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Mol Path FRCPath Part 1 - 2022 > Haematological Malignancies > Flashcards

Haematological Malignancies Flashcards

1
Q

What is the required blast count for a diagnosis of AML (without genetic information)

A

20% myeloid blasts in the bone marrow

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2
Q

Whats rearrangements are diagnostic of AML regardless of the blast count?

A

t(8;21)(q22;q22) - RUNX1-RUNX1T1
inv(16)(p13;q22) / t(16;16)(p13.1;q22) - CBFB-MYH11
t(15;17)(q24;q21) - PML-RARA

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3
Q

What genes should be tested molecularly for all AML cases?

A

NPM1, FLT3 and CEBPA in cases with normal/intermediate risk cytogenetics

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4
Q

What gene should be tested for in core finding factor AML?

A

KIT

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5
Q

What genetic changes are associated with a favourable prognosis in AML?

A

t(8;21)(q22;q22.1) - RUNX1-RUNX1T1
inv(16)(p13;q22) / t(16;16)(p13;q22) - CBFB-MYH111
Muatetd NPM1 without FLT3-ITD or FLT3-ITD(low)
Biallelic mutated CEBPA

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6
Q

What genetic changes are associated with an intermediate prognosis in AML?

A

Mutated NPM1 with FLT3-ITD(high)
WT NPM1 without FLT3-ITD or FLT3-ITD(low)
t(9;11)(p21.3;q23.3) MLLT3-KMT2A
Cytogenetic abnormalites not classified as favourable/adverse

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7
Q

What genetic changes are associated with an adverse prognosis in AML?

A 
t(6;9)(p23;q34.2) - DEK-NUP214
t(v11q23.3)KMT2A rearranged
t(9;22)(q34.1;q11.2) - BCR-ABL1
inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2) - GATA2-MECOM (EVI1)
-5 or del(5q)
-7 
-17 or abnormal 17p
Complex or monosomal karyotype
WT NPM1 and FLT3-ITD(high)
Mutated RUNX1
Mutated ASXL1
Mutated TP53
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8
Q

What rearrangement is diagnostic for CML?

A

t(9;22)(q34.1;q11.2) - BCR-ABL1

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9
Q

What are the three phases of CML?

A

Chronic, Accelerated, Blast

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10
Q

What method is typically used to detect the BCR-ABL1 rearrangement in CML?

A

Qualitative Reverse Transcriptase (RT) PCR (Diagnosis)

Quantitative Reverse Transcriptase (RT) PCR (MRD)

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11
Q

What could cause a false negative when using routine BCR-ABL1 fusion analysis in CML?

A

Atypical breakpoint fusions occur in around 2-4% of CML patients

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12
Q

What type of treatment is used to target the BCR-ABL1 fusion in CML?

A

Tyrosine Kinase Inhibitors (TKIs) - imatiib, dasatinib and nilotinib

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13
Q

How is molecular response assessed in CML?

A

Assessed according to the international scale (IS) as the ratio of BCR-ABL1 transcripts to ABL1 transcripts or an accepted control transcript such as GUSB. Must be reported as BCR-ABL1 % on a log scale

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14
Q

What are the molecular response groups and corresponding % of transcripts in BCR-ABL1 monitoring in CML?

A

Cytogenetic Remission - BCR-ABL1 <1%
Major Molecular Response (MMR) / MR3 - BCR-ABL1 < 0.1%
MR4 - BCR-ABL1 <0.01% or udetectable with >10,000 ABL1 transcripts
MR - BCR-ABL1 <0.0032% or undetectable with >32,000 ABL1 transcripts

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15
Q

25% of CML patients will experience TKI resistance. What mechanisms can cause resistance?

A

Mutations in the kinase domain of BCR-ABL1

Reactivation of signalling pathways downstream of BCR-ABL1 (including MAPK, PI3K, SRC and JAK/STAT)

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16
Q

What call type needs to be >20% in the bone marrow/blood for a diagnosis of ALL

A

Lymphoblasts

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17
Q

What genetic changes are associated with a favourable prognosis in B-ALL?

A 
High hyperdiploidy (>50 chromosomes)
t(12;21)(p12;q22) - ETV6-RUNX1
t(5;14)(q31.1;q32.3) - IL3-IGH 
DUX4 rearranged 
NUTM1 rearrangements
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18
Q

What genetic changes are associated with an adverse prognosis in B-ALL?

