Polcythaemia vera & Myelofibrosis Flashcards
Describe what is meant by a myeloproliferative disorder?
Myeloproliferative disorders involve the uncontrolled proliferation of a single type of stem cell
They are considered a form of cancer occurring in the bone marrow, although they tend to develop and progress slowly.
Myeloproliferative disorders that the potential to turn into which pathology? [1]
They have the potential to transform into acute myeloid leukaemia.
What are the three critical myeloproliferative disorders need to know? [3]
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia
Primary myelofibrosis; polycythaemia vera
and essential thrombocythaemia are all associated with mutations in which genes? [3]
JAK2
MPL
CALR
TOM TIP: The mutation to remember is JAK2. Treatment might involve JAK2 inhibitors, such as ruxolitinib
State the proliferating cell line in each of the following [3]
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia
Primary myelofibrosis:
- Haematopoietic stem cells
Polycythaemia vera:
- Erythroid cells
Essential thrombocythaemia:
- Megakaryocyte
State the blood finding result for each of the following
Primary myelofibrosis [3]
Polycythaemia vera [1]
Essential thrombocythaemia [1]
State the blood finding result for each of the following
Primary myelofibrosis:
- Low haemoglobin
- High or low white cell count
- High or low platelet count
Polycythaemia vera:
- High haemoglobin
Essential thrombocythaemia:
- High platelet count
Describe what is meant by myelofibrosis [1]
Myelofibrosis is where the proliferation of a single cell line leads to bone marrow fibrosis, where bone marrow is replaced by scar tissue.
What is myelofibrosis AKA? [1]
essential thrombocytopaenia
Describe the pathophysiology of myelofibrosis [4]
cytokines are released from the proliferating cells.: especially: fibroblast growth factor
FIbrosis decreases production of blood cells: ledas to low Hb; leukopaenia and thrombocytopaenia
When the bone marrow is replaced with scar tissue extramedullary haematopoiesis occurs
Production of blood cells in the liver and spleen causes hepatomegaly, splenomegaly, and portal hypertension. When it occurs around the spine, it can cause spinal cord compression.
Myelofibrosis usually occurs due to an initial mutation in which cell line? [1]
This is typically in the megakaryocyte cell line
Describe the initial presentation of myelofibrosis
20% asymptomatic
Hepatosplenomegaly
B symptoms: weight loss, fever and night sweats
Anaemia signs (conjunctival pallor etc)
Thrombembolic events
Portal hypertension (ascites, varices and abdominal pain)
Unexplained bleeding (due to low platelets)
[] is a complication of polycythaemia
Gout is a complication of polycythaemia
What peripheral blood film results would indicate myelofibrosis? [4]
pancytopenia and teardrop-shaped red cells
Anisocytosis
Blasts (immature red and white cells)
What investigational method is used to confirm a diagnosis of myelofibrosis? [1]
Testing for which genes can help diagnosis?
Bone marrow biopsy
Testing for the JAK2, MPL and CALR genes can help with diagnosis and management.
What would a biopsy show of a patient with myelofibrosis? [2]
Biopsy may demonstrate fibrosis and abnormal appearance of megakaryocytes
The cells in myelofibrosis are typically described in which way? [1]
dracocytes - tear drops
How would hepatic involement be suggested from investigations? [2]
PT and aPTT may be slightly prolonged
Raised alkaline phosphatase
What would an MRI scan of a patient with myelofibrosis show? [1]
MRI will show a decreased signal from the bone marrow as fat is replaced with fibrosis.
A formal diagnosis is based on the WHO criteria. This requires all three major criteria and one minor criterion.
What are these criteria?
