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Chronic Myeloid Leukaemia Flashcards

1
Q

What is Chronic Myeloid Leukemia (CML)?

A

A type of myeloproliferative neoplasm with granulocyte proliferation as a major component.

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2
Q

What category of diseases does CML belong to?

A

CML belongs to the group of myeloproliferative neoplasms (MPNs).

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3
Q

What cell lineage is mainly proliferative in CML?

A

Found in all myeloid lineages and in some lymphoid cells

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4
Q

What is the primary cause of increased WCC in CML?

A

Failure of apoptosis leads to increased WCC in CML.

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5
Q

What is the hallmark characteristic of CML?

A

Chromosomal translocation t(9;22)(q34;q11.2).

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6
Q

What is the Philadelphia chromosome?

A

An abnormal chromosome 22 resulting from t(9;22).

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7
Q

What percentage of CML patients have the BCR-ABL1 fusion gene?

A

95% of CML patients have the BCR-ABL1 fusion gene.

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8
Q

What other structural abnormalities can be found in CML?

A

In 10% of cases: Ph duplication, isochromosome 17q, trisomy 8/19, and rearrangements at MLL (11q23) or MECOM (3q26.2).

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9
Q

What is the cytogenetic techniques to detect CML at diagnosis?

A

Karyotyping detects chromosomal abnormalities in CML and FISH detects the BCR-ABL1 gene fusion

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10
Q

What is RT-PCR’s role in detecting CML?

A

RT-PCR detects BCR-ABL1 fusion at the molecular level.

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11
Q

How does the BCR-ABL1 fusion affect cellular signalling in CML?

A

Tyrosine kinase activity of BCR-ABL1 activates RAS/MAPK and JAK-STAT pathways, leading to cell proliferation and reduced response to apoptotic stimuli.

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12
Q

What is the function of BCR ?

A

The BCR dimerization domain allows protein interaction.

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13
Q

What is the function of ABL1 ?

A

The ABL1 tyrosine kinase domain activates downstream signaling.

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14
Q

What are the phases of CML?

A

Chronic phase, accelerated phase, and blast crisis.

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15
Q

Describe the chronic phase of CML.

A

Chronic phase shows high WCC (associated with hypercellular bone. Arrow and peripheral leukocytosis), enlarged spleen, and <10% blasts.

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16
Q

What percentage of blasts characterizes the chronic phase of CML?

A

Less than 10% blasts characterize the chronic phase.

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17
Q

What characterizes the accelerated phase of CML?

A

Accelerated phase shows an increase in immature blasts.

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18
Q

Describe blast crisis in CML.

A

Blast crisis is refractory and associated with poor survival. Majority present as AML, however 20-30% of cases, blasts are lymphoid

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19
Q

Typical diagnostic workup: What is the morphology review in CML diagnostic workup?

A

Morphology checks for excess mature myeloid cells.

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20
Q

Typical diagnostic workup: How is immunophenotyping by flow cytometry used in CML?

A

Defines cell lineage, maturation, and aberrancy of abnormal cells.

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21
Q

How many BCR-ABL1 isoforms are there? State transcript size

A

3: p210 x 2, p190, p230

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22
Q

What is the common size of the BCR-ABL1 protein in CML?

A

The p210 BCR-ABL1 fusion protein size.

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23
Q

What breakpoints generate the p210BCR-ABL1 fusion protein?

A

BCR exon 13 or 14 fused with ABL exon 2 generates p210 BCR-ABL1 (e13 or b2 and e14 or b3).

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24
Q

Which transcript size is associated with BCR exon 1 breakpoints?

A

BCR exon 1 breakpoint produces the p190 protein (e1 or a2).

