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Hematology > 101 CML > Flashcards

101 CML Flashcards

1
Q

What drives the disease CML?

A

BCR ABL1 chimeric gene from reciprocal balanced translocation between the long arms of chromosome 9 and 22, known as the Philadelphia chromosome

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2
Q

What are the phases of CML

A

Chronic phase
Accelerated phase
Terminal blastic

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3
Q

The 10 year survival rate of CML with imatinib mesylate is how much?

A

85%

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4
Q

True or false. Allogeneic stem cell transplant is the first line therapy for CML.

A

False. First line is now TKIs and SCT is 2rd or 3rd line treatment

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5
Q

Mean age of diagnosis in CML

A

55-65 years old

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6
Q

True or false. There familial associations in CML

A

False.

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7
Q

True or false. Just like AML, CML is a frequent secondary leukemia from ankylating agents and radiation

A

False.

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8
Q

Is present in more than 90% of classical CML cases

A

t(9;22)(q34.1;q11.2)

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9
Q

Major breakpoint in CML? Centromeric breakpoint? Telomeric breakpoint?

A

Major breakpoint: p210 BCR ABL1
Centromeric breakpoint: p190 BCR ABL1 - - worse outcomes
Telomeric breakpoint: p230 BCR ABL1 - - more indolent course

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10
Q

Least common breakpoint/re arrangement in CML

A

b14a3

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11
Q

How is CML defined?

A

Presence of BCR ABL1 fusion gene in a patient with Myeloproliferative neoplasm

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12
Q

Chromosomal abnormalities associated with transition from chronic phase to accelerated blastic phase

A 
Double Ph
Trisomy 8
Isochromosome 17
Deletion of 17p (loss of TP53)
20q-
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13
Q

Most clinically revelant resistance mechanism

A

Development of different ABL1 kinase domain mutations that may prevent the binding of TKIs to the catalytic site

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14
Q

What lead to the development of 2nd generation TKIs?

A

There are more than 100 BCR ABL1 mutations which confer relative and absolute resistance to imatinib

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15
Q

Example of second generation TKIs

A

Dasatanib
Nilotinib
Bosutinib

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16
Q

Gatekeeper mutation that prevents binding of and causes resistance to all other TKIs

A

T315I

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17
Q

Third generation TKIs

A

Ponatinib

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18
Q

Most common physical finding of CML

A

Splenomegaly

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19
Q

What is peripheral blood smear picture of CML?

A

Left shifted hematopoiesis with predominance of neutrophils, presence of bands, myelocytes, metamyelocytes, promyelocyte and blasts less than 5%

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20
Q

True or false. Thrombocytopenia is commons and suggest a good prognosis

A

False. Thrombocytosis is common. If thrombocytopenia is present, it suggests poor prognosis

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21
Q

What is the bone marrow picture of CML?

A

Marked myeloid hyperplasia and high myeloid to erythroid ration of 15-20:1
Blast is less than 5%

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22
Q

What are the two BCR ABL variants

A

e13a2

e14a2

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23
Q

What is complete cytogenetic response?

A

Absence of Ph positive metaphases (0% Ph positivity)

24
Q

Define accelerated phase in CML

A

15% blast on peripheral blood
30% blasts + promyelocyte on peripheral blood
Thrombocytopenia less 100

25
Q

Define blast phase in CML

A

30% peripheral or marrow blasts

Presence of sheets of blasts in extramedullary disease

26
Q

What the prodominant cell line in blastic phase CML?

A

60% myeloid

25% lymphoid

27
Q

True or false. Lymphoid blastic CML is more responsive to TKIs and CVAD (cyclosphosphamide, vincristine, doxorubucin and dexamethasone) regimen

28
Q

5 oral TKIs approved for CML

A 
Imatinib (Gleveec) 
Nilotinib (Tasigna) 
Dasatinib (Sprycel) 
Bosutinib (Bosulif) 
Ponatinib (Iclusig)
29
Q

Adverse effect of ponatinib

A

Arterio occlussive events

30
Q

Only approved TKIs for chronic and accelerated phase

31
Q

TKIs approved for accelerated and blastic phase

A

Imatinib
Dasatinib
Bosutinib
Ponatinib

32
Q

TKIs with no activity against cKit or PDGFR

33
Q

6th agent approved for CML for treatment of chronic and accelerated phase after failure of two or more TKIs

A

Omacetaxine (Synribo)

34
Q

Main adverse effect of omacetaxine

A

Prolonged myelosuppresion

35
Q

Protein synthesis inhibitor with more selective inhibition of BCR ABL1 onco protein

A

Omacetaxine

36
Q

TKIs given as salvage therapy

A

Dasatinib
Nilotinib
Bosutinib
Ponatinib

37
Q

TKI that cannot be given during blastic phase

38
Q

Notable toxicity is diabetes along with arterio occlusive disease and pancreatitis

39
Q

TKI associated with liver toxicity

40
Q

TKI associated with pleural and pericardial effusion and pulmonary hypertension

41
Q

TKI associated with prolonged QTc syndrome

A

Nilotinib

Dasatinib

42
Q

Should TKIs be changed, when?

A

Loss of molecular response such as increase of BCR ABL transcripts from less 0.1 to more 0.1%

43
Q

When are TKIs discontinued?

A

Discontinuation is still investigational. Undetectable BCR ABL1 transcripts for 2-3 years

44
Q

How are CML patients monitored?

A

PCR studies assesses every 1-2 months for first 6 months then every 2 months until 2 years and every 3-6 months thereafter

45
Q

When is allogeneic stem cell transplant associated with long term. Survival of 40-60%

A

Implemented in chronic phase

46
Q

What is the cure rates of Allogeneic SCT when implemented in accelerated phase?

47
Q

Main therapeutic endpoint in CML?

A

Complete cytogenetic response by 12 months of imatinib

48
Q

When is treatment failure considered and indication to change therapy?

A

Failure to achieve complete cytogenetic response by 12 months or occurance of hematologic relapse

49
Q

How is cytogenetic response monitored in CML?

A

Peripheral blood FISH AND PCR studies every 6 months

50
Q

What is the target cytogenetic response when using 2nd line TKIs

A

To achieve cytogenetic response by 3-6 months of therapy

51
Q

Given to reduce initial CML burden

A

Hydroxyurea 0.5 to 10 g/day

52
Q

Used as allogeneic SCT preparative regimen in CML

53
Q

Side effects of busulfan which limits its use

A

Pulmonary and cardiac fibrosis
Delayed myelosuppresion
Addison like disease

54
Q

What is the treatment regimen of CML in accelerated and blastic phase

A

2nd generation TKIs + chemotherapy
In lymphoid CML, anti All which is CVAD
In myeloid CML, anti AML which is cytarabine + anthracycline

55
Q 
TKIs given during blastic phase except
A. Nilotinib
B. Dasatinib
C. Bosutinib
D. Ponatinib
A

Nilotinib approved for all phases except blastic phase

Table 101-2

Hematology (11 decks)

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