to receive different durations of imatinib therapy along with conventional chemotherapy. Among

the 50 children receiving the longest duration of imatinib, the 4-year progression-free survival rate

was 70%. Increasing duration of imatinib therapy was associated with lower overall mortality.[19]

Genetic Studies and Future Challenges

More than 80% of children with acute lymphoblastic leukemia (ALL) now can be cured.[1]

However,

the cause of treatment failure in the remaining 20% of patients is largely unknown.

More recently, poor outcome has been correlated with alteration ofIKZF1, which encodes the

lymphoid transcription factor IKAROS.[23]

In addition, Janus kinase mutations have been associated

with a high risk of treatment failure.[24]

Because of the diverse nature of the disease, use of risk-directed therapy for all patients on the basis

of molecular and pharmacogenetic characterization of the leukemic cells at the time of diagnosis is

favored.

Studies using microarray gene expression, multiparameter flow-cytometry, quantitative reverse-

transcriptase polymerase chain reaction (RT-PCR), genomics, proteomics, and bioinformatics hold

promise for providing important clues to the mechanisms behind leukemogenesis and response and

resistance to therapy. Future goals include the use of these technologies to identify biologic subsets

of acute lymphoblastic leukemia that require specifically targeted therapies.

Consultations

Numerous consultations may be obtained, depending on the clinical circumstances of patients with

newly diagnosed acute lymphoblastic leukemia (ALL), including the following:

Pediatric oncologist: Refer all patients to a subspecialist to direct their care. Pediatric surgeon: Patients require placement of a central venous catheter. Psychosocial team: Involve psychologists and social workers in the care of patients with

acute lymphoblastic leukemia to aid them and their families in navigating all of the difficult

issues surrounding their care.


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Radiation oncologist: Consultation may be appropriate if there is extramedullary disease notresponding to induction therapy (eg, testicular involvement) or that associated with high-risk

disease (eg, CNS-3 in patients with T-lineage ALL).

Other subspecialists: Consultations with other specialists (ie, infectious disease specialist,nephrologist) may be appropriate, depending on the clinical circumstances.

Long-Term Monitoring

Frequent clinic visits are required to administer outpatient chemotherapy, to monitor blood counts,

and to evaluate new symptoms. In addition, all patients should be on trimethoprim-

sulfamethoxazole (TMP-SMZ) or a similar agent, such as monthly IV pentamidine, to

prevent Pneumocystis cariniipneumonia (PCP). Patients with infant leukemia may benefit from

being on oral fluconazole prophylaxis to reduce the risk of candidiasis.

Medication Summary

Drugs commonly used during remission induction therapy include dexamethasone or prednisone,

vincristine, asparaginase, and daunorubicin. Consolidation therapy often includes methotrexate

(MTX) and 6-mercaptopurine (6-MP) or cyclophosphamide and cytarabine. Drugs used for

intensification include cytarabine, cyclophosphamide, etoposide, dexamethasone, asparaginase,

doxorubicin, MTX, 6-MP, and vincristine. Continuation therapy is based on oral 6-MP and MTX with

pulses of vincristine and glucocorticoid (prednisone or dexamethasone). Intrathecal chemotherapy

includes primarily MTX, which may also be combined with hydrocortisone and cytarabine (triple-

intrathecal therapy). Imatinib is also approved for children newly diagnosed with Ph+ ALL.

It is important to note that corticosteroids can adversely suppress the function of the hypothalamic-

pituitary-adrenal (HPA) axis and such suppression can have adverse effects on a patient's ability to

respond to different stresses, such as severe infection. A Cochrane Database review of 7 studies

showed adrenal insufficiency occurred in nearly all ALL patients in the first days after cessation of

glucocorticoid therapy. Although the majority of patients recovered within a few weeks, a small

number of patients had adrenal insufficiency lasting up to 34 weeks.[25]

Antineoplastic Agents

Class Summary

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this

growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis

(ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie,

phase M).

Cell-division rates vary for different tumors. Most common cancers grow slowly compared with

normal tissues, and the rate may be decreased in large tumors. This difference allows normal cells to

recover from chemotherapy more quickly than malignant ones and is the rationale behind current

cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents act at specific phases of the cell

cycle, whereas others (ie, alkylating agents, anthracyclines, cisplatin) are not phase-specific. Cellular


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apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic

agents.

View full drug information

Vincristine (Vincasar PFS)

Vincristine is a chemotherapeutic agent derived from the periwinkle plant. This agent acts by

inhibiting microtubule formation in mitotic spindles, causing metaphase arrest.


Asparaginase (Elspar)

Extracts of Escherichia coli or Erwinia L-asparaginase impair asparagine synthesis. Asparaginase is

lethal to lymphoblasts that cannot synthesize the essential amino acid asparagine.


