Myeloproliferative Disorders Flashcards
Myeloproliferative Disorders
- Clonal disorders of haemopoiesis with increased progeny of one or more cells
- Can include Chronic Myeloid Leukaemia but regarded as a separate disease
Myeloproliferative Disorder examples
-Polycythaemia rubra vera (PRV)
-Essential thrombocytosis (ET)
-Idiopathic myelofibrosis (IMF)
Can tranform into one another
All can terminate as acute myeloid leukaemia
Clonal pluripotent stem cell, hence transformation
Polycythaemia - Clinical Characteristics
An absolute increase in red cell volume or mass
Raised Hb
Raised PCV/Hct
When associated with a reduced plasma volume then a relative polycythaemia
Primary and Secondary Polycythaemia
Primary polycythaemia – clonal disorder
Secondary – driven either by increased erythropoietin (epo) production with or without hypoxia
Polycythaemia ruba vera (PRV) Clinical Characteristics
- Increased red cell mas with/without increase in platelets or neutrophils
- Stem cell disorders hyperplasia can give increase in three cell lines
- Autonomous erythropoiesis: normal or reduced epo concentration
- Red cell progenitors in PRV can survive in vitro without addition of epo
Myeloproliferative disorders associated cytogenetics
- No specific chromosome abnormaility but 20-30% have some abnormalities in karyotype. Not known if this is cuasative
- Deletion of part of long arm of chromosome 20
- Trisomy 8
Trisomy 9
Duplication of part of the long arm of chromosome 1
Duplication of part of the long arm of chromosome 13
-Abnormalities of chromosomes 5 and 7 are associated with disease progression - May be due to prior therapy
-Over expression of the gene PRV-1 is found on the neutrophils in PRV
-Decreased thrombopoietin receptor expression
Clinical Features of Myeloproliferative Disorders
2-3 cases per 100,000
Male:female ratio 0.3-1.2
55-60 years of age
Rare in childhood but can occur at any age
Thrombotic Complications of Myeloproliferative Disorders
- Most common feature
- Increased risk of arterial, venous and microvascular thrombosis
- Increased PCV causes an increase in the plasma viscosity, rheological abnormalities and abnormal platelet endothelial contact
Arterial Occulsions associated with Myeloproliferative Disorders
Myocardial infarction
Cerebro- vascular –accidents
Transient ischaemic attacks
Amaurosis-vision loss reducedblood flow
Scotomata- areas of lost vision
Mesenteric/limb ischaemia
Budd-Chiari- occlusion of hepatic vein
Neurological Factors associated with Myeloproliferative Disorders
-Headaches
-Drowsiness
-Insomnia
-Amnesia
-Tinitus
-Vertigo
-Chorea- abnormal jerky movements
Pruritis (itching) associated with Myeloproliferative Disorders
- Found in 25% of cases
- Can be severe
-Aquagenic
-Relieved by a reduction in the PCV
Skin conditions/ changes associated with myeloproliferative disorders
-Plethora – red-rosy complexion
-Dilated conjunctivial vessels
-Rosacae-like skin changes
-Sweet’s Syndrome- acute febrile neutrophilic dermatosis
Other associated complications of Myeloprolfierative Disorders
Splenomegaly – 30-50% of cases… ? Associated with myelofibrosis
Gout found in 5% of cases
Hypertension- common
Myeloproliferative Disorders and Disease transformation
- 1-3% of cases treated by venesection will transform into acute leukaemia
- 10-30% of cases treated with radioactive phosphorus, chlorambucil or irradiation will develop acute leukaemia in 5-8 years from diagnosis
- 10-20% of cases will develop myelofibrosis 15 years after diagnosis.
-Gradual transformation and is associated with the development of leukamia.
