Chronic myeloid leukemia magdi sasi 2019 ramadan

MAGDI AWAD SASI 7TH
OCTOPER HOSPITAL LIMU BASIC SCIENCES PHYSIOLOGY 2019
UPDATE OF CML FROM A TO Z by DR MAGDI AWAD SASI RAMADAN 5/2019
Practice Essentials
Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is
a myeloproliferative disorder characterized by increased proliferation of the
granulocytic cell line without the loss of their capacity to differentiate. It accounts
for 20% of all leukemias affecting adults.
Essential for diagnosis:
 Markedly elevated WBC.
 Markedly left shifted myeloid series with a low percentage of promyelocytes and blasts.
 Presence of pheladelphia chromosome.
DEFINITION:
 CML is a myeloproliferative disorder characterized by over production of myeloid cells.
 These myeloid cells retain the capacity of differentiation with normal bone marrow
retained during the early phases.
 The disease remains stable for years and then transforms to malignancy.
CLASSIFICATION OF CML:
CLINICAL VARIANTS__
Typical CML (( Philadelphia chromosome + ))
Atypical CML ((Philadelphia chromosome negative ))
MORPHOLOGICAL VARIANTS__
Chronic eosinophilic leukemia
Chronic basophilic leukemia
Chronic monocytic leukemia
Chronic neytrophilic leukemia
PATHOPHYSIOLOG:
Associated with characterized chromosomal abnormality---((Philadelphia chromosome))—
Is a reciprocal translocation between the long arms of chromosome 9 and 22.
A large portion of 22q is translocated to 9q; smaller piece of 9q is moved to 22q .
The portion of 9q that is traslocated contains abl, a proto-oncogene that is the cellular
homologue of the ableson murine leukemia virus.
The abl gene is received at a specific site on 22q ,the break point cluster ( bcr ).
The fusion gene bcr—abl produces novel protein that differs from the normal transcript of
abl gene in that it passes tyrosine gene activity ((characteristic activity for transforming
genes)).
At time of diagnosis, Philadelphia chromosome positive clone dominates.
Approximately, 5% of CML are negative.
In almost all cases, light microscope is not helpful but molecular studies shows
translocation of abl to 22q.
Patient with CML negative Philadelphia have a poor prognosis.
COURSE:
Has three phases ---chronic, accelerated, crisis

MAGDI AWAD SASI 7TH
Early CML "chronic"
 Doesn't behave like malignant disease
 Normal bone marrow function is retained
 WBCs differentiate
 Decreased LAP
 Neutrophil combat infectious normally
CML is inherently unstable and may progress to accelerated phase and finally after many years to
blast crisis.
There is no added chromosomal abnormality on Philadelphia.
CLINICAL FEATURES:
CML is a disorder of middle age (median age 42 year) 40---60 year
Incidence 1 /100000
90 --- 95% Philadelphia chromosome 22 , 9
In general, the presence and the severity of most symptoms, signs and laboratory abnormalities
parallel directly the degree of leukocytosis.
A. Patient with symptoms related to hyper metabolism by increased WBC
Nonspecific symptoms of fatigue and weight loss may occur long after the onset of the disease. Loss
of energy and decreased exercise tolerance may occur during the chronic phase after several
months.
Some patients with CML have low-grade fever and excessive sweating related to hypermetabolism.
In some patients who present in the accelerated, or acute, leukemia phase of the disease (skipping
the chronic phase), bleeding, petechiae, and ecchymoses may be the prominent symptoms.
In these situations, fever is usually associated with infections. Bone pain and fever, as well as an
increase in bone marrow fibrosis, are harbingers of the blast phase.
Fatigue
Loss of weight
Loss of apetite
Low grade fever
Night sweats ---common
Increased uric acid
B. Patient complain of abdominal fullness related massive splenomegally 85-90%
It can be detected accidently by non specific symptoms.
Patients often have symptoms related to enlargement of the spleen, liver, or both. The
large spleen may encroach on the stomach and cause early satiety and decreased food
intake. Left upper quadrant abdominal pain described as "gripping" may occur from spleen
infarction. The enlarged spleen may also be associated with a hypermetabolic state, fever,
weight loss, and chronic fatigue. The enlarged liver may contribute to the patient's weight
loss.
C. Detected accidently by increased of WBC in 1/3 ((30%)) of patients
The patient is coming for another complain and CBC was requested to reach the diagnosis
for another symptoms like fatigue, palpitation ,bleeding ,fever .

MAGDI AWAD SASI 7TH
D. Rarely ,the patient will present with clinical syndrome related to leuco-stasis with
Headache
Dizziness
Blurring of vision
Respiratory distress
Priapism
This can lead to venous or arterial thrombosis
WBC is usually above 500.000/ml
Less common presentation
 Peptic ulceration, Bleeding, Thrombosis, Bone pain, Arthralgia
 Leukemic infiltration---skin
There is higher frequency of peptic ulceration of stomach or duodenum due to increased
histamine 2ry to hyperplasia of basophilic leukocytes.
Rare ----compression of spinal cord, priapism ,fever
Signs and symptoms in the chronic phase are as follows:
a) Fatigue, weight loss, loss of energy, decreased exercise tolerance
b) Low-grade fever and excessive sweating from hypermetabolism
c) Elevated white blood cell (WBC) count or splenomegaly on routine
assessment
d) Early satiety and decreased food intake from encroachment on stomach by
enlarged spleen
e) Left upper quadrant abdominal pain from spleen infarction
f) Hepatomegaly
The following are signs and symptoms of progressive disease:
1) Bleeding, petechiae, and ecchymoses during the acute phase
2) Bone pain and fever in the blast phase
3) Increasing anemia, thrombocytopenia, basophilia, and a rapidly enlarging
spleen in blast crisis
PHYSICAL FINDING:
Splenomegally
Pallor
Sternal tenderness—part of marrow over expansion
Hepatomegally
Lymphadenopathy
Purpura
Fundic haemorrhage
Spleen ----markedly enlarged
Splenomegaly is the most common physical finding in patients with chronic myelogenous leukemia
(CML). In more than 50% of the patients with CML, the spleen extends more than 5 cm below the
left costal margin at time of discovery.
The size of the spleen correlates with the peripheral blood granulocyte counts, with the largest
spleens being observed in patients with high WBC counts. A very large spleen is usually a harbinger
of the transformation into an acute blast crisis form of the disease.

