CML and Myeloproliferative Disorders Flashcards
Normal Hb
135-175
Normal heamatocrit
0.41-0.53
True polycythaemia
Increased red cell mass
No change in plasma volume
Causes of true polycythaemia
Primary polycythaemia vera (reduced EPO) Secondary polycythaemia (elevated EPO)
Relative (pseudo) polycythaemia
No change in red cell mass
Reduced plasma volume
Causes of pesudo polycythaemia
Alcohol
Obesity
Diuretics
Causes of true secondary (non-malignant) polycythaemia
Raised erythropoietic can be appropriate or inappropriately raised.
Appropriately: High altitude Hypoxic lung disease Cyanotic heart disease High affinity haemoglobin
Inappropriate:
Renal disease (cysts, tumours, inflammation)
Uterine myoma
Other tumours (liver, lung)
Haematological malignancies
Myeloid
Lymphoid: precursor cell malignancy or mature cell malignancy
Myeloid malignancies
Acute myeloid leukaemia (blasts >20%)
Myelodysplasia (blasts 5-19%)
Myeloproliferative disorders: Essential thrombocythaemia (megakaryocyte), Polycythemia vera (erythroid), Primary myeofibrosis
Chronic myeloid leukaemia
Lymphoid: precursor cell malignancies
Acute lymphoblastic leukaemia (B & T)
Lymphoid: mature cell malignancies
Chronic Lymphocytic leukaemia
Multiple myeloma
Lymphoma (Hodgkin & Non Hodgkin)
Myeloproliferative disorders
Ph negative: polycythaemia vera, essential thrombocythaemia, primary myelofibrosis
Ph positive: chronic myeloid leukaemia
What processes are disrupted by mutation in blood cell formation
Impair/block cellular differentiation (type 2) Cellular proliferation (type 1) Prolong cell survival (anti-apoptosis)
Mutation mechanisms
DNA point mutations
Chromosomal translocations: Creation of novel Fusion gene, Disruption of proto-oncogene
Leukaemia mutations
Cellular proliferation (type 1) –> tyrosine kinase activation
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
Tyrosine kinase mutations
Expansion increase in mature/end cells
Red cells; polycythaemia
Platelets; essential thrombocythaemia
Granulocytes; chronic myeloid leukaemia
What gene mutations are associated with myeloproliferative disorders
JAK2
Calreticulin
MPL
Polycythaemia vera epidemiology
Annual incidence 2-3/100000
Slightly more in males 1.2:1
Mean age at diagnosis 60 years
5% below age of 40 years
Polycythaemia vera clinical presentation
Incidental diagnosis on routine blood testing
Symptoms of increased hyper viscosity: Headaches, light-headedness, stroke, Visual disturbances, Fatigue, dyspnoea
Increased histamine release: Aquagenic pruritus, Peptic ulceration
Clinical findings in polycythaemia vera
Variable splenomeagaly 79% of cases
Plethora
Erythromelalgia: red painful extremeties
Thrombosis
Retinal vein engorgement
Gout due to increased red cell turnover and overproduction of uric acid
Absence of other causes of increased haematocrit
Principles of treatment of polycythaemia vera
Aim to reduce viscosity as blood viscosity rises expenonentially with rising HCT : keep HCT <45%: Venesection, Cytoreductive therapy for maintenance hydroxycarbamide
Aim to reduce risks of thrombosis: Aspirin, Keep platelets below 400x109/l (same as treatment of essential thrombocythaemia)
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
Essential thrombocythaemia clinical presentation
Incidental finding in half the patients
Thrombosis: arterial or venous: CVA, gangrene, TIA, DVT or PE
Bleeding: mucous membrane and cutaneous
Minor: headaches, dizziness visual disturbances
Splenomegaly usually modest
Treatment for essential thrombocythaemia
Aspirin: to prevent thrombosis
Anagrelide: specific inhibition of platelet formation, side effects include palpitations and flushing
Hydroxycarbamide: antimetabolite. Suppression of other cells as well. Possible mildly leukaemogenic
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
Primary myelofibrosis
A clonal myeloproliferative disease with proliferation mainly of megakaryocytes and granulocytic cells, associated with reactive bone marrow fibrosis and extramedullary haematopoieisis
Primary presentation:
Incidence 0.5-1.5 /100000
Males=females
7th decade. Less common in younger patients
Secondary to other haematological disease: progression from PV or ET
Clinical presentation of primary myelofibrosis
Incidental finding in 30%
Cytopenias: anaemia or thrombocytopenia
Thrombocytosis
Splenomegaly: may be massive: Budd-Chiari syndrome
Hepatomegaly
Hypermetabolic state: Weight loss, Fatigue and dyspnoea, Night sweats, Hyperuricaemia
Early stages of myelofibrosis
Prefibrotic stage
Blood changes mild but may also be confused with ET
Hypercellular marrow
Later stages of myelofibrosis
Fibrotic stage
Splenomegaly and blood changes
Dry tap, with prominent collagen fibrosis and later osteosclerosis.
