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RACP 2024 > Haematology > Flashcards

Haematology Flashcards

1
Q

When is someone at risk of neutropenic sepsis?

A

When Neuts < 0.5, typically 7-14 days post chemo, and if going to be neutropenic > 7days

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2
Q

How should neutropenic sepsis be managed?

A

Antibiotics within 30 minutes, ideally with blood cultures prior

Tazocin (piperacillin-tazobactam) or cefepime
Penicillin allergic: vancomycin + ciprofloxacin
Add in metronidazole if abdo/GI cover indicated

Gentamicin if septic shock (in addition to above)

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3
Q

What are common organisms that cause neutropenic fevers?

A

60% are gram +ve: coagulase -ve Staph epidermidis, Viridans streptococci, enterococci

30% Gram -ve: E. coli, Klebsiella, Pseudomonas

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4
Q

When are anti-fungals indicated in neutropenia? What should be used?

A

If neutropenia expected to last > 7 days
OR
If persistent or recurrent fever

Need anti-mold cover: posaconazole or amphotericin B

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5
Q

How do BiTEs (Bispecific T-cell engagers) work?

A

Fusion protein of anti-CD3 and 2 specific single chain variable fragment that brings T-cell and target together

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6
Q

How is cytokine release syndrome managed?

A

First line = anti-IL6R (tocilizumab) and anti-IL6 (siltuximab)
2nd line = steroids

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7
Q

What is on-target off-tumour toxicity with CD19 CAR T-cells? How is it managed?

A

B-cell aplasia and hypogammaglobulinaemia
IVIg

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8
Q

How do monoclonal antibodies exert an anti haematological cancer effect?

A

Through antibody-dependent cellular cytotoxicity which is NK-cell mediated

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9
Q

What is the mechanism of action of Brentuximab?

A

antiCD30 found on Reed-Sternberg cells, treatment of Hodgkin lymphoma, some AMLs

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10
Q

What are Blinatumomab and BI 836909?

A

Blinatumomab =a BiTE against CD19

BI 836909 = a BiTE against BCMA (myeloma cells)

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11
Q

What ICI are listed for haematological malignancies?

A

Pembrolizumab for R/R classical Hodgkin lymphoma ineligible for autograft

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12
Q

What is the mechanism of action of thalidomide used for multiple myeloma?

A

Inhibition of angiogenesis and TNFa synthesis

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13
Q

What is the mechanism of action of lenalidomide and pomalidomide?

A

Increase IL-10 production = anti inflammatory
AND
Inhibit TNFa, IL1B and IL6 production
AND
Induce IL-2 and IFNg production = enhance T and NK cell function, inhibit Treg

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14
Q

Through what mechanism do platelets bind to exposed extracellular matrix?

A

Platelet GP1b-V-IX binds to vWF

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15
Q

What are the 2 functions of von Willebrand factor?

A
  • mediating platelet adhesion
  • acts as carrier protein for factor VIII
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16
Q

Describe the processes of platelet activation and aggregation

A

Adhesion of platelet trigger GPIIb-IIIa activation, resulting in irreversible binding, shape change and platelet activation

Activated GPIIb-IIIa mediates aggregation via fibrinogen and vWF.

Activation result sin calcium influx, leading to exposure of phosphatidylserine exposure on the surface and release of granule contents which recruit other platelet and trigger coagulation cascade

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17
Q

What is the substrate for the following platelet adhesion receptors?
GPVI
Protease activated receptors (PARs)
GPIb-V-IX
GPIIb-IIa

A

GPVI = collagen
Protease activated receptors (PARs) = thrombin
GPIb-V-IX = vWF
GPIIb-IIa = Fibrin

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18
Q

Where do the following anti-platelets have thier action?
Aspirin
Clopidogrel
Ticagrelor

A

Aspirin = COX1 inhibitor, prevents TXA2 generation to inhibit platelet activation
Clopidogrel = binds P2Y12R, preventing ADP-mediated platelet activation
Ticagrelor = binds P2Y12R, preventing ADP-mediated platelet activation

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19
Q

What are the problems with the cascade model of coagulation?

A
  • patients with deficiencies in contact factors do not have clinical bleeding
  • implies that Factor VIIa and tissue factor activation should bypass factor VIII or IX deficiency, not true
  • doesn’t explain why factor XII defieciency patients have milder bleeding phenotype
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20
Q

What are the phases of cell based model of coagulation?

A

Overlapping:
1. Initiation: exposed TF binds VIIa and activates factor X and generates trace amounts of thrombin. Excess thrombin cleared by antithrombin

  1. Amplification: thrombin results in activation of factors XI and IX. Also activates platelets which support the assembly of factor complexes Xa (VIIIa+ IXa) and prothrombin a (XaVa)
  2. Propagation: thrombin burst coverts fibrinogen to fibrin and factor XIII crosslinks fibrin leading to stabilisation of clot
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21
Q

What coagulants does anti-thrombin act on?

A

Thrombin (via factor II)
X
IX
XI
XII

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22
Q

What coagulants does protein C and co-factor protein S act on?

A

Activated Va
Activated VIIIa

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23
Q

What is the role of thrombin and plasmin?

A

Thrombin converts fibrinogen to fibrin
Plasmin converts fibrin to FDP

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24
Q

What are the 2 enzymes that activate plasminogen into plasmin?

A

tPA
uPA (urokinase)

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25
Q

What factors does the prothrombin time test?

A

Tests extrinsic pathway (tissues activated = add TF, phospholipid, calcium)

Tests TF, factor VIIa

(AND common pathway = Xa, Va and II(prothrombin)
AND thrombin activation of fibrinogen)

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26
Q

What factors does the APTT test?

A

Intrinsic pathway (surface activated = add silica or eelegic acid, phospholipid, calcium)

PK (plasma kallikrein), HMWK, VIIIa, IXa, XIa, XIIa

AND common pathway = Xa, Va and II(prothrombin)
AND thrombin activation of fibrinogen

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27
Q

What factors does the thrombin time test?

A

Thrombin activation of fibrinogen to fibrin clot

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28
Q

What factors can cause a low thrombin time?

A
  • dabigatran (direct inhibitor)
  • heparin (indirect inhibitor)
  • low thrombin levels
  • low/dyfunctional fibrinogen
  • FDPs (DIC)
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29
Q

A deficiency in the following factors will cause a change in which coagulation assays?
-TF
- II
- IIa
- Va
- VIIa
- VIIIa
- Xa
- IXa
- XIa
- XIIa

A

-TF = PT (extrinsic pathway)
- II (prothrombin) = PT, APTT (common pathway)
- IIa (thrombin) = thrombin time, PT, APTT
- Va = PT, APTT (common pathway)
- VIIa = PT (extrinsic pathway)
- VIIIa = APTT (intrinsic pathway)
- Xa = PT, APTT (common pathway)
- IXa = APTT (intrinsic pathway)
- XIa = APTT (intrinsic pathway)
- XIIa = APTT (intrinsic pathway)

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30
Q

What is the relationship between INR to factor levels?

A

Non-linear, so FFP does improve prolonged INR

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31
Q

What is the role of a mixing study for prolonged APTT?

