2. INTRODUCTION
• (CML) - clonal hematopoietic stem cell disorder.
• BCR-ABL1 chimeric gene product, tyrosine kinase,
• Reciprocal balanced translocation –
long arms of chromosomes 9 and 22, t(9;22) (q34;q11.2),
THE PHILADELPHIA CHROMOSOME
3. PHASE OF CML
biphasic or triphasic
• an early indolent or chronic phase
• Followed often by an accelerated phase
• terminal blastic phase.
4. EPIDEMIOLOGY
• 15% of all cases of leukemia.
• Male: Female = 1.6 : 1
• Median Age = 55-65 yrs
Incidence 1.5/ 1 Lac/ Year
Median Survival : 3-7 yrs ( Before 2000): 10 Years Survival 30%
(After 2000) : 10 Years Survival 85%
Mortality : 10-20% (before TKI)
02% (After TKI)
5. ETIOLOGY
• No familial association
• No monozygotic or other family member
• No relation with Benzine/fertilizer/insecticide /viruses.
• Not frequent after alkylating agent/ radiation
• After Nuclear accident/ Radiation Treatment = 5-10 yrs
• High Dose Radiation
6. PATHOPHYSIOLOGY
• The t(9;22) (q34;q11.2) > 90% of classical CML cases
• a balanced reciprocal translocation long arms of
chromosomes 9 and 22
• It is present in hematopoietic cells (but not stromal
cells)
• Not in other cells in the human body.
7. PATHOPHYSIOLOGY cont...
• ABL1 are translocated next to the major (BCR) gene
on chromosome 22,
BCR-ABL1 A hybrid oncogene
• p210BCR-ABL1 major BCR
• p190BCR-ABL1 (mBCR) -a worse outcome
• p230BCR-ABL1 (μ-BCR)-a more indolent course
8.
9. PATHOPHYSIOLOGY cont...
This BCR-ABL1 exhibits --constitutive kinase activity –
• Excessive proliferation
• Reduced apoptosis
A Growth Advantage Over Their Normal Counterparts.
10. PATHOPHYSIOLOGY cont...
• The constitutive activation of BCR-ABL1 results in
autophosphorylation and activation of multiple
downstream pathways that modify
• Gene Transcription
• Apoptosis
• Skeletal Organization
• Degradation of Inhibitory Proteins
11. PATHOPHYSIOLOGY cont...
• These transduction pathways may involve RAS,
mitogenactivated protein (MAP) kinases, signal
transducers and activators of transcription (STAT),
phosphatidylinositol-3-kinase (PI3k), MYC, and others
• These interactions are mostly mediated through tyrosine
phosphorylation and require binding of BCR-ABL1 to
adapter proteins such as GRB-2, CRK, CRK-like (CRK-L)
protein, and Src homology containing proteins (SHC).
12. BCR-ABL1
The cause of the BCR-ABL1 molecular rearrangement is
unknown
Molecular techniques that detect BCR-ABL1 at a level of 1 in
100000000 identify this molecular abnormality in the blood of
• Up To 25% Of Normal Adults
• 5% Of Infants
• 0% Of Cord Blood Samples
This suggests that BCR-ABL1 is not sufficient to cause overt CML in
the overwhelming majority of individuals in whom it occurs.
Because CML develops in only 1.5 of 100,000 individuals
annually
13. TKI
• TKIs bind to
BCR-ABL1 kinase domain (KD)
• preventing the activation of transformation pathways
• inhibiting downstream signaling
As a result,
• proliferation of CML cell inhibited
• apoptosis induced
Leading to the reemergence of normal hematopoiesis
14. CLINICAL PRESENTATION
Depends on
Health care facility & procedure, Physical Exams / Screening Test
• (90%) present in the indolent or chronic phase.
• Often Asymptomatic
• Manifestations Of Anemia And Splenomegaly.
Fatigue, Malaise, Weight Loss, Early Satiety
Left Upperquadrant Pain Or Masses
15. CLINICAL PRESENTATION
• Less common - thrombotic or vasoocclusive events
(from severe leukocytosis or thrombocytosis).
Who are accelerated or blastic phases have
• unexplained fever
• significant weight loss
• severe fatigue
• bone and joint aches
• bleeding and thrombotic events
• infections.
16. SIGNS
• Splenomegaly - 20–70%
• Hepatomegaly (10–20%)
• lymphadenopathy (5–10%)
• extramedullary disease (skin or subcutaneous
lesions).
