Οξεία λεμφοβλαστική λευχαιμία PDF Print E-mail
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Clinical Background

Acute lymphoblastic leukemia (ALL) is a malignant disease of the lymphoid cell line occurring predominantly in children.

Epidemiology

  • Incidence – 3-4/100,000 children; occurs five times more frequently than acute myeloid leukemia (AML)
  • Age – peak incidence 2-5 years
  • Sex – M>F
  • Ethnicity
    • <3 years – Caucasian predominance
    • ≥3 years – African Americans have higher risk

Risk Factors

Genetics

  • Recurrent genetic abnormalities associated with B-ALL
    • Adults
      • B-ALL with t(9;22)(q34;q11.2)(BCR-ABL1)
      • B-ALL with rearrangement of 11q23 (MLL)
      • B-ALL with t(1;19)(q23;p13.3) [E2A/PBX1  (TCF3-PBX1)]
      • B-ALL with t(5;14)(q31;q32)(IL3-IGH) – ALL with eosinophilia
      • B-ALL with MYC rearrangement (8q24)
    • Pediatric
      • B-ALL with t(9;22)(q34;q11.2)(BCR-ABL1)
      • B-ALL with t(12;21)(p13;q22) (ETV6-RUNX1)
      • B-ALL with rearrangement of 11q23 (AF4-MLL, ENL-MLL)
      • B-ALL with t(1;19)(q23;p13.3) [E2A-PBX1 (TCF3-PBX1)]
      • Hyperdiploidy in association with trisomy, 4, 10 and 17
      • Hypoploidy in association with <46 chromosomes
  • T-ALL
    • No recurrent abnormalities identified
    • Abnormalities typically reveal T-cell receptor rearrangements and abnormal karyotype in 50-70% of cases, often involving rearrangements to T-cell receptor loci (TCRα/β) at 14q11.2
      • Common examples include
        • t(1;14) (p32;q11) (TAL-SCL1)
        • t(10;14) (q24;q11.2) (HOX11)
        • t(5;14) (p35;q32) (HOX11/L2)
        • t(11;14) (LMO1)
        • t(7;11) (LMO2)

Clinical Presentation

  • Vague constitutional symptoms – fever, anemia, pallor, failure to thrive, bruising

Diagnosis

Indications for Testing

  • Abnormal blood count, constitutional symptoms without other etiology

Laboratory Testing

  • CBC with peripheral smear – leukocytosis and blasts are not uncommon
  • Cytochemical staining – used infrequently due to availability of immunophenotyping
    • MPO, Sudan Black B, chloroacetate esterase – usually negative (if used)
    • ALL blasts – often PAS positive
  • Immunophenotyping – determine antigen markers for identifying cell lineage and predicting outcome
    • CD expression helps establish ALL lineage
    • B-ALL is characterized by B-cell antigens – PAX5, CD19, CD20, CD22, CD24, CD79a
      • CD20 only partially expressed in non-mature forms
      • CD10 also frequently expressed
    • T-ALL is characterized by T-cell antigens – CD2, CD3, CD4, CD5, CD7, CD8
      • Also CD1a, CD10, CD34, CD99, HLA-DR, and TdT
      • Subclassification of T-ALL by stage of normal thymocyte maturation

        Subclassification of T-ALL
        by Stage of Normal Thymocyte Maturation

        T-ALL Subtype

        CD1a

        CD2

        cCD3

        sCD3

        CD4

        CD5

        CD7

        CD8

        CD34

        Pro-T

        -

        -

        +

        -

        -

        -

        +

        -

        +

        Pre-T

        -

        +

        +

        -

        -

        ±

        -

        -

        ±

        Cortical T

        +

        +

        +

        -

        +

        ±

        +

        +

        -

        Medullary T

        -

        +

        +

        +

        ±*

        ±

        +

        ±

        -

        *Medullary stage T-ALL shows either CD4 or CD8 expression

      • May also express myeloid antigens – CD11b, CD13, CD15, CD33
  • Cytogenetic studies – important for diagnostic and prognostic workup
    • Most B-ALL contains genetic abnormalities, usually translocations
      • Abnormality highly associated with prognosis
    • T-ALL/LBL contains TCR gene rearrangements
    • See Genetics section for specific abnormalities
  • FISH – more sensitive than conventional cytogenetics in detecting genomic aberrations
    • Routine in initial diagnostic workup, prognostic stratification (especially in children), and determination of treatment approach

