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Pediatric Acute Lymphoblastic Leukemia Workup

  • Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Jennifer Reikes Willert, MD  more...
 
Updated: Dec 04, 2014
 

Approach Considerations

Upon initial evaluation, obtain a complete blood cell (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 × 109/L (>10 × 103/µL) occurs in one half of patients with acute lymphoblastic leukemia (ALL). Neutropenia, anemia, and thrombocytopenia are often observed secondary to inhibition of normal hematopoiesis by leukemic infiltration. It is important to recognize that 20% of patients with ALL initially present with pancytopenia and no evidence of peripheral blasts.[13]

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 in patients with T-lineage ALL and should include tests of the prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level, and D-dimer level to assess for disseminated intravascular coagulation (DIC).

No other imaging studies than chest radiography to evaluate for a mediastinal mass should be required. However, if the physical examination reveals enlarged testes, perform ultrasonography to evaluate for testicular infiltration. In addition, if anthracyclines are to be administered, obtain a baseline echocardiogram and an electrocardiogram (ECG).

To assess for central nervous system (CNS) involvement and to administer intrathecal chemotherapy, lumbar puncture with cytospin morphologic analysis is performed before systemic chemotherapy is administered. Due to increased risk of relapse with a traumatic lumbar puncture, it should be performed by an experienced pediatric oncologist in patients with adequate platelet counts.

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Immunophenotyping

Acute lymphoblastic leukemia (ALL) 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, so that ALL can be classified as B-lineage or T-lineage ALL.

Mature B-cell ALL should be differentiated from other B-lineage ALL and accounts for only 1-3% of childhood ALL. Diagnosis depends on the detection of surface immunoglobulin on leukemic blasts, as well as distinctive morphology, with deeply basophilic cytoplasm containing prominent vacuoles, designated L3 in the French-American-British (FAB) system (see Histologic Features).

B-lineage ALL accounts for 80% of childhood ALL and involves lymphoblasts that have cell-surface expression of 2 or more B-lineage–associated antigens (ie, CD19, CD20, CD24, CD22, CD21, or CD79).[6] CD10 is commonly expressed, which makes it a useful diagnostic marker, and the presence of aberrant myeloid markers (eg, CD7) is occasionally noted but has little prognostic impact. B-cell precursors of ALL can be further subclassified as early pre–B-cell, pre–B-cell, or transitional pre–B-cell, but distinguishing these subtypes is usually not clinically relevant.

T-lineage ALL accounts for 10-15% of childhood ALL, and is identified by the expression of T-cell–associated surface antigens, of which cytoplasmic CD3 is specific. T-cell ALL cases can be classified by early, mid, or late thymocytes, and 10% of cases are early T-precursor (ETP) ALL characterized by absent CD1a and CD8, weak CD5, and one or more myeloid or stem cell markers (eg, CD117, CD34, CD13, CD33). ETP ALL is thought to have worse prognosis, but this assumption may not be valid on modern T-cell ALL chemotherapy protocols.

The overall outcome for T-lineage and high risk B-lineage ALL is similar, provided intensive chemotherapy is used.

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Cytogenetic and Molecular Studies

In 80% of pediatric acute lymphoblastic leukemia (ALL) cases, specific genetic alterations can be found in leukemic blasts using routine karyotype analysis and molecular techniques, such as fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and Southern blot analysis. Important diagnostic, therapeutic, and prognostic implications are associated with the abnormalities described.[14]

See Acute Lymphoblastic Leukemia Staging for summarized information.

B-lineage ALL has a variety of chromosomal abnormalities, which in almost half of cases confer favorable outcomes:

  • t(12;21)(p13;q22) or ETV6-RUNX1 (formerly known as TEL-AML1) (20-25% cases)
  • Hyperdiploidy (>50 chromosomes/cell) (25% cases) associated with non-random trisomies X, 4, 6, 10, 14, 17, 18 and 21. Trisomy 4 and 10 alone (and in the past with trisomy 17 or "triple trisomy”) has been found to confer benefit. It is very important to confirm that "hyperdiploidy" does not represent doubling of a near-haploid clone, which has a poor prognosis

Other, less common, chromosomal abnormalities confer a poor outcome:

  • Extreme hypodiploidy with < 44 chromosomes/cell (1% of cases) which can be subdivided into near-haploid ALL (24–31 chromosomes) harboring mutations affecting receptor tyrosine kinase and RAS signaling, and low-hypodiploid ALL (32–39 chromosomes) characterized by alterations in TP53 as a manifestation of Li-Fraumeni Syndrome.
  • MLL gene rearrangement eg t(4;11)(q21;q23) (6% cases)
  • Philadelphia chromosome positivity t(9;22)(q34;q11) (3% cases)
  • Internal amplification of chromosome 21 (iAMP 21) (2% cases)

And some chromosomal abnormalities are of uncertain significance:

  • t(1;19)(q23;p13) or TCF3-PBX1 (formerly known as E2A-PBX1) (4% cases) was thought to confer poor prognosis with increased risk of CNS relapse, but this is no longer true with contemporary treatment.

