Introduction to Leukaemia

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Introduction to Leukaemia

• Graduate Medical Program

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OVERVIEW

• Definition
• Acute vs Chronic Leukaemia
• Acute Leukaemia
• Aetiology
• Classification
• Morphology FAB
• Immunophenotyping
• Cytogenetics and Molecular Studies
• Principles of Treatment

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OVERVIEW

• Chronic Leukaemia
• Prognostic factors
• Unique features
• Principles of Treatment

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DEFINITION

• Extremely heterogeneous group
• Neoplastic transformation of uncommitted,
  partially committed or fully committed
  haemopoietic stem cells

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ACUTE vs CHRONIC
LEUKAEMIA

• Poorly differentiated blast population
• Rapidly fatal outcome, if untreated
• versus
• Well differentiated cell population
• Associated with longer survival, even if left
  untreated

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AML vs. CML
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CLINICAL PRESENTATION

• Reflects the effects of bone marrow failure
• Unique features, especially in chronic leukaemia

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ACUTE LEUKAEMIA

• Rapidly progressive if untreated survival weeks
  to months
• Always associated with severe bone marrow failure

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Age and sex distribution
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AETIOLOGY

• Ionizing Radiation
• Atomic Bombs
• - Hiroshima and Nagasaki, Utah,
  Chernobyl, Three Mile Island fall-out
• - within 1.5 - 3 years
• - peak incidence 5-10 years
• - dose dependent

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AETIOLOGY

• Occupational exposure
• - radiologists
• - nuclear industry
• Diagnostic radiographic procedures
• - Thorium dioxide
• - foetal exposure from radiographic
• pelvimetry
• Natural background radiation (EMF)

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AETIOLOGY

• Chemicals
• - benzene
• - rubber industry
• - pesticides
• Viruses
• - EBV
• - Human retroviruses (HTLV 12)

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AETIOLOGY

• Host factors
• - familial occurrence
• - genetic disorders (Downs syndrome)

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AETIOLOGY

• Medications
• - Chemotherapy (Alkylating agents)
• within 4-5 years
• proportionate to dose and
  duration
• - Radiotherapy adds extra risk
• - Immunosuppression

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CLASSIFICATION OF ACUTE LEUKAEMIA

• Based on cell origin
• - myeloid some features
  of granulocyte and/or monocyte development
• - lymphoid from
  lymphocyte precursors
• - ambiguous lineage
  undifferentiated, bilineal or biphenotypic

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CLASSIFICATION OF ACUTE LEUKAEMIA

• Standardisation of treatment
• Some acute leukaemias have peculiar features
• - ALL and lymph node, thymus and CNS
  involvement
• - APML and bleeding

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CLASSIFICATION OF ACUTE LEUKAEMIA

• Peripheral blood morphology subjective
• Bone marrow morphology subjective
• Immunophenotyping objective
• Cytogenetics
• Molecular studies

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MORPHOLOGY Romanowsky stained smears
of peripheral blood or bone marrow

• Nuclear chromatin pattern is
  most important

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AML
ALLdelicate chromatin clumped
chromatin much cytoplasm
scant cytoplasmfine granules/Auer rods
no granules
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FAB classification

• Romanowsky-stained morphology
• (Cytochemical stains)

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CLASSIFICATION ACUTE LEUKAEMIASALL

• ALL/L1 80
• - small blast cells
• - high N/C ratio
• ALL/L2 20
• - larger cells, heterogeneous
• - lower N/C ratio

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ALL/L1 ALL/L2
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CLASSIFICATION OF ACUTE LEUKAEMIASALL

• ALL/L3 3-5
• - large, homogeneous cells
• - fine chromatin, prominent nucleoli
• - intensely basophilic cytoplasm,
• vacuoles

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ALL/L3
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CLASSIFICATION OF ACUTE LEUKAEMIASAML

• Granulocytic differentiation 60
• - M0 - Acute myeloblastic leukaemia
• with minimal differentiation
• - M1 - Acute myeloblastic leukaemia
• with minimal maturation
• - M2 - Acute myeloblastic leukaemia
• with significant maturation
• - M3 - Acute promyelocytic leukaemia

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AML/M0 AML/M1
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AML/M2 AML/M3
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• Monocytic differentiation
• - M4 - Acute myelomonocytic leukaemia
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• - M5 - Acute monocytic leukaemia 10
• Erythroid differentiation
• - M6 - Acute erythroleukaemia lt5
• Megakaryocytic differentiation
• - M7 -Acute megakaryoblastic
  leukaemia lt5

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AML/M4 AML/M5
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AML/M6 AML/M7
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IMMUNOPHENOTYPINGobjective

