Haematology Flashcards
Define Multiple Myeloma
Malignant disorder of plasma cells (mature B) characterised by excess secretion of monoclonal antibody
The pathophysiology of Multiple Myeloma involves a two step process. What is the first step?
MGUS development
Initial cytogenic abnormality occurs (normally an abnormal response to antigen) which leads to a plasma cell clone
What does MGUS stand for?
Monoclonal Gammomopathy of unknown significance
The pathophysiology of Multiple Myeloma involves a two step process. What is the second step?
MGUS to MM
Further cytogenic abnormalities occur and changes to marrow microenvironment occur, promoting proliferation
Bone marrow infiltration and excess light chain
What occurs in between the first and second step of myeloma?
Pre malignant state called Asymptomatic Myeloma
The presentation of Myeloma can be memorised as ‘CRAB’. Define it
Calcium levels high
Renal Impairment
Anaemia
Bone Disease
Define the ‘Calcium’ part of the Myeloma CRAB mnemonic
Myeloma induced bone mineralisation
Levels>2.9mmol/l is urgent
Define the ‘Renal Dysfunction’ part of the Myeloma CRAB mnemonic
Light chain nephropathy causes increased creatinine
Define the ‘Anaemia’ part of the Myeloma CRAB mnemonic
Normal bone marrow destroyed by proliferation of plasma cells
Renal disease reduces EPO
Define the ‘Bone Disease’ part of the Myeloma CRAB mnemonic
Wide spread due to disease proliferation
Seen as lytic lesions
Can lead to fractures
Other than the CRAB mnemonic, state three possible presentations of Myeloma
Recurrent bacterial infection
Weight Loss
Hyperviscocity Syndrome
How does Hyperviscocity Syndrome (common to MM) present?
Blurred vision
Headaches
Mucosal bleeding
Dyspnoea (secondary to HF)
How is Hyperviscocity Syndrome managed?
Urgent Plasma Exchange
What age group is typically affected by Multiple Myeloma?
Rare in under 40s
Usually over 60s
What is the aim of screening for Multiple Myeloma?
Looking for MABs which are the secretion product of malignant clones, using protein electrophoresis and immunofixation
What types of antibodies are normally involved in Multiple Myeloma
Normally IgA or IgG
If IgM - suggests Waldenstrom Macroglobulinaemia
Describe the use of Electrophoresis in screening for Multiple Myeloma
Separates different proteins into bands using electric current
Band patterns can be normal, polyclonal or monoclonal
Describe the use of Immunofixation in screening for Multiple Myeloma
Qualitative and fixes proteins in place using antibodies
What is the assumption in using Electrophoresis to screen for MM?
Assumes that the Myelomas secrete intact antibodies
What are light chains and what is the relevance in Multiple Myeloma?
Light chains are secreted in normal individuals when monoclonal cells produce more light chains than heavy
The ratio between Kappa and Lambda light chains is the most important (elevated? - myeloma)
What is Urine Electrophoresis used for in Multiple Myeloma?
Light chains in the serum may have been filtered by the kidney into the urine
What are light chains found in the urine called?
Bence Jones Protein
What would the investigations show if a patient had a non secreting Multiple Myeloma
Electrophoresis and Serum Light Chains Negative
Name three broad investigations in order to diagnose Multiple Myeloma
Monoclonal Antibody detection
Bone Marrow Aspirate and Trephine with Cytogenetics
Assess organ damage
Describe the diagnostic criteria for MGUS
Low monoclonal protein
Bone marrow plasma cells < 10%
Describe the diagnostic criteria for pre malignant Asymptomatic Myeloma
Monoclonal protein >3g/dl
Bone marrow plasma cells >10%
No organ damage
Describe the diagnostic criteria for Multiple Myeloma
Monoclonal protein present
Bone marrow plasma > 10%
Signs of organ damage
What is the aim of treatment for Multiple Myeloma?
Incurable condition
Aim to increase periods of remission
There are four main areas of management for Multiple Myeloma. What is Induction Therapy?
Combination of three drugs (Velcade, Revlimid, Dexamethasone)
There are four main areas of management for Multiple Myeloma. What is Autologous Stem Cell Therapy?
Provides the best option for long term remission
Stem cells mobilised, harvested and stored following induction
High dose chemotherapy
Stem cells then reinfused
There are four main areas of management for Multiple Myeloma. What is Maintenance Therapy?