MAGDI AWAD SASI 7TH
Spleen size correlates reasonably well in positive fashion with the leukocyte count!.
Spleen is rarely palpable until WBC > 40.000/ml.
10% of patients may have a palpable spleen if WBC 6000—14000/ml.
Symptoms start if WBC ranged 30.000 --- 93.000/ml.
The time between diagnosis and therapy is 12 months.
Spleen is quite firm, usually non tender unless splenic infraction is present and splenic
hilum may be palpable.
Sternal tenderness is a reliable sign of disease and usually limited to a small area,
commonly mid point in the sternum.
If true sternal tenderness is present, the patient will withdraw or spontaneously complain
when firm pressure is applied to the tender area.
SYMTOMS AND SIGNS AT DIAGNOSIS IN UTAH HEMATOLOGY CLINIC:
Symptoms at diagnosis----
Fatigue 83%
Weight loss 61%
Abdominal fullness 38%
Easy bruising or bleeding 35%
Abdominal pain 33%
Physical findings----
Splenomegally 95%
Hepatomegally 48%
Sterna tenderness 78%
Purpura 27%
Retinal haemorrhage 21%
Fever 11%
Palpable lymph node 64%
Palpable lymph node > 1cm 8%
3 PHASES:
I-CHRONIC PHASE:
 0—22 years
 Benign course in elderly 45 years
 Asymptomatic increased WBC
 Splenomegally
 Symptoms of hypermetabolism
 CML is diagnosed when blasts comprise > 30% 0f bone marrow cells
II-ACCELERATED PHASE:
 CML associated with fever ,sweating in absence of fever
 Bone pain
 Spenomegally
 Weight loss
 Characterized by
1. Loss of control of WBC
2. Marrow failure
3. Increased basophils
III- BLAST CRISIS:
CML --bleeding, infection related to bone marrow failure
It is an overtly malignant process indistinguishable from acute leukemia.
Majority of patients develop AML 70 --- 80% and ALL 20 --- 30% respond to treatment of
ALL --- Danurobicin ,Vincristine ,Prednisolone with remission 70%

MAGDI AWAD SASI 7TH
This carries a poor prognosis with life expectancy 6 months.
HOW YOU WILL DIAGNOSE BLAST CRISIS ?
1. Increased anemia and thrombocytopenia
2. High blast count in blood and bone marrow
3. Rapid enlargement of liver ,spleen ,lymph nodes
4. Skin infiltration
In female, mennorrhagia may be the presenting feature.
Bruising may occur.
Diagnostic Considerations
Problems to be considered include the following:
a) Acute myeloid leukemia
b) Chronic myelomonocytic leukemia
c) Chronic neutrophilic leukemia
d) Thrombocythemia
e) Leukemoid reactions from infections (chronic granulomatous [eg, tuberculosis])
f) Tumor necrosis
Differential Diagnoses
1) Essential Thrombocytosis
2) Myelodysplastic Syndrome
3) Myeloproliferative Disease
4) Polycythemia Vera
LABORATORY:
The workup for chronic myelogenous leukemia (CML) consists of a complete blood count with
differential, peripheral blood smear, and bone marrow analysis. Although typical hepatomegaly
and splenomegaly may be imaged by using a liver/spleen scan, these abnormalities are often so
obvious clinically that radiologic imaging is not necessary.
The diagnosis of CML is based on the histopathologic findings in the peripheral blood and the
Philadelphia (Ph1) chromosome in bone marrow cells.
Other laboratory abnormalities include hyperuricemia, which is a reflection of high bone marrow
cellular turnover, and markedly elevated serum vitamin B-12–binding protein (TC-I). The latter is
synthesized by the granulocytes and reflects the degree of leukocytosis.
The hall mark of CML is an elevated WBC (( 150.000/ml)).
Peripheral blood film is characteristic given the impression that bone marrow has spilled
over into blood.
In CML, the increase in mature granulocytes and normal lymphocyte counts (low
percentage due to dilution in the differential count) results in a total WBC count of
20,000-60,000 cells/μL. A mild increase in basophils and eosinophils is present and
becomes more prominent during the transition to acute leukemia.
These mature neutrophils, or granulocytes, have decreased apoptosis (programmed cell
death), resulting in accumulation of long-lived cells with low or absent enzymes, such as
alkaline phosphatase (ALP). Consequently, the leukocyte alkaline phosphatase stains very
low to absent in most cells, resulting in a low score.
The peripheral blood smear in patients with CML shows a typical leukoerythroblastic blood picture,
with circulating immature cells from the bone marrow