A

t(9;22)(q34;q11) - BCR-ABL1 (Improved with TKI treatment)
Near haploid ALL (24-30) chromosomes
Low haploid ALL (31-39) chromosomes
KMT2A rearrangements
t(1;19) - TCF3-PBX1 fusion (improved with modern chemo)
TCF3-HLF - Extremely poor
Philadelphia like ALL (Expression profile similar to BCR-ABL1, CRLF2 rearrangement, ABL 1 class rearrangements, ETV6-NTRK, EPOR, IL7)
iAMP21 (>=5 copies of RUNX1)
IKZF1 rearrangements

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19
Q

What are the genetic alterations frequently associated with T-ALL?

A

NOTCH1 mutations (60% of cases)
FBXW7 (8-30%) - Presence of NOTCH1 and FBXW7 associated with a good prognosis
CDKN2A/B (50-80%)
JAK1 - (10-20% adults, rare in children) - Poor prognosis
PTEN (25-35%)
RAS (5-10%)
WT1 (10%)

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20
Q

What molecular tests can be used for ALL?

A
  • Reverse Transcriptase PCT (RT-PCR_ to identify common fusions, also identifies exact breakpoints for monitoring
  • q-PCR/flow cytometry for clonality testing for IGH and TCR rearrangements - can be used for monitoring
  • MLPA / SNP Array for detection of critical new targets in B-ALL
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21
Q

What are the poor prognosis markers in CLL?

A

Umutated IGHV region (>98% germline homology))
Del(11q23) / ATM deletion
Del(17p13) / TP53 deletion / TP53 mutation
IGH rearrangements (14q32)
Mutated NOTCH1
Mutated SF3B1

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22
Q

What are the good/intermediate prognosis markers in CLL?

A

Isolated del(13q14) - Good
Trisomy 12 - Intermediate
Mutated MYD88 - Good

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23
Q

What is the most commonly identified marker in Follicular Lymphoma?

A

t(14;18) - BCL2/IGH fusion (90% of cases)

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24
Q

What is del(1p36) associated with when seen in follicular lymphoma?

A

FL with a diffuse pattern, lack of t(14;18) and a good prognosis

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25
Q

What are IRF4-MUM1 rearrangements associated with?

A

Large B cell lymphoma - poor prognosis & aggressive disease

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26
Q

What variant can be useful to distinguish Waldenström macroglobulinemia from other B-cell malignancies with overlapping phenotypes?

A

MYD88 L265P - Seen in ~90% of WM cases

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27
Q

What are the most common rearrangements in mucosa associated lymphoid tissues (MALT) lymphoma and associated clinical significance?

A

t(11;18) - API2-MALT1 frequently seen in gastric &pulmonary MALT lymphomas - locally advanced disease and resistance to antibiotic treatments

t(1;14) - Overexpression of BCL10 frequently seen in MALT of skin, lung and stomach - locally advanced disease and resistance to antibiotic treatments

t(14;18) - deregulation of MALT frequently seen in liver, skin, ocular and salivary gland MALT - unknown significance

t(3;4) - upregulation of FOXP1 frequently seen in thyroid, ocular and skin - unknown significance

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28
Q

What rearrangement is mantle cell lymphoma associated with?

A

t(11;14) - IGH/CCND1

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29
Q

What can be tested for if the t(11;14) - IGH/CCND1 rearrangement is not present in a suspected mantle cell lymphoma?

A

CCND2 & CCND3 may be overexpressed

SOX11 overexpression is seen in nearly all cases of MCL regardless of CCND1 expression

30
Q

Mutations in what gene are associated with a very poor prognosis in mantle cell lymphoma?

A

TP53

31
Q

What is the marker of high grade B-cell lymphoma?

A

Double/Triple hit of MYC and BCL2 and/or BCL6 rearrangements - poor prognosis

32
Q

What rearrangement is typically seen in Burkitt Lymphoma ?

A

MYC gene rearrangement
t(8;14) - 80% of cases
t(2;8) or t(8;22) in the remaining 20%

33
Q

What marker is associated with Burkitt-like lymphoma

A

11q deletion

34
Q

What non genetic markers are used in the diagnosis of Multiple Myeloma?

A

Monoclonal protein quantification

Bone marrow eval - >=10% bone marrow plasma cells

35
Q

What genetic alterations are considered high risk in Multiple Myeloma?

A

TP53 mutations
IGH rearrangements
del(13q) on metaphase

36
Q

Outline the clonal development of multiple myeloma

A 
Normal Cells 
->
Primary Abnormalities - IGH rearrangements and/or Trisomy (hyperdipolid) establish clone
->
MGUS 
->
Secondary Abnormalities - del(17p/TP53), 1qamp, t(4;14) - All high risk of progression
->
Myeloma 
->
Secondary Abnormalities - del(17p/TP53), del(1p), MYC rearrangements - All high risk of progression
->
Plasma Cell Leukaemia
37
Q

What are the six entities of myelodysplatic syndromes (MDS)?

