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
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)
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
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
5
Q
How is cytokine release syndrome managed?
A
First line = anti-IL6R (tocilizumab) and anti-IL6 (siltuximab)
2nd line = steroids
6
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
7
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
8
Q
What is the duration of anticoagulation for a distal DVT without persisting risk?
A
6 weeks
9
Q
What is the benefit of DOACs over warfarin for VTE?
A
Same efficacy
Lower serious bleeding rate
10
Q
What anticoagulation can be used for APS?
A
Warfarin or LWMH
11
Q
What prophylaxis is given for severe haemophilia A and B?
A
A: Factor VII every 2 days
B: factor IX every 3 days
12
Q
What are causes of microcytic anaemia?
A
MCV < 80
Iron deficiency
Thalassaemia
Haemoglobinopathy
Siderobalstic anaemia
13
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
14
Q
What are causes of macrocytic anaemia?
A
MCV > 100
Megalobastic:
- B12 deficient
- Folate deficient
Non-megalobalstic:
- myelodysplasia
- liver disease
- alcohol
- pregnancy
- hypothyroidism
15
Q
How is fe deficiency diagnosed?
A
Ferritin < 30
OR
Ferritin < 100 in high inflammatory states
OR
Tsat < 20% when Ferritin > 100
16
Q
How is sickle cell managed?
A
- transfusion
- hydroxyurea to increase fetal haemoglobin
- staying warm
17
Q
What are different causes of bone marrow failure?
A
Aplastic:
- idiopathic/autoimmune
- medications
- viral
- inherited (fanconi)
Infiltration:
- malignancy, haem or other
Dysfunction:
- myelodysplasia
18
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
19
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
20
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%)
21
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
22
Q
What is the hierachy of survival for non-CML MPNs?
A
- best = ET
- PV
- pre-PMF
- Worst = overt PMF
23
Q
What are the 3 main treatment goals for MPN?
A
- reduce risk of vascular and thrombotic events
- cytoreductive agents
- antiplatelet/anticoagulant therapy
- CV risk factors - Recognise, acknowledge and manage symptom burden
- Reduce progression and transformation of disease - no therapies proven to do so
24
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
25
What is the treatment of polycythemia vera?
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
26
What are the diagnostic criteria for polycythemia vera?
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
27
What is the role of BMB in polycythemia vera?
- avoids underdiagnosis of masked PV (by FE deficiency) to improve management and outcomes
- prognostic information (cytogenetics, reticulin)
28
What are risk factors in ploycythemia vera for reduced survival and transformation to leukaemia?
Reduced survival:
- Age > 61
- WCC > 10.5
- thrombosis history
- abnormal karyotype
Leukaemia:
- age > 61
- WCC > 15
- abnormal karyotype
29
What is the anti-hypertensive of choice in polycythemia vera?
ACEi, may suppress erythropoiesis
30
What is the rationale for BD aspirin in high risk polycythemia vera?
OD dosing achieves suboptimal suppression of Thromboxane-A2 synthesis
31
What are the indications for aspirin for essential thrombocytopenia?
Age > 60
CV risk factors
JAK2V617F mutation
32
What are the indications for cytoreductive therapy in essential thrombocythemia?
Prior thrombosis
JAK2 mutation + >60
PLT > 1500
Uncontrolled myelproliferation (symptomatic splenomegaly)
Uncontrolled ET-related systemic symptoms
33
What cytoreductive therapy is used in essential thrombocythemia?
Hydroxycarbamide
Recombinant IFN-alpha
34
What are risk factors of ET for reduced survival?
Age > 60
WCC > 11
Previous thrombosis
- male
- elevated LDH
- non driver mutations (SH2B3, SF3B1, U2AF1, TP53, IDH2, EZH2)
35
What are the diagnostic criteria for prefibrotic myelfibrosis?
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
36
What management principles are used in prefibrotic myelfibrosis?
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
37
What are symptoms of primary myelofibrosis?
20% asymptomatic
-Abnormal blood count
-Splenomegaly
80% symptomatic:
- anaemia
- frequent infections
- easy bruising
- splenomegaly or bone pain
- gout
- constitutional symptoms
38
What patients with primary myelofibrosis require treatment?