MAGDI AWAD SASI 7TH
 Myeloid series is left shifting with mature forms dominating
 Blasts are usually < 5%
 Basophilia of granulocytes may be present
 At presentation ,RBC –no anemia with normal morphology ,nucleated RBC rarely seen
 Platelet counts---
normal or increased to high
levels with normal
morphology/large forms+
Bone marrow , hypercellular
with left shifted myelopioesis
with myeloblasts < 5%
 LAP is decreased
 VIT B12 is increased
 Uric acid levels may be
high
 Philadelphia
chromosome is present and may
be detected in bone marrow or
peripheral blood by molecular
technique in PBF to detect bcr---
abl gene(( southern blot ))
 Slide---leukocytosis with the presence of precursor cells of the myeloid lineage. In addition,
basophilia, eosinophilia, and thrombocytosis can be seen.
CBC
PBF
BONE MARROW
LAP
VIT B12
URIC ACID
ANEMIA----
Often mild, Present at time of diagnosis in most patients
Severity ogf anemia is generally directly proportional to the degree of leukocytosis
Normochromic ,normocytic
Reticulocytes N /increased
Nucleated RBCs found but rarely
WBC---
All stages from myeloblasts to segmental neutrophil
Segmented and band neutrophils are the most common types of cells followed by
metmyelocytes ,myelocytes ,promyelocytes and myeloblasts
There is a direct relation between the height of leukocyte count and percentage of
immature cells at time of diagnosis,
 20% blasts and promyelocytes is considered to signify blast crisis
Basophils are increased .Eosinophils and monocytes increased.
Basophils are increased early in the disease and increased in direct proportion to height
of WBC
There is increased number of lymphocytes
Untreated patient----steady progression increase in WBC

MAGDI AWAD SASI 7TH
IN some patients ,there is cyclic variation in blood leukocyte concentration
Normal to 200.000/ml
Within 2—4 months ((peak to peak intervals)) there is functional alterations in neutrophil
and may accompany the cycle but LAP level cycle in inverse relation.
Platelets and reticulocytes show cyclic variation.
Extreme leucocytosis -------paillodema and leukostatic lodgement.
AUER RODS----are observed and indicative of the onset o blast crisis.
BARR BODIES---are less common in mature neutrophils in female with CML and are said
to increase in frequency in the course of disease.
The transitional
or accelerated phase of
CML is characterized by
poor control of blood
counts with
myelosuppressive
medication, the
appearance of peripheral
blast cells (≥15%),
promyelocytes (≥30%),
basophils (≥20%), and
reduction in platelet
counts to less than
100,000 cells/μL unrelated
to therapy. Promyelocytes
and basophils are seen.
Signs of transformation or
accelerated phase in
patients with CML are poor
control of blood counts
with myelosuppression or
interferon, increasing blast
cells in peripheral blood
with basophilia and
thrombocytopenia not
related to therapy, new
cytogenetic abnormalities,
and increasing
splenomegaly and
myelofibrosis.
In approximately two thirds of cases, the blasts are myeloid. However, in the remaining one third of patients,
the blasts exhibit a lymphoid phenotype, further evidence of the stem cell nature of the original disease.
Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional Ph1
chromosomes or other translocations.
Early myeloid cells such as myeloblasts, myelocytes, metamyelocytes, and nucleated red blood cells are
commonly present in the blood smear, mimicking the findings in the bone marrow. The presence of the
different midstage progenitor cells differentiates CML from the acute myelogenous leukemias, in which a
leukemic gap (maturation arrest) or hiatus exists that shows absence of these cells.
A mild to moderate anemia is very common at diagnosis and is usually normochromic and normocytic. The
platelet counts at diagnosis can be low, normal, or even increased in some patients (>1 million in some).

MAGDI AWAD SASI 7TH
PLATELET COUNT
High in 50% of patients
Sever thrombocytopenia is rare
Thrombocytosis may be sever with number > 1000.000/ml not uncommon ,occur
sometime during the course of disease in 25%
The degree of thrombocytosis bears no relationship to the height of the total WBC
Thrombosis is rare even in the presence of extreme thrombocytosis
Abnormalities of platelet function are common.
The platelets are normal.
MORPHOLOGICAL ABNORMALITIES IN CML:
Nucleated RBC 98%
Dyserthropoitic 12%
Target cells 2%
Gaint platelets 2%
Megakaryocyte nuclei 24%
Binucleate or lobular leukocyte nuclei
Blasts 2%
Promyelocytes 2%
Myelocytes
Hypogranular leukocytes 8%
Myelocytes 2%
Segmented neutrophils 12%
Basophils 4%
Cells in mitosis 14%
Gaint metamyelocytes 24%
Pelger huet cells 4%
Hypersegmented neutrophils 12%
Bone Marrow Analysis:
The bone marrow is
characteristically hypercellular,
with expansion of the myeloid
cell line (eg, neutrophils,
eosinophils, basophils) and its
progenitor cells.
Megakaryocytes are prominent
and may be increased. Mild
fibrosis is often seen in the
reticulin stain.
Cytogenetic studies of the bone marrow cells, and even
peripheral blood, should reveal the typical Ph1 chromosome,
which is a reciprocal translocation of chromosomal material
between chromosomes 9 and 22. This is the hallmark of CML,
found in almost all patients with the disease and present
throughout the entire clinical course of CML.
The Philadelphia chromosome, which is a diagnostic karyotypic
abnormality for chronic myelogenous leukemia, is shown in this
picture of the banded chromosomes 9 and 22. Shown is the result of
the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl
to a specific breakpoint cluster region [bcr] of chromosome 22
indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department
of Pathology and Clinical Laboratory of the University of Pennsylvania
School of Medicine.

