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Pediatric Acute Lymphoblastic Leukemia

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Pediatric Acute Lymphoblastic Leukemia

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

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Pediatric diatri c Acute Acu te Lym Lym phobla phobl asti c Leukem Leukem ia  Author:  Author: Vikra Vikramjit mjit S Kanw Kanwar ar,, MBBS, MBA, MRCP(UK), MRCP(UK), FAAP; Chief Chief Editor: Robert J Arceci, MD, MD, PhD more... Updated: Apr 25, 2014

Practi Practi ce Essentials  Acute lymphobla lymphoblastic stic leukemia leukemia (ALL) is the most common maligna malignancy ncy diagnosed diagnosed in children children,, representing 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 and/or extramedullary disease. W hen leukemic blasts replace the bone b one marrow, marrow, patients present pres ent 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 AL L: Bone Bo ne pain, arthritis, arthritis, limping; fe vers (low or high); neutropenia; fatigue, pallor, pallor, petechiae, and bleeding; lymphadenopathy and hepatosplenomegaly Patients with mature-B mature-B ALL: A LL: Extra E xtramedullary medullary masses in i n the abdomen or head/neck; CNS involvement 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.[1] Testicular estic ular involvement involvement at diagnosis is also rare; if p resent, it appears as unilateral unilateral painless painless testicular  enlargement. See Clinical Presentation for Presentation  for more m ore detail. detail.

Diagnosis Testing Complete morphologic, immunologic, and genetic examination of the leukemic cells is necessary to establish the diagnosis 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-cell–associated surface antigens (diagnosis of T-lineage ALL)

Pediatric Acute Lymphoblastic Leukemia

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

Cytogenetic studies - To identify specific genetic alterations in leukemic blasts Molecular studies (eg, FISH, RT-PCR, Southern blot analysis) - To identify translocations not detected on routine karyotype analysis; to distinguish lesions that appear cytogenetically identical but are molecularly different Minimal residual disease studies [2] - To detect chimeric transcripts generated by 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 p athways 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 Procedures 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.

Management Leukemia is a systemic disease, and treatment is primarily based on chemotherapy. However, the different forms of   ALL require different approaches for optimal results. Treatment of subclinical CNS leukemia is an essential component of ALL therapy. Treatment for ALL typically consists of the following phases: Remission-induction phase (eg, dexamethasone or prednisone, vincristine, asparaginase, daunorubicin) Intensification/consolidation phase: 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 B erlin-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 pulses) 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, cyclop hosphamide) Corticosteroids (eg, prednisone, dexamethasone)  Antimicrobials (eg, TMX/SMP, pentamidine)

Pediatric Acute Lymphoblastic Leukemia

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

 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: Effec tively 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 from a child with B-precursor acute lymphoblastic leukemia. The marrow is replaced primarily with small, immature lymphoblasts that show open chromatin, scant cytoplasm, and a high nuclear-cytoplasmic ratio.

Background  Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing 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, [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 congenital immunodeficiencies (eg, Wiskott-Aldrich syndrome , ataxia-telangiectasia), the c ause remains largely unknown. [4] With improvements in diagnosis and treatment, overall cure rates f or children with acute lymphoblastic leukemia have reached 90%. [5] The use of risk-adapted treatment protocols has improved cure rates while limiting the toxicity of  therapy. This article s ummarizes the current diagnosis and treatment of childhood acute lymphoblastic leukemia.

Pathophysiology 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.

Pediatric Acute Lymphoblastic Leukemia

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

Epidemiology  Annually, around 3000 children in the United States are diagnosed with ALL. The annual incidence of ALL within the United States is 3.7-4.9 c ases 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 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 c ause remains largely unknown. [4] Environmental risk factors such as exposure to ionizing radiation and electromagnetic fields and parental use of  alcohol and tobacco have not been shown to cause pediatric acute lymphoblastic leukemia. In addition, no direct link has been established between viral exposure and the development of childhood leukemia.

Prognosis The likelihood of long-term cure in ALL depends on the clinical and laboratory features and the treatment. Prognostic risk assessment includes clinical features (age and white blood cell [WBC] count at diagnosis), biologic characteristics of the leukemic blasts, response to the induction chemotherapy, and minimal residual disease (MRD) burden. Based on these criteria, patients can be effectively stratified into low risk, average or standard risk, high risk, and very high risk.[7] 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 Children’s 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 fo r 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 bo ne 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. 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 1990-1994. [5] 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, [8] and over 78% in Lebanon, [9] 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.

[5]

 Acute complications may involve all organ systems and include the following: Tumor lysis syndrome Renal failure Sepsis Bleeding Thrombosis Typhlitis Neuropathy Encephalopathy Seizures

Pediatric Acute Lymphoblastic Leukemia

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

In addition, lifelong follow-up is necessary, [1] because survivors may experience late effects from treatment for this condition, such as the following: Secondary malignancy Short stature (if craniospinal radiation) Growth hormone deficiency Learning disability Cognitive defects

Patient Education Ensure that the patient's parents and guardians understand that ALL usually does not have a known cause, that accurate stratification helps g uide 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.

Contributor Information and Disclosu res  Author  Vikr amji t S Kanw ar, MBBS, MB A, 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: 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 of  California, Davis, School of Medicine, UC 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 Disclosure: Nothing to disclose. Chief Editor  Robert J Arc eci, 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

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

of Hematology, and American Society of Pediatric Hematology/Oncology Disclosure: Nothing to disclose.  Additional Contributors Timot hy P Crip e, 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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Pediatric Acute Lymphoblastic Leukemia

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Lymphoid Malignancies. J Clin Oncol. Aug 19 2013;[Medline]. 47. Schultz KR, Pullen DJ, Sather HN, et al. Risk- and response-based classification of childhood B-precursor  acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood. Feb 1 2007;109(3):926-35. [Medline]. [Full Text]. 48. Teachey DT, Hunger SP. Predicting relapse risk in childhood acute lymphoblastic leukaemia. Br J Haematol. Sep 2013;162(5):606-20. [Medline]. 49. Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, 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]. Medscape Reference © 2011 WebMD, LLC

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