101 CML

Question 1

What drives the disease CML?

Answer 1

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

Question 2

What are the phases of CML

Answer 2

Chronic phase
Accelerated phase
Terminal blastic

Question 3

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

Answer 3

85%

Question 4

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

Answer 4

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

Question 5

Mean age of diagnosis in CML

Answer 5

55-65 years old

Question 6

True or false. There familial associations in CML

Answer 6

False.

Question 7

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

Answer 7

False.

Question 8

Is present in more than 90% of classical CML cases

Answer 8

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

Question 9

Major breakpoint in CML? Centromeric breakpoint? Telomeric breakpoint?

Answer 9

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

Question 10

Least common breakpoint/re arrangement in CML

Answer 10

b14a3

Question 11

How is CML defined?

Answer 11

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

Question 12

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

Answer 12

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

Question 13

Most clinically revelant resistance mechanism

Answer 13

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

Question 14

What lead to the development of 2nd generation TKIs?

Answer 14

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

Question 15

Example of second generation TKIs

Answer 15

Dasatanib
Nilotinib
Bosutinib

Question 16

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

Answer 16

T315I

Question 17

Third generation TKIs

Answer 17

Ponatinib

Question 18

Most common physical finding of CML

Answer 18

Splenomegaly

Question 19

What is peripheral blood smear picture of CML?

Answer 19

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

Question 20

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

Answer 20

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

Question 21

What is the bone marrow picture of CML?

Answer 21

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

Question 22

What are the two BCR ABL variants

Answer 22

e13a2

e14a2

Question 23

What is complete cytogenetic response?

Answer 23

Absence of Ph positive metaphases (0% Ph positivity)

Question 24

Define accelerated phase in CML

Answer 24

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

Question 25

Define blast phase in CML

Answer 25

30% peripheral or marrow blasts | Presence of sheets of blasts in extramedullary disease

Question 26

What the prodominant cell line in blastic phase CML?

Answer 26

60% myeloid | 25% lymphoid

Question 27

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

Answer 27

True.

Question 28

5 oral TKIs approved for CML

Answer 28

``` Imatinib (Gleveec) Nilotinib (Tasigna) Dasatinib (Sprycel) Bosutinib (Bosulif) Ponatinib (Iclusig) ```

Question 29

Adverse effect of ponatinib

Answer 29

Arterio occlussive events

Question 30

Only approved TKIs for chronic and accelerated phase

Answer 30

Nilotinib

Question 31

TKIs approved for accelerated and blastic phase

Answer 31

Imatinib Dasatinib Bosutinib Ponatinib

Question 32

TKIs with no activity against cKit or PDGFR

Answer 32

Bosutinib

Question 33

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

Answer 33

Omacetaxine (Synribo)

Question 34

Main adverse effect of omacetaxine

Answer 34

Prolonged myelosuppresion

Question 35

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

Answer 35

Omacetaxine

Question 36

TKIs given as salvage therapy

Answer 36

Dasatinib Nilotinib Bosutinib Ponatinib

Question 37

TKI that cannot be given during blastic phase

Answer 37

Nilotinib

Question 38

Notable toxicity is diabetes along with arterio occlusive disease and pancreatitis

Answer 38

Nilotinib

Question 39

TKI associated with liver toxicity

Answer 39

Bosutinib

Question 40

TKI associated with pleural and pericardial effusion and pulmonary hypertension

Answer 40

Dasatinib

Question 41

TKI associated with prolonged QTc syndrome

Answer 41

Nilotinib | Dasatinib

Question 42

Should TKIs be changed, when?

Answer 42

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

Question 43

When are TKIs discontinued?

Answer 43

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

Question 44

How are CML patients monitored?

Answer 44

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

Question 45

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

Answer 45

Implemented in chronic phase

Question 46

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

Answer 46

20-40%

Question 47

Main therapeutic endpoint in CML?

Answer 47

Complete cytogenetic response by 12 months of imatinib

Question 48

When is treatment failure considered and indication to change therapy?

Answer 48

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

Question 49

How is cytogenetic response monitored in CML?

Answer 49

Peripheral blood FISH AND PCR studies every 6 months

Question 50

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

Answer 50

To achieve cytogenetic response by 3-6 months of therapy

Question 51

Given to reduce initial CML burden

Answer 51

Hydroxyurea 0.5 to 10 g/day

Question 52

Used as allogeneic SCT preparative regimen in CML

Answer 52

Busulfan

Question 53

Side effects of busulfan which limits its use

Answer 53

Pulmonary and cardiac fibrosis Delayed myelosuppresion Addison like disease

Question 54

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

Answer 54

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

Question 55

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

Answer 55

Nilotinib approved for all phases except blastic phase | Table 101-2