Haematological Malignancy Flashcards
1
Q
What is the epidemiology of haematological malignancies?
A
Account for 10% of all human cancers
Occur in all age groups
Adult males are more commonly affected than females.
2
Q
What is the pathogenesis of haematological malignancy?
A
Multi-step process
Acquired genetic alterations in a long lived cell.
Proliferative and survival advantage to the mutated cell resulting in a malignant clone.
Malignant clone then grows to dominate the tissue.
3
Q
What is AML?
A
Acute myeloid Leukaemia is a type of cancer where the bone marrow produces abnormal myeloblasts the progenitor cells for myeloid linage.
4
Q
What are myeloproliferative disorders?
A
Cancers that affect differentiated myeloblasts such as red cells, platelets, neutrophils etc.
5
Q
What is ALL?,
A
Acute Lymphoblastic Leukaemia.
Cancer with large numbers of unusually immature white blood cells destined to become lymphocytes within the blood and bone marrow.
6
Q
What is CLL?
A
Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes.
7
Q
What are Lymphomas?
A
Cancer that begins in lymphocytes causing them to change and grow out of control.
8
Q
What is Multiple Myeloma?
A
Cancer of plasma cells causing them to accumulate and grow in bone marrow, overcrowding healthy cells.
9
Q
What are he differences between acute and chronic Leukaemia?
A
Acute: Cells do not differentiate Bone marrow failure Rapidly fatal if untreated Potentially curable if caught early with chemo.
Chronic:
Leukaemia cells retain ability to differentiate.
Proliferation without bone marrow failure
Survival for a few years
Potentially curable with modern therapy e.g. tyrosine kinase inhibitors in CML.
10
Q
Where do lymphocyte populations reside within the lymph node?
A
B cells in follicles
T cells in the paracortex
Plasma cells in the medulla.
11
Q
Where do naive B cells reside?
A
Mantle zone of B cell follicle
12
Q
Where do B cells undergoing expansion and selection reside?
A
Germinal centre of B cell follicle.
13
Q
What are some causes of localised and painful lymphadenopathy?
A
Bacterial infection in draining site.
14
Q
What are some causes of localised and painless lymphadenopathy?
A
Rare infections, catch scratch fever, TB
Metastatic carcinoma from draining site - hard
lymphoma - rubbery
Reactive, idiopathic
15
Q
What are some causes of Generalised and painful/tender lymphadenopathy?
A
Viral infections: EBV, CMV, Hepatitis, HIV
16
Q
What are some causes of generalised and painless lymphadenopathy?
A
Lymphoma Leukaemia Connective tissue diseases Sarcoidosis Reactive Drugs
17
Q
How can Lymphoma present?
A
Nodal disease - >90% of Hodgkins lymphoma present nodally and 60% of NHL.
Extranodal - 40% NHL present with extra nodal component with/without nodal involvement.
Systemic symptoms - fever, drenching sweats, loos of weight, pruritus (itchy skin), fatigue.
18
Q
What are the main types of myeloid malignancy?
A
Acute myeloid leukaemia (AML)
Chronic Myeloid Leukaemia (CML)
Myelodysplastic Syndromes (MDS)
Myeloproliferative neoplasms (MPN)
19
Q
What are the subgroups of acute leukaemia?
A
Acute myeloblastic leukaemia (AML)
Acute Lymphoblastic Leukaemia (ALL)
20
Q
What are the clinical features of acute myeloblastic leukaemia?
A
Bone marrow failure
Anaemia
Thrombocytopenic bleeding (purpura and mucosal membrane bleeding)
Infection because of neutropenia (predominantly bacterial and fungal).
21
Q
What investigations should you carry out for AML?
A
Blood count and blood film
Bone marrow aspirate/trephine (blasts >20% of marrow in AML
Cytogenetics and immunophenotyping from leukaemia blasts.
CSF examination if symptoms.
Targeted molecular genetics for associated acquitted gene mutations e.g. FLT3, NPM1, IDH1 & 2.
Extended NGS myeloid gene panels.
