ASH 2024 | Key ongoing trials investigating combination approaches to the treatment of CLL

In the future, many of us think that in CLL, the combination therapy, namely looking at combination of BTK inhibitors with other agents are important. I would like to highlight a few studies that we are doing here at Fred Hutch. One is an investigator-initiated study looking at the combination of acalabrutinib and venetoclax in relapsed CLL. We saw that the AMPLIFY study show that in first line CLL A plus V plus or minus obinutuzumab. Sounds like it’s becoming one of our standard options. It’s now in the NCCN guidelines. But we are studying the same combination for two years fixed duration in the relapse setting, and that’s the Avenue 2 trial that we have. We’re also very soon opening another study, a combination of sonrotoclax with zanubrutinib. That’s another BTKi plus BCL2 inhibitor. And again, of course, that study, that combination has been tested. But what we’re doing that’s unique to our study, which is another investigator-initiated study, we are doing a very rapid ramp-up of sonrotoclax in five days. Most of this will be done in the inpatient setting with close monitoring. Many patients need to go up on the therapeutic dose, and many patients actually don’t have the ability to come for ramp-up for nine weeks or even five weeks. So the intention is to get them the therapeutic dose of sonrotoclax in a very short period of time, of course, with close monitoring. This study is the SONIX study that we’re doing at the Hutch and also working on other combinations. We’re excited about our combination study of nemtabrutinib, a non-covalent BTK inhibitor in combination with liso-cel for CLL. This is another IIT or investigator-initiated study we’re doing the NEMCAR trial, and that focuses on CLL eligible, I’m sorry, CAR-T eligible patients with CLL diagnosis, and they received liso-cel in combination with nemtabrutinib. We saw at ASH, Dr Wierda presented a combination of ibrutinib with liso-cel, and there seems to be some signal for a better efficacy and safety. Here, we’re using a non-covalent BTK inhibitor, and is expected to provide even more efficacy and the safety profile we need to see. So we’re excited about the combination studies. I would say outside of our institution, the CELESTIAL-CLLTN trial finished enrollment last year, 24, or early 25, this is a head-to-head trial of sonrotoclax and ibrutinib in the investigational arm versus venetoclax obinutuzumab, and this will be a very important study to wait for the results in the next few years.

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