Bortezamid or Lenalidomide
There are four main areas of management for Multiple Myeloma. What is Relapse Therapy?
ASCT/previous regimen or a new therapy
Name four complications of Multiple Myeloma
Bone Disease
Hypercalcaemia
Cord Compression
Renal Impairment
What two parameters contribute to the International Staging System for Myeloma?
Beta 2 Microglobin
Albumin
What do Pluripotent Stem Cells first specialise into?
Myeloid Stem Cells
Lymphoid Stem Cells
What can Myeloid Stem Cells eventually specialise into?
Neutrophils
Eosinophils
Basophils
Monocyes
Platelets
Erythrocytes
What do Lymphoid Stem Cells develop into?
Blast Cells and then Lymphocytes
Define Acute Myeloid Leukaemia
Malignant transformation and proliferation of myeloid progenitor cells
Rare, more common in over 60s
Give four possible aetiologies for AML
Myelodysplastic Syndromes
Downs Syndrome
Radiation Exposure
Previous Chemotherapy
Describe the pathophysiology of AML
Genetic changes in myeloid progenitor cells lead to proliferation of immature cells unresponsive to normal control mechanisms
Reduced production of normal haematopoietic cells
AML can present with signs of Marrow Failure or Tissue Infiltration. Give three signs of marrow failure
Anaemia
Neutropenia
Thrombocytopenia
AML can present with signs of Marrow Failure or Tissue Infiltration. Give three signs of tissue infiltration
Lymphadenopathy
Hepatosplenomegaly
Bone Pain
AML can also cause Leucostasis. How would this present?
Altered Mental State
Headache
Breathlessness
Visual Changes
What is characteristic on a blood test for AML?
Thrombocytopenia
Normocytic Normochromic Anaemia
Raised white cells (maybe lymphopenia)
Raised LDH
What is characteristic on a blood smear for AML?
Auer Rods (pink lines)
What is characteristic on a Bone Marrow Aspiration for AML?
Myeloid Blast count of >20%
Cytogenetics, Immunophenotyping and Flow Cytometry carried out
What are the principles of AML management?
Managed in specialist centres
Enrolled into Clinical Trials
Monitor for infections and coagulopathy
Cytoreduction with Hydroxycarbamide
What should be anticipated with AML treatment?
Tumour Lysis Syndrome
How is AML Chemotherapy set up?
Induction (Intense) and Consolidation cycles
What other treatment could you consider for AML?
ASCT
Give four poor prognostic factors for AML
Age>60
Multiple Comorbidities
Previous Haematological Disorders
Previous Exposure to Chemoradio
Define CML
Chronic Myeloid Leukaemia
Abnormal clonal expansion of cells in myeloid lineage, most common in 50s and 60s
Describe the genetics of CML
Reciprocal translocation between chromosomes 9 and 22
Creates Philadelphia chromosome
Fusion of BCRABL genes
Promotes production of Tyrosine Kinase
CML can be asymptomatic. If not, how could it present?
Splenomegaly
Fatigue, Weight Loss, Early Satiety
Signs of BM infiltration
What would an FBC for CML show?
Marked Neutrophilia
?Basophilia
?Eosinophilia
May show anaemia and thrombocytopenia
What are markers of high cell turnover?
LDH
Urate
Potassium
What is seen on a blood film of CML?
Mixture of immature and mature myeloid precursors
Proportion of blast cells to basophils helps stage
Other than bloods, what investigations are done for CML?
Bone Marrow Aspiration +/- Trephine
Identifying Philadelphia chromosome
How is the Philadelphia Chromosome identified?
Metaphase Cytogenetics
FISH/Reverse Transcriptase PCR can determine presence of BCRABL
There are three different phases in CML. Describe the Chronic Phase
Non Specific symptoms (fatigue, night sweats, weight loss)
Without treatment, this phase lasts 3-5 years
There are three different phases in CML. Describe the Accelerated Phase
Symptoms and features are more apparent and severe
If untreated, phase lasts 6-18 months
Blast Cells 15-29%
Basophils>20%
Persistent thrombocytopenia
There are three different phases in CML. Describe the Blast Phase
Rapid expansion of blasts, without treatment survival is a few months
Blasts>30%
Extramedullary blast proliferation
Describe three management options for CML
Tyrosine Kinase Inhibitors - to directly block enzyme produced by BCRABL
Intensive Chemotherapy - same as AML
ASCT - for chronic phase relapse
Name a first generation Tyrosine Kinase inhibitor
Imatinib
Name two other Tyrosine Kinase inhibitors
Dasatinib
Nilotinib
How should Chronic Phase CML patients be managed?
