Current and Future Selection of First-Line Therapy for Chronic Lymphocytic Leukemia (CLL) — Jeff Sharman, MD

DR SHARMAN: It’s a pleasure to be with you here today. I have quite a bit to talk about here and will try to get it all done in the right timeframe. So I’ve broken this up into kind of BTK strategies and then BCL2 strategies. And the BTK, we’ll be talking primarily about the front-line setting with novel updates in BTK studies for both ibrutinib, acalabrutinib, and zanubrutinib, a little bit in the relapsed/refractory setting with the BTK head-to-head, and then we’ll pivot and talk about some of the updates in the BCL2 space as well.

So starting with ibrutinib, we had at ASH 2021 at update of the ALLIANCE study. This was a pivotal study initially presented in 2018 with shorter follow up. Now this is a near 5-year follow up of the same study. 3-arm study for your typical CLL patients, age 65 and above, randomized in a 3-arm study 1:1:1 with bendamustine/rituximab versus ibrutinib monotherapy versus ibrutinib in combination with rituximab.

In 2018 we had the initial presentation of the data with a Kaplan-Meier curve that looked somewhat similar to this, although this is now just shy of 5 years follow up. And I think that the key findings here are that both ibrutinib, or BTK-containing arms, clearly outperformed what was the most commonly utilized chemoimmunotherapy based approach, at the time bendamustine/rituximab.

What we didn’t know when this study initially launched was whether or not rituximab added to ibrutinib, and I think the conclusion from this study is that it does not. And so the hazard ratio for both BTK arms versus the bendamustine/rituximab was 0.36 with very similar p-values. So I don’t add anti-CD20 therapy to ibrutinib unless there is an autoimmune hemolytic anemia or ITP at the same time, where you’re using the rituximab to get control of that.

We also at ASH of 2021 had the first report of the UK FLAIR study. Now this was ibrutinib/rituximab versus FCR, and we had a very similar study performed by the ECOG group also reported in 2018. So this study follows along a couple years after, and this was because of the size of the study accrual and follow up and so forth. But this UK study had some subtle differences. It included patients up to age 75, whereas the ECOG study had only included patients up to age 70. And this was FCR versus ibrutinib/rituximab, again launched at a time where we didn’t know the relative contribution of rituximab to the regimen.

What we see here, again, is that the ibrutinib-containing arm handily beat the FCR regimen from a progression-free survival standpoint. And you see the curves separate early and continue to widen over time. And so this is nice confirmation that from progression-free survival standpoint BTK therapies can beat even our most potent chemoimmunotherapy regimens.

Now in contrast to the ECOG study we did not see an improvement in overall survival. So in this study those overlap, and I think the reasons for the differences are not really know. This was a slightly different population, a little bit older, where some of the BTK toxicities begin to emerge a little bit more. Also the FCR in slightly older patients, there’s higher toxicity as well. So unclear if that contributed to the difference between the 2 studies, but a clear improvement in progression-free survival for sure.

So switching to acalabrutinib in the front-line setting, 2 studies we wanted to review. One of them deals with a new formulation of acalabrutinib. Now this particular presentation was a poster presentation, and there were not a whole lot of visuals to accompany it, so forgive me for picking this one. But the summary of this that acalabrutinib has been available only in the context of a capsule, and that capsuled absorption of acalabrutinib is very dependent upon gastric pH. And so when patients are on proton pump inhibitors, which is very common in the US, they have considerable reduction of acalabrutinib absorption.

The novel formulation is actually a maleate salt, and that overcomes the proton pump inhibitor effect. And so we will see actually a change in the way that acalabrutinib is distributed in the coming months, where they’re going to be switching from capsule formulation to a tablet formulation, and that tablet formulation should overcome the proton pump inhibition effect. So the figure here, you can stare at in a bunch of different ways, and it doesn’t necessarily tell you the punchline, but that’s what you need to know, that the pills will be changing.

Now we also — our group had the opportunity to present an update of the ELEVATE-TN study, which stands for treatment naïve. We had initially presented this a number of years ago, but this is an update now with median 4 years of follow up. This is the study that led to the approval of acalabrutinib in the front-line setting, and it was a 3-arm study randomized 1:1:1 of acalabrutinib/obinutuzumab versus acalabrutinib monotherapy versus obinutuzumab/chlorambucil. This was for patients aged 65 and above or patients 65 or less with medical comorbidities, and the primary endpoint to this study was progression-free survival.

The results are shown here, and in contrast to the story of rituximab added to ibrutinib, really the findings of this study that merit discussion — it’s really no surprise that the acalabrutinib arms beat the chlorambucil arms. I think that’s expected by everyone. But I think what’s emerging is a narrative where the addition of obinutuzumab adds to the efficacy of acalabrutinib. We actually have a progression-free survival of 87% versus 78%, and that hazard ratio is 0.56, with a statistically significant p-value.

Interestingly, when we look at the overall survival, you see a very subtle difference between these, and that’s what we expect to see in front-line BTK studies. But the difference, there are numerically fewer deaths for the patients who receive the combination of acalabrutinib/obinutuzumab, and interestingly that hazard ratio is also 0.5 with a p-value of 0.06. So not many of the other BTK studies have shown potential survival advantages, but in this study, interestingly, that’s the same hazard ratio for the doublet versus the acalabrutinib monotherapy. So I think this will be something to watch moving forward, whether or not a survival difference emerges.

So switching to the third BTK agent that’s commercially available, zanubrutinib. The SEQUOIA study has released multiple different data sets. And this is kind of a complicated study because there are 3 cohorts and 4 arms, and I’ll kind of address each of them in turn.

The first is a randomized Phase III study, Cohort 1, of zanubrutinib monotherapy versus bendamustine and rituximab. Now intellectually I don’t know if this is the most compelling result because we know from the ALLIANCE study that ibrutinib beat bendamustine/rituximab. However, the clinical significance of this is that it should lead to the FDA approval of zanubrutinib in CLL. It is not yet approved in CLL. It’s approved in mantle cell lymphoma and marginal zone lymphoma, but this should presumably lead to the approval in CLL.

And the results here look quite similar to what we saw in the ALLIANCE study, although the follow up isn’t quite as long. The hazard ratios are quite similar. Hazard ratio here is 0.42.

This study excluded patients with 17p, which was 1 subtle difference between this study and the ALLIANCE study. But overall we see that, again, a BTK strategy beats bendamustine/rituximab. And there are very few reasons anymore for a patient to be treated with traditional chemoimmunotherapy. I think this re-emphasizes that point. And that’s what we see in patterns of care data, is that even in the US traditional chemoimmunotherapy is pretty infrequently used anymore in the front-line setting.