22
Q
What is the treatment for AML?
A
Supportive care Anti-Leukaemia chemotherapy : Daunorubicin & cytosine arabinoside. High dose cytosine arabinoside Gemtuzumab ozogamicin CPX-351
Allogeneic stem cell transplantation
All-trans retinoid acid (ATRA) and arsenic trioxide (ATO) in low risk acute promyelocytic leukaemia.
Targeted treatment e.g. midostaurin in FLT3 mutated AML.
23
Q
What are the new treatment developments in AML?
A
Targeted antibodies
Targeted smal molecules
New chemotherapy delivery systems
24
Q
What is the clinical presentation of Chronic myeloid leukaemia?
A
Anaemia Splenomegaly Weight loss Hyperleukostasis - fundal haemorrhage and venous congestion, altered consciousness, respiratory failure. Gout
25
What are the laboratory features of CML?
High WCC
High platelet count
Anaemia
Blood film shows all stages of white cells differentiation with increased basophils.
Bone marrow is hyper cellular
Bone marrow and blood class contain Philadelphia chromosome - t(9;22)
26
What is the treatment of chronic myeloid leukaemia?
Tyrosine kinase Inhibitors (TKIs) e.g. imatinib, dasatinib, nilotinib, busitinib, ponatinib.
Direct inhibitors of BCR-ABL.
Allogeneic transplantation in TKI failures.
27
What are some different types of myeloproliferative neoplasms (MPN)?
```
Polycythaemia Vera (PV)
Essential Thrombocythaemia (ET)
Idiopathic myelofibrosis
```
28
What are some common mutations in myeloproliferative neoplasms?
JAK2 V617F in 95% of PV and 50% of ET and myelofibrosis.
CALR mutation in 25% of ET
29
What are the clinical features of Polycythaemia vera?
```
Headaches
Itch
Vascular occlusion
Thrombosis
TIA, stroke
Splenomegaly
```
30
What are the laboratory features of PV?
Raised haemoglobin conc and raised haematocrit.
Tendency to have raised WCC and platelet count.
Raised uric acid
True increase in red cell mass when blood volume is measured.
31
What is the treatment for Polycythaemia Vera?
Venesection to keep the haematocrit below 0.45 in men and 0.43 in women.
Aspirin
Hydroxcarbamide/Alpha interferon
Ruxolitinib (JAK2 inhibitor) in HC failures with systemic symptoms.
32
What is the natural history of PV?
Stroke and other arterial or venous thromboses if poorly controlled.
Bone marrow failure from development of secondary myelfibrosis.
Transformation to AML
33
What are some features of Essential Thrombocythaemia?
Myeloproliferative disease with predominant raised platelet count.
50% positive for JAK2V617F mutation.
25% positive for calreticulin (CALR) mutation.
Symptoms of arterial and venous thromboses, digital ischaemia, gout, headache.
Mild splenomegaly
Treatment with aspirin and hydroxycarbamide or anagrelide.
Can progress to myelofibrosis or AML.
34
What is myelofibrosis?
Bone marrow cancer where scar tissue builds up in bone marrow leading to severe anaemia.
35
What is Polycythaemia Vera?
Slow growing cancer that causes bone marrow to make too many red cells. Results in thickening of blood and slowing of its flow.
36
What is essential thrombocythaemia?
Rare chronic blood cancer characterised by the overproduction of platelets by megakaryocytes in the bone marrow.
37
What are the features of Lymphoma?
Cancer of lymphoid origin that can present with enlarged lymph nodes or with extra nodal involvement or with bone marrow involvement.
Systemic symptoms - weight loss (>10% in 6 months), fever night sweats, pruritis and fatigue.
38
How is leukaemia and lymphoma diagnosed?
Biopsy tells us what type it is.
| Examination and imaging tell us where it is and therefore its staging.
39
How is lymphoma often broken-down into subtypes?
Hodgkin's lymphoma (specific condition)
or Non-hodgkin's lymphoma (broad term).
This can then be divided further into high- grade and low-grade conditions.
