Michele Nadeem-Baker: We’re at ASH ‘23. That’s the American Society of Hematology Annual Conference. This is where a lot of the biggest discoveries are announced when it comes to blood cancers, CLL, and SLL.
I’m Michelle Nadeem-Baker, with Patient Power. Welcome to our program. Today I have, with me, Dr. Paul Hampel. He is from the Mayo Clinic, in Rochester, and is a CLL specialist. Thank you so much for joining us today.
Dr. Hampel: My privilege to be here.
Michele Nadeem-Baker: Now, at this ASH, I know that you are presenting on venetoclax (Venclexta) and its benefits. Could you explain, a little bit, about your study for our patient viewer audience?
Dr. Hampel: Absolutely. So venetoclax-based treatments have convincingly demonstrated efficacy, in phase III clinical trials in the frontline setting, or first treatment, as well as relapsed/refractory patient populations on study. What we’re looking at here is patients who received a venetoclax-based treatment, not on a clinical trial, in a routine clinical practice at a tertiary medical center. So real world or not, but off of a study, and to look to see how those patients did across three main treatment scenarios. So first-line treatment naïve, their first CLL-directed therapy, relapsed CLL, but without prior receipt of a BTK inhibitor, the other main, novel agent.
Michele Nadeem-Baker: So can you give a couple of examples of that?
Dr. Hampel: Yeah. So the three approved BTK inhibitors, that we have available for the treatment of patients with CLL in the first-line setting, are all covalent or continuously-binding BTK inhibitors: acalabrutinib (Calquence), zanubrutinib (Brukinsa), and ibrutinib (Imbruvica).
Michele Nadeem-Baker: Mm-hmm (affirmative).
Dr. Hampel: Many patients will have received either that or venetoclax now as their standard of care options. So when we’re breaking down to look at the outcomes of patients treated with venetoclax, we put them into one of these three main subgroups to try and understand those outcomes. No prior therapy, prior therapy that was not a BTK inhibitor, or prior therapy that included a BTK inhibitor, the last group being particularly important. Because those are patients who were not seen in any of the prior prospective work with venetoclax, aside from one study.
Michele Nadeem-Baker: So in your study, what are some of the findings? Who’s been faring the best?
Dr. Hampel: Yeah. So it was very reassuring, particularly because there’s quite a paucity of data for patients receiving venetoclax-based treatment off of a study in the first-line setting. And those patients’ outcomes looked very similar to what was published in CLL14, or what’s been presented and published for CLL13. So the major phase III studies looked at venetoclax-based treatments, meaning the patients did very well and it recapitulated the study data.
The second group, the patients who had relapsed to CLL, and who had not received a prior BTK inhibitor, also did quite well and looked quite similar to the MURANO study. So that was the phase III study, looking at venetoclax plus rituximab (Rituxan), versus bendamustine (Bendeka and Treanda)/rituximab in a patient population that was almost entirely BTK-naïve –had not received a prior Bruton’s tyrosine kinase inhibitor. So, our off-study patients or routine clinical practice patients, who were in that same scenario, did very, similarly, well.
Michele Nadeem-Baker: On venetoclax?
Dr. Hampel: With a venetoclax-based treatment. Correct.
Michele Nadeem-Baker: Mm-hmm (affirmative).
Dr. Hampel: And then the third group is the one that, perhaps, is of most interest with the least amount of data to guide us on. We had 83 patients, who fell into this group of relapsed CLL or SLL, with prior receipt of a BTK inhibitor. Fifty-five of those 83 had had prior disease progression on a BTK inhibitor, with the remainder being exposed, but having discontinued it for another reason, such as toxicity. Those patients’ outcomes were, as a whole, worse than that second group of patients who also had relapsed CLL but had no prior BTK inhibitor.
Michele Nadeem-Baker: So just to summarize a bit. Patients who had been on one of the BTK inhibitors, like ibrutinib, acalabrutinib, and zanubrutinib did not fare as well as patients who had never received one of those before, or those in the frontline setting, when receiving venetoclax next?
Dr. Hampel: Correct. But there’s more to the story, and that group actually splits out along those lines of whether or not the disease had previously progressed on a BTK inhibitor or not.
Michele Nadeem-Baker: Okay.
Dr. Hampel: Where those who had discontinued a BTK inhibitor, in the setting of toxicity or a tolerability issue, did much better compared to those who actually had their disease progress on prior BTKi.
So the outcomes there – we used a little bit – and sorry to get into some of the nuances of this. We used something called TNT-D, or time to next treatment or death, the reason being this is a retrospective study. It’s sometimes difficult, without a unified follow-up assessment for response, to assess progression-free survival. Nonetheless, an important outcome to patients and clinicians is “When am I going to need my next therapy?” It’s a surrogate for progression-free survival, but time until the next therapy is needed after the start of this venetoclax-based treatment.
Michele Nadeem-Baker: So that’s based on day one of starting venetoclax?
