myeloproliferative neoplasms Flashcards
myeloproliferative neoplasms
clonal haemopoietic stem cell disorders with an increased production of one or more types of haemopoietic cells
–> in contrast to leukaemia, maturation is relatively preserved
types of myeloproliferative disorder
BCR-ABL1 negative
- polycythaemia vera - over production of RBC
- essentrial thrombocythaemia - over pro of platelets
- primary myelofirbosis
BCR-ABL1 positive
- chronic myeloid leukaemia - over production of granulocytes (philadelphia chromosome)
when to consider a myeloproliferative neoplasm (MPN)?
No reactive explanation to –
Bloods
High granulocyte +/-
High red cell count / Hb +/-
High platelet count +/-
Eosinophilia/basophilia
o Splenomegaly
o Thrombosis in an unusual place
features commone to MPN
asymptomatic
increased cell turnover - gout, fatigue, weaight loss, sweats
splenomegaly symptoms
marrow failure
thrombosis - arterial or venous, TIA, MI, claudication
chronic myeloid leukaemia
cytogenic change = Philadelphia chromosome t(9;22) translocation
proliferation of myeloid cells - granulocytes + their precursors, other lineages (platelets)
fatal without stem cell/bone marrow transplantation in chronic phase
genetics of chronic myeloid leukaemia
philadelphia chromosome results in a new (chimaeric) gene) -> BCR-ABL1
gene product is a tyrosine kinase which causes abnormal phosphorylation ( signalling) leading to the haematological changes in CML
–> durable disease responses with tyrosine kinase inhibitors
phases of chronic myeloid leukaemia
- chronic phase – can last around 5yrs, often asymptomatic, accidental diagnosis with raised WCC
- accelerated phase –
a. abnormal blast cells take up a high proportion of cells in bone marrow + blood
b. patients become more symptomatic – anemia, thrombocytopenia, immunocompromised - blast phase
a. even high proportion of blast cells + blood
b. severe symptoms + pancytopenia – often fatal
chronic myeloid leukaemia
asymptomatic
splenomegaly
hypermetabolic - weight loss, weating
gout
priapism - prolonged erection
blood count findings in chronic myeloid leukaemia
normal/low Hb
leucocytosis with neutrophilia + myeloid precursors (myelocytes), eosinophilia, basophilia
-> an increase in granulocytes at different stages of maturation +/- thrombocytosis
management of chronic myeloid leukaemia
imatinib
- inhibitor of tyrosine kinase assoc with BCR-ABL defect
(CML is the paradigm for targeted therapies in oncology)
polycythaemia vera
myeloproliferative disorder caused by clonal proliferation of marrow stem cell leading to an increase in red cell volume
- often accompanied by overproduction of neutrophils + platelets
high Hb/haemocrit accompanied by erythrocytosis
JAK2 present in 95%
peak incidence = 60s
different types of polycythaemia vera
primary = polycythaemia vera
secondary polycythaemia -> chronic hypoxia, smoking, erythropoietin-secreting tumour
pseudopolycythaemia (relative) -> dehydration, diuretic therapy, obesity
how to distinguish between true vs pseudo polycythaemia
red cell mass studies
in true -> total red cell mass >35ml/kg in males + >32ml/kg in females
polycythaemia vera presentation
MPN features
headache, fatigue
increased BLOOD viscosity - arterial/venous thrombosis
haemorrhage - secondary to abnormal platelet function
aquagenic puritis (itch after a hot bath)
polycythaemia vera investigation
FBC + Flm
- raised haemocrit, neutrophils, basophils, platelets (raised in half)
- low esr
- raised leukocyte alkaline phosphatase
JAK2 mutation status - mutational analysis
investigate for secondry/pseudo causes
- CXR, O2 sats, arterial blood gases, drug history
JAK2 mutation
JAK2 = a kinase
mutation (substitution) results in a loss of auto-inhibittion
- activation of erythropoiesis in the absence of ligand
mutations present in >95% of polycythaemia vera patients
- *mutational analysis froms part of intital screening + has replaced a number of other tests
management of polycythaemia vera
venesect to haemocrity <0.45
aspirin (reduces thrombosis)
hydroxycarbamide (cytotoxic oral chemo)
5-15% progress to myelofibrosis or acute leukaemia (risk increased with chemo treatment
*thrombotic event = significant cause of morbidity + mortality
essential thrombocythaemia/thrombocytosis (ET)
uncontrolled over production of abnormal platlets
abnormal platelet function leads to
- thrombosis
- at high levels can also cause bleeding due to acquired von Willebrand disease
essential thrombocytosis presentation
MPN futures - esp vaso-occlusive complications
both thrombosis (venous+arterial) + haemorrage
burning sensation in hands
unpredictable bleeding risk, esp at surgery
platelet count >600 x109/l
diagnosis of ET
exclude reactive throbocytosis - blood loss, inflammation, malignancy, iron deficiency
exclude CML
genetics
- JAK2 in 50-60%
- CALR (calreticulin) in 25%
- MPL in 5%
- 10-20% will be “triple negative”
characteristic bone marrow appearances
management of essential thrombocytosis
antiplatelet agents
cytoreductive therapy to control proliferation
- hydroxycarbamide (hydroxyurea)
- anagrelide
- interferon alpha
causes of thrombocytosis
reactive - infection, surgery, iron deficiency anaemia
malignancy
essential thrombocytosis or other myeloproliferative disorder
hyposplenism
myelofibrosis
thought to be caused by hyperplasia of abnormal megakaryocytes
- resultant release of platelet derived growth factor is though to stimulate fibroblasts
haematopoiesis develops in liver + spleen (extramedullary)
can be idiopathic or post polycythaemia or essential thrombocythaemia
myelofibrosis presentation
marrow failure - anemia, bleeding, infection
massive splenomegaly
- LUQ abdo pain, draggin sensation
- complications - portal hypertension
hyercatabolism - weight loss, night sweats
MPN features
myelofibrosis investigation
blood film
- *tear drop shaped RBC
- leucoerythroblastic
dry aspirate
fibrosis on trephine biopsy
JAK2, CALR, MPL mutations - 10% triple neg
myelofibrosis management
supportive care
- blood transfusion
- platelets
- antibiotics
allogenic stem cell transplantatio in a select few
splenectomy - CONTROVERSIAL
JAK2 inhibitors - improve spleen size, constitutional symptoms
reactive causes of inreased granulocytes
infection - pyogenic bacteria causing neutrophilia
physiological - post surgery, steroids
leucoerythroblastic film
presence of granulocyte left shift (immature) as well as nucleated red blood cells on the same blood film
-> this is always an abnormal finding, and may indicate a major acute stress or bone marrow infiltration.
causes
- Acute stress - haemorrhage, shock
- Bone marrow infiltration - myeloproliferative neoplasms, leukaemias, lymphomas, myeloma, metastatic cancer
- G-CSF administration
