The Chronic Lymphocytic Leukemia Channel is supported with funding from AstraZeneca (Diamond), AbbVie (Platinum), Johnson & Johnson (Gold), BeOne Medicines (Silver) and Lilly (Silver).
VJHemOnc is an independent medical education platform. Supporters, including channel supporters, have no influence over the production of content. The levels of sponsorship listed are reflective of the amount of funding given to support the channel.
ESH CLL 2026 | Therapy options after covalent BTK inhibitor failure in CLL
Gianluca Gaidano, MD, PhD, University of Eastern Piedmont, Vercelli, Italy, discusses treatment strategies after failure of covalent BTK inhibitors in chronic lymphocytic leukemia (CLL), including venetoclax-based regimens and non-covalent BTK inhibitors such as pirtobrutinib. He also highlights the importance of balancing efficacy and tolerability when sequencing therapies in an often elderly patient population. This interview took place at the ESH CLL 2026 congress in Stockholm, Sweden.
These works are owned by Magdalen Medical Publishing (MMP) and are protected by copyright laws and treaties around the world. All rights are reserved.
Transcript
Yes, this is an important question. So we have actually two options. One option is targeting another pathway for CLL, that’s the BCL2 pathway. So the option there would be with venetoclax-rituximab based on the Murano study. That’s a fixed duration regimen for two years. But then a more recent option is instead still targeting the BTK pathway, but with a different mode of action, of actually a different mode of binding with the non-covalent BTK inhibitors...
Yes, this is an important question. So we have actually two options. One option is targeting another pathway for CLL, that’s the BCL2 pathway. So the option there would be with venetoclax-rituximab based on the Murano study. That’s a fixed duration regimen for two years. But then a more recent option is instead still targeting the BTK pathway, but with a different mode of action, of actually a different mode of binding with the non-covalent BTK inhibitors. And the one that we know best is at the moment pirtobrutinib, for which we have several clinical trials already available. And this is something we have to think of it as a different, really different mode of action compared to the covalent BTK inhibitors. The co covalent BTK inhibitors target a specific cysteine in the BTK molecule, but instead the non-covalent, like pirtobrutinib, they establish different types of bones, and so they are functioning also in patients with mutated cysteine.
I think that safety is always a priority, especially because the CLL population tends to be an elderly population with a median age diagnosis, 72, median age first treatment, 76. So it’s important. And these patients have many comorbidities. So thinking of safety is very important. And the non-covalent BTK inhibitors have a very high and excellent safety profile. And we know that from several clinical trials, including the recent BRUIN CLL-321 study that compared, in fact, in patients relapsing after COVID-19, compared pirtobrutinib versus investigator’s choice. The rate of atrial fibrillation was very marginable. So very good safety profile. Efficacy is always important also, and we don’t have head-to-head comparisons between the two different options that we have, but with non-covalent inhibitors, we can also guarantee a very good efficacy for the patient.
Read more...
