CHRONIC MYELOID LEUKAEMIA

2. Etiology and Pathogenesis
Clinical
Features
Diagnosis
Differential Diagnosis
Treatment
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3. The 2008 World Health Organization Classification System for
Myeloproliferative Neoplasms

4. • Chronic myelogenous leukemia (CML), also
known as chronic myeloid leukemia, is a
myeloproliferative disorder characterized by
increased proliferation of the granulocytic cell
line. Consequently, the peripheral blood cell
profile shows an increased number of
granulocytes and their immature precursors,
including occasional blast cells.
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5. • In 1845, Bennett in Scotland and Virchow in Germany described
splenic enlargement, severe anemia, and leukocytosis.
• Virchow proposed the term leukämie.
• In 1878, Neumann proposed – marrow origin for leukemia –
myelogene (myelogenus)
• Nowell and Hungerford in 1960 identified the culprit gene at the
Perelman School of Medicine, Philadelphia.
• Dr. Rowley identified the BCR ABLtranslocation.
• 1998 – Discovery of targeted TKI therapy.
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6. • 15% of leukaemias.
• It occurs most often between 40– 60yrs
• slight male predominance
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7. • The initiating factor of CML is still unknown, but
exposure to ionizing radiation increased prevalence
among survivors of the atomic bombing of
Hiroshima and Nagasaki.
• Radiotherapy for a cancer in the past.
• Benzene exposure.
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8.  Genetic hallmark of CML is the presence of BCR-
ABLfusion gene product(Philadelphia chromosome).
 • The fusion protein is a result of reciprocal translocation
between the abelson oncogene on chromosome 9 and break
point cluster region on chromosome 22.
 Other genetic abnormalities:
 • Trisomy 8,p53 loss.
 • Interleukin involved in the progression of CML to the
blastic phase.

10. Etiopathogenesis
• The ABL (Ableson leukemia virus) gene on
chromosome 9 fused to BCR (breakpoint cluster
region) gene on chromosome 22.
• The fusion protein derived from the BCR-ABL gene is
a tyrosine kinase enzyme.
• The ABL gene  regulated tyrosine kinase
• BCR-ABL  unregulated tyrosine kinase.
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Altered
adhesion
• No adhesion to
marrow stroma
• Reduced
regulation by
marrow factors
Mitogenic
activation
• Activation of
various
pathways

proliferation
Inhibition
of
apoptosis
• Uninhibited
proliferation
Etiopathogenesis

12. A. Symptoms
• At diagnosis – 70% symptomatic
• Easy fatigability with low grade fever.
• Loss of sense of well-being.
• Decreased tolerance to exercise.
• Anorexia.
• Bone pain and Abdominal discomfort.
• Early satiety .
• Weight loss.
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13. • Uncommon symptoms
• Night sweats
• Heat intolerance
• Gouty arthitis
• Left upper-quadrant and left shoulder pain.
• Urticaria.
• Hyperleukocytic Syndrome —dyspnea, tachypnea,
hypoxia, lethargy, slurred speech
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Mimics thyrotoxicosis
Clinical features

14. • Pallor.
• Splenomegaly.
• Sternal tenderness.
• Rarely hepatomegaly,
lymphadenopathy – Poor
prognostic indicators.
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Clinical features

16. • Chronic phase
• Accelerated phase
• Blast phase.

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•Most patients are asymptomatic.
• Incidental leukocytosis/splenomegaly
• Bleeding and infectious complications are uncommon
in the chronic phase.
• Blast cells less than 10%.

19. Course of the disease
• 10%–19% blasts in blood or bone marrow
• >20% basophils in blood or bone marrow
• Thrombocytosis, thrombocytopenia unrelated to
therapy
• Anemia progresses and cause fatigue, loss of sense of
well-being
• Splenomegaly
• Ranges from 4-5 years before progressing.
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21. Course of the disease
• ≥20% blasts in blood or bone marrow
• Extramedullary blastic infiltration (Chlorom)
• Resembles acute leukemia
• 2/3 transform to myeloid blastic phase and 1/3 to lymphoid
blastic phase.
• Infection and bleeding common.
• Abdominal pain, bone pain.
• Survival is 6-12 months (worse for myeloid phenotype).
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25. • Approximately 85% of patientsare
diagnosed in the chronic phase and then progress to
the accelerated and blast phases after 3-5 years.
The diagnosis of CML is based on the histopathologic
findings of Philadelphia chromosome in peripheral
blood or bone marrow .

26. A. Laboratory studies
Blood counts and blood smear
• Hemoglobin concentration is decreased
• Nucleated red cells in blood film
• The leukocyte count above 25,000/μl (even > 1,00,000/μl),
• The basophil and eosinophil counts are increased
(Absolute)
• The platelet count is normal or increased
• Blast cells ~ 3 % (<10% in the chronic phase)
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27. 20
Peripheral smear(full spectrum of myeloid series)
Diagnosis

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Bone marrow
Hypercellular
Replacement of fat
Granulopoiesis
Megakaryocytopoiesis
Erythropoiesis
Diagnosis

30. Diagnosis
Other lab features :
• Neutrophil Alkaline Phosphatase reduced
• Serum B12 and transcobalamin increased.
• Serum uric acid increased.
• Lactate dehydrogenase increased.
• Mean histamine levels increased
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31. • Study of the number and structure of chromosomes
• Samples from bone marrow myeloid cells
• The presence of the Philadelphia chromosome –
shortened chromosome 22*
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Diagnosis

32. i. FISH (Fluorescence In Situ Hybridization)
• Detect the BCR-ABL fusion gene on chromosome 22
• Qualitative
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Diagnosis

33. Diagnosis
ii. PCR(Polymerase Chain Reaction)
• Most sensitive test to identify and measure the
BCR-ABL gene (Quantitative).
• Can be performed on blood/marrow cells
• Amplifies the BCR-ABL derived abnormal mRNA.
• One abnormal cell in one million cells can be
detected.
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34. Course of the disease
Neutrophilic CML
• A rare variant of BCR-ABL–positive CML with elevated
white cell count principally of mature neutrophils
• WBC count lower than that of classic CML.
• Basophilia, myeloid immaturity in the blood, prominent splenomegaly,
or low leukocyte alkaline phosphatase scores – are all absent!
• Larger fusion protein than in classic CML
• Usually has an indolent course
• Now classified separately
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35. Course of the disease
Hyperleukocytosis (15% of cases)
• Intravascular flow-impeding effects of white cell counts
greater than 3,00,000/µL.
• Impaired circulation of the lung, central nervous system, special
sensory organs, and penis
• resulting in some combination of:
• Tachypnea, dyspnea, cyanosis.
• Dizziness, slurred speech.
• Visual blurring, diplopia, retinal hemorrhages,
• impaired hearing, And priapism.
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37. 1. Initial Cytoreduction Therapy
2. Tyrosine Kinase Inhibitor Therapy
3. Interferon therapy
4. Chemotherapy
5. Allogeneic Stem Cell Transplantation
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38. • Chronic phase:
• Hydroxyurea or interferon-α, with allopurinol
• Specific treatment:
• Imatinib and Dasatinib (tyrosine kinase inhibitors) act
as inhibitors ofBCR-ABL.
• Stem cell transplantation
Allogeneic or autogenous.

39. • Polycythemia vera
• Essential thrombocythemia
• Primary myelofibrosis
• Leukemoid reactions
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