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Pedi atri c Acute Lymphobl asti c Leukemi a

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

Updated: Apr 25, 2014
Practice Essentials
Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing over a
quarter of all pediatric cancers.
Signs and symptoms
Children with acute lymphoblastic leukemia (ALL) often present with signs and symptoms that reflect bone marrow
infiltration and/or extramedullary disease. When leukemic blasts replace the bone marrow, patients present with signs
of bone marrow failure, including anemia, thrombocytopenia, and neutropenia.
Other presenting signs and symptoms of pediatric ALL include the following:
Patients with B-precursor ALL: Bone pain, arthritis, limping; fevers (low or high); neutropenia; fatigue, pallor,
petechiae, and bleeding; lymphadenopathy and hepatosplenomegaly
Patients with mature-B ALL: Extramedullary masses in the abdomen or head/neck; CNS involvement (eg,
headache, vomiting, lethargy, nuchal rigidity)
Patients with T-lineage ALL: Respiratory distress/stridor due to a mediastinal mass
Symptoms of CNS involvement are rarely noted at initial diagnosis but are more common in T-lineage and mature B
cell ALL.
Testicular involvement at diagnosis is also rare; if present, it appears as unilateral painless testicular
See Clinical Presentation for more detail.
Complete morphologic, immunologic, and genetic examination of the leukemic cells is necessary to establish the
diagnosis of ALL.
Routine laboratory studies in pediatric ALL include the following:
CBC count
Peripheral blood smear
Serum chemistries (eg, potassium, phosphorus, calcium)
Uric acid level
LDH level
Coagulation studies, such as PT, aPTT, levels of fibrinogen and D-dimer
Laboratory tests that help classify the type of ALL include the following:
Immunophenotyping - To detect surface immunoglobulin on leukemic blasts (diagnosis of mature B-cell
leukemia) or the expression of T-cellassociated surface antigens (diagnosis of T-lineage ALL)
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Cytogenetic studies - To identify specific genetic alterations in leukemic blasts
Molecular studies (eg, FISH, RT-PCR, Southern blot analysis) - To identify translocations not detected on
routine karyotype analysis; to distinguish lesions that appear cytogenetically identical but are molecularly
Minimal residual disease studies
- To detect chimeric transcripts generated by fusion genes, detect clonal
TCR or immunoglobulin heavy-chain (IgH) gene rearrangements, or identify a phenotype specific to the
leukemic blasts
Genome-wide association studies - To detect the presence of genetic changes where routine techniques are
unhelpful (eg, activated tyrosine kinase pathways in Ph-like ALL), not in clinical use yet
Imaging studies
No other imaging studies than chest radiography to evaluate for a mediastinal mass should be required in pediatric
ALL. However, the following radiologic studies can be helpful:
Ultrasonography: To evaluate for testicular infiltration in boys with enlarged testes; to evaluate for leukemic
kidney involvement as a risk assessment for tumor lysis syndrome
ECG, echocardiogram: To identify any preexisting cardiac dysfunction before administration of anthracyclines
(baseline studies); to monitor heart function during treatment with anthracyclines
Lumbar puncture with cytospin morphologic analysis: To assess for CNS involvement before administration of
systemic chemotherapy; to administer intrathecal chemotherapy
Bone marrow aspiration and biopsy: To confirm the diagnosis of ALL
CNS disease is divided into the following groups:
CNS 1: Absence of blasts on CSF cytospin preparation, regardless of the WBC count
CNS 2: WBC count of less than 5/mL and blasts on cytospin findings, or WBC count of more than 5/mL but
negative by Steinherz-Bleyer algorithm findings (if traumatic tap)
CNS 3: WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia (eg,
facial nerve palsy, brain/eye involvement, hypothalamic syndrome)
See Workup for more detail.
Leukemia is a systemic disease, and treatment is primarily based on chemotherapy. However, the different forms of
ALL require different approaches for optimal results. Treatment of subclinical CNS leukemia is an essential
component of ALL therapy.
Treatment for ALL typically consists of the following phases:
Remission-induction phase (eg, dexamethasone or prednisone, vincristine, asparaginase, daunorubicin)
Intensification/consolidation phase: The importance of this phase is undisputed, but consensus is scarce on
the best regimens and duration of treatment. Current Childrens Oncology Group (COG) ALL protocols use a
therapeutic backbone that was originally introduced in Berlin-Frankfurt-Muenster (BFM) clinical trials in the
1980s. This includes administration of cytarabine, cyclophosphamide, dexamethasone, asparaginase,
doxorubicin, MTX, 6-MP, 6-thiouguanine, and vincristine.
