18.06.27 MPN

Question 1

What are MPNs?

Answer 1

Clonal haematological malignancies derived from myeloid lineage - granulocytic cells (neutrophil, eosinophil, basophil), monocytic/macrophage, erythroid, megakaryocytic and mast cell lineages.

Increased number of mature cells (erythrocytes, granulocytes and/or platelets) in BM. Normal proliferation and effective maturation, distinction from MDS.

Question 2

Which genes are MPNs associated with?

Answer 2

Involve acquired mutations or rearrangements of genes encoding protein tyrosine kinases or similar result in constitutively active PTKs that activate signal transduction pathways leading to abnormal proliferation e.g. JAK2 V617F.

Question 3

What is one of the common clinical features of MPN?

Answer 3

Organomegaly common (splenomegaly and hepatomegaly), progression leads to BM failure due to myelofibrosis or transformation to AML, overall peak incidence 50-70 years, with some subtypes (CML and ET) also reported in children,

Question 4

What is the incidence of MPNs?

Answer 4

Incidence 6-10/100,000 and life expectancy generally >10 years. The finding of 10-19% blasts in the PB or BM generally signifies accelerated disease and 20% or more is sufficient for diagnosis of blast phase/transformation (to AML).

Question 5

Which category of MPN is associated with BCR-ABL1?

Answer 5

The presence of a BCR-ABL1 fusion gene excludes all possible MPN categories except Chronic Myelogenous Leukaemia.

Question 6

Give three examples of myeloproliferative neoplasms.

Answer 6

1. Chronic Neutrophilic Leukaemia
2. Polycythemia Vera
3. Essential Thrombocythaemia
4. Primary myelofibrosis
5. Chronic Eosinophilia Leukaemia
6. Mastocytosis

Question 7

Give the definition, incidence and clinical features of chronic neurophilic leukaemia

Answer 7

Definition: Sustained peripheral blood neutrophilia (>80% of white blood cells), bone marrow hypercellularity and hepatosplenomegaly.

Incidence: Rare, only a few hundred cases reported. Generally, affects older adults.

Clinical features: Splenomegaly, and often hepatomegaly.

Question 8

Give the definition, incidence and clinical features of chronic neurophilic leukaemia

Answer 8

Definition: Increased red blood cell production. Nearly all patients have somatic gain-of function mutation of JAK2 V617F (or similar) that results in proliferation of erythroid lineage, granulocytes and megakaryocytes

Incidence: Up to 2.6 per 100,000/year. Median age 60 years. Slight male predominance.

Clinical features: Hypertension, vascular abnormalities caused by the increased red cell mass. Splenomegaly, hepatomegaly.

Question 9

Give the definition, incidence and clinical features of Primary myelofibrosis.

Answer 9

Definition: Proliferation of megakaryocytes and granulocytes in BM that is associated with deposition of fibrous connective tissue and extramedullary haematopoiesis.

Incidence: Up to 1.5 per 100,000/year. Most common in 50s and 60s.

Clinical features: Up to 30% are asymptomatic. Splenomegaly, hepatomegaly, anaemia, leukocytosis or thrombocytosis. Fatigue, weight loss, bleeding episodes..

Question 10

Give the definition, incidence and clinical features of Essential Thrombocythaemia.

Answer 10

Definition: Involves primarily the megakaryocytic lineage. Sustained thrombocytosis in PB, increase in mature megakaryocytes in BM.

Incidence: Up to 2.5 per 100,000/year, usually 50-60 yrs. Sometimes in women around 30yrs, and infrequently in children.

Clinical features: 50% are asymptomatic and discovered by high platelet count. Other patients present with vascular occlusion, haemorrhage or thrombosis.

Question 11

Give the definition, incidence and clinical features of Chronic Eosinophilia Leukaemia.

Answer 11

Definition: Increased numbers of eosinophils in PB, BM and tissues due to clonal proliferation of precusors. Important to distinguish CEL from idiopathic hyper-eosinophilia which is not leukaemic.

Incidence: True incidence is unknown but is rare.

Clinical features: Patients can be asymptomatic. Sometimes, fever, fatigue, cough, angioedema. Most serious is restrictive cardiomegaly.

