Lymphomas and and multiple myeloma Flashcards
What is the lymphatic system?
An integrated network of cells, tissues, organs and proteins. It has generative and peripheral functions
What are the functions of the lymphatic system?
- remove and destroy waste
- remove excess fluids from interstitial spaces
- returns proteins and tissue fluids to the blood
- absorbs fats and fat soluble vitamins and delivers to cells
- important component of the immune repsonse
- open system
What do b lymphocytes do?
When they are exposed to soluble antigens, they become sensitised to specific antigens which leads to further division of B lymphocytes into plasma cells which produce antibodies and memory cells which remain dormant until the next exposure to the antigen
What do t lymphocytes do?
- recognise non self cells
- helper t cells recognise self vs non self
- suppressor prevent hypersensitivity when exposed to non self
- cytotoxic lyse antigen cells
What is non-hodgkins lymphoma?
Diverse group of disease and treatments, incidence increased with age. 90% are of B cell origin
What are the clinical features of non-hodgkins lymphoma
- superficial lymphadenopathy: painless asymmetric enlargement of one or more peripheral lymph nodes
- constitutional symptoms
What are the constitutional symptoms of NHL?
- Weight loss due to hyper-metabolic disease
- fever
- night sweats
Which symptoms are associated with organ involvement in NHl?
Dyspnoea, abdo symptoms, anaemia, neutropenia, thrombocytopenia, compression by lymph node
Which grade of lymphoma requires rapid treatment?
High grade
Which investigations are carried out for NHL?
Blood evaluation including lactate dehydrogenase, biopsy, imaging, prognostic evaluation
How is NHL staged?
Ann arbor staging system
What is stage 1 NHL?
1 tumour above the diaphragm
What is stage 2 NHL
More than 1 tumour above the diaphragm
What is stage 3 NHL?
Tumour below diaphragam
What is stage 4 NHL?
More than one below the diaphragam
What does a/b/e mean in relation to NHL staging?
A = absence of symptoms, b= symptoms, E = extra nodal site
Which drug agents are used for NHL?
RCHOP regimine:
rituximab, cyclophosphamide, doxirubicin, vincristine, prednisolone
Which supportive therapies are given alongside treatment of NHL?
- Anti emetic
- tumour lysis prevention
- haemorrhagic cystitis prevention
- hypersensitivty prevention - paracetamol/chloramphenamine
- gastro protection
Which anti-emetics are typically given alongside the RCHOP regimen?
Usually give ondansertron with chemo and to take away, and metclopramide to take away. Steroid would not be given as already part of treatment regimen
Which drugs are given for tumour lysis prevention with NHL and when?
Allopurinol and rasburicase. During the first cycle only, as highest risk of tumour lysis as cellular breakdown is highest here.
What drugs are given for haemorhagic cystitis prevention?
MESNA - binds to acrolein
- hydration pre chemo
What is rituximab and how does it work?
- targetted therapy
1. Causes antibody dependent cellular toxicity
2. Rituximab binds to CD20 on one side of B cell
3. Forms a cap that draws proteins to that side
4. Natural killer cells latch onto cap and are more successful in killing cells (enhances activity of NKCs)
5. Complement mediated toxicity occurs which involves cascade activation of proteins
6. Development of membrane attack complex (MAC)
7. which causes direct lysis
8. leads to apoptosis of cancer cells
What are the adverse effects of ritixumab?
Hypersensitivity reactions, give paracetamol and chloramphenamine
What is relapse associated with in NHL and how does it change treatment?
Worse outcomes. Treated with intensive chemo and autologous stem cell transplant
What is hodgkin’s lyphoma?
A cancer of B cell lymphocytes, characterised by Hodgkin’s reed Sternberg cells. A rare cancer common in males
How do clonal B cells cause cancer in Hodgkin’s lymphoma?
Clonal b cells lack typical b cell surface antigens and evade apoptosis by:
- chromosomal translocations and genetic mutations
- incorporating epstein barr virus or latent membrane proteins
- activation of transcription factors
- interaction with components of the microenvironment
What are the symptoms of hodgkins lymphoma?
