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Cytogenetics > CML > Flashcards

CML Flashcards

1
Q

What is CML? What is it classed as according to WHO 2016?

A

Myeloproliferative disease that originates in bone marrow stem cell (pluripotent ?technically multipotent)

A myeloproliferative neoplasm.

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2
Q

What sample types are acceptable for a diagnostic CML?

A

Bone marrow or whole blood can be used.

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3
Q

What is the hallmark of CML?

A

The t(9;22)(q34;q11) translocation / BCR-ABL1 fusion.

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4
Q

Briefly what is happening within haematopoiesis that causes the symptoms of CML? Are the cells functional?

A

The BCR-ABL1 fusion causes proliferation of granulocytes.

Cells are still functional but they overwhelm the marrow with their numbers and have a knock on effect on the levels of other cells.

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5
Q

What derivative chromosome is associated with CML?

A

The Philadelphia or ‘ph’ chromosome.

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6
Q

What is the incidence and typical age of onset?

A

1-1.5 per 100,000 per year

5th or 6th decade of life - mean 65yrs but can occur at any age.

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7
Q

What is the older name for CML and why?

A

Chronic Granulocytic Leukemia.

Causes an increase in the number granulocytes (mainly neutrophils).

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8
Q

Do all patients with CML have symptoms?

What symptoms might be expected in a patient with untreated CML?

A

No, some patients may be asymptomatic. CML might be picked up as part of a random blood test.

When symptoms are present they may include:
Fatigue (knock on effect onto cells such as red blood cells which carry oxygen)
Weight loss (cancer cells using up energy, enlarged spleen reduces appetite/early satiety)
Anaemia (reduced red blood cells)
Night sweats (body fighting cancer? Hormonal?)
Splenomegaly (extramedullary hematopoiesis)

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9
Q

What are the 3 phases of CML?

A

Chronic phase
Accelerate phase
Blast phase (blast crisis)

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10
Q

What would the blood counts of a chronic phase patient be?

A

Very high white cell count, mainly neutrophils; ~170 x10^9 (normal count would be 4-11 x 10^9)
Normal or raised platelets
<2% blasts in blood
<5% blasts in marrow

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11
Q

What percentage of patients present with the Ph chromosome? What do the remainder have?

A

~95%

Remainder either have a variant or a cryptic BCR-ABL1 which can be detected at the molecular level.

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12
Q

Does every patient have a recognisable accelerated phase?

How might an accelerated phase become apparent?

A

No only some do.
Increase WCC
Increase spleen size
Cytogenetic clonal evolution.

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13
Q

What is blast crisis?

A

Terminal phase
Resembles acute leukemia - usually myeloid but can be lymphoid or even mixed
Often doesn’t respond to treatment

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14
Q

What cytogenetic changes might you see in a patient whose disease is transforming/progressing?

A

+19 and i(17q) are reliable indicators of transformation.
+8, +Ph are also seen but can be seen transiently in chronic phase so you would want to see these in consecutive samples.

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15
Q

What would we do with a sample that comes in with ?CML.

A

Urgent FISH on a direct using BCR/ABL1 probe

Karyotype to check translocation and for any other abnormalities.

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16
Q

Why is it important to check for additional abnormalities at diagnosis?

A

Their presence at diagnosis can be a warning sign.

May suggest patient won’t respond as well to initial treatment and may benefit from closer monitoring.

17
Q

How many cells would we look at on a new CML karyotype?

A

Best practice - 10 cells. Analyse 3, score 7.

Locally we do 20 cells - analyse 10 and score 10.

18
Q

Does a deleted derivative 9 on FISH affect the patients prognosis?

A

No, not in the imatinib era.

Previously it would have though.

19
Q

Why should we be careful with follow up samples that are whole blood? (According to BPG)

A

Scoring might be biased if unselected cells are used.

The level of myelosupression following treatment will cause the number of normal lymphocytes in the blood to vary which will skew the percentage of granulocytes scored in the FISH analysis.

If unselected cells are used this should be noted on the report.

20
Q

What would we do with a follow-up sample for CML? How many cells would we look at?

A

Metaphase analysis to look for t(9;22).
If normal, we would do 30 cells to check for MDS type abnormalities in the negative cells.
If positive, we would treat as per ‘normal’ CML abnormal and do 20 cells.

21
Q

What is the significance of abnormalities in Ph negative cells?

A

This needs careful interpretation as can be seen as a result of imatinib treatment.
This would need consideration along with results of BM morphology report and immunophenotyping report.

22
Q

What are the BPG for reporting times?

A

Urgent FISH: 3 calendar days
Urgent karyotype within 14 calendar days
Routine karyotype within 21 calendar days.

