William Wierda, MD, PhD: We’ve talked a lot about BTK [Bruton tyrosine kinase] inhibitor, BCL2 [B-cell lymphoma 2 protein] small molecule inhibitor. There is another target in the BCL receptor signaling pathway, which is PI3 kinase. There was an ASH [American Society of Hematology] abstract at the 2019 annual meeting, presented with a combination of umbralisib plus ublituximab plus venetoclax. And I know you’ve been participating on that trial. Maybe you can give us your thoughts on that combination and what your experience has been.

Shuo Ma, MD, PhD: The first PI3 kinase delta inhibitor was the idelalisib, which was FDA approved several years ago in combination with rituximab, which has shown benefit in relapsed/refractory CLL [chronic lymphocytic leukemia] when compared to rituximab alone.

There’s another PI3 kinase delta inhibitor, which is duvelisib, that’s been shown in the DUO trial comparing to ofatumumab, showing progression-free survival benefit. Both of those PI3 kinase delta inhibitors actually are considered first generation. The main problem with that is there’s some concern about the potential toxicity, mainly regarding immune-mediated hepatitis, liver toxicity, and immune-mediated colitis, severe diarrhea, as well as the infection risk.

The umbralisib is actually the next-generation PI3 kinase inhibitor that’s also focusing on the delta isoform. There seems to be a much better toxicity profile with this new PI3 kinase in that the hepatic toxicity, as well as the diarrhea, especially the grade 3 or more, toxicities are pretty rare. There are some grade 1 and 2 toxicities, which are easy to tolerate.

In this study, this is designed for patients with relapsed/refractory CLL combining umbralisib, a PI3 kinase inhibitor, plus ublituximab, which is a novel anti-CD20 monoclonal antibody, plus venetoclax. You have an initial phase of debulking with just what we call a U2 [umbralisib, ublituximab] combination for the first 3 months and then adding the venetoclax for 12 months, so the entire treatment is actually for 12 months. And then if at the end you have an MRD [minimal residual disease] undetectable state, then all treatment will be stopped. The first report was presented at ASH 2019, which showed very encouraging results. Most of the patients were able to actually achieve an MRD-negative state at the end of 12-month treatment and came off treatment. All of the patients had a response, so the overall response rate was 100%.

William Wierda, MD, PhD: And tolerability?

Shuo Ma, MD, PhD: Tolerability is actually fairly good. Most patients were able to tolerate it very well. There was only 1 patient who went off treatment because of the grade 3/4 diarrhea.

William Wierda, MD, PhD: Carolyn, have you had a lot of experience with PI3 kinase inhibitors and where they may be useful in our treatment algorithm?

Carolyn Owen, MD: I think that it’s exciting to hear of newer agents being introduced that have an improved toxicity profile because I think many of us had experience with idelalisib, the first-generation PI3 kinase inhibitor, which really had very significant toxicity in a lot of patients. The few patients who didn’t have toxicity problems actually had excellent responses, and I think unfortunately, we didn’t know how to use the drug properly. You could have a lot of treatment holidays, even in the patients with toxicities, and this was in the era before other agents were available. So, the patients would want to restart after their adverse effects resolved and they could restart, and they kept having good responses. You didn’t see a lot of resistance developing for stopping the agent.

I wonder if this is an agent that really does need to have time-limited therapy because continuing the drug is likely to be associated with just too much toxicity. But currently, without clinical trials, most centers still have access to either duvelisib or idelalisib plus rituximab and mostly using it as a bridge to transplant in those patients who failed a BTK inhibitor and venetoclax. Anthony Mato, MD, at this ASH 2019 presented some data from small subsets of patients treated in that way, and it looked not particularly promising with quite a short median duration of response. But you don’t need a long duration of response to bridge to transplant. I think that’s one of the few situations in which we’re using the agent currently.

Shuo Ma, MD, PhD: Carolyn brought up a very important point. When using idelalisib, in managing toxicities sometimes people are very hesitant to interrupt doses or reduce doses. We’ve done a very large retrospective analysis pooling several large clinical trials using idelalisib, and looking at patients who had dose interruption or dose reduction, comparing to those patients who did not. Interestingly, patients who did have dose reduction or interruption actually had better overall survival compared to those patients who did not. So that’s really a hint that if you’re able to manage patients’ toxicity appropriately according to the guidelines, then those patients can actually do pretty well.

Stephen Opat, MBBS: I guess we should mention the ASCEND study…which is a comparison of acalabrutinib with physician’s choice, and the physician’s choice was either idelalisib, rituximab or bendamustine, rituximab. And that study met its end point with progression-free survival, with acalabrutinib being better than the other arms. And so, I guess while idelalisib still has a place in certain patients, I think there’s now evidence that acalabrutinib is a better choice.

Carolyn Owen, MD: The only criticism of that trial though was that there was a crossover and because idelalisib has such a significant toxicity profile, if your patient had any adverse effect, you knew they would be allowed to cross over to the acalabrutinib. There was a clear incentive to not maximize the use of the idelalisib. We participated in the trial and I know that directly. And so, I think that it’s a bit unfortunate. I don’t think that idelalisib, rituximab, even if used really well, could have beaten the acalabrutinib, which is a very tolerable and effective therapy. But I do think the study outcome is influenced by that.

William Wierda, MD, PhD: You think the outcome is potentially skewed by the toxicity and the short duration of treatment for the comparator arm?

Carolyn Owen, MD: Well, the physician and patient likelihood of discontinuing therapy on the idelalisib arm because you were allowed to then cross over.

William Wierda, MD, PhD: It is notable that most of the patients on the comparator arm, on the standard arm, did get PI3 kinase inhibitor-based therapy. So for me, I view that trial somewhat as a targeted therapy versus targeted therapy comparison. But as you say, it is a positive trial and clearly shows a progression-free survival at least favoring BTK inhibitor-based therapy and the acalabrutinib.

Transcript Edited for Clarity