Week 2 - G - New treatments for blood cancers - Chemo/radio, Monoclonal, Molecular targeted- AML/ALL/CML/CLL/NHL/HL Tx

Question 1

Which type of lymphomas are not curable?

Answer 1

These would be the low grade non hodgkins lymphomas

Question 2

There has been vast improvements in the treatment of haematological malignancies in the last 10/15 years and patient prognosis and survival has greatly improved How do chemotherapy and radiotherapy work?

Answer 2

Chemtherapy damages the cancer DNA as the cell divides (mitosis) and the cell recognises it is damaged beyond repair and therefore undergoes apoptosis -programmed cell death

Question 3

What is the protein that is often involved in the programmed cell death in patients? usually is the protein that causes apoptosis after the cell is damaged from chemo/radiotherapy

Answer 3

The p53 gene protein (TP53) is a tumour suppressor gene that is involved in the process of programmed cell death in response to cellular damage

Question 4

In what type of leukaemia can p53 mutations cause great difficulty for treatment? Where does the deletion of p53 take place?

Answer 4

This can cause problems in the treatment of chronic lymphoctyic leukaemias Deletions in part of the short arm of chromsome 17 -17p deletions cause there to be an absence of p53 resulting in uncontrolled proliferation of the tumour cell even when normal chemotherapy is applied

Question 5

How is the chromsome mutation identified in cancers?

Answer 5

Cytogeneitc anaylsis would be used to identify if there were any chromsomal abormalities

Question 6

What is the usual treatment of chronic lymphocytic anaemia? What is the treatment if there are del17p/p53 mutations?

Answer 6

Usual treatment is FCR - multi-agent chemo FLudarabine, cyclophosphamide and rituximab If there is a del17p/p53 mutations, these agents will not work as they rely upon p53 being active and there ibrutinib is used - these affect the B cell signalling pathway and dont rely upon p53

Question 7

Is lower dose or higher dose chemotherapy usually preferred and why?

Answer 7

Lower dose chemotherapy is usually preferred as it damages the cell enough to make it undergo apoptosis and therefore no inflammation occurs High dose chemotherapy however necroses the cell causing it to swell and lyse causing inflammation at the site

Question 8

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

Answer 8

This is because in lymphomas and chronic lymphocytic leukaemias there is an increase in lymphocytes obviously - these cells are very keen to undergo apoptosis and therefore when chemo/radiotherapy triggers cell damage, apoptosis is likely to occur In acute leukaemias, the cells are rapidly dividing meaning the therapy will target all the cells at once

Question 9

Unfortunately, both chemo and radiotherapy also damages normal cell tissue resulting in some side effects What are the immediate and long term effects of chemo/radiotherapy?

Answer 9

Immediate effects of chemo/radiotherapy - the person will be extremely tired, also associated hair loss, naursea and vomiting and increased risk of neutropenic infection Long term effects of chemo/radiotherapy - there could be heart and lung damage and other cancers are more common after chemo/radiotherapy

Question 10

Ideally due to the effects of chemo and radiotherapy affecting normal cells as well as the cancer cells, there is research into more cell-targeted therapies which treat the leukaemia/lymphoma directly A major increase in survival of the haematological malignancies is the big increase in supportive therapy What are some of the supportive therapy measures that are carried out?

Answer 10

* There is immediate IV antibiotics for any signs of neutropenic sepsis * Red cells and platelet transfusions are available * Prophylactic antifungals are given to prevent the rise of any fungal infection in the immunosupprssed * Growth factors - granulocyte colony stimulating factors can also be given

Question 11

To start with - there is an increased improvement in supportive care of neutropenic sepsis Emergency treatment of neutropenic sepsis. Urgent treatment-use of standardised guidelines in all hospitals.

• What is neutropenic sepsis defined as and what is the treatment?
• What are the signs of sepsis?

Answer 11

Defined as sepsis + neutrophil count <0.5 or <1 in a patient who has had chemotherapy in the past 21 days Signs of sepsis

• S - shivering/fever/very cold
• E - extreme pain or discomfort
• P - pale or discoloured skin
• S - sleepy difficult to rouse
• I - i feel like i might die
• S - SOB

Question 12

In sepsis there is a systemic inflammatory response to the bacteria in the blood stream What is the criteria for diagnosing sepsis using the SIRS? (Systemic inflammatory response syndrome)

Answer 12

Two or more than of:

• Temperature >38 or 90bpm
• Respiratory rate >20bpm or PaCO2 <4.3kPa (32mmHg)
• WBC >12x10^9 or <4x10^9 or >10% immature forms on microscopy

Question 13

If patient has had chemo in the last 3 weeks and temp>/38degrees or they have a SIRS score of >/= 2, what should be done immediately?

