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-50s
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.
6. Philadelphia chromosome
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 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 9095% 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 WBCs 4. basophils < 2 % of WBCs 5. monocytes <
10 % of WBCs 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
WBCs 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 WBCs 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 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 14 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 510% 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 Harrisons 18th edition National comprehensive
cancer network guidelines Clinical manual of oncology