Acute Lymphoblastic Leukemia

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eMedicine Specialties > Pediatrics: General Medicine > Oncology

Acute Lymphoblastic LeukemiaNoriko Satake, MD, Assistant Professor, Pediatric Hematology/Oncology, University of California Davis School of Medicine, Davis Medical

Center

Janet M Yoon, MD, Assistant Clinical Professor, Department of Pediatrics, Hematology/Oncology, University of California Davis Medical

Center

Updated: Apr 6, 2010

Introduction

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 lymphoblasticleukemia is approximately 9-10 cases per 100,000 population in childhood.[1 ]The peak incidenceoccurs in children aged 2-5 years.

Although a few cases are associated with inherited genetic syndromes (ie, Down syndrome,Bloom syndrome, Fanconi anemia), the cause remains largely unknown. Many environmentalfactors (ie, exposure to ionizing radiation and electromagnetic fields, parental use of alcohol andtobacco) have been investigated as potential risk factors, but none has been definitively shown tocause acute lymphoblastic leukemia. Various viruses may be linked to the development ofleukemia, particularly when prenatal viral exposure occurs in mothers recently infected withinfluenza or varicella. However, no direct link has been established between viral exposure and thedevelopment of leukemia.

Acute lymphoblastic leukemia may also occur in children with various congenitalimmunodeficiencies (ie, Wiskott-Aldrich syndrome, congenital hypogammaglobulinemia, ataxia-telangiectasia) that have an increased predisposition to develop lymphoid malignancies.

With improvements in diagnosis and treatment, overall cure rates for children with acutelymphoblastic leukemia now approach 80%. Further refinements in therapy, including the use ofrisk-adapted treatment protocols, may improve cure rates for patients at high risk while limiting thetoxicity of therapy for patients with a low risk of relapse. This article summarizes advances in thediagnosis and treatment of childhood acute lymphoblastic leukemia.

Pathophysiology

In acute lymphoblastic leukemia, a lymphoid progenitor cell becomes genetically altered andsubsequently undergoes dysregulated proliferation, survival, and clonal expansion. In most cases,the pathophysiology of transformed lymphoid cells reflects the altered expression of genes whoseproducts contribute to the normal development of B cells and T cells. Several studies indicate thatleukemic stem cells are present in certain types of acute lymphoblastic leukemia.

Frequency

United States

Annually, 2500-3500 children are diagnosed with acute lymphoblastic leukemia.

1/4/2011 Acute Lymphoblastic Leukemia: [P…

…medscape.com/…/990113-print 1/30

International

Throughout the world, the incidence rate is thought to be similar to that in the United States.

Mortality/Morbidity

Overall cure rates for children with acute lymphoblastic leukemia now approach 80%. The 4-yearevent-free survival (EFS) rate for high-risk patients is approximately 65%.

Race

The overall incidence of acute lymphoblastic leukemia varies among different racial groups withinthe United States. White children are more frequently affected than black children.

Sex

Acute lymphoblastic leukemia occurs slightly more frequently in boys than in girls. This difference ismost pronounced for T-cell acute lymphoblastic leukemia.

Age

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

Clinical

History

Children with acute lymphoblastic leukemia (ALL) generally present with signs and symptoms thatreflect bone marrow infiltration and extramedullary disease. Because leukemic blasts replace thebone marrow, patients present with signs of bone marrow failure, including anemia,thrombocytopenia, and neutropenia. Clinical manifestations include fatigue, pallor, petechiae,bleeding, and fever. In addition, leukemic spread may manifest as lymphadenopathy andhepatosplenomegaly. Other signs and symptoms of leukemia include weight loss, bone pain, anddyspnea.

Signs or symptoms of CNS involvement (eg, headache, nausea and vomiting, lethargy, irritability,nuchal rigidity, papilledema) are rarely observed at the time of initial diagnosis. Cranial nerveinvolvement, which most frequently involves the seventh, third, fourth, and sixth cranial nerves, mayoccur. Also, leukemia can present as an intracranial or spinal mass, which causes numerousneurologic symptoms, most of which are due to nerve compression.

Testicular involvement at diagnosis is rare. However, if present, it appears as painless testicularenlargement and is most often unilateral.

Physical

Physical findings in children with acute lymphoblastic leukemia reflect bone marrow infiltration andextramedullary disease. Patients present with pallor caused by anemia, and petechiae andbruising secondary to thrombocytopenia. They also have signs of infection because of neutropenia.In addition, leukemic spread may be seen as lymphadenopathy and hepatosplenomegaly.

Careful neurologic examination to look for CNS involvement is important because of differences intreatment for leukemia with CNS involvement.

In male patients, testicular examination is necessary to look for testicular involvement of leukemia.



Causes

Although a small percentage of cases are associated with inherited genetic syndromes, the causeof acute lymphoblastic leukemia remains largely unknown.

Differential Diagnoses

Acute Myelocytic Leukemia Non-Hodgkin Lymphoma

Anemia, Acute Osteomyelitis

Anemia, Fanconi Parvovirus B19 Infection

Juvenile Rheumatoid Arthritis Rhabdomyosarcoma

Leukocytosis

Mononucleosis and Epstein-Barr Virus Infection

Neuroblastoma

Other Problems to Be Considered

Aplastic anemiaIdiopathic thrombocytopenic purpura (ITP)

Workup

Laboratory Studies

The following studies are indicated in acute lymphoblastic leukemia (ALL):

Basic laboratory tests

Upon initial evaluation, obtain a CBC count. A hematologist or hematopathologist mustevaluate the peripheral smear for the presence and morphology of lymphoblasts. Anelevated leukocyte count of more than 10 X 109/L (>10 X 103/µL) occurs in one half ofpatients with acute lymphoblastic leukemia. Neutropenia, anemia, andthrombocytopenia may be observed secondary to inhibition of normal hematopoiesisby leukemic infiltration. Rare cases of acute lymphoblastic leukemia may initiallymanifest with pancytopenia.

