Chronic myeloid leukemia (CML) is a clonal stem cell disorder caused by the BCR-ABL1 fusion gene from the Philadelphia chromosome. CML progresses through chronic, accelerated, and blast phases. It is characterized by excessive proliferation of myeloid cells. Diagnosis involves detecting the Philadelphia chromosome via cytogenetics or molecular testing. Treatment with tyrosine kinase inhibitors targets the BCR-ABL1 fusion protein and controls disease progression.

1. CHRONIC MYELOID LEUKEMIA
DR SUMAN ROY
PGT- MEDICINE

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

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).

30. • Thank You