Acute Lymphoblastic Leukemia

1/4/2011 Acute Lymphoblastic Leukemia: [P…
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eMedicine Specialties > Pediatrics: General Medicine > Oncology
Acute Lymphoblastic Leukemia

Noriko 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 lymphoblastic
leukemia is approximately 9-10 cases per 100,000 population in childhood.[1 ]The peak incidence
occurs 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 environmental
factors (ie, exposure to ionizing radiation and electromagnetic fields, parental use of alcohol and
tobacco) have been investigated as potential risk factors, but none has been definitively shown to
cause acute lymphoblastic leukemia. Various viruses may be linked to the development of
leukemia, particularly when prenatal viral exposure occurs in mothers recently infected with
influenza or varicella. However, no direct link has been established between viral exposure and the
development of leukemia.
Acute lymphoblastic leukemia may also occur in children with various congenital
immunodeficiencies (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 acute
lymphoblastic leukemia now approach 80%. Further refinements in therapy, including the use of
risk-adapted treatment protocols, may improve cure rates for patients at high risk while limiting the
toxicity of therapy for patients with a low risk of relapse. This article summarizes advances in the
diagnosis and treatment of childhood acute lymphoblastic leukemia.
Pathophysiology
In acute lymphoblastic leukemia, a lymphoid progenitor cell becomes genetically altered and
subsequently undergoes dysregulated proliferation, survival, and clonal expansion. In most cases,
the pathophysiology of transformed lymphoid cells reflects the altered expression of genes whose
products contribute to 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.
Frequency
United States
Annually, 2500-3500 children are diagnosed with acute lymphoblastic leukemia.
…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-year
event-free survival (EFS) rate for high-risk patients is approximately 65%.
Race
The overall incidence of acute lymphoblastic leukemia varies among different racial groups within
the 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 is
most pronounced for T-cell acute lymphoblastic leukemia.
Age
The incidence of acute lymphoblastic leukemia peaks in children aged 2-5 years and subsequently
decreases with age.
Clinical
History
Children with acute lymphoblastic leukemia (ALL) generally present with signs and symptoms that
reflect bone marrow infiltration and extramedullary disease. Because leukemic blasts replace the
bone 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 and
hepatosplenomegaly. Other signs and symptoms of leukemia include weight loss, bone pain, and
dyspnea.
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 nerve
involvement, which most frequently involves the seventh, third, fourth, and sixth cranial nerves, may
occur. Also, leukemia can present as an intracranial or spinal mass, which causes numerous
neurologic symptoms, most of which are due to nerve compression.
Testicular involvement at diagnosis is rare. However, if present, it appears as painless testicular