Various metabolic abnormalities may include increased serum levels of uric acid,potassium, phosphorus, calcium, and lactate dehydrogenase (LDH). The degree ofabnormality reflects the leukemic cell burden and destruction (lysis). Although notuniversally performed, coagulation studies can be helpful, including tests of theprothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level,and D-dimer level to assess for disseminated intravascular coagulation; these studiesare particularly important in a child who is acutely toxic.

Immunophenotyping

Complete morphologic, immunologic, and genetic examination of the leukemic cells isnecessary to establish the diagnosis of acute lymphoblastic leukemia.

An important advancement in the classification of acute lymphoblastic leukemia wasthe observation that malignant lymphoblasts share many of the features of normallymphoid progenitors. Acute lymphoblastic leukemia cells rearrange their

immunoglobulin and T-cell receptor (TCR) genes and express antigen receptormolecules in ways that correspond to such processes in normal developing B and T



lymphocytes. However, leukemic lymphoblasts can also have aberrant gene expressionwith resultant phenotypes that differ from those of normal lymphocyte progenitors.Nevertheless, acute lymphoblastic leukemia can be broadly classified as B-lineage orT-lineage acute lymphoblastic leukemia.

The diagnosis of B-cell leukemia, which accounts for only about 3% of acutelymphoblastic leukemia cases, depends on the detection of surface immunoglobulin onleukemic blasts. Lymphoblasts with this phenotype have a distinctive morphology, withdeeply basophilic cytoplasm containing prominent vacuoles. This morphologic patternis designated L3 in the French-American-British (FAB) system (see HistologicFindings). Prominent clinical features include extramedullary lymphomatous masses inthe abdomen or head and neck, and frequently involve the CNS.

Approximately 80% of childhood acute lymphoblastic leukemia involves lymphoblastswith phenotypes that correspond to those of B-cell progenitors. These cases can beidentified by their cell-surface expression of 2 or more B-lineage–associated antigens(ie, CD19, CD20, CD24, CD22, CD21, or CD79). Only CD79 is specific for B-lineageacute lymphoblastic leukemia. In addition, about one fourth of B-cell precursor casesexpress cytoplasmic immunoglobulin µ heavy-chain proteins and are designated pre–B-cell acute lymphoblastic leukemia. Cases related to B-cell precursors can besubclassified as early pre–B-cell, pre–B-cell, or transitional pre–B-cell cases. Althoughmature B-cell acute lymphoblastic leukemia should be differentiated from B-precursorcases, distinguishing the subtypes of B-precursor acute lymphoblastic leukemia isprobably not clinically relevant.

T-cell acute lymphoblastic leukemia is identified by the expression of T-cell–associatedsurface antigens, of which cytoplasmic CD3 is specific. T-cell acute lymphoblasticleukemia cases can be classified by early, mid, or late thymocytes. Clinical featuresmost closely associated with T-cell acute lymphoblastic leukemia are high bloodleukocyte counts and CNS involvement. About one half of patients have a mediastinalmass at the time of diagnosis. The prognosis of patients with T-cell acute lymphoblasticleukemia has historically been worse than that of patients with B-lineage acutelymphoblastic leukemia. However, the outlook for patients with T-cell leukemia hasimproved to nearly that of precursor B-cell acute lymphoblastic leukemia when intensivechemotherapy is used.

Cytogenetic and molecular diagnosis

In more than 90% of acute lymphoblastic leukemia cases, specific genetic alterationscan be found in the leukemic blasts. These alterations include changes in chromosomenumber (ploidy) and structure; about half of all childhood acute lymphoblastic leukemiainvolves recurrent translocations. Standard cytogenetic analysis is an essential tool inthe workup of all patients with leukemia because the karyotype of the leukemic cellshas important diagnostic, therapeutic, and prognostic implications. In addition,molecular techniques, including fluorescence in situ hybridization (FISH), reversetranscriptase-polymerase chain reaction (RT-PCR), and Southern blot analysis helpimprove diagnostic accuracy. Molecular analysis can be used to identify translocationsnot detected on routine karyotype analysis and to distinguish lesions that appearcytogenetically identical but are molecularly different.

Common chromosomal abnormalities in acute lymphoblastic leukemia include t(9;22)(q34;q11) or BCR-ABL, t(1;19)(q23;p13) or E2A-PBX1, t(12;21)(p13;q22) or TEL-AML1, MLL rearrangements, hyperdiploidy (>50 chromosomes/cell), and hypodiploidy(<44 chromosomes/cell). In general, BCR-ABL, t(4;11) with MLL-AF4, and



hypodiploidy confer a poor outcome, whereas hyperdiploidy, TEL-AML1, and trisomy4, trisomy 10, and trisomy 17 are associated with favorable outcomes.

Minimal residual disease (MRD)

Traditionally, the response to leukemia treatment has been assessed morphologically.However, this method can be challenging when dealing with small numbers of leukemiccells, and due to difficulties distinguishing leukemic from normal cells in bone marrowspecimens recovering from chemotherapy or after transplant.

Although still experimental, molecular analysis appears to play a promising role in thediagnosis and treatment of acute lymphoblastic leukemia and in monitoring patients'responses to therapy.

