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Cml1
1. Dr. Dharam Pal Bansal, M.D, D.M
Dr. Mohd Viquas Uddin Saim
DNB Medicine resident
Medwin Hospital
CHRONIC MYELOID LEUKEMIA
(CML)
2. CML
Is a myeloproliferative disorder with a
characteristic cytogenteic abnormality and
propensity to evolve from a chronic phase into a
blast phase
incidence of chronic myeloid leukemia (CML) is
1.5 per 100,000
higher in men than in women
incidence of CML increases slowly with age until
the middle forties, when it starts to rise rapidly.
Median age at onset is in mid-50’s
3. DEFINITION
The diagnosis of CML is established by
identifying a clonal expansion of a hematopoietic
stem cell possessing a reciprocal translocation
between chromosomes 9 and 22.
This translocation results in the head-to-tail
fusion of the (BCR) gene on chromosome 22q11
with the ABL1 (gene located on chromosome
9q34.
Untreated, the disease inevitably transforms from
a chronic phase to an accelerated phase and on
to blast crisis in a median time of 4 years.
4. ETIOLOGY
cigarette smoking accelerated the progression to
blast crisis and therefore adversely affected
survival in CML.
Atomic bomb survivors had an increased
incidence; the development of a CML cell mass of
10,000/L took 6.3 years.
No increase in CML incidence was found in the
survivors of the Chernobyl accident, suggesting
that only large doses of radiation can induce
CML.
5. Pathophysiology : clonality
CML is a clonal disease of an abnormal stem cell
Myeloid, erythroid, megakaryocytic and B
lymphoid cells are involved in the malignant
clone.
7. Pathophysiology : philadelphia
chromosome
It is the diminutive chromosome produced by an
unbalanced translocation between chromosomes
9 and 22.
This translocation t(9:22) fuses the 3’ portion of
the c-ABL gene on the long arm of chr 9 to 5’ end
of BCR gene on long arm of chr 22.
The resultant fusion gene encodes a chimeric
protein with constitutive tyrosine kinase activity.
The BCR-ABL protein stimulates the proliferation
and enhances the survival of CML hematopoietic
progenitor cells.
8. Clinical Presentation
Asymptomatic in 20 % patients , discovered on
routine blood exams.
Onset : insidious
The excessive number of metabolically active
myeloid cells can cause fevers and sweats.
fatigue, malaise, and weight loss
symptoms from splenic enlargement, like early
satiety and left upper quadrant pain or mass.
Bone pain and tenderness from expanding
leukemic mass
Less common are features related to granulocyte
or platelet dysfunction, such as infections,
thrombosis, or bleeding.
9. Clinical presnetation
Occasionally, patients present with leukostatic
manifestations due to severe leukocytosis or
thrombosis such as :
1. vasoocclusive disease, 2. cerebrovascular
accidents, 3. myocardial infarction, 4. venous
thrombosis, 5. priapism, 6. visual disturbances,
and 7. pulmonary insufficiency.
Progression of CML is associated with worsening
symptoms.
Unexplained fever, significant weight loss,
increasing dose requirement of the drugs
controlling the disease, bone and joint pain,
bleeding, thrombosis, and infections suggest
10. Clinical features : Leukostasis
Marked leukocytosis > 1,00,000/microL can be
associated with symptoms of leukostatsis
Manifestations may include
1. visual changes
2. seizures
3. Cerebral or myocardial infarctions
11. Physical findings
Minimal to moderate splenomegaly is the most
common physical finding;
mild hepatomegaly is found occasionally.
Persistent splenomegaly despite continued
therapy is a sign of disease acceleration.
Lymphadenopathy and myeloid sarcomas are
unusual except late in the course of the disease;
when they are present, the prognosis is poor.
12. Hematologic Findings
Elevated white blood (cell) counts (WBCs), with increases in
both immature and mature granulocytes, are present at
diagnosis.
WBC count usually exceeds > 30,000 and usually ranges from
1,00,000 to 3,00,000.
The peripheral blood smear often resembles a bone marrow
aspirate due to presence of all stages of myeloid maturation.
myeloblasts constitute < 15 % of leukocytes and promyelocytes
combined < 30 % in PBS
Platelet counts are almost always elevated at diagnosis, may
exceed 1,000,000/UL and a mild degree of normocytic
normochromic anemia is present.
Leukocyte alkaline phosphatase is low in CML cells.
Phagocytic functions are usually normal at diagnosis and remain
normal during the chronic phase.
Histamine production secondary to basophilia is increased in
later stages, causing pruritus, diarrhea, and flushing. Basophils <
20 %.
13. Bone marrow aspiration and
biopsy
Should be performed on all patients as a part of
diagnostic evaluation
In all cases marrow is markedly hypercellular due
to massive myeloid hyperplasia
Markedly increased myeloid : erythroid ratio
Fibrosis may also be present
14. Disease acceleration
defined by the development of
1.increasing degrees of anemia unaccounted for
by bleeding or therapy;
2. cytogenetic clonal evolution;
3. blood or marrow blasts between 10 and 20%,
blood or marrow basophils 20%, or platelet count
<100,000/L.