PRV/ PV - Diagnostic Criteria
A1: increased red cell mass or PCV > 0.60 in men or > 0.56 in women
A2: normal arterial O2 concentration (>92%) and no increase in epo
A3: palpable splenomegaly
A4 :acquired clonal genetic abnormality in haemopoietic cells ( not BCR/ABL)
B1: platelet count > 400
B2: neutrophils > 10.0 > 12.5 in smokers
B3: radiological splenomegaly
B4: endogenous erythroid colonies or low serum epo
A1 plus A2 and either another A or another two Bs establishes the diagnosis
PRV/PV: JAK2 mutation
- 95% of PRV are Janus Kinase 2 positive.
- JAK2; tyrosine kinase
- Important role in growth factor signalling
- Mutation causes activation of kinase with cell proliferative independent of normal growth factor control
- JAK2 mutation can be detected in approximately 90-95% of cases of polycythemia vera
50-70% of patients with essential thrombocythemia
40-50% of cases of idiopathic myelofibrosis
Prv/PV Treatment
-In the absence of thrombocytosis- regular venesection target PCV 0.45: Higher PCVs associated with thrombosis, Repeated venesection can cause Fe deficiency but then can cause a reactive thrombocytosis
- Hydroxyurea- free radical nitrous oxide reduces DNA replication: Well tolerated oral therapy can cause painful leg ulcers, gastro-intestinal side-effects and photosensitivity. ? Leukaema-genic
- Interferon alpha- good for younger patients, expensive, sub-cut injection. Flu like symptoms, fatigue and depression
- Anagrelide – used for thombocytosis- inhibits megakaryocyte differentiation. Used in conjunction with hydroxurea- lower doses of each. Can depend on the combination of factors being treated.
PRV Prognosis
Adequately treated PRV has a relatively benign natural history with life expectancy of 11 years
Average age of onset is 60
Myelofibrosis
- Agnogenic myeloid metaplasia
-Idiopathic myelofibrosis (IMF)
Primary Myelofibrosis - Clinical Characteristics/ Microscopy
-reticulin deposition in BM
-ineffective BM haematopoiesis, extramedullary haematopoiesis in spleen and liver, associated with anaemia and splenomegaly
-fibrosis is secondary to megakaryocyte dysplasia
-dysplastic megakaryocytes produce pro-inflammatory cytokines which stimulate fibroblasts to produce collagen fibres
Pathophysiology and cytogenetics of Myelofibrosis
-clonal myeloproliferative disorder of the pluripotent haemopoietic stem cell
-Multiple cell lineages with progressive fibrosis
-Secondary to release of pro-inflammatory cytokines from the clonal cells- primarily megakaryocytes
-Increased numbers of CD34+ cells in the peripheral circulation
-Colony formation without exogenous growth factors
-No specific cytogenetic abnormalities, commonest deletion of 20q, 13q, Trisomy 8 and abnormalities of chromosomes 1,5,7,9
-Oncogene mutations are rare but include point mutations in N-Ras, c-KIT and p53
-Deletion/ down-regulation of retinoic acid receptor.
Patient Distribution of Myelofibrosis
- Predominantly over 50 years old
- Median ago 67 years old
- 1 in 500,000
- Rare in the young
- No sex prevalence
Causes of Myelofibrosis
- Essentially unknown
- Linked to exposure to benzene and radiation
- Acquired mutation of genetic material
Symptoms of Myelofibrosis
Anaemia
Splenomegaly
Bone pain-especially lower legs
Lethargy
Bruising/bleeding
Night sweats
Infections
Pathophysiology of Myelofibrosis
- Bone marrow infiltration/replacement with fibrous tissue
- Extra-medulary haemopoiesis- liver and spleen
Organomegaly associated with Myelofibrosis
Oranomegaly: Enlargement of organs
Splenomegaly due to extra-medullary haemopoiesis
Splenic infarction
Hepatomegaly due to extra-medullary haemopoiesis
Portal hypertension
Ascites
Oesophageal varices
Diagnosis of Myelofibrosis
-Abnormal FBC
-Leuco-erythroblastic picture
-Tear drop poikilocytes
-Bone pain
