Chronic Myeloid Leukaemia

Introduction
• Haematopoiesis: process by which blood cell lineages
are produced by bone marrow.

• White blood cells (leucocytes) subdivided into:

myeloid lineage or lymphoid lineage.

• Haemopoitic stem cells capable of self renewal and

differentiation.

2
 IL-3,
Self reproduction SCF

Pluripotencial stem
cells (SC)

Partially
differentiated
cell lineage
CFU-L CFU-GEMM

Lymphocytic Myelocytic
lineage lineage
4
 Leukaemias

• The leukaemias are a group of disorders characterized by

accumulation of malignant white cells in the bone
marrow and blood.
• Neoplastic transformation occurs as a result of the
accumulation of genetic mutations in cellular genes.
Initiated by:
- loss of genetic material (deletion);
- gain of genetic material (duplication);
- re location of genetic material (translocation).

5
 Leukaemia
Introduction

 Chronic leukaemias:
- Primitive progenitor cells with capacity for further
maturation.
- generally progress in slower pattern.
- more difficult to cure.

6
 ALL ( 10 %) AML (45 %)
lymphoblasts myeloblasts

CLL (30 %) CML (15%)

lymphocytes granulocytes

7
 Chronic
ChronicMyeloid
myeloidLeukaemia (CML)
leukemia(CML)
• Also known as chronic myelogenous leukaemia or
chronic granulocytic leukaemia (CGL).
• Is a clonal disorder that results from an acquired
genetic change in a pluripotential haemopoietic
stem cell.
• This altered stem cell proliferates and generates
a population of differentiated cells that gradually
replaces normal haemopoiesis and leads to a greatly
expanded total myeloid mass.
• Is one of the myeloproliferative diseases.

8
 CML- Epidemiology
CML-Epidemiology

• Occurs in about 1-1.5 per 100,000 of the

population per annum in all countries .
• It accounts for around 15% of leukaemias.
• It occurs at all decades of life, with the median age
of onset of 50-60 years.
• The incidence is slightly higher in males.

9
 CML- Aetiology
• Not clear.
• Increases incidence in:
- survivors of atomic disasters (e.g in Japan )
- post radiation therapy.
• No familiar predisposition and no definite
association with HLA genotypes.
• Philadelphia chromosome is an acquired
cytogenetic anomaly.

10
 Philadelphia (Ph) chromosome

CML was the first malignancy to be linked to a clear genetic

abnormality , the chromosomal translocation known as
philadelphia chromosome.
90-95% of CML patients have Ph. chromosome.
It is formed as a result of reciprocal translocation of long arm of
chromosome 22 and chromosome 9, an event referred to as t
(9;22).
As a result; Breakpoint cluster region (BCR) gene from
chromosome 22 fused to Abelson(ABL) gene on chromosome 9.
The abnormal chromosome 22 is the Ph chromosome.

11
 CML- Clinical features
• In up to 50% of cases the diagnosis is made
incidentally from a routine blood count.
• Fatigue; lethargy and weight loss.
• Splenomegaly is nearly always present (50-70%)
and is frequently massive. In some patients, splenic
enlargement is associated with considerable
discomfort, pain or indigestion. The liver is also
frequently enlarged.
• Features of anaemia may include pallor, dysponea
and tachycardia.

13
 CML- Clinical features
• Increased sweating is characteristic.
• Spontaneous bruising or unexplained bleeding
from gums, intestinal or urinary tract are relatively
common.
• Visual disturbances may occur.
• Gout or renal impairment .
• Priapism in males.
• In advanced phases fever, bone tenderness or signs
of infection.

14
Chronic Phase

Accelerated phase

Blast crisis

15
 CML– Chronic Phase

Most cases (85%) of CML are diagnosed at this phase.

There may be no or minimal symptoms of fatigue and
abdominal fullness.
In this phase there are few blasts (<10%) in the blood and
bone marrow.
Lasts from a few to several years.
Ultimately ,in the absence of curative treatment the disease
progresses to an accelerated phase.

16
 CML– Accelerated phase
Is an intermediate phase.
- 10 -19% myeloblasts in the PB or BM.
- Peripheral blood basophils >20%.
- PLTs count <100,000 unrelated to therapy.
- PLTs count > 1000,000 unresponsiveness to therapy.
- Increasing spleen size and increasing WBC un responsive to
therapy.
- Megakaryocyte proliferation in sheets or clusters in association
with marked reticulin and collagen fibrosis.
The accelerated phase is significant because it signals that the
disease is progressing and transformation to blast crisis is imminent .

17
 CML–Natural history
Blastic phase (crisis)

•Final phase of CML and behaves like an acute leukaemia ( AML

70% ; ALL 20% ; 10% mixed) with rapid progression.
•Characterized by 20% or more blasts in the peripheral blood or
bone marrow.
•Increased symptomatology.
•Large foci or clusters of blasts in the BM biopsy.
•Extramedullary blast proliferation.
•More difficult to treat and survival is rare beyond a few months.

18
19
 CML
Laboratory
findings

20
Peripheral blood:
• Leucocytosis:
usually in the range of 20,000-200,000
occasionally WBC count 200,000-800,000
• WBC differential shows a complete spectrum of all myeloid
cells ranging from blast forms to mature neutrophils with
intermediate myelocytes and neutrophils predominating.
• The percentage of eosinophils and basophils are usually
increased.
• Anaemia ( normochromic, normocytic).
• PLTs are usually increased but may be normal or even
reduced.

21
22
 Bone marrow:-
• Shows marked hypercellularity ( resembling that of
CML blood).
• M/E ratio is increased.
• Myelocytes predominates.
- Assess the degree of fibrosis.
 Biochemical changes:
• NAP score is invariably low.
• ↑Serum uric acid .
• ↑ serum vitamin B12.
• ↑ LDH.
• Hyepercalcaemia and hyperkalaemia may present.
23
Others:-
Cytogenetics analysis of blood and bone marrow for confirmatory
t(9;22).

24
 CML - Treatment

 Patients with CML should be under the care of

haematologist and oncologist.
 Selected patients should be seen by experts in a
BMT program in a tertiary center.
 Psychological support with an explanation of the
diagnosis , treatment and the prognosis should be
done by a senior haematologist

25
 CML - Treatment

Therapeutic options for CML are :

 Imatinib mesylate.
 Hydroxyurea
 Busulfan
 Interferon alpha (INFα).
 Stem cell transplantation(SCT).
 Second generation TKIS.

26
THANK

YOU

27