Hyposegmented neutrophils may appear (Pelger-
Huët anomaly).
15. Blast crisis
WHO criteria :
Blasts > 20% of peripheral white blood cells or of
nucleated bone marrow cells
Extramedullary blast proliferation
Large foci or clusters of blasts in the bone
marrow biopsy
16. Blast crisis
International Bone Marrow Transplant Registry
criteria
> 30% blasts in the blood, marrow, or both
Extramedullary infiltrates of leukemic cells
17. Cytogentic analysis
Should be performed at the time of bone marrow
examination on all patients.
The cytogenetic hallmark of CML, found in 90–95% of
patients, is the t(9;22)(q34;q11.2).
Infrequently complex translocations can occur which
can mask BCR – ABL translocation.
In such situations FISH or PCR BCR-ABL can identify
.
All patients should have evidence of the translocation
molecularly or by cytogenetics or FISH to make a
diagnosis of CML.
FISH is More sensitive than cytogenetics at detecting
minimal residual disease during therapy.
18. Polymerase chain reaction
Is a molecular assay performed on peripheral
blood that identifies the BCR-ABL, translocation.
The quantitative PCR or Q-PCR is the most
sensitve method to follow residual disease during
treatment of CML
A baseline Q-PCR should be obtained in all
patients.
Can also detect complex translocations like FISH
19. Leukocyte alkaline phosphatase and
uric acid levels in CML
LAP activity is decreased or absent in circulating
granulocytes .
Helpful diagnostically.
Hyperuricemia and hyperuricosuria commonly
present.
20. Diagnostic criteria and prognostic
variables
WHO diagnostic criteria for chronic phase
1. leucocytosis
2. prominent dysgranulopoiesis
3. promyeloctyes, myelocytes and
metamyelocytes > 10 % of WBC’s
4. basophils < 2 % of WBC’s
5. monocytes < 10 % of WBC’s
6. hypercellular bone marrow with granulocytic
proliferation and dysplasia
7. < 20 % blasts in the blood or bone marrow
21. Diagnostic criteria and prognostic
variables
WHO criteria for diagnosis of accelerated phase
1. blasts 10% to 19% in the blood or bone
marrow
2. basophils > 20 % of peripheral blood WBC’s
3. platelets > 1,000,000/UL unresponsive to
therapy or < 1,000,000/UL unrelated to therapy
4. increasing spleen size or WBC count
unresponsive to therpy
5. cytogenetic evidence of clonal evolution
22. Diagnostic criteria and prognostic
variables
WHO criteria for diagnosis of blast phase
1. Blasts > 20 % of bone marrow cells or
peripheral WBC’s
2. extramedullary blast formation
3. large foci or clusters of blasts in bone marrow.
23. Prognostic factors
The clinical outcome of patients with CML is variable.
The Sokal index identified percentage of circulating blasts,
spleen size, platelet count, age, and cytogenetic clonal evolution
as the most important prognostic indicators.
The Hasford system was developed based on interferon (IFN) –
treated patients. It identified percentage of circulating blasts,
spleen size, platelet count, age, and percentage of eosinophils
and basophils as the most important prognostic indicators.
Both of these scoring systems stratify patients into three risk
groups (low,
intermediate, and high) and have been used for the risk
stratifications of patients in clinical trials evaluating tyrosine
kinase inhibitors (TKIs).
the Hasford system was better than the Sokal score for
predicting survival time
Ongoing assessment of response during therapy has emerged
as a much more important predictor of progression free survival.
24. Treatment
The therapy of CML is a proven curative treatment
(allogeneic transplantation) that has significant toxicity
and a new targeted treatment (imatinib) with
outstanding outcome.
Its recommended starting with TK inhibitors and
reserving allogeneic transplantation for those who
develop imatinib resistance.
At present, the goal of therapy in CML is to achieve
prolonged, durable, nonneoplastic, nonclonal
hematopoiesis, which entails the eradication of any
residual cells containing the BCR-ABL1 transcript.
Hence, the goal is complete molecular remission and
cure.
25. Imatinib Mesylate
Imatinib mesylate acts by competitive inhibition
at the ATP-binding site of the Abl kinase, which
leads to inhibition of tyrosine phosphorylation of
proteins involved in Bcr-Abl signal transduction.
Treatment is currently recommended for life .
imatinib discontinuation after at least 2 years of
complete molecular remission revealed molecular
relapse in 6 of 12 patients.
Interestingly who were treated with IFN- before
imatinib maintained molecular remission,
26. Imatinib mesylate
Standard dose is 400 mg / day
Can be increased to 600 mg/day if suboptimal
response
800 mg/day in 2 divided doses also used.
People who cannot tolerate < 300 mg / day
warrant a change in therapy.
27. Imatinib Mesylate
Imatinib is administered orally.
The main side effects are fluid retention, nausea,
muscle cramps, diarrhea, and skin rashes.
Myelosuppression is the most common
hematologic side effect. may require holding drug
and/or growth factor support.
Doses <300 mg/d seem ineffective and may lead
to development of resistance.
