EHA 2019 | TP53 in CLL: screening and steering treatment

Your question was on p53, how to monitor it and how it affects treatment decisions. So p53 is a tumor suppressor gene, and when you have dysfunctional or absent p53 function, your CLL will be a worse disease and respond less to chemotherapy. p53 universally worsens the prognosis of all cancers, so CLL is not unique in that, and it can be detected or monitored by a number of techniques.

It can be done by in situ hybridization or FISH, where you look for deletions or absence of the chromosome, on the short arm of chromosome 17. That’s FISH, you’re looking for what’s called a deletion. You can also sequence the gene and look for mutations in the gene, and previously that’s been a laborious technique done by something called Sanger sequencing. But technology has moved forward tremendously now and we can monitor p53 by something called next-generation sequencing where we amplify that section of the gene, looking for mutations in it, and that can be done much quicker and less laboriously, but also the level of detection is even deeper than the traditional methods, so that is likely the future for monitoring of p53.

Why is it important? It does change, currently, it does change what you do frontline, because people with a p53 deletion or a mutation classically don’t respond to chemotherapy or respond only for a short time and relapse quickly. So nowadays we don’t use it frontline. In Ireland we would use ibrutinib, and so it’s relevant today in its detection and it should be monitored at every treatment decision because you may not have CLL, when you have your CLL diagnosis, you may not have this deletion, but you can acquire it through the progression of your disease, so it needs to be checked at every treatment decision before treatment.

There is an argument perhaps that if we move forward to giving everyone either ibrutinib or venetoclax and chemotherapy is no longer in the equation, some people may argue that we don’t need to it any more because it doesn’t affect treatment.

To a certain extent that’s true and that’s why in the new forthcoming CLL17 study all patients are eligible for randomization, whether they have a p53 deletion or not. So, there’s no separation because the new treatments work in p53. However, it does need to be said, when you look at the subset analysis of most of the studies for the novel agents, the patients with p53 deletion, although they do much better, extremely better, logarithmically better, than patients with chemotherapy, they still don’t do as well as people who don’t have the deletion. So I do still think that it’s a test we will continue to need to do in the future for prognosis, and perhaps when we’re aiming for or striving for precision medicine, a tailored approach to each patient, we may find that it’s still the patients with the worst prognostic markers, whether that be p53 or 11q23 or a NOTCH mutation or complex cytogenetics which are the bad prognostic markers, they may be now the subset analysis that need to have the combinations and that need to have MRD negativity, whereas that might be less important in people who don’t have these poor prognostic factors.

So I do think we will continue to do them in the future, but the advantage for all of us is that the detrimental effect on prognosis and progression free survival is considerably improved by the novel agents and they’re probably, the level of improvement we see seems to be better the earlier we use them.