enlargement and is most often unilateral.
Physical
Physical findings in children with acute lymphoblastic leukemia reflect bone marrow infiltration and
extramedullary disease. Patients present with pallor caused by anemia, and petechiae and
bruising 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 in
treatment 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 cause
of 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 anemia
Idiopathic 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 must
evaluate the peripheral smear for the presence and morphology of lymphoblasts. An
elevated leukocyte count of more than 10 X 109/L (>10 X 103/µL) occurs in one half of
patients with acute lymphoblastic leukemia. Neutropenia, anemia, and
thrombocytopenia may be observed secondary to inhibition of normal hematopoiesis
by leukemic infiltration. Rare cases of acute lymphoblastic leukemia may initially
manifest with pancytopenia.
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, including tests of the
prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level,
and D-dimer level to assess for disseminated intravascular coagulation; these studies
are particularly important in a child who is acutely toxic.
Immunophenotyping
Complete morphologic, immunologic, and genetic examination of the leukemic cells is
necessary to establish the diagnosis of acute lymphoblastic leukemia.
An important advancement in the classification of acute lymphoblastic leukemia was
the observation that malignant lymphoblasts share many of the features of normal
lymphoid progenitors. Acute lymphoblastic leukemia 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. However, leukemic lymphoblasts can also have aberrant gene expression
with resultant phenotypes that differ from those of normal lymphocyte progenitors.
Nevertheless, acute lymphoblastic leukemia can be broadly classified as B-lineage or
T-lineage acute lymphoblastic leukemia.
The diagnosis of B-cell leukemia, which accounts for only about 3% of acute
lymphoblastic leukemia cases, 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. This morphologic pattern
is designated L3 in the French-American-British (FAB) system (see Histologic
Findings). Prominent clinical features include extramedullary lymphomatous masses in
the abdomen or head and neck, and frequently involve the CNS.
Approximately 80% of childhood acute lymphoblastic leukemia involves lymphoblasts
with phenotypes that correspond to those of B-cell progenitors. These cases can be
identified 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-lineage
acute lymphoblastic leukemia. In addition, about one fourth of B-cell precursor cases
express cytoplasmic immunoglobulin µ heavy-chain proteins and are designated pre–
B-cell acute lymphoblastic leukemia. Cases related to B-cell precursors can be
subclassified as early pre–B-cell, pre–B-cell, or transitional pre–B-cell cases. Although
mature B-cell acute lymphoblastic leukemia should be differentiated from B-precursor
cases, distinguishing the subtypes of B-precursor acute lymphoblastic leukemia is
probably not clinically relevant.
T-cell acute lymphoblastic leukemia is identified by the expression of T-cell–associated
surface antigens, of which cytoplasmic CD3 is specific. T-cell acute lymphoblastic
leukemia cases can be classified by early, mid, or late thymocytes. Clinical features
most closely associated with T-cell acute lymphoblastic leukemia are high blood
leukocyte counts and CNS involvement. About one half of patients have a mediastinal
mass at the time of diagnosis. The prognosis of patients with T-cell acute lymphoblastic
leukemia has historically been worse than that of patients with B-lineage acute
lymphoblastic leukemia. However, the outlook for patients with T-cell leukemia has
improved to nearly that of precursor B-cell acute lymphoblastic leukemia when intensive
chemotherapy is used.
Cytogenetic and molecular diagnosis

In more than 90% of acute lymphoblastic leukemia cases, specific genetic alterations
can be found in the leukemic blasts. These alterations include changes in chromosome
number (ploidy) and structure; about half of all childhood acute lymphoblastic leukemia
involves recurrent translocations. Standard cytogenetic analysis is an essential tool in
the workup of all patients with leukemia because the karyotype of the leukemic cells
has 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
improve diagnostic accuracy. Molecular analysis can be used to identify translocations
not detected on routine karyotype analysis and to distinguish lesions that appear
cytogenetically 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 trisomy
4, 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 leukemic
cells, and due to difficulties distinguishing leukemic from normal cells in bone marrow
specimens recovering from chemotherapy or after transplant.
Although still experimental, molecular analysis appears to play a promising role in the
diagnosis 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) 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-induction leukemia burden and outcome. As a result,
current treatment protocols are using MRD measurements for acute lymphoblastic
leukemia risk assignment.[3 ]
Risk assessment: Current risk assessment includes clinical features (age and WBC count at
diagnosis), biological characteristics of the leukemic blasts, response to the induction
chemotherapy, and MRD burden. Current studies are ongoing to assess an optimal
treatment for each leukemia group with different risks. Future goals include increased
understanding of the molecular pathways leading to specific phenotypes, minimizing the risk
of relapse by identifying subsets of patients requiring more intensive therapy, and minimizing
the 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 are
required. However, if the physical examination reveals enlarged testes, perform
ultrasonography to evaluate for testicular infiltration.
Testicular ultrasonography: Perform testicular ultrasonography if the testes are enlarged upon
physical examination.
Renal ultrasonography: Some clinicians prefer to evaluate for leukemic kidney involvement
as an assessment of risk for tumor lysis syndrome.
Echocardiography and ECG: Obtain an echocardiogram and an ECG before anthracyclines
are administered.
Procedures
Bone marrow aspirate and biopsy: The results confirm the diagnosis of acute lymphoblastic
leukemia. 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.
Lumbar puncture with cytospin morphologic analysis: These tests are performed before
systemic chemotherapy is administered to assess for CNS involvement and to administer
intrathecal chemotherapy.
Histologic Findings
According to the French-American-British (FAB) classification system, acute lymphoblastic
leukemia is classified into 3 groups based on morphology.
L1: Cells are usually small, with scant cytoplasm and inconspicuous nucleoli. L1 accounts for
85% of all cases of childhood acute lymphoblastic leukemia.
L2: 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: 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.
Treatment
Medical Care
Because leukemia is a systemic disease, therapy is primarily based on chemotherapy. Different
forms of acute lymphoblastic leukemia require different approaches for optimal results. Excluding
mature B-cell acute lymphoblastic leukemia which is treated with short-term intensive
chemotherapy, including high-dose methotrexate (MTX), cytarabine, and cyclophosphamide, 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.
Tumor lysis syndrome

