lymphoma and cancer treatments

Question 1

what is it?

Answer 1

• Malignant tumours derived from cells of the immune system
• Many different forms with variable clinical course and prognosis
• Diagnosis based on clinical, histological, immunophenotypic and genetic studies

Question 2

how does it present?

Answer 2

A ‘lump’: lymphadenopathy – rubbery, soft, non-tender
Itch without rash, alcohol-induced pain
Relevant to compression, infiltration/extranodal disease: renal failure, superior vena cava obstruction, effusions, marrow failure (some, not all)
B symptoms
- fever
- night sweats
- weight loss

Question 3

how is it diagnosed?

Answer 3

Accurate diagnosis and classification needs specific characterisation of cell types by morphology, immunophenotype and genetics
Ensures accurate diagnosis and classification that is the basis for treatment decisions
If lymphoma or other malignancy is suspected-request a surgeon to biopsy.
o Fine needle aspirate is almost always insufficient.
o A core biopsy is often insufficient.
o Need a big sample to assess architecture of the lesion

Question 4

how is it investigated?

Answer 4

CT and PET imaging
Ann Arbor staging system
lactate dehydrogenase (LDH) - prognostic not diagnostic

Question 5

steroids in treating lymphoma

Answer 5

• Lymphocytes are normally sensitive to steroid therapy and some lymphomas are exquisitely sensitive
• Steroids are an integral part of multiagent chemotherapy regimens for the routine treatment of lymphoma
• Steroids can be used in the emergency management of suspected lymphoma but starting steroid before biopsy can cause cell necrosis and distort cellular and tissue architecture to confuse the diagnosis

Question 6

what is non-hodgkin’s lymphoma?

Answer 6

most common form of lymphoma

diverse group of diseases

Question 7

what are the differences in B and T cell NHL?

Answer 7

B cell lymphomas
o Most common form of NHL
o Low grade forms
o High grade forms

T cell lymphomas (high grade)
o Less common
o More complex classification

• Diffuse large B cell lymphoma is a common high-grade NHL
• Extra-nodal disease particularly with T cell NHL, Burkitt lymphoma

Question 8

what is the basis of NHL treatment?

Answer 8

Multi-agent chemotherapy +/- radiotherapy –risks of neutropenia, cardiotoxicity (also in Hodgkin lymphoma)
o Increase the doses in those who need it for cure and accept increased side effects.
o Reduce chemotherapy or miss out radiotherapy in those who don’t need it to avoid long-term side effects.

Question 9

what forms of NHL can be cured?

Answer 9

High-grade NHL is potentially curable, low-grade is incurable but many patients may not need treatment

Question 10

what is the plan B treatment for NHL patients where chemo fails?

Answer 10

High-dose therapy with autologous stem cell rescue or CAR-T therapy

Question 11

what is supportive therapy?

Answer 11

to go with chemotherapy and prevent death from side effects

Question 12

what are the things done in supportive therapy?

Answer 12

o Prompt treatment of neutropenic fever/ infection
o Red cell and platelet transfusion
o Growth factors (GCSF)
o Prophylactic antibiotics and antifungals to prevent infection occurring in the first place eg itraconazole or posaconazole

Question 13

what are the benefits of monoclonal antibody therapy + chemo?

Answer 13

o More effective than chemotherapy alone
o Monoclonal antibodies – Immune treatment, affect only cells which possess target protein, avoid side effects but with chemo so same risks

Question 14

what are the monoclonal antibodies used in NHL treatment?

Answer 14

Rituximab (CD20) in B cell NHL

Brentuximab (CD30) in T cell NHL

Question 15

what are biological agents?

Answer 15

o Not chemo don’t affect cells as they divide
o Variety of modes of action
o Not targeted to malignant cells so side effects

Question 16

what are proteosome inhibitors and IMIDs?

Answer 16

Biological agents

Proteosome – dustbin for old proteins inside cells, breaks into amino acids for recycling. Blocking allows accumulation of toxic proteins in cell causing apoptosis

IMIDs – thalidomide, lenaliodomide and pomalidomide – less side effects like neuropathy. Poorly understood mode of action (immunomodulatory,
anti-angiogenic) used mainly for treatment of myeloma and other plasma cell disorders

Question 17

what are molecularly targeted treatments?

Answer 17

o Ideally – target pathway specific to the cancer cell, avoid side effects, more effective than chemotherapy

Question 18

what do tyrosine kinase inhibitors treat?

Answer 18

chronic myeloid leukaemia

Question 19

what are the properties of tyrosine kinase inhibitors as a molecularly targeted treatment?

Answer 19

Imatinib, nilotinib, dasatinib, bosutinib and ponatinib.
Generally well tolerated
Achieve haematological, cytogenetic and molecular remissions in the majority of patients
Some patients can stop treatment without relapsing (treatment free remission leading to cure)
Only curative treatment option prior to TKIs was allogeneic bone marrow transplantation – very rarely indicated now

Question 20

immune therapy as a cancer treatment?