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25
How is the p230 BCR-ABL1 fusion protein generated?
A larger p230 protein is generated with BCR exon 19 (e19 or c3).
26
How to detect residual disease in CML?
RT-PCR is crucial for monitoring residual disease in CML. A rise in BCR-ABL1 transcripts can be a sign of primary resistance to TKIs or development of resistance.
27
How often should molecular monitoring be performed in CML?
Molecular monitoring is performed every 3 months.
28
What is the significance of monitoring BCR-ABL1 transcript levels?
Tracking BCR-ABL1 levels helps identify therapy resistance early.
29
How is RT-PCR used in CML monitoring?
RT-PCR is used to quantitate the amount of BCR-ABL1 transcript and control genes (BCR or ABL1) to generate an expressed ratio of BCR-ABL1:control.
30
What is multiplex-PCR's role in CML?
Multiplex-PCR allows detection of multiple transcripts in one test.
31
What are treatment methods for CML?
The use of tyrosine kinase inhibitors (TKIs) which have an inhibitory effect by binding to ATP-site of BCR-ABL1 and prevent downstream signalling that gives rise to leukaemia transformation.
32
Name common drug treaments used to treat CML.
Common TKIs include imatinib, dasatinib, nilotinib, and bosutinib.
33
What is primary resistance in CML?
Primary resistance shows failure to achieve therapeutic response; lack of response.
34
What is secondary resistance in CML?
Secondary resistance is disease reapparance after an initial response
35
What type of mutations often cause TKI resistance?
Point mutations in ABL1 often cause TKI resistance.
36
Which mutation is ponatinib effective against?
Ponatinib is effective against Thr315Ile mutations.
37
Why might a patient switch TKIs in CML therapy?
Resistance mutations may require TKI change for efficacy.
38
Which TKI is effective for mutations resistant to nilotinib?
Dasatinib treats mutations resistant to nilotinib (Tyr253His, Glu255Lys, Phe359Val).
39
How is TKI efficacy monitored in CML patients?
Efficacy is monitored through hematologic, cytogenetic, and molecular response.
40
What is kinase domain mutation analysis?
Kinase domain via direct sequencing detects mutations that impact TKI efficacy.
41
Why is mutation analysis recommended in treatment failure?
Mutation analysis directs alternative TKI choices when needed.
42
What are the three types of response classifications in CML monitoring?
Hematological, cytogenetic, and molecular responses.
43
Describe hematological response monitoring in CML.
Hematological response indicates improvement in blood counts.
44
Describe cytogenetic response monitoring in CML.
Cytogenetic response measures Ph chromosome reduction.
45
Describe molecular response monitoring in CML.
Molecular response checks BCR-ABL1 transcript reduction.
46
What does a major molecular response (MMR) indicate in CML?
Major molecular response suggests improved survival outlook.
47
What is the standard interval for CML molecular monitoring?
Standard interval for monitoring is every 3 months.
48
Why is regular monitoring important in CML treatment?
Regular monitoring identifies risks of treatment failure early.
49
What indicates treatment failure in CML monitoring?
Rising BCR-ABL1 indicates potential treatment failure.
50
What does undetectable disease signify in CML patients?
Undetectable disease means complete response with no relapse.
51
When might a patient be eligible to stop TKI therapy?
Eligible patients may stop TKI if disease is undetectable, without relapsing.
52
What does disease progression indicate in CML during or after treatment?
Progression suggests need for alternative treatment strategy.
53
What is a relapse in CML?
Relapse is the reappearance of detectable disease after response.
54
What is an optimal response to CML treatment?
Optimal response meets therapeutic goals and suppresses BCR-ABL1.
55
What is a cryptic Philadelphia chromosome?
Cryptic Ph chromosome is undetectable by G-banded karyotyping- cytogenetics.
56
How is a cryptic Philadelphia chromosome detected?
Detected through FISH or RT-PCR.
57
What gene fusion protein is common in CML with major BCR breakpoints?
Major BCR breakpoints yield p210BCR-ABL1 protein in CML.
58
What pathways are associated with CML proliferation?
RAS/MAPK and JAK-STAT pathways drive CML cell proliferation.
59
Which genetic changes in CML predict poor response to TKI?
Ph duplication, isochromosome 17q, trisomy 8/19 predict poor response.
60
What is isochromosome 17q in CML?
Isochromosome 17q duplication has adverse prognostic impact.
61
What does trisomy 8 indicate in CML prognosis?
Trisomy 8 is linked to poor TKI response.
62
Why are MECOM (3q26.2) abnormalities significant in CML?
3q26.2 rearrangement signifies high risk in CML.
63
What does MLL rearrangement indicate in CML?
MLL rearrangement at 11q23 shows aggressive disease course.
64
What is the impact of Ph duplication on prognosis?
Ph duplication worsens prognosis by enhancing resistance risk.
65
How does ABL1 domain mutation affect TKI therapy?
ABL1 domain mutations interfere with TKI binding.
66
How does Ph chromosome duplication influence treatment response?
Ph chromosome duplication predicts low TKI response rate.
67
What is a typical diagnostic workup for CML?
Morphology-reviewed for evidence of excess of mature myeloid cells (accumulation of mature effector cells) Immunophenotyping by flow cytometry- define lineage, maturation and immunophenotypic aberrancy of abnormal cells Cytogenetics and molecular data- provides further subclassification of disease type and prognostic information to guide treatment strategies
68
Optimal response to TKI at 3 months?
BCR-ABL1 is ≤10% and/or Ph+ ≤35%
69
Optimal response to TKI at 6 months?
BCR-ABL1 is ≤1% and/or Ph+ 0%
70
Optimal response to TKI at 12 months?
BCR-ABL1 is ≤0.1%
71
What are 5 evidence of failure to TKI at any time?
Loss of CHR (complete haematological response), Loss of CCyR (complete cytogenetic response), confirmed loss of MMR (complete major molecular response), New Ph+ clonal cytogenetic abnormalities, ABL1 TKD mutation

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