The next cohort in the same study for those patients who had 17p. Now we’ve gained a fair bit of data in 17p with BTK inhibitors. However, this is probably the largest data set for the prospective front-line use of a BTK inhibitor amongst those patients with 17p. Recall from the chemoimmunotherapy era that these patients really did terribly with traditional FCR or bendamustine/rituximab, with overall survivals that were quite short. And what we see here is a progression-free survival for zanubrutinib in this population that looks unlike anything we had seen for the chemoimmunotherapy group. This is a very effective strategy for this high-risk population. And similarly we see an overall survival that’s very impressive for this group as well.

Admittedly, this isn’t the longest follow up for these groups. However, in the CLL8 study, the CLL10 study, those patients with 17p, they really dropped quite quickly from a progression-free survival standpoint, and this is really quite different.

Now this study was mostly conducted overseas, and they found quite a few more 17p patients than they originally anticipated. I think the demand for the drug was quite high. So they actually added a third cohort to the study that wasn’t originally planned, and this included the combination therapy of zanubrutinib with venetoclax. So we’re seeing more and more data sets of doublet therapy, and we’ll talk about some of these as we go along here today.

It's anticipated that this group will enroll about 80 patients. It’s not fully enrolled. It’s still ongoing. But here, again, you see a progression-free survival and overall survival that really looks quite spectacular for this high-risk group.

I think that once available this will be a very appealing strategy for this group of patients, and really many of the questions will be duration of therapy, and those will be the questions in the future. But this approach looks to have a very high level of efficacy in this high-risk population.

So some of the most important studies to come out this year were head-to-head studies of BTK agents. So ibrutinib was the first-generation BTK inhibitor out there. Now we have acalabrutinib, zanubrutinib. How do you differentiate between them? That’s not always clear to individuals.

And so this study, the ELEVATE-RR study, was launched and was reported by John Seymour at EHA and then subsequently published by John Byrd. This was a randomized Phase III study. This is in the relapsed setting, so relapsed/refractory patients, and in particular they focused on patients that were high risk. So these patients had to have either 17p or deletion 11q to enroll. They were randomized 1:1 to receive acalabrutinib or ibrutinib. No anti-CD20 therapy was selected.

The key differences here in this study are highlighted in red, which is the differential toxicity profile. You see lower rates of atrial fibrillation and flutter, lower rates of hypertension, lower rates of bleeding events when you’re looking at the all-grade. When you look at Grade 3 the numbers aren’t too dissimilar from one another, but if you look at the all-grade, that’s where you see the largest difference.

Acalabrutinib does have headache, which is a unique feature and not present so much with ibrutinib. So you see higher rates with acalabrutinib, and surprisingly slightly higher rates of cough. I don’t totally know what to make of that finding.

But the other place where you see differences are the arthralgias and back pain, muscle spasms and so forth. Those rarely reach Grade 3 toxicity, but they are annoyances to patients.

Patients did stay on acalabrutinib a little bit longer, so they also presented exposure-adjusted incidence, and that really, I think, is a story that’s consistent with what we see in the highlighted areas on the left, where you do see reduced side effects with the second-generation BTK inhibitor.

They also showed the progression-free survival and event-free survival. I think the way this study was designed and executed you really don’t see huge differences. This was a noninferiority study. You might see subtle differences in favor of acalabrutinib. You do see a crossing of the curves slightly, but I think the punchline is that the progression-free survival and the event-free survival are not materially different between the 2, although the toxicity profile is some degree of differentiation. But I think that this should give us confidence that we’re not sacrificing any degree of efficacy with acalabrutinib versus ibrutinib.

Now, another head-to-head study was ibrutinib versus zanubrutinib. And there are a couple of key differences between this and the ELEVATE-RR study. This required simply patients with 1 prior line of therapy or more. There was no requirement for patients to have high risk, so there was no 17p or 11q requirement. There still was an abundance of those patients, but that was not required for participation in this study.

The other key difference, and I think it’s interesting and maybe worthy of discussion, is that the primary endpoint was overall response rate, which might actually just favor the BTK that gets the faster response. We’ve known that ibrutinib has this lymphocytosis that persists, and that’s true of acalabrutinib and zanubrutinib, but there does appear to be some differences in the rate at which that lymphocytosis resolves.

So the primary endpoint here was overall response rate, and that did favor zanubrutinib versus ibrutinib, and that was statistically significant. I guess a reasonable question is, is it clinically significant. You can of course say something’s statistically significant, but it’d be interesting to see disease control rates. You can actually see that a lot of the difference in the overall response rate was on account of the partial response with lymphocytosis, and that group was not included in the primary endpoint. And so there’s been some criticism as to whether or not that primary endpoint is the most meaningful, but I think that that had to do with their discussions with the FDA that it was chosen to be that way.

From an efficacy perspective, they reported the investigator-assessed progression-free survival, and here that favored zanubrutinib over ibrutinib. I again have some concerns that this is an investigator assessment on an unblinded study, and so that’s not a centrally-confirmed PFS benefit, so consider that with that in mind. But again, I think that you can see, in general, the second-generation BTK inhibitors do have at least equal efficacy in many regards, and possibly some advantages.

So I’ll pivot from there into BCL2-based strategies. Now some of this overlaps with BTK, as well, but I would start by the CLL14 update. CLL14 was a clinical trial that led to the approval of obinutuzumab/venetoclax in front-line CLL. It randomly assigned 1:1 obinutuzumab/venetoclax versus obinutuzumab/chlorambucil. This was designed in your typical CLL patients. They had to be aged, I believe it was 65 and above, or less than that with comorbidities. And we did see results of this earlier, but now we have some updates and some interesting, provocative findings that come out of this study as well.

From a progression-free survival standpoint you can see that the venetoclax strategy has advantages over chlorambucil, and that’s true in both the mutated and unmutated, and so not really any huge surprises, although further follow up. And I think what you can look from this, and from what I oftentimes quote patients, is that roughly 75% of patients treated with obinutuzumab/chlorambucil will remain free from progression around the 4-year mark, and I think that’s a good benchmark from which you can present that to your patients.

Some of the update that was available this year looked at rates of minimal residual disease, and not surprisingly that favored the venetoclax.

The part, however, that I think is a real unique finding and one that I’m very intrigued by, is they did serial MRD, and that can give you a quantitative assessment of the clone size. And what they were able to show was that the rate of regrowth was different if you were treated with obinutuzumab/chlorambucil versus obinutuzumab/venetoclax. And the rate of regrowth favored, or was slower if you will, for those patients who received venetoclax rather than chlorambucil. And the way I’ve interpreted that, and a number of people have interpreted that, is that chlorambucil to some degree does have a destabilizing impact on the clone, and it gives it a growth advantage when it recurs, whereas the patients who received venetoclax didn’t have that same effect. And this was highly statistically significant. In fact, they’ve now been able to recreate this analysis in the CLL13 study, which we’re going to look at here shortly.