Major criteria:
* Proliferation and atypia of megakaryocytes accompanied by fibrosis
* Not meeting WHO criteria for other myeloid neoplasms
* Presence of JAK2, CALR or MPL mutation or in the absence of these mutations, presence of another clonal marker or absence of reactive myelofibrosis
Minor criteria:
* Anemia not attributed to a comorbid condition
* Leukocytosis ≥11 x 109/L
* Palpable splenomegaly
* Raised LDH
* Leukoerythroblastosis
State 4 non-haematological causes of myelofibrosis [4]
Hyperparathyroidism
Systemic lupus erythematosus
Vitamin D deficiency
Systemic sclerosis
What is the only curative option for myelofibrosis? [1]
Curative option:
* haematopoietic stem cell transplant.
What are the symptomatic or palliative treatment options for myelofibrosis? [4]
Ruxolitinib:
- a JAK2 inhibitor
- effective regardless of JAK2 mutation status.
Hydroxyurea / (hydroxycarbamide)
interferon-alpha
How can you treat the pain caused by extramedullary haematopoiesis? [1]
foci can be irradiated
Which managment can be used to treat splenomegaly cause by myelofibrosis? [2]
Splenectomy or splenic irradiation
Describe what is meant by polycythaemia vera (PV) [1]
A myeloproliferative disorder caused by clonal proliferation of a marrow stem cell leading to an increase in red cell volume, often accompanied by overproduction of neutrophils and platelets
It is established that a mutation in [] is present in approximately 95% of patients with polycythaemia vera.
Describe the pathophysiology of PV [2]
established that a mutation in JAK2 is present in approximately 95% of patients with polycythaemia vera
The JAK2 gene encodes for a non-receptor tyrosine kinase involved in signal transduction pathways for various hematopoietic growth factors, including erythropoietin (EPO).
The JAK2 V617F mutation results in constitutive activation of the JAK-STAT signaling pathway, leading to increased proliferation and survival of hematopoietic progenitor cells, independent of EPO stimulation.
In addition to affecting erythropoiesis, the JAK2 V617F mutation also influences the proliferation of other myeloid progenitor cells. Consequently, patients with PV may present with increased white blood cell and platelet counts.
What is the difference between primary and secondary polycythaemia? [2]
Primary polycythaemia:
- due to a mutation that results in an increase in the red cell mass.
- PV is the most common cause
Secondary polycythaemia:
- most commonly due to appropriate rises in EPO secondary to hypoxia: e.g. smoking; chronic lung disease; obesity and OSA
- also occurs due to EPO rising from: tumours; illicit EPO use; androgen use
Which tumours typically cause a rise in EPO? [3]
Renal cell cancer
Wilms’ tumour
Adrenal tumours
Describe the clinical features of polcythaemia vera
- Ruddy complexion (red face)
- Conjunctival plethora(the opposite of conjunctival pallor)
- Haemorrhage
- Splenomegaly
- Hypertension
- Pruritis after a hot bath
Describe the investigations for PV? [4]
Full blood count/film:
- raised haematocrit
- raised neutrophils
- raised basophils
- raised platelets in half of patients
JAK2 mutation
Serum ferritin:
- low due to persistent production of RBC
Renal and liver function tests
What diagnostic criteria needs to be met for a diagnosis of JAK2 positive PV? [2]
If JAK2 positive - need both of:
- A1 High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
- A2 Mutation in JAK2
If a patient is JAK2-negative, a diagnosis can occur due to meeting which criteria?
They have further guidance on the diagnosis of PV in the absence of a JAK2 mutation. This is very rare, far more complex and beyond the understanding typically required at an undergraduate level. For those interested see the full BSH guidelines for more detail.
How do you manage PV? [5]
Venesection - first line treatment
- to keep the haemoglobin in the normal range
Aspirin 75mg daily
- to reduce the risk of thrombus formation
Chemotherapy
- (typically hydroxycarbamide: reduces the number of RBC
Phosphorus-32 therapy
Cytoreductive therapy (Hydroxycarbamide / hydroxyurea) is considered in high-risk patients, defined by BSH as? [2]
Age ≥ 65 years and/or
Prior PV-associated arterial or venous thrombosis
Cytoreductive therapy is considered in low risk patients who meet which criteria? [4]
Thrombocytosis (> 1500 × 109/l)
Progressive splenomegaly
Progressive leucocytosis (> 15 × 109/l)
Poor tolerance of venesection
Patients suffering from PV have a high change of what complications?