MAGDI AWAD SASI 7TH
In addition, the chimeric BCR/ABL messenger RNA (mRNA) that characterizes CML can be detected
by polymerase chain reaction (PCR). This is a sensitive test that requires just a few cells and is useful
in monitoring minimal residual disease (MRD) to determine the effectiveness of therapy. BCR-
ABL mRNA transcripts can also be measured in peripheral blood
Karyotypic analysis of bone marrow cells requires the presence of a dividing cell without loss of
viability because the material requires that the cells go into mitosis to obtain individual
chromosomes for identification after banding. This is a slow, labor-intensive process.
The new technique of fluorescence in situ hybridization (FISH) uses labeled probes that are
hybridized to either metaphase chromosomes or interphase nuclei, and the hybridized probe is
detected with fluorochromes. This technique is a rapid and sensitive means of detecting recurring
numerical and structural abnormalities.
Two forms of the BCR/ABL mutation have been identified. These vary according to the location of
their joining regions on bcr 3' domain. Approximately 70% of patients who have the 5' DNA
breakpoint have a b2a2 RNA message, and 30% of patients have a 3' DNA breakpoint and a b3a2
RNA message. The latter is associated with a shorter chronic phase, shorter survival, and
thrombocytosis.
CML should be differentiated from Ph1-negative diseases with negative PCR results
for BCR/ABL mRNA. These diseases include other myeloproliferative disorders and chronic
myelomonocytic leukemia, which is now classified with the myelodysplastic syndromes.
Additional chromosomal abnormalities, such as an additional or double Ph1-positive chromosome
or trisomy 8, 9, 19, or 21; isochromosome 17; or deletion of the Y chromosome, have been
described as the patient enters a transitional form or accelerated phase of the blast crisis as the Ph
chromosome persists.
Patients with conditions other than CML, such as newly diagnosed acute lymphocytic
leukemia (ALL) or nonlymphocytic leukemia, may also be positive for the Ph1 chromosome. Some
consider this the blastic phase of CML without a chronic phase. The chromosome is rarely found in
patients with other myeloproliferative disorders, such as polycythemia vera or essential
thrombocythemia, but these cases are probably misdiagnosed CML. It is rarely observed in
myelodysplastic syndrome.
LAP---
Abnormally low or may be actually abset in 90% of CML.
Low LAP and PH positive donot necessarly correlate.
LAP may increase in:
1. Blast crisis
2. Therapeutic control in chronic phase
3. Patient with CML who develop ulcerative colitis.
D/D:
1. Reactive leucocytosis— leukomoid reaction:
Infection, inflammation, cancer
Fluorescence in situ hybridization using
unique-sequence, double-fusion DNA probes
for bcr (22q11.2) in red and c-abl (9q34) gene
regions in green. The abnormal bcr/abl
fusion present in Philadelphia chromosome–
positive cells is in yellow (right panel)
compared with a control (left panel).
Courtesy of Emmanuel C. Besa, MD

MAGDI AWAD SASI 7TH
WBC ---< 50000/ml
Splenomegally
CML Eosinoohilia ,Basophilia ,Thrombocytosis
Sternal tenderness with positive PH and decrease LAP
Low ALP------seen in military tuberculosis
VIT B12 and transcobalamin increased in CML and leukomoid reaction.
LAP---normal /increased
Splenomegally
Philadelphia chromosome negative
2. Polycythemia rubrae vera
3. Myelofibrpsis
Presence of large spleen with WBC < 100000/ml is suggestive of IMF.
EOSINOPHILS
BASOPHILS
NEUTROPHILS equal in CML ,PRV ,IMF
THROMBOCYTES
TREATMENT:
The goals of treatment of chronic myelogenous leukemia (CML) are threefold and have changed
markedly in the past 10 years. They are as follows:
1. Hematologic remission (normal complete blood cell count (CBC) and physical examination (ie, no
organomegaly)
2. Cytogenetic remission (normal chromosome returns with 0% Philadelphia chromosome–positive
(Ph+) cells)
3. Molecular remission (negative polymerase chain reaction [PCR] result for the
mutational BCR/ABL mRNA), which represents an attempt for cure and prolongation of patient
survival
Typically, CML has three clinical phases: an initial chronic phase, during which the disease
process is easily controlled; then a transitional and unstable course (accelerated phase);
and, finally, a more aggressive course (blast crisis), which is usually fatal. In all three
phases, supportive therapy with transfusions of red blood cells or platelets may be used to
relieve symptoms and improve quality of life.
The chronic phase: varies in duration, depending on the maintenance therapy used: it
usually lasts 2-3 years with hydroxyurea (Hydrea) or busulfan therapy, but it may last for
longer than 9.5 years in patients who respond well to interferon-alfa therapy.
Furthermore, the advent of tyrosine kinase inhibitor (TKI) therapy has dramatically
improved the duration of hematologic and, indeed, cytogenetic remissions. For most
patients with chronic-phase CML who are treated with TKIs, median survival is expected to
approach normal life expectancy.
In Western countries, 90% of patients with CML are diagnosed in the chronic phase. These
patients’ white blood cell (WBC) count is usually controlled with medication (hematologic
remission). The major goal of treatment during this phase is to control symptoms and
complications resulting from anemia, thrombocytopenia, leukocytosis, and splenomegaly.
The standard treatment of choice is the first-generation TKI imatinib mesylate (Gleevec),
which is a specific small-molecule inhibitor of BCR/ABL in all phases of CML.
The second-generation TKIs nilotinib (Tasigna), dasatinib (Sprycel), and bosutinib (Bosulif)
are approved as first-line treatment for CML in the chronic phase. Although all those