Before and during the initial induction phase of chemotherapy, patients may develop
tumor 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. The hyperuricemia
can lead to crystal formation with tubular obstruction and, possibly, 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, usually without potassium.
Sodium bicarbonate is added to the IV fluid to achieve moderate alkalinization of
the urine (pH level, 7.5-8) to enhance the excretion of phosphate and uric acid. A
urine pH level higher than this should be avoided to prevent crystallization of
hypoxanthine or calcium phosphate.
The standard treatment for malignancy-associated hyperuricemia also 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.
Phases of therapy
The treatment of childhood acute lymphoblastic leukemia, with the exception of B-cell
acute lymphoblastic leukemia, has 5 components: induction, consolidation, interim
maintenance, delayed intensification, and maintenance. The goal of induction is to
achieve remission or less than 5% blasts in the bone marrow. Induction therapy
generally consists of 3-4 drugs, which may include 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 has been shown to be much more specific and sensitive than
morphologic examination of blast cells.
The current childhood acute lymphoblastic leukemia clinical trials have incorporated
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 (>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, 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-dose
MTX and 6-mercaptopurine [6-MP]), epipodophyllotoxins with cytarabine, or multiagent
combination therapy. Consolidation therapy also appears to improve the long-term
survival of patients with standard-risk disease. The addition of intensive reinduction
therapy after the completion of the induction phase is similarly beneficial for patients in
both risk groups.
In interim maintenance, oral medications are administered to maintain remission and
allow the bone marrow to recover. This occurs for 4 weeks and is followed by delayed
intensification, which is aimed at treating any remaining resistant leukemia cells.
The last phase of treatment is maintenance. This consists of intrathecal MTX every 3
months, 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-month
course of intensive therapy, achieving acceptable cure rates for patients with B-
precursor and T-cell acute lymphoblastic leukemia requires approximately 2-2.5 years
of continuation therapy. Attempts to reduce this time result in high relapse rates after
therapy is stopped. In the current acute lymphoblastic leukemia clinical trials, the total
duration of therapy for girls is 2 years from the start of interim maintenance and is 3
years from the start of interim maintenance for boys.
Most contemporary protocols include a continuation phase based on weekly
parenterally administered MTX given with daily, orally administered 6-MP interrupted
by monthly pulses of vincristine and a glucocorticoid. Although these pulses improve
outcomes, they are associated with avascular necrosis of the bone. Patients with high-
risk acute lymphoblastic leukemia may also benefit from intensified continuation
therapy that includes the rotational use of drug pairs.
Improvements in relapse-free survival gained by intensification with anthracyclines or
epipodophyllotoxins must be weighed against the late sequelae of these agents, which
include 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 WBCs
CNS 2 - WBC count of less than 5/mL and blasts on cytospin findings, or WBC
count of more than 5/mL but negative Steinherz-Bleyer algorithm findings (used to
assess traumatic taps)
CNS 3 - WBC count of 5/mL or more and blasts on cytospin findings and/or
clinical signs of CNS 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 the lumbar puncture is traumatic
(containing >5/mL WBCs and blasts), CNS disease (CNS 3) is present if CSF WBC
count divided by the CSF RBC count is more than 2 times blood WBC count divided by
the blood RBC count.
Treatment of subclinical CNS leukemia is an essential component of acute
lymphoblastic leukemia therapy.
Although cranial irradiation effectively prevents overt CNS relapse, concern about
subsequent neurotoxicity and brain tumors has led many investigators to replace
irradiation with intensive intrathecal and systemic chemotherapy for most patients. This
strategy has produced excellent survival outcomes, with CNS relapse rates of less than
2% 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) is
unclear.
Pui et al conducted a clinical trial in children with newly diagnosed acute lymphoblastic
leukemia to determine if prophylactic cranial irradiation can be safely omitted from
treatment to avoid irradiation consequences with effective risk-adjusted
chemotherapy.[4 ]
The duration of continuous complete remission in 71 of 498 patients who
previously would have received prophylactic cranial irradiation was compared
with that of 56 historical controls who received irradiation. The 71 patients had
significantly 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, high
level of minimal residual disease after 6 wk of remission induction).
Risk factors for CNS relapse include genetic abnormality, CNS involvement at
diagnosis, and T-cell immunophenotype.
The researchers concluded that prophylactic cranial irradiation can be safely
omitted in many children with acute lymphoblastic leukemia.
High-risk patients
Optimal treatment for patients with very high-risk acute lymphoblastic leukemia has not
been found.
Some centers recommend allogeneic stem-cell transplantation (SCT) soon after first
remission is achieved. For patients without a matched family donor, transplantation of
marrow from an unrelated donor is a reasonable treatment option. 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 cells acquire