Fever, weight loss, night sweats, alcohol induced pain, mediastinal involvement, multiple nodules within organs, lymphadenopathy
What must be carried out pre treatment for HL?
- Blood evaluation for haematological/biochemical markers: mild anaemia, leucocytosis with raised lymphocyte count, liver function
- staging
- favourable/unfavourable prognosis
- fertility preservation
- good cardiac function check for use of anthracycline
- check pulmonary history - bleomycin has pulmonary toxicity
How should a patient with favourable prognosis be treated with HL?
Less intensive treatment, if they have a good response then keep it the same
What is the prognosis for HL?
Generally has a good cure rate, but has potentially dehabilitating treatment. If it is diagnosed early in life it is a long term disease
What is the risk with hodgkins lymphoma?
Long term disease and treatments can be carcinogenic. There is a risk of secondary malignancies and so patients should be advised to avoid cancer via lifestyle changes such as diet, exercise, not smoking
What is the treatment for early favourable stage 1-3 hodgkins lymphoma?
Short course of chemo and radiotherapy
How should early favourable patients with HL be treated if radiotherapy is contraindicated?
RAPID protocol: 3 cycles of ABVD regimen, then sent for a PET scan, further cycle and radiotherapy if the PET scan shows cancer still present
How should patients with early unfavourable HL be treated?
4 cycles of ABVD and radiotherapy
How should patients with advanced HL (stage 3 and 4) be treated?
Full course of chemo: escalated BEACOPP or ABVD
What is the ABVD regimen and how often is it repeated?
Every 28 days
Doxorubicin, bleomycin, vinblastine, dacarbazine
What should be given alongside bleomycin?
Iv hydrocortisone if no dexamethasone in the anti-emetic stratergy
What is multiple myeloma?
A disease of plasma cells
How does multiple myeloma occur?
Genetic changes during differentiation of b lymphocytes into plasma cells, which leads to expansion of malignant immature b cells, which produce monoclonal antibodies that can be detected in the blood and urine Myeloma cells accumulate in the blood and bone marrow, so antibodies cannot be produced and patients are at a risk of infection
Why are patients with multiple myeloma at an increased risk of infection?
Because myeloma cells accumulate in the bone marrow and functional plasma cells are not produced, therefore antibodies cannot be produced.
Discuss the molecular biology of multiple myeloma
Multiple myeloma microenvironment: clonal myeloma cells, extracellular matrix proteins, bone marrow cells, osteoblasts and clasts. There is an increased secretion of cytokines, epidermal growth factor, VEGF, tnf a, which provides protection against apoptosis
What are the 3 stages of MM?
mgus, smoldering mm and active mm
How does mgus and smoldering mm present?
No anaemia/bone lesions, normal calcium and kidney function
How does active MM present?
Anaemia, bone lesions, high calcium, abnormal kidney function
What is the clinical presentation of MM?
- Anaemia: patients are producing more non functional plasma cells, so the production of normal cells is suppressed
- bone disease: overexpression of RANKL leads to increased osteoclasts, lytic lesions can be seen on x rays
- hypercalcaemia - renal dysfunction associated with monoclonal proteins which can accumulate in tubules and crystallise
What are lytic lesions?
Result in bone pain/fracture
Discuss CRAB for clinical presentation of multiple myeloma
hyperCalcaemia
Renal insufficiency
Anaemia
Bone lesions
How is multiple myeloma staged?
Using cytogenetics and serum b2 microglobulins
/What are serum b2 microglobulins?
Tumour markers, elevated in multiple myeloma
What are the initial considerations for chemotherapy for mm patients?
- stage of disease: treatment is not given for smoldering MM
- symptomatic disease: treat the complications prior to chemo
- is the patient a transplant candidate
How are patients evaluated for transplant with mm?
- Performance status
- comorbidities
- frailty
- renal impairment: should not be used alone as it could be disease related and may improve with treatment
- age
What is the process of transplant for mm?
REMOVE stem cells from the patient and treat them pre transufsion
INDUCTION: induce complete remission or partial remission prior to transplantation using bortezomib regimens
STEM CELL HARVESTING: mobilise stem cells
HIGH DOSE MEPHALAN: destroys existing bone marrow
REINFUSE stem cells
POST TRANSPLANT CONSOLIDATION: to improve response rates
ONGOING: thaldiomide/lenalidomide for maintenance
Does transplant cure mm?