A

If APTT normalises with 1:1 mixing, there is factor deficiency

If does not normalise with mixing there is likely a factor inhibitor (either non-specific such as lupus anticoagulant, or specific factor inhibitor)

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32
Q

What may explain the following coag assay results:
PT: N
APTT: N
TT: N
Fibrinogen: N
Platelet count: N

A

Normal haemostasis
Disorder of platelet function
Factor XIII deficiency
Disorder of vascular haemostasis (connective tissue disorder)
Mild coag factor deficiency
Mild von willebrand disease
Disorder of fibrinolysis

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33
Q

What may explain the following coag assay results:
PT: long
APTT: N
TT: N
Fibrinogen: N
Platelet count: N

A

Factor VII deficiency (inherited or acquired)
Warfarin
Xa inhibitors (rivaroxaban)
Mild factor II, V or X deficiency
Lupus anticoagulant

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34
Q

What may explain the following coag assay results:
PT: N
APTT: long
TT: N
Fibrinogen: N
Platelet count: N

A

Factor VIII, IX, XI, XII, PK or HMWK deficiency
Von willebrand disease
Mild factor II, V or X deficiency
Lupus anticoagulant

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35
Q

What may explain the following coag assay results:
PT: long
APTT: long
TT: N
Fibrinogen: N
Platelet count: N

A

Vitamin K deficiency
Warfarin
Factor II, V or X deficiency
Multiple factor deficiencies (Liver failure)
Combined V and VIII deficiency

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36
Q

What may explain the following coag assay results:
PT: long
APTT: long
TT: long
Fibrinogen: N or abnormal
Platelet count: N

A

Heparin
Liver disease
Fibrinogen deficiency/dysfunction
Inhibition of fibrin polymerisation
Hyperfibrinolysis

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37
Q

What may explain the following coag assay results:
PT: N
APTT: N
TT: N
Fibrinogen: N
Platelet count: low

A

Thrombocytopenia

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38
Q

What may explain the following coag assay results:
PT: long
APTT: long
TT: N
Fibrinogen: N or abnormal
Platelet count: low

A

Massive transfusion
Liver disease

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39
Q

What may explain the following coag assay results:
PT: long
APTT: long
TT: long
Fibrinogen: low
Platelet count: low

A

DIC
Acute liver disease

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40
Q

What is the mechanism of action of the following anticoagulants?
Warfarin
Dabigatran
Heparin
Enoxaparin
Rivaroxaban

A

Warfarin = vitamin K antagonist
Dabigatran = direct thrombin inhibitor
Heparin = indirect factor Xa/IIa inhibitor
Enoxaparin = indirect factor Xa/IIa inhibitor
Rivaroxaban = direct factor Xa inhibitor

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41
Q

What is the clearance, safety in pregnancy and breastfeeding and drug interactions of the following anticoagulants?
Warfarin
Dabigatran
Rivaroxaban
Apixaban

A

Warfarin
- hepatic metabolism
- safe
- CYP2C9, 3A4 and 1A2

Dabigatran:
- 80% renal
- not safe
- p-gp inhibitors (amiodarone, verapamil)

Rivaroxaban:
- 33% renal, 18% faecal
- not safe
- CYP3a4 and p-gp inhibitors

Apixaban:
- 25% renal, 56% faecal
- not safe
- CYP3a4 inhibitors

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42
Q

What effect does dabigatran have on the following coag assays?
PT
APTT
TT
Fibrinogen
dRVVT (lupus anticoagulant)

A

PT: normal or prolonged
APTT: prolonged
TT: prolonged (the most sensitive)
Fibrinogen+ low or normal
dRVVT (lupus anticoagulant) = prolonged

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43
Q

What effect does rivaroxaban have on the following coag assays?
PT
APTT
TT
Fibrinogen
dRVVT (lupus anticoagulant)

A

PT = prolonged (most sensitive)
APTT = normal or prolonged
TT = normal
Fibrinogen = normal or low
dRVVT (lupus anticoagulant) = prolonged

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44
Q

What effect does apixaban have on the following coag assays?
PT
APTT
TT
Fibrinogen
dRVVT (lupus anticoagulant)

A

PT = normal or prolonged
APTT = normal or prolonged
TT = normal
Fibrinogen normal or low
dRVVT (lupus anticoagulant) = prolonged

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45
Q

What is the revers of warfarin in a patient who is bleeding?

A

Vitamin K
Prothrombin X

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46
Q

What reversal agents are used for bleeding in NOACs?

A

Idarucizumab 5 g for dabigatran

Prothrombin X for Rivaroxaban, specific agent = adexanet alfa (not funded), Xa mimic

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47
Q

What are indications for extended therapeutic anticoagulation post DVT/PE and what treatment can be used?

A

> 2 unprovoked PE
Anti-phospholipid syndrome
Active cancer

Apixaban 5 mg BD
Rivaroxaban 20 mg OD
Warfarin aiming INR 2-3
LMWH

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48
Q

What anticoagulation should be used for long term prevention in unprovoked DVT/PE?

A

Apixaban 2.5 mg BD
Rivaroxaban 10 mg OD
Warfarin aiming INR 2-3

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49
Q

What is the duration of anticoagulation for a distal DVT without persisting risk?

A

6 weeks

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50
Q

What is the relationship between female sex hormones and VTE?

A

Increased risk
Biggest = post partum followed by pregnancy

1st/2nd gen COC (Norethisterone, levonogestrel) safer than 3rd gen and cyproterone
Depot provera highest contraceptive risk

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51
Q

What is the benefit of DOACs over warfarin for VTE?

A

Same efficacy
Lower serious bleeding rate

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52
Q

What anticoagulation can be used for APS?

A

Warfarin or LWMH

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53
Q

What is the pathophysiology of heparin-induced thrombocytopenia?

A

IgG antibodies bind PF4-heparin complexes resulting in hypercoaguable state through platelet activation
Higher risk if unfractionated heparin

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54
Q

What are clinical features of HIT?

A

Thrombocytopenia (fall 30-50% and count > 50)
Onset after heaprin given
New thrombosis or progression of thrombus
No other cause for thrombocytopenia

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55
Q

How is HIT managed?

A

If intermediate (4-5) or high (6-8) probability: stop heparin, perform testing to confirm

If low probability (0-3) can continue heparin and consider testing if missing data points

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56
Q

Who should undergo platelet monitoring for HIT? What monitoring is required?

A

All patients on unfractionated heparin
Patients on LMWH after amjor surgery or trauma

Every 2 days

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57
Q

What is the pathophysiology of vaccine-induced thrombocytopenia and thrombosis (VITT)?

A

Anti-PF4 antibodies result in FcgRIIa-dependent platelet activation, aggregation and clot formation

Is not HIT as no heparin exposure, and does not display heparin-dependence in assays

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58
Q

What features suggests a platelet bleeding disorder?

A
  • skin or mucosal bleeding
  • prolonged skin cuts (> 5 minutes)
  • petechiae
  • immediate mild bleeding after surgery
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59
Q

What features suggest a clotting factor disorder?

A
  • bleeding in deep soft tissues
  • often in haemarthrosis
  • delayed severe bleeding after surgery
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60
Q

What is the inheritance pattern of haemophilia A and B?

A

Haemophilia A = factor VIII, X-linked recessive

Haemophilia B = factor IX, X-linked recessive

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61
Q

Through what mechanism can women who are carriers of haemophilia experience mild bleeding?

A

Turners syndrome (XO) = severe bleeding
Extreme lyonisation = random X inactivation

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62
Q

What prophylaxis is given for severe haemophilia A and B?

A

A: Factor VII every 2 days
B: factor IX every 3 days

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63
Q

What is the mechanism of action and indication for Emicizumab?

A

Humanised bispecific mAb that bridges Factor IXa and X to restore missing factor VIII

Not affected by factor VIII inhibitors
Given subcut every 4 weeks for haemophilia A with inhibitors

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64
Q

What is the most common inherited bleedign disorder?

A

Von willebrand disease

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65
Q

What is the inheritance pattern of von willebrand disease?

A

Autosomal dominant

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66
Q

What factors can cause a rise in von willebrand factor levels?

A
  • Age
  • African race
  • Non O blood types
  • lewis blood group
  • adrenaline
  • inflammation
  • hormones (pregnancy, OCP)
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67
Q

What is the treatment for von willebrand disease?

A

1st line = desmopressin (releases stored von willebrand factor), TXA
2nd line = von willebrand factor concentrates

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68
Q

What are causes of microcytic anaemia?

A

MCV < 80
Iron deficiency
Thalassaemia
Haemoglobinopathy
Siderobalstic anaemia

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69
Q

What are causes of normocytic anaemia?

A

MCV 80-100
Decreased production:
- bone marrow failure
- chronic disease

Increased red cell loss:
- haemolysis
- acute bleeding

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70
Q

What are causes of macrocytic anaemia?

A

MCV > 100
Megalobastic:
- B12 deficient
- Folate deficient

Non-megalobalstic:
- myelodysplasia
- liver disease
- alcohol
- pregnancy
- hypothyroidism

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71
Q

What are features of iron deficiency anaemia on blood film?

A
  • hypochromic
  • microcytic
  • target cells
  • elliptocytes
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72
Q

How is iron stored in the body?

