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Mol Path Part 1 2022 > Haem > Flashcards

Haem Flashcards

1
Q

What is the typical demographic of patients with CLL and incidence?

A

• CLL is predominantly identified in older patients with a median diagnosis of 74
• Chronic lymphocytic leukaemia (CLL) is the most common leukaemia with 4.9/100,000 incidence in the UK and USA.

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2
Q

What tests are indicated in the initial diagnosis of a ?CLL case

A

o High number of lymphocytes in peripheral blood
o Clonality demonstrated by flow cytometry
o Genetic testing using FISH, karyotype or NGS for chromosomal abnormalities, NGS panel recommended for molecular abnormalities
o Karyotype required to rule out lymphomas.

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3
Q

What are the actionable chromosomal abnormalities in CLL and what is the associated prognosis?

A

o Deletions of 13q14.3 (RB1 & DLEU2/7) is the most common chromosomal alteration and is associated with a good prognosis in the absence of other genetic markers.
o Deletions of 17p (TP53) and TP53 mutations are associated with a poor prognosis and resistance to DNA damaging agents (chemo and immune therapy)
o Deletions of 11q (ATM) is associated with a poot prognosis
o Trisomy 12 is associated with an intermediate prognosis
o Complex karyotype is associated with a poor prognosis

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4
Q

Variants in what genes are linked with resistance to ibrutinab and venetoclax in CLL?

A

o Mutations in BTK and PLCG2 are acquired resistance mutations to BTK inhibitor therapy
o Mutations in BCL2 are acquired resistance mutations to venetoclax monotherapy

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5
Q

What is the initial treatment of CLL and when is further actions indicated?

A

Initially the majority of patients are monitored with a ‘watch and wait’ approach and treatment initiated with onset of symptoms or disease progression.

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6
Q

What are the significance of IGHV mutation status in CLL?

A

o Ig gene (heavy and light) rearrangements can be used to categorise patients into two groups IGHV mutated and IGHV unmutated. IGHV unmutated is associated with a poor prognosis

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7
Q

What are the genetic abnormalities associated with therapeutic targets in CLL and with which drugs are they linked?

A

o Treatment dependant on genetic changes detected alongside any co-morbidities.
o Ibrutinib (BTK inhibitor) inhibits the BTK kinase domain and is used in patient with TP53/del(17p) changes which cause resistance to chemo or immune therapy.
o Venetoclax monotherapy is used in refectory disease patients who have stopped responding to ibrutinib or in patients with TP53/del(17p) who are not suitable for treatment with ibrutinib.

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8
Q

What technique is used to monitor CLL?

A

o Carried out using flow cytometry

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9
Q

What are the three phases of CML and associated blast count?

A

• There are three phases: chronic phase (blast <10%), accelerated phase (blasts10-19%) and blast crisis (blasts >20%).

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10
Q

What are the clinical features CML patients may present with?

A

• 50% of patients present with no symptoms but symptoms can include splenomegaly, weight loss, fatigue and night sweats.

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11
Q

What high level group of disorders is CML part of?

A

• Chronic myeloid leukaemia is a clonal myeloproliferative disorder and belongs to the group of myeloprolifertive neoplasms (MPN)

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12
Q

What is the typical demographic for CML cases?

A

• CML incidence is linked with age, with the highest incidence being in older people with almost a quarter being 75 yrs and older.

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13
Q

What is the hallmark genetic alteration in CML?

A

• The hallmark genetic change of CML is the reciprocal translocation t(9;22)(q34;q11.2) which cause the fusion of the BCR and ABL1 genes (BCR-ABL1)

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14
Q

What are the three main BCR-ABL1 alterations and associated transcript names found in CML?

A
  • BCR Exon 13 – ABL1 exon 2 e13a2 (b2a2) (Major)
  • BCR Exon 14 – ABL1 exon 2 e14a2 (b3a2) (Major)
  • BCR Exon 1 – ABL exon 2 e1a2 (Minor)
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15
Q

What are the first line and second line tyrosine kinase inhibitors used in the treatment of BCR-ABL1 positive CML patients?

A

• Imatinib was the first TKI to be approved for treatment of CML and is typically still first line
• Dasatinib and Nilotinib are second generation TKI’s which initiate a stronger initial response by have overall comparable outcomes to Imatinib.