Answer 13

The patients should have bloods taken and sent for culture and started on antibiotics immediately without waiting for blood results to come back

Question 14

When patients have neutropenic spesis, SEWS score normally very high WHat is the treatment for the patient?

Answer 14

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Question 15

if a patient is suspected of a hickman line infection, what is added to the piperacilin and tazobactam treatment regime?

Answer 15

Add vancomycin as gram +ve organisms suspected

Question 16

What is usually the threshold for giving red cell and platelet transfusions for supportive care in patients who are being started on chemotherapy?

Answer 16

Red cell transfusion - usually given when patients Hb level is around 70g/l (can consider if patient is 80g/L and symptomatic) and Platelets transfusion is the platelet count reaches 10x10^9/L - massively increased risk of bleeding here

Question 17

What do growth factors do? (granulocyte colony stimulating factors) What is given for anti-fungal prophylaxis?

Answer 17

Growth factors stimulate the production of the white cell count to counteract the neutropenia Prophylactic antifungal drugs are given to all at risk to prevent infection eg itraconazole or posaconazole. We hardly ever see infections like this now.

Question 18

There have also been improvements in the way that chemo and radiotherapy is given by adding different scans to measure the extent of tumour sprea WHat scans are used in hodgkins lymphoma? Which scans are used in Non-hodgkins lymphoma?

Answer 18

Use CT/PET scan of chest, abdomen, pelvis for Hodgins lymphoma Use CT/MRI scan of chest, abomen and pelvis for Non-hodgkins lymphoma

Question 19

What are the different 1st line treatments for: Acute myeloid leukaemia? - looking to acheieve remission Acute lymphoblastic leukaemia? - looking to achieve remission Chronic myeloid leukaemia? - to achieve remission Chronic lymphocytic leukaemia? (with and without 17pdeletion or p53 mutation)

Answer 19

* Acute myeloid leukaema - 2-4 cycles of mutli-agent chemotherapy with breaks of 2-4 weeks in between cycles * Acute lymphoblastic leukaemia - treatment course lasts 2-3 years with multi agent chemotherapy * CML - imatinib - tyrosine kinase inhibitor * CLL - FCR treatment - Fludarabine + cyclophasphamide + rituximab - Rituximab is cytotxic and sensitises cells to chemotherapy Ibrutinib if 17p deletion or p53 mutation

Question 20

What is the usual treatments for hodgkins and non-hogkins lymphoma?

Answer 20

Hodgkins lymphoma - treat with ABVD (adriamycin, bleomycin, vinblastine, dacarzabine) and radiotherapy Non-hodgkins lymphoma -high grad - treat with R-CHOP * Rituximab targets the B cells (monoclonal antibody) and sensitises the cells to the chemotherapy CHOP is a combination of cyclophosphamide, hydroxydaunorubicin , vincristine (oncovin) and prednisolone Low grade -maintain remission (rituximab & interferon alpha)

Question 21

Are hodgkins lymphomas usually BorTcell lymphomas? What is antigen expressed on the reed sternberg cells? What are the types of non-hodgkins lymphoma?

Answer 21

Hodgkins lymphoma -although the traditional B-cell markers (such as CD20) are not expressed on all cells, Reed–Sternberg cells are usually of B cell origin The Reed-Sternberg cells express the CD30 marker NHL Tcell - 10% Bcell - 90% - low and high grade

Question 22

Targeted therapies are aimed at targeting the specific leukaemic / lymphoma cells How do mnoclonal antibodies work? what is the best example of a monoclonal antibody and what does it target?

Answer 22

Monoclonal antibodies work by only affecting cells which express the target protein The best example is rituximab Rituximab binds specifically to CD20 on B cells and this is therefore cytotoxic to the B cells in NHL

Question 23

Unfortunately most monoclonal antibody are currently used in combination with chemotherapy rather than instead of-so same risks! More effective than chemotherapy alone. Where on the immunoglobulin does the antigen bind?

