CLL

Question 1

Give a background of CLL

Answer 1

It is a proliferative disease of mature lymphocytes
It is the commonest in the world
and it is commonest in Caucasian populations

Question 2

Give the presenting features of CLL

Answer 2

Usually picked up incidentally as abnormal FBC
Enlarged lymphadenopathy 
Fatigue
Recurrent sinus/chest infections due to hypogammaglobulinaemia and lack of functioning B cells 
Bone Marrow failure :
Thrombocytopaenia
Neutropenia 
Anaemia
Autoimmune phenomena 
AIHA
Autoimmune thrombocytopaenia
Pure red cell aplasia

Question 3

Describe features seen on a blood film of CLL

Answer 3

Smear cells
Lymphocytosis
Low RBCs - normocytic normochromic anaemia
Low platelets

Question 4

What is seen with flow cytometry?

Answer 4

Pan B markers: CD20, CD23, CD19,
Aberrant: CD5
Additionally: FMC7-, CD79b+/-, SmIg +/-
High forward scatter

Question 5

What are the low risk cytogenetic abnormalities in CLL?

Answer 5

Low risk:
Del(13q14) - deletion of non-coding microRNA that regulates MYB expression
Deletion of Retinoblastoma

Question 6

What do the genes MYB and Retinoblastoma do ? What is the important of loss of non coing miRNA?

Answer 6

MYB - triggers cell survival it is an anti-apoptotic gene which encourages the cell to continue in proliferation

Retinoblastoma - sequesters E2F TF and prevents cell cycle progression until deactivated

miRNA controls the expression of MYB and it is thought this is lost when there is 13q deletion so control of MYB is lost and the cell proliferates without control

Question 7

What are the intermediate risk cytogenetic abnormalities in CLL?

Answer 7

del(11q) - ATM gene deletion

Trisomy(12q)

Question 8

What does trisomy 12 cause?

Answer 8

Not sure what it causes! but is commonly found in CLL

Question 9

What does del11q cause?

Answer 9

This is a commonly deleted region including the ATM gene which has a major role in repairing DNA damage in cells specifically double stranded breaks. Important as well in phosphorylation of proteins which promote TP53 signalling
It is a huge gene so can’t be sequenced, to test for this deletion you cause cellular stress to CLL cells and see if they can survive

Question 10

What are the high risk cytogenetic abnormalities in CLL?

Answer 10

del(17q) - deletion of p53 in response to stress/DNA damage

Question 11

What are the functions of the p53 gene?

Answer 11

Arrests growth until damage is repaired
Triggers DNA repairs
Causes apoptosis if damage is unfixable

Question 12

What is another mutation found in CLL?

Answer 12

CD38/Zap70 expression
both are functionally linked and high expression indicates rapidly proliferating CLL population it is a poor prognostic indicator

Question 13

How can the IgG gene mutation status also be an indicator of CLL prognosis?

Answer 13

If there is somatic hypermutation in variable region of Ig heavy chain locus as mutated IGVH confers a better prognosis than unmutated IGVH

Question 14

What are the different treatment options for CLL?

Answer 14

1st Watch and Wait - wait till there is an indication to treat lymphocytosis/progressive - b symptoms, doubling of white cell counts after 6 months or BM failure

are they young enough? then give Chemotherapy IF tp53 is intact
BTK inhibitors - Ibrutinib

SCT allogeneic - younger pts only

Question 15

What are the chemotherapy drugs used?

Answer 15

Tough 1. Fludarabine, Cyclophosphamide, Rituximab
just about tolerable 2. Rituximab and Bendamustine
tolerable 3. Obintuzumab and Chlorambucil

Question 16

What is used to treat relapsed/refractory CLL?

Answer 16

Venetoclax - BCL2 inhibitors

Tumour lysis syndrome very high

have to increase dose slowly so they can tolerate the tls

this can be used in refractory tp53 mutated patients

Question 17

What is a new drug for TP53 deletions?

Answer 17

Ibrutinib - brutine tyrosine kinase inhibitors
Idelalisib - B cell receptor kinase inhibitors
Targets haemopoietic cells with PI3K mutation v. specific and low side effects can be used in elderly
side effects AF but generally well tolerated

Question 18

What is the future of CLL treatment?

Answer 18

CAR-T cell therapy

Question 19

Name a study investigating CAR -T cells and CLL

Answer 19

26% of patients had durable antitumour responses - porter et al 2015

Fraietta et al 2018 found that the differences between responders and non responders was their t cell “health” rich in IL6STAT3 signatures more found in complete remission patients rather than non responders had t cells which upregulated effector differentiation, glycolysis, exhaustion and apoptosis.