Acute Abdomen Pain

Chronic
Myeloid
Leukaemia
(CML)
Presented by
1.Kinza iftikhar
2.Mubeen Akhtar
3.Shahzeb Hussain
What is leukaemia ?
● Leukaemias (or leukemias – U.S. Spelling) are cancers of
the white blood cells, which begin in the bone marrow.
Leukaemias are grouped in two ways: the type of white
blood cell affected – lymphoid or myeloid; and how
quickly the disease develops and gets worse.
Chronic Myeloid Leukaemia (CML)
● Chronic myelogenous leukemia is a disease in which the
bone marrow makes too many white blood cells. Chronic
myelogenous leukemia (also called CML or chronic
granulocytic leukemia) is a slowly progressing blood and
bone marrow disease that usually occurs during or after
middle age, and rarely occurs in children
Etiology and pathogenesis
In majority of 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:
• Increased incidence of CML in survivors of Hiroshima and
Nagasaki atomic blasts.
• Patients who have received radiation for cancer therapy
have higher chances of developing
● MLML compared to normal individuals.
Molecular pathogenesis (Philadelphia
chromosome)
• Philadelphia (Ph) chromosome is an acquired
chromosomal abnormality present in all proliferating
hematopoietic stem cells (erythroid, myeloid, monocytic
and megakaryocytic precursors). Rarely, it is found in B
and T lymphocytes, but never in marrow
fibroblasts.
• Philadelphia chromosome is a balanced reciprocal
translocation between long arm of
chromosome 9 and chromosome 22, i.e. T (9; 22) (q 34;
11.2).
Continue......
This results in an increase in the length of chromosome 9 and
a shortened long arm of one of the chromosome 22. This
shortened chromosome 22 is known as Philadelphia
chromosome.
BCR –ABL 1 GENE
FUSION
At the molecular and genetic level, the proto-oncogene
namely ABL1 (Abelson murine leukemia virus) gene from
chromosome 9 joins the BCR (breakpoint cluster region) on
chromosome 22. This result in a new chimeric (fusion) gene
called BCR-ABL1 which is hallmark of CML and critical for the
molecular events (Fig. 25.2).
• Normally, ABL1 is a proto-oncogene which regulates tyrosine
kinase activity. Tyrosine kinases serve as growth factor
receptors and normally regulate ligand-mediated
dimerization and autophosphorylation.
Continue......
• In CML, BCR-ABL1 fusion results in conversion of ABL1 proto-

oncogene into a functioning oncogene with enhanced tyrosine
kinase activity • The most important oncoprotein produced by
BCR-ABL1 oncogene is p210. The oncoprotein binds directly to
the adaptor proteins which induces signal transduction
pathway without activation of growth factor receptors. [Normally,
signals are generated with ligand binding of growth factor
receptors.
Continue....
• The net effect of these events is cell division and
inhibition of apoptosis independent of ligand binding.
The proliferating CML cells compete with normal cells
and suppress the normal hematopoiesis.
• BCR-ABL1 not only causes proliferation of
granulocytic (megakaryocytic to a lesser degree)
progenitors, but also the abnormal release of
immature granulocytic forms into the peripheral blood
from the marrow
Clinical Features
This disease occurs in either sex (male: female ratio of
1.4 : 1), most frequently between the ages of 40 and 60
years. However, it may occur in children and neonates, and
in the very old. In up to 50% of cases the diagnosis is made
incidentally from a routine blood count. In those cases
where the disease presents clinically, the following features
may be seen:
1 Symptoms related to hypermetabolism (e.g. Weight loss,
lassitude, anorexia or night sweats).
2 Splenomegaly is nearly always present and
considerable discomfort, pain or indigestion.
Clinical Features
3. Features of anaemia may include pallor, dyspnoea and

tachycardia.
4. Bruising, epistaxis, menorrhagia or haemorrhage from other
sites because of abnormal platelet function.
5. Gout or renal impairment caused by hyperuricaemia from
excessive purine breakdown may be a problem.
6. Rare symptoms include visual disturbances and priapism.
Natural history of CML
Natural history of chronic Myeloid Leukaemia is mainly
divided into three main phases!
Indolent or stable phase ;
Most of the patients are diagnosed in the chronic phase
• It usually lasts for 2–6 years
• If not treated properly, it gradually transforms in few
months to accelerated phase or
suddenly to blastic phase (crisis), which is fatal.
Accelerated phase
It is a more aggressive phase which lasts for a few months.
It is becoming less common in present era of TKI therapy.
There are no universally accepted criteria for definition of
AP
. It is characterized by:
– Increasing anemia.
– Persistent or increasing WBC count (more than 10 × 109
/L) unresponsive to therapy.
– Myeloblasts 10–19% are seen in the blood or bone
marrow.
Blast phase
Blood picture resembles acute leukemia. WHO criteria for
diagnosis: (1) blasts equal or greater than 20% of the
peripheral blood WBC or of the nucleated cells of the bone
marrow or (2) when there is an extramedullary blast (myeloid
or lymphoid lineage) proliferation
(skin, lymph node, spleen, bone or central nervous system).
• This final phase lasts for a few weeks to months and has a
poor prognosis.
• Peripheral smear (Figs 25.6A and B)
– Blasts constitute 20% or more of the peripheral blood WBC.
Continue.....
• Bone marrow fibrosis develops and may cause marrow
failure.
• Lymphadenopathy may appear
Lab Diagnosis
1. Leucocytosis is the main feature and may reach levels
greater than 200× 109/L. A complete spectrum of
myeloid cells is seen in the peripheral blood. The levels
of neutrophils and myelocytes exceed those of blast cells
and promyelocytes (Fig. 14.3).
2. Increased circulating basophils are a characteristic
feature.
3. Normochromic normocytic anaemia is usual.
4. Platelet count may be increased (most frequently),
normal or decreased.
Continue...
5 .Bone marrow is hypercellular with granulopoietic

predominance.
6. Presence of the BCR‐ABL1 gene fusion by RT‐PCR
analysis and in 98% of cases Ph chromosome on
cytogenetic analysis.
7. Serum uric acid is usually raised

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Chronic

• In CML, BCR-ABL1 fusion results in conversion of ABL1 proto-

3. Features of anaemia may include pallor, dyspnoea and

5 .Bone marrow is hypercellular with granulopoietic

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