myeloproliferative disorders Flashcards
what are the different kinds of myeloproliferative neoplasms?
- Chronic myeloid leukaemia - too many myeloid cells
- Polycythaemia rubra vera - too many red cells
- Essential thrombocythemia - to may platelets
- Myelofibrosis - fibrosis of the bone marrow secondary to ET/PRV
An overlap of PV/ET/myelofibrosis is not uncommon as there is a common clonal origin from multipotent hematopoietic stem cells.
what genetic abnormalities are associated with polycythaemia vera
Most patients with polycythemia vera have a mutation in the JAK2 gene (97%) but others may have a mutation in calreticulin
JAK2 - Activating tyrosine kinase mutation in pseudokinase domain which causes disruption of auto-inhibitory effect on tyrosine kinase activity causing cell proliferation which is uncontrolled.
Calreticulin - this is a frameshift mutation on chromosome 19. It has normal functions such as
- Within ER - chaperone ensuring quality control of glycoprotein folding and calcium homeostasis
- Outside ER - found in cytoplasm, cell surface and extracellular compartments and plays a role in cell proliferation, apoptosis, phagocytose and immunogenic cell death.
what is the clinical presentation of polycythemia vera ?
Typical - Middle aged man presenting with DVT
- Pruritis after hot bath - red - aquagenic pruritus
- Headache
- Dizziness
- Blurred vision
- Feeling full in the head
on physical examination
- Plethoric
- Palpable spleen
- Conjunctival suffusion
- Engorged retinal vessels
- Tendency to thrombosis - DVT, MI, CVA
- Erythromelalgia
- Tendency to bleeding - epistaxis, GI bleeding
- Hypertension
outline the causes of polycythaemia (increased red cells)
- Polycythemia vera - 95% are Jak-2 positive - not the only cause
Hypoxia - normal physiological response to low oxygen which can be caused by Smoking, Lung disease, Cyanotic heart disease and altitude - Certain rare tumours poi
- Rare Hb variants
- Too much or inappropriate erythropoietin
- Spurious - due to reduced plasma volume so red cell volume appears increased because haematocrit is a volume of blood as a % of total volume eg. in dehydration
how is polycythaemia vera treated?
treatment aims to reduce the risk of thrombosis and haemorrhage and to minimise the risk of transformation to acute leukaemia and myelofibrosis
- Venesection to get Hct less than 0.45
- Antiplatelet treatment - aspirin 75mg
- Hydroxycarbamide therapy for thrombocytosis - this may increase risk of transition to leukaemia and myelofibrosis
what is the survival rate of polycythaemia vera?
65%
what is the typical presentation of essential thrombocytopaenia?
median age of 50-55 with another peak at 30 for females
clinical features
- mostly asymptomatic at diagnosis
- vascular events: arterial thrombosis or microvascular occlusive symptoms (Erythromelalgia, Acroparesthesia, Digital ischaemia, Neurological symptoms - TIA, migraine like headache, dizziness, Vision disturbances - transient blindness, blurred vision, photobia)
- bleeding
- aquired von willibrands disease
what are the differential diagnosis for essential thrombocytopaenia? (other causes of thrombocytopenia)
- secondary/reactive
- Cancer
- Iron deficiency
- Acute haemorrhage
- Infections
- Inflammatory states
- Asplenia
what are the differential diagnosis for essential thrombocytopaenia? (other causes of thrombocytopenia)
- secondary/reactive
- Cancer
- Iron deficiency
- Acute haemorrhage
- Infections
- Inflammatory states
- Asplenia
how are treatment options decided for essential thrombocytopaenia?
risk assessment is done splitting people into low, intermediate and high risk
Low risk - no cytoreductive therapy
- Age less than 60
- Platelets less than 1500
- No prior TED or bleeding
- No CV risks op
- No hereditary thrombophilia
Intermediate risk - individualised treatment decision
- Platelets less than 1500
- Age less than 60
- No TED/bleeding
- CVS risk factors
- Hereditary thrombophilia
High risk - ASA and cytoreduction
- Age more than 60
- Platelets more than 1500
- Prior TED
how is essential thrombocytopaenia treated?
Cytoreductive treatment
- 1st line - hydroxyurea - ribonucleotide reductase inhibitor. It is essentially a chemotherapy drug but given at low doses (15mg/kg). Side effects of BM suppression, diarrhea, leukemogenic, skin cancer
- 2nd line - anagrelide - inhibits megakaryocyte differentiation and platelets aggregation. ⅓ discontinue due to side effects
ASA
Normal life expectancy for most patients following treatment. Less survival in patients presenting after symptoms.
what is the typical presentation of myelofibrosis?