If WCC>100 then cytoreduction
Oral Hydration and Allopurinol
First line - Imatinib
How is Advanced Phase CML managed?
Ideally patients should be enrolled onto a clinical trial
Second generation TKI with or without Chemotherapy
What is the survival rate of CML?
15-64 has a 90% 5 year survival
>65 has a 40% 5 year survival
Define Acute Lymphoblastic Leukaemia
Most common malignancy of childhood
Lymphoid progenitor cells undergo malignant transformation (mostly B)
Clonal expansion causes lymphoid precursors to replace normal cells
At what age does ALL incidence peak?
0-4
What is the aetiology of ALL?
Poorly understood
Thought to be a genetic predisposition and a trigger (such as a virus)
Name three cytogenic abnormalities in ALL
12:21 translocation
9:22 translocation (Philadelphia)
4:11 translocation
How does ALL normally present?
Normally a short history of marrow supression or lymphadenopathy
Marrow Failure, Tissue Infiltration, Leucostasis
How is ALL investigated?
FBC
Imaging - CXR/CT
BM Aspirate and Biopsy
Give three poor prognostic factors of ALL
Age (worse with advancing age)
Performance Status>1
CNS involvement
What should be done pre ALL management?
Steroids, IV Hydration and Allopurinol to prevent Tumour Lysis Syndrome
Anaemia and Thrombocytopenia mx
G-CSF for Neutropenia
What is the aim of induction therapy in ALL?
Aim to achieve complete remission, or ideally complete molecular remission
What is Complete Remission in ALL?
Leukaemia not seen in bone marrow, CSF or Peripheral Blood
What is Complete Molecular Remission in ALL?
Minimal residual disease not detectable by sensitive molecular probe
What is the maintenance therapy for ALL?
Reduce recurrence risk
Daily 6 Mercaptopurine and weekly methotrexate
Give three complications of ALL
Neutropenic Sepsis
Tumour Lysis Syndrome
SVCO
Define Chronic Lymphocytic Leukaemia
Lymphoproliferative disorder of B lymphoyctes leading to widespread lymphadenopathy and secondary complications
Most common form of Leukaemia in adults in western world
Describe the pathophysiology of CLL
Initial alterations causes pre malignant monoclonal B cell lymphocytosis
Further genetic and bone marrow transformation allows change to CLL
How does CLL present?
Can be asymtomatic and remain stable for many years, or can have aggressive form and deteriorates quickly
Typical B symptoms
Lymphadenopathy
Hepatomegaly
Splenomegaly
What is diagnostic of CLL?
Absolute B lymphocyte count >5 for more than 3 months
With a characteristic immunophenotype
What is a complication of CLL?
Autoimmune Haemolytic Anaemia
What is seen on a blood film of CLL?
Lymphocytosis and Smudge/Smear cells (caused by damage to lymphocytes in preparation)
Why is Flow Cytometry used in CLL?
Shows its due to a clonal lymphocyte
When would you consider doing a Bone Marrow aspiration, or imaging in CLL?
If an alternative diagnosis was suspected
There are two possible stagings for CLL. Describe the Binet Staging
A - <3 lymphoid sites
B - >3 lymphoid sites
C - Presence of anaemia/thrombocytopenia
There are two possible stagings for CLL. Describe the Rai Staging
0 - Lymphocytosis
I-II - Lymphocytosis, Lymphadenopathy and Organomegaly
III-IV - Anaemia and Thrombocytopenia
Give three prognostic indicators in CLL
Lymphocyte doubling time
Genetic Abnormalities
Beta 2 microglobulin
What is Watch and Wait management for CLL?
For asymptomatic patients with low stages
3 monthly bloods
Give four indications for management in CLL
Bone Marrow Failure
Lymphadenopathy
Progressive Lymphocytosis
Autoimmune complications
How is CLL managed?