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16
Q

How is residual disease monitored in CML and the associated response levels?

A

Response to treatment is monitored through analysis of the levels of the BCR-ABL1 transcript

Major molecular response (MMR or MR3) corresponds to <0.1% BCR-ABL1 on the IS,
MR4 is <0.01% BCR-ABL1 or undetectable with >10,000 ABL1 transcripts,
MR 4.5 is <0.0032% or undetectable with >32,000 ABL1 transcripts

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17
Q

Why can TKI treatment fail in CML?

A

Treatment can fail for a number of reasons including patients not complying with therapy (most common), acquired resistance mutations in the tyrosine kinase domain of BCR-ABL1 and pharmacokinetic interactions such as accelerated TKI metabolism.

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18
Q

What is the most common resistance mutation in TKI treated CML patients and what are the treatment implications?

A

The most common resistance variant is the ABL1 T315I mutation. This mutation cannot be treated with imatinib, dasatinib or nilotinib. There is only one TKI which can currently treat these patients; ponatinib

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19
Q

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

A

Mutated NPM1 *
RUNX1-RUNX1T1 *
PML-RARA (APL)
CBFB-MYH11 *
KMT2A-MLLT3

*Most robust markers

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20
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

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21
Q

According to the Europen LeukaemiaNet guidance (2022), which genetic abnormalities in AML are associated with a poor prognosis?

A

t(6;9)(q23;q34.1) DEK-NUP214
t(v;11q23.3) KMT2A rearranged
t(9;22)(q34.1;q11.2) BCR-ABL1
t(8;16)(p11;p13) KAT6A-CREBBP
inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2) GATA2, MECOM
t(3126.2;v) MECOM rearranged
-5 or del(5q)
-7
-17/abn(17p) (TP53)
- Complex or monosomal karyotype
- Mutated ASXL1, BCOR, EZH2, RUNX2, SF3B1, SRSF2, STAG2, U2AF1 or ZRSR2
- Mutated TP53 (at least 10% VAF)

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22
Q

According to the European LeukaemiaNet (2022) guidance, what genetic abnormalities are associated with an intermediate prognosis in AML?

A

Mutated NPM1 with FLT3-ITD
Wild type NPM1 with FLT3-ITD
t(9;11)(q21.3;q23.3) - MLLT3-KMT2A
Cytogenetic abnormalities not classified as favourable or adverse

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23
Q

According to the European LeukaemiaNet AML guidance (2022), 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
Biallelic mutated CEBPA or bZIP in-frame mutated CEBPA

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24
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
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25
Q

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

A

Cytomorphology
Immunophenotyping
Cytogenetics
molecular Genetics

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26
Q

By what mechanisms can AML occur?

A

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

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27
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.

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28
Q

What cell types can be involved in Non-Hodgkin Lymphomas?

A

B-lymphocytes, T-lymphocytes and Natural Killer cells (rare)

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29
Q

What are some symptoms of Non-Hodgkin Lymphomas?

A

Fever, night sweats, unintentional weight loss, swelling in lymph nodes, fatigue, loss of appetite.

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30
Q

What proportion of Non-HodgkinLymphoma does Diffuse B-cell lymphoma account for and what is the prognosis?

A

Diffuse B cell lymphoma accounts for 30-40% of Non-Hodgkin lymphoma cases and has an aggressive phenotype

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31
Q

What proportion of Diffuse large B-cell lymphoma have an MYC rearrangement?

A

10-15%

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32
Q

What is required for a diagnosis of High grade B-cell lyphoma?

A

Patients will have an MYC rearrangement with a BCL2 rearrangement and/or BCL6 rearrangement

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33
Q

What are the most common MYC rearrangements seen in Diffuse large B-cell lymphoma and Burkitts lymphoma?

A

t(8;14)(q34;q32) IGH-MYC rearrangement in 80% of cases
t(8;22)(q24;q11) IGK-MYC and t(2;8)(p12;q24) IGL-MYC account for other 20%

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34
Q

What proportion of Diffuse large B-cell lymphoma is high grade and what is the prognosis?