Studies of MRD may be based on the detection of chimeric transcripts generated by

fusion genes, the detection of clonal TCR or immunoglobulin heavy-chain (IgH) generearrangements, 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 sensitivitythan that of morphology. All studies using MRD techniques have shown significantcorrelations between end-of-induction leukemia burden and outcome. As a result,current treatment protocols are using MRD measurements for acute lymphoblasticleukemia risk assignment.[3 ]

Risk assessment: Current risk assessment includes clinical features (age and WBC count atdiagnosis), biological characteristics of the leukemic blasts, response to the inductionchemotherapy, and MRD burden. Current studies are ongoing to assess an optimaltreatment for each leukemia group with different risks. Future goals include increasedunderstanding of the molecular pathways leading to specific phenotypes, minimizing the riskof relapse by identifying subsets of patients requiring more intensive therapy, and minimizingthe toxicity for those patients with a high likelihood of cure using currently available therapies.

Imaging Studies

Chest radiography: Evaluate for a mediastinal mass. In general, no other imaging studies arerequired. However, if the physical examination reveals enlarged testes, performultrasonography to evaluate for testicular infiltration.

Testicular ultrasonography: Perform testicular ultrasonography if the testes are enlarged uponphysical examination.

Renal ultrasonography: Some clinicians prefer to evaluate for leukemic kidney involvementas an assessment of risk for tumor lysis syndrome.

Echocardiography and ECG: Obtain an echocardiogram and an ECG before anthracyclinesare administered.

Procedures

Bone marrow aspirate and biopsy: The results confirm the diagnosis of acute lymphoblasticleukemia. In addition, special stains (immunohistochemistry), immunophenotyping,cytogenetic analysis, and molecular analysis help in classifying each case. See the imagesbelow 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.

Lumbar puncture with cytospin morphologic analysis: These tests are performed beforesystemic chemotherapy is administered to assess for CNS involvement and to administerintrathecal chemotherapy.

Histologic Findings

According to the French-American-British (FAB) classification system, acute lymphoblasticleukemia is classified into 3 groups based on morphology.

L1: Cells are usually small, with scant cytoplasm and inconspicuous nucleoli. L1 accounts for85% of all cases of childhood acute lymphoblastic leukemia.

L2: Cells are larger than in L1. The cells demonstrate considerable heterogeneity in size, withprominent nucleoli, and abundant cytoplasm. L2 accounts for 14% of all childhood acutelymphoblastic leukemia.

L3: Cells are large and notable for their deep cytoplasmic basophilia. They frequently haveprominent cytoplasmic vacuolation and are morphologically identical to Burkitt lymphomacells. 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) becausecurrent standard diagnosis is based on immunophenotype and molecular techniques.

Treatment

Medical Care

Because leukemia is a systemic disease, therapy is primarily based on chemotherapy. Differentforms of acute lymphoblastic leukemia require different approaches for optimal results. Excludingmature B-cell acute lymphoblastic leukemia which is treated with short-term intensive



chemotherapy, including high-dose methotrexate (MTX), cytarabine, and cyclophosphamide, acutelymphoblastic leukemia treatment typically consists of a remission-induction phase, intensification(consolidation) phase, and continuation therapy targeted at eliminating residual disease. Theaddition of cyclophosphamide and intensive treatment with asparaginase is also beneficial in thetreatment of T-cell acute lymphoblastic leukemia.

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 thesystemic and rapid release of intracellular contents as chemotherapy destroysleukemic blasts. Because some cells can die before therapy, such metabolic changescan occur even before therapy begins.

Primary features of tumor lysis syndrome include hyperuricemia (due to metabolism ofpurines), hyperphosphatemia, hypocalcemia, and hyperkalemia. The hyperuricemiacan lead to crystal formation with tubular obstruction and, possibly, acute renal failurerequiring dialysis. Therefore, electrolyte and uric acid levels should be closelymonitored throughout initial therapy.

To prevent complications of tumor lysis syndrome, patients should initially receiveintravenous (IV) fluids at twice the maintenance rates, usually without potassium.

Sodium bicarbonate is added to the IV fluid to achieve moderate alkalinization ofthe urine (pH level, 7.5-8) to enhance the excretion of phosphate and uric acid. Aurine pH level higher than this should be avoided to prevent crystallization ofhypoxanthine or calcium phosphate.The standard treatment for malignancy-associated hyperuricemia also includesallopurinol. By blocking the enzyme xanthine oxidase, allopurinol blocks uric acidformation. Patients at high risk for tumor lysis still need to excrete preexisting uricacid, which is unaffected by the use of allopurinol.Rasburicase, a recombinant urate oxidase, has demonstrated increased efficacyin pediatric patients at high risk for tumor lysis by catalyzing the enzymaticoxidation of uric acid to a much more urine soluble product, allantoin.

Phases of therapy

The treatment of childhood acute lymphoblastic leukemia, with the exception of B-cellacute lymphoblastic leukemia, has 5 components: induction, consolidation, interimmaintenance, delayed intensification, and maintenance. The goal of induction is toachieve remission or less than 5% blasts in the bone marrow. Induction therapygenerally consists of 3-4 drugs, which may include a glucocorticoid, vincristine,asparaginase, and possibly an anthracycline. This type of therapy induces completeremission based on morphology in more than 98% of patients. However, themeasurement of minimal residual disease (MRD) by flow cytometry or polymerasechain reaction has been shown to be much more specific and sensitive thanmorphologic examination of blast cells.