resistance to exposed chemotherapy drugs. Therefore, treatment of relapse is intensive and
often 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 leukemias
can have potent and specific antileukemic activity while producing minimal toxicity to
normal 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 a
standard front-line treatment for Ph-positive chronic myeloid leukemia
(CML).[5,6,7,8 ]
Imatinib has shown efficacy in Ph-positive acute lymphoblastic leukemia, and
combination regimens with imatinib and conventional chemotherapy or SCT have
been evaluated in clinical trials.
Because the poor prognosis of Ph-positive acute lymphoblastic leukemia has
been related to a slow response to induction therapy, imatinib has been added
during early treatment phases to improve therapeutic response. Adult data in Ph-
positive acute lymphoblastic leukemia has demonstrated excellent results using
this approach.
Imatinib has been shown to be safe and efficacious in children with advanced Ph-
positive acute lymphoblastic leukemia, raising the possibility of incorporating its
use into front-line therapy prior to SCT. Although some evidence suggests this
approach could improve overall outcome, the low incidence of childhood Ph-
positive acute lymphoblastic leukemia (2-4% of childhood acute lymphoblastic
leukemia 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 largely
unknown.
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 analysis, improved multiparameter flow-
cytometric analysis, quantitative reverse-transcriptase polymerase chain reaction (RT-
PCR), genomics, proteomics and sophisticated bioinformatics hold promise for
providing important clues to the mechanisms behind leukemogenesis and response
and resistance to current therapies. Future goals include the use of these technologies
to identify additional biologic subsets of acute lymphoblastic leukemia that require
specifically targeted therapies.
Surgical Care
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.
Consultations
Numerous consultations should be obtained, depending on the clinical circumstances of patients
with 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 with
acute lymphoblastic leukemia to aid them and their families in navigating all of the difficult
issues surrounding their care.
Radiation oncologist: Depending on their risk group, some patients require craniospinal
radiation 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 include
cytarabine, 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 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 are specific to phases of the
cell cycle, whereas others (ie, alkylating agents, anthracyclines, cisplatin) are not. Cellular
apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic
agents.
Prednisone (Deltasone)
Corticosteroid. Important chemotherapeutic agent in treatment of ALL. Used in induction and