A

Absorbed in small intestine
Carried in plasma by transferrin
Used to form myoglobin and haemoglobin
Stored in ferritin by the liver

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73
Q

What is the role of hepcidin?

A

Formed in liver, blocks cellular iron export by ferroportin to regulate systemic iron

Hepcidin is down regulated in anaemia

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74
Q

How is fe deficiency diagnosed?

A

Ferritin < 30
OR
Ferritin < 100 in high inflammatory states
OR
Tsat < 20% when Ferritin > 100

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75
Q

What key differences do iron studies show between iron deficiency anaemia and anaemia of chronic disease?

A

IDA: high transferrin, low ferritin

Chronic disease: low/N transferrin, normal/high ferritin

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76
Q

What is the inheritance pattern of most haemoglobinopathies?

A

Autosomal recessive

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77
Q

Where are the alpha and beta haemoglobin genes and how many copies are present?

A

Alpha: chromosome 16, 2 copies = 4 genes inherited
Beta: chromosome 11, 1 copy = 2 genes inhertied

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78
Q

What are the different types of Beta-thalassemia and their phenotypes?

A

Beta thalaseemia minor = 1 abnormal gene = no or mild anaemia with normal or low MCV

intermedia = 2 midly abnormal genes or 1 severe = mild-mod anaemia with low MCV

Major = 2 abnormal genes = severe anaemia with low MCV

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79
Q

What are the different types of Alpha-thalassemia and their phenotypes?

A

Silent = 1 missing gene = no anaemia, normal MCV

2-gene minor = 2 missing genes, no or midl anaemia with normal or low MCV

HbH disease = 3 missing genes = moderate to severe anaemia with low MCV

Barts disease (hydrop fetalis) = 4 missing genes, death in utero

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80
Q

What are the different types of Sickle cell and their phenotypes?

A

Sickle cell trait = 1 abnormal gene = no anaemia and normal MCV

Sickle cell disease = 2 abnormal genes = mild to severe anaemia and normal or low MCV

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81
Q

What is the haemoglobin electrophoresis finding for Beta thalassemia trait, alpha thalassemia trait and sickle cell trait?

A

Beta : elevated HbA2
Alpha: normal HbA2
Sickle: elevated HbS

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82
Q

How should transfusion dependent thalassemia’s be managed?

A
  • regular RBCs
  • iron chelation (deferasirox, deferiprone, desferrioxamine)
  • MDT input for endocrinopathies, fertility, cardiac (due to iron overload)
  • rarely HSCT
  • luspatercept
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83
Q

What are features of sickle cell disease on blood film?

A

Sickle cells
(Target cells an howell-jolly bodies due to hyposplenism)

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84
Q

What is the pathological basis of sickle cell disease?

A

Glu-Val substitution in beta globin gene resulting in HbS
Is less soluble and forms gelatinous network of fibrous polymers
Red cells become distorted in low pO2, bind to endothelium and result in occlusion of microvascular -> infarction

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85
Q

How is sickle cell managed?

A
  • transfusion
  • hydroxyurea to increase fetal haemoglobin
  • staying warm
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86
Q

What are different causes of bone marrow failure?

A

Aplastic:
- idiopathic/autoimmune
- medications
- viral
- inherited (fanconi)

Infiltration:
- malignancy, haem or other

Dysfunction:
- myelodysplasia

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87
Q

What is the pathophysiology of anaemia of chronic disease?

A

Reduction in RBC production due to
- hepcidin alteration in iron metabolism (reduced GI absorption, trapping of iron in macrophages)
- inability to increase erythropoiesis
- relative decrease in EPO

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88
Q

What are the different mechanisms of haemolysis?

A
  1. Intrinsic:
    - enzyme deficiency: PK, G6PD
    - membrane defect: hereditary spherocytosis
    - Hb synthesis: sickle cell disease
    - Acquired: paroxysmal nocturnal haemoglobinuria
  2. Extrinsic:
    - Immune: autoimmune haemolytic anaemia
    - microangiopathic: DIC, HUS (shiga toxin), prosthetic valve, HELLP, preeclampsia, TTP
    - Infections: malaria, clostridium welchii
    - Lead
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89
Q

What is the function of DAT (coombs) test?

A

To detect the presence of autoantibodies on the surface of red cells

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90
Q

What is the pathological basis for hereditary spherocytosis and how is it diagnosed?

A

Spectrin deficiency with variable inheritance result in loss of red cell membrane resulting in spherocytes

Differentiated from autoimmune haemolysis by negative DAT test

Diagnosed by reduced EMA fluorescence on flow cytometry

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91
Q

What is the pathophysiology of paroxysmal nocturnal haemoglobinuria?

A

Acquired somatic mutation in PIGA gene in multipotent stem cell results in inability to synthesise GPI anchor and absence of complement inhibitors on cell surface

Results in increased complement-mediated haemolysis resulting in intravascular and extravascular haemolysis

Can also have aplastic anaemia, atypical venous and arterial thrombosis, smooth muscle dystonia

Diagnosed on flow cytometry by loss of GPI-linked proteins CD59 and CD55

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92
Q

What blood test findings suggest haemolytic anaemia?

A

Raised reticulocytes
LDH raised
Bilirubin raised
Low haptoglobin

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93
Q

What blood film finding suggest megaloblastic anaemia?

A

Oval macrocytes
Hypersegmented neutrophils

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94
Q

Where does extravascular haemolysis occur?

A

In reticuloendothelial system

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95
Q

What are the 3 groups that cause haemolytic anaemia?

A
  1. RBC defects:
    - enzyme dysfunction
    - abnormal haemoglobins
    - thalassemia
  2. Loss of structural integrity of membranes and cytoskeleton
    - hereditary spherocytosis
    - hereditary elliptocytosis
    - paroxysmal nocturnal haemoglobinuria
    - immune and drug-asscoiated antibody damage
  3. Damage by extrinsic factors:
    - mechanical trauma
    - microangiopathic conditions
    - chemical toxins
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96
Q

What feature differentiates a spherocyte from a normal RBC?

A

Loss of the pale centre

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97
Q

What results in bite and blister cells?

A

Oxidative damage

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98
Q

What is the underlying principle of the EMA test for hereditary spherocytosis?

A

EMA binds covalently to lysine component of extracellular protein that anchors to red cell membrane

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99
Q

What is the most common inheritance pattern of pyruvate kinase deficiency?

A

Autosomal recessive
(can also be AD)

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100
Q

How does pyruvate kinase deficiency result in hameolysis?

A

Unable to generate ATP and pyruvate, which are essential for red cell membrane function

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101
Q

What test should be performed for suspected drug-induced haemolytic anaemia?

A

G6PD

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102
Q

What tests should be performed for suspected mechanical stress?

A

Red cell morphology on blood film
Exclude other causes

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103
Q

How is paroxysmal noctural haemoglobinuria diagnosed?

A

Flow cytometric analysis of erythrocyte and neutrophil GPI-linked antigens

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104
Q

What diagnoses are suggested by the following DAT and blood film findings:
1. positive DAT and spherocytes
2. positive DAT and red cell agglutination
3. negative DAT and spherocytes
4. negative DAT and fragmentation
5. negative DAT and bite + blister cells

A
  1. positive DAT and spherocytes
    - warm autoimmune haemolytic anaemia
  2. positive DAT and red cell agglutination
    - cold autoimmune haemolytic anaemia
  3. negative DAT and spherocytes
    - PNH or hereditary spherocytosis
  4. negative DAT and fragmentation
    - microangiopathic haemolytic anaemias
  5. negative DAT and bite + blister cells
    - G6PD deficiency
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105
Q

What steps are involved in the direct antiglobulin test?

A

Sample spun down and RBCs separated from plasma
RBCs resuspended in saline
Anti-human Ig and Complement antibodies are added
Aggregate if positive

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106
Q

What steps are involved in the indirect antiglobulin test?

A

Sample spun down and RBCs separated from plasma
Plasma added to human group O RBCs, and if present autoantibodies bind
Anti-human Ig and Complement antibodies are added
Aggregate if positive

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107
Q

What is the pathological basis of g9PD deficiency?

