ASH 2025 | Second-line treatment in CLL after venetoclax-based frontline: insights from GAIA/CLL13 and CLL17

I’m going to present on Monday here would be the long-term follow-up from the GAIA-CLL13 trial. You might not remember the GAIA-CLL13 trial. That’s testing chemoimmunotherapy as compared to venetoclax rituximab and venetoclax obinutuzumab and venetoclax obinutuzumab ibrutinib, thats a four arm first-line trial. It showed superiority of the venetoclax obinutuzumab, in particular the triplet with venetoclax obinutuzumab ibrutinib in terms of progression-free survival. But now we have also demonstrated that patients with CLL being treated in the frontline setting have such good outcomes that it might not be that much about what is the progression-free survival after the first-line treatment. We need to collect information on the long-term, on the sequencing of different treatments for patients with CLL. And that’s what we’re presenting here. The outcome for 177 patients with CLL treated in the GAIA-CLL13 trial now having received second-line treatment. And it’s important to emphasize this is not randomized. It was based on the treating physician and the patient to decide what would be the next-line treatment. And these 177 patients, they were treated in four different groups, more or less. One being BTK inhibitor-based, that could be together with a CD20 monoclonal for some patients with different additions. One group was venetoclax-based. Most of those received venetoclax together with a CD20 monoclonal. And then we had a small group receiving chemoimmunotherapy. Don’t do that. They had a worse outcome than the others. And then the final group received venetoclax and a BTK inhibitor. So this means that we had three groups of patients either receiving a BTK inhibitor or two of the groups receiving a venetoclax-based regimen either with a CD20 addition or with an addition of a BTK inhibitor. And these patients, all of them received venetoclax together with a CD20 monoclonal in the first-line setting, and now we see that they have excellent outcomes from the time of second-line treatment with a venetoclax-based regimen, with time-defined treatment used in the relapsed/refractory setting after the patients had received venetoclax-based treatment in the frontline setting. And seeing that we at the moment have, say, three different options, at least in Europe, to treat patients in the frontline setting, being venetoclax together with a BTK inhibitor, either ibrutinib or acalabrutinib, venetoclax together with a CD20 monoclonal in terms of venetoclax obinutuzumab, or we could use an indefinite BTK inhibitor. And now from the CLL17 trial being presented here on Sunday, we’ll see that the two venetoclax-based time-defined treatments either with venetoclax ibrutinib or venetoclax obinutuzumab are non-inferior to a continuous BTK inhibitor in the frontline setting. At the same time, we can demonstrate in the GAIA-CLL13 trial in this long-term follow-up that it’s also safe and very efficient to retreat with a venetoclax-based regimen, whether venetoclax with a CD20 monoclonal or venetoclax with a BTK inhibitor after first-line venetoclax-based treatment. Thus, now we are establishing that it’s actually safe to treat with time-defined treatment, follow the patient at time of relapse, retreat with a new time-defined treatment. This gives us the concept of having to look for progression-free survival 2 or even 3 and demonstrating that it’s feasible and safe and probably reducing the toxicity for patients to treat them with time-defined treatment, breaks without treatment and then re-treatment with a time-defined treatment. And this gives us a perspective in CLL focusing on the quality of life for patients with CLL and the importance for the patients to actually be off treatment. And when one of my colleagues interviewed patient representatives from the Danish Cancer Society, a patient organization, they mentioned two things being really important for them in terms of what they focus on for treatment. One, they didn’t want to be in the hospital, so they wanted to reduce the contact and I used to tell that I actually really enjoy and like my job at the hospital but it seems my patients do not agree. So that’s one focus. The other focus is that the patients are actually willing to accept quite significant toxicity from treatment as long as they know it’s for a defined period of time but staying on treatment indefinitely, even with lower amounts of toxicities, but knowing that they’ll never get rid of them because they have to stay on the medication, was a real issue for the patients that they wanted to avoid. So this emphasized that at this ASH meeting, we actually present both the data in the frontline setting, that time-defined treatment is non-inferior to continuous BTK inhibitor and for the second-line treatment that it’s feasible to retreat with a time-defined treatment also in the second line.

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