Cancer Case Studies

Question 1

A 68 year old male patient with no clinical symptoms has splenomegaly (palpable 5cm below left rib cage). The blood test shows low Hb, high leukocyte count, high platelets.
What is the diagnosis?

Answer 1

Chronic myeloid leukaemia (CML)

Question 2

All chemotherapeutic agents do not act specifically, but target…? What does this cause?

Answer 2

All doubling cells

Hair loss, nausea, severe mucositis with diarrhoea, anemia, low platelet counts and low white blood cell counts

Question 3

What group of disorders does chronic myeloid leukaemia belong to?

Answer 3

Myeloproliferative disorders (developing blood cells proliferate without control and accumulate)

Question 4

What is the cell of origin in CML?

Answer 4

Pluripotent stem cell

Question 5

In CML what cells are elevated?

Answer 5

Myeloid cells (neutrophil, eosinophil, basophil) and sometimes also the platelets

Question 6

CML was the disease first to be termed leukaemia by which German pathologist in 1845?

Answer 6

Rudolf Virchow

Question 7

Why is leukaemia called leukaemia?

Answer 7

= White blood, as these patients have very high white blood cell counts

Question 8

Describe the bone marrow smear of a CML patient. (3)

Answer 8

Bone marrow is totally packed with cells.
The amount of fat is reduced.
Mainly find developing myeloid cells and hardly any red blood cell development.

Question 9

What are the clinical symptoms in CML patients? (3)

Answer 9

Anaemia
Splenomegaly
Hepatomegaly

Question 10

What are the clinical phases of CML? (3)

Answer 10

Chronic phase (3-5 years) - asymptomatic
Accelerated (12 to 18 months) – blasts >15%, basophils >20%, platelets <100,000/mcl
Blast crisis (3 to 9 months) – blasts >30%

Question 11

What happens as CML progresses?

Answer 11

More and more progenitor cells find their way into the peripheral blood

Question 12

What is the incidence of CML?

Answer 12

1.5/100,000 per year

675 newly diagnosed in the UK a year

Question 13

Is CML more prevalent in males or females?

Answer 13

Males

Question 14

CML is predominantly diagnosed in what age of patients?

Answer 14

Elder patients

Question 15

What was used to treat CML before tyrosine kinase inhibitors? (3)

Answer 15

Allogeneic stem cell transplantation
Interferon (immune modulating agent)
Cytoreduction

Question 16

What are the disadvantages of conventional chemotherapy? (4)

Answer 16

Unspecific
Dose-intensive polychemotherapy
Non-tolerable side-effects in elder patients and patients with comorbidities
Often intraveneous application, have to stay in hospital

Question 17

What can allogenic stem cell transplantation cause? (2)

Answer 17

Graft versus host disease

Toxicity due to chemotherapy

Question 18

The patient’s prognosis in CML depends on…?

Answer 18

The phase when the disease is diagnosed (earlier = better prognosis)

Question 19

What was survival in CML like before TKIs?

Answer 19

Not really good even when the disease was discovered early on e.g. in chronic phase, 20 years post treatment only 50% are alive. In accelerated phase, 30% of patients survived 12 years after treatment. In blast crisis, 2 years post treatment no patients survived.

Question 20

What is the aim of targeted cancer therapy? What are the benefits?

Answer 20

Target differences between the tumour cells and the normal, healthy cells. Also they are given orally so ambulant therapy can be done. They can be given as monotherapy ideally, or integrated into existing chemotherapy protocols to improve the survival rates/chance of cure.

Question 21

Give some examples of tyrosine kinase inhibitors. (3)

Answer 21

Imantinib (1st generation)
Dasatinib (2nd generation)
Bosutinib (3rd generation)

Question 22

What translocation do almost all patients with CML have? What does this cause?

Answer 22

A reciprocal translocation between chromosome 9 and chromosome 22, leading to an abnormally short chromosome 22 (the Philadephia Chromosome). The translocation affected a gene called Abelson Tyrosine Kinase, responsible for the phosphorylation and activation of other proteins, and the translocation made it far more active than it normally should be. Leads to proliferation of the cell. The new gene product resulting from the translocation was called the bcr-abl-fusion gene.

Question 23

Where do TKIs bind? What type of inhibition is this and what does this lead to?

Answer 23

The site of the kinase where normally the substrates for phosphorylation bind
Competitive inhibitor – less proliferation of cells

Question 24

What are the benefits of Imantinib? (3)

Answer 24

Well tolerated so can be given to older patients and those with comorbidities
Oral so can do ambulant therapy
Improved survival rates

Question 25

In this patient cohort on Imantinib after 5 years how many % of treated patients were still alive?

Answer 25

95%

Question 26

What is the big disadvantage of the TKI?

Answer 26

Their costs – very expensive (40,000 Euros for Imatinib, 70,000 for Dasatinib and 50,000 for Nilotinib annually)

Question 27

What causes resistance to Imatinib?

Answer 27

Gene mutations that effect the protein’s binding domain for the substrates and therefore also the Imatinib binding domain e.g. T315I mutation

Question 28

Ponatinib – what is the main benefit? What are the disadvantages? (3)

Answer 28

Has efficiency in T315I mutated CML

Not very well tolerated, causes liver toxicity and skin rashes

Question 29

What is the current treatment algorithm for CML?

Answer 29

After diagnosis you start with one TKI of your choice. Once there is an inadequate response, resistance or intolerance you change it for a second and you might think of a dose escalation. And only in the case of progressive disease or a T315I mutation you take allogeneic stem cell transplantation into consideration.

Question 30

How might TKIs be discontinued when a cure is achieved?

Answer 30

Patients are treated with Nilotinib for a year and if they receive a deep molecular remission after that year the medication is withdrawn. The disease is then very carefully monitored by regular quantitative PCR analyses for the bcr-abl fusion gene and in case the deep molecular remission gets lost, the treatment is reinitiated.

Question 31

35 years old female, with decreasing physical performance, short of breath even at rest. She also has night sweats and signs for an upper venous congestion are seen on examination. The blood count was normal, LDH and the CRP were slightly increased. Chest x-ray and CT have striking results – tumour seen in anterior mediastinum.
What is the diagnosis?

Answer 31

Primary mediastinal B-cell lymphoma

Question 32

Lymphomas take their origin from…?

Answer 32

Lymphocytes

Question 33

Why is there a huge variety of subtypes of lymphoma?

Answer 33

Since lymphocytes go through so many different stages of development

Question 34

What is the hallmark of lymphomas in most cases?

Answer 34

Lymphadenopathy

Question 35

How many lymphoid neoplasms entities are there?

Answer 35

About 60

Question 36

How are lymphomas classified simply?

Answer 36

Hodgkin

Non-Hodgkin lymphoma (split into B-cell, either aggressive or indolent, and T-cell)

Question 37

How is B-cell lymphoma treated?

Answer 37

Cytostatic drugs plus targeted immunotherapy e.g. Rituximab - antibody against CD20, as lymphoma cell has CD20 antigen

Question 38

How do monoclonal antibodies work? (3)

Answer 38

Complement dependent cytotoxicity
Antibody dependent cellular cytotoxicity
Direct cell death (apoptosis)

Question 39

What alternative treatment strategies are there for B cell lymphoma? How do they work? (3)

Answer 39

Immunomodulating agents, e.g. thalidomide and lenalidomide. Antiproliferative, anti-angiogenic, co-stimulation of T cells and activation of NK cells.
Bortezomib – proteasome inhibitor
Temsirolimus – Mtor-inhibitor