40
What are the features of Acute lymphoblastic leukaemia (ALL)?
Cancerous disorder of typhoid progenitor cells.
No differentiation occurs in cells just rapid uncontrolled growth/accumulation.
Usually in bone marrow but can go anywhere in body.
Most are B cell.
Common in children.
41
How does ALL usually present?
```
2-3 week history of bone marrow failure or bone/joint pain.
Can still have a normal blood count.
Low Hb
Raised WCC
Low Platelets
High B cells.
```
42
What are the characteristics of ALL cells?
```
Large cells
Express CD19 marker like B cells.
CD34, TDT markers of very early immature cells.
Not much else as no chance to develop.
Aggressive, fast growing.
```
43
What is the treatment for ALL?
```
Chemo to obtain remission
Consolidation therapy
CNS directed treatment as they like to hide in brain.
Maintenance treatment for 18months.
Stem cell transplantation if high risk.
```
44
What are some new therapies being used in ALL treatment?
Bi-specific T-cell engagers - harness immune system to go after tumour cells by massively activating T cells.
Chimeric antigen receptor T-cells (CAR) - take T-cells out of patient and genetically modify them to kill cancer cells.
45
What are the risk factors for ALL?
Increasing age
Increased WCC
Cytogenetics/molecular genetics - Philadelphia gene.
Slow/poor response to treatment.
46
What is the outcome of ALL patients?
Most adults and children go into complete remission although most adults do require a bone marrow transplant for this.
47
What are the features of CLL?
The abnormal cells are mature and resemble normal well behaved lymphocytes.
Grow slowly
Low-grade condition
Carry many normal markers that B-cells have.
Requires a B cell count of >5.
Commonest leukaemia worldwide.
48
How does CLL present?
Often asymptomatic
Bone marrow failure, lymphadenopathy, splenomegaly, fever, sweats.
Occasionally hepatomegaly, infections and weight loss.
Immune paresis - loss of normal immunoglobulin production.
Haemolytic anaemia.
49
How is CLL staged?
Binet staging.
A = 3 lymph node areas. Survival is same as aged matched controls.
B = 3 or more lymph node areas. 8year survival
C = Stage B + anaemia or thrombocytopenia. 6year survival.
50
What are the indications to treat CLL?
```
Progressive bone marrow failure.
Massive lymphadenopathy
Progressive splenomegaly
Lymphocyte doubling time <6 months or >50% increase over 2 months.
Systemic symptoms
Autoimmune cytopenias.
```
51
What is the treatment for CLL?
Watch and wait.
Cytotoxic chemotherapy
Monoclonal antibodies
Novel agents (target specific pathways) - Bruton tyrosine kinase inhibitor, PI3K inhibitor, BCL-2 inhibitor.
52
What are some poor prognostic markers of CLL?
```
Advanced disease (B or C)
Atypical lymphocyte morphology
Rapid lymphocyte doubling time.
CD38+ expression
Loss/mutation p53, del 11q23 (ATM gene).
Unmutated IgVH gene status
```
53
How does Lymphoma present?
Lymphadenopathy
Hepatosplenomegaly
B symptoms (systemic symptoms)
Bone marrow involvement.
54
What are some investigations you may carry out for Lymphoma?
Lymph node biopsy
CT scan
Bone marrow aspirate and trephine.
55
How is lymphoma staged?
Ann Arbour staging
Stage 1 - 1 node involvement
Stage 2 - 2 lymphatic regions involved on one side of diaphragm.
Stage 3 - no extranodal but either side of diaphragm.
Stage 4 - disseminated disuse with extra nodal sites.
A - absence of B symptoms
B - fever, night sweats, weight loss.
56
What are some characteristics of Low grade lymphoma?
Indolent often asymptomatic
| Responds to chemo but incurable.
57
What are some characteristics of high grade lymphoma?
Aggressive, fast growing
Require combination chemo
Can be cured
58
What is Diffuse large B cell lymphoma?
Commonest subtype of lymphoma.
High grade.