Dr. Hampel: Correct.
Michele Nadeem-Baker: Okay.
Dr. Hampel: And so, our TNT-D or PFS surrogate, in that group of patients receiving venetoclax-based treatment in the relapsed setting, and with prior disease progression on BTKi, was actually quite similar to what Jeff Jones had presented, now, over five years ago, in the only prospective data for venetoclax-based treatment after a BTK inhibitor, which was around two years. Those numbers are sobering to us, and much lower than we’re used to seeing or expecting with venetoclax-based treatment in someone who has not already received a BTK inhibitor.
Michele Nadeem-Baker: So, how long are they on the venetoclax, or is it varying amounts of time?
Dr. Hampel: Yeah. That’s a difficult thing to parse out without bias, and I’ll tell you why. Because the standard of care for venetoclax-based treatment in the relapsed setting would be, either, two years’ duration, with the addition of the anti-CD20 for six months. This is based on MURANO, and this is what our clinical trials are essentially mandated to use, per the FDA.
Michele Nadeem-Baker: And for people on an anti-CD20, like obinutuzumab (Gazyva)?
Dr. Hampel: Yeah. Thank you for keeping me honest on this.
Michele Nadeem-Baker: That’s my job. (laughs)
Dr. Hampel: Yeah. Rituximab or obinutuzumab, and actually, the data is with rituximab. So sometimes – even though now, I think there’s an evolving body of literature to support obinutuzumab as maybe being a better anti-CD20 in the setting of CLL, based on some study data and from CLL13 in the frontline setting that we’re extrapolating, from retrospective studies from myself, as well as – I think there’s another abstract from the group at UCSD – this ASH – suggesting that obinutuzumab is perhaps a better anti-CD20. I’m getting off on a tangent, sorry.
Michele Nadeem-Baker: Nods (affirmative). It’s okay.
Dr. Hampel: So the standard of care, though, being two years’ duration of therapy, that is not measurable residual disease guided or anything else. It’s a fixed duration based on those prospective studies, or venetoclax on its own that is given on a continuous, indefinite basis.
However, when our – and the split amongst that group was about a third of patients, who had gotten venetoclax monotherapy, and then some patients getting venetoclax and obinutuzumab when we were able to get it approved, or venetoclax and rituximab, and it was a split amongst those. But to say that somebody truly had the intent of continuing indefinitely, or stopping at two years becomes a little bit nuanced in a retrospective evaluation. Because if about half of patients are having their disease progress before two years, you’re taking a leap to say, “Well, this person would have, for sure, stopped at their two-year mark, or they would have continued.”
Michele Nadeem-Baker: So this is while they’re on the venetoclax that they relapsed? Is what you’re saying?
Dr. Hampel: Correct. Yeah.
Michele Nadeem-Baker: Wow.
Dr. Hampel: So I think that’s the piece. We all think of how much time are we going to get off of the therapy altogether. But if the median is actually around the time when you would normally be stopping the therapy, it ends up, somewhat, of a moot point for a large chunk of patients, unfortunately.
Michele Nadeem-Baker: Did you study patients who are on venetoclax just for a year, which, I know, is the standard for some?
Dr. Hampel: Yeah. So the patients who would have received treatment in the first-line setting, those patients all got a CLL14 type of approach, where they just got a year’s worth of therapy. The heterogeneity comes along in the relapsed/refractory setting, where there’s a lot of rationale to do one thing or the other, particularly as people are experimenting with the use of MRD in a non-trial perspective, and saying, “If I have somebody’s disease in a very deep remission, am I helping that person by continuing therapy beyond that? Or am I just selecting for resistance?”
We’ve seen some data that suggests keeping that selective pressure on and keeping that drug on actually drives some of the resistance. That if you pull back, it dissipates and allows the ability to potentially use that again in the future.
Michele Nadeem-Baker: Do you believe that does happen?
Dr. Hampel: Yeah. I believe that there’s a strong argument to make in that regard. Again, I don’t want to speculate too much because we need the data, and you need prospective studies to prove this. I think getting to a deep remission and then coming off of therapy is, in general, a good goal. It’s something that will, rather than using our multiple cards in the deck, allow us to revisit those, hopefully, in the future.
That’s certainly panned out, quite strongly, in the beginning, in the frontline setting. Where we’re seeing patients who got – this is a common question that I get from patients, when we’re talking about first-line studies that include a BTK inhibitor and venetoclax, or a Bcl-2 inhibitor. And I’m asked “Am I using all of my cards at once? You told me the standards of care are this or this, and now, you’re giving both of them to me. What do I do when the disease comes back?”
Actually, what we’ve seen so far is that if you get into a nice remission – stop the therapy – many patients will have many years, hopefully, off of therapy altogether, if they need more, period. But in the folks where the disease does come back, there’s updated data from the CAPTIVATE study, which is an ibrutinib and venetoclax-containing study, where none of those patients had BTK or PLC gamma 2 resistance mutations.