Two different regimens each containing three chemotherapy agents
Which one depends if TP53 mutation is present
Give an example of a chemotherapy drug used in CLL
Chlorambucil (cross links DNA)
Give an example of a small molecule drug used in CLL
Ibrutinib (Tyrosine Kinase Inhibitor)
Give an example of a monoclonal antibody used in CLL
Rituximab
Other than chemotherapy, what treatment should be considered in CLL?
ASCT
Vaccinations
Steroids
Name three complications of CLL
Richter transformation (formation of agressive lymhpoma with rapid deterioration)
Secondary infections
Hyperviscocity Syndrome
Define Hodgekin’s Lymphoma
Rare malignancy of bimodal distribution, peaking at 20-30 and again at older age
Describe the aetiology of Hodgekin’s Lymphoma
Cause unknown
Links to Immunosupression, EBV, HIV, Smoking
There are two main types of Hodgekin’s Lymphoma, what are they?
Classical
Nodular
What are the four subtypes of Hodgekin’s Lymphoma?
Nodular Sclerosis
Mixed Cellularity
Lymphocyte Rich
Lymphocyte Depleted
Describe the pathophysiology of Classical HL
Characteristic binucleate Reed Sternberg Cells (Owls)
Infiltrating cells are T Regulator cells
Describe the pathophysiology of Nodular HL
Characterised by L and H Hodgekin Cells (aka Popcorn Cells)
Can run a relapsing and remitting course
How does Hodgekin’s Lymphoma present?
Painless rubbery lymphadenopathy
B Symptoms
Itch
Alcohol induced LN pain
May have hepatosplenomegaly or mediastinal mass
What are B symptoms?
Unexplained Fever
Unexplained Night Sweats
>10% Weight Loss in 6m
How do you diagnose Hodgekin’s Lymphoma?
Excisional Biopsy of Lymph Nodes
What other investigations are recommended in HL?
PET CT
Bloods
CXR/MRI (spread dependent)
What is the problem with using a PET CT for Hodgekin’s Lymphoma?
Negative Predictive Value is high
Long term monitoring is not recommended due to false positives
Give three features indicating a poor Hodgekin’s prognosis
Albumin <40
Male
Lymphocytes<0.08
The treatability of Hodgekin’s Lymphoma is good, the issue is the toxicities of treatment. Name three
Secondary Malignancies
Fibrosis
Coronary Artery Disease
How is early stage Hodgekin’s Lymphoma managed?
2-4 cycles of ABVD chemotherapy, and radiotherapy
What is the ABVD chemotherapy regime?
Doxorubicin (Inhibits DNA synthesis)
Bleomycin (Inhibits DNA synthesis)
Vinblastine (Inhibits microtubule formation)
Decarbazine (Alkylating agent)
How is advanced stage Hodgekin’s Lymphoma managed?
6-8 cycles ABVD (or other regimes such as BEACOPP)
Radiotherapy
How should a Hodgekins Lymphoma relapse be treated?
Depends on prognostic indicators and timing
If >12m then salvage therapy (IVE, DHAP, ESHAP)
What is important to note on medical records of previous Hodgekin’s Lymphoma patients?
Should recieve irradiated blood and platelets for life
Define Non Hodgekin’s Lymphoma
Spectrum ranges from low grade lymphomas that are incurable but compatible with many years of life to high grade (left untreated are rapidly fatal)
Give four possible causes of Non Hodgekin’s Lymphoma
Age
Prolonged Immunosupression
EBV
H.Pylori (Gastric)
How can Non-Hodgekins Lymphoma be classified?
Based on whether lymphomas are B or T cells, percieved origin cell and molecular characteristics
There are many different subtypes of Non Hodgekins Lymphoma. Name three
Follicular B Cell
Mature B Cell
Leukaemic
Describe the characteristics of Low Grade Non Hodgekins Lymphoma
Relatively long survival
Incurable (relapsing and remitting)
Non destructive growth patterns
CNS involvement is rare
Describe the characteristics of High Grade Non Hodgekins Lymphoma
Aggressive clinical course and rapidly fatal without treatment
Curable in a significant proportion
Destructive growth pattern
CNS involvement is common
How does Low Grade Non Hodgekins Lymphoma present?
