W4-L3-Myeloproliferative Neoplasms

Question 1

What is Myeloproliferative neoplasms?

Answer 1

Overproduction of blood cells in the marrow

Question 2

Chronic MPN in which granulocytes (neutrophils and neutrophil precursors)
are the major proliferative component

Answer 2

Chronic Myeloid Leukemia

Question 2

Characterised by the chromosomal translocation t(9;22), which results in
the formation of the Philadelphila (Ph) chromosome containing the BCR-
ABL1 fusion gene

Answer 2

Chronic Myeloid Leukemia

Question 2

Classify the various types of Myeloproliferative neoplasms

Answer 2

1. Chronic myeloid leukaemia (CML) excessive granulocyte precursor production
2. Polycythemia Vera (PV) predominance of excessive red cell production
3. Essential thrombocythemia (ET) excessive platelet production
4. Primary myelofibrosis (PMF) excessive bone marrow fibrosis and scarring.
   -Chronic neutrophilic leukammia*
   -Chronic eosinopohilic leukaemia*
   -Juvenile myelomonocytic leukaemia

Question 3

What is required for a diagnosis of CML?

Answer 3

The presence of the Ph chromosome (noted on karyotyping) or t(9;22) noted
on other molecular tests (PCR, FISH)

Question 3

What can one expect to see on the peripheral blood smear of CML patient?

Answer 3

• INCREASED:
  -WCC
  -Granulocyte
  precursors
  -Eosinophils &
  basophils

*NOT an increase in
blasts!
HB normal or
decreased

Question 3

T/F
With respect to Chronic Myeloid Leukemia, The t(9;22) mutation arises in the haematopoietic stem cell, and is present in the
subsequent differentiated myeloid cells.

Answer 3

TRUE

Question 4

List the clinical features of CML

Answer 4

• Mainly adults. Peak at 40-50yrs
• Often picked incidentally on FBC alone, south Africa, patients may present with symptoms
• Splenomegaly – extramedulary
  haemopoiesis
• Hyperviscosity
• Fatigue
• Weight loss

Question 5

Discuss how the philadelphia chromosome in the CML is derived and its impact

Answer 5

• Translocation between part of chromosome chromosome 9 (ABL1) and chromosome 22 (BCR) region – t(9;22)
• Results in the production of an abnormal chromosome –
  Philadelphia Chromosome and the formation of a new gene at the point of translocation called BCR-ABL1
• The abnormal gene that is constitutionally activated tyrosine kinases within the cells that signal for cell proliferation.
• This abnormal gene is produced in the haematopoietic stem cell and is present in each generation of the differentiated daughter cells

Question 6

Describe the natural history of CML

Answer 6

WITHOUT TREATMENT:
100% transformation
To acute leukaemia within
5 years

WITH TREATMENT:
~70-90% Complete response
To Imatinib
~5 yr survival ~95%

Poor response Due to De novo Or acquired mutations
To therapy

Question 6

What is the possible treatment for CML?

Answer 6

Supportive:
* Management of symptoms
* Blood product support if
needed
* Prevention of infections
* Monitory for
hyperviscosity symptoms

SPECIFIC:
* Tyrosine Kinase
inhibitors (e.g.
Imatinib)

Question 7

Discuss Polycythemia Vera

Answer 7

• It’s a chronic MPN
• Characterised by increase in red cell production
• JAK2-V617F mutation in >95% cases and JAK2 exon12 ~3%
• Median age at diagnosis is ~60 years
• Rarely seen in patients <20 years

Question 8

What’s the main driver mutations for Polycythemia Vera (PV), Essential Thrombocytosis (ET) and Myeloproliferative Neoplasms (MPN)?

Answer 8

JAK 2 mutations and CARL mutations (mostly in ET and MPN; rarely in PV)

Question 9

List the clinical features of polycythemia vera

Answer 9

• Increased red cell mass
• Hypertension
• Arterial and venous thrombosis
• Hyperviscosity – headaches, dizziness, visual disturbances
• Pruritis
• Splenomegaly
• Gout
• Peptic ulceration

Question 9

Discuss the progression of Policythemia vera (PV)

Answer 9

• Majority;
  -progressively increasing fibrosis of the bone marrow with
  increasing splenomegaly
• Less common (~2-3% untreated patient)
  –transformation to acute leukaemia

Question 10

What is the possible treament for polycythemia Vera (PV)?

Answer 10

• Supportive
  *Symptom control through
  repeated venesection to
  decrease the HCT
  *Prevent iron deficiency to
  prevent increased
  erythroid drive
• Specific
  *JAK2 inhibitors Ruxolitanib
  (only available in study
  trials in South Africa)

Question 10

Discuss the features of ET

Answer 10

• Chronic MPN
• Primarily involves megakaryocytes. Platelet counts ≥450 x109/L
• Occurs mostly in patients aged 50-60 years, second peak ~30
  years (particularly women)
• Often asymptomatic at diagnosis,
  -splenomegaly in ~50% of cases
• Genetic mutations: JAK2-V617F (50-60%), CALR (30%), MPL (3%)
• Up to 12% may be triple negative but may have other gain-of-function
  mutations.

Question 11

What are the clinical features of ET?

Answer 11

Signs and symptoms:
* Elevated PLT count
* Usually isolated, however, patient may have elevated HB if JAK2 mutation present
* Splenomegaly is rare
* BM marked increase in abnormal large and giant megakaryocytes

Complications:
* Thrombosis (unusual places)
* Bleeding events (abnormal platelet function
* May progress to bone marrow
fibrosis
* Transformation to acute myeloid leukaemia or myelodysplasia (rare)

Question 11

Discuss the features of primary myelofibrosis

Answer 11

• Increase in abnormal granulocytes and abnormal
  megakaryocytes in the bone marrow, with increase
  collagen and reticulin fibrosis in the bone marrow
• Increased WCC >11x 109/L
• JAK2V617F (~50-60%), CALR (~24%), MPL (~8)
• Exposure to Benzene or ionizing radiation has been
  documented in some cases

Question 12

What are the clinical features of primary myelofibrosis?

Answer 12

• ~30% asymptomatic
• > 50% present with constitutional symptoms
• MASSIVE SPLENOMEGALY in up to 90% of patients
• Peripheral blood – leucoeythoblastic picture (LER) with teardrops
• May have thrombocytosis or normal PLT count
• Late stages- develop hepatosplenomegaly (e and bone marrow
  failure resulting in pancytopenia.