Developps abnormal B cells and larger healthy cells.
More common in older people.
59
What is Follicular lymphoma?
2nd commonest subtype of lymphoma.
Low grade
Abnormal B cells collect as follicles (clumps) in lymph glands.
60
What is the treatment for Diffuse large B cell lymphoma and Follicular lymphoma?
Combination chemotherapy - typically anti-CD20 monoclonal antibody + chemo.
61
What are some features of Hodgkin's lymphoma?
Bimodal age curve with 1st peak at 15-35yrs and 2nd later in life.
1st peak is not associated with EBV but 2nd usually is.
Lymph glands are affected in a continuous spread.
62
What is the treatment of Hodgkin lymphoma?
```
Combination therapy (ABVD)
Radio therapy
Monoclonal antibodies (anti-CD30)
Immunotherapy (checkpoint inhibitors)
```
PET scan essential to assessment of response to treatment.
63
What are the different options of light chains on an antibody?
Kappa
Lamdba
Each cell with only make e1 type of light chain with 1 specificity.
64
What is the structure of an immunoglobulin?
Fab region - variable, defines target binding.
Fc region - constant, denies subclass.
65
What is a paraprotein?
A monoclonal immunoglobulin present in blood or urine.
| 1 antibody has proliferated and cloned itself to produce several copies.
66
What is serum protein electrophoresis?
Test that separates proteins based on their size and charge. Assesses antibody diversity and identifies if a paraprotein is present.
67
What does total immunoglobulin levels tell us?
Measures Ig subclasses by heavy chains/Fc section.
68
What does Immunofixation do?
Identifies what class of paraprotein is present e.g. IgM or IgG.
69
What does light chain tests do?
Assess imbalance/excess of light chains in urine and serum. In normal patients there is a balance of kappa and lambda chains.
70
What disease are IgM paraproteins associated with?
Lymphoma.
Maturing B-lymphocytes make IgM antibody at start of the immune response so cells aren't mature enough to be plasma cells and therefore can't be myeloma.
71
What disease are IgG paraproteins associated with?
Myeloma.
| Mature plasma cells generate these types of immunoglobulin after isotope switching.
72
What is myeloma?
Neoplastic disorder of plasma cells resulting in excessive production of a single type of immunoglobulin (paraprotein).
Peaks in 7th decade.
Commoner in black population then white.
Clinical manifestations may result from direct effect of plasma cells or effect of paraprotein.
73
What are the features of Myeloma?
```
CRAB:
HyperCalcaemia
Renal failure
Anaemia
Bone disease - lytic bone lesions, pathological fractures, cord compression.
```
Also may get infections.
74
What are some effects of paraprotein?
Renal failure - Ig deposition and blockage of renal tubules.
Hyperviscosity - increased blood viscosity, impaired microcirculation and hypo perfusion. Commonly seen as bleeding. Can also cause cardiac failure, pulmonary congestion, renal failure.
Hypogammaglobulinaemia - impaired production of normal immunoglobulins, tendency to infection.
Amyloidosis
75
What is Amyloidosis?
Group of diseases characterised by deposition of fibrillar protein. Crystal like structure. Can be caused by paraprotein or light chains (AL amyloid).
76
What are some conditions amyloidosis may lead to?
```
Nephrotic syndrome
Cardiac failure (LVH)
Carpal tunnel syndrome
Autonomic neuropathy
Cutaneous infiltration
```
77
How is myeloma diagnosed?
Excess plasma cells in the bone marrow. Must comprise >10% of total bone marrow cell population.
78
What is Monoclonal gammopathy of uncertain significance (MGUS)?
Presence of paraprotein incidentally, usually there is nothing wrong with the patient. It is just a slight growth.
79
How is myeloma staged?
Based on albumin and beta-2 microglobulin.
80
What is the treatment for Myeloma?
Chemotherapy - proteasome inhibitors, monoclonal antibodies, IMiDs.
Bisphosphonate therapy - zoledronic acid.
Radiotherapy
Steroids
Surgery - pining of long bones, decompression of spinal cord.