A

8-10%, more aggressive disease and worse prognosis after treatment with R-CHOP.

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35
Q

Follicular lymphoma accounts for what proportion of Non-Hidgkin lymphoma and what is the prognosis?

A

22% and is indolent

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36
Q

What rearrangement is identified in 90% of follicular lymphomas?

A

t(14;18)(q32;q21) IGH-BCL2

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37
Q

What characterises follicular lymphoma with a diffuse pattern?

A

Deletion of 1p36 and a lack of t(14;18)(q32;q21)

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38
Q

What rearrangement is seen most frequently in mantle cell lymphoma?

A

t(11;14)(q13;q32) IGH-CCND1

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39
Q

What proportion of Non-Hodgkin lymphoma cases are mantle cell and what is the prognosis

A

2%, aggressive disease

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40
Q

In which gene are mutations associated with a poor prognosis in mantle cell lymphoma found?

A

TP53 - particularly aggressive clinical course required upfront, associated with a poor prognosis when treated with conventional therapy

41
Q

What is the aetiology of Marginal Zone/MALT lymphoma?

A

Association with chronic inflammation due to infection and inflammation

42
Q

What are the typical rearrangements seen in MALT lymphoma and can also be seen in Waldenstroms macroglobulinemia

A

t(11;18)(q21;q21) BIRC3-MALT1, t(1;14)(q22;q32) IGH-BCL10 and t(14;18)(q32;q31) IGH-MALT are the most common genetic aberrations implicated in the pathogenesis of MALT lymphomas. The presence of the t(11;18)(q21;q21) BIRC3-MALT1 rearrangement is associated with locally advanced disease. t(3;14)(p14.1;q32) IGH-FOXP1 results in the upregulation of the FOXP1 gene and is associated with the MALT lymphomas of thyroid, ocular adnexa and skin

43
Q

What is key to. diagnosis of Waldenstrom macroglobulinemia?

A

Demonstration of bone marrow infiltration

44
Q

What genomic change is seen in 90% of Waldenstrom marcoblobulinemia and can be used to rule out marginal zone/MALT lymphoma?

A

MYD88 L265P

45
Q

Ibrutinib, a BCL2 inhibitor can be used to treat which lymphoma and why?

A

Ibrutinib can be used to treat Waldenstrom macroglobulinemia MYD88 mutations confer sensitivity to Ibrutinib (BCL2 inhibitor) as BCL2 functions downstream of MYD88.

46
Q

Mutations in what gene cause resistance to Ibrutinib for the treatment of Waldenstroms marcoglobulinemia?

A

CXCR4

47
Q

According to the ELN (2022) guidelines for AML, what are the genetic abnormalities which can be used for a diagnosis of AML with >10% blasts in the BM or PB?

A

• APL with t(15;17)(q24.1;q21.2)/PML::RARAb
• AML with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1
• AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11
• AML with t(9;11)(p21.3;q23.3)/MLLT3::KMT2A
• AML with t(6;9)(p22.3;q34.1)/DEK::NUP214
• AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM(EVI1)
• AML with other rare recurring translocations
• AML with mutated NPM1
• AML with in-frame bZIP mutated CEBPA
• AML with t(9;22)(q34.1;q11.2)/BCR::ABL1

48
Q

According to the ELN (2022) guidelines for AML, what are the genetic abnormalities which can be used for a diagnosis of AML with >20% or a diagnosis of MDS/AML with 10-19% blasts in the BM or PB?

A

• AML with mutated TP53
• AML with myelodysplasia-related gene mutations
Defined by mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2
• AML with myelodysplasia-related cytogenetic abnormalities
• AML not otherwise specified (NOS)

49
Q

In AML molecular genetic changes in what genes are consistent with MDS-related AML?

A

ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2

50
Q

In AML what cytogenetics changes are consistent with MDS-related AML?

A

Cytogenetic abnormalities sufficient for the diagnosis of AML with MDS-related cytogenetic abnormalities and the absence of other AML-defining disease categories.
o Complex karyotype: ≥3 unrelated chromosome abnormalities in the absence of other class-defining
recurring genetic abnormalities; excludes hyperdiploid karyotypes with three or more trisomies (or
polysomies) without structural abnormalities.
o Unbalanced clonal abnormalities: del(5q)/t(5q)/add(5q); -7/del(7q); +8; del(12p)/t(12p)/(add(12p); i(17q), -
17/add(17p) or del(17p); del(20q); and/or idic(X)(q13)

51
Q

What are the different stagees of myeloma progression?