However - locally we use HODS and therefore all samples are 14 days.

23
Q

Briefly how is CMLs response to treatment (specifically imatinib) defined?

A

By level of cytogenetic response in bone marrow metaphase cells.
E.g. no Ph cells seen = complete cytogenetic response.

The other categories are partial (1-35%), minor (36-65%), minimal (66-95%) and no response (96-100%).

These figures are then used in a table which compares this to length of treatment time with imatinib and has time points at 3 months, 6 months, 12 months etc post treatment.

24
Q

If a patient after 12 months has the following what would it be classed as:
Partial cytogenetic response after 12 months?
Minimal or minor cytogenetic response after 12 months?

A

Partial - suboptimal response

Minimal or minor - treatment failure

25
Q

What is imatinib? Briefly how does it work? Is it a cure?

A

Treatment for CML - it is a tyrosine kinase inhibitor

Acts on the BCR-ABL protein.

Works by binding close to the ATP binding site and preventing ATP from binding. This switches off the downstream pathways that promote leukemogenesis.

It is not a ‘cure’ but it suppresses the BCR-ABL cell line to as low as possible, for as long as possible.

26
Q

What is a tyrosine kinase?

A

Essentially an on and off switch of many cellular functions such as apoptosis, cell division and growth.

It is an enzyme that can transfer a phosphate from ATP to a protein in a cell.

27
Q

What is the treatment goal with imatinib?

A

A major molecular response - 3 log reduction in 2 consecutive samples.

28
Q

Why might treatment with imatinib not work:

  • from the start?
  • after a period of successful treatment E.g. acquired resistance?
A

Individual metabolism of the drug specific to the patient.
Patient may have a mutation which stops imatinib from working.

Patient may have a low level mutation. So imatinib works on surpressing main clone but this allows low level mutated clone to expand and become main clone.

29
Q

Is the t(9;22) always the same rearrangement when seen across multiple disorders?

A

No, it can vary at the molecular level. The breakpoint on BCR determines the size of the protein produced.

30
Q

What protein size is produced in the majority of CML?

A

The majority of CMLs will have a protein size of p210 at the molecular level which is known as the major (M) breakpoint.
A very small number of CML patients might have the micro breakpoint and a p230 protein.

The p190 protein may be detectable at a low level in CML patients due to alternate splicing.

31
Q

How does CML progress from chronic to acute?

A

By acquisition of additional genetic abnormalities which then block cell differentiation.

This causes the appearance and increase of blast cells which are immature and can’t function. The additional mutations are what determine whether the blast cells are myeloid (usual), lymphoid (less common) or mixed (rare).

32
Q

If the stem cell responsible for CML is multipotent why don’t we see a chronic lymphoid version with the t(9;22)?

A

Unsure but possibly because the presence of the t(9;22) in the stem cell is not agreeable with lymphopoiesis?

?maybe there are other underlying mutations that drive the t(9;22) down the lymphoid pathway but once these occur it immediately becomes acute lymphoid leukemia?

33
Q

Would there be a way to tell the difference between a patient with CML in lymphoid blast crisis and an patient with ALL?

A

One way would be by FISH with the BCR-ABL1 ES probe. If the minor breakpoint is detected this would indicate ALL.

34
Q

What is a key feature of karyotyping a CML v an AML or ALL with BCR-ABL? What is the explanation for this?

A

In CML almost all cells karyotyped will show the rearrangement.

Chronic builds slowly and abnormality can be at a really high level with mild symptoms as the cells still have function.

Acute is immature blast cells which can’t function, patient presents with bad symptoms much earlier. Lower levels of blast cells with the abnormality are tolerated in the marrow.

35
Q

How long are patients typically followed up by with cyto?

A

Until 12 months and then they tend to be monitored by PCR.

Cyto required by ELN guidelines at 3, 6 and 12 months.

36
Q

How can we determine which breakpoint is involved?

A

The FISH probe BCR-ABL1 ES can be used as it is designed to produce an ‘extra signal’ when the minor (p190) breakpoint has occurred.

37
Q

What are the major and minor routes of disease progression? What does imatinib follow?

A

Major: i(17q) and +19, also +8 and +Ph (but these can be transient).

Minor: -7, +21, -Y and also t(3;21) or other rearrangement of 3q.

Imatinib follows the major route.

38
Q

What percentage of blasts indicates acute transformation/blast phase CML?

A

20%+

39
Q

What is Ponatinib used for?

A

Treatment of patients who specifically have the T315I mutation which confers resistance to both imatinib and all second generation TKIs.

Cytogenetics (44 decks)

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