- significant symptoms
- anaemia
- splenomegaly (>10cm)
- WCC > 25
- PLT > 1000
39
How is myelfibrosis-associated anaemia treated?
Androgens
Prednisone
Erythropoietin stimulating agents
40
How is splenomegaly, leucocytosis or thrombocytosis managed in primary myelofibrosis?
Cytoreductive therapy:
-1st line: hydroxyurea or rIFN-a
- 2nd line: ruxolitinib
- splenectomy rare
PLT > 1000, WCC > 25, spleen > 10 cm
41
What is the mechanism of action of ruxolitinib and what benefits does it have?
Oral JAK inhibitor
In primary myelofibrosis improves splenomegaly, weight loss, pruritis
Cons: anaemia, thrombocytopenia, risk of cancer
42
How is CLL diagnosed?
Blood film: mature lymphocytosis, smudge cells
CD5+(aberrant)CD19+CD23+
> 5x 10^9/L of abnormal B-cell population
43
What are blood film features of CLL?
- smudge cells
- small, mature lymphocytes with thin rim of cytoplasm
- no nucleoli to indicate immature lymphoids
44
What are clinical features of CLL?
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
45
What is a richter transformation?
Transformation of CLL to high grade lymphoma
- 90% DLBCL
- 10% hodgkin lymphoma
46
How is CLL treated?
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
47
What is the effect of bruton's tyrosine kinase inhibitor?
Ibrutinib, acalabrutinib, zanubrutinib
Blocks BCR signalling to induce apoptosis in B-cells
Blocks B-cell migration and adherence
48
What are side effects of ibrutinib?
Atrial Fibrillation
Arthralgia, rash, hypertension, diarrhoea, fungal infections
Needs 3-7 day washout prior to surgery due to reduced collagen mediated platelet aggregation
49
What are the side effects of venetoclax?
Tumour lysis syndrome - graduated dosing
Neutropenia - G-CSF
CYP3A4 interactions
50
What influences the risk of MGUS progression?
M-protein size > 15g/L
Non-IgG isotype
Abnormal serum free light chains
51
What is the diagnostic criteria of MGUS?
- M protein < 3 g/dL
- clonal plasma cells in BM < 10%
- no myeloma defining features
52
What is the diagnostic criteria of smoldering myeloma?
- M protein > 3 g/dL
- clonal plasma cells in bone marrow 10-60%
- no myeloma defining events
53
What is the diagnostic criteria for multiple myeloma?
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
54
How does multiple myeloma present?
- 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
55
What is hyperviscosity, its causes and treatment?
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
56
What are the indications for autograft?
- multiple myeloma
- mantle cell lymphoma
- T-cell lymphoma
- relapsed/refractory lymphoma, DLBCL, follicular lymphoma
57
What are the risks of autograft?
-death (0.5-1%)
Early:
- sepsis
- mucositis
Late:
- infection: viral, PJP
- secondary cancers: MDS/AML, skin, solid tumours
- psychological
58
How is AML diagnosed?
On BMB:
1. Aspirate with >20% myeloblasts
2. Flow cytometry confirming myeloid lineage
3. Cytogenetics/FISH and molecular assays (NPM1, FLT3)
59
How is AML treated in someone fit for intensive therapy?
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
2. FLT3 inhibitors in addition to chemo for FLT3 mutations = midostaurin
3. Favourable cytogenetic risk: gemtuzumab ozogamicin = antiCD33- drug conjugate
60
How is AML treated in someone NOT fit for intensive therapy?
Age > 75, Age > 60 with significant co-morbidity
Venetoclax (PO BCL2 inhibitor) + azacitidine (subcut hpomethylating agent)
61
What are features of myelodysplastic syndrome?
- low blood counts
- dysplasia
- ineffective haematopoiesis
- increased risk of AML
62
How is MDS managed?
RBC or platelet transfusion
TXA
If high risk: azacitidine
If young (<65): allo BM transplant
If 5q-syndrome: lenalidomide
63
How does lymphoma present?