A

1) MGUS - Monoclonal gammopathy of undetermined significance
2) SMM - Smouldering Multiple Myeloma
3) MM - Multiple Myeloma
4 ) PCL = Plasma cell leukaemia

52
Q

What are the primary genetic abnormalities in multiple myeloma?

A

Trisomy of odd number chromosomes, apart from chromosomes 1, 12 and 21
IGH gene rearrangements

53
Q

What are the secondary genetic abnormalities in multiple myeloma?

A

del(17p) (TP35)
Monosomy chromosome 17
1q gain
1p loss
del(13q)
Monosomy chromosome 13
MYC rearrangements

54
Q

What are the poor prognostic markers in multiple myeloma?

A

del(17p) (Tp53)
Monosomy chromosome 17
IGH-FGFR3 t(4;14)(p13;q32)
IGH-MAF t(14;16)(q32;q23)
IGH-MAFB t(14;20)(q32;q11)
1q gain
1p32 loss (CDKN2C) - intensive treatment

55
Q

What is the most common IGH rearrangement identified in multiple myeloma and the associated prognosis?

A

IGH-CCND1 t(11;14)(q13;q32) - Intermediate

56
Q

What are the clinical features of B-ALL and T-ALL?

A

B-ALL
Bone marrow is involved in all cases alongside peripheral blood and extramedullary involvement (CNS, lymph nodes, spleen, liver and testes). Clinical features include bone marrow failure, lymphadenopathy, hepatomegaly and splenomegaly. Presence in CNS at diagnosis is considered an adverse risk factor.

T-ALL
Extensive marrow and peripheral blood involvement (>25% marrow blasts). Clinical features include large mediastinal/other tissue mass and lymphadenopathy and hepatosplenomegaly common.

57
Q

What types of abnormalities are usually primary changes in ALL?

A

Chromosomal - Translocation or Aneuploidy

58
Q

What genetic changes are associated with good outcomes in B-ALL?

A

• t(12;21)(p13;q22) ETV6-RUNX1 (cryptic so FISH or RT-PCR required)
• High hyperdipolidy (51-65 chromosomes) – Can be seen cytogenetically but locus specific and centromeric FISH probes best as chromosomal gain is non-random – moving towards SNP array

59
Q

What genetic changes are associated with a high risk in B-ALL?

A

Genetic changes associated with high risk
• KMT2A translocations (11q23)
• BCR-ABL1 (also a marker for treatment with TKI – imatinib or dasatinib)
• ABL-class fusions (ABL1, ABL2, PDGFRA, PDGFRB, CSF1R, CRLF2, JAK2 and EPOR)
• t(17;19)(q22;q13) TCF-HLF (very rare)
• Near haploidy (<30 chromosomes) and low hypodiploidy (30-39 chromosomes) – Associated with TP53 and RAS mutations (note possible TP53 germline)
• Complex karyotype (5 or more abnormalities)
• iAMP21 – three or more extra copies of RUNX1 gene on a single abnormal chromosome 21 – i.e. more than 5 signals per cell – high risk of relapse with standard treatment – better with intense therapy)

60
Q

What genetic changes are associated with an intermediate risk in B-ALL?

A

• t(1;19)(q23;p13) TCF-PBX1 fusion (however, presence at relapse is poor prognosis)

61
Q

What are the typical secondary genetic alterations in B-ALL?

A

• Microdeletions in key cellular pathways such as those involved in differentiation and proliferation.
• Copy number alteration profiles – applicable to intermediate cytogenetic groups – separated into two subgroups (good vs intermediate based on 8 most commonly affected genes – EBF1, IKZF1, PAX5, CDKN2A, CDKN2B, ETV6, BTG, RB1 and PAR1)

62
Q

What is required for a diagnosis of MDS?