28. Acquired imatinib resistance
Is defined as a loss previous hematologic or
cytogenetic response.
Best understood mechanism is development of
point mutations in BCR-ABL.
CML with BCR-ABL mutation can be successfully
treated with 2nd generation kinase inhibitors like
dasatinib and nilotinib.
BCR-ABL harboring T315I is resistant to even
these drugs.
29. Monitoring response to imatinib
Patients who do not achieve response end points
within appropriate time frames should be treated
by
1. dose escalation of Imatinib
2. therapy with alternate TK inhibitor
3. allogenic bone marrow transplantation
30. Response end points
Complete hematologic response (CHR)
Definition : CHR is defined as normalization of
peripheral blood counts and can be expected in >
95% of chronic phase patients,
Failure to achieve this by 3 months warrants
reassessment of treatment approach.
31. Response end points
Major cytogenetic response
Definition : its defined as reduction of the
percentage of philadelphia chromosome to < 35%
of bone marrow metaphases.
Complete cytogenetic response is defined as
normalization of bone marrow cytogenetics.
Ideally MCR should be observed by 6 months
and CCR by 1 yr.
Absence of any cytogenetic response at 6
months ,< MCR at 12 months, or < CCR at 18
months should prompt consideration of change in
Rx.
32. Response end points
Major molecular response
Definition : at least a 3 log (1000 fold) reduction in
the level of disease measured by Q-PCR.
Patients who achieve this end point by 1 yr have
a zero percent risk of disease progression to AP
or BP at 5 years.
Monitoring should also include Bone marrow
aspiration and biopsy at baseline and every
6months, untill a complete cytogenetic response
is achieved.
Q-PCR should be performed every 3 months.
33. Newer drugs for imatinib
resistance
Mutations at the kinase domain occur in
approximately half of imatinib-resistant chronic-
phase cases.
These mutations are being targeted by novel TK
inhibitors that have a different conformation than
imatinib,
Nilotinib (Tasigma)
Dasatinib (Sprycel) .
34. Newer drugs for imatinib
resistance
Dasatinib is approved by the FDA at a dose of
100 mg/day for the treatment of all stages of CML
with resistance or intolerance to prior therapy,
including imatinib.
Nilotinib is approved by the FDA at a dose of 400
mg twice daily for the treatment of chronic- and
accelerated-phase CML with resistance or
intolerance to prior therapy, including imatinib.
Both are oral agents, Dasatinib causes pleural
effusions in 22% of patients.
Omacetaxine ,Sorafenib, Bosutinib ,Ponatinib
35. Allogeneic HSCT
Allogeneic HSCT is complicated by early mortality
owing to the transplant procedure.
Outcome of HSCT depends on multiple factors,
including
(1) the patient (e.g., age and phase of disease);
(2) the type of donor [e.g., syngeneic
(monozygotic twins) or HLA-compatible
allogeneic, related or unrelated];
(3) the preparative regimen (myeloablative or
reduced-intensity);
(4) GVHD; and
(5) posttransplantation treatment.
36. chemotherapy
Initial management of patients with chemotherapy is
currently reserved for rapid lowering of WBCs,
reduction of symptoms, and reversal of symptomatic
splenomegaly
. Hydroxyurea, a ribonucleotide reductase inhibitor,
induces rapid disease control. The initial dose is 1–4
g/d; the dose should be halved with each 50%
reduction of the leukocyte count
Busulphan, an alkylating agent that acts on early
progenitor cells, has a more prolonged effect.
However, its not recommend its use because of its
serious side effects, which include
unexpected, and occasionally fatal, myelosuppression
in 5–10% of patients; pulmonary, endocardial, and
marrow fibrosis; and an Addison-like wasting
syndrome.
37. Leukapheresis and Splenectomy
Intensive leukapheresis may control the blood counts
in chronic-phase CML;
It is useful in emergencies where leukostasis-related
complications such as pulmonary failure or
cerebrovascular accidents are likely.
It may also have a role in the treatment of pregnant
women, in whom it is important to avoid potentially
teratogenic drugs.
Splenectomy was used in CML in the past because of
the suggestion that evolution to the acute phase might
occur in the spleen.
splenectomy is now reserved for symptomatic relief of
painful splenomegaly unresponsive to imatinib or
chemotherapy, or for significant anemia or
thrombocytopenia associated with hypersplenism.
Splenic radiation is used rarely to reduce the size of
the spleen.
38. Treatment of Blast Crisis
Treatments for primary blast crisis, including imatinib,
are generally ineffective.
Only 52% of patients treated with imatinib achieved
hematologic remission and the median overall
survival was 6.6 months.
Patients who achieve complete hematologic
remission or whose disease returns to a second
chronic phase should be considered for allogeneic
HSCT.
Other approaches include induction chemotherapy
tailored to the phenotype of the blast cell followed by
TK inhibitors, with or without additional chemotherapy
and HSCT.
Blast crisis following initial therapy with imatinib
carries a dismal prognosis even if treated with
39. References
Harrison’s 18th edition
National comprehensive cancer network
guidelines
Clinical manual of oncology