Question 12

Give the definition, incidence and clinical features of Mastocytosis

Answer 12

Definition: Clonal, neoplastic proliferation of mast cells that accumulate in skin (cutaneous) or other organ(s) (systemic).

Incidence: Can occur at any age. Mainly children (cutaneous) or >20yrs (systemic)

Clinical features: Heterogenous, from skin lesions that may spontaneously regress, to highly aggressive neoplasms associated with multiorgan failure.

Question 13

What are the genetic changes associated with Chronic Neutrophilic Leukaemia?

Answer 13

Cytogenetics normal in 90% patients. If present, abnormalities include +8, +9, +21, del(20q), del(11q) and del(12p).

Occasional JAK2 mutations have been reported.

CSF3R mutations seen in majority of patients and SETBP1 in 33% (NB based on one paper only)

Question 14

What is the prognosis of Chronic Neutrophilic Leukaemia?

Answer 14

Slow progressive disorder, but survival varies from 6 months to >20 years.
Development of myelodysplastic features may signal transformation to AML.

Question 15

What are the genetic changes associated with Polycythemia Vera?

Answer 15

Most frequent genetic abnormality is JAK2 V617F mutation, found in >95% of patients.

Cytogenetic abnormalities found in 20% patients, including +8,+9, del(20q), del(13q) and del(9p), and seen more frequently with progression.

Question 16

What is the prognosis of Polycythemia Vera?

Answer 16

Median survival time >10 years. Most patients die form thrombosis or haemorrhage, but up to 20% progress to MDS/AML.

Question 17

What are the genetic changes associated with Primary myelofibrosis?

Answer 17

50% have JAK2 V617F mutation.

Cytogenetic abnormalities found in 30%. Del(13q), der(6)t(1;6) both suggestive of PMF. Del(20q), partial trisomy of 1q, +8, +9, del(5q),del(7q).

Question 18

What is the prognosis of Primary myelofibrosis ?

Answer 18

Survival ranges from months to decades – prognosis is much better if diagnosed in the early prefibrotic phase.
DIPSS-plus prognostic scoring system including karyotype

Question 19

What are the genetic changes associated with Essential Thrombocythaemia?

Answer 19

Up to 50% have the JAK2 V617F mutation.

Abnormal karyotype found in only 5-10% (e.g. +8, 9q abnormalities and del(20q)

Question 20

What is the prognosis of Essential Thrombocythaemias ?

Answer 20

Median survival 10-15 years. Transformation to AML/MDS occurs in <5%

Question 21

What are the genetic changes associated with Chronic Eosinophilia Leukaemia?

Answer 21

Rearrangement of PDGFRA/PDGFRB/FGFR1 excludes a diagnosis of CEL.

Myeloid-type abnormalities e.g. +8 or i(17q) supports a diagnosis of CEL.

Question 22

What is the prognosis of Chronic Eosinophilia Leukaemia ?

Answer 22

Variable, but 5-year survival nearly 80%

Question 23

What are the genetic changes associated with Mastocytosis?

Answer 23

Frequently associated with somatic activating point mutations within KIT.

Question 24

What is the prognosis of Mastocytosis?

Answer 24

Variable, depending various factors including age, stage of disease, stage at which symptoms appear.

Question 25

Some cases of MPN are unclassifiable. What does this mean in practice and how many cases of MPN is this thought to account for?

Answer 25

Defintion: Only applies to cases with features of MPN that don’t meet the criteria for any of the specifc MPN entities, or that overlap two or more.

Presentation: Minimal organomegaly in early disease but massive in advanced disease.

Incidence: May account for 10-15% of MPN cases.

Question 26

For unclassifiable MPN, what are the associated genetic changes and prognosis?

Answer 26

Absence of both BCR-ABL1 fusion, and rearrangement of PDGFRA/
PDGFRB/ FGFR1

Often later re-classified after follow-up studies. Poor prognosis for advanced disease.

Question 27

Give the definition, incidence and clinical features of Chronic myelogenous leukaemia, BCR-ABL1 positive

Answer 27

Definition: Myeloproliferative neoplasm, consistently associated with the BCR-ABL1 fusion. This fusion is found in all myeloid
lineage , some lymphoid cells and endothelial cells. Phases when untreated: Initial indolent chronic phase, accelerated phase, blast phase( at least 2% of blast in BM or
blood).

