2. LEARNING OBJECTIVES
Describe the pathogenesis of Chronic myeloid
leukaemia
Describe the lab diagnosis of Chronic myeloid
leukaemia
3. MYELOPROLIFERATIVE DISORDERS (NEOPLASMS)
• The Myeloproliferative disorders are a group of diseases;
characterized by:
1. Monoclonal ,neoplastic transformation of pluripotent
stem cell
2. Mutated and intrinsically activated tyrosine kinases
3. Growth factor independent proliferation and survival of
marrow progenitors
4. Unregulated proliferation of neoplastic stem cells & their
differentiation into multiple or single cell line
5. CHRONIC MYELOID LEUKAEMIA
It is monoclonal neoplastic disorder which results
from an acquired genetic defect in a pluripotential
haemopoietic stem cell
The altered stem cell proliferates and
generates a population of differentiated
cells that gradually replace normal
haematopoiesis
Leading to greatly expanded total myeloid mass
6. GENETICS
• The most consistent chromosomal abnormality
found in more than 95% of CML patients is
Philadelphia (Ph) chromosome
• It represents a reciprocal translocation between
chromosome 9 and 22 t(9;22)(q34;q11)
7. MOLECULAR PATHOGENESIS
• The reciprocal translocation between
chromosome 9 (ABL gene) and chromosome 22
(BCR gene) results in the formation of BCR/ABL
fusion gene also called BCR/ABL rearrangement
• This fusion gene directs the synthesis of a novel
chimeric protein(210-kDa) which has enhanced
tyrosine Kinase activity
• The enhanced Tyrosine Kinase
activity of BCR-ABL fusion
protein causes intrinsic activation
of several signals transduction pathways
10. PAHTOGENESIS…..(Contd)
• Markedly hyperplastic marrow(100% cellularity)
• Proliferation of granulocytic precursors and
differentiated cells
• Appearance of neoplastic cells in the peripheral blood
and subsequent invasion of various body organs
• Settling of neoplastic stem cells in spleen/ liver and
giving rise to neoplastic extramedullary
hematopoiesis at these sites
11. CLINICAL FEATURES
• Insidious Onset
• Age distribution; 25-60 Years
• Peak age in 5th to 6th decades
• Sometimes accidental diagnosis on routine blood CP
• Weakness, weight loss, anorexia
• Dragging sensation in the abdomen
• Moderate to massive splenomegaly
13. LAB DIAGNOSIS
1. BLOOD CBC
TLC- Markedly increased
Range from 50x109/l-600x109/l
Hb – Usually decreased
Platelets – Increased in chronic phase but
decreased in accelerated and
blast crises
14. LAB DIAGNOSIS
1. BLOOD CBC
DLC
Bimodal peak of neutrophils and
myelocytes
Metamyelocytes
Eosinophilia & Basophilia is common
Variable number of blast cells
15. LAB DIAGNOSIS
2. PERIPHERAL SMEAR
Bimodal peak of neutrophils and
myelocytes
Metamyelocytes are always less than
myelocytes
Eosinophils
Basophils
Variable number of blast cells
16. LAB DIAGNOSIS (CONTD…)
3. BONE MARROW
- Markedly hypercellular(100%)
- Myeloid precursors predominate
- Erythropoiesis depressed
- Megakaryocytes increased or normal
- Blasts variable in number
4. CYTOCHEMISTRY
LAP score: Decreased
(normal 30-100 %)
17. LAB DIAGNOSIS (CONTD…)
5. CYTOGENETICS
Philadelphia (ph) positive (95%)
6. MOLECULAR ANALYSIS
Fluorescent in situ hybridization (FISH)
or Reverse transcriptase polymerase chain
reaction (RT-PCR) for:
Detection of BCR/ABL fusion gene (100%)
18. A case of CML peripheral blood film showing a myeloblast,
Myelocytes , band and segmented neutrophils
19. A case of CML peripheral blood films showing myeloblastic
transformation ( numerous myeloblast, abnormal promyelocytes
and atypical neutrophils
20. COURSE
• PHASES OF CML
• Chronic indolent phase
• Accelerated phase
• Blastic transformation or Blastic crisis
21. COURSE
• Chronic indolent phase
• TLC Markedly increased
• Anemia
• Thrombocytosis
• Blasts 2-9% in bone marrow
• Eosinophils
• Basophils
• Splenomegaly
• Bimodal peak of neutrophils and myelocytes
-
23. COURSE
Chronic Mteloid Leukaemia
Slowly progressive course
Approximately half of CML cases enter into accelerated
phase and then into blast crises
In the remaining half, blast crises occur without accelerated
phase
Tyrosine kinase inhibitors – sustained remission during early
phase and prevents progression towards blast crises
Blastic transformation - 70% AML and 30% ALL
24. COURSE
Median survival
Without effective treatment: 2-3 years
Allogenic stem cell transplant: 10 year DFS 10-70%
Current TKI therapy: complete cytogenetic
response rate 70-90%; DFS 10 years 80-90%
25. Leukaemoid Reaction
• Known cause; moderate to severe underlying infection
• TLC less than 100x109/l
• DLC: Mostly neutrophils with toxic granulations, band
forms and few metamyelocytes
• Basophils/eosinophils not increased
• Promyelocytes/blast cells are infrequent
• LAP score is increased (usually >100%)
• Platelet count is normal
• Hb level normal or minimally decreased
• BCR-ABL fusion gene Absent