Histology

  • Bone marrow biopsy – enumerate blasts and collect material for ancillary testing (eg, cytogenetics)
  • Immunohistochemistry
    • Most useful stains include TdT; CD3; CD10 (CALLA); CD20, L26; CD79A

Prognosis

  • Age – strong prognostic effect
    • Children (1-9 years) have a better outcome than infants, adolescents or adults
  • Immunophenotyping – presence of CD10 or CD95 indicates favorable prognosis
  • Molecular markers
    • Favorable prognosis
      • Hyperploidy (51-65 chromosomes or DNA index ≥1.6) with trisomies of 4, 10, 17
      • TEL-AML1 t(12;21) fusion positive, E2A-PBX1 t(1;19)
    • Poor prognosis – 11q23 MLL rearrangement; BCR-ABL1 t(9;22) fusion and hypodiploidy (if <45 chromosomes), near haploidy
      • BCR-ABL1 relapse – typically occurs following short chronic relapse (CR) and correlates with extremely poor prognosis
        • Second CR cannot be induced in many patients
  • Leukocytosis is a continuous variable – poor prognosis
    • >100x109/L increases risk of relapse in the central nervous system (CNS)
    • >400x109/L – high risk for CNS hemorrhage along with pulmonary and neurologic leukostasis event
  • Minimal residual disease present – poor prognosis in adults

Differential Diagnosis

Pharmacogenetics and Therapeutic Drug Monitoring

  • Thiopurine S-methyltransferase (TPMT)
    • Thiopurine prodrugs are metabolized via TPMT enzymatic activity
    • Deficiency of TPMT predicts hematopoietic toxicity after thiopurine treatment
    • Increased risk of therapy-related acute myeloid leukemia (AML) and radiation-induced brain tumors in patients receiving intensive thiopurine therapy
    • Testing to determine activity level may be helpful in dosing thiopurine drugs and also help avert bone marrow suppression
      • For deficient activity, dose reduction of 80-90% may be required
      • For intermediate activity, dose reduction of 20-50% may be required
  • Other pharmacogenetic pathways (no testing currently available)
    • During induction therapy for ALL
      • Predominant drug metabolism pathway is via CYP3A
      • CYP3A5 GG genotype (lower CYP3A5 activity) predicts gastrointestinal (GI) toxicity and rates of infection
    • During consolidation and continuation phase of therapy
      • Reduced folate carrier (RFC) AA or AG genotype predicts GI toxicity
    • During all phases
      • UGT1A1 promotor repeat polymorphism (UGT1A1 7h) predicts hyperbilirubinemia
    • MTHFR polymorphism
      • Probably affects methotrexate toxicity
      • MTHFR C677T variant associated with higher rate of relapse
    • Therapy molecular targets
      • Investigational use of Imatinib for BCR-ABL1-positive ALL
    • Adverse drug effects
      • Polymorphism in eight genes significantly associated with glucocorticoid-induced hypertension (CNTNAP2, LEPR, CRHR1, NTAN1, SLCI2A3, ALPL, BGLAP, and APOB)
      • PAI-1 polymorphism associated with GA/AA genotype – increased risk of glucocorticoid-induced osteonecrosis