Blood film findings on primary myelofibrosis
Leucoerythroblastic picture
Tear drop poikilocytes
Giant platelets
Circulating megakaryocytes
Liver and spleen: extramedullary haemopoiesis in spleen and liver
Bone marrow findings in primary myelofibrosis
Dry tap
Trephine: increased reticulin or collagen fibrosis, prominent megakaryocyte hyperplasia and clustering with abnormalities
New bone formation
Prognosis for primary myelofibrosis
Median 3-5 years, but very variable
Bad prognostic signs in primary myelofibrosis
Severe anaemia <10g/dL
Thrombocytopenia <100x109/l
Massive splenomegaly
Prognostic scoring system (DIPPS):
Score 0 – median survival 15years
Score 4-6– median survival 1.3 years
Treatment of primary myelofibrosis
Often symptomatic
Anaemia: transfusions: may become increasingly difficult because of splenomegaly
Platelet transfusions often ineffective
Splenectomy for symptomatic relief: often hazardous and followed by worsening of condition
Cytoreductive therapy: hydroxycarbamide for thrombocytosis, may lead to worsening of anaemia
Ruxolotinib JAK2 inhibitor (high prognostic score)
Bone marrow transplant in young patients may be curative (experimental)
Clinical features of CML
M:F 1.4:1 40-60 years (but can occur at any age) Weight loss, lethargy, night sweats Lethargy/ hypermetabolism/ thrombotic event : monocular blindness CVA Splenomegaly +/- hepatomegaly: enlarged due to infiltration of cords and red pulp by granulocytes - this same process occurs in the liver hepatic sinusoids. Features of anaemia Bruising/bleeding Gout
FBC findings in CML
Hb and platelets well preserved or raised
Massive leucocytosis 50-200
Blood film in CML
Mature myeloid cells
Neutrophils and some myelocytes (not blasts if chronic phase)
Basophilia
No excess (<5%) myeloblasts
CML
CML is one of the Myeloprolifive disorders that arises from an abnormal pluripotent BM stem cell
Natural history of CML
Not the clinical course, as this is altered by treatment
Chronic phase:
-approximately 80% of patients with CML are diagnosed
in the chronic-phase
-can last from a few months to about 4-5 years
-nearly 80% of patients with CML will progress from the
chronic-phase to the accelerated-phase
-5% or fewer of the cells in the blood and bone marrow
are blast cells
Accelerated phase:
10-19% of the cells in the blood and bone
marrow are blast cells
Median 6-12 months
Blast crisis:
≥20% of the cells in the blood and bone
marrow are blast cells
Median survival 3-6 months
What is the Philadelphia chromosome
Produced by t(9;22) producing a fusion oncoprotein with tyrosine kinase activity (BCR-ABL fusion gene)
Translocation of part of the long arm (q) of c/some 22 to c/some 9
And reciprocal translocation of part of c/some 9, which includes the ABL oncogene to a specific breakpoint cluster region (BCR) of c/some 22
A fusion gene results on the derived c/some 22
This leads to the synthesis of an abnormal protein with TK activity greater than the normal ABL protein
Detection of Philadelphia chromosome
FISH
How can you monitor disease and response to therapy in CML
FBC and leucocyte count: restored to normal FBC (complete haematological response WBC<10)
Cytogenetics and detection of Ph chromosome: reduction in percentage of Ph metaphases (partial 1-35% Ph +ve, complete 0% Ph +ve)
RT-PCR of BCR-ABL: log reduction in BCR-ABL ratio (BCR-ABL transcripts reduce 100% >10% >1% >0.1%. Major molecular response <0.1%)
Types of BCL-ABL
Various BCR ABL mRNA transcripts are formed according to the position of the breakpoint in BCR
In CML the breakpoint on the BCR gene is nearly always in the major breakpoint cluster region (M-BCR)
Breaks in the major BCR occur either between exons b2 and b3, generating a fusion transcript with a b2a2 junction, or between exons b3 and b4 generating a fusion transcript with a b3a2 junction
Breaks in the minor BCR give rise to BCR ABL mRNA molecules with an e1a2 junction
Treatment of CML
Pathogenesis is an activated Tyrosine Kinase cABL
Oral active ABL kinase Inhibitor (TKIs):
1st Generation Imatinib (Glivec)
2nd generation Dasatanib, and Nilotinib
Prognosis for CML
Commence on oral TKI 1st generation
Monitor response FBC, Cytogenetics, RQ-PCR: CCyR at 12mo 97% FFP at 6 years (Fail to achieve CCyr 80%)
Average 95% 5 year survival
Annual mortality 2%
If loss or failure to respond switch to second generation TKI and consider allogeneic stem cell transplant