reinduction 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 may

decrease effectiveness
Contraindications
Documented hypersensitivity; serious infections (excluding meningitis and septic shock) and fungal
infections; 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 fluid
retention, hypertension, increased appetite, transient diabetes, acne, striae, personality changes,
peptic ulcer, immunosuppression, osteoporosis, growth retardation; caution in diabetes, fungal
infections, and osteonecrosis
Dexamethasone (Decadron, Dexone)
Corticosteroid. Important chemotherapeutic agent in treatment of ALL. Used in induction and

reinduction 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 may

decrease effectiveness
Contraindications
Documented hypersensitivity; serious infections (excluding meningitis and septic shock) and fungal
infections; varicella infections
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus
Precautions
Gradually taper after prolonged use; adverse effects include gastritis, hypertension, hyperglycemia,
salt and water retention, personality changes, growth retardation, osteoporosis; caution in diabetes
and osteonecrosis
Vincristine (Oncovin, Vincasar)
Chemotherapeutic agent derived from periwinkle plant. Inhibits microtubule formation in mitotic
spindle, causing metaphase arrest.
Dosing
Adult
Induction therapy: 2 mg IV qwk

Continuation 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, cytochrome
P450 (CYP) 3A4 inhibitors (eg, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir),
granulocyte-macrophage colony-stimulating factor (GM-CSF, eg, sargramostim, filgrastim), or
nifedipine 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; intrathecal

administration
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 inappropriate
antidiuretic hormone secretion (SIADH)
Asparaginase (Elspar, Kidrolase)
Extracts of Escherichia coli or Erwinia L-asparaginase impair asparagine synthesis. Lethal to cells
that cannot synthesize essential amino acid asparagine.
Dosing
Adult
Induction therapy: 6000-25,000 U/m2 IM 3 times/wk

Continuation 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 after

administration and cardiomyopathy after long-term use; nausea, vomiting, stomatitis, and alopecia;
extravasation may occur, resulting in severe tissue necrosis; caution in impaired hepatic, renal, or
biliary function
Methotrexate (Folex PFS, MTX)
Folate analog that competitively inhibits dihydrofolate reductase, inhibiting DNA, RNA, and protein
synthesis.
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 lowers
levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivatives
contained in some vitamins may decrease response; coadministration with nonsteroidal anti-
inflammatory drugs (NSAIDs) may be fatal; indomethacin and phenylbutazone can increase
plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and
sulfonamides, including trimethoprim-sulfamethoxazole (TMP-SMZ), may increase effects and
toxicity; may increase plasma levels of thiopurines
Contraindications
Documented hypersensitivity; alcoholism, hepatic insufficiency, documented immunodeficiency

syndromes, 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 counts
substantially 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 qid

Continuation therapy: <qmo
Pediatric
Interactions
Decreased effects of gentamicin and flucytosine; increased toxicity with other alkylating agents and
radiation
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 or
early 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 additive
effects 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 active

metabolites may involve cross-linking of DNA, which may interfere with growth of normal and
neoplastic cells.
Dosing
Adult
Induction therapy: 300-1000 mg/m2 IV once

Continuation therapy: <qmo
Pediatric
Interactions
Possibly increased risk of bleeding or infection and enhanced myelosuppressive effects with
coadministration of allopurinol; may potentiate doxorubicin-induced cardiotoxicity; may reduce
digoxin 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 and
leukopenic 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 nucleoside
analog. Leukemic blast cells accumulate ara-GTP. This allows for incorporation into DNA, leading
to inhibition of DNA synthesis and cell death.
Approved by US Food and Drug Administration [FDA] as orphan drug to treat T-cell lymphoblastic
lymphoma (type of non-Hodgkin lymphoma [NHL]) that does not respond or that relapsing with at
least 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, and
diarrhea; severe neurologic events reported and include extreme somnolence, convulsions,
demyelination, ascending peripheral neuropathies similar to Guillain-Barré syndrome, and
peripheral 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 deoxynucleotide
triphosphate decreased by inhibiting ribonucleotide reductase and terminating DNA chain
elongation and repair. Also disrupts mitochondrial membrane integrity. Indicated for relapsed or
refractory ALL in pediatric patients.
Dosing
Adult
>21 years: Not established