Monitoring

  • Repeat PCR or FISH testing using leukemia-associated phenotype defined at diagnosis for detection of minimal residual disease (MRD)
    • MRD by PCR or FISH defined as >10-4 cells or >0.01% blasts
    • Qualitative/quantitative PCR testing is very sensitive and may detect MRD that is not of clinical concern
      •  PCR has lower sensitivity than FISH
    • >10% MRD portends higher relapse rate
    • B-cell lines MRD detected by bone marrow; T-cell lines MRD can be detected by peripheral blood
      • T-ALL – detection of TdT or CD34 confirms MDR
    • Relapse mandates new immunophenotyping and molecular testing – karyotype may change and, rarely, second de novo ALL discovered

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and NumberRecommended UseLimitationsFollow Up
CBC with Platelet Count & Automated Differential 0040003
Method: Automated Cell Count with Flow Cell Differential

Initial evaluation of suspected leukemia

   
Sudan Black B Stain 0049040
Method: Stain

Differentiate type of leukemia

   
Esterase Stain, Specific 0049055
Method: Cytochemical Stain

Differentiate type of leukemia

   
Leukemia/Lymphoma Phenotyping (Comprehensive - Whole Blood) 0096299
Method: Flow Cytometry

Important test for workup as therapy; prognosis is different for B- and T-cells

Available Antigens Included:
T-cell:
CD1, CD2, CD3, CD4, CD5, CD7, CD8, TCR alpha-beta, TCR gamma-delta, cytoplasmic CD3
B-cell: CD10, CD19, CD20, CD22, CD23, CD103, kappa, lambda, FMC7, cytoplasmic kappa, cytoplasmic lambda
Myelo/Mono: CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase

   
Leukemia/Lymphoma Phenotyping (Comprehensive - Bone Marrow) 0095244
Method: Flow Cytometry

Important test for workup as therapy; prognosis is different for B- and T-cells

Available Antigens Included:
T-cell:
CD1, CD2, CD3, CD4, CD5, CD7, CD8, TCR alpha-beta, TCR gamma-delta, cytoplasmic CD3
B-cell: CD10, CD19, CD20, CD22, CD23, CD103, kappa, lambda, FMC7, cytoplasmic kappa, cytoplasmic lambda
Myelo/Mono: CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase
Misc: CD11c, CD16, CD25, CD30, CD34, CD38, CD41, CD42b, CD45, CD56, CD57, CD61, HLA-DR, glycophorin, TdT, bcl-2

   
TdT by Immunohistochemistry 2004142
Method: Immunohistochemistry

Aid in histologic diagnosis of ALL

Stained and returned to client pathologist; consultation available if needed

   
CD10 (CALLA) by Immunohistochemistry 2003523
Method: Immunohistochemistry

Aid in histologic diagnosis of ALL

Stained and returned to client pathologist; consultation available if needed

   
CD19 by Immunohistochemistry 2005114
Method: Immunohistochemistry

Aid in histologic diagnosis of B-cell leukemia/lymphoma

Stained and returned to client pathologist for interpretation; consultation available if needed

   
CD20, L26 by Immunohistochemistry 2003532
Method: Immunohistochemistry

Aid in histologic diagnosis of ALL

Stained and returned to client pathologist; consultation available if needed

   
CD79A by Immunohistochemistry 2003800
Method: Immunohistochemistry

Aid in histologic diagnosis of ALL

Stained and returned to client pathologist; consultation available if needed

   
CD3 by Immunohistochemistry 2003508
Method: Immunohistochemistry

Aid in histologic diagnosis of ALL

Stained and returned to client pathologist; consultation available if needed

   
Acute Lymphocytic Leukemia (ALL) Panel by FISH, Adult 2002647
Method: Fluorescence in situ Hybridization

Provides prognostic information and supplements diagnosis in adult patients with B-ALL

Detects the following genetic abnormalities: t(9;22) (BCR-ABL1) and rearrangements of MLL, TCF3(E2A), and IGH

Rearrangement of MYC rarely present in pre-B-ALL adults; probe detects this abnormality

Chromosome alterations outside regions complementary to these probes are not detected

Other recurrent aberrations, such as hyperdiploidy and t(12;21), are rarely present in adults with B-ALL but may warrant additional FISH tests/chromosome analysis

