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Chronic myeloid Leukemia
1.
2. General Hello hi to CML
Chronic
myelogenous (or myeloid or myelocytic) leu
kemia (CML), also known as chronic
granulocytic leukemia (CGL), is a cancer of
the white blood cells.
It is a form of leukemia characterized by
the increased and unregulated growth of
predominantly myeloid cells in the bone
marrow and the accumulation of these cells
in the blood.
3. MPD
• CML is a clonal bone marrow stem
cell disorder in which a proliferation of
mature granulocytes (neutrophils, eosinophils
and basophils) and their precursors is found.
• It is a type of myeloproliferative
disease associated with a
characteristic chromosomal
translocation called the Philadelphia
chromosome.
4. Risk factors
• CML is more common in males than in
females (male to female ratio of 1.4:1) and
appears more commonly in the elderly with a
median age at diagnosis of 65 years.Exposure
to ionising radiation appears to be a risk
factor, based on a 50 fold higher incidence of
CML in Hiroshima and Nagasaki nuclear
bombing survivors.[ The rate of CML in these
individuals seems to peak about 10 years after
the exposure.
8. CML
Definition:
CML is an acquired clonal Myeloproliferative neoplasm
of the abnormal Pluripotent hematopoietic stem cell.
It is characterized by:
•Neoplastic proliferation causing excessive production
•Reduced apoptosis of cells of the myeloid series
9. Chronic Myelogenous Leukemia (CML)
• CML is a clonal myeloproliferative disorder
characterized by
• Specific genetic abnormality i.e BCR-abl fusion
gene
• Leukocytosis with complete left shift
• Basophillia
• Hepatosplenomegaly
• Thrombocytosis
11. Classification
• Based on the presence or absence of Philadelphia
chromosome and the cell precursors involved:
• 1.Classical CML with Philadelphia positive
• 2.CML without Philadelphia chromosome
• 3.CML of neutrophilic cell
• 4.CML of eosinophilic cell
• 5.CML of myelomonocyte
• 6.Juvenile CML
12. Epidemiology
• CML occurs in all age groups
• Most common in the middle-aged and elderly.
• Incidence 1–2 per 100,000 people
• More common in men
• Represents 15–20% of all cases of adult leukemia in
Western populations.
• Increased rates of CML were seen in people exposed to
the atomic bombings of Hiroshima and Nagasaki.
• Long-term exposure to benzene may also contribute
13. Clinical features
• Splenomegaly
• Gout like symptoms
• Anemia
• Hyperurecemia
• Bruising
• Hemorrhages from other sites
• Visual disturbance
14. 1. Weight loss, lassitude (lack of energy), Anorexia or Night sweet.
2. Massive splenomegaly
3. Features of anaemia: pallor, tachycardia.
4. Low platelet count and/or platelet dysfunction: bruising,
epistaxis, menorrhagia etc
5. Gout or renal impairment due to excessive purine breakdown
6. Visual disturbance
15. Clinical presentation
• CML is a malignant blood disorder
• Involves early hematopoietic cells
• Become clonally expanded.
• Disease originates from a single abnormal
hematopoietic stem cell which proliferates over
months and years so that at diagnosis blood
granulocytosis and marrow granulocytopoiesis
are apparent.
• The bone marrow becomes hypercellular.
• CML may be clinically categorized as follows
16.
17. Phases of CML
• C h r o n i c p h a s e
• A c c e l e r a t e d p h a s e
• B l a s t c r i s e s
18. C hro nic pha se
• Approximately 85% of patients are in the chronic phase at
the time of diagnosis.
• Asymptomatic or have only mild symptoms
• splenomegaly
• Lab diagnosis:
• Raised granulocyte count
• Blast less than 10%
• 100x10”9/l
• Circulating myelocytes and mature neutrophil.
• Typically myeloblast and promyelocytes is low
• N/N anemia
• Thrombocytosis
• Duration is variable
19. • Deficiency of granules ,lactoferin ,MPO,ALP
• Hypercellularity
• Hyper uracemia
• + fatigue lethargy abdominal disturbence
• Bone pain purpura…………
• Duration of this stage is 3-5 years
• M a y p r o g r e s s t o a n a c c e l e r a t e d
p h a s e
21. Accelerated phase
• In 70% of patient ,chronic phase gradually evolves in to
accelerated phase…
• Loss of differentiation and maturation
• 10–19% blasts in the blood or bone marrow
• >30% of blast and promyelocytes in peripheral blood.
• >20% basophils in the peripheral blood or bone marrow
• Platelet count <100,000/ul
• In addition to the Philadelphia chromosome other
chromosomal abnormalities may be present
• Marked splenomegaly and increasing white blood cell
count, unresponsive to therapy
22. • The median duration of the chronic phase
from presentation is 3 years,
• Progression to the blastic phase usally occour
with in few months.