A

Diagnosis is made on a consistent history of cytopenia, exclusion of other potential disorders and one of three MDS-related criteria:
• Dysplasia (>= 10% in one or more of the three major bone marrow lineages)
• A blast cell count of 5-19%
• A specific MDS associated karyotype
Co-criteria may help confirm a diagnosis and can include an aberrant immunophenotype by flow cytometry, abnormal bone marrow histology and immunohistochemistry or the presence of molecular markers.

63
Q

How are patients with MDS treated?

A

Treatment depends on the type of MDS and risk group. For low risk patients, supportive treatment is indicated which involves blood transfusions to replace cells, growth factors to encourage the bone marrow to make more blood cells and antibiotics may be required to fight infections. For intermediate or high risk MDS, treatment may take the form of chemotherapy or stem cell transplantation. The only way to cure MDS is through stem cell transplantation but this type of treatment is not suitable for everyone.

64
Q

What are the main cytogenetic abnormalities identified in MDS and their clinical significance?

A

The main cytogenetic abnormalities are:
• Del(5q) – Good prognosis and response to lenaldomide
• -7/del(7q) – Poor prognosis, more common in therapy related MDS
• Trisomy 8 – Can predict response to immune suppression, some evidence may be a marker of progression to AML, intermediate prognosis
• Del(20q) – Better prognosis
• Complex karyotype (3 or more abnormalities) – Poor prognosis, associated with TP53 mutation

65
Q

Mutations in which gene are strongly associated with MDS with ring sideroblasts?

A

SF3B1

66
Q

Mutations in what genes are independently associated with a poor prognosis in MDS?

A

TP53, RUNX1, ASXL1, ETV6 and EZH2

67
Q

What are the three subtypes of MPN?

A

Myelofibrosis (MF)
Polycythemia Vera (PV)
Essential Thrombocythemia (ET)

68
Q

What of the MPN subtypes has the worst prognosis?

A

Myelofibrosis (MF)

69
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

70
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

71
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.

72
Q

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

A

ASXL1, SRSF2, IDH1/2, RUNX1

73
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.

74
Q

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

A

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

75
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

76
Q

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

A

• JAK V617F – Intermediate prognosis
• MPL W5151 – Intermediate prognosis
• CALR – Good prognosis, type 1 (52bp deletion) better compared to type 2 (5bp insertion)
• Triple Negative – Poor prognosis
• ASXL1, EZH1, RAS, IDH1/2. SRSF2, TP53, U2AF1 –poor prognosis
• CALR (+) / ASXL1 (+) - Intermediate

77
Q

What diagnostic testing should be carried out for MPNs?

A

PMF and ET - JAK2, CALR, MPL
PV - JAK2 V167F and JAK2 exon 12

78
Q

What treatment can be used for the treatment of JAK2 +ve MPNs?

A

Ruxolitinib JAKinhibitors

79
Q

Fusions of what genes are associated with Myeloid/Lymphoid Neoplasms with Eosinophilia?

A

Tyrosine Kinase Genes
- PDGFRA, PDGFRB, FLT3, FGFR1, JAK2 and ABL1

80
Q

What gene fusion is associated with Chronic eosinophilic leukaemia, how does it occur and how is it tested?

A

FIP1L1-PDGFRA rearrangement

The rearrangement is a result of a 800kb submicroscopic deletion in chromosome 4q12 of the CHIC2 gene. Karyotype does not detect this and a diagnosis can be made by FISH, RT-PCR or NGS. The breakpoint in PDGFRA occurs exclusively in exon 12 but the breakpoints in FIP1L1 are variable. Fusion can be difficult to detect and so multiple approach testing is recommended if there is a strong clinical suspicion. FISH probes targed the CHIC2 gene deletion.

81
Q

What targeted treatment can be used for myeloid/lymphoid neoplasms with eosinophilia and under what circumstances?

A

Imatinib - Tyrosine Kinase Inhibitor
When a tyrosine kinase fusion is present

82
Q

What mutation occurs in the majority of systemic mastocytosis cases?What treatment

A

KIT D816V

83
Q

What targeted treatment can be used for systemic mastocytosis?

A

Midostaurin - TKI inhibitor

84
Q

What IGH rearrangement is associated with a poor prognosis in multiple myeloma?

