Haematology - Non-Leukaemic Myeloproliferative Neoplasms Flashcards
What are myeloproliferative neoplasms? Name 3 important neoplasms
- Myeloproliferative neoplasms: group of conditions arising from marrow stem cells and characterised by clonal proliferation of one or more haemopoietic components in the BM, the liver and spleen.
- These neoplasms are closely related to each other and transitional forms can occur with evolution from one entity to another during the course of the disease.
The three main non-leukemic disorders included in this classification are:
- Polycythaemia Vera
- Essential thrombocytopenia
- Primary myelofibrosis
Name an important gene that is associated with these three conditions
These diseases are associated with clonal abnormalities involving genes that encode cytoplasmic or receptor tyrosine kinase
- Single acquired mutation of cytoplasmic tyrosine kinase Janus-associated kinase 2 (JAK 2) occurs in marrow and blood of almost all patients with PV, and in approx. 50% of patients with ET and myelofibrosis
- JAK 2: has major role in normal myeloid development by transducing signals from diverse cytokines and growth factors (IL3, GM-CSF and G-CSF).
What is polycythaemia vera? Name some important investigation findings
- Uncontrolled production of red cell volume - caused by a clonal malignancy of a marrow stem cell
- A mutation in JAK2 is found in over 95% of patients
- Investigation findings:
- FBC: increase in red cells (diagnostic finding), haematocrit (raised)
- Overproduction of granulocytes (neutrophils, eosinophils and basophils)
- Thrombosis
- low serum EPO levels
- Raised LDH
Polycythaemia vera: important clinical findings
- Disease of older subjects with equal sex incidence, clinical features are the result of hyperviscosity, hypervolaemia and hypermetabolism
- Headaches, dyspnea, blurred vision and night sweats + pruritus after a hot bath (can be very severe)
- Plethoric appearance: ruddy cyanosis and retinal venous engorgement
- Splenomegaly
- Haemorrhage or thrombosis (arterial or venous)
- HTN
- Gout (as a result of raised uric acid production)
Polycythaemia Vera: treatment
- Aimed at maintaining normal blood count: haematocrit should be >0.45 and platelet count <400 x 10^9/L
- Venesection: useful and rapid – good for younger and milder disease patients (does not control platelet count)
- Cytotoxic myelosuppression: aspirin, hydroxycarbamide, peggylated interferon
*Always give allopurinol when initiating treatment to prevent TLS induced AKI
What is essential thrombocythaemia?
Definition: sustained increase in platelet count due to megakaryocyte proliferation and overproduction of platelets.
What investigations should you perform in essential thrombocythaemia?
- Bloods:
- Persisting platelet count >450 x 10^9/L (main diagnostic criteria)
- Haematocrit is normal and the Philadelphia chromosome or BCR-APL 1 rearrangement are absent
- JAK2 mutation present in 50% of cases
- BM trephine:
- Shows increased megakaryocytes with prominent large hyperlobulated forms
- Does not have collagen fibrosis
- Blood film:
- Abnormal large platelets and megakaryocyte fragments
*Need to exclude other causes of raised platelet count (iron deficiency, inflammatory or malignant disorder, and myelodysplasia) before can diagnose ET.
Give some clinical features of essential thrombocythaemia
- Thrombosis and haemorrhage (acute or chronic) are main clinical features but most cases are asymptomatic
- Splenomegaly (unless is atrophic due to infarction)
- Erythromelalgia: burning sensation in hands and feet relieved by aspirin
Outline the treatment for essential thrombocythaemia
- Principle is to reduce risk of thrombosis and haemorrhage – may need splenomegaly
- Risk factors: >60 years old, JAK2 mutation, smoking, HTN, previous thrombotic episodes
- Low dose aspirin (75mg/day) for all at risk patients, higher risk patients can get chemotherapy (hydroxycarbamide) or interferon
- Course of disease: often stationary for 10-20 years – may transform after a number of years to myelofibrosis but risk of transformation to acute leukaemia is low.
What is primary myelofibrosis?
Definition: progressive generalised reactive fibrosis of BM in association with the development of haemopoiesis in the spleen and liver (myeloid metaplasia).
- Myelofibrosis is a clonal stem cell disease –fibrosis of BM is secondary to hyperplasia of abnormal megakaryocytes.
- It is thought that fibroblasts are stimulated by platelet derived growth factor and other cytokines secreted by megakaryocytes and platelets.
Outline some clinical features of primary myelofibrosis
- Insidious onset in older people + symptoms of anaemia
- Massive splenomegaly (main physical finding): abdo discomfort, pain indigestion
- Hypermetabolic symptoms: weight loss, anorexia, fever, night sweats
- Bleeding problems, bone pain or gout (minority of patients)
- Transformation into acute myeloid leukaemia occurs in 10-20% of patients.
*Primary fibrosis and CML are responsible for most cases of massive (>20cm) splenic enlargement in UK and North America
Outline some investigation findings for primary myelofibrosis
- Bloods:
- Anaemia
- Raised WCC and platelets at presentation (later in disease get leukopenia and thrombocytopenia)
- Leucoerythroblastic blood film: ‘tear drop’ poikilocytes and nucleated RBCs
- Jak 2 kinase in >50% cases
- Raised serum urate and LDH: reflects increased but ineffective turnover of haemopoietic stem cells.
- BM findings:
- Aspiration normally unobtainable
- Trephine biopsy: BM architecture is lost and haemopoietic cells are surrounded by increased fibrous tissue and intercellular substance. Increased megakaryocytes
Outline the treatment options for primary myelofibrosis
- Supportive care:
- Blood transfusions
- Regular folic acid
- Splenectomy to relieve sx of splenomegaly
- Allopurinol: prevents gout and urate nephropathy from hyperuricaemia
- Cytotoxic drugs: hydroxycarbamide, JAK 2 inhibitors, SCT (high risks associated with transplants)