- median age of 60
clinical features
- Fibrotic marrow - marrow failure
- Cytopenias
- Very large spleen - splenomegaly
- Hepatomegaly
- Hypermetabolic symptoms
- Hyperuricemia
- May be asymptomatic
- Spleen pain
- Fevers, sweats
- Back pain
- Infections
how is myelofibrosis diagnosed?
diagnosis requires A1 and A2 and any 2 B criteria
A1 - bone marrow fibrosis 3 (on 0-4 scale)
A2 - pathogenic mutation (eg. JAK2, MPL, CALR) or absence of both BCR-ABL1 and reactive causes of bone marrow fibrosis
B1 - palpable splenomegaly B2 - unexplained anaemia B3- leuko-erythroblastosis B4- tear drop red cells B5- constitutional symptoms B6 - histological evidence of extramedullary haematopoasis
how is myelofibrosis diagnosed?
diagnosis requires A1 and A2 and any 2 B criteria
A1 - bone marrow fibrosis 3 (on 0-4 scale)
A2 - pathogenic mutation (eg. JAK2, MPL, CALR) or absence of both BCR-ABL1 and reactive causes of bone marrow fibrosis
B1 - palpable splenomegaly B2 - unexplained anaemia B3- leuko-erythroblastosis B4- tear drop red cells B5- constitutional symptoms B6 - histological evidence of extramedullary haematopoasis
how is myelofibrosis treated?
- Blood transfusions
- Allogenic stem cell transplant if young and fit
- Thalidomide
- Medroxyprogesterone
- Ruxolitinib - JAK inhibitor. this causes a Rapid improvement in constitutional symptoms, Rapid reduction in splenomegaly, Improvement in blood counts, Transfusion independence, Rapid improvement in quality of life, Early data on improved survival
Do not stop abruptly due to withdrawal syndrome
how is myelofibrosis treated?
- Blood transfusions
- Allogenic stem cell transplant if young and fit
- Thalidomide
- Medroxyprogesterone
- Ruxolitinib - JAK inhibitor. this causes a Rapid improvement in constitutional symptoms, Rapid reduction in splenomegaly, Improvement in blood counts, Transfusion independence, Rapid improvement in quality of life, Early data on improved survival
Do not stop abruptly due to withdrawal syndrome
what is chronic myeloid leukaemia (CML)?
A type of myeloproliferative disease which involves the accumulation of myeloid progenitors causing a high white blood cell count and a large spleen. it can transform into acute leukaemia
it is caused by a reciprocal translocation between chromosome 9 and 22 (philadelphia chromosome) which creates the bcr-abl protein that uncontrollably drives proliferation of myeloid cells. This is used to monitor the disease as you can monitor levels.
how is CML treated?
previous treatment
- myelosuppressive therapy - hydroxycarbamide
- transplantation
new treatment
- Imatinib - inhibits the binding of ATP to ABL tyrosine kinase - has a major haematological, cytogenetic and molecular response, effectively curing patients.
- Mutations in BCR-ABL which stop imatinib working so next generation drugs are made:
Nilotinib
Dasatinib
Bosutinib
Ponatinib
what is myelodysplasia ?
Bone marrow cancer (used to be called pre leukaemia). characterised by Variable reduced numbers of mature red, white cells and platelets.
Cells that are produced are not quite right and can look abnormal under the microscope and function less well. Primitive cells may accumulate as they fail to mature normally. Cells are less healthy and die quicker
there are multiple subtypes that exist
what are the causes of myelodysplasia?
No obvious cause
Can be secondary to chemotherapy
Weak familial risk - family history of MDS and AML
Rare inherited bone marrow failure syndromes
how does myelodysplasia present?
- Affects the elderly mostly
- Presents as bone marrow failure - 1 or more of anaemia, neutropenia, thrombocytopenia
- Chronic myelomonocytic leukaemia has raised monocytes - more than 1
- Can progress to acute myeloid leukaemia
- Dysmorphic features suggesting congenital bone marrow failure
how is myelodysplasia treated?
- Allosteric stem cell transplant if patient young and fit but this is rare
- Most will need transfusion - may cause iron overload
- Supportive care
- HMA
- Clinical trials
- ATG
- Lenalidomide
- Erythropoietin - Reduces rates lower in MDS than in other malignancies with a Mean response rate of 16%-20%. Stimulates red cells. Response rates may improve when given in combination with G-CSF
