Title: Introduction to Leukaemia
1 Introduction to Leukaemia
2OVERVIEW
- Definition
- Acute vs Chronic Leukaemia
- Acute Leukaemia
- Aetiology
- Classification
- Morphology FAB
- Immunophenotyping
- Cytogenetics and Molecular Studies
- Principles of Treatment
3OVERVIEW
- 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
8CLINICAL 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
-
-
16CLASSIFICATION 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
17CLASSIFICATION OF ACUTE LEUKAEMIA
- Standardisation of treatment
- Some acute leukaemias have peculiar features
- - ALL and lymph node, thymus and CNS
involvement - - APML and bleeding
18CLASSIFICATION 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
21FAB 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
24CLASSIFICATION OF ACUTE LEUKAEMIASALL
- ALL/L3 3-5
- - large, homogeneous cells
- - fine chromatin, prominent nucleoli
- - intensely basophilic cytoplasm,
- vacuoles
25 ALL/L3
26CLASSIFICATION 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
32IMMUNOPHENOTYPINGobjective
- 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
- LYMPHOID
- B lineage
- CD19
- CD22
- CD10
- T lineage
- CD7
- CD3
- TdT
35CYTOGENETICS IN ACUTE LEUKAEMIA
- Translocations, deletions, inversions etc
- Diagnosis
- Prognosis
- Minimal Residual Disease (MRD)
36GENETICS
- 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
37ACUTE LEUKAEMIA EXAMPLES of SOME CYTOGENETIC
and MOLECULAR ABNORMALITIES
38t(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
40t (9,22) Philadelphia chromosomeand BCRabl
- - 30 adult ALL, 3-10 childhood ALL
- - (95 CML)
41Ph 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
43t (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
45PRINCIPLES 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
47CHRONIC LEUKAEMIAS
- Slower course, even non-progressive
- with survival
- (with or without treatment)
- for years
48CLASSIFICATION
- CML Chronic myeloid leukaemia features of all
stages of granulocyte development, including
mature forms - CLL Chronic lymphoid leukaemia mostly mature
lymphocytes
49 CML CLL
50CLINICAL FEATURES
- CML
- - incidental finding
- - splenomegaly
- - low or high platelet count
- - high white blood cell count
hyperviscosity -
51CLINICAL FEATURES
- CLL
- - incidental finding
- - lymphadenopathy
- - hepatosplenomegaly
- - bone marrow failure anaemia,
neutropenia (with immunosuppression) and - thrombocytopenia
- - autoimmune complications
52CML
- The Philadelphia chromosome t(9,22)
- Fusion gene BCR-ABL on chromosome 22
- Targeted therapy Imatinib
53Ph 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
55PRINCIPLES 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
56OVERVIEW
- 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