Haematology

Question 1

Translocation in APML

Answer 1

t(15:17) (q22;q12)

Translocation involving the retinoic acid receptor alpha (RARA)

Question 2

Strongest advserse clinical predictors for AML

Answer 2

Risk of death:
Advanced Age
Poor performance status

Risk of treatment resistance or early recurrence:
Cytogenetic and molecular factors - (deletion of chromosome 5 or 7)
History of exposure to cytotoxic agents or radiation
History of myledysplasia or myeloproliferative neoplasms (ie secondary AML)

Question 3

Cytogenetics indicating poor prognosis in AML

Answer 3

Any deletion of chromosome 5 or 7
Complex karyotype
Monosomy karyotype (monosomy 17)

Question 4

Most common mutation in AML?

Answer 4

FLT3
- transmembrane tyrosine kinase receptor that stimulates cellular proliferation.

Question 5

Induction treatment for AML

Answer 5

7+3 induction
7 days of cytarabine
3 days of anthracycline (daunorubacin)

If patients have a FLT mutation - the addition of midostaurin

Question 6

Aplastic Anaemia cause

Answer 6

Decrease in haematopoitic stem cells. Many causes:
- Autoimmunity
- Medications - carbimazole, PTU, B lactams, sulfonamides.
- Infections

Whilst its called aplastic anaemia. Usually affects all cell lines.

Question 7

Aplastic Anaemia treatment

Answer 7

Age > 50: immunosupression with ATG, cyclosporine and prednisolone.

Age <50: allogeneic stem cell transplant

Question 8

Pure Red cell aplasia

Answer 8

Normocytic or red cell aplasia with decreased reticulocytes and decreased red cell precursors in the blood. However normal leukocytes and platelets.

Causes:
- Infections - Parvovirus B19 (worse in immunocomprompromised patients who may need IVIg, and in patients with chronic haemolysis who depend on haemolysis.
- Thymoma
- Lympoid malignancy
- Ant-EPO antibodies in patients having EPO therapy
- Pregnancy
-

Question 9

Pathology of Mylodysplastic syndrome

Answer 9

Clonal stem cell disorder with ineffective haematopoiesis leading to dysplastic and hypercellular bone marrow and peripheral blood cytopenias.

Mostly idiopathic, but can be secondary to chemo, radiation or chemical exposure.

Need to rule out reversible causes of dysplasa: B12, folate, and copper deficiency; alcohol consumption, medications, infections (HIV).

Question 10

Classification of MDS:

Answer 10

WHO Classification:
<5% blasts - dividedd into unilingeage, multilineage + special category for isolated 5q-
5-10% blasts - excess blasts 1 (EB1)
10-19% blasts - excess blasts 2 (EB2)

Question 11

MDS associated with 5q-

Answer 11

subset of MDS. Features increased hypolobulated megakaryocytes. Separated as is low risk and can be treated with lenalidomide if they are transfusion dependent (decreased transfusion requirements).

Question 12

Management of MDS:

Answer 12

Low Risk - monitor, transfuse or EPO if required.

High risk MDS - treatment with hypomethylating agents has been shown to decrease risk of conversion to AML.

5q- can be treated with lenalidomide.

Question 13

Myeloproliferative neoplasms

Answer 13

Clonal stem cell disorder characterised by proliferation of the components of the myeloid, erythroid, or megakaryocyte lineage:
- Polycythemia
- Essential thrombocythemia
- Chronic myeloid leukaemia
- Myelofibrosis

Question 14

Chronic Myeloid Leukaemia phases

Answer 14

Chronic Phase - <10% blasts
Accelerated Phase 10-20% blasts
Blast crisis / Secondary AML - >20% blasts

Question 15

Diagnosis of CML

Answer 15

Identification of the Philadelphia chromosome, either by:
- BCR-ABL gene transcript by PCR
- t(9,22) via FISH

Question 16

Treatment of CML

Answer 16

Tyrosine Kinase Inhibitors:
- Imatinib
-dasatinib
- nilotinib

Question 17

Side effects of TKIs in CML:

Answer 17

Imatinib, dasatinib, nilotinib.

