ASH 2015

Experimental oral therapy for high-risk CLL shows promise

Prof Stephan Stilgenbauer - University of Ulm, Ulm, Germany

You’ve been talking about ultra-high risk relapsed or refractory chronic lymphocytic leukaemia and using an agent, venetoclax. What were you trying to establish here, what was the big issue you were investigating?

Chronic lymphocytic leukaemia, or CLL, can be characterised by various features. One of the key adverse markers is the 17p deletion that is destroying the TP53 tumour suppressor gene. We know that these patients don’t respond to conventional chemotherapy and their survival, unfortunately, is poor. So in this population we need to develop new treatment options and the treatment option on the study here is venetoclax targeting Bcl2, a key biological feature of the CLL cells.

So what’s the option for targeting Bcl2 if you don’t have venetoclax then?

Venetoclax is a first in class drug that really works. Bcl2 is highly expressed in CLL cells so it’s really an attractive target and venetoclax is really the first agent available clinically that is doing that job.

So in this first opportunity, then, what did you do in the study?

This study was defined by patients who failed chemotherapy and who had the 17p deletion. So this very high risk population was in this international effort homogenously treated with single agent oral therapy with venetoclax.This treatment is tremendously well tolerated, it needs to be handled with care because it induces remissions very rapidly but if so it can achieve very good outcome for the patients.

Can you run me through the numbers? What were the improvements in remission? What were the remission rates?

So 107 patients were enrolled on the trial, the overall response rate, as established by an independent review committee, was close to 80% which is a number unheard of. Importantly, these remissions were induced very rapidly, the time to onset of the first remission was less than a month.

And what about the depth of response and minimum residual disease?

The problem with many agents that we have available today is that they can lead to a very good outcome but don’t really eradicate the disease. So with venetoclax we have a different therapeutic paradigm here that it’s inducing very deep remissions rapidly. In fact, in this ultra-high risk population on this trial we actually had patients who became minimal residual disease, MRD, negative which is something that we haven’t experienced in this population ever before.

What is this telling us about the clinical potential of using venetoclax, then, in this setting – very high risk disease?

This is, as I said, the first result ever achieved in that population. We can get rid of the disease, in particular it can lead to the development of finite treatment durations so not endless therapy but only a limited duration treatment which is obviously desirable to the patient.

So what should cancer doctors be thinking about this right now?

In CLL I think it is very critical before you institute treatment to test for 17p deletion and TP53 mutation and then guide your patient to the appropriate therapy which today is not chemotherapy anymore.

Does it look as if there will be a new standard of care?

Several lines of evidence argue in favour of the fact that the new standard of care in the future may go away from chemotherapy, certainly from chemotherapy alone as an option for the patient.

The take-home message for doctors?

Be aware of the new developments, take care of your patients and it’s great times. If you have to have CLL it is better to live with CLL today than ever before.