1) Chronic myeloid leukemia is a myeloproliferative neoplasm caused by the Philadelphia chromosome, a reciprocal translocation between chromosomes 9 and 22 that results in the BCR-ABL fusion gene. 2) This fusion gene encodes a novel protein with unregulated tyrosine kinase activity that drives uncontrolled proliferation of myeloid cells. 3) CML progresses through chronic, accelerated, and blast crisis phases marked by increasing myeloid blasts and worsening prognosis if untreated. Current tyrosine kinase inhibitors can achieve long-term remission.

1. CHRONIC MYELOID LEUKAEMIA
DRAYESHANAYYAR
CONSULTANTHAEMATOLOGIST

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

4. MYELOPROLIFERATIVENEOPLASMS
(CONTD..)
MPN’s comprised of:
 Chronic Myeloid Leukaemia
 Polycythemia Vera
 Essential Thrombocythemia
 Idiopathic Myelofibrosis

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

8. Schematic representation of formation of the
Philadelphia Chromosome

9. Growth factor independent poliferation and survival
Normal differentiation

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

12. LAB DIAGNOSIS
1. BLOOD CP
2. Peripheral smear
3. Bone marrow examination
4. LAP Score
5. Cytogenetics
6. Molecular genetics

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
-

22. COURSE
• Accelerated phase
• TLC Markedly increased
• Anemia, thrombocytopenia
• blasts 10-19% in bone marrow
• Peripheral blood Basophils > 20%
• Splenomegaly
• Blastic transformation or Blastic crisis
• TLC Markedly increased
• Blasts >20% + additional cytogenetic mutations

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

26. THE END