MLS 421 Chronic Leukemias - 2023

Dr.Uzoma I.
C
Department of Medical Laboratory Sciences,
FHST, College of Medicine, University of Nigeria,
Enugu Campus.
 Ph+ = Philadelphia positive chromosome
 CML = Chronic myeloid leukaemia
 ALL = Acute lymphoblastic leukaemia
 BCR = Breakpoint Cluster Region gene
 ABL = Abelson oncogene
❑ Chronic
myeloid leukaemia (CML) is a clonal
myeloproliferative disorder.
❑ Thedisorder arises in a pluripotent haemopoietic

stem cell and is characterised by leucocytosis,
splenomegaly and the presence of the Ph+
chromosome( in >95% of CML and some times in>
25% of ALL).
 The aetiology of the chromosomal
translocation leading to CML is unknown.
However high dose radiation has been
implicated.
 Annual Incidence:1 to 2 people per 100,000
persons in the population worldwide.
 Male are more affected than females. Ratio:
1.8:1 .
 Median age of occurrence is 67 years.
 It is uncommon after the age of 60years in
Africans
 CML is rare in children.
❑ The Philadelphia (Ph+) chromosome was first described
by Peter Nowell and David Hungerford in Philadelphia
in 1960
❑ Molecularlyit is defined by the reciprocal translocation

between the long arm of chromosome 9q34. of the
Abelson gene and the long arm of chromosome 22q11
of the Break point cluster region (BCR) gene forming a
chimeric gene, BCR-ABL
❑ JanetRowley, in 1972, deciphered the Ph chromosome

as a reciprocal translocation between chromosomes 9
and 22. She showed the BCR-ABL fusion gene is an
oncogene.
 Thisfusion gene codes for an abnormal
protein with Tyrosine Kinase activity. This
Tyrosine Kinase is involved in signal
transduction and activates pathways within
the affected cells leading to malignant
transformation. Tyrosine kinases work by
transferring a phosphate group from ATP to
intracellular proteins that regulate cell
division.
 The oncogene c-abl is normally located in the
long arm of chromosome 9 and codes for a
protein with tyrosine kinase activity. The
physiological function of the breakpoint
cluster region is currently uncertain.
 Duringthe reciprocal translocation, that

causes CML, c-abl is moved to chromosome 22
and a truncated part of the bcr gene to
chromosome 9.
 The abnormal chromosome 22 is called the

Philadelphia chromosome while the longer
than normal chromosome 9 containing
genomic material from chromosome 22 is
termed der9.
der 9
Cytogenetics
detects Ph+ cells
when they are
more than 5% in
the cell population
The preferred
methods of
detection are
karyotyping and
FISH (fluorescent
in situ
hybridization
methods
 Chronic indolent phase
 Accelerated phase
 Blastic phase
Natural Evolution of CML
 Chronic phase: usually presents in this phase,

with progressive leucocytosis and splenomegaly.
The disease is responsive to cytotoxic therapy.
 Accelerated phase: Symptoms are worse, with
night sweats, bone pain, splenomegaly less
responsive to therapy. Peripheral blood shows
increasing numbers of basophilic, blasts and
promyelocytes. Disease is difficult to control.
 Blastic phase: symptoms- extramedullary
deposits (chloromas) appears, > 30% blasts in
blood or bone marrow. Blast transformation may
be lymphoid (15%) or myeloid (85%)
Laboratory findings
 Leucocytosis is usually >50 x 109/L and sometimes

>500 x 109/L . A complete spectrum of myeloid cells is
seen in the peripheral blood.
 Increased neutrophils and myelocytes more than blast

cells and promyelocytes
 Increased circulating basophils.
 Normochromic, normocytic anaemia is common.

 Could be normal or decreased.
 Increased in MPD and in infection.
 Low in AML
 Platelet count is frequently increased
 Neutrophil alkaline phosphatase score is

always low.
 Hypercellular bone marrow with predominance

of the granulocytes
 Cytogenetic analysis on blood or bone marrow

(conventional or FISH) shows the Ph chromosome
 Serum uric acid is usually raised.

 Ina minority of patients, the Ph abnormality
cannot be seen by microscopic karyotypic
analysis.
1. The chromosomal rearrangement can be

detected by FISH (fluorescence insitu
hybridization)
2. PCR. (multiplex PCR)
➢ The transcript types e13a2 and e14a2 encode the p210
oncoprotein known as BCR-ABL major.
➢ BCR-ABL major occurs in more than 90% of CML patients
➢ The e1a2 encodes the p190 oncoprotein known as the BCR-

ABL minor.
➢ BCR-ABL minor occurs in 1% of CML and 75% of ALL patients.

Management of CML
A. Diagnostic Work-up for CML Diagnosis
1. Clinical History and Presentation
(haematological and bone marrow
examinations
2. Karyotyping using Giemsa banding
3. Fluorescent In Situ hybridization
4. Reverse transcriptase real time
quantitative PCR (RT-qPCR)
5. Tyrosine kinase domain mutation analysis
(TKD)
B. WHO gold standard is BCR-ABL testing by
real time qPCR
Tyrosine kinase inhibitors (TKIs):
❑Imatinib (Gleevec)----400mg per day

❑Nilotinib (Tasigna)
❑Desatinib (Sprycel)

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Dr.Uzoma I.

❑ Thedisorder arises in a pluripotent haemopoietic

❑ Molecularlyit is defined by the reciprocal translocation

❑ JanetRowley, in 1972, deciphered the Ph chromosome

 Duringthe reciprocal translocation, that

 The abnormal chromosome 22 is called the

 Chronic phase: usually presents in this phase,

 Leucocytosis is usually >50 x 109/L and sometimes

 Increased neutrophils and myelocytes more than blast

 Increased circulating basophils.

 Normochromic, normocytic anaemia is common.

 Neutrophil alkaline phosphatase score is

 Hypercellular bone marrow with predominance

 Cytogenetic analysis on blood or bone marrow

 Serum uric acid is usually raised.

1. The chromosomal rearrangement can be

➢ BCR-ABL major occurs in more than 90% of CML patients

➢ The e1a2 encodes the p190 oncoprotein known as the BCR-

➢ BCR-ABL minor occurs in 1% of CML and 75% of ALL patients.

❑Imatinib (Gleevec)----400mg per day

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