Answer 20

o Allogenic bone marrow transplant (from a matched donor) is immune therapy
o T cells from donor cause immune attack on cancer. Graft versus Leukaemia or lymphoma Effect (GvL) but also have immune attack of normal cells. Very toxic. Graft versus Host Disease (GVHD).

Question 21

what is the principle of adoptive immunotherapy?

Answer 21

Make patients own immune cells recognise the cancer as foreign and attack it, avoids toxicity of graft versus host disease. Most promising is CAR-T cell therapy (Chimeric Antigen Receptor (CAR) T cells)

Question 22

What is CAR-T therapy used for in the NHS?

Answer 22

• relapsed/refractory diffuse large B cell lymphoma and primary mediastinal B cell lymphoma (types of high grade B cell non-Hodgkin’s lymphoma)
• relapsed/refractory B cell acute lymphoblastic leukaemia in people aged up to 25 years

Question 23

what is burkitt lymphoma and how is it managed?

Answer 23

• Fastest growing human tumour
• Endemic type (EBV link) vs sporadic
• HIV association
• Chromosomal translocations involving c-myc
• High cure rates in high income countries – beware of tumour lysis at the start

Question 24

what is hodgkin’s lymphoma?

Answer 24

• Less common than NHL
• Usually very good prognosis
• Peak incidence in third decade
• Spread to lymph node groups is orderly

Question 25

what variant is the minority in hodgkin’s lymphoma?

Answer 25

• Reed-Sternberg Cell (variant – ‘lacunar’ cell), the tumour cell is in a minority

Question 26

how is hodgkin’s lymphoma managed?

Answer 26

Multi-agent chemotherapy +/- radiotherapy
o Increase the doses in those who need it for cure and accept increased side effects.
o Reduce chemotherapy or miss out radiotherapy in those who don’t need it to avoid long-term side effects.
o Use PET scan in Hodgkin’s lymphoma to help us do this
• Immunotherapy/stem cell transplantation an option for patients not responding to chemotherapy

Question 27

what are the side effects for multi-agent chemotherapy +/- radiotherapy in hodgkin lymphoma patients?

Answer 27

• Bleomycin in treatment can cause pneumonitis
• Good cure rates particularly in younger patients
• Long-term toxicity including secondary cancers, cardiovascular disease, infertility (with more intensive treatment)

Question 28

what are the rules of therapeutics in cancer treatment?

Answer 28

o If what you are doing is doing good, keep doing it
o If what you are doing is not doing good, stop doing it
o If you don’t know what to do, do nothing
o Never make the treatment worse than the disease

Question 29

how do chemotherapy and radiotherapy work?

Answer 29

• Damages DNA of cancer cells as it divides (mitosis)
• Cell recognises it is damaged beyond repair and dies by process of apoptosis (programmed cell death)
• Often involves a protein in the cell nucleus – P53, mutations of P53 make it more difficult to treat with chemotherapy and radiotherapy

Question 30

what are 2 types of cell cycle specific agents?

Answer 30

antimetabolites - impair nucleotide synthesis/ incorporation (e.g. methotrexate)
mitoitic spindle inhibitors

Question 31

what are the side effects of non cell cycle specific agents?

Answer 31

• Non-tumour specific, damage normal stem cells

* Cumulative dose more important than duration

Question 32

what are some different types of non-cell cycle specific agents?

Answer 32

• Alkylating agents
o Chlorambucil/melphalan
o Bind covalently to bases of DNA (adducts)
o Produces DNA strand breaks (mutation) by free radical production

• Platinum derivatives – cis-platinum/carboplatin

•	Cytotoxic antibiotics 
o	anthracyclines: daunorubicin / doxorubicin / idarubicin
o	DNA intercalation: reversible
o	impairs RNA transcription
o	strand breaks in DNA (free radicals)

Question 33

what are the immediate side effects of cytotoxic drugs?

Answer 33

affects rapidly dividing organs 
o	Bone marrow suppression 
o	Gut mucosal damage 
o	Hair loss (alopecia)
Vinca alkaloids – neuropathy 
Anthracyclines – cardiotoxicity 
Cis-platinum – nephrotoxicity

Question 34

what are the long-term side effects of cytotoxic drugs?

Answer 34

Alkylating agents
o	Infertility
o	Secondary malignancy
Anthracyclines
o	Cardiomyopathy

Question 35

keys to combination chemotherapy?

Answer 35

• Non-cross resistant drug combinations
• Non-overlapping toxic spectra
• Additive/synergistic mechanisms of action

Question 36

what causes chemotherapy to fail?

Answer 36

• Slow tumour doubling time
• Tumour “sanctuaries”
• Drug resistance mechanisms

Question 37

source of stem cells for transplant

Answer 37

tissue source - blood vs bone marrow 
patient source 
autologous 
allogeneic 
- sibling 
- unrelated