• Measured by flow cytometry as intensity
• with which a fluorescence - conjugated
• antibody stains cell surface proteins.
• Indicates lineage commitment
• Indicates position along the normal haemopoietic
• pathway at the time of transformation

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Immunophenotyping
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Immunophenotyping

• MYELOID
• CD33
• CD13

• LYMPHOID
• B lineage
• CD19
• CD22
• CD10
• T lineage
• CD7
• CD3
• TdT

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CYTOGENETICS IN ACUTE LEUKAEMIA

• Translocations, deletions, inversions etc
• Diagnosis
• Prognosis
• Minimal Residual Disease (MRD)

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GENETICS

• Molecular abnormality, which corresponds to a
  cytogenetic abnormality
• May lead to the development of specific targeted
  therapy
• Contribution to basic science may represent the
  critical step in leukaemogenesis

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ACUTE LEUKAEMIA EXAMPLES of SOME CYTOGENETIC
and MOLECULAR ABNORMALITIES
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t(15,17)and the PML/RAR? gene

• Acute Promyelocytic Leukaemia
• - gene retinoic acid receptor (RAR?) gene
  
• fused with PML gene
• (PML/RAR? gene)
• - the PML/RAR alpha fusion protein
• makes APML a suitable target for ATRA

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APML and ATRA

• ATRA is a vitamin A derivative or retinoid
• Inhibition of cell cycling by ATRA leads to
  differentiation and cell death
• The previously drug resistant APML is now
  potentially curable

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t (9,22) Philadelphia chromosomeand BCRabl

• - 30 adult ALL, 3-10 childhood ALL
• - (95 CML)

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Ph chromosome BCR abl t(9,22)
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BCRabl and Imatinib

• The tyrosine kinase activity of BCR-abl is
  autonomous and leads to malignant transformation
• Imatinib is an inhibitor of the BCR-abl tyrosine
  kinase
• First patient June 1998-now 15 000

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t (12,21)

• - most common in childhood ALL
• - gene AML1 and TEL
• - extremely high long-term survival

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Approach to acute leukaemia

• In all, but the elderly or medically unfit,
  intensive initial treatment with combinations of
  chemotherapeutic drugs is indicated
• The aim is to rapidly clear leukaemic cells from
  the marrow and to restore normal bone marrow
  function,
• ie achieve REMISSION
• CURE is the goal

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PRINCIPLES OF TREATMENTAcute Leukaemias

• 1. Induction chemotherapy
• 2. Consolidation chemotherapy
• 3. Maintenance chemotherapy in ALL
• 4. Transplantation
• - autologous
• - allogeneic, sibling
• - MUD

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Response to treatment

• Childhood ALL gt98 remission
• 80 cure
• Adult AML and ALL 60-75 remission
• 25-35
  cure

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CHRONIC LEUKAEMIAS

• Slower course, even non-progressive
• with survival
• (with or without treatment)
• for years

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CLASSIFICATION

• CML Chronic myeloid leukaemia features of all
  stages of granulocyte development, including
  mature forms
• CLL Chronic lymphoid leukaemia mostly mature
  lymphocytes

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CML CLL
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CLINICAL FEATURES

• CML
• - incidental finding
• - splenomegaly
• - low or high platelet count
• - high white blood cell count
  hyperviscosity

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CLINICAL FEATURES

• CLL
• - incidental finding
• - lymphadenopathy
• - hepatosplenomegaly
• - bone marrow failure anaemia,
  neutropenia (with immunosuppression) and
• thrombocytopenia
• - autoimmune complications

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CML

• The Philadelphia chromosome t(9,22)
• Fusion gene BCR-ABL on chromosome 22
• Targeted therapy Imatinib

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Ph chromosome BCR abl t(9,22)
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CLL

• Immunophenotyping (CD5, CD19 and surface
  immunoglobulin kappa OR lambda)
• Identifies lymphocytosis as due to the clonal
  expansion of a single cell

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PRINCIPLES OF TREATMENT Chronic Leukaemias

• 1. CML
• -Imatinib (Glivec), based on the
  BCR-abl fusion gene
• - transplantation
• - (chemotherapy)
• 2. CLL
• - depends on extent of disease
  (staging)
• - nil or chemotherapy/anti-CD20 antibody

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OVERVIEW

• Definition
• Acute vs Chronic Leukaemia
• Acute Leukaemia
• Aetiology
• Classification
• Morphology FAB
• Immunophenotyping
• Cytogenetics and molecular studies
• Principles of Treatment

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• Chronic Leukaemia
• Unique features
• Principles of Treatment