Asparaginase Erwinia chrysanthemi (Erwinaze)

Catalyzes deamidation of asparagine to aspartic acid and ammonia, thereby reducing circulating

levels of asparagine. Lack of asparagine synthetase activity results in cytotoxicity specific forleukemic cells that depend on an exogenous source of the amino acid asparagine. Indicated as part

of a multiagent chemotherapeutic regimen for patients with acute lymphoblastic leukemia (ALL)

who have developed hypersensitivity to E coliderived asparaginase. It is estimated that 15-20% of

patients with ALL develop a hypersensitivity to E coliderived asparaginase, which extrapolates to

approximately 450-600 children in the United States annually.


Daunorubicin (Cerubidine)

Daunorubicin is an anthracycline that intercalates with DNA and interferes with DNA synthesis.


Methotrexate (Trexall)

Methotrexate is a folate analogue that competitively inhibits dihydrofolate reductase, thus inhibiting

DNA, RNA, and protein synthesis.
http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/elspar-l-asparaginase-342099#1http://reference.medscape.com/drug/elspar-l-asparaginase-342099#1http://reference.medscape.com/drug/elspar-l-asparaginase-342099#1http://reference.medscape.com/drug/elspar-l-asparaginase-342099#1http://reference.medscape.com/drug/erwinaze-asparaginase-erwinia-chrysanthemi-999704#1http://reference.medscape.com/drug/erwinaze-asparaginase-erwinia-chrysanthemi-999704#1http://reference.medscape.com/drug/erwinaze-asparaginase-erwinia-chrysanthemi-999704#1http://reference.medscape.com/drug/erwinaze-asparaginase-erwinia-chrysanthemi-999704#1http://reference.medscape.com/drug/daunorubicin-342118#1http://reference.medscape.com/drug/daunorubicin-342118#1http://reference.medscape.com/drug/daunorubicin-342118#1http://reference.medscape.com/drug/daunorubicin-342118#1http://reference.medscape.com/drug/trexall-methotrexate-343201#1http://reference.medscape.com/drug/trexall-methotrexate-343201#1http://reference.medscape.com/drug/trexall-methotrexate-343201#1http://reference.medscape.com/drug/trexall-methotrexate-343201#1http://reference.medscape.com/drug/trexall-methotrexate-343201#1http://reference.medscape.com/drug/trexall-methotrexate-343201#1http://reference.medscape.com/drug/daunorubicin-342118#1http://reference.medscape.com/drug/daunorubicin-342118#1http://reference.medscape.com/drug/erwinaze-asparaginase-erwinia-chrysanthemi-999704#1http://reference.medscape.com/drug/erwinaze-asparaginase-erwinia-chrysanthemi-999704#1http://reference.medscape.com/drug/elspar-l-asparaginase-342099#1http://reference.medscape.com/drug/elspar-l-asparaginase-342099#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1


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Mercaptopurine (Purinethol)

Mercaptopurine is a synthetic purine analogue that kills cells by incorporating into DNA as a false

base.


Cytarabine

Cytarabine is a synthetic analogue of nucleoside deoxycytidine. This agent undergoes

phosphorylation to arabinofuranosyl-cytarabine-triphosphate (ara-CTP), a competitive inhibitor of

DNA polymerase.


Etoposide (Toposar)

Etoposide inhibits topoisomerase II and breaks DNA strands, causing cell proliferation to arrest in the

late S or early G2 portion of the cell cycle.


Cyclophosphamide

Cyclophosphamide is chemically related to the nitrogen mustards. When this drug is used as an

alkylating agent, the mechanism of action of its active metabolites may involve cross-linking of DNA,

which may interfere with the growth of normal and neoplastic cells.


Nelarabine (Arranon)

Nelarabine is a prodrug of 9-beta-D-arabinofuranosylguanine (ara-G). This agent is converted to the

active arabinofuranosyl-guanine-5'-triphosphate (ara-GTP), a T-cellselective nucleoside analogue.

Leukemic blast cells accumulate ara-GTP, which allows for incorporation into DNA, leading to

inhibition of DNA synthesis and cell death.

Nelarabine was approved by the US Food and Drug Administration [FDA] as an orphan drug to treat

T-cell lymphoblastic lymphoma (a type of non-Hodgkin lymphoma [NHL]) that does not respond orthat relapses with at least 2 chemotherapy regimens.
http://reference.medscape.com/drug/purinethol-6mercaptopurine-mercaptopurine-342094#1http://reference.medscape.com/drug/purinethol-6mercaptopurine-mercaptopurine-342094#1http://reference.medscape.com/drug/purinethol-6mercaptopurine-mercaptopurine-342094#1http://reference.medscape.com/drug/purinethol-6mercaptopurine-mercaptopurine-342094#1http://reference.medscape.com/drug/cytosar-u-depocyt-cytarabine-342089#1http://reference.medscape.com/drug/cytosar-u-depocyt-cytarabine-342089#1http://reference.medscape.com/drug/cytosar-u-depocyt-cytarabine-342089#1http://reference.medscape.com/drug/cytosar-u-depocyt-cytarabine-342089#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/arranon-nelarabine-342090#1http://reference.medscape.com/drug/arranon-nelarabine-342090#1http://reference.medscape.com/drug/arranon-nelarabine-342090#1http://reference.medscape.com/drug/arranon-nelarabine-342090#1http://reference.medscape.com/drug/arranon-nelarabine-342090#1http://reference.medscape.com/drug/arranon-nelarabine-342090#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/cytosar-u-depocyt-cytarabine-342089#1http://reference.medscape.com/drug/cytosar-u-depocyt-cytarabine-342089#1http://reference.medscape.com/drug/purinethol-6mercaptopurine-mercaptopurine-342094#1http://reference.medscape.com/drug/purinethol-6mercaptopurine-mercaptopurine-342094#1


