EVERY MEDICO SHOULD KNOW ABOUT "CHRONIC MYELOID LEUKAEMIA"

Definition and Pathophysiology

By WHO definition,

1. CML is  identification of the clone of haematopoietic stem cell that possesses the balanced reciprocal translocation between chromosomes 9 and 22, forming Philadelphia chromosome.
2. The t(9;22) involves fusion of BCR (breakpoint cluster region) gene onThe Philadelphia (Ph) chromosome. 
3. There is reciprocal translocation of the part of the long arms of chromosome 22 to the long arms of chromosome 9 written as t(9;22). gene located on chromosome 9q34. 
4. 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. 


Pathophysiology

includes the mechanism of human CML is based on observing the
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
 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 generally insidious.
 Some of the common presenting manifestations are :-
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 .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
blood picture alone... but bone marrow, cytochemical stains can be used

I. BLOOD PICTURE 
1. Anaemia:-  
moderate degree
normocytic normochromic
Occasional normoblasts may be present.

2. White blood cells 
 marked leucocytosis 
(approximately 200,000/μl or more at the time of presentation). 

The natural history of CML consists of 3 phases—

1. Chronic
2. accelerated 
3. blastic.

””Chronic phase of CML 
myeloproliferative disorder
proliferation of 

1. myeloid cells  (i.e. myelocytes and metamyelocytes) 
2. 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 impending blastic transformation.
An accelerated phase of CML is also 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.

 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).

WHO CLASSIFICATION OF MYELOID NEOPLASM
MYELOPROLIFERATIVE DISEASES
1. Chronic myeloid leukaemia (CML), {Ph chromosome t(9;22)
(q34;11), BCR/ABL-positive}
2. Chronic neutrophilic leukaemia
3. Chronic eosinophilic leukaemia/ hypereosinophilic
syndrome
4. Chronic idiopathic myelofibrosis
5. Polycythaemia vera (PV)
6. Essential thrombocythaemia (ET)
7. Chronic myeloproliferative disease, unclassifiable
II. MYELODYSPLASTIC/MYELOPROLIFERATIVE DISEASES
1. Chronic myelomonocytic leukaemia (CMML)
III. MYELODYSPLASTIC SYNDROME (MDS)
1. Refractory anaemia (RA)
2. Refractory anaemia with ring sideroblasts (RARS)
3. Refractory cytopenia with multilineage dysplasia (RCMD)
4. RCMD with ringed sideroblasts (RCMD-RS)
5. Refractory anaemia with excess blasts (RAEB-1)
6. RAEB-2
7. Myelodysplastic syndrome unclassified (MDS-U)
8. MDS with isolated del 5q
IV. ACUTE MYELOID LEUKAEMIA (AML)
1. Acute myeloid leukaemias with recurrent genetic
abnormalities
i. AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
ii. AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBF
& b-MYH11
iii. Acute promyelocytic leukaemia (M3) with t(15;17)
(q22;q12); PML/RAR-a and variants
iv. AML with t(9;11)(p22;q23); MLLT3-MLL
v. AML with t(6;9)(p23;q34); DEK-NUP214
vi. AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-
EVI1
vii. AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-
MKL1
viii. AML with mutated NPM1
ix. AML with mutated CEBPA
2. Acute myeloid leukaemia with myelodysplasia related
changes
3. Therapy related acute myeloid leukaemia
i. Alkylating agent related
ii. Topoisomerase II inhibitor related (some may be
lymphoid)
4. Acute myeloid leukaemia, not otherwise categorised
i. AML minimally differentiated (M0)
ii. AML without maturation (M1)
iii. AML with maturation (M2)*
iv. Acute myelomonocytic leukaemia (M4)
v. Acute monoblastic and monocytic leukaemia (M5a,
M5b)
vi. Acute erythroid leukaemia (M6)
vii. Acute megakaryoblastic leukaemia (M7)
viii. Acute basophilic leukaemia
ix. Acute panmyelosis with myelofibrosis
5. Myeloid sarcoma
6. Myeloid proliferations related to Down’s syndrome
i. Transient abnormal myelopoiesis
ii. Myeloid leukaemia associated with Down’s syndrome
7. Blastic plasmacytoid dentritic cell neoplasm
V. ACUTE BIPHENOTYPIC LEUKEMIA