The current childhood acute lymphoblastic leukemia clinical trials have incorporatedMRD as a criterion for determining rapid early responder versus slow early responderstatus during induction chemotherapy. Based on MRD measurements, treatment maybe intensified in patients with high amounts of residual blasts (>1%).

Consolidation therapy is given soon after remission is achieved to further reduce theleukemic cell burden before the emergence of drug resistance and relapse in sanctuarysites (ie, testes, CNS). In this phase of therapy, the drugs are given at doses higher



than those used during induction or the patient is given different drugs (ie, high-doseMTX and 6-mercaptopurine [6-MP]), epipodophyllotoxins with cytarabine, or multiagentcombination therapy. Consolidation therapy also appears to improve the long-termsurvival of patients with standard-risk disease. The addition of intensive reinductiontherapy after the completion of the induction phase is similarly beneficial for patients inboth risk groups.

In interim maintenance, oral medications are administered to maintain remission andallow the bone marrow to recover. This occurs for 4 weeks and is followed by delayedintensification, which is aimed at treating any remaining resistant leukemia cells.

The last phase of treatment is maintenance. This consists of intrathecal MTX every 3months, monthly vincristine, daily 6-MP and weekly MTX.

Duration of therapy

Whereas B-cell acute lymphoblastic leukemia is treated with a 2-month to 8-monthcourse of intensive therapy, achieving acceptable cure rates for patients with B-precursor and T-cell acute lymphoblastic leukemia requires approximately 2-2.5 yearsof continuation therapy. Attempts to reduce this time result in high relapse rates aftertherapy is stopped. In the current acute lymphoblastic leukemia clinical trials, the totalduration of therapy for girls is 2 years from the start of interim maintenance and is 3years from the start of interim maintenance for boys.

Most contemporary protocols include a continuation phase based on weeklyparenterally administered MTX given with daily, orally administered 6-MP interruptedby monthly pulses of vincristine and a glucocorticoid. Although these pulses improveoutcomes, they are associated with avascular necrosis of the bone. Patients with high-risk acute lymphoblastic leukemia may also benefit from intensified continuationtherapy that includes the rotational use of drug pairs.

Improvements in relapse-free survival gained by intensification with anthracyclines orepipodophyllotoxins must be weighed against the late sequelae of these agents, whichinclude cardiotoxicity and treatment-related acute myeloid leukemia.

CNS disease

CNS disease is divided into the following:CNS 1 - Absence of blasts on cytospin preparation of cerebrospinal fluid (CSF),regardless of the number of WBCsCNS 2 - WBC count of less than 5/mL and blasts on cytospin findings, or WBCcount of more than 5/mL but negative Steinherz-Bleyer algorithm findings (used toassess traumatic taps)CNS 3 - WBC count of 5/mL or more and blasts on cytospin findings and/orclinical signs of CNS leukemia such as facial nerve palsy, brain/eye involvement,and hypothalamic syndrome (Additional intrathecal therapy is only given for CNS3 disease.)

If the patient has blasts in the peripheral blood and the lumbar puncture is traumatic(containing >5/mL WBCs and blasts), CNS disease (CNS 3) is present if CSF WBCcount divided by the CSF RBC count is more than 2 times blood WBC count divided bythe blood RBC count.

Treatment of subclinical CNS leukemia is an essential component of acutelymphoblastic leukemia therapy.

Although cranial irradiation effectively prevents overt CNS relapse, concern about



subsequent neurotoxicity and brain tumors has led many investigators to replaceirradiation with intensive intrathecal and systemic chemotherapy for most patients. Thisstrategy has produced excellent survival outcomes, with CNS relapse rates of less than2% in some studies.

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

lymphoblastic leukemia (patients with BCR-ABL or MLL gene rearrangements) isunclear.

Pui et al conducted a clinical trial in children with newly diagnosed acute lymphoblasticleukemia to determine if prophylactic cranial irradiation can be safely omitted fromtreatment to avoid irradiation consequences with effective risk-adjustedchemotherapy.[4 ]

The duration of continuous complete remission in 71 of 498 patients whopreviously would have received prophylactic cranial irradiation was comparedwith that of 56 historical controls who received irradiation. The 71 patients hadsignificantly longer continuous complete remission than the 56 historical controls(P=0.04).Certain populations were significantly associated with poorer event-free survival(ie, CNS leukemia or traumatic lumbar puncture with blast cells at diagnosis, highlevel of minimal residual disease after 6 wk of remission induction).Risk factors for CNS relapse include genetic abnormality, CNS involvement atdiagnosis, and T-cell immunophenotype.The researchers concluded that prophylactic cranial irradiation can be safelyomitted in many children with acute lymphoblastic leukemia.

High-risk patients

Optimal treatment for patients with very high-risk acute lymphoblastic leukemia has notbeen found.

Some centers recommend allogeneic stem-cell transplantation (SCT) soon after firstremission is achieved. For patients without a matched family donor, transplantation ofmarrow from an unrelated donor is a reasonable treatment option. Results of SCT,often reported from single institutions, have been inconsistent and sometimesdisappointing. Large, multi-institutional, controlled trials are clearly needed todetermine the effectiveness of this therapy for patients without a matched donor.

Treatment of relapse: In general, relapsed acute lymphoblastic leukemia cells acquireresistance to exposed chemotherapy drugs. Therefore, treatment of relapse is intensive andoften includes SCT. However, the outcome of relapse is poor.

Molecular targeted therapy

A drug targeted at the underlying molecular defect that is unique to certain leukemiascan have potent and specific antileukemic activity while producing minimal toxicity tonormal cells.