But I think it highlights the fact that when we treat patients with cytotoxic therapy we are inducing DNA mutations and potentially conferring growth advantages to those patients. So an interesting finding that we’ll be curious to see if that holds up in future studies as well.

Now in my mind one of the most important studies is the initial report of the CLL13 study. So we’re already talking about updates of the CLL14 study. This is now the first reports of the CLL13 study. These were launched roughly contemporaneously, but this was in a younger, more fit population and compared 4 different strategies. And I’m always in awe of how the German Study Group is able to execute these enormous studies. This was a 920-patient study, 4 arms, randomly assigning patients to either a chemoimmunotherapy-based strategy, and that was investigator’s choice of FCR or BR, versus rituximab/venetoclax versus obinutuzumab/venetoclax versus triplet therapy of obinutuzumab/venetoclax in combination with a BTK agent, ibrutinib in this case.

So equally randomized between the 4 arms. This was for a young, fit population, and that’s why it probably took longer to get these results. And there were coprimary endpoints on this study of MRD at 15 months and progression-free survival. Now due to the event rate what they’ve reported so far is the MRD. We don’t anticipate having the PFS until a little bit later this year, hopefully pretty early. But what they’re able to report right now is the MRD, and there’s some interesting findings in this.

It's as follows. Rituximab/venetoclax offers a small statistically insignificant benefit for MRD relative to either FCR or BR. So rituximab/venetoclax in the front-line setting, relatively small benefit vis a vis chemoimmunotherapy. However, when you change the anti-CD20 antibody to obinutuzumab/venetoclax that MRD rate is considerably different when compared to chemoimmunotherapy, with a rate of 86% versus 52%.

Similarly, when you compare triplet therapy, triplet novel agents, obinutuzumab, venetoclax and ibrutinib to chemoimmunotherapy, similarly you see improvements in MRD acquisition, 92% versus 52%. That’s statistically significant. The statistical comparison not made, but I think that’s interesting, is whether or not adding ibrutinib to doublet therapy of obinutuzumab/venetoclax adds much. You can see 86% versus 92%. Yes, there’s a numerically slightly higher rate of MRD acquisition, but I think that the interesting thing will be whether or not we can see any PFS difference that emerges from that.

Because what does emerge from that, when you look at Grade 3 and above toxicity, focusing primarily on the right 2 columns of obinutuzumab/venetoclax versus triplet therapy, you do see higher rates of febrile neutropenia, considerably higher rates of infection, and relatively similar rates of tumor lysis syndrome. So you get a modest improvement with triplet therapy. However, that improvement in outcome is associated with some increased toxicity as well. And so I think the progression-free survival analysis will be really important to see to interpret these data. All we have right now is the MRD data on that.

DR LOVE: How does the MRD rate of venetoclax/obinutuzumab, I think 86% or something, how does that compare to CLL14?

DR SHARMAN: So the MRD rates here compared to CLL14, these were actually somewhat higher.

DR LOVE: Yeah.

DR SHARMAN: And the experience has been in a younger, more fit population you might be able to obtain higher dose intensity or dose adherence, less neutropenia and so forth in a younger population. In our trial of — we did a debulking study of obinutuzumab/venetoclax. It was similarly in a younger population, and we had rates of MRD that were quite comparable to this. So I think this is done by flow cytometry in this report, and we’ll see once we can look at it at the next-gen sequencing level whether or not that holds true. But this is higher than what we saw in the CLL14 study.

DR LOVE: Because I’ve always kind of wondered about the BTK/venetoclax combinations in terms of MRD because it’s been pretty high for just venetoclax/obinutuzumab, here it’s even higher, whether or not you really can meaningfully bump it up. Although in a way 92 versus 86 could be considered pretty significant.

DR SHARMAN: Yeah.

DR LOVE: Even though the absolute number, like the relative risk, is actually pretty high when you look at it. But still, I just kind of — I mean of course everybody wants to know whether or not it’s better to combine or do it sequentially.

DR SHARMAN: Right.

DR LOVE: And I know you’re going to talk about that — talk about that more, but generally speaking, how would you say these new data of the triplet compare to other trials of ven plus BTK?

DR SHARMAN: Right. So I think one of the really important things is to be sensitive to the age differences in patients, and I think we’ll see that as I get into some of the GLOW data, that the age makes a huge difference in these studies.

In terms of doublet versus triplet, we’re just now seeing really some of the first randomized data to evaluate that. I think that for my own practice, recognizing that in the near term we’re going to have access to ibrutinib/venetoclax and obinutuzumab/venetoclax, I’ll be reserving my treatment choices to doublet therapy versus triplet. I probably will not be moving to the triplet until there’s a more compelling reason to do so.

DR LOVE: Yeah. I mean if it went from like 50% to 85% that’d be different.

DR SHARMAN: Right.

So this was presented at European Hematology Association. It was the first presentation of ibrutinib/venetoclax in a pivotal design setting. And this was a population similar to what we had seen with obinutuzumab/venetoclax registration data, age 65 and above or less than age 65 with comorbidities. So this was kind of your typical CLL population. And obinutuzumab/chlorambucil was the standard whipping, beat up — the control arm. I think we’re going to see very few studies with that as a control arm anymore. But again, so novel/novel versus obinutuzumab/chlorambucil.

And here’s the results. And you have a good PFS advantage for ibrutinib/venetoclax over obinutuzumab/chlorambucil, largely what you would expect. Of course there’s all sorts of problems with cross-trial comparison. However, I would point out that we already said from the CLL14, that general landmark, that about 75% to 80% of patients with obinutuzumab/venetoclax are going to be progression-free at about 4 years. That’s not too dissimilar from what we’re seeing here at 2 1/2 years with the combination of ibrutinib/venetoclax.

Similarly, with ibrutinib monotherapy it’s relatively similar outcomes. And so I guess the question would be in this population whether or not this combination offers advantages over either sequential therapy or obinutuzumab/venetoclax. Interestingly, if you look at Grade 3 or higher AEs of ibrutinib/venetoclax, Grade 3, right? Look at the rates of diarrhea of the combination, 10.4%. That’s quite high. Recall that the pivotal studies of idelalisib had Grade 3 diarrhea of 14%, and people were quite critical of that agent due to the rates of diarrhea. This is Grade 3 of 10%. Similarly, neutropenia of 34%, infections of 17%. Pretty high numbers.

If you contrast that to the CAPTIVATE study, data I don’t have here in this presentation, but CAPTIVATE was ibrutinib/venetoclax in a younger population, and that was led by the MD Anderson group, and we’ve seen updates of that this year. We see lower rates of toxicity of ibrutinib/venetoclax in that study and frankly better outcomes in that younger population as well.

So this particular study will lead to the approval, likely, I anticipate, of ibrutinib/venetoclax. Whether or not 65 and above is the right group to use it in or not I think is a different question. I probably would reserve it for younger patients where the toxicity profile tends to be more favorable with ibrutinib.

