Optimizing CLL Treatment: BTK Resistance and Dual Therapy | Kerry Rogers, MD | ASH 2023

Hi, I'm Carrie Rogers. I'm a hematologist and associate professor at The Ohio State University, and I'm here at ASH 2023. I'm very excited about a lot of the research happening here at ASH in CLL. And at this meeting, I'm presenting some really interesting results from a clinical did at our institution. So as many people know, BTK inhibitors, which is a class of drugs that includes ibrutinib, acalabrutinib, and xanabrutinib are current standard of care in chronic lymphocytic leukemia, and that they're usually given indefinitely until either people don't tolerate them anymore, or the CLL cells become resistant to it and people's CLL relapses or returns while they're continuing to take the drug. So this study is looking at how best we might treat people whose CLL cells have developed resistance to BTK inhibitors. The best standard and in fact, the only drug we had that was commercially available or approved until recently that worked in this setting was a drug called benetoclax, which also, you know, sometimes is given indefinitely in this setting. So what we were interested in is could you identify people who are taking the BTK inhibitor ibrutinib for their CLL and add benetoclax to ibrutinib and take them in combination to see if you could get very low levels of leukemia and have them stop taking treatment and enjoy time off of treatment for the CLL. So it's taking people whose CLL has developed resistance to ibrutinib and instead of giving them just benetoclax kind of indefinitely sometimes, could you give them like just add the benetoclax and get very deep remissions allowing them to be off treatment. So this study included 28 people who participated and in order to participate people had to be taking ibrutinib for CLL and have mutation in their CLL cells in either a protein called BTK, which is the drug binding target or PLC gamma 2, which is kind of the protein that interacts with BTK and both are associated with resistance to the drug not working anymore. And some people had, you know, progressive disease where their CLL returned and some didn't. And we actually found that this was a very effective strategy to add benetoclax. The median amount of time that people remain alive and in remission on benetoclax alone in this setting is about two years and in this study something we call median progression free survival, which is the median amount of time people are alive without their leukemia returning, was 40.7 months, so longer. So we think that treating in some cases earlier, but definitely with this add-on strategy of adding the second drug as opposed to changing to it, does improve how long remissions last. We also had a high number of people that were able to discontinue the drug relatively high, so it wasn't quite half, it was around 43% that discontinued in a very deep remission and we are still following people that have not needed to start a next drug treatment. So for this in particular we need to follow people that participated in the study a little longer. We're also looking at testing on their CLL cells to try to figure out, you know, if there are biologic differences in the CLL cells that responded well or didn't to this treatment so that we can design better therapies in the future. But I think this idea of adding a second drug and getting deep remissions was really demonstrated that that could work for people who participated in this study. I think with the variety of other drugs we have available that target BTK and also have the same target as benetoclax, which is Bcl2, we might even have better strategies of targeting both these proteins in people whose CLLs become resistant to BTK inhibitors like iverutinib. So I'm very excited about what this study has shown us could happen biologically and I look forward to seeing how people who participated in this study did in the future and how this might help us design better combinations in this patient population.