CLL Flashcards
Give a background of CLL
It is a proliferative disease of mature lymphocytes
It is the commonest in the world
and it is commonest in Caucasian populations
Give the presenting features of CLL
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
Describe features seen on a blood film of CLL
Smear cells
Lymphocytosis
Low RBCs - normocytic normochromic anaemia
Low platelets
What is seen with flow cytometry?
Pan B markers: CD20, CD23, CD19,
Aberrant: CD5
Additionally: FMC7-, CD79b+/-, SmIg +/-
High forward scatter
What are the low risk cytogenetic abnormalities in CLL?
Low risk:
Del(13q14) - deletion of non-coding microRNA that regulates MYB expression
Deletion of Retinoblastoma
What do the genes MYB and Retinoblastoma do ? What is the important of loss of non coing miRNA?
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
What are the intermediate risk cytogenetic abnormalities in CLL?
del(11q) - ATM gene deletion
Trisomy(12q)
What does trisomy 12 cause?
Not sure what it causes! but is commonly found in CLL
What does del11q cause?
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
What are the high risk cytogenetic abnormalities in CLL?
del(17q) - deletion of p53 in response to stress/DNA damage
What are the functions of the p53 gene?
Arrests growth until damage is repaired
Triggers DNA repairs
Causes apoptosis if damage is unfixable
What is another mutation found in CLL?
CD38/Zap70 expression
both are functionally linked and high expression indicates rapidly proliferating CLL population it is a poor prognostic indicator
How can the IgG gene mutation status also be an indicator of CLL prognosis?
If there is somatic hypermutation in variable region of Ig heavy chain locus as mutated IGVH confers a better prognosis than unmutated IGVH
What are the different treatment options for CLL?
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
What are the chemotherapy drugs used?
Tough 1. Fludarabine, Cyclophosphamide, Rituximab
just about tolerable 2. Rituximab and Bendamustine
tolerable 3. Obintuzumab and Chlorambucil
What is used to treat relapsed/refractory CLL?
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
What is a new drug for TP53 deletions?
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
What is the future of CLL treatment?
CAR-T cell therapy
Name a study investigating CAR -T cells and CLL
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.