A
  • MDS with single lineage dysplastia (MDS-SLD)
  • MDS with ring sideroblasts (MDS-RS)
  • MDS with multilineage dysplasia (MDS-MLD)
  • MDS with excess blasts (MDS-EB)
  • MDS with isolated del(5q) +/- one other abnormality apart from -7/del(7q)
  • MDS unclassifiable (MDS-U)
38
Q

Mutations in which gene are considered diagnostic of MDS-RS and under what conditions?

A

SRSF2

- lacks excess blasts or isolated del(5q)

39
Q

What is the prognostic impact of del(5q) in MDS?

A

Good prognosis (if seen isolated or one other abnormality which is not -7/del(7q))

40
Q

What is the prognostic impact of -7/del(7q)in MDS?

A

Poor prognosis

41
Q

What are the subtypes of Myelodysplastic/Myeloproliferative (MDS/MPN) neoplasms?

A
  • Chronic myelomonocytic leukaemia (CMML)
  • Atypical chronic myeloid leukaemia (aCML)
  • BCR-ABL1 negative
  • Juvenile myelomonocytic leukaemia (JMML)
  • MDS/MPN with ring sideroblasts and thrombocytosis
  • MDS/MPN unclassifiable (MDS/MPN-U)
42
Q

Mutations in which genes are frequently identified in CMML?

A

TET2, SRSF2, ASXL1, RUNX1, NRAS and CBL

43
Q

What is aCML phenotypically similar to and what molecular markers can be used to help distinguish between them?

A

aCML is phenotypically similar to the chronic neutrophilic leukaemia (CNL) of MPN.

  • Copy number neutral loss of heterozygosity is found in 6-41% of MDS/MPN
  • CSF3R mutations are strongly associated with CNL but is also present in <10% of aCML.
44
Q

Mutations in which genes are seen frequently in JMML?

A

PTPN11 (40-50%), NRAS (15-20%), KRAS (10-15%), CBL(15-18%) and NF1 (10-15%)

45
Q

How does the occurrence of an SRSF2 variant impact diagnosis in MDS/MPN-RT-T

A

Up tp 60% of MDS/MPN-RT-T cases have an SRSF2 variant. Unlike when identified in MDS, the occurrence of a SRSF2 variant does not change the required number of ring sideroblasts for diagnosis

46
Q

In MDS, mutations in which genes are associated with a poor prognosis (Tier I)

A 
TP53 (also associated with complex karyotypes)
RUNX1
NRAS
EZH2
ETV6
ASXL1
47
Q

What Tier II level genes have been associated with a poor prognosis in MDS?

A 
DNMT3A
U2AF1
SRSF2
CBL
PRPF8
SETBP1
KRAS
48
Q

Mutations in which gene(s) are associated with a favorable prognosis in MDS?

A

SRSF2

49
Q

What are the three subtypes of MPN?

A 
Myelofibrosis (MF)
Polycythemia Vera (PV)
Essential Thrombocythemia (ET)
50
Q

What of the MPN subtypes has the worst prognosis?

A

Myelofibrosis (MF)

51
Q

What is the frequency of the JAK2 V617F variant in the MPN subtypes?

A

JAK2 V617F variants are identified in the majority of patients with PV (>90%) and in 60% of patients with MF or ET

52
Q

What is the frequency of the MPL W515L/K variant in the MPN subtypes?

A

5-8% of patients with MF

1-4% of patients with ET

53
Q

What is the frequency of theCALR exon 9 variant in the MPN subtypes and which types are more frequent in these?

A

20-25% of patients with ET and MF (accounts for 60-80% of JAK2 - patients)

Type 1 variants (52bp deletions) are more frequent in MF and Type 2 variants (5bp insertions) are more frequent in ET.

54
Q

Mutations in which genes are associated with a poor prognosis in PV?

A

ASXL1, SRSF2, IDH1/2, RUNX1

55
Q

JAK2 exon 12 mutations in PV are associated with what clinical features compare to JAK2 V617F?

A

Young age, increased mean haemoglobin, lower white blood cell and platelet counts.

Both have a similar rate of thrombocytosis.

56
Q

Mutations in which genes are associated with a poor prognosis in ET?

A

TP53, SH2B3, IDH2, U2AF1, SRSF2, SF3B1, EZH2, RUNX1

57
Q

What is the significance of a CALR variant in ET?

A

Low risk of thromocytosis compared to JAK2 mutated ET

No difference in OS or transformation compared to JAK2 mutated

58
Q

Mutations in which genes have clinical significance in in PMF and what is the significance?

