Cancer 1) Introduction Flashcards
What is leukaemia?
Cancer of the blood
Why does leukaemia occur?
Failure of haematopoietic differentiation leading to accumulation of immature or dysfunctional leucocytes
What are the 4 types of leukaemia?
Acute myeloid leukaemia
Acute lymphocytic leukaemia
Chronic myeloid leukaemia
Chronic lymphocytic leukaemia
How do acute and chronic leukaemia differ?
Acute leukaemia has low WCC whereas chronic leukaemia has elevated WCC
Acute leukaemia occurs when differentiation arrests early in haematopoiesis leading to accumulating of immature lymphocytes in bone marrow
In chronic leukaemia the cells are more differentiated so have a dysfunctional phenotype
What is CLL characterised by?
Clonal disorder of mature CD5+/CD19+ B-cells
Describe CLL
Tumour found in bone marrow, peripheral blood and secondary lymphoid tissue
Immune dysfunction leading to recurrent infection and autoimmune complications
Bone marrow failuree
What is the epidemiology of CLL?
2-5/100,000 a year
Median age is 65-70yo
Incidence is increasing in younger patients and 20-30% are diagnosed below 55 years
What is the presentation of CLL?
25-30% are asymptomatic Enlarged lymph nodes Repeat infections Abdominal discomfort due to enlarged spleen Night sweats and fever Weight loss and muscle wastage Anaemia and or bruising
What are the causes of CLL?
Don’t know
Can arise following infectious disease or exposure to chemicals
Following autoimmune complications e.g. T1DM
Incidence if 1st degree relative is double
How is CLL diagnosed?
Traditional using Matutes scoring system
Blood films - structural membrane defect on B cells causing smudge smear cells
Rawstron flow cytometry
What is Matutes scoring system?
Flow cytometry based scoring system measure surface immunoglobulin CD5, CD23, CD79B and FMC7
What does Rawstron flow cytometry look at?
Kappa / lambda light chain
CD5+/CD19+ phenotype
CD20, CD23, CD200 and ROR1
How is CLL a multi-compartment disease?
Peripheral blood - non proliferating so relatively susceptible to standard chemotherapy
Lymph node CLL - higher level of proliferative drive
Bone marrow - more resistant to chemotherapy
Describe the interaction of CLL with lymph nodes
CLL B cells are often found in direct contact with CD3+ T-cells
CLL B cells are often proliferating due to T-cell help
Describe the rule of thirds for CLL
1/3 diagnosed with stage A CLL and won’t progress through disease
1/3 diagnosed with early CLL but will progress through disease and require treatment
1/3 diagnosed with advanced disease and require immediate treatment
What prognostic markers can be used for CLL?
Lymphocyte doubling time Cytogenetics Sex Age Cellular markers - McL-1, CD49d, CD23, telomere length
What are the requirements of a good prognostic tool?
Markers predict which patients are likely to progress
Markers predict whether patients will respond to treatment
Cheap and easy to perform
Must be reproducible
Markers should tell us something about the biology of the disease
Why is clinical staging not enough?
CLL is a variable disease
Clinical stage is poorly prognostic for early stage and younger patients
New therapeutics are now available
Need more risk-benefit evaluation based on individuals risk of disease
Describe the Stage A only cohort study
Lymphocyte doubling time (LDT) - proxy for proliferative drive for tumour. Patients with shorter LDT require earlier treatment
Cytogenetics
- low or intermediate risk cytogenetic aberrations e.g. deletions in chromosome 13q, trisomy 12
- high risk cytogenetic aberrations e.g. tp53 mutation
IGHV mutation status
Flow cytometry markers - CD38, CD49d, ZAP-70
What chemotherapy is used for CLL treatment?
Fludarabine Bendamustine Pentostatin Cyclophosphamide Chlorambucil
What is fludarabine?
Purine nucleoside analogue
What is bendamustine?
Alkylating agent
What are some targeted antibodies?
Rituximab
Ofatumumab
Obinutuzumab
Alemtuzumab
What antibodies target CD20?
Rituximab
Ofatumumab
Obinutuzumab
What are the mechanisms of action for the targeted antibodies?
Complement mediated lysis - antibody binds to complementary receptor leading to recruitment of complement to antibody and form of cell death
Antibody-dependent cytotoxicity - antibody binds to complementary receptors which flags to other cells to induce a response
Direct cytotoxic effect lading to trigger through binding to its receptor
Give examples of targeted therapies
Ibrutinib
Idelalisib
ABT199
Lenalidomide
Give examples of 1st line setting for fit patients with no comorbidities and without deletion of 17p or tp53 mutation
FCR BR FR PCR Obinutuzumab + chlorambucil
What is FCR?
Fludarabine + cyclophosphamide + rituximab
What is BR?
Bendamustine + rituximab
What is FR?
Fludarabine + rituximab
What is PCR?
Pentostatin + cyclophosphamide + rituximab
Give examples of 1st line setting for elderly with comorbidities and without deletion of 17p or tp53 mutation
BR Obinutuzumab + chlorambucil Rituximab + chlorambucil Rituximab Cladribine Fluradabine + rituximab Chlorambucil
What are the goals of novel therapies?
Use increasing understanding of biology & technology to improve therapy
Develop targeted treatments selective for malignant cells & less toxic to healthy cells
Recruit body’s immune system to fight disease
Improve effects of existing treatments in combination
Induce longer remission & ultimately cure with fewer side effects
What is CAR-T therapy?
Chimeric antigen receptor T-cells
What is the method of CAR-T therapy?
1) Patient’s own T-cells harvested from peripheral blood then transformed through genetic manipulation to express chimeric antigen receptor eg CD19
2) T-cells are then re-infused into patient (autologous)
3) T-cells then recognise patient’s own disease
4) patient is monitored
How is the patient monitored for CAR-T therapy?
Disease response – CT scans, bone marrow biopsies, peripheral blood, flow cytometry
CAR-T cell persistence – immunohistochemistry of bone marrow biopsy, RT-PCR & flow cytometry of blood & bone marrow aspirate
