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Kat's Pathology > CML and Myeloproliferative Disorders > Flashcards

CML and Myeloproliferative Disorders Flashcards

1
Q

Normal Hb

A

135-175

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2
Q

Normal heamatocrit

A

0.41-0.53

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3
Q

True polycythaemia

A

Increased red cell mass

No change in plasma volume

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4
Q

Causes of true polycythaemia

A 
Primary polycythaemia vera (reduced EPO) 
Secondary polycythaemia (elevated EPO)
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5
Q

Relative (pseudo) polycythaemia

A

No change in red cell mass

Reduced plasma volume

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6
Q

Causes of pesudo polycythaemia

A

Alcohol
Obesity
Diuretics

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7
Q

Causes of true secondary (non-malignant) polycythaemia

A

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)

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8
Q

Haematological malignancies

A

Myeloid

Lymphoid: precursor cell malignancy or mature cell malignancy

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9
Q

Myeloid malignancies

A

Acute myeloid leukaemia (blasts >20%)
Myelodysplasia (blasts 5-19%)
Myeloproliferative disorders: Essential thrombocythaemia (megakaryocyte), Polycythemia vera (erythroid), Primary myeofibrosis
Chronic myeloid leukaemia

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10
Q

Lymphoid: precursor cell malignancies

A

Acute lymphoblastic leukaemia (B & T)

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11
Q

Lymphoid: mature cell malignancies

A

Chronic Lymphocytic leukaemia
Multiple myeloma
Lymphoma (Hodgkin & Non Hodgkin)

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12
Q

Myeloproliferative disorders

A

Ph negative: polycythaemia vera, essential thrombocythaemia, primary myelofibrosis

Ph positive: chronic myeloid leukaemia

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13
Q

What processes are disrupted by mutation in blood cell formation

A 
Impair/block cellular differentiation (type 2) 
Cellular proliferation (type 1) 
Prolong cell survival (anti-apoptosis)
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14
Q

Mutation mechanisms

A

DNA point mutations

Chromosomal translocations: Creation of novel Fusion gene, Disruption of proto-oncogene

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15
Q

Leukaemia mutations

A

Cellular proliferation (type 1) –> tyrosine kinase activation

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16
Q

Tyrosine kinases

A

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

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17
Q

Tyrosine kinase mutations

A

Expansion increase in mature/end cells
Red cells; polycythaemia
Platelets; essential thrombocythaemia
Granulocytes; chronic myeloid leukaemia

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18
Q

What gene mutations are associated with myeloproliferative disorders

A

JAK2
Calreticulin
MPL

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19
Q

Polycythaemia vera epidemiology

A

Annual incidence 2-3/100000
Slightly more in males 1.2:1
Mean age at diagnosis 60 years
5% below age of 40 years

20
Q

Polycythaemia vera clinical presentation

A

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

21
Q

Clinical findings in polycythaemia vera

A

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

22
Q

Principles of treatment of polycythaemia vera

A

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)

23
Q

Essential thrombocythaemia

A

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

24
Q

Essential thrombocythaemia clinical presentation

A

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

25
Q

Treatment for essential thrombocythaemia

A

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

26
Q

Prognosis of essential thrombocythaemia

A

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

27
Q

Primary myelofibrosis

A

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

28
Q

Clinical presentation of primary myelofibrosis

A

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

29
Q

Early stages of myelofibrosis

A

Prefibrotic stage
Blood changes mild but may also be confused with ET
Hypercellular marrow

30
Q

Later stages of myelofibrosis

A

Fibrotic stage
Splenomegaly and blood changes
Dry tap, with prominent collagen fibrosis and later osteosclerosis.

31
Q

Blood film findings on primary myelofibrosis

A

Leucoerythroblastic picture
Tear drop poikilocytes
Giant platelets
Circulating megakaryocytes

Liver and spleen: extramedullary haemopoiesis in spleen and liver

32
Q

Bone marrow findings in primary myelofibrosis

A

Dry tap
Trephine: increased reticulin or collagen fibrosis, prominent megakaryocyte hyperplasia and clustering with abnormalities
New bone formation

33
Q

Prognosis for primary myelofibrosis

A

Median 3-5 years, but very variable

34
Q

Bad prognostic signs in primary myelofibrosis

A

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

35
Q

Treatment of primary myelofibrosis

A

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)

36
Q

Clinical features of CML

A 
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
37
Q

FBC findings in CML

A

Hb and platelets well preserved or raised

Massive leucocytosis 50-200

38
Q

Blood film in CML

A

Mature myeloid cells
Neutrophils and some myelocytes (not blasts if chronic phase)
Basophilia
No excess (<5%) myeloblasts

39
Q

CML

A

CML is one of the Myeloprolifive disorders that arises from an abnormal pluripotent BM stem cell

40
Q

Natural history of CML

A

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

41
Q

What is the Philadelphia chromosome

A

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

42
Q

Detection of Philadelphia chromosome

A

FISH

43
Q

How can you monitor disease and response to therapy in CML

A

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%)

44
Q

Types of BCL-ABL

A

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

45
Q

Treatment of CML

A

Pathogenesis is an activated Tyrosine Kinase cABL

Oral active ABL kinase Inhibitor (TKIs):
1st Generation Imatinib (Glivec)
2nd generation Dasatanib, and Nilotinib

46
Q

Prognosis for CML

A

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

Kat's Pathology (105 decks)

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