The best example of molecular targeted therapy is imatinib mesylate, a selective BCR-

ABL tyrosine kinase inhibitor.Imatinib has demonstrated significant anti-leukemic activity and is now astandard front-line treatment for Ph-positive chronic myeloid leukemia(CML).[5,6,7,8 ]

Imatinib has shown efficacy in Ph-positive acute lymphoblastic leukemia, andcombination regimens with imatinib and conventional chemotherapy or SCT have



been evaluated in clinical trials.Because the poor prognosis of Ph-positive acute lymphoblastic leukemia hasbeen related to a slow response to induction therapy, imatinib has been addedduring early treatment phases to improve therapeutic response. Adult data in Ph-positive acute lymphoblastic leukemia has demonstrated excellent results usingthis approach.Imatinib has been shown to be safe and efficacious in children with advanced Ph-positive acute lymphoblastic leukemia, raising the possibility of incorporating itsuse into front-line therapy prior to SCT. Although some evidence suggests thisapproach could improve overall outcome, the low incidence of childhood Ph-positive acute lymphoblastic leukemia (2-4% of childhood acute lymphoblasticleukemia cases) makes evaluating its efficacy in a randomized trial difficult.

Genetic studies and future challenges

More than 80% of children with acute lymphoblastic leukemia now can be cured.However, the cause of treatment failure in the remaining 20% of patients is largelyunknown.

Because of the diverse nature of the disease, use of risk-directed therapy for allpatients on the basis of molecular and pharmacogenetic characterization of theleukemic cells at the time of diagnosis is favored.

Studies using microarray gene expression analysis, improved multiparameter flow-cytometric analysis, quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), genomics, proteomics and sophisticated bioinformatics hold promise forproviding important clues to the mechanisms behind leukemogenesis and responseand resistance to current therapies. Future goals include the use of these technologiesto identify additional biologic subsets of acute lymphoblastic leukemia that requirespecifically targeted therapies.

Surgical Care

Surgical care is generally not required in the treatment of acute lymphoblastic leukemia, except forthe placement of a central venous catheter. Such catheters are used for administeringchemotherapy, blood products, and antibiotics, and for obtaining blood samples.

Consultations

Numerous consultations should be obtained, depending on the clinical circumstances of patientswith newly diagnosed acute lymphoblastic leukemia.

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 withacute lymphoblastic leukemia to aid them and their families in navigating all of the difficultissues surrounding their care.

Radiation oncologist: Depending on their risk group, some patients require craniospinalradiation as part of the treatment plan.

Other subspecialists: Consultations with other specialists (ie, infectious disease specialist,



nephrologist) may be appropriate, depending on the clinical circumstances.

Diet

Because of the use of MTX, avoid folate supplementation.

Medication

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). Drugs used for intensification or continuation includecytarabine, cyclophosphamide, etoposide, dexamethasone, asparaginase, doxorubicin, MTX, 6-MP, and vincristine. Intrathecal chemotherapy includes MTX, hydrocortisone, and cytarabine.

Antineoplastics agents

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect thisgrowth. 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 withnormal tissues, and the rate may be decreased in large tumors. This difference allows normal cellsto recover from chemotherapy more quickly than malignant ones and is the rationale behind currentcyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are specific to phases of thecell cycle, whereas others (ie, alkylating agents, anthracyclines, cisplatin) are not. Cellularapoptosis (ie, programmed cell death) is another potential mechanism of many antineoplasticagents.

Prednisone (Deltasone)

Corticosteroid. Important chemotherapeutic agent in treatment of ALL. Used in induction andreinduction therapy. Also given as intermittent pulses during continuation therapy.

Dosing

Adult

20-25 mg PO tid

Pediatric

40 mg/m2/d PO divided tid

Interactions

May potentiate thrombogenic effects of asparaginase; barbiturates, phenytoin; rifampin maydecrease effectiveness

Contraindications

Documented hypersensitivity; serious infections (excluding meningitis and septic shock) and fungalinfections; varicella infections



Precautions

Pregnancy

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

Precautions

Gradual tapering of dose required after prolonged treatment (ie, >2 wk); toxicity includes fluidretention, hypertension, increased appetite, transient diabetes, acne, striae, personality changes,peptic ulcer, immunosuppression, osteoporosis, growth retardation; caution in diabetes, fungalinfections, and osteonecrosis

Dexamethasone (Decadron, Dexone)

Corticosteroid. Important chemotherapeutic agent in treatment of ALL. Used in induction andreinduction therapy. Also given as intermittent pulses during continuation therapy.

Dosing

Adult

6-8 mg/m2/d PO divided tid

Pediatric

Administer as in adults

Interactions

May potentiate thrombogenic effects of asparaginase; barbiturates, phenytoin; rifampin maydecrease effectiveness

Contraindications

Documented hypersensitivity; serious infections (excluding meningitis and septic shock) and fungalinfections; varicella infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may useif benefits outweigh risk to fetus

Precautions

Gradually taper after prolonged use; adverse effects include gastritis, hypertension, hyperglycemia,salt and water retention, personality changes, growth retardation, osteoporosis; caution in diabetesand osteonecrosis

Vincristine (Oncovin, Vincasar)

Chemotherapeutic agent derived from periwinkle plant. Inhibits microtubule formation in mitoticspindle, causing metaphase arrest.

