CHRONIC MYELOID

LEUKAEMIA

MRS. NEERAJA RAJIV

BPT MPT MIAP
 INCIDENCE AND EPIDEMIOLOGY

• CML accounts for 15% of all cases of leukemia

• The annual incidence of CML is 1.5 cases per 100,000
individuals
• Male : female ratio 1.6:1
• The median age at diagnosis is 55–65 years.
• It is uncommon in children; only 3% of patients with
CML are younger than 20 years.
• The median survival in CML was 3–7 years but, with
introduction of TKI therapy (tyrosine kinase
inhibitors),the annual mortality has been reduced from
10–20% to about 2%.
 DEFINITION

 CML is defined by the presence of BCR-ABL1 fusion

gene in a patient with a myeloproliferative neoplasm.
 The clone of haematopoietic stem cell that possesses
the reciprocal translocation between chromosomes 9
and 22, forming Philadelphia chromosome.
Philadelphia chromosome (Ph)
The t(9;22) involves fusion of BCR (breakpoint cluster
region) gene on chromosome 22q11 with ABL (named after
Abelson murine leukaemia virus) gene located on
chromosome 9q34.
The fusion product so formed is termed “Ph chromosome
t(9;22) (q34;11), BCR/ABL” which should be positive for
making the diagnosis of CML.
The underlying pathophysiologic mechanism of human
CML is based on BCR/ABL fusion product proteins are
capable of transforming haematopoietic progenitor cells in
vitro and form malignant clone.
BCR/ABL fusion product brings about following
functional changes:
i) ABL protein is activated to function as a tyrosine
kinase enzyme that in turn activates other kinases
which inhibits apoptosis.
 ii) Ability of ABL to act as DNA-binding protein is
altered.
iii) Binding of ABL to actin microfilaments of the
cytoskeleton is increased.
Exact mechanism of progression of CML to the blastic
phase is unclear but following mechanisms may be
involved:
i) Structural alterations in tumour suppressor p53 gene.
ii) Structural alterations in tumour suppressor Rb gene.
iii) Alterations in RAS oncogene.
 iv) Alterations in MYC oncogene.
 v) Release of cytokine IL-1β.
vi) Functional inactivation of tumour suppressor
protein, phosphatase
 ETIOLOGY

 • No familial associations in CML

• Exposure to ionizing radiation (e.g., nuclear
accidents, radiation treatment for ankylosing
spondylitis or cervical cancer) has increased the risk
of CML, which peaks at 5–10 years after exposure
and is dose-related (larger dose)
• Because of adequate protection, the risk of CML is
not increased in individuals working in the nuclear
industry or among radiologists in recent times
 CLINICAL FEATURES

Chronic myeloid (myelogenous, granulocytic)

leukaemia comprises about 15-20% of all leukaemias
and its peak incidence is seen in 5th and 6th decades
of life.
A distinctive variant of CML seen in children is
called juvenile CML.
Both sexes are affected equally.
The onset of CML is generally insidious.
 Some of the common presenting manifestations are
as under:

1. Features of anaemia such as weakness, pallor,

dyspnoea and tachycardia.
2. Symptoms due to hypermetabolism such as weight
loss, lassitude, anorexia, night sweats.
3. Splenomegaly is almost always present and is
frequently massive. In some patients, it may be
associated with acute pain due to splenic infarction.
4. Bleeding tendencies such as easy bruising,
epistaxis, menorrhagia and haematomas may occur.
5. Less common features include gout, visual
disturbance, neurologic manifestations and
priapism.
6. Juvenile CML is more often associated with lymph
node enlargement than splenomegaly.
Other features are frequent infections, haemorrhagic
manifestations and facial rash.
 PHASES OF CHRONIC MYELOID LEUKEMIA

The phases are based mainly on the number of immature WBC

(blasts) in the blood or bone marrow.
1. Chronic phase
 • less than 10% blasts in their blood or bone marrow.
 • fairly mild symptoms (if any) and usually respond to standard
treatments.
 • Most patients are diagnosed in the chronic phase.

