101 CML Flashcards
What drives the disease CML?
BCR ABL1 chimeric gene from reciprocal balanced translocation between the long arms of chromosome 9 and 22, known as the Philadelphia chromosome
What are the phases of CML
Chronic phase
Accelerated phase
Terminal blastic
The 10 year survival rate of CML with imatinib mesylate is how much?
85%
True or false. Allogeneic stem cell transplant is the first line therapy for CML.
False. First line is now TKIs and SCT is 2rd or 3rd line treatment
Mean age of diagnosis in CML
55-65 years old
True or false. There familial associations in CML
False.
True or false. Just like AML, CML is a frequent secondary leukemia from ankylating agents and radiation
False.
Is present in more than 90% of classical CML cases
t(9;22)(q34.1;q11.2)
Major breakpoint in CML? Centromeric breakpoint? Telomeric breakpoint?
Major breakpoint: p210 BCR ABL1
Centromeric breakpoint: p190 BCR ABL1 - - worse outcomes
Telomeric breakpoint: p230 BCR ABL1 - - more indolent course
Least common breakpoint/re arrangement in CML
b14a3
How is CML defined?
Presence of BCR ABL1 fusion gene in a patient with Myeloproliferative neoplasm
Chromosomal abnormalities associated with transition from chronic phase to accelerated blastic phase
Double Ph Trisomy 8 Isochromosome 17 Deletion of 17p (loss of TP53) 20q-
Most clinically revelant resistance mechanism
Development of different ABL1 kinase domain mutations that may prevent the binding of TKIs to the catalytic site
What lead to the development of 2nd generation TKIs?
There are more than 100 BCR ABL1 mutations which confer relative and absolute resistance to imatinib
Example of second generation TKIs
Dasatanib
Nilotinib
Bosutinib
Gatekeeper mutation that prevents binding of and causes resistance to all other TKIs
T315I
Third generation TKIs
Ponatinib
Most common physical finding of CML
Splenomegaly
What is peripheral blood smear picture of CML?
Left shifted hematopoiesis with predominance of neutrophils, presence of bands, myelocytes, metamyelocytes, promyelocyte and blasts less than 5%
True or false. Thrombocytopenia is commons and suggest a good prognosis
False. Thrombocytosis is common. If thrombocytopenia is present, it suggests poor prognosis
What is the bone marrow picture of CML?
Marked myeloid hyperplasia and high myeloid to erythroid ration of 15-20:1
Blast is less than 5%
What are the two BCR ABL variants
e13a2
e14a2
What is complete cytogenetic response?
Absence of Ph positive metaphases (0% Ph positivity)
Define accelerated phase in CML
15% blast on peripheral blood
30% blasts + promyelocyte on peripheral blood
Thrombocytopenia less 100
Define blast phase in CML
30% peripheral or marrow blasts
Presence of sheets of blasts in extramedullary disease
What the prodominant cell line in blastic phase CML?
60% myeloid
25% lymphoid
True or false. Lymphoid blastic CML is more responsive to TKIs and CVAD (cyclosphosphamide, vincristine, doxorubucin and dexamethasone) regimen
True.
5 oral TKIs approved for CML
Imatinib (Gleveec) Nilotinib (Tasigna) Dasatinib (Sprycel) Bosutinib (Bosulif) Ponatinib (Iclusig)
Adverse effect of ponatinib
Arterio occlussive events
Only approved TKIs for chronic and accelerated phase
Nilotinib
TKIs approved for accelerated and blastic phase
Imatinib
Dasatinib
Bosutinib
Ponatinib
TKIs with no activity against cKit or PDGFR
Bosutinib
6th agent approved for CML for treatment of chronic and accelerated phase after failure of two or more TKIs
Omacetaxine (Synribo)
Main adverse effect of omacetaxine
Prolonged myelosuppresion
Protein synthesis inhibitor with more selective inhibition of BCR ABL1 onco protein
Omacetaxine
TKIs given as salvage therapy
Dasatinib
Nilotinib
Bosutinib
Ponatinib
TKI that cannot be given during blastic phase
Nilotinib
Notable toxicity is diabetes along with arterio occlusive disease and pancreatitis
Nilotinib
TKI associated with liver toxicity
Bosutinib
TKI associated with pleural and pericardial effusion and pulmonary hypertension
Dasatinib
TKI associated with prolonged QTc syndrome
Nilotinib
Dasatinib
Should TKIs be changed, when?
Loss of molecular response such as increase of BCR ABL transcripts from less 0.1 to more 0.1%
When are TKIs discontinued?
Discontinuation is still investigational. Undetectable BCR ABL1 transcripts for 2-3 years
How are CML patients monitored?
PCR studies assesses every 1-2 months for first 6 months then every 2 months until 2 years and every 3-6 months thereafter
When is allogeneic stem cell transplant associated with long term. Survival of 40-60%
Implemented in chronic phase
What is the cure rates of Allogeneic SCT when implemented in accelerated phase?
20-40%
Main therapeutic endpoint in CML?
Complete cytogenetic response by 12 months of imatinib
When is treatment failure considered and indication to change therapy?
Failure to achieve complete cytogenetic response by 12 months or occurance of hematologic relapse
How is cytogenetic response monitored in CML?
Peripheral blood FISH AND PCR studies every 6 months
What is the target cytogenetic response when using 2nd line TKIs
To achieve cytogenetic response by 3-6 months of therapy
Given to reduce initial CML burden
Hydroxyurea 0.5 to 10 g/day
Used as allogeneic SCT preparative regimen in CML
Busulfan
Side effects of busulfan which limits its use
Pulmonary and cardiac fibrosis
Delayed myelosuppresion
Addison like disease
What is the treatment regimen of CML in accelerated and blastic phase
2nd generation TKIs + chemotherapy
In lymphoid CML, anti All which is CVAD
In myeloid CML, anti AML which is cytarabine + anthracycline
TKIs given during blastic phase except A. Nilotinib B. Dasatinib C. Bosutinib D. Ponatinib
Nilotinib approved for all phases except blastic phase
Table 101-2