A

X-linked inheritance (males + homozygous females)
Loss or reduction in enzyme protecting from oxidative stress (pentose phosphate pathway)
Common in Greece and Middle East

Haemolysis (with jaundice) triggered by oxidative stress: intercurrent infection, fava beans, naphthalene or oxidant drugs

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108
Q

What may be seen on the blood film of someone with G6PD?

A

Irregularly contracted cells
Small protrusion = heinz bodies (denatured Hb)
Bite cells = heinz bodies removed by spleen
Hemi-ghost red cells = Hb retracted to one side of cell
- polychromatic macrocytes
- features of hyposplenism (howell-jolly bodies = remnant DNA)

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109
Q

What is the appearance of warm autoimmune anaemia on blood film?

A

Spherocytes
Polychromatic macrocytes (bone marrow response)
Severe = nucleated RBCs, hyposplenic changes

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110
Q

What is the difference between warm and cold antibody induced haemolytic anaemia?

A

Warm = Results from Ig (typically IgG) directed at RBC membrane antigens

Cold = IgM, results in red cell agglutination and complement mediated haemolysis

111
Q

What are causes of cold antibody induced haemolytic anaemia?

A

Infectious mononucleosis
Mycoplasma
Clonal production of cold-agglutinin cold haemoglutinin disease (CHAD)

112
Q

What are blood film features of cold antibody induced haemolytic anaemia?

A

Red cell agglutination
Spherocytes
Polychromasia

113
Q

What are blood film features of microangiopathic haemolytic anaemias?

A

Keratocytes
Schistocytes
Microspherocytes
Thrombocytopenia
Bone marrow response: Reticulocytosis, polychromasia

114
Q

What is the causes of HUS?

A

Enterohaemorrhagic (shiga toxin producing) E. coli

Binds glycosphingolipid receptors on glomerular endothelial cells resulting in vasconstriction and acute renal failure via endothelin 1

Shiga toxin also activates neutrophils, which damage glomerular endothelial cell and results thrombus

115
Q

What is the cause of thrombotic thombocytopenia purpura?

A

Idiopathic/autoantibody mediated
Results from reduced ADASMTS-13, a metalloprotease responsible for processing von willebrand’s factor in circulation. This results in ultra-large VWF multimers cause large platelet activation

116
Q

What is the difference between DIC and TTP thrombi?

A

TTP = platelet rich thrombi
DIC = fibrin rich thrombi

117
Q

What are the pentad and dyad of TTP?

A

Dyad = allows early treatment
- microangiopathic haemolytic anaemia
- thrombocytopenia

Pentad
- fevers
- microangiopathic haemolytic anaemia
- thrombocytopenia
- neurological signs and symptoms
- renal dysfunction

118
Q

How can TTP be differentiated from HUS?

A

ARF more common in HUS
ADAMTS-13 assay

119
Q

How is TTP treated?

A

Plasma exchange

If autoantibody present may respond to steroid + rituximab

120
Q

What is a myeloproliferative neoplasm?

A

Clonal proliferation of one or more haematopoietic cell lineages, predmoninantly in the bone marrow, but also in the liver and spleen that result in terminal myeloid expansion in the peripheral blood

121
Q

What is the aetiology of myeloproliferative neoplasias?

A

Viruses
Environmental toxins
In familial clusters somatic mutations in JAK2, CALR and MPL

122
Q

What blood count abnormalities sugges the following MPNs:
- polycythemia vera
- Essential thrombocythaemia
- primary myelofibrosis (overt fibrotic)
- primary myelofibrosis (prefibrotic)

A

polycythemia vera
- increase Hb and Hct
- panmyelosis with neutrophilia and thrombocytosis

Essential thrombocythaemia
-thrombocytosis

primary myelofibrosis (overt fibrotic)
- leukoerythroblastic blood film
- tear drop RBC

primary myelofibrosis (prefibrotic)
- thrombocytosis
- mild anaemia
- high LDH
- splenomegaly

123
Q

What gene mutation testing should be undertaken in the work up of MPN?

A
  • JAK2V617F (exon 14) = most common
  • if JAK2 negative and have ET or MF: MPL and CALR
  • if JAK2V617F negative in PV, can test for JAK mutations across exons 12, 13 and 14 (3%)
124
Q

What is the role of bone marrow biopsy in assessment of MPN?

A
  • morphology aids polycythemia vera diagnosis
  • distinguishes between pre-fibrotic myelofiboris and essential thrombocythemia
  • excludes CML presenting as thrombocytosis
125
Q

What is the mechanism of action of the 2 driver mutation types in MPNs?

A
  1. JAK2
    Constitutively active JAK2 associates with cytoplasmic portion of EPO, thromboietin and G-CSF receptors, resulting in variable levels of erythroid, megakaryotic and granulocytic proliferation and differentiation
  2. CALR and MPL
    Mutations result in aberrant activation and downstream of signalling of the MPL (thrompoeitin) receptor, which result in the activation of JAK2 pathway
126
Q

What is the final common pathway of all driver mutations for MPNs?

A

JAK2

127
Q

What are the 3 types of CALR mutations relevant to MPN?

A
  1. somatic mutation of CALR exon 9
    - cause thrombocytosis (ET, PMF, RARS-T)
    - mutant calreticulin acitvates JAK-STAT pathway via thrombopoeitin receptor
  2. CALR type 1 (deletion) mutation
    - myelofibrosis phenotype
    - higher risk of MF transformation
    - M > F
  3. CALR type 2 (insertion) mutation
    - ET phenotype
    - younger patients
    - low risk of thrombosis
    - very high platelet counts
    - indolent clinical course
128
Q

What is the hierachy of survival for non-CML MPNs?

A
  • best = ET
  • PV
  • pre-PMF
  • Worst = overt PMF
129
Q

What are the 3 main treatment goals for MPN?

A
  1. reduce risk of vascular and thrombotic events
    - cytoreductive agents
    - antiplatelet/anticoagulant therapy
    - CV risk factors
  2. Recognise, acknowledge and manage symptom burden
  3. Reduce progression and transformation of disease - no therapies proven to do so
130
Q

What are common thrombotic complications of polycythemia vera?

A

More common than bleeding
- hypervisocosity: headache, blurred vision, plethora
- large vessel thrombosis: MI, stroke, DVT, PE, splanchnic
- small vessel thrombosis: cyanosis, erythromelalgia, digit ulceration/gangrene

131
Q

What is the treatment of polycythemia vera?

A
  1. Phlebotomy aiming Hct < 45%
  2. Cytoreductive tehrapy (hydroxycarbamide = hydroxyurea, IFN-a) if > 60 OR high risk disease OR previous thrombosis
  3. Aspirin:
    - 100 mg OD if low risk disease and no thrombosis
    - 100 mg BD if < 60 and microvascular sx, CV risk factors, leucocytosis
    - 100 mg BD if > 60 and previous arterial thrombosis
    - Anticoagulation if > 60 and venous thrombosis (typically warfarin)
  4. CV risk factor management
132
Q

What are the diagnostic criteria for polycythemia vera?

A

Major:
- Hb >165 or Hct > 49% in men
- Hb > 160 or Hct > 48% in women
- BMB: hypercellular, panmyelosis, pleomorphic MGK
- JAK2V617F or JAK2 exon 12 mutation

Minor:
- subnormal EPO level

Either all 3 major, or Hb+BMB+EPO criteria met

133
Q

What is the role of BMB in polycythemia vera?

A
  • avoids underdiagnosis of masked PV (by FE deficiency) to improve management and outcomes
  • prognostic information (cytogenetics, reticulin)
134
Q

What are risk factors in ploycythemia vera for reduced survival and transformation to leukaemia?

A

Reduced survival:
- Age > 61
- WCC > 10.5
- thrombosis history
- abnormal karyotype

Leukaemia:
- age > 61
- WCC > 15
- abnormal karyotype

135
Q

What is the anti-hypertensive of choice in polycythemia vera?

A

ACEi, may suppress erythropoiesis

136
Q

What is the rationale for BD aspirin in high risk polycythemia vera?

A

OD dosing achieves suboptimal suppression of Thromboxane-A2 synthesis

137
Q

What is the risk of leukaemia transformation of:
- PMF
- PV
- ET

A
  • PMF: 10-20% in 10 years
  • PV: 2.3% in 10 years, 7.9% in 20 years
  • ET: < 1% in 10 years
138
Q

What are the indications for aspirin for essential thrombocytopenia?

