CML and Myeloproliferative Disorders Flashcards
What is polycythaemia?
Raised Hb concentration and Haematocrit %
What are causes of polycythaemia?
Relative: Lack of plasma - Non-malignant
True: Excess erythrocytes
- Secondary: Non-malignant
- Primary: Myeloproliferative neoplasm
What are examples of myeloproliferative neoplasms?
Ph (Philadelphia Chromosome) negative:
- Polycythaemia vera (PV)
- Essential Thrombocythaemia (ET)
- Primary Myelofibrosis (PMF)
Ph positive:
- Chronic myeloid leukaemia (CML)
What are dilution studies?
To differentiate between true and relative polycythaemia
Red Cell Mass: 51Cr labelled RBC
Plasma Vol: 131I labelled albumin
What are causes of relative/pseudo-polycythaemia?
Alcohol
Obesity
Diuretics
What happens to EPO in primary and secondary true polycythaemia?
Primary: Reduced
Secondary: Elevated
What are appropriate causes of elevated EPO?
High altitude
Hypoxic lung disease
Cyanotic heart disease
High affinity haemoglobin
What are inappropriate causes of elevated EPO?
Renal disease (cysts, tumours inflammation)
Uterine myoma
Other tumours (liver, lung)
What are examples of myeloid haematological malignancies?
Acute myeloid leukaemia (blasts >20%)
Myelodysplasia (blasts 5-19%)
Myeloproliferative disorders:
- Essential thrombocythaemia (megakaryocyte)
- Polycythemia vera (erythroid)
- Primary myeofibrosis
Chronic myeloid leukaemia
What are examples of lymphoid haematological malignancies?
Precursor cell malignancy:
- Acute lymphoblastic leukaemia (B & T)
Mature cell malignancy:
- Chronic Lymphocytic leukaemia
- Multiple myeloma
- Lymphoma (Hodgkin & Non Hodgkin)
Which processes are disrupted by mutation?
Cellular proliferation (type 1)
Impair/block cellular differentiation (type 2)
Prolong cell survival (anti-apoptosis)
Mutation mechanisms:
- DNA point mutations
- Chromosomal translocations:
- Creation of novel fusion gene
- Disruption of proto-oncogene
What is the normal function of tyrosine kinases?
Transmit cell growth signals from surface receptors to nucleus.
Activated by transferring phosphate groups to self and downstream proteins.
Normally held tightly in inactive state.
Promote cell growth do not block maturation.
What happens when mutations cause activation of tyrosine kinase?
Expansion increase in mature/end cells
Red cells: Polycythaemia
Platelets: Essential thrombocythaemia
Granulocytes: Chronic myeloid leukaemia
Which genes are associated with myeloproliferative neoplasms?
JAK2
Calreticulin
MPL
How is the diagnosis of myeloproliferative disorder (Ph negative) made?
Based on combination of:
Clinical features:
- Symptoms
- Splenomegaly
FBC +/- Bone marrow biopsy
Erythropoietin level (EPO)
Mutation testing: Phenotype linked to acquired mutation
What is the epidemiology of polycythaemia vera?
Annual incidence 2-3/100000
Slightly more in males 1.2:1
Mean age at diagnosis 60 years
5% below age of 40 years
How does PV present clinically? How is it diagnosed?
Incidental diagnosis routine FBC (median Hb 184g/l, Hct 0.55).
Symptoms of increased hyper viscosity:
- Headaches, light-headedness, stroke
- Visual disturbances
- Fatigue, dyspnoea
Increased histamine release:
- Aquagenic pruritus
- Peptic ulceration
Test for JAK2 V617F mutation
How is PV treated?
Aim to reduce HCT:
- Target HCT <45%
- Venesection
- Cytoreductive therapy hydroxycarbamide
Aim to reduce risks of thrombosis:
- Control HCT
- Aspirin
- Keep platelets below 400x109 /l (see treatment of ET)
What is essential thrombocythaemia?
Chronic MPN mainly involving megakaryocytic lineage.
Sustained thrombocytosis >600x109 /L.
Incidence 1.5 per 100000.
Mean age two peaks 55 years and minor peak 30 years.
Females:males - Equal first peak but females predominate second peak.
What is the presentation of essential thrombocythaemia?
Incidental finding on FBC (50% cases).
Thrombosis: Arterial or venous – CVA, gangrene, TIA – DVT or PE.
Bleeding: Mucous membrane and cutaneous.
Headaches, dizziness visual disturbances.
Splenomegaly (modest).
What is the treatment of essential thrombocythaemia?
Aspirin: To prevent thrombosis.
Hydroxycarbamide: Antimetabolite. Suppression of other cells as well.
Anagrelide: Specific inhibition of platelet formation, side effects include palpitations and flushing.