 
Acute Lymphocytic Leukemia (ALL) Panel by FISH, Pediatric 2002719
Method: Fluorescence in situ Hybridization

Provides prognostic information and supplements diagnosis in pediatric patients with B-ALL

Detects the following genetic abnormalities: hyperdiploidy, t(9;22) (BCR-ABL1), t(12;21) (ETV6-RUNX1) and rearrangements of MLL, and TCF3(E2A)

   
Chromosome FISH, Interphase 2002298
Method: Fluorescence in situ Hybridization

May be used to order individual probes rather than adult or pediatric ALL panels

Translocations detected include:  t(12;21) TEL-AML1(ETV6-RUNX1) fusion; t(9;22) BCR-ABL1 fusion; 14q32 IGH rearrangement; E2A rearrangement, 11q23 MLL rearrangement, and hyperdiploidy; CDNK2 (p16) deletions

Indicate names of probes needed for testing

ARUP Oncology FISH Probes menu
   
Chromosome Analysis, Bone Marrow 2002292
Method: Giemsa-Band Analysis

Detect chromosome abnormalities in bone marrow aspirate consistent with the diagnosis of ALL, some of which also have classification and prognostic significance

   
ETV6-RUNX1 (TEL-AML1) Translocation, t(12;21) by RT-PCR 0056008
Method: Reverse Transcription Polymerase Chain Reaction

Prognosticator for ALL

Not designed to detect minimal residual disease

Limit of detection is 1/100 cells

 
MLL-AFF1 (MLL-AF4) Translocation, t(4;11) by RT-PCR 0050446
Method: Reverse Transcription Polymerase Chain Reaction

Prognosticator for ALL

Negative result does not exclude the presence of t(4;11) translocation

Not designed to detect minimal residual disease

Limit of detection is 1/100 cells

 
TCF3-PBX1 (E2A-PBX1) Translocation, t(1;19) by RT-PCR 0055346
Method: Reverse Transcription Polymer/Polymerase Chain Reaction

Follow up minimal residual disease

Prognosticator for ALL

Negative result does not exclude the presence of t(1;19) translocation

 
BCR-ABL1, Major (p210), Quantitative 2005017
Method: Reverse Transcription/Quantitative Polymerase Chain Reaction

Identify and monitor p210 BCR-ABL1 mRNA fusion in a subset of ALL with confirmed p210 Ph+

Assess treatment milestones and detect early signs of resistance to TKI therapy

Results must always be interpreted in context of morphologic and other relevant data and should not be used alone for  diagnosis of malignancy

Samples identified as negative may still harbor BCR-ABL1-positive cells at levels below limit of detection

BCR-ABL1 mRNA with minor breakpoint (e1a2; p190) not detected

 
BCR-ABL1, Minor (p190), Quantitative 2005016
Method: Reverse Transcription/Quantitative Polymerase Chain Reaction

Detect and monitor p190 BCR-ABL1 fusion found in an ALL subset

Diagnosis, prognosis, and therapeutic monitoring in patients with confirmed p190 Ph+ leukemia

Results must always be interpreted in context of morphologic and other relevant data and should not be used alone for diagnosis of malignancy

Samples identified as negative may still harbor BCR-ABL1-positive cells at levels below limit of detection

BCR-ABL1 mRNA with major breakpoint (e13a2, e14a2; p210) not detected

 
BCR-ABL1, Qualitative with Reflex to BCR-ABL1 Quantitative 2005010
Method: Reverse Transcription Polymerase Chain Reaction

Detect presence of BCR-ABL1 fusion when form is unknown or unclear

If either p210 or p190 fusion detected, appropriate quantitative test will be performed

   
BCR-ABL1, T315I Mutation Detection, Quantitative 2004924
Method: Reverse Transcription Polymerase Chain Reaction/Pyrosequencing

Identify T315I mutation in patients using TKI-directed therapy (Gleevec) who have a known BCR-ABL1 translocation to determine therapy options

Only the T315I mutation will be identified

 
 
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