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Year 3 Clinical > New and Future Treatments of Blood Cancers > Flashcards

New and Future Treatments of Blood Cancers Flashcards

1
Q

Functions of chemo/radiotherapy?

A

Damages DNA of cancer cells as they divide; the cell then recognises that it is damaged beyond repaired and dies via apoptosis

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2
Q

Protein controlling apoptosis?

A

P53

Mutations in P53, e.g: in Chronic Lymphocytic Leukaemia (CLL), make it more difficult to treat with chemo or radiotherapy

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3
Q

Relationship between the dose of chemo and the side effects?

A

Lower dose - fewer side effects

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4
Q

Why do lymphoma, CLL and acute leukaemias respond to chemo and radiotherapy better than most other cancers?

A

Lymphocytes are keen to undergo apoptosis in the normal lymph node and so, in lymphoma and CLL, the lymphocytes can be readily triggered to undergo apoptosis

Cells in acute leukaemia are dividing so rapidly that there are more cells to be affected by chemotherapy

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5
Q

Why do side effects occur with chemo or radiotherapy?

A

Normal cells and their DNA are also damaged and undergo apoptosis

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6
Q

Immediate effects of chemo and radiotherapy?

A

Hair loss

N&V

Neutropenic infection

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7
Q

Long-term effects of chemo and radiotherapy?

A

Heart and lung damage

Can cause other cancers

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8
Q

Define targeted therapy?

A

More specific treatments affecting only the leukaemia / lymphoma cells (ideal)

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9
Q

Supportive therapy used during chemo and radiotherapy?

A

Prompt treatment of neutropenic fever/infection with empirical, broad-spectrum antibiotics

Red cell and platelet transfusions, is required

Growth factors, e.g: GCSF, and be used to stimulate bone marrow to release white cells into the bloodstream

Prophylactic antibiotics and anti-fungals

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10
Q

Why is death from fungal infections now rare in patients receiving chemotherapy?

A

Prophylactic anti-fungals are given to all patients at risk, e.g: itraconazole or posaconazole

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11
Q

How has the method of administering chemo or radiotherapy improved?

A

If the patient responds quickly, they are likely to be cured and so doses can be reduced/missed, to avoid long-term effects

Increase the dose in patients who need it to be cured; must accept the increased incidence of side effects

This is called risk adapted therapy

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12
Q

How can the response to chemo and radiotherapy be assessed?

A

PET scan before and after treatment of Hodgkin’s lymphoma

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13
Q

Examples of targeted therapies?

A
  • Monoclonal antibodies
  • Biological agents
  • Molecularly targeted treatments
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14
Q

What are monoclonal antibodies?

A

Immune treatments that affect only the cells possessing the target protein, thus avoiding side effects

Used in combination with chemotherapy, which is more effective than chemotherapy alone

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15
Q

What is rituximab?

A

A chimeric anti-CD20 monoclonal antibody

NOTE - it is a ‘naked’ antibody

Administered as a 5 minute injection subcutaneously, rather than as an IV infusion

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16
Q

Other anti-B cell antibodies?

A

Ofatumunab and Obinutumab - responsible for the more ‘direct’ killing of malignant B cells than Rituximab

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17
Q

Uses of Ofatumunab and Obinutumab?

A

Better than rituximab for patients with CLL who are less fit, in combination with gentle chemotherapy

They are mainly used in patients who are not responding to Rituximab

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18
Q

What is Brentuximab Vedotin?

A

A targeted chemotherapy used in Hodgkin’s disease

Targeted chemotherapy means that the chemotherapy is conjugated to the antibody, in this case an anti-CD30 antibody; the naked antibody does not work alone

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19
Q

Side effects of targeted chemotherapy?

A

Less side effects but there are a few, e.g: nerve damage, low neutrophils and fatigue

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20
Q

What are biological agents?

A

Not chemotherapy, i.e: they do not affect cells as they divide

There are a variety of modes of action

21
Q

Side effects of biological agents?

A

Not targeted to the malignant cells and so there are side effects

22
Q

Examples of biological agents used for lymphoma?

A

Proteosome inhibitors

IMIDs

23
Q

What is the proteosome?

A

Intracellular organelle responsible for the breakdown of old proteins and subsequent recycling of amino acids

24
Q

MoA of proteosome inhibitors?

A

Blocking the proteosome allows accumulation of toxic proteins in the cell, leading to apoptosis

25
Q

Uses of proteosome inhibitors?

A

Used in some low grade NHL, e.g: Waldenstrom’s

26
Q

Side effects of proteosome inhibitors?

A

Nerve damage and low platelets

27
Q

What are IMIDs?