24. Blast crises
• Final phase in the evolution of CML
• Behaves like an acute leukemia
• Rapid progression and short survival
• Diagnosis based on the presence of;
• >20% myeloblasts or lymphoblast in the blood or
bone marrow
• Large clusters of blasts in the bone marrow on
biopsy
• Development of a chloroma (solid focus of
leukemia outside the bone marrow)
25. • Treatment of blastic phase is CML is the same
as that of AML M1 & M2.
• Most common cause of death in blastic phase
CML is infections secondary to neutropenia
• And Haemorrhage secondary to
thrombocytopenia ,
29. Pathophysiology
• Every cell contains chromosomes
• To be more specific, 23 pairs of chromosomes
• parts of two chromosomes (the 9th and 22nd)
switch places
30. Philadelphia(Ph) chromosome
Is the chromosome which result from
the t(9;22)(q34;q11)part of the
Abelson proto-oncogene ABL is moved
to the BCR gene on chromosome 22 &
part of chromosome 22 moves to
chromosome 9.
32. Philadelphia(Ph) chromosome
This results from the translocation between
chromosomes 9 and 22 results in the transfer of
ABL( Abelson Proto-oncogene) to BCR (breakpoint
cluster region)
The abnormal chromosome 22 is the Philadelphia
chromosome
33. •
The most important cause of CML
translocation of two of them:
Chromosome 9 (the ABL gene) Chromosome 22 (the
BCR gene).
Fusion Tyrosine kinase stimulates uncontrolled
production of abnormal blood cells by B/M.
34. • During the division of the cells
• These two chromosomes cris -cross, break, and
fuse to each other
• In doing so, they create so called Philadelphia
chromosome
• Philadelphia chromosome is made up of two
parts
• Also called BCR-ABL fusion gene.
• This new gene produces a specific 210kD tyrosine
kinase
35. • Enhanced tyrosine kinase activity increases
phosphorylation within the cells
• Regulates metabolic pathways and serve as a
receptor for growth factors
• Oncogenic role of p210 is found in association
with increased G-CSF and platelet-derived
growth factor
• Its activation may also suppress apoptosis in
hemopoietic cells
36. • Normally, WBCs grow and divide in a controlled way
• In leukemia the process gets out of control, cells
divide too quickly but do not mature
• Too many myeloid cells produced and released into
the blood
• Blasts fill up the bone marrow and prevent it from
making blood cells properly.
• Can’t make enough healthy red cells and platelets
• Leads to an increased risk of infection
40. Lab investigation of CML
CBC :Blood cell count
WBC count ranges between 50 to 500 x109/l
Platelet count ThrombocytopeniaThrombocytosis
• Laboratory finding:
• Leukocytosis is usuallly > 50 ×109/L and some times >
500×109/L
• Hemoglobin: It is usually less than 11 gm/dL.
• Increased circulating basophil count
• Normocytic normochromic anaemia is usual
• Platelet count may be increased normal or decreased
/
41. Peripheral blood film examination
• Normocytic, normochromic anemia
• Neutrophils show left shift
• Eosinophils normal or some time increased
• NRBCs are seen
• Absolute Basophilia
44. 2. Bone marrow
• Hypercellular
• Increased M:E ratio i.e: 10:1
• With mature neoplastic myeloid cells
• Erythroid precursors decreased
• Megakaryoblasts normal or increased
45. • Immature myeloid precursor can be found
away from bony trabeculae
• Blasts not more than 10% in chronic phase
• Eosinophilic and basophilic granules are
abnormal
• Nuclear to cytoplasmic asynchrony
46. 3. Biochemical findings
• Serum Uric acid
Increased due to increased purine destruction
• Serum iron
Increased
• Serum B12 and B12 binding capacity
Increased
• NAP score
Decreased
• Serum LDH
Elevated
• Ca++
increase
50. Leukemoid reaction
• A benign condition in which the high number
of white blood cells found in a blood test
resembles the numbers seen in leukemia. For
example, infectious mononucleosis can return
blood-test results with a leukemoid reaction
52. Characteristics Lekemoid Reaction CML
total WBC count Usally less than 50K/ul Usally more than 1Lack/ul
left shift
Myelocyte Neutrophil peak
myelocyte 5 to 15%
blasts 5%
Absent
usually numerous
more than 30% blasts
Present
toxic granulation Marked mild or absent
anaemia slight or absent present & progressive
eosinophils &basophils decreased increased
platelets normal or increased increased
bone marrow hyperplasia of WBC
but to a mild extent
marked hyperplasia
with increased
proportion of immature
cells
clinical features Just infections ,Fever Splenomegaly
Lymphadenopathy
Hemorrhage
NAP score Increased Decreased