Gradual lymphadenopathy
Malaise
Marrow Involvement
How does High Grade Non Hodgekins Lymphoma present?
Rapidly enlarging mass
B symptoms
End Stage - Ascites and Pleural Effusion
Name three places of Extranodal involvement in Non Hodgekins Lymphoma
CNS
Cutaneous
GI Tract
Name two types of High Grade Non Hodgekins Lymphoma
Burkitts
Lymphoblastic
How is Non Hodgekins Lymphoma investigated?
Lymph Node Biopsy (ideally excisional)
Bloods
Imaging (CXR, CT, PET CT)
Bone Marrow Aspirate
What is used to stage Non Hodgekins Lymphoma?
CXR
CT
Blood count and film
BM Aspirate
Renal Biochem
Markers of tumour burden
What is the Lymphoma staging tool called?
Lugano staging
(Limited, Bulky, Advanced)
What is the management of Non Hodgekins Lymphoma?
R CHOP
Rituximab, Cyclophosphamide, Doxorubicin, Vincristine
Prednisolone
+/- Radiotherapy as adjuvant
What is the most common form of NHL?
Diffuse Large B Cell
What is the second most common form of NHL?
Follicular lymphoma
85% have translocations between 14 and 18
What is Burkitt’s Lymphoma?
High grade rapidly proliferating B cell NHL commonly affecting children
Striongly associated with EBV
How does Burkitt’s Lymphoma present?
Rapidly enlarging tumour in jaw/neck/abdomen
May have bowel obstruction
May have B symptoms
How is Burkitt’s Lymphoma managed?
High grade lymphoma so very chemosensitive
Ideally R-BFM regime, but if not then use less intensive R-CHOP
Monitor for Tumour Lysis
Name three differences between Acute and Chronic Leukaemias
1) Acute Leukaemias have a more rapid onset compared to chronic
2) Acute Leukaemias can have affect children whereas chronic Leukaemias tend to only affect adults
3) Acute Leukaemias are characterised by blast cells on the film whereas Chronic are more well differentiated
Give a primary and secondary cause of Polycythaemia
Primary - Polycythaemia Ruba Vera
Secondary - Chronic Lung Disease, Dehydrated
How could Polycythaemia present?
Headaches
Thrombosis
Blurred Vision
Itchy skin after bathing
How should Polycythaemia be investigated?
Haematocrit
EPO levels (if raised look for phaeochromocytoma or fibroids)
Assess spleen size
Describe the first and second line management of Polycythaemia Rubavera
First Line - Therapeutic venesection (once the levels are low enough, their ‘treatment’ can be giving blood)
Second Line - Hydroxycarbamide (second due to malignancy risk)
What other supportive management is advised for Polycythaemia?
75mg Aspirin
Remain well hydrated
Be careful of long haul flights
Give four differentials for Essential Thrombocytosis
Malignancy
Infection
Inflammation
Post Op
Management for essential thrombocytosis depends on risk. Describe this
Low risk (<40) - Aspirin
High Risk (>60) - Hydroxycarbamide
Intermediate - clinical judgement
Describe the phases of Myelofibrosis
Cellular Phase - raised cell count, extramedullary haematopoiesis
Post Cellular Phase - Transfusion dependent, uncomfortable enlarged spleen
What is the main concerning complication of Myelofibrosis
AML
What should you monitor for with respective paraproteinaemias?
IgM - Lymphoma (Low Grade Waldenstroms Macroglobulinaemia)
IgA/IgG - Myeloma
What are the categories for red cell transfusion?
R1 : Acute Blood Loss
R2: Hb <70
R3: Hb<80 (CVS Disease)
R4: Chronic Anaemia (individual threshold)
R5: Maintaining Hb>110 for Radiothefaph
R6: Exchange transfusion
Name two causes of spherocytosis
Hereditary Spherocytosis
Haemolytic Anaemia
Name four categories of immunological complications from transfusion
Sensitisation to red cell antigens (immediate or delayed)
Sensitisation to white cell antigens (febrile reaction, TRALI)
Sensitisation to platelet antigens (Post transfusion)
Graft vs host
Name three categories of non immunological complications from transfusion
Infective disease transmission
Circulatory overload
Transfusion Haemosiderosis
What other investigations need to be done in Myeloma?
Full body MRI
Bloods
Bone marrow trephine and aspiration
