Polycythaemia and myeloproliferative disorders Flashcards by RK Splendid

what is PV and what is the MOA behind it?

PV: overproduction of BLOOD CELLS of the haematopoeitic stem cell lineage (rbc, platelet, and wbc - the dominating cell linee in PV will be rbc)

EPO normally binds to the stem cells and activates = blood cells made

JAK2 defect (Janus kinase 2) affects the haematopoeitic stem cells meaning they are always active - even without EPO binding

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what are the phases of PV?

“poly phase” - overproduction of cells

spent phase - when the cells take up the bone marrow volume - hypercellular resulting in cytopaenia

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what would ivx show in PV? (basic outline)

Bloods:
Increased Hb
Increased Haematocrit
Increased platelet and WCC

EPO levels - low may be high (2ndary)

+- Bone marrow biopsy: fibrosis

Mutation testing: V617F mutation -> JAK 2 defect

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give some examples of myeloproliferative neoplasms ?

Myeloid lineage cell prolifration:

BCR-ABL positive:
CML

BCR-ABL negative:
Polycythaemia vera
Primary Myelofibrosis
Essential thrombocytosis

the above 3 are the mpf disorders

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myeloproliferative disorders have risk of progression to what?

AML (not ALL as is from myeloid line)

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how does one tell the difference between True and relative Polycythemia?

Relative - plasma volume is decreased giving the impression that RBC conc has increased when it hasn’t.

true - rbc conc has increased

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list some causes of relative polycythemia

Alcohol
obesity
diuretics

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when isotope dilution studies reveal true polycythaemia, what are the possible causes?

Primary polycythemia vera (reduced EPO)

Secondary Polycythaemia (elevated EPO)

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list some causes of True secondary polycythemia

Is Non malignant condition

Appropriate:
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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what is the result of the V617F Mutation?

Activating Tyrosine kinase mutation:

expansion increase in MATURE/end cells not blasts:

Red cells; polycythaemia
Platelets; essential thrombocythaemia
Granulocytes; chronic myeloid leukaemia

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which genes are responsible in the MPD?

PV - JAK2 V61F 100%

ET - Jak2 60%, Calreticulin 30%, MPL 5%

PMF - Jak2 60%, Calreticulin 30%

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what is EPO level in polycythaemia?

Primary - low EPO

Secondary - high EPO

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What is the clinical presentation of PV? what will be the clnical findings ?

Symptoms of increased hyper viscosity:
Headaches, light-headedness, stroke
Visual disturbances
Fatigue, dyspnoea

Increased histamine release:
Aquagenic pruritus - itching post hot shower
Peptic ulceration

Clinical findings:
 Erythromelalgia: red painful extremeties
 Thrombosis
 Retinal vein engorgement
 Gout due to increased red cell turnover and
overproduction of uric acid

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what is the rx for PV?

Aim to reduce HCT : target HCT <45%
Venesection
Cytoreductive therapy - Hydroxycarbamide

Aim to reduce risks of thrombosis:
Control HCT
Aspirin

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Sustained thrombocytosis >600x109/L

is indicated of?

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What is the clinical presentation of PV?

Incidental finding on FBC (50% cases)
Thrombosis: arterial or venous
CVA, gangrene, TIA
DVT or PE

Bleeding: mucous membrane and cutaneous (because not a clotting fx issue)

Headaches, dizziness visual disturbances
Splenomegaly (modest)

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what is the rx for ET?

Aspirin: to prevent thrombosis

Anagrelide: specific inhibition of platelet formation, side effects include palpitations and flushing

Hydroxycarbamide: antimetabolite. Suppression of other cells as well.

Alpha interferon - can be used if under 40

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how does Primary Myelofibrosis present?

Incidental in 30%

Presentations related to:
Cytopenias: anaemia or thrombocytopenia
Thrombocytosis
Splenomegaly: may be massive
  - Budd-Chiari syndrome

Hepatomegaly

Hypermetabolic state:

Weight loss
Fatigue and dyspnoea
Night sweats
Hyperuricaemia (= GOUT)

the following Haematological findings are consistent with which condition

Leucoerythroblastic picture
Tear drop poikilocytes
Giant platelets
Circulating megakaryocytes

Extramedullary haemopoiesis and enlargement in spleen and liver and

Primary Myelofibrosis

- arer 2 pahses prerfibrotic and fibrotic - no hepatosplenomegaly in prefibrotic

what are the findings on ivx for PM?

Blood film
Bone marrow - (must always, not optional):

‘Dry tap’ (Hypercellular marrow in prefibrotic stage)

Trephine biopsy:
Increased reticulin or collagen fibrosis
Prominent megakaryocyte hyperplasia and clustering with abnormalities
New bone formation
Osteosclerosis - hardening and increased density

DNA : JAK2 or CALR mutation

what is the rx for PM?

