pediatric acute lymphoblastic leukemia

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

Updated: Apr 25, 2014

Practice EssentialsAcute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing over aquarter of all pediatric cancers.

Signs and symptoms

Children with acute lymphoblastic leukemia (ALL) often present with signs and symptoms that reflect bone marrowinfiltration and/or extramedullary disease. When leukemic blasts replace the bone marrow, patients present with signsof 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 hepatosplenomegalyPatients 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 Bcell ALL.[1] Testicular involvement at diagnosis is also rare; if present, it appears as unilateral painless testicularenlargement.

See Clinical Presentation for more detail.

Diagnosis

Testing

Complete morphologic, immunologic, and genetic examination of the leukemic cells is necessary to establish thediagnosis of ALL.

Routine laboratory studies in pediatric ALL include the following:

CBC countPeripheral blood smearSerum chemistries (eg, potassium, phosphorus, calcium)Uric acid levelLDH levelCoagulation 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-cellleukemia) 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 blastsMolecular studies (eg, FISH, RT-PCR, Southern blot analysis) - To identify translocations not detected onroutine karyotype analysis; to distinguish lesions that appear cytogenetically identical but are molecularlydifferentMinimal residual disease studies[2] - To detect chimeric transcripts generated by fusion genes, detect clonalTCR or immunoglobulin heavy-chain (IgH) gene rearrangements, or identify a phenotype specific to theleukemic blastsGenome-wide association studies - To detect the presence of genetic changes where routine techniques areunhelpful (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 pediatricALL. However, the following radiologic studies can be helpful:

Ultrasonography: To evaluate for testicular infiltration in boys with enlarged testes; to evaluate for leukemickidney involvement as a risk assessment for tumor lysis syndromeECG, echocardiogram: To identify any preexisting cardiac dysfunction before administration of anthracyclines(baseline studies); to monitor heart function during treatment with anthracyclines

Procedures

Lumbar puncture with cytospin morphologic analysis: To assess for CNS involvement before administration ofsystemic chemotherapy; to administer intrathecal chemotherapyBone 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 countCNS 2: WBC count of less than 5/mL and blasts on cytospin findings, or WBC count of more than 5/mL butnegative 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.

Management

Leukemia is a systemic disease, and treatment is primarily based on chemotherapy. However, the different forms ofALL require different approaches for optimal results. Treatment of subclinical CNS leukemia is an essentialcomponent 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 onthe best regimens and duration of treatment. Current Childrens Oncology Group (COG) ALL protocols use atherapeutic backbone that was originally introduced in Berlin-Frankfurt-Muenster (BFM) clinical trials in the1980s. 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 intrathecalchemotherapy administered throughout the entire course of treatment, which is primarily MTX but sometimesincludes hydrocortisone and cytarabine (triple-intrathecal therapy).Continuation therapy targeted at eliminating residual disease (eg, MTX, 6-MP, vincristine and glucocorticoidpulses)

Pharmacotherapy

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 dataregarding these two interventions is still pending. Mature B-cell ALL needs to be treated in the same way asdisseminated Burkitt lymphoma, with short-term intensive chemotherapy, including high-dose MTX, cytarabine, andcyclophosphamide over a 6-month period.

Blood transfusions or antibiotics may be required to deal with complications of ALL therapy. Do not administer folatesupplementation 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 bicarbonateCranial irradiation: Effectively prevents overt CNS relapse but potentially causes neurotoxicity and brain tumors;largely replaced by intensive intrathecal and systemic chemotherapyAllogeneic HSCT (hematopoietic stem cell transplant): Usually following second complete remission afterrelapse (if early) or first remission in high risk patients; potentially prevents relapse and/or mortality vschemotherapy alone.

Surgical options

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

BackgroundAcute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing one quarterof all pediatric cancers. The annual incidence of acute lymphoblastic leukemia within the United States is 3.7-4.9 casesper 100,000 children age 0-14 years,[3] with a peak incidence in children aged 2-5 years.

Although a few cases are associated with inherited genetic syndromes (eg, Down syndrome) or congenitalimmunodeficiencies (eg, Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause remains largely unknown.[4]

With improvements in diagnosis and treatment, overall cure rates for children with acute lymphoblastic leukemia havereached 90%.[5] The use of risk-adapted treatment protocols has improved cure rates while limiting the toxicity oftherapy. This article summarizes the current diagnosis and treatment of childhood acute lymphoblastic leukemia.

PathophysiologyIn acute lymphoblastic leukemia (ALL), a lymphoid progenitor cell becomes genetically altered and subsequentlyundergoes dysregulated proliferation, with clonal expansion. In ALL, the transformed lymphoid cells reflect the alteredexpression of genes usually involved in the normal development of B cells and T cells. Several studies indicate thatleukemic stem cells are present in certain types of ALL.


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EpidemiologyAnnually, around 3000 children in the United States are diagnosed with ALL. The annual incidence of ALL within theUnited States is 3.7-4.9 cases per 100,000 children 0-14 years of age.[3] with a similar estimated worldwide incidence,although it has been questioned whether the incidence may be less in low-income countries.[6] White children are morefrequently affected than black children, and there is a slight male preponderance, which is most pronounced for T-cellacute lymphoblastic leukemia. The incidence of acute lymphoblastic leukemia peaks in children aged 2-5 years andsubsequently decreases with age.

