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Cancer Genetics > Cytogentic Services in Leukaemia - Myeloid Malignancies > Flashcards

Cytogentic Services in Leukaemia - Myeloid Malignancies Flashcards

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1
Q

What is the purpose of cytogenetic testing for myeloid malignancies?

A

1) . DIAGNOSIS - t(15;17) in Acute Promyelocytic Leukaemia (APML).
2) . PROGNOSIS - inv(16) in AML is good prognosis, but a complex karyotype in AML is poor.
3) . MONITORING - response to treatment, remission/relapse statues, loss or return of abnormalities seen at diagnosis, post BMT look for recipient/donor cells.
4) . TRIAL REQUIREMENTS - may ask for particular levels of analysis.

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2
Q

Discuss CML

A
  • CML is Chronic Myeloid Leukaemia.
  • The acquired chromosome translocation t(9;22)(q34;q11) is an example which leads to a new fusion protein BCR-ABL1.
  • Can detect this abnormality by karyotype, FISH, PCR.
  • ABL1 on chromosome 9, BCR on chromosome 22.
  • BCR-ABL1 gene fusion formed on the the derivative chromosome 22 (Philadelphia chromosome).
  • The reciprocal ABL1-BCR gene fusion is formed on the derivative chromosome 9.
  • Can have variants.
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3
Q

What chromosome is ABL1 on?

A
  • ABL1 is on chromosome 9
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4
Q

What chromosome is BCR on?

A
  • BCR is on chromosome 22
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5
Q

What translocations leads to the formation of the BCR-ABL1 fusion protein? What chromosome is this formed on?

A
  • BCR-ABL1 gene fusion formed on the the derivative chromosome 22 (Philadelphia chromosome).
  • The reciprocal ABL1-BCR gene fusion is formed on the derivative chromosome 9.
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6
Q

What fusion protein will always be found in CML?

A
  • BCR-ABL1 gene fusion formed on the the derivative chromosome 22 (Philadelphia chromosome).
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7
Q

How can we detect the BCR-ABL1 fusion using FISH?

A
  • Using probes which span the breakpoints of ABL1 in the 9 and BCR on the 22 we will be able to see both probes present in on the derivative chromosome in which the BCR-ABL1 and ABL1-BCR gene fusions have formed.
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8
Q

What the consequence of the BCR-ABL1 fusion gene that is present in CML cases? How can the effects of this gene fusion be treated?

A
  • The BCR-ABL1 fusion gene produces a chimeric abnormal protein which has enhanced tyrosine kinase activity.
  • Tyrosine Kinase Inhibitors (TKI) are used to treat CML.
  • The drug Imatinib (Glivec, Gleevec, STI571) is designed to fit into the ATP binding site of this chimeric protein.
  • If the binding site is blocked the BCR-ABL1 protein is effectively switched off.
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9
Q

What is Imatinib?

A
  • The BCR-ABL1 fusion gene produces a chimeric abnormal protein which has enhanced tyrosine kinase activity.
  • Tyrosine Kinase Inhibitors (TKI) are used to treat CML.
  • The drug Imatinib (Glivec, Gleevec, STI571) is designed to fit into the ATP binding site of this chimeric protein.
  • If the binding site is blocked the BCR-ABL1 protein is effectively switched off.
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10
Q

What guidelines are available for monitoring the response to treatment in CML?

A
  • There are British Committee for Standards in Haematology (BCSH) guidelines to monitor response, updated in Baccarani (2009), on belhalf of European Leukaemia net (ELN).
  • ACC BPGs.
  • May have local policies.
  • After diagnosis, follow up samples at intervals.
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11
Q

What are the definitions for how CML patients are responding to treatment in cytogenetic terms?

A
  • Definitions of cytogenetic an molecular responses (Baccarani et al 2009).
  • Cytogenetic Response is measured by (CgR) Ph+ve (Philadelphia positive) cell levels.
  • Based on Ph positive metaphase cells in marrow.
  • If someone still has 96-100% Ph+ve levels after Imatinib treatment they are considered to have no cytogenetic response to treatment (noCgR).
  • If someone still has 66-95% Ph+ve levels after Imatinib treatment they are considered to have minimal cytogenetic response to treatment (minCgR).
  • If someone still has 36-65% Ph+ve levels after Imatinib treatment they are considered to have minor cytogenetic response to treatment (mCgR).
  • If someone still has 1-35% Ph+ve levels after Imatinib treatment they are considered to have partial cytogenetic response to treatment (PCgR).
  • If someone still has 0% Ph+ve levels after Imatinib treatment they are considered to have complete cytogenetic response to treatment (CCgR).
  • Once you have achieved a complete cytogenetic response it is recommended that you then detect biomolecular means from then on.
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12
Q

In cytogenetic terms what is considered to be no response to Imatinib treatment for CML?

A
  • If someone still has 96-100% Ph+ve levels after Imatinib treatment they are considered to have no cytogenetic response to treatment (noCgR).
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13
Q

In cytogenetic terms what is considered to be minimal response to Imatinib treatment for CML?

A
  • If someone still has 66-95% Ph+ve levels after Imatinib treatment they are considered to have minimal cytogenetic response to treatment (minCgR).
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14
Q

In cytogenetic terms what is considered to be minor response to Imatinib treatment for CML?

A
  • If someone still has 36-65% Ph+ve levels after Imatinib treatment they are considered to have minor cytogenetic response to treatment (mCgR).
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15
Q

In cytogenetic terms what is considered to be partial response to Imatinib treatment for CML?

A
  • If someone still has 1-35% Ph+ve levels after Imatinib treatment they are considered to have partial cytogenetic response to treatment (PCgR).
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16
Q

In cytogenetic terms what is considered to be complete response to Imatinib treatment for CML?