A

Age > 60
CV risk factors
JAK2V617F mutation

139
Q

What are the indications for cytoreductive therapy in essential thrombocythemia?

A

Prior thrombosis
JAK2 mutation + >60
PLT > 1500
Uncontrolled myelproliferation (symptomatic splenomegaly)
Uncontrolled ET-related systemic symptoms

140
Q

What cytoreductive therapy is used in essential thrombocythemia?

A

Hydroxycarbamide
Recombinant IFN-alpha

141
Q

What are risk factors of ET for reduced survival?

A

Age > 60
WCC > 11
Previous thrombosis
- male
- elevated LDH
- non driver mutations (SH2B3, SF3B1, U2AF1, TP53, IDH2, EZH2)

142
Q

What are the bone marrow features of pre-fibrotic myelofibrosis?

A

Low grade bone marrow fibrosis
Characteristic megakaryocytes

143
Q

What are the diagnostic criteria for prefibrotic myelfibrosis?

A

Major:
- Megakaryocyte proliferation and atypia
- not meeting criteria for CML, PV, ET, MDS
- presence of driver mutation, or another clonal marker, or absence of reactive BM reticulin fibrosis

Minor:
- anaemia
- WCC > 11
- palpable splenomegaly
- increased LDH

144
Q

What management principles are used in prefibrotic myelfibrosis?

A

Individualised approach
- aspirin or cytoreductive if vascualr risk of thrombosis
- JAKi if impact on quality of life
- JAKi or cytoreductives for symptomatic splenomegaly
- All-SCT if high risk disease

145
Q

What are symptoms of primary myelofibrosis?

A

20% asymptomatic
-Abnormal blood count
-Splenomegaly

80% symptomatic:
- anaemia
- frequent infections
- easy bruising
- splenomegaly or bone pain
- gout
- constitutional symptoms

146
Q

What patients with primary myelofibrosis require treatment?

A
  • significant symptoms
  • anaemia
  • splenomegaly (>10cm)
  • WCC > 25
  • PLT > 1000
147
Q

How is myelfibrosis-associated anaemia treated?

A

Androgens
Prednisone
Erythropoietin stimulating agents

148
Q

How is splenomegaly, leucocytosis or thrombocytosis managed in primary myelofibrosis?

A

Cytoreductive therapy:
-1st line: hydroxyurea or rIFN-a
- 2nd line: ruxolitinib
- splenectomy rare

PLT > 1000, WCC > 25, spleen > 10 cm

149
Q

What is the mechanism of action of ruxolitinib and what benefits does it have?

A

Oral JAK inhibitor

In primary myelofibrosis improves splenomegaly, weight loss, pruritis

Cons: anaemia, thrombocytopenia, risk of cancer

150
Q

What are the 3 steps in B-cell differentiation?

A
  1. somatic rearrangement of Ag receptor genes
  2. somatic hypermutation
  3. class switch recombination
151
Q

Which B-cell lineage stages do each of these malignancies correlate?
- ALL
- CLL
- MCL
- FL
- DLBCL
- MM

A
  • ALL: stem cell, pro-B or pre-B
  • CLL: immature B-cell or memory B-cell
  • MCL: naive or germinal B-cell
  • FL: naive or germinal B-cell
  • DLBCL: naive or germinal B-cell
  • MM: plasma cell
152
Q

What antigens are expressed by all B-cell maturation stages?

A

HLA-DR
CD-19

153
Q

What antigens are only expressed by immature (bone marrow resident) B-cell stages?

A

Tdt

154
Q

What B-cells express CD20?

A

Pre B-cell (not pro)
Immature B-cell
Maturing, activated and memory B-cells
Not plasma cells

155
Q

What B-cells express CD10? CD138?

A

CD10:
- pro, pre and immature B-cells
- activated B-cells

CD138
- plasma cells

156
Q

How is CLL diagnosed?

A

Blood film: mature lymphocytosis, smudge cells
CD5+(aberrant)CD19+CD23+
> 5x 10^9/L of abnormal B-cell population

157
Q

What is the most common type of leukaemia in Western countries?

A

CLL

158
Q

What is the difference between CLL and small lymphocytic lymphoma?

A

Small lymphocytic lymphoma invades nodes but no abnormal B-cells in peripheral blood

159
Q

What are blood film features of CLL?

A
  • smudge cells
  • small, mature lymphocytes with thin rim of cytoplasm
  • no nucleoli to indicate immature lymphoids
160
Q

How is the monoclonality of CLL determined?

A

Light chain restriction on flow cytometry

161
Q

How are CLL mutations detected?

A

FISH
Conventional karyotyping

162
Q

What mutations are seen in CLL?

A

del(13q14) = good prognosis
Trisomy 12
del(17p12) = TP53poor prognosis
del(11q22)

163
Q

What are clinical features of CLL?

A

70% asymptomatic

Symptoms:
- lymphadenopathy
- hepatosplenomegaly
- weight loss
- fevers
- drenching night sweats
- fatigue

Signs:
- progressive anaemia, thrombocytopenia
- immunoparesis
- Autoimmune: haemolytic anaemia, ITP, bullous pemphigoid, pure red cell aplasia

164
Q

What is a richter transformation?

A

Transformation of CLL to high grade lymphoma
- 90% DLBCL
- 10% hodgkin lymphoma

165
Q

How is CLL treated?

A

Typically no treatment unless symptomatic

Specific treatment:
- typically avoid chemo
- BTKi (ibrutinib, acalabrutinib, zanubrutinib)
- venetoclax

Supportive care:
Avoid live vaccines
Flu, varicella, pneumococcus, COVID vaccines
IVIg for hypogammaglobulinaemia (<6) and recurrent lung or sinus infections
Cancer screening

166
Q

What is the effect of bruton’s tyrosine kinase inhibitor?

A

Ibrutinib, acalabrutinib, zanubrutinib

Blocks BCR signalling to induce apoptosis in B-cells
Blocks B-cell migration and adherence

167
Q

What are side effects of ibrutinib?

A

Atrial Fibrillation
Arthralgia, rash, hypertension, diarrhoea, fungal infections
Needs 3-7 day washout prior to surgery due to reduced collagen mediated platelet aggregation

168
Q

What is the mechanism of action of venetoclax?

A

BCL2 inhibitor by BH3 mimetic - disinhibits mitochondrial pathway of apoptosis

169
Q

What are the side effects of venetoclax?

A

Tumour lysis syndrome - graduated dosing
Neutropenia - G-CSF
CYP3A4 interactions

170
Q

What influences the risk of MGUS progression?

A

M-protein size > 15g/L
Non-IgG isotype
Abnormal serum free light chains

171
Q

What are the two most common founder genetic changes that contribute to mutliple myeloma?

A

Primary IgH translocations (Ig heavy chain translocates next to proto-oncogene)

Hyperdiploidy

172
Q

What is POEMS syndrome?

A

Monoclonal plasma cell disorder with paraneoplatic features
Polyneuropathy
Organomegaly
Endocrinopathy
Monoclonal plasma cell disorde
Skin changes

173
Q

What is TEMPI syndrome?

A

Telangiectasias
Elevated erythropoietin and erythrocytosis
Monoclonal gammopathy
Perinephric fluid collections
Intrapulmonary shunting

174
Q

What is the diagnostic criteria of MGUS?

A
  • M protein < 3 g/dL
  • clonal plasma cells in BM < 10%
  • no myeloma defining features
175
Q

What is the diagnostic criteria of smoldering myeloma?

A
  • M protein > 3 g/dL
  • clonal plasma cells in bone marrow 10-60%
  • no myeloma defining events
176
Q

What is the diagnostic criteria for multiple myeloma?

A

clonal bone marrow plasma cells >10% or >1 biopsy-proven plasmacytoma AND 1 or more myeloma defining events:
- CRAB (hypercalcaemia, renal insufficiency, anaemia, lytic bone lesion)
- BM clonal plasma cells > 60%
- serum free light chain ration >100
- 1 or more focal lesion > 5mm on MRI

177
Q

How does multiple myeloma present?