Although a few cases are associated with inherited genetic syndromes (eg, Down syndrome) or congenitalimmunodeficiencies (eg, Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause remains largely unknown.[4]

Environmental risk factors such as exposure to ionizing radiation and electromagnetic fields and parental use ofalcohol and tobacco have not been shown to cause pediatric acute lymphoblastic leukemia. In addition, no direct linkhas been established between viral exposure and the development of childhood leukemia.

PrognosisThe likelihood of long-term cure in ALL depends on the clinical and laboratory features and the treatment. Prognosticrisk assessment includes clinical features (age and white blood cell [WBC] count at diagnosis), biologic characteristicsof the leukemic blasts, response to the induction chemotherapy, and minimal residual disease (MRD) burden. Basedon these criteria, patients can be effectively stratified into low risk, average or standard risk, high risk, and very highrisk.[7]

Standard-risk patients are aged 1-9.9 years with WBC of less than 50,000 at presentation, lack unfavorablecytogenetic 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 marrowby 29 days (rapid early response). Low-risk patients have < 0.01% blasts for both time points and have favorablecytogenetics (eg, trisomy 4, 10). High-risk patients do not meet these criteria or have extramedullary involvement thatmakes it inappropriate for them to be treated as standard risk. Very-high-risk patients have unfavorable cytogeneticfeatures (Philadelphia chromosome, hypodiploidy (n < 44), MLL gene rearrangement or poor response to initialchemotherapy (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.[8]

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. COGredefined very high risk to include high risk patients 13 years of age, which made the range of outcomes wider forthis 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% in1990-1994.[5] Improvement in survival was observed for all age groups of children, except for infants younger than 1year. In low-income countries (LIC), therapeuticresults for pediatric ALL have been less encouraging due to delayeddiagnosis, abandonment of therapy, and death from toxicity due to suboptimal supportive care. Nevertheless, current4-year event-free survival rates are 61% in India,[8] and over 78% in Lebanon,[9] demonstrating that pediatric ALL iscurable in LIC.

An analysis of long-term survival among 21,626 children with ALL treated in COG trials from 1990-2005 found that10-year survival rose to almost 84% in 1995-1999 from 80% in 1990-1994. The analysis also found that survivalimproved for almost all groups, including older children and black children.[5]

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

Tumor lysis syndromeRenal failureSepsisBleedingThrombosisTyphlitisNeuropathyEncephalopathySeizures


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In addition, lifelong follow-up is necessary,[1] because survivors may experience late effects from treatment for thiscondition, such as the following:

Secondary malignancyShort stature (if craniospinal radiation)Growth hormone deficiencyLearning disabilityCognitive defects

Patient EducationEnsure that the patient's parents and guardians understand that ALL usually does not have a known cause, thataccurate stratification helps guide therapy, and that participating in institutional or consortium-based clinical trials mayhelp lead to better outcomes in the future. In addition, parents and guardians must know the expected adverse effectsof each medication and be able to recognize signs and symptoms that require immediate medical attention, such asthose for anemia, thrombocytopenia, and infection. Furthermore, parents and patients must know how to quicklyaccess medical help from the oncology team.

For patient education information, see Cancer and Tumors Center, as well as Leukemia.

Contributor Information and DisclosuresAuthorVikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP Associate Professor and Division Chief of PediatricHematology and Oncology, Department of Pediatrics, Albany Medical Center

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP is a member of the following medical societies: AmericanAcademy of Pediatrics, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, andRoyal College of Physicians of the United Kingdom

Disclosure: Jazz Pharmaceutical Honoraria Speaking and teaching

Coauthor(s)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 ofCalifornia, Davis, School of Medicine, UC Davis Medical Center

Janet M Yoon, MD is a member of the following medical societies: American Society of PediatricHematology/Oncology and Children's Oncology Group


Chief EditorRobert J Arceci, MD, PhD Director, Children's Center for Cancer and Blood Disorders, Department ofHematology/Oncology, Co-Director of the Ron Matricaria Institute of Molecular Medicine, Phoenix Children'sHospital; Editor-in-Chief, Pediatric Blood and Cancer; Professor, Department of Child Health, University of ArizonaCollege of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for CancerResearch, American Association for the Advancement of Science, American Pediatric Society, American Society


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of Hematology, and American Society of Pediatric Hematology/Oncology


Additional ContributorsTimothy P Cripe, MD, PhD Professor of Pediatrics, Division of Hematology/Oncology, Cincinnati Children'sHospital Medical Center; Clinical Director, Musculoskeletal Tumor Program, Co-Medical Director, Office for Clinicaland Translational Research, Cincinnati Children's Hospital Medical Center; Director of Pilot and CollaborativeClinical and Translational Studies Core, Center for Clinical and Translational Science and Training, University ofCincinnati College of Medicine

Timothy P Cripe, MD, PhD is a member of the following medical societies: American Association for theAdvancement of Science, American Pediatric Society, American Society of Hematology, American Society ofPediatric Hematology/Oncology, and Society for Pediatric Research


Stephan A Grupp, MD, PhD Director, Stem Cell Biology Program, Department of Pediatrics, Division ofOncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania Schoolof Medicine

Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for CancerResearch, American Society for Blood and Marrow Transplantation, American Society of Hematology, AmericanSociety of Pediatric Hematology/Oncology, and Society for Pediatric Research


Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College ofPharmacy; Pharmacy Editor, eMedicine


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