MAGDI AWAD SASI 7TH
agents produce a higher rate of deep molecular response and provide better early control
of disease than imatinib, the benefits and risks of these newer agents compared with
imatinib, as well as their comparative long-term safety profiles, have not yet been
established.
A significant “adverse effect” of imatinib is its high cost (approximately $100,000
annually). Moreover, current guidelines recommend that most patients who achieve
remission with TKI therapy continue taking the drugs indefinitely. Successful
discontinuation of TKIs has been reported, however, and the National Comprehensive
Cancer Network (NCCN) has published criteria for discontinuing TKI therapy.
The European Stop TKI Study (EURO-SKI), found that stopping TKI therapy is feasible and
that about half of patients remain free from relapse after 2 years of follow-up. In EURO-
SKI, the optimal duration of TKI therapy prior to discontinuation was 5.8 years or
longer.The NCCN guidelines list a minimum of 3 years of approved TKI therapy as a
criterion.
Some patients with CML progress to a transitional or accelerated phase, which may last for
several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase
is characterized by poor control of blood counts with myelosuppressive medication and
the appearance of peripheral blast cells (≥15%), promyelocytes (≥30%), basophils (≥20%),
and platelet counts less than 100,000 cells/μL unrelated to therapy.
Many of the treatment decisions in CML, including possible hematopoietic stem cell
transplantationand investigative options for younger patients, are extremely complex and
in constant flux.
To control WBC mass
1. HYPERLEUKOCYTOSIS(( LEUCOSTASIS ))--- leukaphresis urgently with
myelosuppression drugs
Characterized by mental confusion ,blurred vision ,priapism ,respiratory distress
Why to treat?
because majority of myeloid cells are mature that are smaller and deformable
than primitive blasts.
2. HYDROXYUREA:
2—4 g/d orally
Maintain 0.5 –2 g/d
To maintain WBC 5000----10.000/ml
It should be given without interruption
Response --- WBC decrease ,spleen decrease in size , patient become
asymptomatic
3. Alpha –interferon :
It has the ability to suppress Philadelphia chromosome and to allow
cytogenetically normal cells to appear.
Up to 80% of patients have good hematological response.
Biological effect ----complete 5 – 10% , partial 15 –30% after 1 year of treatment
Curative therapy ----
Allogenic bone marrow transplantation
60% ,age 40year , 1 year of diagnosis , HLA sibling

MAGDI AWAD SASI 7TH
What is Imatinib Mesylate?
Imatinib mesylate (Gleevec) is a tyrosine kinase inhibitor (TKI) that inhibits the abnormal
bcr-abl tyrosine kinase created by the Philadelphia (Ph1) chromosome translocation
abnormality. Imatinib inhibits proliferation and induces apoptosis in cells positive
for BCR/ABL.
For patients with chronic-phase CML, imatinib at 400 mg/day is the best dosage for
primary therapy, because it induces a complete hematologic response in almost all
patients and causes a high cytogenetic response rate. With imatinib at 400 mg/day orally
in patients with newly diagnosed Ph1-positive CML in the chronic phase, the complete
cytogenetic response rate is 70% and the estimated 3-year survival rate is 94%.
With higher doses of 800 mg/day, the complete cytogenetic response rate increases to
98%, the major molecular response rate is 70%, and the complete molecular response rate
is 40-50%. Despite those improved early responses, however, randomized phase III studies
suggest that higher-dose imatinib was not associated with lower rates of disease
progression than imatinib, 400 mg, but was associated with higher rates of dose
interruption, reduction, or discontinuation due to grade 3 or 4 adverse events.
The presence of severe anemia in these patients was associated with worse survival and
response.
Molecular remission is the goal as measured by PCR. Continuation of the drug is important
because approximately 20% of patients lose complete cytogenic response, at a rate of 1.4
per 100 person-years. This is due to poor adherence or poor tolerance of the drug in
patients who had an adherence rate of less than 85% as the main reason for complete
cytogenic response loss.
Treatment of patients with CML in the accelerated phase or in blast crisis has yielded
dismal results. Although imatinib can induce a hematologic response in 52-82% of
patients, the response is sustained for at least 4 weeks in only 31-64% of patients. Higher
doses (ie, 600 mg/d) result in improved response rates, cytogenetic response, and disease-
free and overall survival.
Resistance of CML cells to imatinib occurs through multiple mechanisms such as
overexpression of BCR/ABL and mutations of the abl gene.
Kinase-domain mutations in BCR/ABL represent the most common mechanism of
secondary or acquired resistance to imatinib, accounting for 50-90% of cases; 40 different
mutations have currently been described. Because imatinib binds to the ABL kinase
domain in the inactive, or closed, conformation to induce conformational changes,
resistance occurs when the mutation prevents the kinase domain from adopting the
specific conformation upon binding.
Patients whose CML demonstrates resistance to imatinib should be switched to a different
TKI and considered for hematopoietic stem cell transplantation.
Renal damage is an important adverse effect of imatinib.
Imatinib resistance:
Newer Tyrosine Kinase Inhibitors
In the near future, the choice of initial tyrosine kinase inhibitor (TKI) is likely to be driven
by two considerations: one clinical (because survivals with different agents appear
equivalent despite differences in efficacy), and the other financial (the price of generic
imatinib is likely to fall to 20%-30% of the cost of the branded drug and the second-
generation TKIs). Equally important determinants for which drug to use for an individual
patient include the following:
 Tolerance (because it influences treatment adherence as well as quality of life
 Comorbidities (and thus potential late complications)