-Splenomegaly
-General symptoms associated with haematological malignancy
- Bone marrow aspirate
- Trephine biopsy
Treatment of Myelofibrosis
-Transfusion to support anaemia
-Erythropoietin
-Hydroxyurea with steroids, can improve haemopoiesis
-Andreogens- testosterone, oxymetholone can improve haemopoiesis
-Radiotherapy t0 reduce spleen
-Thalidomide with steroids- reduces spleen size, improves anaemia and better haemopoiesis: Experimental
Essential Thrombocythaemia (ET)
-Persistent elevation of the platelet count above 600 x10 9/l
-Poorly understood- lack of positive diagnostic criteria
Pathophysiology of ET
Clonality is difficult to establish-heterogeneous disease
-Thrombopoietin (TPO) mutations not found, whereas in congenital thrombocytosis they have
-TPO levels similar to reactive thrombytosis and therefore not diagnostic
Clinical features of ET
1.5 – 2.0 cases per 100,000
Median age of onset 50-55 years
Rare in childhood but can occur at any age
Thrombotic Complications of ET
-15-20% of cases present with a thrombosis, arterial or venous
-Risk factors include age >60, platelet count >1000 x 10 9/l, hyperlipidaemia, hypertension and smoking
Adverse prognostic indicators of ET
-Males
-Monoclonal haemopoiesis
-Anti-phospholipid antibodies
-Spontaneous megakryocyte or erythroid colonies
-Factor V Leiden
Haemorrhagic Complications of ET
-More common with platelet count >1000 x10 9/L
-No risk predictors
-Acquired von Willebrands disease decrease in HMW multimers
Splenomegaly and hyposplenism associated with ET
-20-25% of cases
-Rarely more than moderate
-Progressive splenomegaly- suspicious of development of myelofibrosis
-May develop splenic atrophy due to micro-infarctions
Leukaemic Transformation seen in ET
-Evolve into myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) but only rarely ( small risk)
-Increased risk associated with cytogenetic abnormalities and treatment with alkylating agents
-3% treated with hydroxurea will develop AML or MDS
Myeloproliferative disorders transformation to PRV and Myelofibrosis
-Less than 10% transform to myelofibrosis
-1-2% transform to PRV
Investigations and diagnostic criteria of Myelofibrosis
-Diagnosis of exclusion
-Persistent raised platelet count (>600)
-Other clonal disorders must be ruled out
-Platelet count >600 for a minimum of 2 months
-No evidence of PRV
-No reactive cause for thrombocytosis
-No evidence of iron deficiency
-No evidence of CML
-No evidence of MDS; no significant dysplasia, no cytogenetic abnormalities associated with MDS
-No evidence of myelofibrosis; no collagen fibrosis, minimal or no reticulin fibrosis
Causes of reactive thrombocytosis ( Secondary thrombocytosis)
Iron deficiency
Blood loss acute or chronic
Hyposplenism/splenectomy
Surgery
Malignancies
Drugs; vincristine
What is reactive thrombocytosis
Reactive thrombocytosis, also known as secondary thrombocytosis, is a condition characterized by an elevated platelet count in response to an underlying cause or stimulus.
Treatment of reactive thrombocytosis
-High-risk over 60 >1500 platelet count, previous history of thrombosis, diabetes and hypertension. Hydroxyurea, anagrelide and aspirin have been used.
-Intermediate risk – none of above risks usually aspirin alone and some Hydroxyurea. 40-60 years old
-Low risk- less than 40 years old, no risk factors, low dose aspirin, some platelet inhibitors
Prognosis of reactive thrombocytosis
-Some studies suggest mortality at 10 years is the same as matched controls but some studies contrary
-In high risk patients Hydroxyurea reduces the risk of vaso-occlusive events from 10.7 to 1.6 per 100 patient years
ET and Pregnancy
-Most common MPD encountered in pregnant women
-Commonest complication is miscarriage in the first trimester in up to 30% of pregnancies.