DR LOVE: I don’t know that I hear a lot about diarrhea with either venetoclax or BTK. Is that a common toxicity, or is this some kind of like synergy causing a toxicity? The diarrhea.

DR SHARMAN: You have low rates with both drugs, but I think when you put them together you do see rates of diarrhea that exceeded what we would have anticipated from either agent alone. And we’ve talked about MRD. That was updated recently here. And in the peripheral blood, here you have MRD rates of 54.7% in the peripheral blood and 51% in the marrow, so there’s nice concordance between the peripheral blood and the marrow.

It is difficult to compare rates of MRD across studies without taking into account is it done by flow or is it done by PCR. What’s the rate of dropout? Is it done only in CR rate versus those — all comers and so forth? So you have to be a little bit careful about cross-study comparisons. But this — I would say there’s obviously a nice improvement between ibrutinib/venetoclax and obinutuzumab/chlorambucil, but again I would question what’s the optimal partner to venetoclax? Is it a BTK or is it an anti-CD20? That will be the subject of the upcoming MAJIC study, which is an acalabrutinib study in which venetoclax is partnered with either acalabrutinib or obinutuzumab. So we’ll be able to evaluate that directly.

Finally, the last data set I have for you is, again, we’re seeing doublets. We’re seeing data on triplets. This study was led by Matt Davids of what’s called the AVO regimen, or acalabrutinib, venetoclax, and obinutuzumab. Primary endpoint of this study was MRD negativity. This is a relatively small study, still early with follow up, PFS not yet mature. And what we see here are rates of MRD. This is actually different timepoints.

High rates of MRD negativity with the combination.

So we will be seeing data of acalabrutinib/venetoclax in a pivotal study design, as well as AVO in an upcoming — what’s called the 311 study. So hopefully we’ll be seeing that this upcoming year.

So conclusions. BTK is an effective front-line strategy versus chemoimmunotherapy. Second-generation BTK inhibitors do offer a distinct safety profile, and we see that in head-to-head studies. We can see that zanubrutinib is effective in front-line 17p as either monotherapy or combination, and I think the BTK approach is particularly strong in the 17p population.

Venetoclax is really emerging to allow fixed-duration therapy, and fixed duration is very appealing to many patients. And it appears that it partners with obinutuzumab probably better than rituximab, and I think that’s felt in the field that obinutuzumab’s probably a better anti-CD20 amongst patients with CLL.

I alluded to the MAJIC study, which is to clarify if BTK or anti-CD20 partners better with venetoclax. So we’ll be getting information there. We’re really beginning to see doublet versus triplet data emerging, and that will be a theme that develops over the next — next 12 to 24 months.

DR LOVE: First, in the FLAIR study. You might have said this, but I didn’t see the data there. Did they break it down based on IGVH status?

DR SHARMAN: They did. They did. And I think that the findings were similar to what we’ve seen before, that the IGHV unmutated do less well with chemoimmunotherapy. The — one of the questions in a lot of ways is there’s still this lingering group. So the favorable — favorable group of young individuals, chemoimmunotherapy eligible, favorable IGHV, favorable FISH, are those patients suitable for FCR? I have to say I’m impressed by the data that we see from the CLL13 study with deeper rates of MRD with obinutuzumab/venetoclax. Partner that with the impact of slower regrowth kinetics that we’re starting to see, I am more and more, in that younger, fit population, even with favorable genetics, thinking that those patients are really good for a fixed-duration obinutuzumab/venetoclax. However, in that particular setting, if somebody still wished to use FCR, I think there’s an argument that can be made for those patients.

DR LOVE: So can you talk a little bit more about this thing that you were mentioning, the regrowth, and whether or not if you think about it — I mean do you think that would apply to chemotherapy in general? Chemotherapy with solid tumors, et cetera? And has this been discussed before? Just because I’ve never heard of it doesn’t mean anything. But has it been seen before?

DR SHARMAN: I think this is an area of emerging thought, right? And it’s still quite early, and I think that I’m keeping an open mind about this and haven’t necessarily come to firm conclusions. However, I think when you look at old studies, and reaching into the GBM literature, right? So if you looked at DNA mutations in glioblastomas pre and post temozolomide you saw that there was quite a few more mutations present in the previously-treated patients. And I don’t think it should be terribly farfetched to think that you could confer a growth advantage by introducing novel mutations into the DNA.

Cyclophosphamide is an alkylating agent. Chlorambucil, alkylating agent. Fludarabine. These are drugs that have DNA destabilizing impact and select, in many ways, for — we know that we select for adverse clones, such as 17p, 11q. With the traditional chemoimmunotherapies seeing clonal evolution is frequent.

It stands to reason that venetoclax will probably select some form of resistance, but it may be that those are less — have less of a growth advantage then we’re seeing with the traditional DNA-mutating agents. I don’t know that that’s going to prove to be true, but I think it’s provocative, and it does influence my thinking.

DR LOVE: Well, just to take it one step further, if it is true, I mean it kind of makes sense, but if it is true do you think it’s possible that in many situations, or any situations, chemo is actually causing harm? So for example, if you give a later-line chemotherapy, and maybe I’m thinking more about more likely in a solid tumor, but in any event, where you have 20% response rate, almost no PFS, whatever. Do you think in the long run you could actually be decreasing a patient’s survival by treating?

DR SHARMAN: I think that if we go back — and again, I’m going to stay in CLL to answer your question. But really one of the very early studies was watch and wait versus chlorambucil, and who did better. In some cases it was watch and wait patients, going way, way back in the literature.

DR LOVE: That’s interesting.

DR SHARMAN: I think that — I think there is risk, right, that traditional cytotoxic chemotherapy — look, if we’re giving adverse events and we’re not improving progression-free survival, in theory we can be harming patients by overtreating them in terminal situations. So that’s a conversation I frequently have with my solid tumor patients that I still treat, is how far do we go with this, and looking for both quality and quality of life. If we’re giving side effects without benefit there is a risk of harm, right?

DR LOVE: Yeah. I mean I realize this is really just very, very theoretical at this point, but this is not just a side effect. This is kind of like something more about effecting the underlying biology.

DR SHARMAN: Yeah. Right.

DR LOVE: Well anyhow, I’m going to kind of keep my eye on that as things go along.

You also mentioned, I was going to ask you about this anyhow because I saw it in your CV, the paper you all presented on debulking with venetoclax. And again, I was surprised. I never heard of BR debulking. That’s what you were looking at?

DR SHARMAN: Yeah. Well, you shrug, and I think a lot of other people shrug now about it too.

DR LOVE: No. I thought it was cool.

DR SHARMAN: Yeah.

DR LOVE: Oh, really?