MAGDI AWAD SASI 7TH
 Calculated risk status at diagnosis
 Achievement of early molecular response (EMR)
The second-generation TKIs dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif)
are more potent inhibitors of BCR/ABL than imatinib. Moreover, they exhibit significant
activity against all resistant mutations except BCR/ABL/T315I . All three have been
approved by the US Food and Drug Administration (FDA) for the treatment of adult
patients with newly diagnosed Philadelphia chromosome–positive (Ph1+
) chronic-phase
CML, as well as for chronic-phase CML resistant or intolerant to prior therapy that included
imatinib.
Dasatinib and bosutinib are also FDA-approved for blast-phase Ph1+
CML in patients
resistant to or intolerant of other therapies, including imatinib.
Dasatinib has been associated with pleural effusions and pulmonary arterial
hypertension,while nilotinib has been linked to biochemical changes in liver function and
QT-interval prolongation. Development of resistance may also occur with these agents.
Moreover, imatinib is still very effective. It is also less expensive than the new TKIs, and
will go out of patent in the near future.
Nilotinib
Nilotinib has been found superior to imatinib in patients with newly diagnosed chronic-
phase Ph+ CML. Compared with imatinib, significantly more patients receiving nilotinib
achieved a major molecular response, or a complete molecular response at any time, and
fewer progressed to accelerated or blast phase. These authors concluded that these results
support the use of nilotinib as a first-line treatment option.
In March 2018, FDA approved nilotinib for first- and second-line treatment of pediatric
patients aged 1 year and older with Ph+ CML-CP. Approval was based on a cohort of 69
pediatric patients with Ph+ CML-CP enrolled across 2 trials. Patients were either newly
diagnosed or resistant/intolerant to prior treatment with a tyrosine kinase inhibitor.
Bosutinib
In December 2017, the FDA also gave accelerated approval for newly diagnosed chronic-
phase Ph+ CML. Approval was based on an ongoing, multinational, phase III study in 536
patients with newly diagnosed chronic-phase CML, in which the major molecular response
rate at 12 months (the primary end point) was significantly higher with bosutinib versus
imatinib (47.2% vs 36.9%, respectively), as was the complete cytogenetic response (CCyR)
rate by 12 months (77.2% v 66.4%, respectively.
Ponatinib
The third-generation TKI ponatinib (Iclusig) was approved by the FDA in December 2012
for use in patients with CML that had relapsed or become refractory to other therapies.
Many of these patients will have developed a T315I mutation, which confers resistance to
imatinib and other tyrosine kinase inhibitors.
In the phase 2 PACE (Ponatinib PH+
ALL [acute lymphoblastic leukemia] and CML
Evaluation) trial, the drug successfully treated patients with chronic-phase CML (major
cytogenetic response in 55% of cases, including 70% of patients with the T315I mutation,
within 12 months), with accelerated-phase CML (major hematologic response in 57% of
cases within 6 months), or with blast-phase CML/Ph1-positive ALL (major hematologic
response in 34% of cases within 6 months).
In October 2013, at the FDA’s request, ponatinib was temporarily removed from the
market because of safety concerns. The FDA cited an increased risk for life-threatening
blood clots and severe narrowing of blood vessels. In December 2013, the FDA allowed

MAGDI AWAD SASI 7TH
resumption of marketing, since the benefits of response to ponatinib far outweigh the risk
of complications from the drug.[
However, the FDA required the addition of a black box warning regarding arterial and
venous thrombosis and occlusions, which have occurred in at least 27% of patients in early
trials, typically within 2 weeks of starting ponatinib.
In addition, the FDA limited the indications for use of ponatinib to the following:
 Adult patients with T315I -positive CML in chronic, accelerated, or blast phase
(or T315I -positive, Ph1-positive ALL)
 Adult patients with chronic, accelerated, or blast phase CML for whom no other TKI
therapy is indicated
The T315I mutation for which ponatinib is effective is very rare, affecting only a small
minority of CML patients. Nevertheless, for some of those patients, ponatinib has proved
lifesaving.
Deciding which TKI Agent to use as first-line therapy in chronic phase CMK:
The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) over the past 20 years has
dramatically improved the outcomes for patients with every stage of Philadelphia
chromosome-positive (Ph+) chronic myeloid leukemia (CML). Clinicians now have access to
5 oral, generally well-tolerated, and highly effective TKIs. How should these agents be
used for an individual patient to ensure the best possible duration and quality-of-life, to
avoid treatment-related complications, and potentially to achieve a cure at an affordable
cost? Because CML patients may need to continue TKI therapy indefinitely, the long-term
safety of each treatment option must be considered. Evidence-based care requires an
understanding of the optimal use of these drugs, their specific early and late toxicities, the
prognostic significance of achieving treatment milestones, and the critical importance of
molecular monitoring. Efficacy is important, but treatment choice does not depend only
on efficacy. Choosing among various treatment options is informed by understanding the
distinct benefits and risks of each agent, along with careful consideration of patient-
specific factors, such as risk status, age, and comorbidities.
In the near future, the choice of initial TKI is likely to be driven by two facts; one clinical
(because survivals appear equivalent despite differences in efficacy), and the other
financial (the price of generic imatinib is likely to fall to 20%-30% of the cost of the
branded drug and the second generation TKIs). Equally important determinants for which
drug to use for an individual patient include tolerance (because it influences treatment
adherence as well as quality-of-life), comorbidities and thus potential late complications,
calculated risk status at diagnosis, and the achievement of EMR. Eventually, gene
expression profiling may give us a better way to identify which patients require a second
generation TKI from the outset.
Protein Translation Inhibitors
In October 2012, the US Food and Drug Administration (FDA) approved omacetaxine (Synribo).
Omacetaxine is a protein translation inhibitor that is indicated for chronic- or accelerated-phase
CML with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors (TKIs) (eg, dasatinib,
nilotinib, imatinib).
Myelosuppressive Therapy
Myelosuppressive therapy was formerly the mainstay of treatment to convert a patient
with CML from an uncontrolled initial presentation to one with hematologic remission and
normalization of the physical examination and laboratory findings. However, it may soon
fall out of favor as the new agents prove to be more effective, with fewer adverse events
and longer survival.