Incidence: 1-2 cases per 100k per annum. can occur at any age but usually 50 or 60.

Clinical features: 20-40% patients asymptomatic. Common findings: fatigue weight loss, night sweats, splenomegaly and anaemia.

Question 28

What are the genetic changes and prognosis associated with Chronic myelogenous leukaemia, BCR-ABL1 positive?

Answer 28

90-95% BCR-ABL1 +ve
If progression, usually associated to clonal evolution with cytogenetic changes in addition to the Ph
chromosome such as: an extra PH, +8, +19, or i(17).

Complete cytogenetic response rate to imatinib is 70-90% with a 5 yearprogression free survival and OS
between 80-95%.

Question 29

What is the role of JAK2?

Answer 29

Janus 2 kinase (JAK2)

1. Non-receptor tyrosine kinase involved in the JAK/STAT signaling pathway
2. Acts as a signal transducer and activator for the MAPK and PI3K pathways to promote transformation and proliferation
3. deregulation strongly associated with development of MPNs, causing the characteristic increased proliferation and survival of malignant cells and increased levels of inflammatory cytokines

Question 30

In which MPNs are JAK2 mutations found?

Answer 30

JAK2 mutations are found in nearly all cases of PV (<95%) and ~50% of cases with ET or MF

Presence of the mutation can make a definitive diagnosis of MPN but absence does not exclude

Question 31

What is the most common JAK2 mutation?

Answer 31

Most common mutation V617F

G>T in exon 14 at position 1849 substitutes a Valine for Phenylalanine at amino acid 617

Gain of function releasing auto inhibition

Question 32

Other than the common V617F JAK2 mutation, what other mutations can be seen in JAK2 in MPN patients?

Answer 32

Less common mutations in exon 12 (up to 40 different mutations identified)

Can see LOH of chromosome 9p

Difference in disease types may reflect the levels of clones with homozygous mutation (homozygosity for V617F is common in PV and MF but uncommon in ET)

Question 33

What is the function of MPL and the effect of mutation in this gene?

Answer 33

Myeloproliferative leukaemia virus oncogene (MPL)

Encodes for thrombopoietin which regulates the differentiation of megakaryocytes and platelets

Mutation constitutively activates signalling pathways including JAK/STAT, MAPK and PI3K

Question 34

In which MPN patients are MPL mutations identified?

Answer 34

Mutations are found in ~3-4% of patients with ET and 4-8% of patients with IMF (not seen in PV)

Mutations occur within exon 10 e.g. MPLW515Ki, MPLW515Kii, MPLW515R, MPLW515A and MPLS505N

Can occur concurrently with JAK2 mutations

Patients with MPL mutations tend have lower haemoglobin levels than with JAK2

Question 35

What is the function of CALR and the effect of mutation in this gene?

Answer 35

Calreticulin (CALR): May play a role in transcription regulation

Various mutations in exon 9 - 80% are either a 52bp del or a 5bp insertion

All mutations result in a +1bp frameshift, replacing the normal C-terminus with a common, novel amino acid sequence

Question 36

In which MPN patients are CALR mutations identified?

Answer 36

CALR mutations are seen in 60-80% of ET and PMF cases that are negative for JAK2 and MPL mutations

Rarely seen in PV and may rarely be seen with JAK2 (but generally considered mutually exclusive of JAK2 and MPL)

Provide proof of clonality, diagnosis importance and influence prognosis.

Question 37

What does ‘triple negative MPN’ refer to?

Answer 37

Triple negative’ MPN refers to being negative for JAK2, MPL and CALR mutations

Question 38

What is Myeloid and lymphoid neoplasms with eosinophilia?

Answer 38

Clonal proliferation of eosinophil precursors leads to increased numbers of eosinophils in PB, BM and peripheral tissue.

Peripheral organ damage (heart, lungs, splenomegaly, skin rash) occurs either as a result of leukemic infiltration or the release of cytokines, enzymes or other proteins by the eosinophils.

These neoplasms are all rare.

Question 39

Which genes are associatied with Myeloid and lymphoid neoplasms with eosinophilia?

Answer 39

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

Question 40

What is the location of PDGFRA?

Answer 40

4q14

Question 41

What is the location of PDGFRB?

Answer 41

5q33

Question 42

What is the location of FGFR1?

Answer 42

8p11