Download The Philadelphia chromosome

- Slower rate of cellular prolifiration
- Sometimes discovered accidentaly during a routine
bL count.
-Cells are more mature ----> gain access to the
circulation more easy ---> very high WBCs count.
On the otherhand overcrowding of the marrow
occurs late ----> weakness, bleeding tendency occur
relatively late.
-Thus this early presentation are the effect of
metastasis
e.g.
splenomegaly which may be huge.
Characterized
by
prolifiration of white cells which invade the
blood stream, may infiltrate any part of the
body.
Definition:It is a form of
leukemia characterized by the
increased and unregulated growth
of predominantly myeloid cells in
the bone marrow and the
accumulation of these cells in the
blood. CML is a clonal bone
marrow stem cell disorder in which
proliferation of mature
granulocytes (neutrophils,
eosinophils, and basophils) and
their precursors is the main finding..
Epidemiology:
CML occurs in all age groups, but
most commonly in the middle-aged
and elderly. Its annual incidence is
1–2 per 100,000 people, and
slightly more men than women are
affected. CML represents about 15–
20% of all cases of adult leukemia
in Western populations.The only
well-described risk factor for CML
is exposure to ionizing radiation;
for example, increased rates of
CML were seen in people exposed
to the atomic bombings of
Hiroshima and Nagasaki[16
It is a type of myeloproliferative
disease associated with a
characteristic chromosomal
translocation called the
Philadelphia chromosome
CML was the first malignancy
to be linked to a clear genetic
abnormality, the chromosomal
translocation known as the
Philadelphia chromosome.
This chromosomal
abnormality is so named
because it was first discovered
and described in 1960 by two
scientists from
Philadelphia,Pennsylvania:
This exchange brings together
two genes: the BCR
(breakpoint cluster region)
gene on chromosome 22 and
the proto-oncogene ABL
(Ableson leukemia virus) on
chromosome 9. The resulting
hybrid gene BCR-ABL codes
for a fusion protein with
tyrosine kinase activity, which
activates signal transduction
pathways, leading to
uncontrolled cell growth.
The Philadelphia chromosome:
T (9:22) translocation.
The Ph chromosome is a shortened
chromosome 22, which result from Reciprocal
translocation between the long arms of
chromosomes 9 & 22 ,The result is a hybrid
bcr-abl gene (fusion protein) with increased
tyrosine Kinase acm resulting in leukemic
transformation.
AGE: CML is a disease of young adults ( ) 20 - 45
years, but may occur at any age.
Sex: Females more than males.
Onset: Gradual.
Course : Spontenous remissions and exacerbations.
The
disease generally
terminates in
marrow
transformation (AML)
or failure associated with
fibrosis.
Prognosis Patient usually die within 6 months --> 2
years but may live for 5 years or more.
Cl. Picture :
Symptoms:
* may be diagnosed accidentaly.
* general lassitude, rapid fatigability, bone ache.
* Symptoms caused by splenomegally : -->
dragging
Lt hypochondrial pain, may be:
---> acute Lt hypochondrial pain.
---> abd. swelling
---> dyspepsia
*Symptoms caused by leukemic infilterations:
*Skin : Pruritis . nodules, eruptions, pigmentations
*Chest : cough and hemoptysis.
*urinary : hematuria.
*GIT - Haemorrhage.
-discomfort or pain from gastric infilterations
*Genital: Priampism in males, infertility and
haemorrhage in females
*Eyes : impairment of vision (haemorrhage-exudate(
*Symptoms 2 ry to thrombocytopenia :(bleeding gums,
other bleeding tendency(
*Symptoms 2 ry to acute exacerbations: - fever -sore
throat
- bone ache - Haemorrhage
Signs:
1- General : -low grade fever if exacerbations --> high
fever
-pallor
-under weight
- Tender sternum.
2-Splenomegally (Huge, Firm, irregular, may be areas
of tenderness (perisplenism), may be splenic rub (over
areas of infarction)
3- Lymphadenopathy : uncommon
4- Hepatomegally : variable
5- Signs of leukemic infilterations
Skin
N.S
Laboratory Findings:
1 -Blood picture : RBCs . very early may be polycythemia,
late anemia.
platelets: very early may be rise, late decrease
WBCs : Total count: may be very high () 200 - 400.000
Differential count: predominantely myelocytes, some
mature granuulocytes, Myeloblastes (1- 5%) if more -->
acute exacerbation
Basophils, Eosinophils are increased.
The total count may drop if:
- Spont. remission
-Therapeutic remission
-Acute exacerbation.
-Acute pyogenic infection
Leucocyte alkaline
phosphatase: (LAP) score
This test was once used to
see if the cause of a high
white blood cell count
might be CML. It is rarely
used now, since there are
better ways to check the
blood for suspected CML.
The leucocyte alkaline phosphatase (LAP)
score is a cytochemistry test -- cells from the
sample are placed on microscope slides, and
chemical stains (dyes) that react only with
certain types of cells are added. The stains
cause color changes which can be seen only
under a microscope. Normally the LAP score
goes up as the white blood cell (WBC) count
goes up. But people with CML tend to have
high WBC counts with low LAP scores
Ultimately, CML is diagnosed by
detecting the Philadelphia chromosome.