Pediatric
<1 year: Not established

1-21 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 and
cytokine release (eg, tachypnea, tachycardia, hypotension, pulmonary edema) that may develop
into systemic inflammatory response syndrome or capillary leak syndrome and organ dysfunction;
may cause bone marrow depression and risk of severe opportunistic infections; may cause
vomiting, 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 from
Streptomyces noursei; effective against various yeasts and yeastlike fungi. Changes permeability
of 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 GI
tract.
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 that
inhibits 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 sensitivity
develops, discontinue and start appropriate therapy
Itraconazole (Sporanox)
Used to prevent fungal infections in high-risk patients. Fungistatic activity. Synthetic triazole
antifungal 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 of
calcium 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 A
reductase (HMG-CoA) reductase inhibitors (lovastatin or simvastatin); coadministration with
cisapride 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 cardiovascular

effects (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 lymphoblastic

leukemia (ALL) therapy, including the need for blood transfusions or antibiotics.
Immediately admit any patient who is neutropenic and who develops chills or fever to
administer intravenous (IV) broad-spectrum antibiotics.
Further Outpatient Care
Frequent clinic visits are required to administer outpatient chemotherapy, to monitor blood
counts, 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 may
also 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 is

known.
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 the
expected adverse effects of each medication.
In addition, parents and guardians must be able to recognize signs and symptoms that
require medical attention, such as signs and symptoms of anemia, thrombocytopenia, and
especially 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.
References
1. Ribera JM, Oriol A. Acute lymphoblastic leukemia in adolescents and young adults. Hematol
Oncol Clin North Am . Oct 2009;23(5):1033-42, vi. [Medline].
2. Campana D. Role of minimal residual disease monitoring in adult and pediatric acute
lymphoblastic leukemia. Hematol Oncol Clin North Am . Oct 2009;23(5):1083-98,
vii. [Medline].
3. Nathan PC, Wasilewski-Masker K, Janzen LA. Long-term outcomes in survivors of childhood

acute lymphoblastic leukemia. Hematol Oncol Clin North Am . Oct 2009;23(5):1065-82, vi-
vii. [Medline].
4. [Best Evidence] Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic
leukemia without cranial irradiation. N Engl J Med. Jun 25 2009;360(26):2730-41. [Medline].
5. de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Imatinib combined with induction or

consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive
acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. Feb
15 2007;109(4):1408-13. [Medline].
6. Fuster JL, Bermudez M, Galera A, Llinares ME, Calle D, Ortuno FJ. Imatinib mesylate in
combination with chemotherapy in four children with de novo and advanced stage
Philadelphia chromosome-positive acute lymphoblastic
leukemia. Haematologica. Dec 2007;92(12):1723-4. [Medline].
7. Lee S, Kim YJ, Min CK, et al. The effect of first-line imatinib interim therapy on the outcome
of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia
chromosome-positive acute lymphoblastic leukemia. Blood. May 1 2005;105(9):3449-
57. [Medline].
8. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute

lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. Jun
15 2004;103(12):4396-407. [Medline].
9. Landier W, Bhatia S, Eshelman DA, et al. Development of risk-based guidelines for pediatric
cancer survivors: the Children's Oncology Group Long-Term Follow-Up Guidelines from the
Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin
Oncol . Dec 15 2004;22(24):4979-90. [Medline].
10. Cave H, van der Werff ten Bosch J, Suciu S, et al. Clinical significance of minimal residual
disease in childhood acute lymphoblastic leukemia. European Organization for Research
and Treatment of Cancer--Childhood Leukemia Cooperative Group. N Engl J Med. Aug
27 1998;339(9):591-8. [Medline].
11. Cheok MH, Evans WE. Acute lymphoblastic leukaemia: a model for the pharmacogenomics
of cancer therapy. Nat Rev Cancer. Feb 2006;6(2):117-29. [Medline].
12. Coustan-Smith E, Behm FG, Sanchez J, et al. Immunological detection of minimal residual
disease in children with acute lymphoblastic leukaemia. Lancet. Feb
21 1998;351(9102):550-4. [Medline].
13. Dordelmann M, Reiter A, Borkhardt A, et al. Prednisone response is the strongest predictor
of treatment outcome in infant acute lymphoblastic leukemia. Blood. Aug
15 1999;94(4):1209-17. [Medline].
14. Gaynon PS. Childhood acute lymphoblastic leukaemia and relapse. Br J