No, patients will relapse
What does the induction regime for transplant for mm involve?
It is complicated, includes bortezamib, thalidomide and dexamethasone
What follow ups are carried out for hodgkins lymphoma?
outpatient based for up to 5 years, to check for t cell defects, malignancies, cv disease, pulmonary toxicity, thyroid dysfunction, fertility
How are transplant non-eligible patients handled with mm?
Disease is controlled to achieve long term progression free survival and maintain quality of life.
Induction with thalidomide/lenalidomide, bortezomib, alkylating agent and a corticosteroid
How do proteasome inhibitors work?
The ubiquitin-proteasome pathway is responsible for the degradation of the majority of regulatory proteins. Disruption of proteasome activity leads to accumulation of incompatible regulatory proteins and the induction of a cytotoxic cascade. Cancer cells have higher levels of proteasome activity, and are more sensitive to the pro apoptotic effects of proteasome inhibitors. Inhibit proteasome and tumour cells cannot regulate their proteins, which leads to apoptosis of cells
What is an example of a proteasome inhibitor?
Bortezamib
How does bortezamib work?
It is a reversible proteasome inhibitor, which acts via multiple mechanisms:
- induce apoptosis
- inhibit the NFK-kb pathway
- reduce IL6 production and signalling
What are the side effects of bortezamib?
- peripheral neuropathy which can be dose limiting
- GI disturbance
- hypotension
- bone marrow suppression
- tumour lysis syndrome
- pulmonary, cv and liver toxicity
- inhibits cyp450 enzymes
- contraception advised
How does thalidomide work?
- immunodulatory activity
- inhibition of angiogenesis
- anti-proliferative effects
- can directly inhibit cytokines in the myeloma cellular environment
- can stimulate the effects of natural killer cells
- inhibits tumour growth
What are adverse effects/cautions that should be given when initiating thalidomide?
- it is teratogenic so a pregnancy prevention programme should be put in place
- can cause venous thromboembolism
- can cause constipation, so prescribe laxatives
- rash
- can cause somnolence so take at night
- thyroid function
Give examples of 2nd/3rd generation immunodulatory agents and discuss their relationship to thalidomide
Lenazalidomide and domalidomide. They are analogues of thalidomide, have less side effects but are more potent
When is lenalidomide indicated and what are the side effects?
In myeloma cells, has reduced side effects to thalidomide but can cause myelosuppression
When in domalidomide indicated and what are the side effects?
In myeloma cells resistant to thalidomide and lenalidomide. well tolerated
Which supportive therapies are prescribed alongside multiple myeloma chemotherapy agents?
Bisphosphonates VTE prophylaxis GI protection Tumour lysis prevention infection prevention
Why are bisphosphonates prescribed in mm?
They inhibit bone resorption by suppressing osteoclast activity. Results in fewer lytic bone lesions but has also been found to have effects on myeloma cells. Dental checks necessary to prevent osteonecrosis of the jaw. Renal impairment considerations
How is VTE prophylaxis prescribed in mm?
Thalidomide has risk of venous thromboembolism. Asses risk, avoid warfarin as you want to keep the INR stable
Why is GI protection given alongside MM chemotherapy agents?
Alongside dexamethasone as theres risk of GI effects. Give a PPI
What is given as tumour lysis prophylaxis?
Allopurinol
What is given to prevent infection alongside MM treatment?
Antibiotics, antivirals
What is given alongside high dose steroids?
Co-trimoxazole for prophylaxis of pneumocystis jirovecci
What should happen when mm patients relapse?
Patients should be entered into a clinical trial wherever possible. Individualised treatment strategy should be applied. With each relapse, there likelihood of progression-free survival is shorter and the disease becomes resistant. Therapy should be swapped to a therapy with a different mechanism of action. If poor performance status, use more intensive treatments
What are the challenges with mm?
We need an improved understanding of the pathophysiology, and there is a considerable symptom burden therefore supportive therapies are important.