This characteristic chromosomal
abnormality can be detected by routine
cytogenetics, by fluorescent in situ
hybridization, or by PCR for the bcr-abl
fusion gene
2 -BM Aspiration: complete
replacement of fat by cellular
elements mostly granulocytes,
but few blasts with exclusion
of other hemopatopoietic
elements.
Diff. Diagnosis:
1- leukemoid reaction: syndrome
with morphologic changes similar
to leukemia in peripheral blood
usually 2ry to infections:T.B.,
pneumonia,
meningitis
or
metabolic causes
But * Eosinophils and bosophils
are decreased (rather than
increased).
*WBCs are alkaline
phosphatase stongly +ve (rather
than -ve)
*B.M. is only moderately
hyperplastic.
2-Myelofibrosis : splenomegally,
only
moderate
leukocytosis,
Fibrotic marrow. WBCs ALK.
phosph
+ve,
no philadephia
chromosome
Classification:
CML is often divided into three
phases based on clinical
characteristics and laboratory
findings.
CML typically begins in the
chronic phase, and over the
course of several years
progresses to an accelerated
phase and ultimately to a blast
crisis.
Blast crisis is the terminal phase of
CML and clinically behaves like an
acute leukemia. One of the drivers of
the progression from chronic phase
through acceleration and blast crisis is
the acquisition of new chromosomal
abnormalities (in addition to the
Philadelphia chromosome).Some
patients may already be in the
accelerated phase or blast crisis by the
time they are diagnosed.
Chronic phase:
Approximately 85% of patients with CML are
in the chronic phase at the time of diagnosis.
During this phase, patients are usually
asymptomatic or have only mild symptoms of
fatigue or abdominal fullness. The duration of
chronic phase is variable and depends on how
early the disease was diagnosed as well as the
therapies used. Ultimately, in the absence of
curative treatment, the disease progresses to an
accelerated phase.
Accelerated phase
Criteria for diagnosing transition into the
accelerated phase are somewhat variable; the most
widely used criteria are those put forward by
investigators at M.D. The World Health
Organization.The WHO criteria are perhaps most
widely used, and define the accelerated phase by
any of the following:
*10–19% myeloblasts in the blood or bone
marrow
*>20% basophils in the blood or bone marrow
*Platelet count <100,000, unrelated to therapy
*Platelet count >1,000,000, unresponsive to
therapy
.
*Cytogenetic evolution with new
abnormalities in addition to the
Philadelphia chromosome
*Increasing splenomegaly or white
blood cell count, unresponsive to
therapy
The patient is considered to be in
the accelerated phase if any of the
above are present. The accelerated
phase is significant because it
signals that the disease is
progressing and transformation to
blast crisis is imminent
Blast crisis
Blast crisis is the final phase in the
evolution of CML, and behaves
like an acute leukemia, with rapid
progression and short survival.
Blast crisis is diagnosed if any of
the following are present in a
patient with CML:
*>20% myeloblasts or
lymphoblasts in the blood or bone
marrow
*Large clusters of blasts in the
bone marrow on biopsy
*Development of a chloroma (solid
focus of leukemia outside the bone
marrow)
Treatment
Chronic phase
Chronic phase CML is treated with
inhibitors of tyrosine kinase, the first of
which was imatinib mesylate (marketed as
Gleevec or Glivec. In the past,
antimetabolites (e.g. cytarabine,
hydroxyurea), alkylating agents, interferon
alfa 2b, and steroids were used, but these
drugs have been replaced by imatinib.
Imatinib was approved by the United
States FDA in 2001 and specifically
targets BCR/abl, the constitutively
activated tyrosine kinase fusion protein
caused by the Philadelphia chromosome
translocation.
Bone marrow transplantation
was also used as initial
treatment for CML in younger
patients before the advent of
imatinib, and while it can
often be curative, there was a
high rate of transplant-related
mortality. The transplantrelated mortality rate in the
present is less than 5%.
A number of newer drugs are being used to
treat the minority of patients who develop
imatinib resistance.
To overcome imatinib resistance and to
increase responsiveness of TK inhibitors,
two novel agents have been developed. The
first, dasatinib, is a TK inhibitor that blocks
several oncogenic proteins and has been
approved by the US FDA to treat CML
patients who are either resistant to or
intolerant of imatinib in 2007. Another TK
inhibitor, nilotinib, is also approved by the
US FDA for the same indication
Dasatanib and nilotinib failed to
overcome the imatinib resistance caused
by the T315I mutation. All current
treatments for this mutation are
experimental. Recently omacetaxine,
administered subcutaneously in CML
patients who had failed imatinib and
who have the highly drug resistant
T315I kinase domain mutation.
Stem cell transplantation
is an option for those
patients who developed
T315I mutation.
In 2005 favourable results of
vaccination were reported with the
BCR/abl p210 fusion protein in
patients with stable disease, with
GM-CSF as an adjuvant
Prognosis :
Three different risk groups were identified
based on a prognostic scoring system that
includes several variables: age, spleen size,
blast count, platelet count, eosinophil count
and basophil count..
In the lowest risk group, the median survival time
was 98 months.
In the middle group, the median was 65 months,
and in the highest risk group, the median was about
42 months. Of all patients analyzed, the longest
survival time was 117 months. However, this study
pre-dates the advent of treatments using targeted
therapy. A follow-up on patients using imatinib
published in the New England Journal of Medicine
shows an overall survival rate of 89% after five years