Haematol. Dec 2005;131(5):579-87. [Medline].
15. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between
rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor
lysis. Blood. May 15 2001;97(10):2998-3003. [Medline].
16. Greaves MF. Aetiology of acute leukaemia. Lancet. Feb 1 1997;349(9048):344-9. [Medline].
17. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J
Clin. Jan-Feb 2000;50(1):7-33. [Medline].
18. Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer in children in the United
States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer. Apr
15 1995;75(8):2186-95. [Medline].
19. Hong D, Gupta R, Ancliff P, et al. Initiating and cancer-propagating cells in TEL-AML1-
associated childhood leukemia. Science. Jan 18 2008;319(5861):336-9. [Medline].
20. Jones LK, Saha V. Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J
Haematol. Aug 2005;130(4):489-500. [Medline].
21. Kersey JH. Fifty years of studies of the biology and therapy of childhood
leukemia. Blood. Sep 1 1998;92(5):1838. [Medline].
22. le Viseur C, Hotfilder M, Bomken S, et al. In childhood acute lymphoblastic leukemia, blasts
at different stages of immunophenotypic maturation have stem cell properties. Cancer
Cell. Jul 8 2008;14(1):47-58. [Medline].
23. Linet MS, Hatch EE, Kleinerman RA, et al. Residential exposure to magnetic fields and acute
lymphoblastic leukemia in children. N Engl J Med. Jul 3 1997;337(1):1-7. [Medline].
24. Margolin JF, Steuber CP, Poplack DG. Acute lymphoblastic leukemia. In: Principles and
Practice of Pediatric Oncology. 15th ed. 2006:538-90.
25. McNeil DE, Cote TR, Clegg L, Mauer A. SEER update of incidence and trends in pediatric
malignancies: acute lymphoblastic leukemia. Med Pediatr Oncol . Dec 2002;39(6):554-7;
discussion 552-3. [Medline].
26. Neglia JP, Robison LL. Epidemiology of the childhood acute leukemias. Pediatr Clin North
Am . Aug 1988;35(4):675-92. [Medline].
27. Pui CH. Childhood Leukemias. Cambridge University Press; 1996.
28. Pui CH, Campana D, Evans WE. Childhood acute lymphoblastic leukaemia--current status
and future perspectives. Lancet Oncol . Oct 2001;2(10):597-607. [Medline].
29. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. Jan
12 2006;354(2):166-78. [Medline].
30. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. Mar
22 2008;371(9617):1030-43. [Medline].
31. Rubnitz JE, Pui CH. Molecular diagnostics in the treatment of leukemia. Curr Opin
Hematol. Jul 1999;6(4):229-35. [Medline].
32. Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P. Uniform approach to risk
classification and treatment assignment for children with acute lymphoblastic leukemia. J
Clin Oncol . Jan 1996;14(1):18-24. [Medline].
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 California

Davis School of Medicine, Davis Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Janet M Yoon, MD, Assistant Clinical Professor, Department of Pediatrics,

Hematology/Oncology, University of California Davis Medical Center
Janet M Yoon, MD is a member of the following medical societies: American Society of Pediatric
Hematology/Oncology and Children's Oncology Group
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 Pennsylvania
Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association
for Cancer Research, American Society for Blood and Marrow Transplantation, American Society
of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric
Research
Pharmacy Editor
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center
College of Pharmacy; Pharmacy Editor, eMedicine
Managing Editor
Timothy P Cripe, MD, PhD, Professor of Pediatrics, Division of Hematology/Oncology, Cincinnati

