Susan M. O’Brien, MD: Going into 2022, you won’t see a lot of small molecule combination therapy because that is not approved. The GLOW trial [NCT03462719] should lead to the approval of the first combination small molecule that we would have, which would be ibrutinib [Imbruvica] and venetoclax [Venclexta]. Going into 2022, I don’t think treatment patterns initially are going to change that much. It’s a very interesting question as to when the ibrutinib and venetoclax combination does get approved, how difficult or easy is it to use in terms of the financial cost? It’s 2 expensive drugs, but also it allows for the possibility of finite therapy. I personally have not done the cost calculation for what might be more efficacious in the long run, but I’m going to take a guess that using 2 drugs upfront for 1 year is actually going to be cheaper in the long run.

The second question, and this is a scientific question not a practical question, is how much will people want to use those combinations upfront? What I mean is when I was enrolling patients on the CAPTIVATE trial [NCT02910583], quite a few of my patients said to me, ‘if you’re going to use ibrutinib and venetoclax together, then what are you going to do if my disease comes back?’ We know that the hypothesis is that if you use these combinations, and you use them for a fixed period of time and their remissions are very durable, that when the disease comes back, because you’re not driving a resistant clone by the constant pressure of the drug, that you would be able to use those agents again. Now, are there any data to support that? In fact, there are data. Most of it has come out of the MURANO trial [NCT02005471], which was the trial in relapsed CLL [chronic lymphocytic leukemia] of venetoclax and rituximab [Rituxan], a finite therapy after 2 years versus bendamustine and rituximab. We have gotten some good data on retreatment information from that trial that falls into 2 categories.

Number 1, and it’s emerging because, as we get longer follow-up on the trial and as patients relapse, we will get even more data. The numbers are not large right now, but they’re encouraging. In other words, in patients who’ve had venetoclax and rituximab and relapsed down the line off therapy, there are some limited data on retreatment with venetoclax, either alone or in combination with rituximab, showing high response rates. The other point is that in that trial, most of the patients had not had a BTK inhibitor. Although it was a relapse trial, they had mainly had chemotherapy or chemoimmunotherapy as their frontline treatment. What it also provided are data for going from venetoclax to ibrutinib or acalabrutinib. We didn’t really have those data before because ibrutinib was approved long ago, so most patients who went on the venetoclax trials in the United States had seen a BTK inhibitor. Since the MURANO trial was mostly done outside of the United States, they hadn’t. That’s providing data for what happens when you go from venetoclax to a BTK inhibitor. That data, again, are limited, but looks good. The important point I’m making is that there are some retreatment data for venetoclax suggesting that you can retreat. Right now, you can’t retreat with a first-generation BTK inhibitor because the patient’s on the drug when they develop resistance, but when we go to the combination of acalabrutinib and venetoclax, they’ll be off both drugs. Then the question becomes, will your outcomes be better using the combination upfront assuming that you can go back to those drugs, or are the results with the single agent so good that it won’t be better? In other words, if we have data from RESONATE-2 [NCT01722487] that ibrutinib still hasn’t produced a median PFS [progression-free survival] at 6.5 years in the frontline setting, and we have data from the MURANO trial that the median progression-free survival is 4 or 5 years in the relapse setting, are we actually going to do better with combinations in most patients who have a median age at diagnosis of 71? Don’t forget, we start with watch and wait. If I do a couple of years of watch and wait, if I give a BTK inhibitor up front and get 6 or 7 years out of that, you can see where I’m going with this.

The patient population that we’re most excited about the combination therapy [for] is our younger patients. Why would we be so excited in that group? Well, because what we really want is a cure. That’s what all of us involved in CLL research are looking for, and I don’t think that MRD [minimal residual disease] undetectability is sufficient, but I think it’s necessary. I don’t think that if we get MRD undetectability, we’re going to be curing anybody. It’s the first step. It would be really exciting if we actually had a cure fraction, and that’s why I’m saying it might be important for the younger generation. if I have a patient who’s in their 50s who developed CLL, those great data with 7 and 8 years of frontline therapy with ibrutinib is only going to take them to their 60s.

For your average patient who is [in] watch and wait and who gets diagnosed at 71, they may need therapy at 75, I’m going to go out on a limb and say I can keep that patient alive right now today until they die of something else, so maybe these upfront combinations won’t be so important for them. On the other hand, playing devil’s advocate, maybe they will be [important] because the adverse effects may be lessed. The BTK adverse effects [that] can occur, particularly hypertension which can occur late in the therapy, will probably be markedly reduced if we go to combination therapy. Even if it’s not a matter of keeping somebody alive longer because I can keep them alive a long time right now, it might still be a preferable way to go in terms of the combinations to minimize the adverse effects by having a finite duration of therapy.