Fluid retention
QTc prolongation

Question 18

Polycythemia Vera Pathology:

Answer 18

Activating mutation of the JAK2 gene in 97% of cases. (JAK V617F).

Question 19

Causes of secondary polycythemia:

Answer 19

Hypoxia: Lung disease, sleep apnoea, congenital heart disease / shunting
Ectopic EPO production - RCC, HCC, uterine fibroids.
Unusual - high oxygen affinity Hb

Question 20

Treatment of Polycythemia vera

Answer 20

Phlebotomy with goal of Hct <45%
Aspirin.
Hydroxyurea if high risk for thrombosis: age >60, previous thrombosis.
Jak1/2 inhibitor Rutolitinib - for refractory PV, intolerant to hydroxyurea.

Question 21

Pathology of essential thrombocythema

Answer 21

Jak2 mutation in 50%
- Calreticulin
- MPL

Question 22

Treatment of ET

Answer 22

Monitor
Treat if high risk:
- Age >60
- Previous thrombosis
- Platelet count > 1500 (high risk for bleeding)

Treatment if high risk:
- Hydroxyurea
- Aspirin

Lower risk of transformation than other MPNs

Question 23

Primary Myelofibrosis pathology

Answer 23

Worst prognosis of all of the MPNs

Clonal myloid stem cell disorder characterised by marrow fibrosis and extramedullary haematopoiesis.

Path:
- JAk2 mutation in 50%
- proliferation of megakeryocytes, secretion of FGF
- marrow fibrosis, often dry tap on biopsy
- leukoerythroblastic blood picture

Question 24

Myelofibrosis presentation

Answer 24

Cytokine related hypercatabolic state - weight loss, fatigue, fever chills. Massive hepatosplenomegally.

Question 25

Myelofibrosis treatment

Answer 25

High risk: Only curative treatment is alloHSCT

Low risk: Hydroxyurea

If Jak2 positive - Rutolitinib (if not a candidate for HSCT)

Question 26

Causes of Eosinophilia:

Answer 26

CHINA
C - Collagen Vascular disease
H - Helminth - Strongyloides
I - idiopathic
N - Neoplasia (lymphoma most common, MPN)
A - Allergy, atopy, asthma, drug induced - carbamazepine, sulfonamides)

Question 27

Management of differentiation syndrome

Answer 27

Complication of all trans retinoic acid therapy (ATRA, or tretinoin) for APML.

Features: Fever, oedema, pulmonary opacities, pleural and pericardial effusion, renal and liver dysfunction.

Caused by a “cytokine storm” from malignant promyelocytes.

Treatment:
- IV Dexamethasone
- Usually continue ATRA, unless severe then cease (organ dysfunction)

Question 28

Indications for treatment in CLL (6)

Answer 28

1 Evidence of progressive marrow failure:
- Hb <100, Plt <100 and declining
- Autoimmune anaemia or thrombocytopeina - only if not responding to treatment.

2 Massive splenomegaly >6cm below costal margin, or symptomatic

3 Massive lymphadenopathy >10cm or symptomatic

4 Progressive lymphocytosis:
- >50% increase in 2 months
- Lymphocyte doubling time of <6months

5 Symptomatic extranodal involvement - skin, kidney, lung, spine

6 Constitutional symptoms.

Question 29

Treatment options for CLL

Answer 29

Fludarabine, cyclophosphamide and rituximab (most efficacious, most toxic)

Bendamustin and rituximab (less efficacy, less toxic)

Chlorambucil and obinutuzumab (less efficacy, and less toxicity again)

Targeted therapy
- Ibrutinib (brutons tyrosine kinase inhibitor, targets B cells)
- acalabrutinib
- Venetoclax (BCL2 inhibitor, apoptosis)

For IGHV UNmutated - chemo-immunotherapy
For IGHV mutation - targeted therapy
17p deletion or TP53 mutation - targeted therapy