CHRONIC MYELOID LEUKAEMIA (CML)

Definition and Pathophysiology

By WHO definition, CML is established by identification of the

Clone of haematopoietic stem cell that possesses the balanced

Reciprocal translocation between chromosomes 9 and 22,

Forming Philadelphia chromosome (Fig. 12.11). 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. This identification may be done by PCR

or by FISH. The underlying pathophysiologic mechanism of

human CML is based on the observation that 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-1b.

vi) Functional inactivation of tumour suppressor protein,

phosphatase A2.

Clinical Features

Chronic myeloid (myelogenous, granulocytic) leukaemia

comprises about 20% of all leukaemias and its peak incidence

is seen in 3rd and 4th 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.

Laboratory Findings

The diagnosis of CML is generally possible on blood picture

Alone. However, bone marrow, cytochemical stains and

Other investigations are of help.

I. BLOOD PICTURE The typical blood picture in a case of

CML at the time of presentation shows the following features

(Fig. 12.13):
 1. Anaemia Anaemia is usually of moderate degree and is

Normocytic normochromic in type. Occasional normoblasts

May be present.

2. White blood cells Characteristically, there is marked of presentation). The natural history of CML
consists of 3

phases—chronic, accelerated, and blastic.

” Chronic phase of CML begins as a myeloprolife-

rative disorder and consists of excessive proliferation

of myeloid cells of intermediate grade (i.e. myelocytes

and metamyelocytes) and mature segmented neutro-

phils. 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 impending

blastic transformation. An accelerated phase of CML is also

described in which there is progressively rising leucocytosis

associated with thrombocytosis or thrombocytopenia and

splenomegaly. Accelerated phase has 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.

” 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. However,

unlike AML, Auer rods are not seen in myeloblasts of CML

in blast crisis.

3. Platelets Platelet count may be normal but is raised in

about half the cases.

II. 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.

5. Cytogenetics Cytogenetic studies on blood and

bone marrow cells show the characteristic chromosomal

abnormality called Philadelphia (Ph) chromosome seen

in 90-95% cases of CML. Ph chromosome is formed by

reciprocal balanced translocation between part of long arm

of chromosome 22 and part of long arm of chromosome

9{(t(9;22) (q34;11)} forming product of fusion gene, BCR/

ABL (see Fig. 12.11).

III. 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 (see Fig. 12.10,B, and Table 12.3). However, NAP

scores in CML return to normal with successful therapy,

corticosteroid administration and in infections.

IV. 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).

General principles of Treatment and Prognosis

Insight into molecular mechanism of CML has brought about

Major changes in its therapy. 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-a Prior to imatinib and allogenic transplanta-

Tion, chronic phase of CML used to be treated with interferon-a

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.