Risk of bleeding-related adverse events in ibrutinib treated CLL patients
Dr Adrian Weistner - National Heart, Lung and Blood Institute, Maryland, USA
Could you tell me a little bit about your research?
I work clinically and in the laboratory on chronic lymphocytic leukaemia and our main question, really, has been what are the targets for therapy. Now that we have new drugs that actually very specifically interrupt pathways, meaning circuits within the cells that contribute to cell survival, we’re focussing on what these drugs do both to the CLL cells as well as to normal cells.
And what results are you presenting here at this meeting?
What I’m presenting are two studies, both have to do with a drug called ibrutinib. It’s an inhibitor of Bruton’s tyrosine kinase which is basically an essential switch within these CLL cells. What ibrutinib does, it turns that switch off which arrests the cells from growing and eventually they also die away when you inhibit this pathway. But then this is not a drug that can only affect CLL cells; we’re learning that it affects some other cells as well, first of all other B-cells because that’s where CLL cells come from. So the study we looked at whether ibrutinib has a positive, no effect or a negative effect on normal immune function, normal B-cells. What we found is that in patients treated with ibrutinib the CLL was reduced and we start seeing, actually, some recovery of a better immune system. Better in the sense that we’re seeing proteins that come back, immunoglobulins that come back, that help us fight infections. That was somewhat a surprise because the drug inhibits this BTK which is also important in how normal B-cells start making these immunoglobulins. We see that with the duration on treatment patients have fewer infections so with time their immune system seems to be improving and maybe that’s directly correlated to each other with this improvement in the immunoglobulins. Maybe it’s just an overall sign that things are getting better, that some of the effects of the CLL on the normal immune system are actually going away on the drug.
And what about adverse events?
One of the adverse events you see are infections and again those are actually diminishing the longer people stay on the drug. Another observation we’ve made, everybody has made who uses ibrutinib, is that patients often have bruising and maybe some minor bleeding – a nosebleed or really minor moderate bleeding. Initially there were a few patients who had severe bleeds, that was mostly in patients who had another blood thinner, so who had an additional risk factor for bleeding. What we did in our study, we have 86 patients we enrolled, we had nobody with a serious bleed in over three years of observation. But we tried to identify whether there are any effects of ibrutinib on cells that help us stop bleeding, so platelets, and maybe on the coagulation factors, so the proteins that lead to clotting. Yes, there are some mild effects on that. What we’ve seen is that most of the measurements in the laboratory that predict whether somebody will have bruising were actually present before we started the ibrutinib. They have to do maybe with whether people are on aspirin or taking fish oils which we know can have a similar effect or have maybe some other unidentified reason. But all the good predictors of who gets bruising and who doesn’t were present before we even started the drug.
There is some effect of the ibrutinib on platelet function but there is also an effect against the CLL cells. So patients with CLL actually have more bruising than other people in the same age group and there is some contribution of CLL cells to make people bruise more easily. Ibrutinib inhibits some of these negative effects of the CLL cells. So, yes, it has some effect against platelets but it has positive effects in reducing the CLL cells and inhibiting some of these negative effects of the CLL cells. So in aggregate I think we have not been able to identify any worrisome effect of the drug. What’s limiting in our study is that we have nobody with a serious bleed, fortunately, so we can’t really with certainty say what would set people up for more serious bleeding. But as the randomised trials are progressing we will get better estimates whether there’s really an increased risk of serious bleeding on ibrutinib and we will also get a measure of how significant that is. I think there the jury is really out, that we don’t have enough data from randomised trials to be sure whether and to what degree ibrutinib really increases the risk of serious bleeding.
And what’s the future for your research?
We like to call them smart drugs, right? That maybe some of the people who developed these who were really smart about thinking about the right targets to go after. But it’s a totally new world compared to what we did before with chemotherapy that had also targeted… it targeted damaging the DNA of cells and making them die through that. These new drugs are more really specific to turning off circuits within the cells. There’s a lot to learn, it’s really a totally new concept for CLL at least. There have been drugs like that in other diseases for a while. There’s a lot to learn, these drugs impact the immune system, there is a lot to learn what that means and how we potentially enhance positive effects. Then there is the question of what happens when these drugs stop working, when there is resistance. So we’re using genomic techniques to identify what are the mechanisms when cells resist the treatment and how do we treat those that have resistance mutations.
