Week 2- advanced in haematological therapies

Question 1

How does chemotherapy and radiotherapy work?

Answer 1

They damage the DNA of dividing cells. Therefore the body recognises them as damaged and performs apoptosis. Often it involves a protein in the cell nucleus called P53.

Question 2

What can mutations in P53 cause?

Answer 2

Difficulty in treating the condition with chemo and radiotherapy.

Question 3

Why is a lower dose of chemotherapy better?

Answer 3

It means you don’t have as much toxicity side effects. You don’t get inflammation etc.

Question 4

Why do lymphoma, chronic lymphocytic leukaemias and acute leukemias respond to chemotherapy better than most other cancers?

Answer 4

Lymphocytes are keen to undergo apoptosis in the normal lymph node. Therefore when triggered by chemo/radiotherapy they are keen to conform.
Acute leukaemia means the cells are dividing quickly and are therefore susceptible to chemo/radiotherapy.

Question 5

What are the side effects seen with chemo? why do these occur?

Answer 5

Normal cells also undergo division and therefore are also susceptible to the chemotherapy.
Hair loss, N & V, neutropenic infection, tiredness.
Long term effects can be heart damage, lung damage and other cancers.

Question 6

What supportive therapy is given to people on chemotherapy?

Answer 6

Broad spectrum ABs
Red cell and platelet transfusions
Growth factors (GCSF)
Prophylactic antibiotics and antifungals (itraconazole).

Question 7

What sort of scan is used in Hodgkins lymphoma to see how well chemotherapy is working?

Answer 7

PET scans- uses radiolabelled glucose to see which tissues uptake it the most. Cancer cells will have a high uptake of glucose.

Question 8

What agents are used for targeted therapies in the treatment of haematological malignancies?

Answer 8

Monoclonal antibodies
Biological agents
Molecularly targeted treatments

Question 9

How do monoclonal antibodies work in the treatment of haematological malignancies?

Answer 9

They attack cells which express certain antigens. Meaning they avoid attacking healthy cells unlike in chemotherapy.

Question 10

What is the drawback of monoclonal antibodies being used as treatment?

Answer 10

They are currently only used as additive treatment to chemotherapy so you still get the same side effects due to the chemo. However they do improve outcome.

Question 11

How does ritixumab work? (it is a monoclonal AB)

Answer 11

When the antibody binds to CD20 (expressed on non-hodgkin lymphoma and chronic lymphocytic leukaemia), it has an Fc receptor that sticks out. This then interacts with the immune system and T cells come and destroy the antigen-antibody complex.

Question 12

How do other anti B cell antibodies differ from ritixumab?

Answer 12

They are more direct at killing. When they bind they kill the malignant cells rather than activating the immune system to do so.

Question 13

Give some examples of other anti B cell antibodies?

When are they used clinically?

Answer 13

Ofatumunab (Azerra).
Obinutumab (Gazyvaro).
Used in patients not responding to ritixumab.

Question 14

Describe the use of Brentuximab Vedotin in Non-Hodgkin lymphoma?

Answer 14

A chemotherapy drug is attached to the antibody and targets the CD30 protein expressed in Hodgkins cells and some T cells non-hodgkin lymphomas.

Question 15

Describe biological treatments?

Answer 15

They use a range of different modes of actions to stop cancers. However they are not targeted therapies and therefore you get side effects.
The best examples are proteasome inhibitors and IMIDs

Question 16

What is the proteosome?

Answer 16

The organelle in the cell responsible for recirculation of amino acids. Cells recognise proteins need to be broken down by sticking ubiquitin onto them.

Question 17

How do proteasome inhibitors work?

Answer 17

They block the proteasome meaning you get accumulation of toxic intracellular products and therefore apoptosis occurs.

Question 18

When are proteasome inhibitors used?

Answer 18

They are used in myeloma, mantle cell non-hodkin lymphoma and low grade non-hodgkin lymphoma.

Question 19

What are IMIDs?

How do they work?

Answer 19

They are a derivative of thalidomide. Their mode of action isn’t well understood.

Question 20

Who are IMIDs used for?

Answer 20

Used for patients with low grade NHL and CLL not responding to chemotherapy.

Question 21

What side effects can you experience with IMIDs?

Answer 21

Nerve damage
Risk to fetus
Effects on blood counts
May cause other cancers.

Question 22

What translocation causes chronic myeloid leukaemia?

Answer 22

The philledelphia translocation

Question 23

What molecular therapies are used in the treatment of chronic myeloid leukaemias?

Answer 23

Tyrosine kinase inhibitors e.g. Imatinib, nilotinib,

dasatinib, ponatinib

Question 24

Which drugs can affect B cell signalling pathways?

What cancers are these effective in?

Answer 24

Ibrutinib (Imbruvica) and Idelalisib (Zydelig)

Effective in low grade NHL and B cell CLL that don’t respond to ritixumab or chemo.

Question 25

What side effects can be seen with Ibrutinib?

Answer 25

Fever, low platelets, anaemias, SOB

Question 26

What side effects can be seen with Idelalisib?

Answer 26

Diarrhoea, rash, fatigue, liver abnormality, fever.

Question 27

How does Nivulomab work?

Answer 27

Nivulomab stops the chemicals binding to the PD1 receptor therefore the immune system remains switched on.

Question 28

What sort of drug is Nivulomab?

Answer 28

A checkpoint inhibitor.

Question 29

What can checkpoint inhibitors be used in?

Answer 29

Relapsing/resistant lymphoma

Question 30

How can you treat graft versus host disease?

Answer 30

Treated with steroids. However you don’t want to over treat because you still want the T cells to attack the malignancy.

Question 31

What is the concept of adoptive immunotherapy?

Answer 31

Make the patients own immune cells recognise the cancer as foreign and attack it. This avoids the toxicity of graft versus host disease. Most promising example is CART therapy.

Question 32

How does CART therapy work?

Answer 32

A sample of the patients own T cells are taken from the blood. In the lab, genetically modified antigen receptors are added to them. The modified cells are allowed to multiply and then the engineered T cells are put back into the patient. The new antigens allow them to target and destroy malignant cells.