Supportive: RBC and platelet transfusion often ineffective because of splenomegaly
Cytoreductive therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia)

High prognostiic score/poor surival chance:

Ruxolotinib: JAK2 inhibitor
Allogeneic SCT (potentially curative)
Splenectomy for symptomatic relief: hazardous and often followed by worsening of condition

which cell does CML Chronic myeloid leukaemia arise from?

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

what would ivx findings reveal for CML?

Exam
Massive splenomegaly +/- hepatomegaly

FBC
Hb and platelets well preserved or raised
Massive leucocytosis 50-200x109/L

Blood film:
1. Bi-phasic peak of Neutrophils AND myelocytes
(not blasts if chronic phase - infact v few blasts present)
2. Basophilia

Platelet count raised/upper normal

what are the presenting sx of CML?

Lethargy/ hypermetabolism/ thrombotic event : monocular blindness CVA, bruising bleeding

what drives myeloid proliferation in CML?

BCR ABL fusion gene expresses a fusion oncoprotein with constitutive tyrosine kinase activity.

how can monitoring of response to therapy occur in CML? what is the ideal response?

RT-PCR of BCR-ABL fusion transcript for diagnosis BUT 1. quantify with RQ-PCR to determine response to therapy 2. FBC (leucocytosis) 3. Cytogenetics (FISH: bcr-abl gene % presence) ideal response - at 1 year: 0% cells with BCL-ABR (otherwise inc risk recurrence) 0% blasts Normal WCC

what are the phases of CML? what are their lengths?

CAB Chronic phase: Median 3-4 years duration Advanced phases: 1. Accelerated phase (10-19% blasts) - up to 1 year ( presence of basophilia) 2. Blast crisis (>20% blasts) - Median survival 3–6 months refractory to rx

what kind of drug is imatinib?

Abl Tyrosine Kinase inhibitor

Which are the most sensitive ways of detecting disease in CML?

Molecular most sensitive - BCR-ABL transcripts Followed by cytogenetic analysis - the FISH metaphase/interphase BCR-ABL: - Partial 1-35% Philadelphia positive - Complete 0% Ph positive Haematological response - Complete Haematological Response WBC<10x109/l

in the treatment of CML, which TKIs should be used?

Commence on oral TKI 1st generation Failure (1) > switch to 2Gen or 3G TKI - if No complete cytogenetic response @ 1year Failure (2) > consider allogeneic SCT - If progression to accelerated or blast phase Imatinib (1Gen,) Dasatanib Nilotonib (2G) Bosutinib (3G)

case 3 + the notes i made on it is quite good for consolidation.

okay

what other conditions can imatinib be used for?

ALL - anything with BCR-ABL gene

what is An important initial goal of treatment CML?

to achieve a complete cytogenetic response (0% cells with bcr abl): a patient no longer has evidence of cells with the Philadelphia chromosome in the bone marrow and has normal levels of blood cells

what is The most sensitive test to look for remaining CML ?

a quantitative reverse transcriptase PCR (Q-RT-PCR) test.

if a patient continues taking the medication - eg Imatinib as directed and the results of this test begin to rise, what does this mean?

the current treatment is no longer working. sometimes, a TKI stops working because the CML develops resistance to it

which therapy is started at what phase in leukaemia? which stage is Imatinib most effective?

Chronic phase - imatinib most effective here. Allo SCT if drugs dont work Accelerated phase - can use 2nd/3rd gen TKI. best todo Allo SCT Blast phase - 2nd/3rd gen + chemo (wont cure). hydroxyurea.

what is JAK2 and its role in the control of haematopoesis?

are tyrosine kinases bound to the haemopoeitic cell growth factor receptors - HCGFR become phosphorylated (by ATP) when growth factors bind to receptor leads to activation of the STAT pathway (PI3K, ERK etc) ultimately leading to cell proliferation

which are the constitutionally active JAKs?

Mutated ones: JAK2 V617F JAK2 Exon 12

what is the chief diagnostic ivx in PV?

JAK 2 V617F mutation present (diagnostic)

what do the following mutations cause: JAK2 V617F JAK2 Exon 12

JAK2 V617F - polycythaemia vera JAK2 Exon 12 - primary erythrocytosis

what is the old Diagnostic criteria in PV? (detailed)

``` Raised RCM (red cell mass) >25% of mean normal predicted value  Hb >18.5g/dL in men >16.5g/dL in women ```  BM histology: ■ Increased cellularity ■ Megakaryocytic abnormalities ■ Variable increase in reticulin fibres then there are other thigns that would confirm but are not diagnostic. Curernt criteria: Increased red cell production and usually also increased platelets and sometimes neuutrophils  Most patients will have the JAK2 V617F mutation

which myeloproliferative disorder affects women more?

Essential thrombocytosis Females : males equal first peak (30y/o) but females predominate second peak (55years +)

which condition is associated with reactive bone marrow fibrosis and extramedullary haematopoieisis?

Chronic idiopathic myelofibrosis / P Myelofibrosis

what is the rx in myelofibrosis?

Blood transfusions Splenectomy Thalidomide with or without prednisolone hydroxycarbamide for thrombocytosis