MAGDI AWAD SASI 7TH
Hydroxyurea
Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis, is the most common
myelosuppressive agent used to achieve hematologic remission. The initial blood cell
count is monitored every 2-4 weeks, and the dose is adjusted depending on the WBC and
platelet counts. Most patients achieve hematologic remission within 1-2 months.
This medication causes only a short duration of myelosuppression; thus, even if the counts
go lower than intended, stopping treatment or decreasing the dose usually controls the
blood counts. Maintenance with hydroxyurea rarely results in cytogenetic or molecular
remissions.
European Society for Medical Oncology (ESMO) guidelines suggest that hydroxyurea
(40 mg/kg daily) may be used as initial therapy, before confirmation of the BCR–
ABL1 fusion in patients with immediate need for therapy because of high leukocyte counts
or clinical symptoms. TKI therapy should be started immediately after confirmation
of BCR–ABL1 positivity, and the hydroxyurea dose tapered before discontinuation.
Busulfan
Busulfan (Myleran) is an alkylating agent that has traditionally been used to keep the WBC
counts below 15,000 cells/µL. However, the myelosuppressive effects may occur much
later and persist longer, which makes maintaining the numbers within normal limits more
difficult. Long-term use can cause pulmonary fibrosis, hyperpigmentation, and prolonged
marrow suppression lasting for months.
Leukapheresis:
Leukapheresis using a cell separator can lower WBC counts rapidly and safely in patients
with WBC counts greater than 300,000 cells/µL, and it can alleviate acute symptoms of
leukostasis, hyperviscosity, and tissue infiltration.
Leukapheresis usually reduces the WBC count only temporarily. Thus, it is often combined
with cytoreductive chemotherapy for more lasting effects.
Interferon alfa:
In the past, interferon alfa was the treatment of choice for most patients with CML who
were too old for bone marrow transplantation (BMT) or who did not have a matched bone
marrow donor. With the advent of tyrosine kinase inhibitors, interferon alfa is no longer
considered first-line therapy for CML. It may be used in combination with newer drugs for
treatment of refractory cases.
A study by Simonsson et al found that the addition of even relatively short periods of
pegylated interferon alfa2b to imatinib increased the major molecular response rate at 12
months of therapy. Lower doses of pegylated interferon alfa2b may enhance tolerability
while retaining efficacy and could be considered in future studies.
Splenectomy:
Splenectomy and splenic irradiation have been used in patients with large and painful
spleens, usually in the late phase of CML. This is rarely needed in patients whose disease is
well controlled.
Some authors believe that splenectomy accelerates the onset of myeloid metaplasia in the
liver. In addition, splenectomy is associated with high perioperative morbidity and
mortality rates because of bleeding or thrombotic complications.

MAGDI AWAD SASI 7TH
Poor prognostic factors:
1. Male
2. Sever anemia
3. Blast crisis
4. High basophil count 10%
5. Thrombocytosis
6. Thrombocytopenia
7. Absence of Philadelphia
Good prognostic factors:
1. Philadelphia chromosome
2. Prolonged unmaintained 1
st
remission following busulfan
3. Mosaicism (( PH + and PH - ))
No effect on prognosis:
1. Age
2. Sex
3. Spleen and liver size
4. Degree of leukocytosis
5. High percentage of blasts
6. anemia
CAUSES OF DEATH IN CML:
1. Blast crisis
2. Aplastic anemia
3. Infection
4. Hemorrhage
5. Uremia
6. Hepatitis
7. CCF / MI
Guidelines for the management of chronic myelogenous leukemia (CML) have been issued
by the following organizations:
1) National Comprehensive Cancer Network (NCCN)
2) European Society of Medical Oncology (ESMO)
3) European LeukemiaNet (ELN)
For chronic-phase CML, treatment recommendations are as follows:
All of the guidelines recommend the tyrosine kinase inhibitors (TKIs) imatinib,
nilotinib, or dasatinib as first-line treatment for CML; NCCN also
includes bosutinib, and ESMO notes that other strategies include using higher
doses of imatinib or combining a TKI with an additional agent, such as interferon-
α.
All the guidelines agree that the selection of first-line TKI therapy should be based
on the patient's risk score, ability to tolerate therapy, and comorbid conditions
and the adverse effect profile of the TKI
In case of intolerance, patients can be switched to another TKI; ESMO and ELN list
bosutinib as an option in this setting
All TKIs can be used as second-line treatment; doses may differ in the second- line
setting, depending on the agent chosen
BCR-ABL kinase domain mutation analysis, evaluation of drug interactions, and
compliance to therapy are recommended before the start of second-line TKI
therapy.

MAGDI AWAD SASI 7TH
Ponatinib is an option for patients with T315I mutation and for those with disease
that has not responded to several TKIs.
Allogeneic hematopoietic stem cell transplantation (HSCT) should be considered in
the case of failure of two TKIs
For accelerated-phase CML, all the guidelines recommend the following:
 TKI (imatinib, nilotinib, dasatinib, or bosutinib).
 Choice of TKI is based on prior therapy and/or BCR-ABL kinase domain mutation
status
 Recommended doses of imatinib, nilotinib, and dasatinib are higher for
accelerated phase than for chronic phase
 If resistance and/or intolerance to two or more TKIs occurs, consider omacetaxine
 Consider HSCT, based on treatment response and patient age
For blast-phase CML, all the guidelines recommend the following:
 HSCT, preferably after response to induction therapy
 Patients in lymphoid blast phase can be treated with acute lymphoblastic leukemia
(ALL) induction chemotherapy regimens in combination with a TKI
 Patients in myeloid blast crisis can be treated with acute myeloid leukemia (AML)
induction chemotherapy regimens in combination with a TKI
Monitoring
National Comprehensive Cancer Network (NCCN), European LeukemiaNet (ELN), and
European Society of Medical Oncology (ESMO) guidelines recommend the following tests
for monitoring response to TKI therapy:
 Bone marrow cytogenetics
 Quantitative reverse transcription polymerase chain reaction (qPCR) standardized by
International Scale (IS)
The three guidelines vary in their recommendations regarding response to first-line
treatment, as outlined below.
NCCN Recommendations
The desired responses to first-line treatment are as follows:
 3 months: BCR-ABL1 transcripts ≤10% by qPCR
 6 months: BCR-ABL1 transcripts ≤10% by qPCR
 12 months: ≤1% BCR-ABL1
 15 months: ≤ 1% BCR-ABL1
 After BCR-ABL1 (IS) ≤1% (>0.1%–1%) has been achieved, every 3 months for 2 years
and every 3–6 months thereafter; if there is 1-log increase in BCR-ABL1transcript levels
with major molecular response, qPCR should be repeated in 1-3 months
European LeukemiaNet
The optimal responses to first-line treatment are as follows:
 3 months: Ph+≤35%, and/or BCR-ABL1≤10%
 6 months: : PH+ 0%, and/or BCR-ABL1 < 1%
 12 months: BCR-ABL1≤0.1%
European Society of Medical Oncology (ESMO)
The optimal responses to first-line treatment are as follows:
 3 months: Philadelphia chromosome positive (Ph+) ≤95%, or BCR-ABL< 10%
 6 months: Ph+ ≤35%, or BCR-ABL < 10%
 12 months: PH+ 0, or BCR-ABL ≤1%