A
  • bone pain with negative bone scan (osteolytic)
  • low BMD with paraprotein
    -Anaemia (normo/macro) with high total protein
  • acute renal failure with anaemia
  • back pain with anaemia
  • hyperviscosity
178
Q

What is hyperviscosity, its causes and treatment?

A

Thickening of blood due to large number of cells or increased protein in blood

Presents with confusion, headache, visual change, mucosal haemorrhage, high output CCF

Worry if IgM > 50, IgA > 70 or IgG > 100

Managed with plasmapharesis, specific treatment of underlying cause

179
Q

What is the staging system of multiple myeloma?

A

Stage I:
- B2m < 3.5
- Alb > 35
- normal LDH
- no high risk genetic features: t(4;14), t(14;16), del(17p)

Stage II: not fitting into stage I or III

Stage III:
- B2m > 5.5 AND raised LDH OR high risk genetic features: t(4;14), t(14;16), del(17p

180
Q

What are the high risk genetic features of multiple myeloma?

A

All detected by FISH:
- 17p
- t (14;16)
- t(16;20)
- t (4;14) good prognosis
- 1q+
- del 1p

181
Q

What is the principle underlying protein electrophoresis in work up of multiple myeloma?

A

Smaller proteins migrate faster = albumin
M protein = large, migrates less
Can use anti-bodies to detect isotype of M protein

182
Q

How does the serum free light chain assay work?

A

Antibody coated latex beads bind to inner surface of light chain which is obscured when bound to heavy chains

183
Q

What is the cause of an abnormal kappa/lambda free light chain ratio

A

monoclonal plasma cell disorders
- multiple myeloma
- AL amyloidosis
- plasmacytomas
- MGUS

184
Q

What are the mechanisms that multiple myeloma can cause renal impairment?

A
  • myeloma cast nephropathy (NFkB-dependent cytotoxic pathway in proximal tubule)
  • light chain deposition disease
  • amyloidosis
  • acquired fanconi
  • hypercalcaemia
  • hyperuricaemia
185
Q

What are the cytogenetic techniques used in the assessment of multiple myeloma?

A
  • conventional cytogenetics (impaired by low mitotic index)
  • DNA array (good for amplification + deletion, misses balanced translocation)
  • FISH (gold standard for translocation)
186
Q

What is the principle behind multi-agent induction therapy for multiple myeloma?

A

Treats multiple clones to prevent the selection of treatment resistant clones

187
Q

What are the indications for autograft?

A
  • multiple myeloma
  • mantle cell lymphoma
  • T-cell lymphoma
  • relapsed/refractory lymphoma, DLBCL, follicular lymphoma
188
Q

What are the risks of autograft?

A

-death (0.5-1%)
Early:
- sepsis
- mucositis
Late:
- infection: viral, PJP
- secondary cancers: MDS/AML, skin, solid tumours
- psychological

189
Q

What is the pathogenesis of AML?

A

Series of genetic changes in haematopoietic precursor cell that affect growth and differentiation

190
Q

What is the source of relapse in AML?

A

Leukaemic stem cells, usually quiescent and less sensitive the chemotherapy

191
Q

How is AML diagnosed?

A

On BMB:
1. Aspirate with >20% myeloblasts
2. Flow cytometry confirming myeloid lineage
3. Cytogenetics/FISH and molecular assays (NPM1, FLT3)

192
Q

How is AML risk defined?

A

NPM1 mutation without FLT3 = favourable

Intermediate = FLT3 mutations

Adverse = bad cytogenetics, secondary AML, TP53 mutations

193
Q

How is AML treated in someone fit for intensive therapy?

A
  1. Chemo: cytarabine continuous infusion for 7 days + anthracycline for 3 days (danorubicin or idarubicin)

Bone marrow biopsy when counts recover, remission = <5% blasts

Once in remission receive consolidation therapy with cytarabine. Can consider AlloSCT

  1. FLT3 inhibitors in addition to chemo for FLT3 mutations = midostaurin
  2. Favourable cytogenetic risk: gemtuzumab ozogamicin = antiCD33- drug conjugate
194
Q

How is AML treated in someone NOT fit for intensive therapy?

A

Age > 75, Age > 60 with significant co-morbidity

Venetoclax (PO BCL2 inhibitor) + azacitidine (subcut hpomethylating agent)

195
Q

What is acute promyelocytic leukaemia? How is it diagnosed?

A

AML susbet characterised by malignant promyelocytes and profound coagulation abnormalities = medical emergency

Characteristic morphology = prominent granulation, numerous auer rods

Rapid diagnosis with PML-RARA PCR or FISH
Karyotype t(15;17)

196
Q

How is acute promyelocytic leukaemia treated?

A

Urgent control of DIC:
- platelet transfusion aiming plt 30-50
- cryoprecipitate aiming fibrinogen 1-1.5
- FFP to keep INR < 1.5

ATRA (vitamin A metabolite) + arsenic

Can be complicated by differentiation syndrome (fevers, oedema, hypoxia, lung infiltrate, hepatic dysfunction) = dexamethasone 10 mg BD

197
Q

What are features of myelodysplastic syndrome?

A
  • low blood counts
  • dysplasia
  • ineffective haematopoiesis
  • increased risk of AML
198
Q

What is CHIP?

A

Clonal Haematopoiesis of Indeterminate Potential = MDS precursor state
Mutations that accumulate leading to clonal populations, commonly in DNMT3A, TET2, ASXL1

199
Q

What genetic abnormalities are associated with MDS?

A

5q deletion
SF3B1 mutation
TP53 mutations

200
Q

How is MDS managed?

A

RBC or platelet transfusion
TXA

If high risk: azacitidine
If young (<65): allo BM transplant
If 5q-syndrome: lenalidomide

201
Q

What is the 5qminus syndrome?

A

MDS with:
- anaemia
- normal or elevated platelets
- atypical marrow megakaryocytes
- interstitial deletion in long arm of chromosome 5

202
Q

What is lymphoma?

A

Neoplasms of lypmhoid cells that clonally expand to cause disease in lymph nodes and soft tissue

203
Q

What are the different types of lymphoma and their precentages?

A
  • hodgkin lymphoma 9%
  • Mature B-cell non-hodgkin lymphoma 90% NHL (60%NHL are DLBCL or follicular lymphoma)
  • Mature T-cell non-hodgkin lymphoma 9%
204
Q

How does lymphoma present?

A
  • lymphadenopathy
  • cough or abdo pain with bulky disease
  • weight loss, fever and sweats uncommon
  • rarely extranodal involvement
    • skin more commonly T-cell
    • GIT
205
Q

How are NHL classified?

A
  • indolent/low grade (follicular, MALT)
  • Aggressive/intermediate (DLBCL, peripheral T-cell lymphomas, mantle cell)
  • highly aggressive/high grade (Burkitt lymphoma, T Lymphoblastic Lymphoma)
206
Q

What proportional of patients with lymphoma will have extra-nodal involvement?

A

25%

207
Q

What is the recommended imaging modality to assess lymphoma response to treatment?

A

PET-CT (lymphoma needs to be FDG-avid at baseline)

208
Q

What are the clinical features of follicular lymphoma?

A
  • most common low grade lymphoma
  • aysmptomatic lymphadenopathy
  • CD10+/19+/20+ BCL2+ BCL6+
  • 85% patients have t(14;18), resulting in overexpression of BCL-2 (translocation also seen in DLBCL and present in people without cancer)
  • incurable, but long median survival 20 years
209
Q

How is follicular lymphoma treated?

A

Grade1-3a= mature centrocytes = treat as indolent
- watch and wait if asymptomatic
- limited disease = radiotherapy alone
- symptomatic disease = antiCD20 (rituximab OR obinutuzumab) + bendamustine OR CVP (cyclophosphamide, vincristine, prednisolone) OR CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)

Grade 3b = diffuse infiltrate of centroblasts = treat as DLBCL due to risk of transformation

210
Q

What treatment for flow grade follicular lymphoma has the highest risk of infections?

A

Obinutuzumab (anti-CD20) + bendamustine

211
Q

What are the mechanisms of action of rituximab for lymphoma?

