Chronic myelogenous leukemia

1. CHRONIC LEUKAEMIAS
SUNIL KUMR.P
Department of Haematology
St.John'sMedical College
Bangalore 1SUNIL KUMAR.P

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4. CHRONIC MYELOGENOUS
LEUKEMIA
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5. Contents………………….
• -Definition
• -Molecular genetics
• -Epidemiology
• -Etiopathogenesis
• - Molecular pathogenesis
• -Clinical Presentation
• -Laboratory Diagnosis
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6. CHRONIC MYELOGENOUS LEUKAEMIA
• - Chronic Myelocytic leukaemia
• - Chronic Myeloid leukaemia
• - Chronic Granulocytic Leukaemia
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7. Definition
• CML is an acquired clonal myeloproliferative
neoplasm of the abnormal pluripotent
hematopoietic stem cell.
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8. • It is distinguished by other MPN by the presence of
chimeric fusion BCR-ABL gene characteristic
chromosomal abnormality, i.e. Philadelphia (Ph)
chromosome in > 90% cases.
• It is characterized by neoplastic proliferation causing
excessive production and reduced apoptosis of cells
of the myeloid series in the bone marrow.
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9. EPIDEMIOLOGY
• CML is the commonest leukemia constituting
25 – 30 % of all leukaemia in India.
• Sex : Males are affected more than females.
• Age : CML occurs in all age groups, but most
commonly in the middle- aged and elderly
• Adults 40-50 yrs are affected mainly.
• Disease is uncommon in < 20 yrs of age.
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10. • Its annual incidence is 1–2 per 100,000
people,
• CML represents about 15–20% of all cases of
adult leukemia in Western populations.
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11. ETIOLOGY AND PATHOGENESIS
• In majority of the cases the etiology is not
known.
• Exposure to ionizing radiation may increase
the risk and is dose-dependent.
• The evidences which support this risk factor
are……….
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12. • 1. Increased incidence of CML in survivors of
Hiroshima and Nagasaki atomic blasts.
• 2.Patients who have received radiation for
cancer therapy have higher chances of
developing CML compared to normal
individuals
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13. Molecular pathogenesis
• CML is an acquired disease of hematopoietic
stem cell and BCR-ABL fusion gene is
demonstrable in erythroid, myeloid ,
megakaryocytic precursors .
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18. Pathophysiology
Translocation, parts of two chromosomes (the 9th and 22nd)
Part of the BCR("breakpoint cluster region") genefrom
chromosome 22 is fused with the ABLgene on chromosome9.
Thisabnormal "fusion" gene generates aprotein of p210or
sometimes p185
Becauseabl carries adomain that can add phosphate groups to
tyrosine residues (a tyrosine kinase), the bcr-abl fusiongene
product is also atyrosine kinase.
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19. The fused bcr-abl protein interacts with the interleukin 3beta(c)
receptor subunit
Thebcr-abl transcript is continuously active and does not require
activation by other cellular messaging proteins. In turn, bcr-abl
activates acascadeof proteins which control the cell cycle,
speeding up cell division
Bcr-abl protein inhibits DNArepair, causing genomic instabilityand
making the cell more susceptible to developing further genetic
abnormalities.
Theaction ofthe bcr-abl protein is the pathophysiologic causeof
chronic myelogenous leukemia.
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22. PHASES OF CML
• There are 3 phases of CML
• - Chronic phase
• - Accelerated Phase
• - Blastic phase
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23. CHRONIC PHASE
• Chronic CML :
• most of the patients present in this phase.
• It is stable phase, lasts for 2-6 yrs.
• Blasts are usually 2 – 5 % in blood/ marrow.
• It may gradually transform to accelerated
phase or abruptly to Blastic phase.
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25. NEUTROPHIL
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26. EOSINOPHIL
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27. BASOPHIL
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28. LYMPHOCYTE
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29. MONOCYTE
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30. C/F…….. Chronic phase
• Onset of the disease is insidious .
• Tiredness
• Anorexia
• ABD discomfort
• Wt.loss & excessive sweating
• Visual disturbances
• Venous thrombosis
• Splenomegaly
• Hepatomegaly
• Lymphadenopathy
• Sternal tenderness
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31. ACCELEARTATED PHASE
• More aggressive phase.
• Lasts for few months and usually transforms into
blastic phase.
• Blasts are > 10 % , but < 20%.
• Spleen fails to regress with treatment or size starts
increasing.
• Basophils > 20%.
• Hb < 7 g/ dl.
• PLT < 1 lakh or > 10 lakhs /mm3 & unresponsive
therapy.
• NAP score may be increased
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32. BLASTIC PHASE
• Blasts > 20% in blood or BM ( WHO) may be
myeloid type ( 70 % cases ) or type (30% cases).
• Flowcytometry confirms the nature of the blast
crisis.
• Lymphadenopathy may be appear
• Lasts for a few weeks – months
• Granulocytic sarcomas may develop
• Marrow fibrosis may result in marrow failure
• Thrombocytopenia results in bleeding episodes
• Extramedullary blasts proliferation
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34. Diagnosis
• Hematological findings
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35. • 1. Anaemia : Hb decreased ( 7 -11 gm/dl).
Red cells are N/N.
• 2. Leukocytosis : Increased ( 1.0 Lakh – 5.0 lakh ).
• TLC progressively increased in untreated patients
.
• Very few patients demonstrate TLC < 50 x 109 /L
at presentation
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40. • 3.immature white cells
• PBS – demonstrates immature white cells of
all stages i.e. neutrophils, metamyelocytes,
myelocytes, promyelocytes and blasts cells .
• There is a predominance of myelocytes in
untreated patients.
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41. CELLS %
BLASTS CELLS 1-5 %
PROMYELOCYTES 4 -10%
MYELOCYTES 30 – 40 %
METAMYELOCYTES 20-30%
NEUTROPHILS 30-50%
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42. • 4.Basophilia and Eosinophilia :
• Basophilia and Eosinophilia are features of
CML .
• Basophils and Eosinophils may be increased to
5 -15 %
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43. • 5. NAP score :
• NAP ( Neutrophil Alkaline Phosphatase ) score
in CML is decreased to (0-20 % ) in more than
90 % cases and is a differentiating features
from leukemoid reactions.
• Normal NAP Score ( 40-100)
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44. • 6.Platelet count :
• Thrombocytosis in the range of 300-500 x
109/L is a feature in CML , however half of
the patients demonstrates normal PLT count.
• Thrombocytopenia in CML is an ominous sign
and suggests an impending accelerated or
blastic phase.
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45. BIOCHEMICAL FINDINGS
• S. uric Acid – increased due to high turnover
of white cells.
• S.LDH – Increased
• S.Alkaline Phosphatase : increased
• Transcobalamine -1 levels - increased
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46. BONE MARROW
• Markedly hypercelular
• There is marked myeloid hyperplasia.
• M:E Ratio : Is markedly increased to 20:1 to
49:1
• Blast cells : are usually 2-5% in chronic phase.
• Basophils & their precursors and Eosinophils
and their precursors are demonstrable.
• Erythroid precursors : decreased.
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47. • Myeloid Hyperplasia
• Megakaryocytes normal / Increased
• Dwarf –megakaryocytes present
• Gaucher like cells ( Large Histiocytes present)
• Marrow fibrosis present.
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