DR SHARMAN: We used bendamustine/obinutuzumab in that study, but I think that one of the concerns that practitioners have with venetoclax is tumor lysis, right? I mean that’s one of the barriers to more broad utilization. And we know that tumor lysis, to some degree, has a risk that is based upon how much disease somebody has, right? So somebody who has more lymph nodes, more lymphocytosis, is at higher risk of tumor lysis than someone without those features. And so it stands to reason that by eliminating bulk of disease before starting venetoclax you could reduce the risk of tumor lysis.

And so in that particular study we gave investigators freedom to choose obinutuzumab alone or the combination of obinutuzumab/bendamustine. In truth, I think if I could redesign the study now I would probably either do obinutuzumab or a BTK strategy, and I don’t know how much bendamustine/obinutuzumab is going to be relevant. However, in that particular study I think what could be concluded is that 2 months of obinutuzumab is great at eradicating lymphocytosis. It doesn’t do a whole lot to eradicate bulky lymph nodes. And so as you approach a patient, one that has bulkier lymph nodes may be better served by debulking with a BTK, and those that are perhaps more leukemic or marrow and blood might do well with an anti-CD20-based debulking approach.

DR LOVE: Yeah. That would be a great study to take a look at. I actually had somebody, I can’t remember who it was, not too long ago say something again I’ve never heard, which is that they are much more concerned about lymphadenopathy as it relates to TLS than white count. Now I don’t know if that relates to the fact it’s easier to get the white count down with obinutuzumab, but is there some reason to think that adenopathy is more relevant in terms of TLS?

DR SHARMAN: I haven’t heard the same concern articulated, and my suspicion would be that obinutuzumab is so effective at getting rid of the lymphocytes and not so good at clearing out lymph nodes. I don’t — I don’t have in my own mind clarity on the balance of bulk, right? So how many malignant lymphocytes are in the blood, how many malignant lymphocytes are in the lymph nodes. And you can imagine volumetrically I don’t know which compartment, in essence, holds more potential for TLS.

DR LOVE: When you use a BTK to debulk someone, how does the bump in white count that you see fit in? Does that usually come down before you give the venetoclax?

DR SHARMAN: So this actually has been looked at now in a couple studies, and in particular, say, the CAPTIVATE study, which gave a 3-month run in of ibrutinib before starting venetoclax. If you look at the number of patients who are high risk when they started ibrutinib, that number goes down considerably by the time you hit the 3-month mark. Now to your point, the lymphocytosis is variable. It tends to go up and has started falling to a significant degree by the time 3 months are up. But you’ll still have quite a bit of lymphocytosis at 3 months.

So in essence you’re improving those patients with more lymph nodes when you pretreat with a BTK agent, and you’re getting in the aggregate probably some reduction of lymphocytosis. But to your point, there is a rise followed by a fall that we expect with BTK agents. So there is debulking, but it’s more node based than blood counts when you’re using a BTK.

DR LOVE: I have heard cases of people with very prolonged white counts. What do you do if you start out? Let’s say they start out low risk, they get the BTK, they get a bump in their white count, and it’s still up when you’re ready to give the venetoclax, and it would have bumped them up. Do you treat them like the new one or the old one?

DR SHARMAN: Right. So could you actually increase risk group, if you will, understood. The patients — in my own experience the patients who get more lymphocytosis are the patients who have more lymph nodes to begin with. Somebody who’s gotten bulky lymph nodes, it’s been my experience that they tend to get more of a lymphocytosis than just the patients who have lymphocytosis to begin with. The cells have got to come from somewhere, and in my mind they’re coming out of the lymph nodes and spleen and marrow.

So I haven’t encountered that to occur all that often, where you’re increasing the risk group. I mean I can understand theoretically why it might happen, but practically speaking it doesn’t happen so much. And I think we try to quantify based on lymph node size and lymphocytosis who’s medium risk, high risk, and so forth. But I think — I think these are — we’re trying to make black and white boxes out of something that’s a continuous variable. And you always have the option to admit somebody to the hospital. And so my answer to your question may differ in a 47-year-old fit, easy to follow instructions than it would for an 82-year-old who doesn’t drive and has some kidney disease. So I’m going to admit the latter to the hospital, where I might not in the former case. So I still think you have to take it on a per patient basis.

Management of Relapsed/Refractory CLL; Novel Investigational Strategies — Lindsey Roeker, MD

DR ROEKER: Today I’m going to be highlighting the Year in Review in CLL, and we’re going to specifically focus on relapsed/refractory CLL, looking at 10 papers and abstracts that really have shaped this last year.

So the first one that we’ll highlight is acalabrutinib versus rituximab plus idelalisib or bendamustine in relapsed/refractory CLL. And these are the 3-year follow up data from the ASCEND trial. This was just presented at ASH in 2021. And as an overview, this is just a reminder of what the study design is. So the study population was people who had had at least 2 prior systemic therapy for CLL, but no prior exposure to either a BCL2 inhibitor or a B-cell receptor inhibitor. So these are novel agent naïve patients.

And 310 patients were enrolled and randomized to acalabrutinib versus idela/R or bendamustine/rituximab. That was investigator’s choice. And the primary endpoint of this study was progression-free survival. The groups were pretty well matched in terms of age and Rai stage and all of the baseline characteristics you would expect. And here’s a look at kind of the characteristics. So 18% of those had — treated with acalabrutinib had deletion of 17p; 32% had a complex karyotype. And again, this is a chemoimmunotherapy-exposed population.

Here’s a look at the outcomes. So this is looking at a median time on study of — median follow up of 3 years, and the median time on study for those treated with acalabrutinib was 36 months. For those on idela/R it was 35.2 months, so nearly similar. And the overall response rate was relatively similar, so 83% for those with acalabrutinib; 85% for those in the investigator’s choice arm.

The really notable difference is the progression-free survival, which you can see in the curve on the top left. So the PFS benefit was observed for the overall population. But then there were also prespecified subgroups that were examined, so those with deletion 17p, those with poorer performance status, stratified by lines of therapy, age, sex, Rai stage, wither or not a patient had bulky disease, complex karyotype, a TP53 mutation, or what their IGHV mutational status was. And across all of those groups the PFS benefit for acalabrutinib is maintained.

The 36-month overall survival is estimated to be 80% for those with acalabrutinib. It’s not a significant difference, but notably crossover was allowed here.

So these data really suggest that acalabrutinib is a great option in the relapsed/refractory setting for patients with prior chemoimmunotherapy exposure and is certainly superior to either chemoimmunotherapy or idelalisib and rituximab.

In terms of the implications for what this is going to do for future research, I think the question that still remains is whether BTKi monotherapy is really the best first novel agent. We also know that there are venetoclax data as the first novel agent. And then the next question is should we be moving toward novel/novel combinations. Does a BTKi need to be with CD20? I think these are all really the unanswered questions that this trial didn’t address but are probably the next steps.