Children's Hospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-
Medical Director, Office for Clinical and Translational Research, Cincinnati Children's Hospital
Medical Center; Director of Pilot and Collaborative Clinical and Translational Studies Core, Center
for Clinical and Translational Science and Training, University of Cincinnati College of Medicine
Timothy P Cripe, MD, PhD is a member of the following medical societies: American Association
for the Advancement of Science, American Pediatric Society, American Society of Hematology,
American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
CME Editor
Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical
Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department
of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for
Cancer Research, American Society for Blood and Marrow Transplantation, American Society of
Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Chief Editor
Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics,
Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive
Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association
for Cancer Research, American Association for the Advancement of Science, American Pediatric
Society, American Society of Hematology, and American Society of Pediatric
Hematology/Oncology
Further Reading
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Acute Lymphoblastic Leukemia

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

eMedicine Specialties > Pediatrics: General Medicine > Oncology

Acute Lymphoblastic Leukemia

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

Testicular involvement at diagnosis is rare. However, if present, it appears as painless testicular

Basic laboratory tests

Cytogenetic and molecular diagnosis

Minimal residual disease (MRD)

Tumor lysis syndrome

Treatment of relapse: In general, relapsed acute lymphoblastic leukemia cells acquire

Genetic studies and future challenges

Pediatric oncologist: Refer all patients to a subspecialist to direct their care.

Corticosteroid. Important chemotherapeutic agent in treatment of ALL. Used in induction and

40 mg/m2/d PO divided tid

May potentiate thrombogenic effects of asparaginase; barbiturates, phenytoin; rifampin may

Dexamethasone (Decadron, Dexone)

Corticosteroid. Important chemotherapeutic agent in treatment of ALL. Used in induction and

6-8 mg/m2/d PO divided tid

May potentiate thrombogenic effects of asparaginase; barbiturates, phenytoin; rifampin may

Vincristine (Oncovin, Vincasar)

Induction therapy: 2 mg IV qwk

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

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

Asparaginase (Elspar, Kidrolase)

Induction therapy: 6000-25,000 U/m2 IM 3 times/wk

Documented hypersensitivity; history of pancreatitis

25 mg/m2 IV qwk during induction therapy

Coadministration of trastuzumab increases cardiotoxic effects

Documented hypersensitivity; congestive heart failure, arrhythmias, or cardiopathy

Myelosuppression and thrombocytopenia; may cause cardiac arrhythmias immediately after

Methotrexate (Folex PFS, MTX)

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

Documented hypersensitivity; alcoholism, hepatic insufficiency, documented immunodeficiency

X - Contraindicated; benefit does not outweigh risk

Mercaptopurine (Purinethol, 6-MP)

Synthetic analog of nucleoside deoxycytidine. Undergoes phosphorylation to arabinofuranosyl-

Induction therapy: 300-3000 mg/m2 IV qid

Documented hypersensitivity; cerebellar toxicity

Severe leukopenia and thrombocytopenia; immunosuppression, nausea, vomiting, anorexia,

Etoposide (Toposar, VePesid)

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

Documented hypersensitivity; IT administration may cause death

Myelosuppression; secondary acute myeloid leukemia

Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active

Induction therapy: 300-1000 mg/m2 IV once

Documented hypersensitivity; severely depressed bone marrow function

Alopecia, nausea, vomiting, stomatitis, diarrhea, myelosuppression, immunosuppression,

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

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

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

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

>21 years: Not established

<1 year: Not established

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

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

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

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

Documented hypersensitivity; megaloblastic anemia due to folate deficiency

10 mL PO swish and swallow qid

5 mL PO swish and swallow qid

Not for treatment of systemic fungal infections

1 troche dissolved PO qid

Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular