Comprehensive Overview of Chronic Myelogenous Leukemia (CML) and Related Disorders, Epidemiology, Clinical Features, Clinical Presentations, Phases, Pathophysiology and Lab Diagnosis
Chronic myelogenous leukemia
Definition: CML is a type of cancer that starts in the blood-forming cells of the bone marrow and leads to an overproduction of abnormal white blood cells.
OR
Chronic
myelogenous leukemia (CML) is a clonal myeloproliferative disorder defined b
y
the presence of the BCR-ABL fusion gene, resulting in leukocytosis accompanied
by a full left shift.
Myeloproliferative Disorder: A group of blood disorders characterized by the excessive production of one or more types of blood cells in the bone marrow. OR are classified as clonal malignancies originating from hematopoietic stem cells.
The WHO categorizes chronic myeloproliferative
diseases (CMPDs) as follows:
1. Chronic Myelogenous Leukemia (CML):
a. Chronic Phase
b. Accelerated Phase
c. Blast Phase
2. Polycythemia Vera (PV)
3. Essential Thrombocythemia (ET)
4. Primary Myelofibrosis (PMF):
a. Profibrotic Phase
b. Fibrotic Phase
5. Chronic Neutrophilic Leukemia (CNL)
6. Chronic Eosinophilic Leukemia, Not
Otherwise Specified (CEL, NOS)
7. Masto cytosis (including systemic Masto
cytosis, cutaneous Masto cytosis, and mast cell leukemia)
Epidemiology
·
CML
occurs across all ages but is most common in middle-aged and elderly
individuals.
·
Its
incidence is around 1-2 per 100,000 people.
·
CML
is more frequently diagnosed in men.
·
It
accounts for 15-20% of all cases of adult leukemia in Western populations.
·
Increased
rates of CML have been observed in individuals exposed to the atomic bombings
of Hiroshima and Nagasaki.
· Long-term exposure to benzene may also play a role in its development.
Clinical Features
·
Splenomegaly
·
Gout
like symptoms
·
Anemia
·
Hyperuricemia
·
Bruising
·
Hemorrhages
from other sites
·
Visual
disturbance
Clinical Presentations
·
CML
is a malignant blood disorder.
·
It
involves early hematopoietic cells and leads to their clonal expansion.
·
The
disease originates from a single abnormal hematopoietic stem cell.
·
Over
months and years, this abnormal cell proliferates, leading to increased blood agranulocytosis
and marrow granulocytopenia’s at diagnosis.
· The bone marrow becomes hypercellular as the disease progresses.
Phases of Chronic Myelogenous Leukemia (CML)
Chronic Phase (CP):
·
Initial
phase at diagnosis for approximately 85% of patients.
·
Patients
are often asymptomatic or have mild symptoms.
·
Blast
count typically remains less than 10%.
·
Absence
of splenomegaly and anemia.
·
Thrombocytosis
may be present.
·
Duration
of the chronic phase varies among patients.
Accelerated Phase (AP):
·
Represents
a transition phase between chronic and blast phases.
·
Characterized
by increasing blast cell count (10-19%) and/or the appearance of new
cytogenetic abnormalities.
·
Symptoms
become more pronounced, and the disease may be more difficult to control with
treatment.
· Progression to blast phase is imminent if left untreated.
Blast Phase (BP) or Acute
Myeloid Leukemia (AML):
· Blast
cell count exceeds 20%.
·
Rapid
progression resembling acute leukemia.
·
Patients
may present with symptoms of acute leukemia, including bone marrow failure and
organ infiltration.
· Prognosis is poor, and treatment options are limited.
Pathophysiology
·
Each
cell contains 23 pairs of chromosomes.
·
Chromosome
9 holds the ABL gene, and chromosome 22 carries the BCR gene.
·
During
cell division, these chromosomes cross, break, and fuse, forming the
Philadelphia chromosome.
·
The
Philadelphia chromosome, also known as BCR-ABL, produces a 210kD tyrosine
kinase.
·
This
fusion tyrosine kinase stimulates uncontrolled production of abnormal blood
cells in the bone marrow.
·
In
normal conditions, white blood cells (WBCs) grow and divide in a controlled
manner.
·
In
leukemia, cells divide too rapidly but fail to mature properly.
·
Excessive
production of myeloid cells, including immature blasts, occurs.
·
Blasts
accumulate in the bone marrow, hindering normal blood cell production.
·
There's
a shortage of healthy red cells and platelets, leading to an increased risk of
infection.
·
Enhanced
tyrosine kinase activity regulates metabolic pathways and acts as a receptor
for growth factors.
·
The
oncogenic role of p210 is associated with increased G-CSF and platelet-derived
growth factor levels.
· Activation of p210 may also inhibit apoptosis in hematopoietic cells.
Lab Diagnosis
1. CBC
2.
Biochemical tests:
·
Serum
Uric acid: Increased due to purine destruction
·
Serum
iron: Increased
·
Serum
B12 and B12 binding capacity: Increased
·
NAP
score: Decreased
·
Serum
LDH: Elevated
·
Ca++:
Increased
3. Bone
marrow:
·
Hypercellular
·
Increased
M:E ratio (10:1)
·
Mature
neoplastic myeloid cells
·
Decreased
erythroid precursors
·
Normal
or increased megakaryoblasts
·
Immature
myeloid precursor away from trabeculae
·
Blasts
<10% in chronic phase
·
Abnormal
eosinophilic and basophilic granules
4.
Immunological markers:
·
CD13
+
·
CD14
+
·
CD15
+
·
CD33
+
5.
Cytogenetics:
·
Ph
positive
·
BCR-ABL
positive
6.
Molecular assays
Other
findings:
·
WBC:
50 to 500 x 10^9/l
·
Platelet
count: thrombocytosis
·
Peripheral
blood film:
·
Normocytic,
normochromic anemia
·
Left
shift in neutrophils
·
Eosinophils
normal or increased
·
NRBCs
present
·
Absolute
Basophilia
·
Moderate
thrombocytosis
·
Macrocytosis
·
Hypo
granulated myeloid cells
Leukemoid Reaction: Benign condition resembling
leukemia due to high white blood cell counts.
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