Dosing



Adult

Induction therapy: 2 mg IV qwkContinuation therapy: 2 mg IV every mo

Pediatric

1.5 mg/m2 IV; not to exceed 2 mg/dose

Interactions

Acute pulmonary reaction may occur with concurrent mitomycin-C; asparaginase, cytochromeP450 (CYP) 3A4 inhibitors (eg, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir),granulocyte-macrophage colony-stimulating factor (GM-CSF, eg, sargramostim, filgrastim), ornifedipine increase toxicity; CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital,rifampin) may decrease effects; zidovudine increases risk of bone marrow suppression

Contraindications

Documented hypersensitivity; demyelinating form of Charcot-Marie-Tooth syndrome; intrathecaladministration

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Peripheral neuropathy manifested by constipation, ileus, ptosis, vocal cord paralysis, jaw pain,abdominal pain, loss of deep tendon reflexes; reduce dosage with severe peripheral neuropathy;bone marrow depression; local ulceration with extravasation, syndrome of inappropriateantidiuretic hormone secretion (SIADH)

Asparaginase (Elspar, Kidrolase)

Extracts of Escherichia coli or Erwinia L-asparaginase impair asparagine synthesis. Lethal to cellsthat cannot synthesize essential amino acid asparagine.

Dosing

Adult

Induction therapy: 6000-25,000 U/m2 IM 3 times/wkContinuation therapy: Administer qwk

Pediatric


Interactions

Possible inhibition of MTX effect; possible increased toxicity with vincristine or prednisone

Contraindications

Documented hypersensitivity; history of pancreatitis



Precautions

Pregnancy


Precautions

Hypersensitivity reactions with local rash, hives, anaphylaxis; bone marrow depression,hyperglycemia, hepatotoxicity, and bleeding may occur

Daunorubicin (Cerubidine)

Anthracycline that intercalates with DNA and interferes with DNA synthesis.

Dosing

Adult

25 mg/m2 IV qwk during induction therapy

Pediatric


Interactions

Coadministration of trastuzumab increases cardiotoxic effects

Contraindications

Documented hypersensitivity; congestive heart failure, arrhythmias, or cardiopathy

Precautions

Pregnancy


Precautions

Myelosuppression and thrombocytopenia; may cause cardiac arrhythmias immediately afteradministration and cardiomyopathy after long-term use; nausea, vomiting, stomatitis, and alopecia;extravasation may occur, resulting in severe tissue necrosis; caution in impaired hepatic, renal, orbiliary function

Methotrexate (Folex PFS, MTX)

Folate analog that competitively inhibits dihydrofolate reductase, inhibiting DNA, RNA, and proteinsynthesis.

Dosing

Adult

20-8000 mg/m2 PO/IV/IM qwk to every mo, depending on protocol

Pediatric




Interactions

Concurrent PO aminoglycosides may decrease absorption and blood levels; charcoal lowerslevels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivativescontained in some vitamins may decrease response; coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may be fatal; indomethacin and phenylbutazone can increaseplasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, andsulfonamides, including trimethoprim-sulfamethoxazole (TMP-SMZ), may increase effects andtoxicity; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism, hepatic insufficiency, documented immunodeficiencysyndromes, preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia,thrombocytopenia, significant anemia)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if blood countssubstantially decrease; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly;increased toxicity with NSAIDs, including salicylates, not tested

Mercaptopurine (Purinethol, 6-MP)

Synthetic purine analog that kills cells by incorporating into DNA as false base.

Dosing

Adult

50-75 mg/m2/dose PO qd

Pediatric


Interactions

Increased toxicity with allopurinol; increased hepatic toxicity when combined with doxorubicin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy


Precautions



Renal or hepatic impairment; high risk of pancreatitis; monitor for myelosuppression

Cytarabine (Cytosar-U)

Synthetic analog of nucleoside deoxycytidine. Undergoes phosphorylation to arabinofuranosyl-cytarabine-triphosphate (ara-CTP), competitive inhibitor of DNA polymerase.

Dosing

Adult

Induction therapy: 300-3000 mg/m2 IV qidContinuation therapy: <qmo

Pediatric


Interactions

Decreased effects of gentamicin and flucytosine; increased toxicity with other alkylating agents andradiation

Contraindications

Documented hypersensitivity; cerebellar toxicity

Precautions

Pregnancy


Precautions

Severe leukopenia and thrombocytopenia; immunosuppression, nausea, vomiting, anorexia,stomatitis, GI ulceration, fever, alopecia, and rash; cerebellar toxicity and ataxia may develop

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and breaks DNA strands, causing cell proliferation to arrest in late S orearly G2 portion of cell cycle.

Dosing

Adult

300 mg/m2 IV, frequency depends on protocol; often not used

Pediatric


Interactions

May prolong effects of warfarin and increase clearance of MTX; with cyclosporine, has additiveeffects on cytotoxicity of tumor cells

Contraindications



Documented hypersensitivity; IT administration may cause death

Precautions

Pregnancy


Precautions

Myelosuppression; secondary acute myeloid leukemia

Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of activemetabolites may involve cross-linking of DNA, which may interfere with growth of normal andneoplastic cells.

Dosing

Adult

Induction therapy: 300-1000 mg/m2 IV onceContinuation therapy: <qmo

Pediatric


Interactions

Possibly increased risk of bleeding or infection and enhanced myelosuppressive effects withcoadministration of allopurinol; may potentiate doxorubicin-induced cardiotoxicity; may reducedigoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants;coadministration with high doses of phenobarbital may increase rate of metabolism andleukopenic activity of cyclophosphamide; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity.