MAGDI AWAD SASI 7TH
Transplantation
Allogeneic bone marrow transplantation (BMT) or stem cell transplantation is currently
the only proven cure for CML. ideally,it should be performed in the chronic phase of the
disease rather than in the transformation phase or in blast crisis. Candidate patients
should be offered the procedure if they have a matched or single–antigen-mismatched
related donor available. In general, younger patients fare better than older patients.
BMT should be considered early in young patients (< 55 y) who have a matched sibling
donor. All siblings should be typed for human leukocyte antigen (HLA)-A, HLA-B, and HLA-
DR. If no match is available, the HLA type can be entered into a bone marrow registry for a
completely matched unrelated donor.
Allogeneic BMT with matched unrelated donors has yielded very encouraging results in
this disease. The procedure has a higher rate of early and late graft failures (16%), grade
III-IV acute graft versus host disease (50%), and extensive chronic graft versus host disease
(55%). The overall survival rate ranges from 31% to 43% for patients younger than 30 years
and from 14% to 27% for older patients. Benefits and risks should be assessed carefully
with each patient.
Transplantation has been relegated to patients who do not achieve molecular remissions
or show resistance to imatinib and failure of second-generation bcr-abl kinase inhibitors
such as dasatinib. Previous exposure to imatinib before transplantation does not adversely
affect posttransplant outcomes such as overall survival and progression-free survival.
No current consensus exists on these issues. However, a widely accepted
consensus is that patients who progress beyond chronic phase on imatinib should
be offered hematopoietic stem cell transplantation if this is an option.
With patients in blast crisis who are imatinib naive, the drug is used in combination with
induction regimens similar to those used in acute myelogenous or lymphoblastic leukemia.
However, because a high percentage of imatinib-resistant mutations exist in these
patients, relapses occur more frequently and at an earlier time from induction. Thus, all
efforts are made to perform an allogeneic hematopoietic stem cell transplantation as soon
as possible.
Most patients with minimal residual disease (MRD) after transplantation require
interferon maintenance therapy. Alternatively, they may require a reinfusion of T cells
collected from the donor.
Prognosis:
One widely used prognostic index, the Sokal score, is calculated for patients aged 5-84 years by the
following equation:
Hazard ratio = exp 0.0116 (age - 43) + 0 .0345 (spleen size [cm below costal margin] - 7.5 cm) + 0.188
[(platelet count/700)
2
- 0.563] + 0.0887 (% blasts in blood - 2.1)
The three categories of the Sokal score are as follows:
1. Low risk: score < 0.8
2. Intermediate risk: score 0.8-1.2
3. High risk: score >1.2
The Sokal score correlates with the likelihood of achieving complete cytogenetic response, as
follows:
 Low-risk patients: 91%
 Intermediate-risk patients: 84%
 High-risk patients: 69%

MAGDI AWAD SASI 7TH
Poor-prognosis characteristics include the following clinical and laboratory factors:
1) Older age
2) African-American descent
3) Symptomatic presentation
4) Poor performance status
5) Hepatomegaly
6) Splenomegaly
7) Anemia
8) Thrombocytopenia
9) Thrombocytosis
10) Decreased megakaryocytes
11) Basophilia
12) Negative Ph chromosome or BCR/ABL
13) Myelofibrosis (increased reticulin or collagen)
The following therapy-associated factors may indicate a poor prognosis in patients
with CML:
1) Longer time to hematologic remission with myelosuppression therapy
2) Short duration of remission
3) High total dose of hydroxyurea or busulfan
4) Poor suppression of Ph-positive cells by chemotherapy or interferon alfa therapy
A study by Wang et al addressed the prognostic impact of specific additional
chromosomal abnormalities (ACAs) in CML. The concurrent presence of two or more ACAs
conferred inferior survival. In patients with a single chromosomal change at the time of
ACA emergence, the following three were associated with a relatively good prognosis [13]
:
1) Trisomy 8
2) -Y
3) An extra copy of Philadelphia chromosome
In contrast, the following three ACAs were associated with a relatively poor prognosis:
1) i(17)(q10)
2) -7/7q (-7/del7q)
3) 3q26.2 rearrangements
SURVIVAL UPDATE
The advent of TKI therapy has dramatically changed the overall survival in
patients with CML.
The recent update of patients both treated with IFN then shifted to Imatinib
and those started on Imatinib alone was show to have an overall survival of
83.3% with a complete cytogenetic response rate of 82.8% .
The study indicate that TKI in particular Imatinib is effective in inducing a
long term survival close to the normal population without any long term
adverse events. The social side effect of these form of treatment is the
excessive cost at ~$100.000 annually at the time when the patent of the
drug has expired but the advent of generic forms are being priced in the
same expensive range with doubtful efficay.

Chronic myeloid leukemia magdi sasi 2019 ramadan

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Chronic myeloid leukemia magdi sasi 2019 ramadan

Similar to Chronic myeloid leukemia magdi sasi 2019 ramadan (20)

More from cardilogy

More from cardilogy (20)

Recently uploaded

Recently uploaded (20)

Chronic myeloid leukemia magdi sasi 2019 ramadan