Myeloproliferative neoplasms Flashcards
What are the four main WHO classifications of myeloproliferative neoplasms?
- CML
- Polycythaemia Vera
- Essential thrombocythaemia
- Primary myelofibrosis
When does clonal expansion occur in CML?
- During accelerated phase (= blast crisis)
- This clone tends to be lineage specific (usually myeloid, less commonly lymphoid)
Production of what cells are affected in CML?
- RBCs
- Platelets
- WBC subsets (basophils, neutrophils, eosinophils and monocytes)
What full blood count measure is a good indicator of CML?
- Increased basophil count
What is the major cytogenetic abnormality in CML and how can it be detected?
- t(9;22)(q34;q11) leading to BCR-ABL1 gene fusion on der(22) = Philadelphia chr
- chimaeric abnormal protein = enhanced tyrosine kinase activity
- can be detected by karyotype, FISH and PCR
What is the main drug that targets CML and what type of drug is it?
- imatinib
- tyrosine kinase inhibitor
- designed to fit into ATP binding site of chimaeric protein - if blocked it is effectively switched off
What type of FISH probe is used for detection of BCR-ABL1 gene fusion?
- Dual fusion probe
- Normal interphase pattern is 2R2G
- BCR-ABL1 positive cells = 1R1G2F (2 fusions)
What are the three main types of response in CML therapy?
- Haematological response
- Cytogenetic response
- Molecular response
What are the sub-criteria for haematological response in CML?
- Normalisation of blood counts
- Disappearance of splenomegaly
What are the sub-criteria for cytogenetic response in CML?
- Major cyto response = more than 65% Ph negative
- Complete Cyto response = 100% Ph negative
What percentage of newly diagnosed CML patients taking imatinib achieve complete cytogenetic remission?
Three quarters (75%)
Do patients with complete cytogenetic remission still harbour leukaemic cells in their bodies?
- Yes but at a very low level
- Patients with low transcript numbers are less likely to relapse
Molecular response to treatment in CML is assessed based on size of the log reduction in number of Philadelphia chr positive cells. What are the subcategories?
- Less than major = less than 3 LR
- Major = greater than or equal to 3 LR in two consecutive samples
- Complete = BCR-ABL1 negative in two consecutive samples of adequate sensitivity (greater than or equal to 4 LR)
A 3+ log reduction in BCR-ABL is achieved by an estimated how many imatinib patients?
Two thirds (66%)
What is the difference between primary and acquired resistance in CML?
- Primary resistance = failure to achieve a response
- Acquired resistance = loss of a confirmed response
Provide some details on primary resistance in the context of haematological and cytogenetic response
Primary haematological resistance:
- failure to achieve a complete haematological response in chronic phrase
- failure to return to chronic phase when in advanced disease
Primary cytogenetic resistance:
- failure to achieve a complete/major cytogenetic response
What are the most common mechanisms of resistance in CML?
- BCR/ABL mutations
- Kinase domain mutations account for more than 50% of acquired resistance
In what scenarios should mutation analysis be performed in CML?
- Primary treatment failure
- Loss of haematological/cytogenetic response
- Sub-optimal response
- Transcript level increase more than 1 log on 2 occasions
- Before switching to a second line tyrosine kinase inhibitor
If a BCR-ABL mutation is identified what happens?
A specific tyrosine kinase inhibitor will be given dependent on the mutation involved
What is polycythaemia Vera?
Expansion of the erythrocyte lineage characterised by high peripheral red blood cell count numbers
What is essential thrombocythaemia?
Sustained increase in platelets with associated effects
What is primary myelofibrosis?
Clonal disorder caused by transformation of early haematopoietic progenitor cells resulting in bone marrow fibrosis
Mutations in three main genes are involved in polycythaemia Vera, essential thrombocytopenia and primary myelofibrosis. What are they?
- JAK2
- CALR
- MPL
Provide details on MPL mutations in myeloproliferative neoplasms
- MPL encodes thrombopoietin receptor
- Mutations found in 3-10% of patients with essential thrombocytopenia or myelofibrosis
- Most common mutation hotspot is W515
Provide some details on JAK2 mutations in myeloproliferative neoplasms
- JAK2 is a tyrosine kinase downstream of many receptors including that of EPO
- JAK2 mutations found in 97% of patients with PCV and 50-60 of those with essential thrombocytopenia and primary myelofibrosis
- Common mutation is V617F (mutations may also occur in exon 12)
Provide details on CALR mutations in myeloproliferative neoplasms
- CALR mutations affect 1/3 of patients with essential thrombocytopenia or myelofibrosis
- Mainly Frameshift mutations
- Most common are a 5bp insertion (50%) or a 52bp deletion