A

t(4;14)(p13;q32) IGH-FGFR3

85
Q

What of the secondary abnormalities in multiple myeloma are associated with a poor prognosis?

A

loss 1p
gain 1q
monosomy 13 / del(13q)
TP53 mut / del(17p)
Adverse IGH translocations

86
Q

What is the biological basis, symptoms and treatment for polycythaemia vera?

A
  • PV is caused by the BM making too making blood cells causing thickening of the blood
  • Early no symptoms, later - headaches, shortness of break, itchiness, bleeding and dizziness.
  • Cannot be cured, managed as a chronic condition. Standard treatment is phlebotomy on a regular basis. Some patients may have chemo instead to stop excess production of red blood cells. For patients who have chemo and have. poor response or die effects, the JAK2 inhibitor ruxolitinib may be used.
87
Q

What is the biological basis, symptoms and treatment for myelofibrosis?

A
  • Myelofibrosis occurs when the bone marrow cells called fibroblasts make too much fibrous (scar) tissue. As a result fewer blood cells are created and they are destroyed more rapidly. This causes anaemia, a low platelet count and a tendency to develop infections.
  • Few symptoms at first, when anaemia develops can cause fatigue, weakness and abdominal pain from enlarged spleen.
  • Variety of treatment, some do not require any active treatment and are followed closely (active surveillance). Treatment decision made on symptoms and how disease acts. Ruxolitibib (JAK2 inhibior) can target JAK2 mutations and reduce size of spleen and many myelofibrosis symptoms. Other options include chemotherapy. Anaemia is treated with blood transfusions, Only potential cure is bone marrow transplant.
88
Q

What is the biological basis, symptoms and treatment for essential thrombocytopenia?

A
  • ET occurs when the BM produces too many platelets causing blood clots throughout the body which affect vital organs.
  • Chemotherapy is used to prevent the excess production of platelets.
89
Q

What proportion of AML cases have a FLT3 mutation and specifically a FLT3-ITD?

A

Mutations occur in 30% of AML
FLT3-ITD in 25% of AML

90
Q

What proportion of AML cases have an NPM1 mutation?

A

8-10%

91
Q

What are the different subtypes of MPN, underlying biological consequence and survival?

A
  • Polycythaemia Vera (PV)
    o Overproduction of red blood cells
    o Life expectancy same as general population
  • Essential Thrombocythemia (ET)
    o Overproduction of platelets
    o Life expectancy same as general population
  • Myelofibrosis (MF)
    o Overproduction of fibroblasts
    o Survival 4-5.5 years
    o May evolve from ET / PV
92
Q

What are the symptoms of Polycythaemia Vera (PV)

A

o Thick blood
o Headaches
o Blurred Vision
o Bleeding
o Itching
o Splenomegaly

93
Q

What are the symptoms of - Myelofibrosis (MF)

A

o Anaemia
o Tiredness
o Bruising
o Night sweats
o Fever
o splenomegaly

94
Q

What are the symptoms of - Essential Thrombocythemia (ET)

A

o Headaches
o Dizziness
o Enlarged Spleen
o Blood clots
o splenomegaly

95
Q

What are the variants and clinical significance in myelofibrosis?

A
  • JAK2 V617F
    o Intermediate
    o Treatment with JAK2 inhibitors
  • MPL W515L/K
    o Intermediate
  • CALR
    o Good prognosis
    o Type 1 better than type 2
  • Triple negative – Poor prognosis
96
Q

What are the three TKIs which can be used for treatment of CML?

A

Imatinib, Dasatenib, Nilotinib

97
Q

The WHO 2017 classification of eosinophilic disorders describes eosinophilic disorders as having a tyrosine kinase fusion with one of these genes…. –

A

PDGFRA, PDGFRB or FGFR1.

98
Q

What disorders overlap with CEL and how can they be distinguished?

A
  • Myeloproliferative Neoplasms and Systemic Mastocytosis.
  • Presence of a TK fusion separates from other MPNs (PDGFRA, PDGFRB, FGFR1) (not BCR-ABL1 which is diagnostic of CML)
  • Systemic Mastocytosis can be distinguished by the presence of a KIT D816V mutation which is found in >90% of SM cases.

Mol Path Part 1 2022 (7 decks)

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