Answer 23

The antigen binds to the antigen binding site present on the antibody - When the antibody binds to Cd20, the Fc part that sticks out activates the immune system – complement, T cells etc

Question 24

What is rituximab used in combination with for the treatment of NHL? How is this treatment different for both low and high grade B cell tumours? Usually is only curative sometimes in high grade

Answer 24

R-CHOP - used in high grade Rituximab + 4 chemo agenets Cyclophosphamide, hydroxydaunorubic, vincristine (oncovin) and prednisolone Rituximab + interferon alpha used to maintain remission in low grade B cell NHL - due to tumours being low grade, chemo isnt as effective at targeting the dividing cells as they arent dividing rapidly

Question 25

Biological agents have been superceded by more targeted therapy so dont really need to know What was the third type of targeted therapy again?

Answer 25

Molecularly targeted treatments are the other the type of targeted therapy

Question 26

Molecularly targeted therapies: Ideally: Target pathway specific to the cancer cell. Avoid side effects. More effective than chemotherapy. What are two different types of molecular targeted therapies?

Answer 26

Two different types are: Tyrosine kinase inhibitors - imatinib Targeting malignant B cells signalling pathways - ibrutinib

Question 27

What are the three different phases of chronic myeloid leukaemia? What is found on cytogenetic analysis of the bone marrow?

Answer 27

Chronic phase - lasts months to years Accelerated phase - increasing sypmtoms including spleen size and blood counts Blast crisis - there is blast transformation where features of acute leuaemia arise On cytogenetic analsysi - see the reciprocal translocation between chromsome 9and22 - BCR-ABL1 causing tyrosiien kinase activity which leads to uncontrolled proliferationn

Question 28

The tyrosine kinase inhibitors are exactly the same shape as the tyrosine kinase molecule Therefore instead of tyrosine kinase giving ATP to the phosphates (Substrate) – the inhibitors bind in here and prevent the action of BCR-ABL What is an example of the tyrosine kinase inhibitor given in CML?

Answer 28

Imatinib

Question 29

Patients are monitored very carefully and looked for any levels of BCR-ABL in the blood These targeted therapies are still not free of side effects What are some side effects of tyrosine kinase inhibitors?

Answer 29

Usually GI side effects - diarrhoea, nasuea, camps Can also cause myelosuppression (just like chemo agents)

Question 30

B cells require stimulation by antigens to survive – they have Ig receptors on the surface of the cell which is stimulated by antigens to proliferate and survive IN some cancers this process is circumveneted so that some proteins in this system are mutated . The transductuion proteins are the proteins that give the information to the nucleus and in some cancers, this protein will mutate causing it to send information to the nucleus to keep proliferating and mitosing even in the absence of antigens What usually causes apoptosis in cells if they are damaged?

Answer 30

Usually if a cell is damaged p53 will cause apoptosis In B cell lymphomas and chronic lymphocytic leukaemia - even in the presence of normal p53 the cells may be dividing rapidly as the mutation in the proteins isnt seen as cell damage and therefore normally chemo is given to (FCR chemo) to dmaage the cell inducing apoptosis

Question 31

Drugs affecting the B cell signalling pathway are effective in low grade NHl and B cell CLL that don’t respond to rituximab and chemotherapy Give an example of a drug affecting this pathway? When is it used?

Answer 31

* Ibrutinib - used if non responding to fludarabine + cyclophosphamide + ritxumab in CLL * Or to R-CHOP in NHL (idelasib is another type of B cell signalling pathway inhibitor) * First line if p53 mutation or deletion in short arm of chromosome 15 (17p del) * These drugs don’t require p53 to work

Question 32

What cells are seen in?

Answer 32

These are Reed sternberg cells - see the mirror image nuclei here

Question 33

When collecting cells from donor, T lymphocytes are also collected and therefore when giving them stem cells, the Tlymhocytes are also given and these cells recognise the patient as foreign and mount an attack You want the T cells to recognise the disease as foreign and mount an attack against the disease (Graft versus Leukaameia effect) but the T cells also recgonize every cell in the patient as foreign causing Graft versus host disease What type of marrow transplant is this involved in?

Answer 33

This is involved in allogenic bone marrow transplants Stem cell transplantation refers to a process whereby the patient's HSCs are replaced by new cells (either from yourself [autologous] or someone else [allogeneic] that grow into a healthy hematopoietic system.

Question 34

What can be used to treat the GVHD (graft versus host disease) in bone marrow transplants but what can this cause?

Answer 34

You can treat GVHD with steroids and immunosuppresants – but if doing this too much, the T cells from the donor will stop attacking the tumour leading to relapse