- lymphadenopathy
- cough or abdo pain with bulky disease
- weight loss, fever and sweats uncommon
- rarely extranodal involvement
- skin more commonly T-cell
- GIT
64
What proportional of patients with lymphoma will have extra-nodal involvement?
25%
65
What is the recommended imaging modality to assess lymphoma response to treatment?
PET-CT (lymphoma needs to be FDG-avid at baseline)
66
What are clinical features of Mantle cell lymphoma?
- 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
67
How does indolent and aggressive mantle cell lymphoma present?
Indolent = splenomegaly, bone marrow involvement, circulating lymphoma cells
Aggressive: lymphadenopathy, type B symptoms
68
How is mantle cell lymphoma treated?
Indolent asymptomatic = observe
Standard treatment = Rituximab + chemo followed by rituximab maintenance
- R-DHAOx + ASCT in young
- R-bendamustine in old
69
How is relapsed mantle cell lymphoma treated?
BTKi (ibrutinib or zanubrutinib)
70
What are characteristics of lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinaemia)?
- low grade NHL
- involves B-cells + plasma cells in bone marrow, spleen and lymph nodes with circulating monoclonal IgM
- M > F
71
What does IgM MGUS progress to?
10% progress to lymphplasmacytic lymphoma
Does not progress to myeloma
72
What are characteristics of lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinaemia) present?
- 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
73
How is lymphoplasmacytic lymphoma treated?
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
74
What are clinical features of DLBCL?
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
75
What is the treatment for DLBCL?
1st line = R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednsione)
2nd line = R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin)
3rd line:
- AutoSCT
- CAR-T cells
76
What is the mechanism of action of cyclophosphamide and its side effects?
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
77
What is the mechanism of action of doxorubicin and its side effects?
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
78
What is the mechanism of action of vincristine and its side effects?
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
79
What is the gold standard for staging and measuring treatment response in DLBCL?
FDG-PETCT
80
How is Burkitt lymphoma treated?
Alternating cycles of intensive multi-agent chemo
81
What cancers are high risk for tumour lysis syndrome?
- high grade lymphoma (Burkitts, T lymphoblastic)
- ALL
82
What is the treatment for tumour lysis syndrome?
-Prevent hyperuricaemia + promote high urine flow
-Rasburicase
83
What are clinical features of Hodgkin lymphoma?
- 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
84
How is Hodgkin lymphoma treated?
1st line Chemo: ABVD or escalated BEACOPP
2nd line: ABVD or escalated BEACOPP
3rd line: Pembrolizumab, brentuximab vedotin
85
What are the treatment complications fo Hodgkins lymphoma?
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
86
What are the roles of bone marrow transplant?
- 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
87
What are the indications for autologous stem cell transplant?
- myeloma
-non hodgkins lymphoma
- relapsed hodgkin lymphoma
- germ cell tumours
- CNS tumours
- Amyloidosis
- AML/ALL
- CML without allo-donor
- autoimmune disease
88
What are the steps of autologous stem cell transplant?
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
89
What are indications for allogeneic transplant?
- AML (remission or relapse)
- ALL (remission or relapse)
- Myelodysplasia
- severe aplastic anaemia
- NHL
- CML
90
What are the steps of allogeneic transplant?
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
91
What are risk factors for acute GVHD?
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
92
What are clinical features of GvHD?
- rash
- diarrhoea
- raised bili, cholestatic hepatopathy
- fever
- decreased performance status
93
How is GvHD diagnosed?
On biopsy of affected organ
94
What are the long term complications of BMT?
- relapse
- chronic GvHD
- infections
- cardio-respiratory disease
- endocrinopathies
- infertility
- eye disease (cataracts)
- osteoporosis
- renal disease
- secondary cancers
- psychosocial impact
95
What are blood film features of CML?
Leucocytosis with left shift
Presence of basophils
96
How is CML diagnosed?
Cytogenetics for philadelphia chromosome, if negative, then FISH analysis
Can quantify BCR-ABL with RT-PCR
97
What is the treatment for CML?
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