And then the last piece is what is the appropriate control arm for relapsed/refractory CLL studies because we’ve now had several studies where the investigational arm has beaten bendamustine/rituximab or idelalisib/rituximab. And I think this is really a pertinent question.

The next study that I want to highlight is a Phase II study of acalabrutinib in patients with ibrutinib intolerance. So this was looking at patients who had a protocol-defined intolerance event from ibrutinib and had come off therapy but required therapy per iwCLL criteria. And for this patient population the median prior lines of therapy was 2; range was 1 to 10. As you can see, progression-free survival median is not reached, and the 36-month PFS rate is about 58% in this population, with a median follow up of about 35 months.

Half of the patients remain on acalabrutinib with that follow up, and of those who discontinued, about half were because of progression. Only 17% of patients had to discontinue for an adverse event.

So the takeaway here is that acalabrutinib is active in patients who have had ibrutinib and been intolerant, and it also seems to be relatively well tolerated.

There was a further look at basically what toxicity there had been prior with ibrutinib and what was coming up with acalabrutinib now.

So here’s a look at some AEs of special interest, so atrial fibrillation, diarrhea, rash, bleeding, arthralgias. You can see that 41 patients here had prior ibrutinib intolerance, and the proportion of patients who had a recurrence of that toxicity was relatively low, and for most patients it was lower grade. So of these events we see that it’s relatively well tolerated, which is great news for our patients.

So in conclusion, these — for patients with ibrutinib intolerance, acalabrutinib is a data-driven choice, and in terms of implications for future research, I think it’s going to be interesting to see what extended follow up looked like in this patient population. We also know that there are ongoing studies of zanubrutinib in the same population, umbralisib in the same population. So I think this is really highlighting that if you have a patient with an intolerance event other agents are options.

The next study is an update on the Phase III MURANO trial. So as a reminder, MURANO is looking at venetoclax/rituximab versus bendamustine/rituximab in patients with relapsed/refractory CLL. So that ven/R combination is given as a 2-years fixed duration, and patients were stratified by their deletion 17p status and their responsiveness to prior therapy. The primary endpoint was PFS.

And here are the 5-year follow up data. So here’s a median follow up of 59 months, and you can see that the median progression-free survival is about 54 months for the ven/R treated population, and the 5-year overall survival is 82%. So with the 5-year update we see that there haven’t been a lot of new safety signals, and there does seem to be some durability of these responses after patients finish that 2 years fixed duration of venetoclax/rituximab. We get a better sense of how this regimen is working over time.

The next thing that was interesting that was presented is that MRD status at the end of treatment really does impact how patients do. So here you can see on the left-hand pie chart what the MRD status was at the end of therapy for the 130 patients that received venetoclax/rituximab. So 83 of those 130 had undetectable MRD at a level of 10^-4.

And if you look at the PFS curve on the bottom left you see PFS post end of treatment, and that’s stratified by what patients’ MRD status was. So those with undetectable MRD are in green. Those with low MRD are in yellow, and those with high MRD are in red. So as you can see, the MRD status at the end of therapy really does impact how patients do after we stop therapy.

So we now know the median progression-free survival after 2 years of ven is about — ven with rituximab is about 54 months, and undetectable MRD status at the end of treatment is really associated with improved outcomes after stopping fixed-duration venetoclax/rituximab.

I think in terms of what this does for future research, I think we need to question whether fixed-duration therapy is really the appropriate approach or whether we should be working toward a biological endpoint. We’ll talk a little bit more about MRD and how we should incorporate that into our decision-making in a couple of abstracts, but I think what — that is a question that’s really still open.

And then the second question is, is rituximab the best partner for venetoclax in the relapsed/refractory setting. We know that CLL14, which has been used in the front-line setting, combines venetoclax with obinutuzumab, and the question of whether that is the best regimen or whether venetoclax with rituximab is the best regimen in the relapsed/refractory setting remains to be seen.

The next abstract that I highlight is this Phase II VISION HO141 trial. And this is looking at time-limited venetoclax and ibrutinib, so IV, for patients with relapsed CLL who have undetectable MRD. And this is really an MRD-guided stop-and-start trial that was just presented at ASH, and the trial design is patients start with ibrutinib, then do a ven ramp up and continue therapy for a total of 15 months. If they have detectable MRD at the end of study, they stay on ibrutinib monotherapy. If they have undetectable MRD with a sensitivity of 10^-4, then they’re randomized in a 1:2 ratio to ibrutinib until they have progression or toxicity versus observation.

Patients who enter observation are then followed with the idea that when they become — when they have an MRD progression event, that’s when the restart therapy. And you can see the definition for what constitutes MRD progression here. But this is not clinical progression. This is patients who are really having just that MRD conversion.

The primary endpoint in Arm B, which is the observation endpoint, is the progression-free survival at 12 months after stopping therapy. And in terms of inclusion criteria, this is taking anybody with relapsed/refractory CLL who has adequate performance status and renal function and has not previously received ibrutinib or venetoclax.

So here’s a look at progression-free survival. As you can see, outstanding for both Arm A and B, which are the 2 arms of patients who had had undetectable MRD. For those who continued ibrutinib, there were no progression events. For those with observation, as you can see, the progress free survival 12 months after stopping therapy, at month 27, was 98%, so obviously excellent.

Here’s a look at undetectable MRD over time starting at cycle — basically until cycle 15. So you can see that all of the patients have undetectable MRD at the start of their observation period. For those with ibrutinib there actually is some recurrence of MRD even when they are on ibrutinib continuously. And then the observation arm is on the bottom, and as you can see, the proportion of patients who achieve high MRD is — that pops up in that population. So as we can see, even when people are continuing on ibrutinib monotherapy there still is some MRD recurrence here.

Here’s a look at MRD over time for those who did not achieve undetectable MRD, and you can see that the proportion of patients with detectable MRD over time is kind of fluctuating.

After completing a fixed duration of ibrutinib/rituximab there isn’t any significant MRD eradication observed if patients continue on ibrutinib maintenance. And it does seem like retreatment with a consolidation strategy for those who have been observed is a totally feasible experimental approach.

So in terms of the implications for future research, I think there is still a question of what is a clinically meaningful progression event. Should we be retreated patients when they have relapse of MRD, or should we be waiting until clinical progression? And then the appropriate duration of novel agent-guided therapy is still a TBD item, and should we really be using MRD to guide this? Should we be using a fixed duration? And I think this trial really highlights some of those ongoing questions.

Next, we’ll look at these consensus recommendations. So this is kind of an interesting paper. It was an international steering committee with 174 members, all multidisciplinary. And here they really go through what are the recommendations regarding methodology for MRD determination; what assays should we be using, what’s the timing and frequency of assessment. How should we be using MRD in clinical practice versus clinical trials, and what is the usefulness of MRD assessment in the future?