-Secondary to placental infarcts
-Greater risk of maternal thrombosis/haemorrhage
-Treat with aspirin and interferon
-Not Hydroxyurea or anagrelide as they can be teratogenic
Myelodysplastic Syndrome Definition
clonal disorder of haematopoietic stem cells characterised by production of abnormal (dysplastic) cells in 1 or more lineages
Myelodysplastic Syndrome (MDS)Subtypes
refractory anaemia (RA)
refractory anaemia with ring sideroblasts (RARS)
del(5q) syndrome
refractory neutropaenia (RN)
refractory thrombocytopaenia (RT)
refractory cytopaenia with multilineage dysplasia (RCMD)
refractory anaemia with excess blasts type 1 (RAEB-1)
refractory anaemia with excess blasts type 2 (RAEB-2)
Clinical features / symptoms of MDS
vague symptomology – often found by chance on a routine FBC
lethargy
bruising and bleeding
susceptibility to infection
MDS Diagnosis
most patients are >70 years old at diagnosis
diagnosis dependent on both quantitative (eg FBC) and qualitative (eg dysplasia on blood films) abnormalities
Common dysplastic ( change in size and shape of cells) features in MDS
- RBC poikilocytosis
- Pseudo-Pelger Nucleus
- Ringer Sideroblast (erythroblast with iron laden mitochondria
- Macropolycyte (giant neutrophils)
- Excess blasts (RAEB-2)
WHO classification/ Diagnosis of MDS
classification based on:
blood count
morphological appearance
percentage of blast cells in blood/bone marrow
MDS are pre-leukaemic disorders and highly prone to transformation to AML - higher blast % is associated with poorer prognosis
> 20% blast percentage is considered AML
revised WHO criteria tries to streamline MDS diagnosis by focusing on:
number of dysplastic lineages (SLD vs MLD)
number of cytopaenias
percentage of ring sideroblasts
percentage of blast cells in blood/bone marrow
Genetic Aetiology of MDS ( pathogenesis and cytogenetics)
Risk factors for mutations
- pathogenesis is unclear but thought to be due to accumulation of driver mutations in key genes in a multipotent haematopoietic progenitor cell
- chromosome abnormailities and mutations are frequent, commonly effecting these across all MDS subtypes:
-RNA splicing (SRSF2, SF3B1, U2AF1)
-epigenetic regulators (DNA methylation, histone modification)
-transcription factors (RUNX1, GATA2)
-cytokine signaling (JAK2, KIT)
-chromatin architecture (cohesin, mediator) - Risk factors for mutations :smoking, ionising radiation, pesticides and chemicals e.g. benzene.
- usually primary and can be secondary to chemotherapy and radiotherapy ( called therapy-related MDS or t-MDS)
Prognosis of MDS. Scoring system.
-Prognosis is variable - depends on MDS type
-Scoring systems help predict prognosis e.g. International Prognostic Scoring System (IPSS) e,g:
–degree of cytopaenia influences the incidence of complications and treatment
–% blast cells is a predictive risk of developing leukaemia
–some cytogenetic groups indicate good prognosis (eg. Del(5q) syndrome) or indicate poor prognosis (MDS with complex cytogenetic changes)
- Death may be caused by infection, hemorrhage, iron overload from multiple transufsion or transformation into AML
Treatment of MDS
For Low Risk MDS (low grade):
(less than 5% of blasts in the marrow, only one cytopaenia and favourable cytogenetics)
Treatment may not be necessary
Haemopoietic growth factors e.g. Eythropoietin, G-CSF, to correct cytopaenias
Antibiotics/anti-fungals etc
Transfusions e.g. platelets, red cells
Iron Chelation
Lenalidomide in MDS associated with del(5q)
Treatment for High Risk MDS:
Chemotherapy (azacytidine, decitabine)
DNA methyl-transferase inhibitors (hypomethylating agents)
Stem cell transplantation
Supportive care only
MDS with del (5q)
-characterized by deletion of q arm of chromosome 5
– total deletion in most cases are ~70Mb which results in haploinsufficiency of up to 40 genes
-one crucial gene in del(5q) region is CSNK1A1 which encodes a protein casein kinase 1a