Thrombotic events (DVT / PE) are a significant cause of morbidity and mortality
5-15% patients go on to develop which two pathologies from PV? [2]
5-15% of patients progress to myelofibrosis
5-15% of patients progress to acute leukaemia (risk increased with chemotherapy treatment)
PV typically presents at which age? [1]
PV can present at any age but most commonly presents in the 60’s and is very rare in childhood. It appears to be slightly more prevalent in men.
When performing venesection, how much blood is typically removed from a patient? [1]
What is the target haemotocrit?
200-500ml at a time at intervals dependent on patient factors (e.g. size).
target of maintaining a haematocrit of < 0.45.
A patient presents with unexplained splenomegaly, leukoerythroblastosis, and peripheral blood cytopenias. Which diagnostic test is most appropriate for confirming the diagnosis of myelofibrosis?
a) Bone marrow biopsy
b) Complete blood count (CBC)
c) Serum erythropoietin levels
d) JAK2 mutation testing
A patient presents with unexplained splenomegaly, leukoerythroblastosis, and peripheral blood cytopenias. Which diagnostic test is most appropriate for confirming the diagnosis of myelofibrosis?
a) Bone marrow biopsy
b) Complete blood count (CBC)
c) Serum erythropoietin levels
d) JAK2 mutation testing
What constitutional symptoms are commonly associated with myelofibrosis?
a) Weight gain and fatigue
b) Night sweats and weight loss
c) Fever and headache
d) Hypertension and bradycardia
What constitutional symptoms are commonly associated with myelofibrosis?
a) Weight gain and fatigue
b) Night sweats and weight loss
c) Fever and headache
d) Hypertension and bradycardia
When should cytoreductive therapy be initiated in myelofibrosis patients, according to NICE guidelines?
a) At the time of diagnosis
b) Only if the patient is symptomatic
c) After confirmation of JAK2 mutation
d) When platelet count exceeds 500 x 10^9/L
When should cytoreductive therapy be initiated in myelofibrosis patients, according to NICE guidelines?
a) At the time of diagnosis
b) Only if the patient is symptomatic
c) After confirmation of JAK2 mutation
d) When platelet count exceeds 500 x 10^9/L
What is the recommended first-line therapy for myelofibrosis with intermediate-2 or high-risk disease, according to NICE guidelines?
a) Hydroxyurea
b) Ruxolitinib
c) Interferon-alpha
d) Allogeneic stem cell transplant
What is the recommended first-line therapy for myelofibrosis with intermediate-2 or high-risk disease, according to NICE guidelines?
a) Hydroxyurea
b) Ruxolitinib
c) Interferon-alpha
d) Allogeneic stem cell transplant
For a patient with significant splenomegaly causing discomfort and early satiety, what is the first-line approach recommended by NICE?
a) Splenectomy
b) Radiation therapy
c) Ruxolitinib
d) Supportive care only
For a patient with significant splenomegaly causing discomfort and early satiety, what is the first-line approach recommended by NICE?
a) Splenectomy
b) Radiation therapy
c) Ruxolitinib
d) Supportive care only
Which complication should be actively monitored in myelofibrosis patients receiving long-term hydroxyurea therapy?
a) Thrombocytosis
b) Pulmonary hypertension
c) Gastrointestinal bleeding
d) Secondary malignancies
Which complication should be actively monitored in myelofibrosis patients receiving long-term hydroxyurea therapy?
a) Thrombocytosis
b) Pulmonary hypertension
c) Gastrointestinal bleeding
d) Secondary malignancies
Hydroxyurea
Venesection
polycythaemia secondary to erythropoietin secretion
Budd-Chiari syndrome
Mutation in JAK2