And I’ll just highlight a couple of the recommendations. This is not meant to be comprehensive, but this is kind of a cool document because it allows us to really harmonize how we approach MRD in the clinical trial setting.

So the first recommendation is that MRD should stand for measurable residual disease rather than minimal residual disease. And they also suggest that UMRD is the appropriate statement versus MRD negative. In terms of MRD methodology, they highlight that a validated assay meeting standards is needed. That’s either flow with ERIC criteria or RQ-PCR that’s EuroMRD compliant, which is a set of basically guidelines and standards.

In terms of the compartment, they really emphasize that in clinical trials that are aimed at disease eradication, MRD status should be assessed in both the peripheral blood and the bone marrow. And in terms of timing of MRD assessment, they suggest that MRD should be checked at least 2 months after completion of therapy or after achievement of best response for those patients treated with continuous therapy and that clinical trials should incorporate MRD kinetics and that relationship between MRD kinetics and time to event outcomes.

Then they talk about how we should be using MRD in clinical trials. They basically say undetectable MRD is useful as a potential surrogate endpoint, but we really do need more data to determine the utility of MRD in treatment-specific context, basically saying this worked in chemoimmunotherapy, we still need to figure out how it should work in novel agent treated patients.

Then we looked at disease-related factors. And there was a suggestion that clinical trials should really look at what factors are associated with achieving undetectable MRD for each treatment regimen. And MRD relapse, they basically said that we further need to define MRD relapse in terms of what should be our threshold, what should be the duration of relapse, and really associate that with outcomes.

In terms of using clinical practice, they again reiterate that current guidelines are not recommending MRD testing in clinical practice, and more data is needed to really use MRD to guide treatment decision-making.

So this is really a consensus recommendation that tells us when, how, and for whom to test MRD and suggests that MRD should be reserved as a clinical decision-making tool for clinical trial settings. And it’s not – it doesn’t currently have a place — a role in routine clinical practice, though they do highlight that that’s probably coming, and it really does set a standard for the use of MRD in clinical trials in order to generalize results, which I think is a harmonization effort that is definitely worth doing.

The next study or set of studies that I want to highlight is the BRUIN study. So this was the update at ASH. There was also a paper from The Lancet — in The Lancet this year on this agent. This was formerly LOXO-305, and pirtobrutinib has been studied in previously-treated CLL/SLL as well as other non-Hodgkin’s lymphomas.

So the first slide I’ll highlight, The Lancet paper. This is a waterfall plot of the activity in different histologies. So you can see CLL, MCL, Waldenstrӧm’s, and other NHLs, and you can see that responses really do seem to deepen over time. So for the patients who have been treated for at least 10 months, the overall response rate here is 86%. And you can see that a lot of patients did have disease reduction with this agent.

Then in the ASH presentation at the end of the year they further dove into what is the efficacy of pirtobrutinib in BTK pretreated CLL/SLL patients. So this was a deeper dive into 252 patients treated on this Phase I/II, and here’s a look at patients who had stopped drug either for progression, in dark blue, or toxicity, in light blue, and you can see it works in both clinical contexts. You can also see the most — many of these patients had a prior BCL2 inhibitor, so prior venetoclax, and with that we’re still able to achieve response. In this group the overall response rate is 68%, with most of those being PRs.

And here’s a look at PFS based on BTK Cys481 mutation. So just as a refresher, the Cys481 mutation in BTK is often the resistance mechanism for covalent BTK inhibitors, and here we see that regardless of the Cys481 mutational status, whether it’s mutated or wild type, pirtobrutinib seems to have activity.

In terms of the safety profile, this was from the ASH presentation, really highlights that there were no DLTs reported. The MTD was not reached, and this is highlighting all treatment-emergent adverse events that occurred in 15% or greater of patients, and the toxicity profile of this agent is really pretty favorable.

From these data we know that pirtobrutinib is a novel noncovalent BTK inhibitor that seems to be very safe and highly effective in patients who’ve relapsed after prior BTK, including those with Cys481 mutations. And there are a lot of ongoing studies looking at this agent in novel-agent refractory populations and in combination with other novel agents. So I think we’re really going to learn how to best use this agent with the studies that are ongoing.

DR LOVE: — agree or disagree, the optimal treatment of choice of a patient who’s refractory to 1 of the 3 BTK inhibitors or venetoclax/obinutuzumab is pirtobrutinib?

DR ROEKER: I think certainly it’s a consideration. So I think those who have relapsed after covalent BTK inhibitors, we see that there’s activity in that population. And there is rationale for kind of using the class, so really relying on BTK inhibitors and continuing with pirtobrutinib.

In terms of activity after venetoclax, it definitely seems to be active in that class. We also know that — from retrospective data there seem to be activity of covalent BTK inhibitors in that setting too. So I think what the optimal approach is is still — still needs to be worked out, but I think it’s a completely reasonable approach in either of those settings.

DR LOVE: That’s really interesting. I’ve never thought about the fact that it hasn’t been looked at after venetoclax. I mean I guess there’s no reason to think it necessarily would change anything, but I guess it could.

DR ROEKER: Yeah, exactly. So there are a number of dual agent — dual novel agent-exposed patients in this study. So if you look at this waterfall plot —

DR LOVE: Oh, really.

DR ROEKER: — the red — the red hashtag kind of specifies —

DR LOVE: Right.

DR ROEKER: — those who had had both BTK plus venetoclax. So it’s not — only the dark blue ones are those who had progressed on BTK and had venetoclax, but there is great activity in that dual-exposed population.

DR LOVE: It’s so hard to get a feel for new drugs. I had thought that it was like a slam dunk. I’d look at that waterfall plot, and like do you get that with PI3-kinase inhibitors, not to mention the toxicity.

DR ROEKER: Yeah. Absolutely.

DR LOVE: So I thought it was like why isn’t this approved? Why aren’t we using it? But I mean from a clinical point of view, do you think it’s — I’m not saying like official guidelines. I’m just saying clinically do you think that’s the most likely option? Or would you maybe hesitate more? Would you hesitate if you could use it?

DR ROEKER: If I could use it and had free access to it in terms of an approval, I think it’s a great option in the relapsed/refractory setting. There are patients who, after relapsing on a covalent BTK inhibitor, want a time-limited therapy, and maybe that’s where venetoclax comes in. Or there are also ongoing studies looking at venetoclax/rituximab with or without pirtobrutinib, so that’s another option. So whether it should be incorporated into a second line option, whether it should be safe for the third line. I think all of those are kind of unanswered questions.

But it’s a great drug —

DR LOVE: No. I mean I was —

DR ROEKER: — with a great toxicity profile for sure.

DR LOVE: Yeah, no. I was thinking really double refractory. So I wasn’t even thinking second line. But I mean you can make an argument, I guess, there too. But I was thinking more double refractory, that it’s kind of like a no-brainer.

