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CHRONIC MYELOID LEUKEMIA

GENERAL FEAUTURES

Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a kind
of leukemia that causes an increase in the number of white blood cells in the blood. It's a
form of cancer that starts in the blood-forming cells of the bone marrow. The spongy
substance inside some bones (bone marrow) creates an excessive number of myeloid cells,
which are immature white blood cells that do not function correctly.

CML generally appears after the age of 60. Excessive weariness (fatigue), fever, and weight
loss are all prevalent features. Many people who are impacted suffer splenomegaly, which
causes a sense of fullness in the belly and a loss of appetite. CML does not always manifest
itself in the form of signs and symptoms. It's possible that it'll be discovered via a blood test;
test results may reveal that their white blood cell count is abnormally high. Because CML is a
slow-progressing disease, many patients do not experience any symptoms.

The disease is divided into three stages: chronic, accelerated, and burst (or blast crisis). The
amount of mature white blood cells increases in the chronic phase, and myeloblasts make up
fewer than 10% of blood cells. During this stage, the illness's signs and symptoms are usually
modest or nonexistent, and the condition gradually worsens. The chronic stage might last
anywhere from a few months to several years. The amount of myeloblasts is slightly larger in
the accelerated phase, accounting for 10 to 29% of blood cells. The indications and
symptoms are becoming increasingly severe. The accelerated phase normally lasts 4 to 6
months, however it might be skipped in certain people who are afflicted. Myeloblasts make
about 30 percent or more of blood or bone marrow cells during a blast crisis. This phase
involves the most severe signs and symptoms, such as a greatly enlarged spleen, bone pain,
and weight loss. Severe infections and uncontrollable bleeding can be fatal.

PHENOTYPE

As mentioned above, it is difficult to diagnose this disease without a blood test. Since
leukemia cells replace the bone marrow's normal blood-making cells, many of the signs and
symptoms of CML develop. As a result, patients with CML don't produce enough red blood
cells, white blood cells that work correctly, or platelets.

• Anemia is defined as a lack of red blood cells. Weakness, fatigue, and shortness of
breath are all possible side effects.
• Leukopenia is a condition in which the normal white blood cells are in
insufficient supply. Infections are more likely as a result of the scarcity. Despite the
fact that people with leukemia have a large number of white blood cells, the leukemia
cells do not protect the body against infection like regular white blood cells do.
• Neutropenia is defined as a low level of normal neutrophils. Neutrophils are a kind
of white blood cell that aids in the fight against bacterial illness. Neutropenic people
are at a higher risk of bacterial infections that can be fatal.
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• Thrombocytopenia is a lack of platelets in the blood. It can cause easy bruising or

bleeding, as well as nosebleeds and bleeding gums on a regular or severe basis. Some
CML patients have an abnormally high number of platelets (thrombocytosis).
However, because platelets don't always operate as they should, these patients
frequently have bleeding and bruises.

TYPE OF INHERITANCE

Chronic myeloid leukemia affects roughly 1 in every 555 people. It accounts for around 10%
of all malignancies of the blood cells (leukemias). The mutation that causes CML is not
transmitted down through the generations. This mutation is thought to be acquired, which
means it appears after birth. It mostly affects elderly and rather rarely affects kids, while it
can strike anyone at any age. Therefore, family history is not a risk factor, more specifically a
patient's chances of passing the sickness on to his or her offspring are zero.

The following are the only known risk factors for chronic myeloid leukemia (CML):

• Radiation exposure: High-dose radiation exposure (such as being a survivor of an

atomic bomb blast or a nuclear reactor accident) raises the risk of CML.
• Age: The risk of CML increases as you become older.
• Gender: Males are significantly more likely than females to have this condition,
although the reason for this is unknown.

RECCURNCE RISK

CML relapse is the recurrence of CML in individuals who have already been treated and are
in remission. Remission can be determined by looking at:

• Samples of blood (haematological remission): Blood counts return to within the

normal range.
• At the cellular level, blood and marrow (cytogenetic remission): In the bone
marrow, malignant cells have been considerably decreased or vanished.
• Molecular examination of blood and marrow utilizing sensitive techniques like
polymerase chain reaction analysis or flow cytometry(molecular remission):
There is no sign of illness in the blood cells or bone marrow.

When a relapse develops, the blasts in the bone marrow begin to overmultiply again, reaching
levels greater than those required for remission, regardless of the kind of remission.

Targeted therapy with tyrosine kinase inhibitors is the current treatment for CML. Imatinib
was the first tyrosine kinase inhibitor to hit the market, and it helped people with CML live
longer. Around 60% of individuals who received imatinib had positive outcomes. However,
between 15-30% of patients relapsed or failed to react to initial treatment (also known as
refractory treatment) over time, owing to tyrosine kinase inhibitor resistance.
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The BCR-ABL1 mutation has been associated to imatinib resistance in people with CML.
CML is defined by the presence of the Philadelphia chromosome mutation, which is
produced by a translocation of DNA material between chromosomes 9 and 22, resulting in
the development of the cancer protein BCR-ABL. The BCR-ABL protein causes myeloid
cells to overproduce and prevents them from being destroyed, allowing them to multiply.

The Philadelphia chromosome is found in 95% of CML patients, with the other 5% harboring
alterations that have comparable consequences. Some biological variables have been linked
to an increased risk of recurrence after stopping tyrosine kinase inhibitor therapy. This is a
topic that is actively being researched.

The diagnosis of these mutations during imatinib treatment has enabled for the prediction of
relapses or poor response. These abnormalities will need a change in therapy for patients.

Around 60% of CML patients will relapse after stopping imatinib medication. The majority
of relapses occur within the first six months of treatment. Patients, on the other hand,
frequently react to imatinib reintroduction. Relapse rates of up to 8% have been recorded
following allogeneic stem cell transplantation (ASCT). After an ASCT, the most recent
relapse was 18 years ago.

CHRONIC MYELOID LEUKEMIA

GENE, GENETIC MECHANISM/RELATED PATHWAY

TYPE OF MUTATION

GENETIC TERMS DETECTED

Chronic myeloid leukemia occurs with Philadelphia chromosome. Philadelphia chromosome

is a mutated chromosome that has chromosomal translocation between region 34 on
chromosome 9 short arm and region 11 on chromosome 22 short arm. This translocation
combines ABL gene, which is for encoding a nonreceptor tyrosine kinase, and BCR gene,
which is for encoding a phosphoprotein. The BCR-ABL fusion gene produces a fusion
protein whose size is determined by the length of the BCR peptide linked to the amino
terminus.
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PDQ® Adult Treatment Editorial Board. PDQ Chronic Myelogenous Leukemia Treatment. Bethesda, MD:
National Cancer Institute. Updated <MM/DD/YYYY>. Available
at: https://www.cancer.gov/types/leukemia/patient/cml-treatment-pdq. Accessed <09/06/2022>. [PMID:
26389183]

Clinical stages of chronic myeloid leukemia (A) Normal hematopoiesis are defined by the
presence of hematopoietic stem cells capable of controlled self-renewal and multipotency,
resulting in balanced hematopoiesis between myeloid and lymphoid lineages. (B) During the
chronic phase, the myeloproliferative differentiation pathway gains a competitive edge,
resulting in a large myeloid expansion. Blast crisis is defined by a halt in the maturation of
myeloid or lymphoid cells. In leukemic stem cells (LSCs), newly acquired genetic and
epigenetic abnormalities appear, and blast cells migrate from the bone marrow to the
peripheral circulation.
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