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Clofarabine (Clolar)

Clofarabine is a purine nucleoside antimetabolite that inhibits DNA synthesis and is indicated for

relapsed or refractory acute lymphoblastic leukemia in pediatric patients. Pools of cellular

deoxynucleotide triphosphate are decreased by inhibiting ribonucleotide reductase and terminating

DNA chain elongation and repair. This agent also disrupts mitochondrial membrane integrity.


Imatinib (Gleevec)

Imatinib is a selective BCR-ABL tyrosine kinase inhibitor. It is approved for children newly diagnosed

with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Corticosteroids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects.

Corticosteroids modify the bodys immune response to diverse stimuli. These agents are significantly

toxic to lymphoblasts, and two thirds of patients with pediatric ALL who receive steroid therapy

alone go into remission.


Prednisone

Prednisone is a corticosteroid and an important chemotherapeutic agent in the treatment of acute

lymphoblastic leukemia (ALL). This agent is used in induction therapy and is also given as

intermittent pulses during continuation therapy.


Dexamethasone (Baycadron, Maxidex, Ozurdex)

Dexamethasone is another corticosteroid that acts as an important chemotherapeutic agent in the

treatment of ALL. Like prednisone, this agent is used in induction and reinduction therapy and is also

given as intermittent pulses during continuation therapy.

Antimicrobials

Class Summary
http://reference.medscape.com/drug/clolar-clofarabine-342196#1http://reference.medscape.com/drug/clolar-clofarabine-342196#1http://reference.medscape.com/drug/clolar-clofarabine-342196#1http://reference.medscape.com/drug/clolar-clofarabine-342196#1http://reference.medscape.com/drug/gleevec-imatinib-342239#1http://reference.medscape.com/drug/gleevec-imatinib-342239#1http://reference.medscape.com/drug/gleevec-imatinib-342239#1http://reference.medscape.com/drug/gleevec-imatinib-342239#1http://reference.medscape.com/drug/prednisone-intensol-342747#1http://reference.medscape.com/drug/prednisone-intensol-342747#1http://reference.medscape.com/drug/prednisone-intensol-342747#1http://reference.medscape.com/drug/prednisone-intensol-342747#1http://reference.medscape.com/drug/decadron-dexamethasone-intensol-dexamethasone-342741#1http://reference.medscape.com/drug/decadron-dexamethasone-intensol-dexamethasone-342741#1http://reference.medscape.com/drug/decadron-dexamethasone-intensol-dexamethasone-342741#1http://reference.medscape.com/drug/decadron-dexamethasone-intensol-dexamethasone-342741#1http://reference.medscape.com/drug/decadron-dexamethasone-intensol-dexamethasone-342741#1http://reference.medscape.com/drug/decadron-dexamethasone-intensol-dexamethasone-342741#1http://reference.medscape.com/drug/prednisone-intensol-342747#1http://reference.medscape.com/drug/prednisone-intensol-342747#1http://reference.medscape.com/drug/gleevec-imatinib-342239#1http://reference.medscape.com/drug/gleevec-imatinib-342239#1http://reference.medscape.com/drug/clolar-clofarabine-342196#1http://reference.medscape.com/drug/clolar-clofarabine-342196#1


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Prophylactic antimicrobial drugs are given to prevent infection in patients receiving chemotherapy.


Sulfamethoxazole and trimethoprim (Septra, Bactrim)

Sulfamethoxazole and trimethoprim inhibits bacterial growth by inhibiting synthesis of dihydrofolic

acid. All immunocompromised patients can be given cotrimoxazole to prevent Pneumocystis carinii

pneumonia (PCP).


Pentamidine

Immunocompromised patients who do not tolerate cotrimoxazole due to myelosuppression may

receive IV pentamidine to prevent Pneumocystis carinii pneumonia (PCP).

Antifungals

Class Summary

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


Fluconazole

Fluconazole may be used in patients at high risk (eg, infant ALL) to prevent fungal infections. It is a

synthetic triazole that inhibits fungal cell growth by inhibiting CYP-dependent synthesis of

ergosterol, a vital component of fungal cell membranes.
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