Genome-wide association studies (GWAS) use techniques that are not widely available to define genetic abnormalities in the 20% of B-lineage ALL cases where routine testing is unrevealing, demonstrating changes associated with poor outcome:

  • "Ph-like" ALL (10-15% of cases) with gene expression similar to Ph+ ALL which commonly have IZKF1 alteration, and in half of cases cryptic rearrangements of CRLF2 (cytokine receptor like factor 2). Approximately half of CRLF2 -rearranged cases have point mutations in Janus kinase (JAK) family members JAK1 and JAK2
  • Increased CRLF2 (cytokine receptor like factor 2) expression, which may have an underlying CRLF2 mutation (5-7% of cases). Interestingly, increased CRLF2 expression is also seen in 50% of the patients with Down syndrome and ALL, where its prognostic value is uncertain.

T-lineage ALL also has a variety of chromosomal abnormalities with less well-defined prognostic value:

  • Constitutive activation of NOTCH1 signaling is the most common abnormality and secondary to activating mutations in NOTCH1 (>50% of cases of T-ALL), FBXW7 mutations (15% of cases), and t(7;9)(q34;q34.3) (< 1% of cases), and may convey favorable outcome.
  • Genetic lesions also include homeobox ( HOX), LMO, and bHLH family members. Amongst the HOX genes TLX1 rearrangement t(10;14)(q24;q11) was thought to confer a favorable prognosis (5-10% cases) and TLX3 rearrangement t(5;14)(q35;q32) less favorable (20-25% cases).
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Minimal Residual Disease Studies

Traditionally, the response to leukemia treatment has been assessed morphologically, which can be challenging when looking for small numbers of leukemic cells, especially in bone marrow specimens recovering from chemotherapy or after transplantation.

Studies of minimal residual disease (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 immunophenotype specific to the leukemic blasts.[4] All of the methods for detecting MRD have a much higher sensitivity than that of morphology, and all studies using MRD techniques have shown significant correlations between end-of-induction leukemia burden and outcome.[15] As a result, current treatment protocols use MRD measurements for acute lymphoblastic leukemia risk assignment.[16]

For B-lineage ALL patients, MRD is used as follows:

  • On COG P9904/5/6 clinical trials, multivariate analysis found Day 29 (end of induction)bone marrow (BM) MRD measured by flow cytometry with a cut-off of 0.01% was the most significant predictor of outcome in patients with B-ALL. The effect of MRD was quantitatively different among genetic subgroups and NCI risk groups. These studies also found that Day 8 peripheral blood MRD level was an independent predictor of outcome in multivariate analysis.
  • The UK ALL 2003 clinical trial also confirmed MRD as the single most important predictor of relapse, and patients with day 29 BM MRD ≥ 0.01% had a threefold higher relapse rate (5-year EFS 79%) compared with low-risk patients (5-year EFS 94-95%).

For T-lineage ALL patients:

  • The Italian Association of Pediatric Haematology-Oncology (AIEOP)-Berlin-Frankfurt-Muenster (BFM) 2000 study used PCR to measure MRD on Day 33 (end induction) and Day 78 (end of consolidation, EOC) and found EOC MRD a better predictor of adverse outcome in T-lineage ALL. Regardless of Day 33 MRD, patients who had EOC MRD < .01% had a 7-year EFS of at least 80%, in contrast to patients with EOC MRD >.01% who had a7-year EFS of 49%.
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Ultrasonography

Perform testicular ultrasonography if the testes are enlarged upon physical examination.

Some clinicians use renal ultrasonography to evaluate for leukemic kidney involvement as an assessment of risk for tumor lysis syndrome.

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Bone Marrow Aspiration and Biopsy

Bone marrow aspirate and biopsy results confirm the diagnosis of acute lymphoblastic leukemia (ALL). 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 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 acut 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 acut Bone marrow aspirate from a child with B-cell acute lymphoblastic leukemia. The lymphoblasts are large and have basophilic cytoplasm with prominent vacuoles.
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Histologic Features

According to the French-American-British (FAB) classification system, acute lymphoblastic leukemia (ALL) is classified into 3 groups based on morphology, as follows:

  • L1: The lymphoblast cells are usually small, with scant cytoplasm and inconspicuous nucleoli. L1 accounts for 85% of all cases of childhood acute lymphoblastic leukemia.
  • L2: The lymphoblast 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: The lymphoblast 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.

See Acute Lymphoblastic Leukemia Staging for more complete information.

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Contributor Information and Disclosures
Author

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP Professor of Pediatrics, Albany Medical College; Chief, Division of Pediatric Hematology-Oncology, John and Anna Landis Endowed Chair for Pediatric Hematology-Oncology, Medical Director, Melodies Center for Childhood Cancer and Blood Disorders, 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 Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, International Society of Pediatric Oncology

Disclosure: Nothing to disclose.

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, Children's Oncology Group

Disclosure: Nothing to disclose.

Chief Editor

Jennifer Reikes Willert, MD Associate Clinical Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Section of Stem Cell Transplantation, Stanford University Medical Center, Lucile Packard Children's Hospital

Jennifer Reikes Willert, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society for Blood and Marrow Transplantation, Children's Oncology Group, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Acknowledgements

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; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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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.
 
 
 
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