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Introduction to Leukaemia

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Neoplastic transformation of uncommitted, partially committed or fully ... intensely basophilic cytoplasm, vacuoles. ALL/L3. CLASSIFICATION OF ACUTE LEUKAEMIAS ... – PowerPoint PPT presentation

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Title: Introduction to Leukaemia


1
Introduction to Leukaemia
  • Graduate Medical Program

2
OVERVIEW
  • Definition
  • Acute vs Chronic Leukaemia
  • Acute Leukaemia
  • Aetiology
  • Classification
  • Morphology FAB
  • Immunophenotyping
  • Cytogenetics and Molecular Studies
  • Principles of Treatment

3
OVERVIEW
  • Chronic Leukaemia
  • Prognostic factors
  • Unique features
  • Principles of Treatment

4
DEFINITION
  • Extremely heterogeneous group
  • Neoplastic transformation of uncommitted,
    partially committed or fully committed
    haemopoietic stem cells

5
(No Transcript)
6
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

7
AML vs. CML
8
CLINICAL PRESENTATION
  • Reflects the effects of bone marrow failure
  • Unique features, especially in chronic leukaemia

9
ACUTE LEUKAEMIA
  • Rapidly progressive if untreated survival weeks
    to months
  • Always associated with severe bone marrow failure

10
Age and sex distribution
11
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

12
AETIOLOGY
  • Occupational exposure
  • - radiologists
  • - nuclear industry
  • Diagnostic radiographic procedures
  • - Thorium dioxide
  • - foetal exposure from radiographic
  • pelvimetry
  • Natural background radiation (EMF)

13
AETIOLOGY
  • Chemicals
  • - benzene
  • - rubber industry
  • - pesticides
  • Viruses
  • - EBV
  • - Human retroviruses (HTLV 12)

14
AETIOLOGY
  • Host factors
  • - familial occurrence
  • - genetic disorders (Downs syndrome)

15
AETIOLOGY
  • Medications
  • - Chemotherapy (Alkylating agents)
  • within 4-5 years
  • proportionate to dose and
    duration
  • - Radiotherapy adds extra risk
  • - Immunosuppression

16
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

17
CLASSIFICATION OF ACUTE LEUKAEMIA
  • Standardisation of treatment
  • Some acute leukaemias have peculiar features
  • - ALL and lymph node, thymus and CNS
    involvement
  • - APML and bleeding

18
CLASSIFICATION OF ACUTE LEUKAEMIA
  • Peripheral blood morphology subjective
  • Bone marrow morphology subjective
  • Immunophenotyping objective
  • Cytogenetics
  • Molecular studies

19
MORPHOLOGY Romanowsky stained smears
of peripheral blood or bone marrow
  • Nuclear chromatin pattern is
    most important

20
AML
ALLdelicate chromatin clumped
chromatin much cytoplasm
scant cytoplasmfine granules/Auer rods
no granules
21
FAB classification
  • Romanowsky-stained morphology
  • (Cytochemical stains)

22
CLASSIFICATION ACUTE LEUKAEMIASALL
  • ALL/L1 80
  • - small blast cells
  • - high N/C ratio
  • ALL/L2 20
  • - larger cells, heterogeneous
  • - lower N/C ratio

23
ALL/L1 ALL/L2
24
CLASSIFICATION OF ACUTE LEUKAEMIASALL
  • ALL/L3 3-5
  • - large, homogeneous cells
  • - fine chromatin, prominent nucleoli
  • - intensely basophilic cytoplasm,
  • vacuoles

25
ALL/L3
26
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

27
AML/M0 AML/M1
28
AML/M2 AML/M3
29
  • Monocytic differentiation
  • - M4 - Acute myelomonocytic leukaemia
    25
  • - M5 - Acute monocytic leukaemia 10
  • Erythroid differentiation
  • - M6 - Acute erythroleukaemia lt5
  • Megakaryocytic differentiation
  • - M7 -Acute megakaryoblastic
    leukaemia lt5

30
AML/M4 AML/M5
31
AML/M6 AML/M7
32
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

33
Immunophenotyping
34
Immunophenotyping
  • MYELOID
  • CD33
  • CD13
  • LYMPHOID
  • B lineage
  • CD19
  • CD22
  • CD10
  • T lineage
  • CD7
  • CD3
  • TdT

35
CYTOGENETICS IN ACUTE LEUKAEMIA
  • Translocations, deletions, inversions etc
  • Diagnosis
  • Prognosis
  • Minimal Residual Disease (MRD)

36
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

37
ACUTE LEUKAEMIA EXAMPLES of SOME CYTOGENETIC
and MOLECULAR ABNORMALITIES
38
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

39
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

40
t (9,22) Philadelphia chromosomeand BCRabl
  • - 30 adult ALL, 3-10 childhood ALL
  • - (95 CML)

41
Ph chromosome BCR abl t(9,22)
42
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

43
t (12,21)
  • - most common in childhood ALL
  • - gene AML1 and TEL
  • - extremely high long-term survival

44
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

45
PRINCIPLES OF TREATMENTAcute Leukaemias
  • 1. Induction chemotherapy
  • 2. Consolidation chemotherapy
  • 3. Maintenance chemotherapy in ALL
  • 4. Transplantation
  • - autologous
  • - allogeneic, sibling
  • - MUD

46
Response to treatment
  • Childhood ALL gt98 remission
  • 80 cure
  • Adult AML and ALL 60-75 remission
  • 25-35
    cure

47
CHRONIC LEUKAEMIAS
  • Slower course, even non-progressive
  • with survival
  • (with or without treatment)
  • for years

48
CLASSIFICATION
  • CML Chronic myeloid leukaemia features of all
    stages of granulocyte development, including
    mature forms
  • CLL Chronic lymphoid leukaemia mostly mature
    lymphocytes

49
CML CLL
50
CLINICAL FEATURES
  • CML
  • - incidental finding
  • - splenomegaly
  • - low or high platelet count
  • - high white blood cell count
    hyperviscosity

51
CLINICAL FEATURES
  • CLL
  • - incidental finding
  • - lymphadenopathy
  • - hepatosplenomegaly
  • - bone marrow failure anaemia,
    neutropenia (with immunosuppression) and
  • thrombocytopenia
  • - autoimmune complications

52
CML
  • The Philadelphia chromosome t(9,22)
  • Fusion gene BCR-ABL on chromosome 22
  • Targeted therapy Imatinib

53
Ph chromosome BCR abl t(9,22)
54
CLL
  • Immunophenotyping (CD5, CD19 and surface
    immunoglobulin kappa OR lambda)
  • Identifies lymphocytosis as due to the clonal
    expansion of a single cell

55
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

56
OVERVIEW
  • Definition
  • Acute vs Chronic Leukaemia
  • Acute Leukaemia
  • Aetiology
  • Classification
  • Morphology FAB
  • Immunophenotyping
  • Cytogenetics and molecular studies
  • Principles of Treatment

57
  • Chronic Leukaemia
  • Unique features
  • Principles of Treatment
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