Autologous stem cell transplant.
81
How do IgM paraproteins present?
```
Alongside low grade lymphomas.
Bone marrow failure - anaemia, thrombocytopenia.
Lymphadenopathy
Hepatosplenomegaly
B symptoms
Paraprotein related symptoms
Bone disease is very rare.
```
82
Which immune cells are hit hardest by haematological malignancies and their treatment?
Neutrophils and T-lymphocytes.
83
What are some supportive measures aimed at reducing risk of sepsis in haematological malignancy?
Prophylaxis - antibiotics, anti-fungals, anti-virals, PJP.
Growth factors e.g. G-CSF
Stem cell rescue/transplant
Protective environment e.g. laminar flow rooms to push out pathogens.
Intravenous immunoglobulin replacement.
Vaccination.
84
What prophylaxis drugs are commonly used in haematological malignancy?
Antibiotics - Ciprofloxacin
Anti-fungal - fluconazole or itraconazole
Anti-viral - Aciclovir
PJP - Co-trimoxazole.
85
What are some determinants of neutropenic risk?
<0.5x10^9/L - significant risk
<0.2x10^9/L - high risk
Neutropenia lasting > 7days is high risk.
AML therapy and stem cell transplantation produces profound neutropenia for approx 14-21 days.
Marrow failure higher risk than immune destruction.
86
What are some additional risk factors for infection in haematological malignancies?
Disrupted skin/mucosal surfaces - Hickman line, mucositis affecting GI tract, GVHD.
Altered flora/antibiotic resistance.
Lymphopenia - disease process, treatment, stem cell transplantation, GVHD.
Monocytopenia - hairy cell leukaemia, chemo.
87
What are the main bacterial causes of febrile neutropenia?
Gram positive bacteria 60-70%
| Gram negative bacilli 30-40%
88
What are the main gram positive organisms that cause febrile neutropenia?
Staphylococci: MSSA, MRSA, coagulase negative.
| Strepotococcit : Viridans
89
What are the main gram negative bacteria that cause febrile neutropenia?
Escherichia coli
Klebsiella spp: ESBL
Pseudomonas aeruginosa
90
What are some possible sites of infection?
```
Respiratory tract
Gastrointestinal (typhlitis)
Dental sepsis
Mouth ulcers
Skin sores
Exit site of central venous catheters
Perianal
```
91
What are the main fungi that cause febrile neutropenia?
Candida species
Aspergillus
Monocytopenia and monocyte dysfunction contributes to risk of fungal infection.
92
How does neutropenic sepsis present?
```
Fever with no localising signs (no neutrophils to go to site).
Rigors
Chest infection/pneumonia
Skin sepsis - cellulitis
UTI
Septic shock
```
93
What is the treatment for septic shock?
Sepsis 6
Administer high flow oxygen
Take blood cultures, other cultures, consider source control.
Give appropriate IV antibiotics within 1 hour.
Measure serum lactate conc.
Start IV fluid resuscitation
Assess/measure urine output.
94
What is the management for neutropenic sepsis?
Resuscitation
Broad spectrum Iv antibiotics e.g tazocin and gentamicin.
If gram positive add vancomycin or teicoplanin.
If no response at 72hrs add Iv anti-fungal e.g. caspofungin (empiric therapy)
CT chest/abdo/pelvis to look for source
Modify treatment based on culture results.
95
What are some causes of lymphopenic patients?
```
Stem cell transplant recipients especially allogeneic.
Recipients of total body irradiation.
Graft vs host disease
Nucleoside analogues or ATG
Lymphoid malignancy
```
96
What are the common infections that occur in severely lymphopenic patients?
Atypical pneumonia: Pneumocystitis Jirovecii (PJP)
CMV
RSV
```
Viral:
Shingles (varicella zoster)
Mouth ulcers (herpes simplex)
Adenovirus
EBV (PTLD)
```
Fungal:
Candida
Aspergillus
Mucormycosis
Atypical mycobacteria: skin lesions, pulmonary and septic involvement.