What is the prognosis of essential thrombocythaemia?
Normal life span may not be changed in many patients.
Leukaemic transformation in about 5% after >10 years.
Myelofibrosis also uncommon, unless there is fibrosis at the beginning.
What is primary myelofibrosis?
A clonal myeloproliferative disease associated with reactive bone marrow fibrosis.
Extramedullary haematopoieisis.
Primary presentation:
- Incidence 0.5-1.5 /100000
- Males=females – 7 th decade.
- Less common in younger patients
- Other MPDs (ET & PV) may transform to PMF
What is the clinical presentation of primary myelofibrosis? How is it diagnosed?
Incidental in 30%:
Presentations related to:
- Cytopenias: Anaemia or thrombocytopenia
- Thrombocytosis
- Splenomegaly: May be massive
- Budd-Chiari syndrome
- Hepatomegaly
- Hypermetabolic state:
- Weight loss
- Fatigue and dyspnoea
- Night sweats
- Hyperuricaemia
What are findings of primary myelofibrosis on a blood film?
Leucoerythroblastic picture
Tear drop poikilocytes
Giant platelets
Circulating megakaryocytes
What are findings of primary myelofibrosis in the bone marrow?
‘Dry tap’
Trephine:
- Increased reticulin or collagen fibrosis
- Prominent megakaryocyte hyperplasia and clustering with abnormalities
- New bone formation
What are additional findings of primary myelofibrosis?
Liver and spleen: Extramedullary haemopoiesis in spleen and liver
DNA: JAK2 or CALR mutation
What is the prognosis of primary myelofibrosis?
Median 3-5 years but very variable
What are bad prognostic signs of primary myelofibrosis?
Severe anaemia <100g/L
Thrombocytopenia <100x109 /l
Massive splenomegaly
Which prognostic scoring system can be used for primary myelofibrosis?
Prognostic scoring system (DIPPS):
Score 0: Median survival 15 years
Score 4-6: Median survival 1.3 years
What is the treatment of primary myelofibrosis?
Limited range of options:
Supportive: RBC and platelet transfusion often ineffective because of splenomegaly
Cytoreductive therapy: Hydroxycarbamide (for thrombocytosis, may worsen anaemia).
Ruxolotinib: JAK2 inhibitor (high prognostic score cases)
Allogeneic SCT: Potentially curative reserved for high risk eligible cases.
Splenectomy for symptomatic relief: Hazardous and often followed by worsening of condition.
What is CML?
Ph positive myeloproliferative neoplasia.
Incidence 1-2/100,000
M:F 1.4:1
40-60 years at presentation
Radiation exposure risk factor
What are clinical signs of CML?
History:
Lethargy/hypermetabolism/thrombotic event: Monocular blindness CVA, bruising bleeding.
Exam: Massive splenomegaly +/- hepatomegaly
What can be seen in terms of bloods for CML?
FBC:
- Hb and platelets well preserved or raised
- Massive leucocytosis 50-200x109 /L
Blood film:
- Neutrophils and myelocytes (not blasts if chronic phase)
- Basophilia
What are laboratory findings for CML?
Leucocytosis between 50 – 500x10 9 /l
Mature myeloid cells
Biphasic peak: Neutrophils and myelocytes
Basophils
No excess (<5%) myeloblasts
Platelet count raised/upper normal (contrast acute leuk)
Which translocation produces the Ph chromosome?
t(9;22)
BCR-ABL
How does BCR-ABL contribute to myeloproliferative neoplasms?
Expresses a fusion oncoprotein with constitutive tyrosine kinase activity. Drives myeloid proliferation.
Which available diagnostic techniques can be used to identify the translocation/fusion?
Conventional Karyotyping
FISH metaphase or interphase karyotyping
RT-PCR amplification and detection
How are myeloproliferative diseases and their responses monitored?
FBC and measure leucocyte count.
Cytogenetics and detection of Philadelphia chromosome.
RT-PCR of BCR-ABL fusion transcript which can be quantified by RQ-PCR to determine response to therapy.
What is the sequelae of disease of CML?
Chronic phase: Median 3-4 years duration
Accelerated phase (10-19% blasts): Median duration 6–12 months
Blast crisis (>20% blasts): Median survival 3–6 months
What is the treatment of CML?
Chronic phase:
Tyrosine kinase Inhibitor (TKI): Imatinib (1Gen,) Dasatanib, Nilotonib (2G), Bosutinib (3G)
Failure (1) > Switch to 2Gen or 3G TKI:
- No complete cytogenetic response at 1year
- Respond but acquire resistance
Failure (2) > Consider allogeneic SCT
- Inadequate response or intolerant of 2G TKIs
- Progression to accelerated or blast phase