Indicates CML transformation if a biopsy
confirms the presence of sheets of blasts
• complications of high tumor burden (e.g.,
cardiovascular, cerebrovascular, bleeding)
• High basophil counts
17. Signs and Symptom s of Ph+ve CML in
Chronic Phase
Parameter Percentage
• Age ≥60 years (median) 18 (46)
• Female gender 35–45
• Splenomegaly 30
• Hepatomegaly 5
• Lymphadenopathy 5
• Other extramedullary disease 2
• Hemoglobin <10 g/dL 10–15
• Platelets
>450 × 109 cells/L 30–35
<100 × 109 cells/L 3–5
18. Signs and Symptom s of Ph+ve CML in
Chronic Phase cont...
Parameter Percentage
• WBC ≥50 × 109 cells/L 35–40
Marrow
• ≥5% blasts 5
• ≥5% basophils 10–15
Peripheral blood
• ≥3% blasts 8–10
• ≥7% basophils 10
• Cytogenetic clonal evolution other than 4–5
the Philadelphia chromosome
• Sokal risk
Low 60–65
Intermediate 25–30
High 10
19. Hematologic Findings
• Leukocytosis ranging from 10–500 × 109/L
• Left-shifted hematopoiesis with predominance of
neutrophils and the presence of bands, myelocytes,
metamyelocytes, promyelocytes, and blasts (usually
≤5%)
• Basophils and/or eosinophils increased.
• Thrombocytosis is common
• Anemia is present in one-third of patients
20. Biochemical abnormalities
• Low Leukocyte Alkaline Phosphatase Score
• High Levels of Vitamin B12
Uric Acid
Lactic Dehydrogenase
Lysozyme.
The presence of unexplained and sustained leukocytosis,
with or without splenomegaly, should lead to a marrow
examination and cytogenetic analysis
21. Marrow Findings
• Hypercellular with marked myeloid hyperplasia
• High myeloid-to-erythroid ratio of 15–20:1
• Marrow blasts are 5% or less; when higher, they carry a
worse prognosis or represent acceleration (if they are
≥15%)
• Increased reticulin fibrosis (by Snook’s silver stain) is
common, with 30–40% of patients demonstrating grade
3–4 reticulin fibrosis.
22. Cytogenetic & Molecular studies
• t(9;22)(q34;q11.2), which is found in 90% of cases
• Philadelphia-chromosome abnormality
• Complex translocations (variantPh)
involving three or more translocations
masked Ph
• Prognosis & Rx Response – similar
• 5–10% of patients may have additional
chromosomal abnormalities
23. Cytogenetic & Molecular studies cont...
• FISH and PCR -diagnosis of CML more sensitive- CML burden
• peripheral samples
• FISH analysis - quantify the percentage of Ph-positive cells,
• if FISH is used to replace marrow cytogenetic analysis in monitoring
response to therapy.
• FISH may not detect additional chromosomal abnormalities (clonal
evolution); thus,
• a cytogenetic analysis is usually recommended at the time of
diagnosis.
24. Cytogenetic Response
• A partial cytogenetic response is defined as
the presence of 35% less Ph-positive
metaphases by routine cytogenetic analysis.
• This is roughly equivalent to BCR-
ABL1transcripts by the International Scale (IS)
of 10% or less.
25. Cytogenetic Response
• A complete cytogenetic response - the absence of Ph-
positive metaphases (0% Ph positivity).
• equivalent to BCR-ABL1 transcripts (IS) of 1% or less.
• Major molecular response - BCR-ABL1 transcripts (IS)
≤0.1%, or roughly a 3-log or greater reduction of CML
burden from baseline.
• A complete molecular response - BCR-ABL1 transcripts
(IS) <0.0032% (undetectable by current techniques),
roughly equivalent to a more than 4.5-log reduction of
CML burden from baseline
26. Findings in CML Transformation
• Progression of CML is usually associated with
leukocytosis resistant to therapy
• increasing anemia
• fever
• and constitutional symptoms
• increased blasts and basophils in the
peripheral blood or marrow.
27. Criteria of accelerated-phase CML
Historically associated with median survival of less than
1.5 years
• the presence of 15% or more peripheral blasts
• 30% or more peripheral blasts plus promyelocytes,
• 20% or more peripheral basophils
• cytogenetic clonal evolution (presence of chromosomal
abnormalities in addition to Ph),
• thrombocytopenia <100 × 109/L (unrelated to Therapy)
28. Criteria of accelerated-phase CML
• The median survival of accelerated phase
evolving from chronic phase has also
improved from a historical median survival of
18 months to an estimated 4-year survival rate
of 70% on TKI therapy.
• Therefore, the criteria for accelerated-phase
CML should be revisited because most have
lost much of their prognostic significance.
29. Blast Phase
• Blastic-phase CML is defined by the presence
of 30% or more peripheral or marrow blasts
• or the presence of sheets of blasts in
extramedullary disease (usually skin, soft
tissues, or lytic bone lesions).