A

Chimeric anti-CD20
- direct inhibition of cell proliferation
- ADCC
- complement activation leading to apoptosis

212
Q

What is the difference between rituximab and obinutuzumab?

A

Rituximab = chimeric antiCD20
Obinutuzumab = humanized antiCD20

Obutuzumab has enhanced direct cell death and ADCC, but reduced complement activation

213
Q

How is relapsed follicular lymphoma treated?

A

CD20 mAb + chemo, typically different combination than used prior

AutoSCT if well enough

214
Q

What is the mechanism of action of mosunetuzumab?

A

CD20-CD3 T-cell engager

215
Q

What are clinical features of MALT lymphoma?

A
  • extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue
  • 50% of gastric lymphoma
  • preceded by chronic inflammation:
    • H. pylori gastritis
    • Chlamydophila psittaci in conjunctival MALT
    • hashimoto thyroiditis
  • gastric MALT regresses with H. pylori eradication
  • Orbital (2nd most common) treated with local radiotherapy
216
Q

What are clinical features of Mantle cell lymphoma?

A
  • diagnosis requires cyclin D1 nuclear expression (90%) or t(11;14) on cytogenetics or FISH
  • atypical small lymphoid cells in mantle zones around normal germinal centres
  • Pan B-cell antigens (CD19+20+) and CD5+
  • advanced stage at presentation
  • M > F
217
Q

How is mantle cell distinguished from CLL?

A

Mantle cell is CD20bright, CD23-, CD200-

218
Q

How does indolent and aggressive mantle cell lymphoma present?

A

Indolent = splenomegaly, bone marrow involvement, circulating lymphoma cells

Aggressive: lymphadenopathy, type B symptoms

219
Q

How is mantle cell lymphoma treated?

A

Indolent asymptomatic = observe

Standard treatment = Rituximab + chemo followed by rituximab maintenance
- R-DHAOx + ASCT in young
- R-bendamustine in old

220
Q

How is relapsed mantle cell lymphoma treated?

A

BTKi (ibrutinib or zanubrutinib)

221
Q

What are characteristics of lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinaemia)?

A
  • low grade NHL
  • involves B-cells + plasma cells in bone marrow, spleen and lymph nodes with circulating monoclonal IgM
  • M > F
222
Q

What does IgM MGUS progress to?

A

10% progress to lymphplasmacytic lymphoma
Does not progress to myeloma

223
Q

What mutations are seen in lymphoplasmacytic lymphoma?

A
  • 95% have point mutation (L265P) in mYD88 gene which regulates signalling in B-cell activation
  • 30-40% have CXCR4 mutation = more aggressive and poorer response to BTKi
224
Q

How doesWhat are characteristics of lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinaemia) present?

A
  • asymptomatic elevated protein on routine bloods
    -Anaemia
  • hyperviscosity: faitgue, nose bleeds, headahce, blurred vision, drowsy/confused
  • lymphadenopathy
  • B symptoms (10% weight loss, fever, night sweats)
  • IgM-associated peripheral neuropathy
225
Q

What is the pathophysiology of IgM-associated peripheral neuropathy?

A

Paraprotein binds to myelin sheath resulting in demyelination + widened myelin lamellae

35% have IgM antiganglioside antibody binds to myelin associated glycoprotein (not specific to lymphoplasmacytic lymphoma)

Glove and stocking distribution

226
Q

How is lymphoplasmacytic lymphoma treated?

A

Indolent disease can be observed

Rituximab + chemo (bendamustine OR R-DC = dexamethasone + cyclophosphamide)

BTKi (zanubrutinib) if unsuitable for chemo

Supportive care:
- Fe transfusion (overproduce hepcidin)
- hypogammaglobulinaemia = vaccination, IVIg
- nutritional support for hypoalbuminaemia

227
Q

What are the clinical features of hairy cell leukaemia?

A
  • small B-cells with hairy cytoplasmic projections
  • M >F (5:1)
  • present with infection, splenomegaly, cytopenias
228
Q

What is the immunophenotype of hairy cell leukaemia?

A

B-cell antigens + CD11c+ CD25+ and CD103+
TRAP+ on histology
BRAF V600E mutation

229
Q

How is hairy cell leukaemia treated?

A

1st line: Cladiribine +/- rituximab
Relapsed: Cladiribine + rituximab
Multipel relapses: BRAFi (vemurafenib, dabrafenib) pr BTKi (zanubrutinib)

230
Q

What are clinical features of DLBCL?

A

Rule of 30s:
- 30% present early stage
- 30% have extra-nodal disease: CNS, gastric, prostate, breast, testis
- 30% have B symptoms

Curable with rituximab + multi-agent chemo

231
Q

What are pathological features of DLBCL?

A
  • large, transformed B-cells with prominent nucleoli and basophilic cytoplasm
  • loss of follicular architecture
  • CD19+20+22+79a+ (pan B-cell)
  • Ki67 40-90% (proliferation marker)

Double hit lymphoma (myc+ and bcl-2/bcl-6) on FISH = very poor prognosis

232
Q

What is the Ann Arbor staging of lymphoma?

A

I: single lymph node region or structure

II: 2 or more lymph node regions on the same side of the diaphragm

III: involvement of lymph regions on both sides of diaphragm

IV: involvement of extranodal site(s) beyond E

For all stages:
-A = no symptoms
-B = fever, >10% weight loss, night sweats

For stages I-III:
-E: involvement of single extranodal site contiguous or proximal to known site

233
Q

What is the treatment for DLBCL?

A

1st line = R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednsione)
2nd line = R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin)
3rd line:
- AutoSCT
- CAR-T cells

234
Q

What is the mechanism of action of cyclophosphamide and its side effects?

A

Alkylating agent = damages cell DNA to prevent them from dividing

Side effects:
- haemorrhagic cystitis
- pancytopenia
- Nausea and vomiting
- diarrhoea
- hair thinning
- sun sensitivity
- brittle nails
- malignancies
- electrolyte abnormalities
- pneumonitis or pulmonary fibrosis
- prolonged QTc
- liver thrombus

235
Q

What is the mechanism of action of doxorubicin and its side effects?

A

Anthracycline =
1. intercalates with DNA bases pairs causing breakage of DNA strands and inhibition of both DNA and RNA synthesis
2. Inhibits topoisomerase II causing DNA damage and induction of apoptosis
3. Oxidative DNA damage when combined with iron

Side effects:
- alopecia
- nausea and vomiting
- oral sores
- pancytopenia
- secondary malignancy
- extravasation = severe ulcers + necrosis
- early cardiac = myopericarditis + HF + arrhythmia
- late cardiac = HFrEF

236
Q

What is the mechanism of action of vincristine and its side effects?

A

Vinca alkaloids = interferes with microtubule polymerisation to disrupt mitosis and induce apoptosis

Side effects:
- peripheral neuropathy (sensory, motor and autonomic)
- seizures
- SIADH
- constipation
- pancytopenia
- alopecia
- mucositis
- nausea, vomiting, diarrhoea

237
Q

What is the gold standard for staging and measuring treatment response in DLBCL?

A

FDG-PETCT

238
Q

What are the targets of Yescarta (axicabtegen ciloleucel) and Kymriah (tisangenlecleucel)?

A

Both target CD19

239
Q

What are peripheral T-cell lymphomas?

A

Heterogenous CD3+ malignancy derived from post-thymic T-cells (CD1-TdT-)

Often cutaneous involvement, hepatosplenoemgaly and eosinophilia

Worse prognosis than DLBCL

240
Q

What is the mechanism of action of Brentuximab vedotin?

A

Anti-CD30 mAB conjugated to monomethyl auristatin E (MMAE)= tubulin toxin. MMAE loclises to lysozymes causing arrest of cell cycle between G2 and mitosis

241
Q

How are peripheral T-cell lymphomas treated?

A

CHOP
If CD30+ then use Brentuximab vedotin

242
Q

What are clinical features of Burkitt lymphoma?

A
  • Aggressive + chemosensitive
  • endemic (EBV associated) or sporadic or immunodeficiency associated
  • high risk for tumour lysis
243
Q

What genetic alterations are seen in Burkitt lyphoma?

A

Characteristic is translocation of myc oncogene on Chromosome 8 to Ig promotor region:
- t(8;14) = most common, Ig heavy chain on Chr14
- t(2;8) or t(8;22) light chain loci

244
Q

How is Burkitt lymphoma treated?