CNS-directed therapy consists of systemic chemotherapy that enters the CSF, as well as intrathecal
chemotherapy administered throughout the entire course of treatment, which is primarily MTX but sometimes
includes hydrocortisone and cytarabine (triple-intrathecal therapy).
Continuation therapy targeted at eliminating residual disease (eg, MTX, 6-MP, vincristine and glucocorticoid
Medications used in the treatment of pediatric ALL include the following:
Antineoplastics (eg, vincristine, asparaginase Escherichia coli, asparaginase Erwinia chrysanthemi,
daunorubicin, doxorubicin, MTX, 6-MP, cytarabine, cyclophosphamide)
Corticosteroids (eg, prednisone, dexamethasone)
Antimicrobials (eg, TMX/SMP, pentamidine)
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Antifungals (eg, fluconazole)
Treatment of T-cell ALL may benefit from high dose methotrexate and the addition of nelarabine, but clinical trial data
regarding these two interventions is still pending. Mature B-cell ALL needs to be treated in the same way as
disseminated Burkitt lymphoma, with short-term intensive chemotherapy, including high-dose MTX, cytarabine, and
cyclophosphamide over a 6-month period.
Blood transfusions or antibiotics may be required to deal with complications of ALL therapy. Do not administer folate
supplementation owing to interactions with MTX.
Nonpharmacologic therapy
Other treatments involved in managing pediatric ALL may include the following:
Administration of IV fluids: Without potassium, with or without sodium bicarbonate
Cranial irradiation: Effectively prevents overt CNS relapse but potentially causes neurotoxicity and brain tumors;
largely replaced by intensive intrathecal and systemic chemotherapy
Allogeneic HSCT (hematopoietic stem cell transplant): Usually following second complete remission after
relapse (if early) or first remission in high risk patients; potentially prevents relapse and/or mortality vs
chemotherapy alone.
Surgical options
In generally, surgical care is not required in the treatment of ALL. However, placement of a central venous catheter is
needed for administering chemotherapy, blood products, and antibiotics, as well as for obtaining blood samples.
See Treatment and Medication for more detail.
Image library
Bone marrow aspirate froma 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.
Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing one quarter
of all pediatric cancers. The annual incidence of acute lymphoblastic leukemia within the United States is 3.7-4.9 cases
per 100,000 children age 0-14 years,
with a peak incidence in children aged 2-5 years.
Although a few cases are associated with inherited genetic syndromes (eg, Down syndrome) or congenital
immunodeficiencies (eg, Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause remains largely unknown.
With improvements in diagnosis and treatment, overall cure rates for children with acute lymphoblastic leukemia have
reached 90%.
The use of risk-adapted treatment protocols has improved cure rates while limiting the toxicity of
therapy. This article summarizes the current diagnosis and treatment of childhood acute lymphoblastic leukemia.
In acute lymphoblastic leukemia (ALL), a lymphoid progenitor cell becomes genetically altered and subsequently
undergoes dysregulated proliferation, with clonal expansion. In ALL, the transformed lymphoid cells reflect the altered
expression of genes usually involved in the normal development of B cells and T cells. Several studies indicate that
leukemic stem cells are present in certain types of ALL.
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Annually, around 3000 children in the United States are diagnosed with ALL. The annual incidence of ALL within the
United States is 3.7-4.9 cases per 100,000 children 0-14 years of age.
with a similar estimated worldwide incidence,
although it has been questioned whether the incidence may be less in low-income countries.
White children are more
frequently affected than black children, and there is a slight male preponderance, which is most pronounced for T-cell
acute lymphoblastic leukemia. The incidence of acute lymphoblastic leukemia peaks in children aged 2-5 years and
subsequently decreases with age.
Although a few cases are associated with inherited genetic syndromes (eg, Down syndrome) or congenital
immunodeficiencies (eg, Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause remains largely unknown.
Environmental risk factors such as exposure to ionizing radiation and electromagnetic fields and parental use of
alcohol and tobacco have not been shown to cause pediatric acute lymphoblastic leukemia. In addition, no direct link
has been established between viral exposure and the development of childhood leukemia.