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy


Precautions

Alopecia, nausea, vomiting, stomatitis, diarrhea, myelosuppression, immunosuppression,hemorrhagic cystitis, SIADH; may cause sterility in male patients

Nelarabine (Arranon)

Prodrug of deoxyguanosine analog 9-beta-D-arabinofuranosylguanine (ara-G). Converted to active



5'-triphosphate, arabinofuranosyl-guanine-5'-triphosphate (ara-GTP), T-cell–selective nucleosideanalog. Leukemic blast cells accumulate ara-GTP. This allows for incorporation into DNA, leadingto inhibition of DNA synthesis and cell death.Approved by US Food and Drug Administration [FDA] as orphan drug to treat T-cell lymphoblasticlymphoma (type of non-Hodgkin lymphoma [NHL]) that does not respond or that relapsing with atleast 2 chemotherapy regimens.

Dosing

Adult

1500 mg/m2 IV (infuse over 2 h) on days 1, 3, and 5; repeat q21d

Pediatric

650 mg/m2 IV (infuse over 1 h) qd for 5 consecutive days; repeat q21d

Interactions

None reported

Contraindications


Precautions

Pregnancy

D - Fetal risk shown; may use if benefits outweigh risk to fetus.

Precautions

Common adverse effects include hematologic toxicity (eg, leukopenia, thrombocytopenia, anemia,neutropenia), hypokalemia, hypoalbuminemia, hyperbilirubinemia, fatigue, nausea, vomiting, anddiarrhea; severe neurologic events reported and include extreme somnolence, convulsions,demyelination, ascending peripheral neuropathies similar to Guillain-Barré syndrome, andperipheral neuropathy ranging from numbness and paresthesia to motor weakness and paralysis;do not dilute before administration; preventive measures for hyperuricemia of tumor lysis syndrome(eg, hydration, urine alkalinization, allopurinol prophylaxis) must be taken

Clofarabine (Clolar)

Purine nucleoside antimetabolite that inhibits DNA synthesis. Pools of cellular deoxynucleotidetriphosphate decreased by inhibiting ribonucleotide reductase and terminating DNA chainelongation and repair. Also disrupts mitochondrial membrane integrity. Indicated for relapsed orrefractory ALL in pediatric patients.

Dosing

Adult

>21 years: Not established

Pediatric

<1 year: Not established1-21 years: 52 mg/m2 IV infused over 2 h qd for 5 consecutive days; repeat cycle after recovery or



return to baseline organ function (about q2-6wk)

Interactions

Avoid coadministration with drugs toxic to kidneys or liver (eg, aminoglycosides, amphotericin B,loop diuretics, inhaled anesthetics, high doses of acetaminophen)

Contraindications

None known

Precautions

Pregnancy


Precautions

Because of rapid reduction in leukemia cells after treatment, may cause tumor lysis syndrome andcytokine release (eg, tachypnea, tachycardia, hypotension, pulmonary edema) that may developinto systemic inflammatory response syndrome or capillary leak syndrome and organ dysfunction;may cause bone marrow depression and risk of severe opportunistic infections; may causevomiting, diarrhea, and subsequent dehydration

Prophylactic antimicrobials

These drugs are given to prevent infection in patients receiving chemotherapy.

Sulfamethoxazole and trimethoprim (Cotrim, Septra, Bactrim, SMZ/TMP)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. All immunocompromised

patients should be treated with cotrimoxazole to prevent Pneumocystis carinii pneumonia (PCP).

Dosing

Adult

2 tabs PO bid 3 d/wk; alternatively 1 double-strength tab bid 3 d/wk

Pediatric

5-10 mg/kg/d (based on TMP component) PO divided q12h 3 times/wk

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly);most other interactions minor in severity when dosed 3 times/wk

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency

Precautions

Pregnancy




Precautions

Discontinue at first appearance of rash or sign of adverse reaction; caution in folate deficiency;hemolysis may occur in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency;patients with AIDS may not tolerate or respond to TMP-SMZ

Nystatin (Nilstat)

Used to prevent fungal infections in mucositis. Fungicidal and fungistatic antibiotic fromStreptomyces noursei; effective against various yeasts and yeastlike fungi. Changes permeabilityof fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak.Treatment should continue until 48 h after symptoms disappear. Not substantially absorbed from GItract.

Dosing

Adult

10 mL PO swish and swallow qid

Pediatric

5 mL PO swish and swallow qid

Interactions

None reported

Contraindications


Precautions

Pregnancy


Precautions

Not for treatment of systemic fungal infections

Clotrimazole (Mycelex)

May be used instead of nystatin to prevent fungal infections. Broad-spectrum antifungal agent thatinhibits yeast growth by altering cell membrane permeability, causing death of fungal cells.

Dosing

Adult

1 troche dissolved PO qid

Pediatric


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

Not for treatment of systemic fungal infections; avoid contact with eyes; if irritation or sensitivitydevelops, discontinue and start appropriate therapy

Itraconazole (Sporanox)

Used to prevent fungal infections in high-risk patients. Fungistatic activity. Synthetic triazoleantifungal agent that slows fungal cell growth by inhibiting CYP-dependent synthesis of ergosterol,vital component of fungal cell membranes. Bioavailability greater for PO solution than for cap.