A

Derivatives of thalidomide, e.g: lenalidomide (Revlimid)

MoA is poorly understood

28
Q

Efficacy of IMIDs?

A

Can produce remission in some patients with low-grade NHL and CLL that is no longer responding to chemotherapy

It is slightly better in combination with chemotherapy (CHOP), compared to chemotherapy alone in mantle cell NHL

29
Q

Side effects of IMIDs?

A

Nerve damage

Effect on blood counts

Risk to foetus

Other cancers

30
Q

Examples of molecular/targeted treatments?

A

Tyrosine kinase inhibitors in CML

Targeting malignant B cells (ibrutinib and idelalisib) in CLL or NHL

Prevent tumours from evading the immune system (nivolumab)

31
Q

Progression of chronic myeloid leukaemia (CML)?

A

Chronic phase - slow development with minimal symptoms; <10% of cells in bone marrow are immature blasts

Accelerated phase - more symptomatic; 10-30% of cells in bone marrow are immature blasts

Blast crisis - leukaemia transforms into an acute leukaemia, usually AML, and >30% of cells in the bone marrow are immature blast cells; patients have splenomegaly

32
Q

Cause of Chronic Myeloid Leukaemia (CML)?

A

A chromosomal translocation from chromosome 9 to 22 produces the Philadelphia chromosome, which produces a new oncoprotein (BCR-ABL)

33
Q

Treatment of CML?

A

Imatinib mesylate (a tyrosine kinase inhibitor)

Normally, BCR-ABL has an ATP molecule occupying its kinase pocket; due to phosphorylation of one of its tyrosine residues, the substrate bound to BCR-ABL can is activated and can then active downstream effector molecules

Imatinib occupies the kinase pocket, preventing ATP from doing so

34
Q

Side effects of tyrosine kinase inhibitors?

A

Most patients tolerate the drug very well

It is a chemo-free treatment but there are some side effects:
• Diarrhoea
• Fluid in lungs
• Neutropenia

35
Q

Why are drugs that affect B cell signalling pathways effective in CLL and lymphoma?

A

CLL and lymphoma cells have abnormally active signalling mechanisms inside the cell

Blockage of these signalling proteins can causes apoptosis, even if P53 is abnormal

36
Q

Examples of drugs that affect B cell signalling pathways?

A

Ibrutinib and Idelalisib

37
Q

Uses of Ibrutinib and Idelalisib?

A

Effective in low-grade NHL and B-cell CLL that do have failed to respond to rituximab and chemotherapy

Licensed for use in CLL with P53 mutations, which previously had no/brief response to chemotherapy

38
Q

Side effects of Ibrutinib?

A

Fever

Low platelets

Anaemia

SoB

39
Q

Side effects of Idelalisib?

A

Diarrhoea

Rash

Fatigue

Liver abnormality

Fever

40
Q

Explain how tumour cells evade the immune system

A

Cancer cells evade cells of the immune system by binding to receptors, called PD-1 receptor, on immune cell surfaces

When PD-1 receptors are stimulated, the cell of the immune system is switched off and it ignores the tumour; this is called immune evasion

41
Q

Examples of checkpoint inhibitors?

A

Nivolumab

42
Q

MoA of Nivolumab?

A

Sticks to the chemicals produced by the tumour cell; in doing so, it prevents the chemicals from binding to PD-1 receptors

Thus, the immune system remains switched on and can attack the tumour cell

43
Q

Side effects of checkpoint inhibitors in relapsed/resistance lymphoma?

A

Well-tolerated

Most side effects resolve with dose reduction

44
Q

What is immune therapy and how does it work?

A

Allogenic bone marrow transplant (from a matched donor)

The T cells from the donor cause immune attack on cancer, in a Graft vs Leukaemia/Lymphoma effect (GvL)

45
Q

Issues assoc. with immune therapy?

A

Very toxic as there is also Graft vs Host Disease (GVHD)

A balance needs to be obtained between graft vs tumour and graft vs host disease

46
Q

What is adoptive immunotherapy?

A

Make the patients own immune cells recognise the cancer as foreign and attack it

E.g: Chimeric Antigen Receptor T cell therapy (CART cell therapy) is very promising

47
Q

Process of CART cell therapy?

A

Inv. taking the patient’s T cells and genetically engineering them to create a TCR that recognises tumour cells; as the T cells are the patient’s own, they will not attack anything other than the tumour cells

48
Q

Uses of CART cell therapy?

A

Effective in patients with ‘last chance’ ALL

Response in 1/2 of patients with a variety of B cell NHL types where all other treatments failed

There is no reason why other types cannot be treated, using a different target, e.g: CD30 in Hodgkin’s and some T cell NHL

Year 3 Clinical (100 decks)

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