DR ROEKER: This is totally the — this is the only drug that we have data on in — prospective data in the double-refractory setting. The PI3K studies available haven’t looked at that double-refractory population. So I think this is the only drug we have with prospective data suggesting activity in that setting. So yeah, totally.

The next 2 papers that I want to highlight are TRANSCEND CLL 004, which is looking at liso-cel in relapsed/refractory CLL. This was — this is a Blood paper that is looking at the Phase I study. It’s looking at 25 patients who were enrolled, 24 who received product, and 23 are evaluable for safety. So the median age was 66, and most patients had a high-risk feature. So 83% had a high-risk feature, including mutated TP53 in 61%, deletion 17p in 35%, unmutated IGHV in 35%, and complex karyotype in about half.

Prior lines of therapy was 4, and 100% had received prior ibrutinib, 65% had received prior venetoclax. So this is another study, obviously not a drug, but where we do have some data on a double-refractory population.

And here’s a look at a swimmers’ plot. So we can see that the overall response rate is about 82%. Complete response rate is 45%, and 75% achieved undetectable MRD in blood, whereas 65 achieved undetectable MRD in bone marrow. And you can see how durable these responses are based on the swimmers’ plot, as well as the progression-free survival curve on the bottom right. So the median progression-free survival in this population of whom a proportion are double refractory is about 18 months.

This is a busy slide, but the things that I want to pull out are basically the adverse events. So every patient on the study had a treatment-emergent adverse event, most commonly being anemia, CRS, thrombocytopenia, or neutropenia. So it’s really marrow suppression plus cytokine release syndrome. 74% had any-grade CRS, with most being low grade, and 39% had neurologic events, which is highlighted on that right side.

There were 2 dose levels tested here, so it was 50 x 10⁶ and 100 x 10⁶ cells, and there does seem to be a little bit more neurologic event with the higher dose level, but that was — that is the recommended Phase II dose.

So this is a CAR T product that does seem to have efficacy in a heavily pretreated high-risk group with an overall response rate of 82%, and CRS seems to be relatively common, with neurologic events happening in 39%. There’s an ongoing Phase II that’s examining, like I said, 100 x 10⁶ CAR T cell dose.

And then the next paper is looking at the same study but looking at a cohort that enrolled patients with liso-cel combined with ibrutinib for relapsed/refractory CLL. So patients were eligible for this study if they had progressed on ibrutinib or had high-risk features and were on ibrutinib for at least 6 months without a CR, had a BTK or a PLCγ2 mutation or had previous ibrutinib and no contraindication to continuing it. So you had to have at least 1 of those criteria.

And patients were started or continued on ibrutinib at enrollment and continued through day 90 following the cell infusion. And there were 2 dose levels tested in this study as well. Primary objective was safety and recommended Phase II dose. And most patients in this population were high risk, so 95% had a TP53 aberration and/or a complex karyotype. And in terms of those double-refractory patients, it was about half, 58%.

Here we have — get a good look at outcomes in this study. So Grade 3 treatment-emergent adverse events occurred in 95% of patients, with the most common being marrow suppression, similar to what we found before. In terms of the CRS events, 74% had some CRS, 32% had some neurologic event, and the ibrutinib-related treatment-emergent adverse events were relatively common, in 79%, with 37 being higher grade. Objective response rate was 95%, so it does seem to be very active, and 63% achieved a CR.

So here we see that liso-cel and ibrutinib is associated with a manageable safety — safety profile and promising efficacy in a high-risk patient population, including those with double-refractory disease. And I think in terms of future research we need to really figure out do novel agents truly enhance the activity or improve the safety profile of CAR T in CLL. And if so, which novel agent is really the optimal partner for CAR T therapy. We know we have various BTK options, covalent/noncovalent. We also know that we have venetoclax, and I think how we should best combine CAR T with a novel agent remains to be seen.

And then last study to highlight today is a look at COVID-19 in patients with CLL. And this was a look over time at patients collected at 45 centers. This was an international collaboration, and data was collected on 374 patients who were diagnosed with COVID between February of 2020 and February of 2021. And there was a look at basically the early cohort, which was in the spring of 2020, versus the later cohort, which was after that, and that mirrors other population-based studies.

Here you can see the overall survival of the entire cohort. So if you remember back to kind of the first reports of COVID-19 in CLL patients, the case fatality rates were reported between 30% and 35%. Here it seems to be a little bit better, and it seems like those in the later group have lower mortality, or case fatality rate, than those in the early cohort, which mirrors population-based studies. In this population hospital admission was required for 75%, ICU admission was required for 27%, and as you would expect, the case fatality rate was a lot higher for those who were admitted, at 36%, versus 4% in non-admitted patients.

Here is a look at basically differences in how patients were managed between the early cohort and the later cohort. And univariable analyses were done to look at the administration of specific COVID-19-directed therapies and overall survival. And it was found that remdesivir and convalescent plasma administration were associated with improved overall survival in this population, whereas those who received corticosteroids or hydroxychloroquine, which obviously is not relevant anymore, but steroids, had an increased risk of death. And there was a suggestion that the rate of secondary infections was somewhat higher for patients who received steroids versus those who didn’t. So obviously this is — all of the caveats about a retrospective study are in play here, but it does seem like perhaps steroids might increase that risk of infection in this population.

So in conclusion, COVID-19-related mortality has fallen over time, which mirrors population-based studies, and we see that COVID-directed therapies might be associated with outcomes that are a little bit different than we see in the general population. So really looking at COVID-19-directed therapy in patient-specific populations I think is important. We’ve figured that out in terms of how patients are responding to vaccines, how patients are doing with antibodies. I think we really need to look at this as a separate patient population because the biology is different in terms of how patients are responding.

So that is an overview of relapsed/refractory CLL in 2021.

DR LOVE: I’m just kind of curious what’s going on nowadays in terms of COVID in your clinic. I’m guessing a lot of your patients are infected?

DR ROEKER: Yeah. It seemed like it had really died down quite a bit, and then more recently has just exploded again. The good news is, knock on wood, we haven’t had a lot of bad outcomes recently. We do have people who have had kind of lingering symptoms, and we’ve been using a fair amount of monoclonal antibody.

DR LOVE: Are you generally keeping, for example, BTK inhibitors going if they’re infected? Are you keeping venetoclax going?

DR ROEKER: So I’m not modifying CLL-directed therapy for patients who are having mild symptoms. I’ve been trying to keep BTK inhibitors on. If you remember back early in the pandemic there was kind of this hypothesis that BTK inhibitors might modulate macrophage polarization, and that might limit the inflammatory response to COVID and perhaps this could be a COVID-directed therapy. So that was studied in a general population, both acalabrutinib and zanubrutinib were studied in general populations. Those were negative studies.

But, for patients who need it anyway, I think it didn’t show a lot of harm. And I think that disease control is another important consideration. So I’ve been keeping it on, typically.