Blood Cancer Treatment

Question 1

Why is CLL difficult to treat with chemo and radiotherapy?

Answer 1

Mutations of P53

Question 2

What occurs with a lower dose of chemo or RT (fewer side effects)?

Answer 2

Apoptosis
Formation of blebbing
Cell breaks apart into several apoptotic bodies, when are then phagocytosed. No inflammation

Question 3

What occurs with a bigger dose of chemo or RT (more side effects)?

Answer 3

Necrosis
Cell swells
Plasma membrane rupture. Cellular and nuclear lysis causes inflammation

Question 4

Why do lymphoma/CLL and acute leukaemia respond better than most other cancers to chemo and RT ?

Answer 4

Lymphocytes are keen to undergo apoptosis in the normal lymph node.
Lymphoma and CLL cells can be triggered to undergo apoptosis readily with chemo- or radiotherapy.
Acute leukaemia is dividing do quickly-more cells are dividing and so are affected by chemotherapy.

Question 5

What are the S/E of chemo and RT?

Answer 5

Immediate effects- Hair loss, nausea and vomiting, neutropenic infection, Tiredness +++
Long term effects- Heart damage, lung damage, other cancers

Question 6

What is supportive therapy in cancer treatment?

Answer 6

Prompt treatment of neutropenic fever/infection.
Broad Spectrum antibiotics.
Red cell and platelet transfusion.
Growth Factors (GCSF).
Prophylactic antibiotics and antifungals (e.g. itraconazole and posaconazole) to prevent infection occurring in the first place.

Question 7

Describe risk adapted therapy in Hodgkin’s after 2/6 courses of ABVD

Answer 7

Very likely to be cured.
Avoid side effects by missing out Bleomycin in cycles 3-6 (AVD)
If PET was still positive at this stage, very high chance of relapse.
Escalate treatment to escBEACOPP, despite more toxicity.

Question 8

What targeted therapies exist?

Answer 8

Monoclonal antibodies
Biological agents
Molecularly targeted treatments

Question 9

Describe monoclonal antibodies

Answer 9

Immune treatment.
Affect only cells which possess target protein.
Avoid side effects.
Unfortunately most are currently used in combination with chemotherapy rather than instead of-so same risks!
More effective than chemotherapy alone

Question 10

What kind of antibody is Rituximab described as?

Answer 10

‘Naked’

Question 11

How is Rituximab used in therapy?

Answer 11

RCHOP Improves responses and cures in patients with high grade B cell NHL.
R-mini-CHOP for elderly patients.
FCR improves survival and prolongs remissions in CLL.
R-chemo improves responses and prolongs time to next treatment in low grade and mantle cell NHL.
Maintenance Rituximab prolongs survival and time to next treatment in low grade and mantle cell NHL.
Now given as 5 minute injection under skin rather than IV infusion to save time.

Question 12

What are some other anti-B cell antibodies?

Answer 12

Ofatumunab
Obinutumab
More direct kill of malignant B cells than Rituximab, better than it in CLL in less fit patients along with gentle chemo (chlorambucil)

Question 13

Describe targeted chemo in Hodgkin’s

Answer 13

CD30 is protein on Hodgkin’s cells and some T cell NHL.
Naked anti-CD 30 antibody doesn’t work.
Chemotherapy drug tagged on (conjugated)- Brentuximab Vedotin

Question 14

Describe biological treatments

Answer 14

Not chemotherapy-don’t affect cells as they divide.
Variety of modes of action.
Not targeted to malignant cells therefore side effects.
Best examples: Proteosome inhibitors and IMIDs.
Use established in multiple myeloma.
Being evaluated in lymphoma.

Question 15

What is the proteasome?

Answer 15

‘Dustbin’ for old proteins inside cells.
Breaks them down into amino acids for recycling.
Blocking this allows accumulation of toxic proteins in cell causing apoptosis

Question 16

Describe Bortezomib

Answer 16

Proteosome inhibitor
Used in low grade NHL, some activity in mantle cell NHL
Can cause nerve damage and low platelets

Question 17

Describe IMIDs

Answer 17

Derivative of thalidomide. Eg lenalidomide (Revlimid).
Mode of action poorly understood.
Can produce remission in some patients with low grade NHL and CLL no longer responding to chemo.
Slightly better in combination with chemotherapy (CHOP) than chemo alone in mantle cell NHL.

Question 18

What are the S/Es of IMIDs?

Answer 18

Nerve damage
Risk to fetus
Effect on blood counts
Other cancers

Question 19

What are some examples of molecular/targeted treatments?

Answer 19

Tyrosine Kinase inhibitors in Chronic Myeloid Leukaemia.
Targeting malignant B cells (ibrutinib and idelalisib) in CLL/NHL.
Stopping tumours evade the immune system (nivolumab)

Question 20

What are the three phases of CML?

Answer 20

Chronic Phase
Accelerated phase
Blast crisis

Question 21

Describe tyrosine kinase inhibitor use in CML

Answer 21

Imatinib, nilotinib, 
dasatinib, ponatinib.
Now a chronic 
disease.
Blood counts normal, 
Chromosomes normal, no detectable BCR-ABL in blood.
Most tolerate very well. Some side effects: diarrhoea, fluid in lungs, neutropenia.
Chemo free treatment

Question 22

What are some drugs affecting B cell signalling pathways?

Answer 22

Ibrutinib (Imbruvica) and Idelalisib (Zydelig)
Effective in low grade NHl and B cell CLL that don’t respond to rituximab and chemotherapy.
Idelalisib approved for use in CLL with P53 mutation. Huge improvement-previously no/brief response to chemotherapy.

Question 23

What are the S/Es of Idelalisib?

Answer 23

Diarrhoea
Rash
Fatigue
Liver abnormality
Fever

Question 24

What are the S/Es of Ibrutinib?

Answer 24

Fever
Low Platelets
Anaemia
SOB

Question 25

Describe checkpoint inhibitors

Answer 25

Nivolumab in malignant melanoma, even more effective in lymphoma, especially Hodgkin’s disease.
Cancer cells avoid cells of the immune system. Produce chemicals that bind to receptors on surface of cells of the immune system called PD-1 receptor.
When receptor is stimulated the immune system cell is switched off and ‘ignores’ the tumour. Immune evasion.
Nivolumab sticks to this chemical and stops it binding to the effector cell.
The immune system therefore remains switched on and attacks the cancer cell

Question 26

What are some examples of immune therapy?

Answer 26

Allogenic bone marrow transplant (from a matched donor) is immune therapy.
T cells from the donor cause immune attack on cancer

Question 27

What is Graft versus Host Disease?

Answer 27

Immune attack of normal cells in immune therapy

Question 28

What is adoptive immunotherapy?

Answer 28

Make the 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.