We’re interested in resistance mechanisms to venetoclax. Venetoclax is a very effective medication for CLL, however the majority of patients who take venetoclax will relapse and up until now we haven’t really known why that is. We’ve done next generation sequencing on patients with relapsed CLL on venetoclax and we’ve found a mutation in BCL2 and that is the G101V mutation, or a glycine being substituted to a valine inside BCL2. This single mutation causes a 180-fold reduction in affinity of venetoclax for its target, BCL2 and in patients who develop it they inevitably go on to develop clinical relapse in our study.
So this has implications for a few parts of CLL care. The first is that it gives a strong indication for using combination therapies. If you give a single targeted agent for a complex genomic malignancy things like this can develop so hitting it from multiple angles is always more effective, just as we’ve learned in infectious diseases and in other cancers. So using things like venetoclax plus rituximab or venetoclax plus ibrutinib may well stop this mutation from being able to develop. Secondly, it gives a strong rationale for using time limited therapy. We didn’t see this mutation developing up until two years on therapy so limiting venetoclax therapy for patients who have achieved minimal residual disease negativity may well stop this mutation from developing because we’ve watched it develop under selective pressure in vitro when venetoclax is given to cells containing a low level of G101V. The third, I think it can be tested for in patients in the clinic in the same way as the BTK C481S mutation. So there is another mutation which affects ibrutinib’s ability to bind to BTK and function. So I see this mutation being tested for in a similar way to that for patients in the clinic.
Are there cost and time implications for this testing?
It’s a single nucleotide change, it’s very easy to test for. It can be tested. We’ve only found one mutation that does this so it is would be very easy to design a single assay to test this mutation. It could also be included as part of next generation sequencing panels which are being done to detect things like p53 mutations or BTK mutations in patients. So, yes, it will cost money to look for but if it develops in a patient it gives the haematologists a strong rationale to look for other therapies or add in another therapy in order to get rid of this mutation. Because venetoclax won’t get rid of that G101V mutated clone.
So this has the potential to be of help to the clinic?
Yes, definitely. I run a diagnostic laboratory and we do lots of testing for BTK for this BTK C481S in lots of different clinical circumstances and people progressing on ibrutinib. I see a similar role for G101V in BCL2 as the BTK C481S.
