iwCLL 2025 | Where will the field of CLL move in the coming years?

I think in the general sense I would say, I don’t have a crystal ball, but I would predict or even slash hope that we are moving more and more towards time-limited therapies. So we have very effective doublets now, of course venetoclax and obinutuzumab has been around for some time, but we also now have doublets and triplets in Europe, Ibrutinib plus venetoclax and in the US Acalabrutinib, Venetoclax, doublet, and triplet with Obinutuzumab have been part of NCCN guidelines and achieving really good results. Zanubrutinib doublets are also being investigated. I think it’s very important to give patients time off therapy, to reduce financial toxicity, to reduce long-term cumulative toxic effects of the drug, and I do believe most patients like it. You know, they take it for a year and then they are free to play. I do think we will see more and more use of these novel doublets as also those regimens seem to mitigate the risks of tumor lysis syndrome with venetoclax. 

And as you know, there is a lot of development in relapsed/refractory CLL. Non-covalent BTK inhibitor pirtobrutinib has some studies which are moving into front line. So it would be interesting to see how pirtobrutinib compares to covalent BTK inhibitors in frontline setting, but that we will not know for some time. And certainly degraders are coming up, BTK degraders are coming up, and they’re very effective drugs. They work well in covalent inhibitor-resistant and pirtobrutinib-resistant CLL. So it would be also interesting to see how these combinations pan out. 

I’m also excited about advances in the field of CAR T-cells, where we have now very exciting data in lymphoid malignancies, not so much CLL yet, with novel CAR T-cell targets such as BAFF-R. We have a study at City of Hope, as well as in vivo CAR-T approaches, which will simplify CAR-T administration if they work. So I do think this is also a very exciting development in that field. 

And finally, bispecific antibodies have made huge strides in therapy of lymphoid malignancies and may actually push CAR-Ts a little bit down the road, potentially, we’ll see. Glofitamab, mosunetuzumab, and epcoritamab have been approved in different lymphomas. So we now have data with epcoritamab in CLL, and the study will now include some combination strategies as well. So I do think this is also where we may want to use bispecific antibodies and CAR-T, in earlier lines of therapy and treatment of patients with CLL as they rely on patients’ own immune system, which is not intact to begin with, and things actually do get worse as patients progress on multiple treatments. So I think moving immunotherapies into earlier lines of therapy of CLL would also be something that we should see in the future.

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