The likelihood of long-term cure in ALL depends on the clinical and laboratory features and the treatment. Prognostic
risk assessment includes clinical features (age and white blood cell [WBC] count at diagnosis), biologic characteristics
of the leukemic blasts, response to the induction chemotherapy, and minimal residual disease (MRD) burden. Based
on these criteria, patients can be effectively stratified into low risk, average or standard risk, high risk, and very high
Standard-risk patients are aged 1-9.9 years with WBC of less than 50,000 at presentation, lack unfavorable
cytogenetic features, and show a good response to initial chemotherapy. The Childrens Oncology Group (COG)
defines standard risk as less than 1% blasts in peripheral blood by 8 days and less than 0.01% blasts in bone marrow
by 29 days (rapid early response). Low-risk patients have <0.01% blasts for both time points and have favorable
cytogenetics (eg, trisomy 4, 10). High-risk patients do not meet these criteria or have extramedullary involvement that
makes it inappropriate for them to be treated as standard risk. Very-high-risk patients have unfavorable cytogenetic
features (Philadelphia chromosome, hypodiploidy (n <44), MLL gene rearrangement or poor response to initial
chemotherapy (induction failure orDay 29 bone marrowwith MRD >0.01%).
Patients younger than 1 year with acute leukemia have disease that is biologically distinct with a poor outcome.
The 5-year event-free survival (EFS) varies considerably depending on risk category, from 95% (low risk) to 30-80%
(very high risk), with infant leukemia having the worst outcomes: 20% for patients younger than 90 days. COG
redefined very high risk to include high risk patients 13 years of age, which made the range of outcomes wider for
this subgroup. Overall, the cure rate for childhood acute lymphoblastic leukemia (ALL) is more than 80%.
Five-year survival rates for children diagnosed with ALL rose to 90% from 2000-2005, which was up from 84% in
Improvement in survival was observed for all age groups of children, except for infants younger than 1
year. In low-income countries (LIC), therapeuticresults for pediatric ALL have been less encouraging due to delayed
diagnosis, abandonment of therapy, and death from toxicity due to suboptimal supportive care. Nevertheless, current
4-year event-free survival rates are 61% in India,
and over 78% in Lebanon,
demonstrating that pediatric ALL is
curable in LIC.
An analysis of long-term survival among 21,626 children with ALL treated in COG trials from 1990-2005 found that
10-year survival rose to almost 84% in 1995-1999 from 80% in 1990-1994. The analysis also found that survival
improved for almost all groups, including older children and black children.
Acute complications may involve all organ systems and include the following:
Tumor lysis syndrome
Renal failure
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In addition, lifelong follow-up is necessary,
because survivors may experience late effects from treatment for this
condition, such as the following:
Secondary malignancy
Short stature (if craniospinal radiation)
Growth hormone deficiency
Learning disability
Cognitive defects
Patient Education
Ensure that the patient's parents and guardians understand that ALL usually does not have a known cause, that
accurate stratification helps guide therapy, and that participating in institutional or consortium-based clinical trials may
help lead to better outcomes in the future. In addition, parents and guardians must know the expected adverse effects
of each medication and be able to recognize signs and symptoms that require immediate medical attention, such as
those for anemia, thrombocytopenia, and infection. Furthermore, parents and patients must know how to quickly
access medical help from the oncology team.
For patient education information, see Cancer and Tumors Center, as well as Leukemia.

Contri butor Informati on and Di scl osures
Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP Associate Professor and Division Chief of Pediatric
Hematology and Oncology, Department of Pediatrics, Albany Medical Center
Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP is a member of the following medical societies: American
Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and
Royal College of Physicians of the United Kingdom
Disclosure: J azz Pharmaceutical Honoraria Speaking and teaching
Noriko Satake, MD Assistant Professor, Department of Pediatric Hematology/Oncology, University of California,
Davis, School of Medicine, UC Davis Medical Center
Disclosure: Nothing to disclose.
Janet M Yoon, MD Assistant Clinical Professor, Department of Pediatric Hematology/Oncology, University of
California, Davis, School of Medicine, UC Davis Medical Center
J anet M Yoon, MD is a member of the following medical societies: American Society of Pediatric
Hematology/Oncology and Children's Oncology Group
Disclosure: Nothing to disclose.
Chief Editor
Robert J Arceci, MD, PhD Director, Children's Center for Cancer and Blood Disorders, Department of
Hematology/Oncology, Co-Director of the Ron Matricaria Institute of Molecular Medicine, Phoenix Children's
Hospital; Editor-in-Chief, Pediatric Blood and Cancer; Professor, Department of Child Health, University of Arizona
College 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
Pediatric Acute Lymphoblastic Leukemia
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of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.
Additional Contributors
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
Disclosure: Nothing to disclose.
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 School
of Medicine
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
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of
Pharmacy; Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.
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