Dosing

Adult

200-400 mg/d PO

Pediatric

10 mg/kg/d PO

Interactions

Inhibits CYP3A4; antacids may reduce absorption; edema may occur with coadministration ofcalcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas;may increase tacrolimus and cyclosporine plasma concentrations when high doses are used;rhabdomyolysis may occur with coadministration of 3-hydroxy-3-methylgluatryl coenzyme Areductase (HMG-CoA) reductase inhibitors (lovastatin or simvastatin); coadministration withcisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels;coadministration may increase plasma levels of CYP3A4 substrates (eg, midazolam, triazolam,cyclosporine); phenytoin and rifampin may reduce levels (may alter phenytoin metabolism)

Contraindications

Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovasculareffects (possibly death)

Precautions

Pregnancy


Precautions



Caution in hepatic insufficiencies

Follow-up

Further Inpatient Care

Frequent hospitalizations may be required to deal with complications of acute lymphoblasticleukemia (ALL) therapy, including the need for blood transfusions or antibiotics.

Immediately admit any patient who is neutropenic and who develops chills or fever toadminister intravenous (IV) broad-spectrum antibiotics.

Further Outpatient Care

Frequent clinic visits are required to administer outpatient chemotherapy, to monitor bloodcounts, and to evaluate new symptoms.

Inpatient & Outpatient Medications

Pneumocystis prophylaxis: All patients should be on TMP-SMZ to prevent Pneumocystis

carinii pneumonia (PCP).

Fungal prophylaxis: Patients may benefit from receiving oral nystatin or clotrimazole(Mycelex) troches to reduce the risk of candidiasis. Patients with a high risk of relapse mayalso need additional anti-fungal therapy such as itraconazole.

Mouth care: Patients should swish and spit with an antimicrobial, such as chlorhexidine(Peridex) or antibacterial enzymatic mouthwash (Biotene), 4 times a day.

Transfer

Initially transfer patients 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.

Deterrence/Prevention

Because the cause of acute lymphoblastic leukemia is unknown, no method of prevention isknown.

Complications

Complications of leukemia and its therapy include the following:

Tumor lysis syndrome

Renal failure

Sepsis

Bleeding

Thrombosis

Typhlitis



Neuropathy

Encephalopathy

Seizures

Secondary malignancy

Short stature (if craniospinal radiation)

Growth hormone deficiency

Cognitive defects

Prognosis

Overall, the cure rate for childhood acute lymphoblastic leukemia is more than 80%.However, the prognosis depends on the clinical and laboratory features described above.

In general, the prognosis is best in children aged 1-10 years.

Adolescents have intermediate outcomes.

Infants younger than 1 year have a poor outcome, with cure rates of about 30%.

Survivors may experience late effects from treatment, which involve all organ systems.Therefore, lifelong follow-up is necessary.[9 ]

Patient Education

Ensure that the patient's parents and guardians have a reasonable understanding of theexpected adverse effects of each medication.

In addition, parents and guardians must be able to recognize signs and symptoms thatrequire medical attention, such as signs and symptoms of anemia, thrombocytopenia, andespecially infection.

Parents must know how to quickly access medical help from the oncology team.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center.Also, see eMedicine's patient education article Leukemia.

Multimedia



Media file 1: 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.

Media file 2: 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.



Media file 3: Bone marrow aspirate from a child with B-cell acute lymphoblastic leukemia. The

lymphoblasts are large and have basophilic cytoplasm with prominent vacuoles.

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Keywords

acute lymphocytic leukemia, acute lymphatic leukemia, ALL, pediatric cancer, childhood cancer,childhood malignancy, lymphoblastic leukemia, hematopoietic stem cell transplantation, HSCT,bone marrow failure, treatment, diagnosis

Contributor Information and Disclosures

Author

Noriko Satake, MD, Assistant Professor, Pediatric Hematology/Oncology, University of CaliforniaDavis School of Medicine, Davis Medical CenterDisclosure: Nothing to disclose.

Coauthor(s)

Janet M Yoon, MD, Assistant Clinical Professor, Department of Pediatrics,Hematology/Oncology, University of California Davis Medical CenterJanet M Yoon, MD is a member of the following medical societies: American Society of PediatricHematology/Oncology and Children's Oncology Group Disclosure: Nothing to disclose.



Medical Editor

Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Department of Pediatrics,Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics,University of PennsylvaniaStephan A Grupp, MD, PhD is a member of the following medical societies: American Associationfor Cancer Research, American Society for Blood and Marrow Transplantation, American Societyof Hematology, American Society of Pediatric Hematology/Oncology, and Society for PediatricResearch Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical CenterCollege of Pharmacy; Pharmacy Editor, eMedicineDisclosure: Nothing to disclose.

Managing Editor

Timothy P Cripe, MD, PhD, Professor of Pediatrics, Division of Hematology/Oncology, CincinnatiChildren's Hospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-Medical Director, Office for Clinical and Translational Research, Cincinnati Children's HospitalMedical Center; Director of Pilot and Collaborative Clinical and Translational Studies Core, Centerfor 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 Associationfor the Advancement of Science, American Pediatric Society, American Society of Hematology,American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; ClinicalProfessor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Departmentof Pediatrics, Duke UniversitySamuel Gross, MD is a member of the following medical societies: American Association forCancer Research, American Society for Blood and Marrow Transplantation, American Society ofClinical Oncology, American Society of Hematology, and Society for Pediatric Research Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics,Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel ComprehensiveCancer Center at Johns Hopkins University School of MedicineRobert J Arceci, MD, PhD is a member of the following medical societies: American Associationfor Cancer Research, American Association for the Advancement of Science, American PediatricSociety, American Society of Hematology, and American Society of PediatricHematology/Oncology Disclosure: Nothing to disclose.

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Acute Lymphoblastic Leukemia

Documents

symptoms of leukemia

development of leukemia

black children

clinicalhistory children

white children

signs of bone marrow

bone marrow infiltration

lymphoid cells