New and Future Treatments of Blood Cancer

Question 1

how do chemo and radiotherapy work generally?

Answer 1

damages DNA of cancer cells as they divide (Mitosis)

cell recognises it is damaged beyond repair and undergoes apoptosis

Question 2

mutations in which genes make it more difficult to treat with chemo or radiotherapy?

Answer 2

P53

CLL

Question 3

how does dose of chemo/radiotherapy affect method of cell death?

Answer 3

lower dose = apoptosis (cell breaks into several parts which are phagocytosed, no inflammation)
higher dose = necrosis (membrane ruptures causing cell lysis and inflammation)

Question 4

why do lymphoma/CLL and acute leukaemia respond better to chemo and RT then most cancers?

Answer 4

lymphocytes are keen to undergo apoptosis in the normal lymph node
therefore lymphoma and CLL cells can be triggered to undergo apoptosis readily with chemo/radiotherapy
acute leukaemia is dividing quickly so more cells dividing and so are more affected by chemo

Question 5

side effects of chemo/RT?

Answer 5

normal cells also affected so undergo apoptosis
immediate effects = hair loss, nausea and vomiting, neutropenic infection, extreme tiredness
long term effects = heart/lung damage, other cancers

Question 6

what supportive factors are used in treatment of blood cancer?

Answer 6

prompt treatment of neutropenic infection
broad spectrum antibiotics
RBC and platelet transfusion
growth factors (G-CSF)
prophylactic antibiotics and antifungals

Question 7

guidelines for management of neutropenic sepsis if standard risk (NEWS <6)?

Answer 7

assess within 15 mins
piperacillin/tazobactam or teicoplanin + aztreonam if penicillin allergic
teicoplanin + ciprofloxacin if anaphylaxis or angioedema

Question 8

guidelines for management of neutropenic sepsis if high risk (NEWS >6)?

Answer 8

assess within 15 mins
piperacillin/tazobactam + gentamicin
teicoplanin + aztreonam + gentamicin if penicillin allergic
teicoplanin + ciprofloxacin + gentamicin if anaphylaxis or angioedema

Question 9

how soon should antibiotics be started in neutropenic sepsis?

Answer 9

1 hr

Question 10

what prophylactic antifungals are given to all at risk?

Answer 10

itraconazole or posaconazole

Question 11

how can dosing of chemo be altered to fit case?

Answer 11

increased dose in those who need it for cure and accept side effects
reduced or missed doses in those who don’t need it to avoid long term side effects
(can use PET scan to help decide)

Question 12

how effective is ABVD chemo in hodgkins?

Answer 12

very likely to be cured

side effects can be avoided by missing out bleomycin in cycles 3-6

Question 13

types of targeted therapy in blood cancer?

Answer 13

monoclonal antibodies
biological agents
molecularly targeted treatments

Question 14

describe how monoclonal antibodies are used

Answer 14

type of immune treatment which affects only cells which possess target protein
most are currently used in combination with chemo
more effective than chemo alone

Question 15

give an example of monoclonal antibody

Answer 15

rituximab (mouse/human chimeric monoclonal antibody)
type of IgG
variable region binds to CD20 on B cells
“naked antibody”

Question 16

other B cell antibodies used in blood cancer?

Answer 16

ofatumunam (azerra)

obinutumab (gazyvaro)

Question 17

how do other B cell antibodies differ from rituximab in treatment of blood cancer?

Answer 17

more direct kill of malignant B cells

better than rituximab in CLL in less fit patients alongside gentle chemo

Question 18

what is brentuximab vedotin?

Answer 18

conjugate drug made of biologics and anti CD30 monoclonal antitbody

Question 19

examples of biological treatments?

Answer 19

proteasome inhibitors and IMIDs

Question 20

when are biological treatments used?

Answer 20

currently in multiple myeloma and being evaluated in lymphoma

Question 21

how do proteasome inhibitors work?

Answer 21

proteasome = bin for old proteins inside the cell, breaks them down into amino acids for recycling
therefore blocking proteasome allows accumulation of toxic proteins in cell causing apoptosis

Question 22

side effects of proteasome inhibitors?

Answer 22

nerve damage and low platelets

Question 23

what are IMIDs?

Answer 23

derivatives of thalidomide

mode of action poorly understood

Question 24

how are IMIDs used?

Answer 24

can produce remission in some with low grade NHL and CLL which no longer respond to chemo
slightly better when in combination with chemo then chemo alone in mantle cell NHL

Question 25

side effects of IMIDs?

Answer 25

nerve damage
risk to foetus
effect on blood counts
other cancers

Question 26

aims of molecular/targeted treatments?

Answer 26

target pathway specific to the cancer cell
avoid side effects
more effective than chemo

Question 27

examples of molecular/targeted treatments?

Answer 27

tyrosine kinase inhibitors in CML
targeting malignant B cells in CLL/NHL
stopping tumours evade immune system

Question 28

effects of tyrosine kinase inhibitors on CML?

Answer 28

normal blood counts
normal chromosomes
no detectable BCR-ABL in blood
usually well tolerated but can cause diarrhoea and fluid in lungs and neutropenia

Question 29

how do drugs affecting B cell signalling pathways work?

Answer 29

CLL and lymphoma cells have abnormally active signalling mechanisms inside cells
blockage of these signalling proteins can cause apoptosis even if P53 is abnormal

Question 30

examples of drugs which affect B cell signalling pathways?

Answer 30

ibrutinib (imbuvica)

idelalisib (zydelig)

Question 31

how are ibrutinib and idelalisib used?

Answer 31

effective in low grade NHL and B cell CLL that don’t respond to rituximab and chemo
idelalisib approved for use in CLL with P53 mutation

Question 32

side effects if ibrutinib and idelalisib?

Answer 32

ibrutinib = fever, low platelets, anaemia, SOB
idelalisib = diarrhoea, rash, fatigue, liver abnormality, fever

Question 33

example of a checkpoint inhibitor?

Answer 33

nivolumab

used in malignant melanoma, even more in lymphoma (esp hidkins disease)

Question 34

how do checkpoint inhibitors work?

Answer 34

cancer cells avoid cells of the immune system by producing chemicals that bind to receptors on surface of immune cells called PD-1 receptors
stimulation of receptor causes cell to switch off and ignore the tumour cells (immune evasion)
nivolumab sticks to this chemical and stops it binding to the effector cell so the immune system remains switched on and attacks the cancer cell

Question 35

side effects of nivolumab?

Answer 35

rash
low platelets
fatigue
pyrexia
diarrhoea
nausea
pruritic
cough
hypothyroid

Question 36

how is immune therapy used in blood cancer?

Answer 36

allogenic bone marrow transplant from matched donor
T cells from donor cause immune attack on cancer
graft vs leukaemia/lymphoma effect
also have attack of normal cells however (graft vs host disease)

Question 37

what is adoptive immunotherapy?

Answer 37

new type of immunotherapy in development where you make the patient’s own immune cells recognise the cancer as foreign and attack it
avoids toxicity of graft vs host disease
(most promising type = CAR T cell therapy)