A

IDH1/2, SRSF2, TP53, U2AF1 Q157 (Inferior OS compared to U1AF1 S34 or unmutated), U2AF1, DNMT3A and CBL - Poor prognosis (Inferior OS/Inferior risk of leukaemic transformation)

Combined CALR and ASXL1
Longest OS - CALR(+)/ASXL1(-)
Intermediate OS - CALR(+)/ASXL1(+)
Shortest Survival CALR(-)/ASXL1(+)

59
Q

What diagnostic testing should be carried out for MPNs?

A

PMF and ET - JAK2, CALR, MPL

PV - JAK2 V167F and JAK2 exon 12

60
Q

What gene rearrangements are associated with B-cell and T-cell clonality

A

B-cell - IGH

Tcell - TCR

61
Q

What is the demographic of AML and what is incidence linked to?

A

AML can occur at any age but is more prevalent later in life with the incidence increasing in correlation with age.

62
Q

By what mechanisms can AML occur?

A

AML can arise de novo or can be secondary to underlying myeloproliferative neoplasms or myelodysplastic syndromes.

63
Q

Diagnosis and classification requires a multidisciplinary diagnostic approach . What forms of testing are required?

A

Cytomorphology
Immunophenotyping
Cytogenetics
molecular Genetics

64
Q

What are the 11 AML subtypes as classified by WHO

A
  • AML with t(8;21)(q22;q22.1) RUNX1-RUNX1T1
  • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22) CBFB-MYH11
  • Acute promyelocytic leukaemia with t(15;17) (q24;q21) PML-RARA
  • AML with t(9;11)(p21.3;q23.3) KMT2A-MLLT3
  • AML with t(6;9)(p23;q34.1) DEK-NUP214
  • AML with inv(3)(q21.3;q26.2) or t(3;3;)(q21.3;q26.2) GATA2, MECOM
  • AML (megakaryoblastic) with t(1;2)(p13..3;q13.1) RBM15-MKL1
  • Provision entity - AML with BCR-ABL1 t(9;22)(q34;q11)
  • Provision Entity - AML with mutated NPM1
  • Provision entity - AML with biallelic CEBPA
  • Provisional entity - AML with mutated RUNX1
65
Q

What are the genetic abnormalities which can be used to diagnosis AML regardless of blast count?

A

t(8;21)(q22;q22.1) - RUNX1-RUNX1T1
inv(16)(q13.1;q22) - CBFB-MYH11
t(15;17)(q24;q21) - PML-RARA

66
Q

What is required for a classification of AML with myelodysplastic changes?

A

A diagnosis can be made if the AML exhibits MDS like features and includes

i) history of MDS or MDS/MPN
ii) MDS related cytogenetic abnormalities
iii) multilineage dysplasia

67
Q

According to the European LeukaemiaNet AML guidance, which genetic abnormalities are associated with a favourable prognosis?

A

t(8;21)(q22.1;q22) - RUNX1-RUNX1T1
inv(16)(q13;q22) or t(16;16)(q13;q22) CBFB-MYH11
NPM1 mutated with no FLT3-ITD or FLT3-ITD (low)
Biallelic mutated CEBPA

68
Q

According to the European LeukaemiaNet guidance, what genetic abnormalities are associated with an intermediate prognosis?

A

Mutated NPM1 with FLT3-ITD high
Wild type NPM1 without FLT3-ITD or with FLT3-ITD(low) (no other adverse genetic changes)
t(9;11)(q21.3;q23.3) - MLLT3-KMT2A
Cytogenetic abnormalities not classified as favourable or adverse

69
Q

According to the Europen LeukaemiaNet guidance, which genetic abnormalities in AML are associated with a poor prognosis?

A 
inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2) GATA2, MECOM
t(6;9)(q23;q34.1) DEK-NUP214
t(v;11q23.3) KMT2A rearranged
t(9;22)(q34.1;q11.2) BCR-ABL1
-5 or del(5q)
-7
-17/abn(17p) (TP53)
70
Q

What targeted treatment is available for AML and with which genetic aberration is it associated?

A

Midostaurin is recommended by NICE for the treatment of newly diagnosed FLT3-mutation positive AML. Midostaurin is a multi target kinase inhibitor

71
Q

What are the recommended genetic biomarkers which can be used for MRD analysis in AML?

A

RUNX1-RUNX1T1
PML-RARA (APL)
CBFB-MYH11

72
Q

What type of inherited disorder is associated with MDS and what genes are typically involved?

A

Bone marrow failure syndromes

Genes - RUNX1, ANKRD26, DDX41, ETV6, GATA2 and SRP7

Mol Path FRCPath Part 1 - 2022 (14 decks)

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