2. Blast phase ( blast crisis)

 • 20% or more blasts
 • Large clusters of blasts are seen in the bone marrow.
 • The blast cells have spread to tissues and organs beyond the bone
marrow. These patients often have fever, poor appetite, and weight
loss. In this phase, the CML acts a lot like an acute leukemia.
3. Accelerated phase: Patients are considered to be in
accelerated phase if any of the following are true:
 •15% or more, but less than 30% blasts
•Basophils make up 20% or more of the blood
•Blasts and promyelocytes combined make up 30% or
more of the blood
•Very low platelet counts (100 x 1,000/mm3 or less)
•New chromosome changes in the leukemia cells with the
Philadelphia chromosome
•Symptoms such as fever, poor appetite, and weight loss.
CML in the accelerated phase doesn't respond as well to
treatment as CML in the chronic phase.
 LABORATORY FINDINGS

BLOOD PICTURE.
The typical blood picture in a case of CML at the
time of presentation shows the following features
Anaemia.
Anaemia is usually of moderate degree and is
normocytic normochromic in type.
 Occasional normoblasts may be present.
WHITE BLOOD CELLS.
Characteristically, there is marked leucocytosis
(approximately 200,000/μl or more at the time of
presentation).
The natural history of CML consists of 3 phases—chronic,
accelerated, and blastic.
Chronic phase of CML begins as a myeloproliferative
disorder and consists of excessive proliferation of
myeloid cells of intermediate grade (i.e. myelocytes
and metamyelocytes) and mature segmented
neutrophils. Myeloblasts usually do not exceed 10% of
cells in the peripheral blood and bone marrow. An increase
in the proportion of basophils up to 10% is a characteristic
feature of CML. A rising basophilia is indicative of
 Blastic phase or blast crisis in CML fulfills the
definition of acute leukaemia in having blood
or marrow blasts >20%. These blast cells may be
myeloid, lymphoid, erythroid or undifferentiated and
are established by morphology, cytochemistry, or
immunophenotyping. Myeloid blast crisis in CML is
more common and resembles AML.
An accelerated phase of CML is also described in
which there is progressively rising leucocytosis
associated with thrombocytosis or
thrombocytopenia and splenomegaly.
Accelerated phase is defined as increasing degree of
anaemia, blast count in blood or marrow between
10-20%, marrow basophils 20% or more, and
platelet count falling below 1,00,000/μl.

Platelets. Platelet count may be normal but is raised
in about half the cases.

BONE MARROW EXAMINATION.

Examination of marrow aspiration yields the following results:

 1. Cellularity. Generally, there is hypercellularity with total or partial
replacement of fat spaces by proliferating myeloid cells.

 2. Myeloid cells. The myeloid cells predominate in the bone marrow with
increased myeloid-erythroid ratio. The differential counts of myeloid cells in
the marrow show similar findings as seen in the peripheral blood with
predominance of myelocytes.

 3. Erythropoiesis. Erythropoiesis is normoblastic but there is reduction in

erythropoietic cells.

 4. Megakaryocytes. Megakaryocytes are conspicuous but are usually smaller

in size than normal.
CYTOCHEMISTRY.
 The only significant finding on cytochemical stains is
reduced scores of neutrophil alkaline phosphatase
(NAP) which helps to distinguish CML from myeloid
leukaemoid reaction in which case NAP scores are
elevated

OTHER INVESTIGATIONS.
A few other accompanying findings are seen in CML:
 1. Elevated serum B12 and vitamin B12 binding capacity.
 2. Elevated serum uric acid (hyperuricaemia).
 TREATMENT AND COMPLICATIONS

The approach of modern therapy in CML is targetted at removal

of all malignant clones of cells bearing BCR/ABL fusion protein,
so that patient reverts back to prolonged non-clonal
haematopoiesis i.e. molecular remission from disease. This is
achievable by the following approaches
1. Imatinib oral therapy:
The basic principle underlying imatinib oral treatment is to
competitively inhibit ATP binding site of the ABL kinase, which
in turn, inhibits signal transduction BCR/ABL fusion protein.
Imatinib induces apoptosis in BCR/ABL-positive cells and thus
eliminates them.
Imatinib is found more effective in newly diagnosed cases of
CML. Complete haematologic remission is achieved for 18
months in 97% cases treated with imatinib.
2. Allogenic bone marrow (stem cell) transplantation.
Although this treatment modality offers proven cure,
it is complicated with mortality due to procedure and
development of post-transplant graft-versus-host
disease (GVHD) and, therefore, post-transplant
immunosuppressive treatment has to be continued.

3. Interferon-α. Prior to imatinib and allogenic

transplantation, chronic phase of CML used to be
treated with interferon-α was the drug of choice.

4. Chemotherapy. Chemotherapeutic agents are used in
treatment of CML for lowering the total population of
WBCs. These include use of busulfan, cyclophosphamide
(melphalan) and hydroxyurea.

5. Others. Besides above, other forms of treatment

include splenic irradiation, splenectomy and
leucopheresis.

The most common cause of death (in 80% cases) in CML

is disease acceleration and blastic transformation.