A
  • If someone still has 0% Ph+ve levels after Imatinib treatment they are considered to have complete cytogenetic response to treatment (CCgR).
17
Q

What are the definitions for how CML patients are responding to treatment in molecular terms?

A
  • Can do molecular testing instead of cytogenetic to see how much BCR-ABL transcription you can detect.
  • Once you have achieved a complete cytogenetic response it is recommended that you then detect biomolecular means from then on.
  • Molecular response is based upon measuring the log reduction (LR) BCR-ABL protein in the marrow.
  • A less than major molecular response is defined as a log reduction less than 3.
  • A major molecular response is defined as a log reduction of more than 3 in 2 consecutive samples.
  • A complete molecular response / molecular remission is BCR-ABL1 negative in 2 consecutive samples of adequate sensitivity (>=4 LR).
18
Q

In molecular terms what is considered to be a less than major molecular response to Imatinib treatment for CML?

A
  • Molecular response is based upon measuring the log reduction (LR) BCR-ABL protein in the marrow.
  • A less than major molecular response is defined as a log reduction less than 3.
19
Q

In molecular terms what is considered to be a major molecular response to Imatinib treatment for CML?

A
  • Molecular response is based upon measuring the log reduction (LR) BCR-ABL protein in the marrow.
  • A major molecular response is defined as a log reduction of more than 3 in 2 consecutive samples.
20
Q

In molecular terms what is considered to be complete

molecular response / molecular remission for CML in response to Imatinib?

A
  • Molecular response is based upon measuring the log reduction (LR) BCR-ABL protein in the marrow.
  • A complete molecular response / molecular remission is BCR-ABL1 negative in 2 consecutive samples of adequate sensitivity (>=4 LR).
21
Q

How do we evaluate the response to treatment for CML?

A
  • Definitions of cytogenetic an molecular responses (Baccarani et al 2009).
  • Cytogenetic Response is measured by (CgR) Ph+ve (Philadelphia positive) cell levels. Based on Ph positive metaphase cells in marrow.
  • Molecular response is based upon measuring the log reduction (LR) BCR-ABL protein in the marrow.
  • There are recommendations for evaluating response to Imatinib by testing at regular time intervals of 3, 6, 12, 18 months.
  • The response is graded as optimal, suboptimal, or failure in defined terms of haematological response, cytogenetic response, and molecular response.
  • There are also definitions of response to 2nd generation TKIs Dasatinib and Nilotinib as second line therapy - also trials of first line therapy.
  • 3rd generation Bosutinib is being evaluated.
22
Q

What treatments are currently available or being evaluated for the treatment of CML?

A
  • Currently used treatment is an TKI called Imatinib.
  • There are also definitions of response to 2nd generation TKIs Dasatinib and Nilotinib as second line therapy - also trials of first line therapy.
  • 3rd generation Bosutinib is being evaluated.
23
Q

Discuss AML.

A
  • AML is Acute Myeloid Leukaemia.
  • Acquired abnormalities at the chromosome level can give you information regarding diagnosis, prognosis, and response to treatment e.g. t(15;17), t(8;21), inv(16) are all diagnostic.
  • Cytogenetic results from previous adult and childhood treatment trials have been used to contribute to the assessment of the prognostic risk.
24
Q

AML can be classified into different risk groups based upon cytogenetic abnormalities present. Outline these.

A
  • Grimwade ‘98 - cytogenetics give quite reliable information with regards to the risk associated and the outcome of the CML.
  • Favourable risk = t(8;21), t(15;17), inv(16).
  • Intermediate risk - normal cytogenetic abnormalities not associated as favourable or adverse.
  • Adverse risk = -5, -7, del(5q), Abn 3q, Complex.
  • Updated in 2010 but only in adults.
  • Child reports in 2010 reported slightly different risk associations than in both adult and children combined.
25
Q

What CML abnormalities are in the favourable risk group?

A
  • Favourable risk = t(8;21), t(15;17), inv(16).
26
Q

What CML abnormalities are in the intermediate risk group?

A
  • Intermediate risk - normal cytogenetic abnormalities not associated as favourable or adverse.
27
Q

What CML abnormalities are in the adverse risk group?

A
  • Adverse risk = -5, -7, del(5q), Abn 3q, Complex.
28
Q

AML can be classified into different risk groups based upon cytogenetic abnormalities present. Outline the abnormalities reported in these risk groups for children only.

A
  • Favourable risk = t(8;21), inv(16).
  • Intermediate risk - 11q23
  • Adverse risk = -7, Abn 5q, t(6;9)
29
Q

Discuss MDS.

A
  • MDS is myelodysplasia..
  • Chromosome abnormalities contribute to the International Prognostic Scoring (IPSS).
  • Good = normal, -Y, del(5q), del(20q).
  • Intermediate = other abnormalities.
  • Poor = complex (>3 abnormalities) or chromosome 7 anomalies.
30
Q

What cytogenetic abnormalities are associated with a good prognosis in MDS?

A
  • Good = normal, -Y, del(5q), del(20q).
31
Q

What cytogenetic abnormalities are associated with an intermediate prognosis in MDS?

A
  • Intermediate = other abnormalities.
32
Q

What cytogenetic abnormalities are associated with a poor prognosis in MDS?

A
  • Poor = complex (>3 abnormalities) or chromosome 7 anomalies.
33
Q

What are the 3 main myeloid malignancies?

A
  • CML = Chronic Myeloid Leukaemia
  • AML = Acute Myeloid Leukaemia
  • MDS = Myelodysplasia

Cancer Genetics (21 decks)

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