A

Alternating cycles of intensive multi-agent chemo

245
Q

What cancers are high risk for tumour lysis syndrome?

A
  • high grade lymphoma (Burkitts, T lymphoblastic)
  • ALL
246
Q

What is pathophysiology of tumour lysis syndrome?

A

Seen in tumours with high proliferative rate + high death fraction of cells

Cytotoxic therapy and glucocorticoids exacerbate:
- hyperuricaemia
- hyperuricosuria
- hyperkalaemia
- hyperphosphataemia and secondary hpocalcaemia

The precipitation of uric acid, xanthine and/or phosphate in renal tubules + colelcting system results in obstructive nephropathy and renal failure

247
Q

What is the treatment for tumour lysis syndrome?

A

-Prevent hyperuricaemia + promote high urine flow
-Rasburicase

248
Q

What is the mechanism of action of rasburicase?

A

Urate oxidase
Oxidises uric acid to alantoins which are more soluble and less nephortoxic
Results in a rapid decrease in serum uric acid and reduces acute renal failure

249
Q

What lymphomas are associated with the following pathogens:
- HIV
- HLTV-1
- EBV
- HHV-8
- HCV
- H. pylori
- Borrelia burgdoferi

A
  • HIV: DLBCL, Burkitts, castleman’s disease, hodgkin lymphoma
  • HLTV-1: Adult T-cell leukaemia/lymphoma
  • EBV: Burkitt’s lymphoma, T/NK-cell lymphoma (nasal), post-transplant lymphoma
  • HHV-8: kaposi sarcoma, primary effusion lymphoma, castleman disease
  • HCV: splenic marginal zone lymphoma, mixed cryoglobulinaemia
  • H. pylori: gastric MALT lymphoma
  • Borrelia burgdoferi: cutaneous MALT lymphoma
250
Q

What is the proposed mechanism causing lymphomas for following pathogens:
- HIV
- HLTV-1
- EBV
- HHV-8
- H. pylori

A
  • HIV: depression of immune function with activation of c-MYC, inactivation of p53 and EBV infection
  • HLTV-1: inactivation of tumour suppressor genes mediated by Tax
  • EBV: chronic latent infection with encoding of BHFR1 and LMP-1 that inhibit apoptosis
  • HHV-8: co-infection with EBV, viral protein expression
  • H. pylori: chronic antigen stimulation followed by secondary activation of NF-kB pathway
251
Q

What are the histological features of Hodgkin lymphoma?

A
  • Reed-sternberg cell
  • CD15+ (80%), CD30+ (95%)
  • usually CD20-
252
Q

What are clinical features of Hodgkin lymphoma?

A
  • bimodal age distribution
  • high rates in same sex siblings
  • supra-diaphragmatic disease most common
  • 40% have systemic symptoms
  • 90% untreated die in 2 years
  • 80% cured with chemo
253
Q

How is Hodgkin lymphoma treated?

A

1st line Chemo: ABVD or escalated BEACOPP
2nd line: ABVD or escalated BEACOPP
3rd line: Pembrolizumab, brentuximab vedotin

254
Q

What are the treatment complications fo Hodgkins lymphoma?

A

Chemo:
- MDS and leukaemia
- bleomycin lung toxicitty
- premature IHD and valvular disease
- infertility (BEACOPP)

Radiotherapy:
- cardiac
- solid tumours
- fertility (if in field)

Brentuximab: peripheral neuropathy
Anti-PD1: autoimmune toxicity

255
Q

What are the roles of bone marrow transplant?

A
  • facilitates delivery of high dose chemotherapy for treatment of malignant disease
  • generate allogeneic immune response to tumour cells to eradicate residual disease and prevent relapse
  • replace defective marrow stem cells
  • replace defective immuen system
  • facilitate delivery of immuno-suppression in auto-immune disease
256
Q

What are the indications for autologous stem cell transplant?

A
  • myeloma
    -non hodgkins lymphoma
  • relapsed hodgkin lymphoma
  • germ cell tumours
  • CNS tumours
  • Amyloidosis
  • AML/ALL
  • CML without allo-donor
  • autoimmune disease
257
Q

What are the steps of autologous stem cell transplant?

A
  1. Patient selection
  2. Induce complete or good partial remission (must be chemosensitive)
  3. Collect stem cells from marrow or blood after mobilising or priming
  4. Transplant conditioning chemo
  5. Stem cell reinfusion
  6. Recovery (12-18 days)
  7. Disease restage
  8. Second transplant or consolidation or maintenance
  9. Gradual immune reconstitution
  10. Long term effects
258
Q

What are indications for allogeneic transplant?

A
  • AML (remission or relapse)
  • ALL (remission or relapse)
  • Myelodysplasia
  • severe aplastic anaemia
  • NHL
  • CML
259
Q

What are the steps of allogeneic transplant?

A
  1. Patient selection
  2. Donor selection
  3. Transplant type selection and conditioning
  4. Disease control
  5. Transplant conditioning
  6. Rest day
  7. Stem cell infusion
  8. Neutropenic period (prophylaxis)
  9. Engraftment
  10. Disease restaging
  11. Immune reconstitution (12-18 months)
  12. Long term effects
  13. Monitoring for and treating relapse
260
Q

Which application of allogeneic SCT has the best survival?

A

Aplastic anaemia

261
Q

What is the early transplant mortality of allo-BMT?

A

5-12% in first 100 days
16-25% in first year

262
Q

What is the pathological basis of graft vs host disease?

A

Reaction of donor’s immune system (T-cells, B-cells and cytokines) against the recipient’s tissues

  1. Conditioning regimen damage (mucoas, cytokines, bacteria)
  2. Donor T-cell activation and expansion
  3. Effector phase/ tissue damage
263
Q

What are risk factors for acute GVHD?

A

Donor related:
- HLA compatibility
- Sex mismatch (F to M)
- Alloimmunity
- source of stem cells (PB > BM > CB)
- CMV seropositivity

Recipient related:
- Age
- Conditioning regimen
- GvHD prophylaxis used

264
Q

What are clinical features of GvHD?

A
  • rash
  • diarrhoea
  • raised bili, cholestatic hepatopathy
  • fever
  • decreased performance status
265
Q

How is GvHD diagnosed?

A

On biopsy of affected organ

266
Q

What are the long term complications of BMT?

A
  • relapse
  • chronic GvHD
  • infections
  • cardio-respiratory disease
  • endocrinopathies
  • infertility
  • eye disease (cataracts)
  • osteoporosis
  • renal disease
  • secondary cancers
  • psychosocial impact
267
Q

What is the pathological basis of CML?

A

t(9;22) results in formation of Philadelphia chromosome and BCR-ABL fusion gene (occassionally do not have philadelphia chromosome but BCR-ABL fusion gene is present)
Leads to proliferation of myeloid precrusor in bone marrow and blood

268
Q

What are blood film features of CML?

A

Leucocytosis with left shift
Presence of basophils

269
Q

How is CML diagnosed?

A

Cytogenetics for philadelphia chromosome, if negative, then FISH analysis
Can quantify BCR-ABL with RT-PCR

270
Q

What is the treatment for CML?

A

1st line: TKI (imatinib, Nilotinib, dasatinib)
2nd line: need BCR-ABL kinase domain mutation analysis to guide, Ponatinib or ascitinib for 315I mutation

Rarely AlloBMT: used if resistant to 2nd line TKI or if present in blast crisis after achieving second chronic phase

Use alpha-interferon in pregnancy

271
Q

What is the mechanism of action of Rituximab, ofatumumab, obinutuzumab and what haematological malignancies are they used in?

A

antiCD20 mAb

Used in CD20+ cancers (B-CLL, mantle cell lymphoma)

272
Q

What is the mechanism of action of Daratumumab and what haematological malignancy is it used in?

A

anti-CD28

2nd line multiple myeloma

273
Q

What is the mechanism of action of Elotuzumab?

A

anti-SLAMF7

274
Q

What is the mechanism of action of Polatuzumab

A

antiCD79 conjugated to MMAE

relapsed or refractory DLBCL

RACP 2024 (15 decks)

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