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Key opinion leader Mazyar Shadman, MD, MPH, reviews data from a clinical trial studying zanubrutinib in the context of ibrutinib- and/or acalabrutinib-intolerant CLL/SLL.   

A Phase 2 Study of Zanubrutinib in Previously Treated B-Cell Malignancies Intolerant to Ibrutinib and/or Acalabrutinib: Preliminary Results for Patients With CLL/SLL

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division at Fred Hutchinson Cancer Center, discusses the examination of zanubrutinib (Brukinsa) in patients with B-cell malignancies who were intolerant to acalabrutinib (Calquence).

The ongoing phase 2 BGB-3111-215 trial (NCT04116437) is evaluating the use of zanubrutinib in patients with previously treated B-cell lymphoma who were intolerant to prior treatment with a BTK inhibitor, such as ibrutinib (Imbruvica) or acalabrutinib. Data were presented at the 2022 ASH Annual Meeting from the cohort of patients treated with zanubrutinib who were intolerant to prior treatment with acalabrutinib.

Findings showed that patients experienced a median treatment exposure time of 7.6 months with zanubrutinib compared with 4.6 months for acalabrutinib, Shadman explains. Although patients experienced a longer time on treatment with zanubrutinib, the majority of them did not experience a recurrence of adverse effects (AEs) that led to intolerance of acalabrutinib, Shadman notes.

Additionally, no high-grade AEs were observed for treatment with zanubrutinib vs acalabrutinib, Shadman continues. Notably, the efficacy and disease control rate were promising, Shadman adds. No patients who experienced disease progression on prior acalabrutinib were included in the trial, meaning patients could continue to experience an efficacy benefit with zanubrutinib, Shadman concludes.

Mazyar Shadman, MD, MPH, discusses the examination of zanubrutinib in patients with B-cell malignancies who were intolerant to acalabrutinib. 

Dr Shadman on Zanubrutinib in Acalabrutinib-Intolerant Patients With B-cell Malignancies

 Thanks to all of you for this rich and informative discussion. Before we conclude, I’d like to get your final thoughts and ask what you’re most excited about in therapeutics for CLL [chronic lymphocytic leukemia]. We’ll start with Dr Burke to give Dr Allan a chance to catch his breath.

 A couple of things strike me as particularly exciting. One is the novel BTK [Bruton tyrosine kinase] inhibitors, the noncovalent BTK inhibitors that we just heard about from Dr Allan. Those offer a lot of promise. The biggest challenge right now in the field are the patients with hard-to-treat CLL who progressed through the BTK inhibitor and venetoclax and maybe a PI3K inhibitor, those desperate patients who need help. The noncovalent BTK inhibitors offer potential for those folks.

The other big, exciting development is the use of MRD [minimal residual disease] to adjust therapy, not just in CLL but in a lot of fields. Think about lymphomas where we have treatments that work for a good majority of patients, but then there are patients whose cancers become resistant and then they relapse and do poorly. If we can identify who those patients are by using MRD assays to see who has residual disease, then we can tailor therapies earlier and try to make an impact when we know we have the potential to help more. In CLL, tailoring therapy based on MRD assays and result is an exciting way forward for the field.

 Dr Allan, what are you most excited about?

 I’m excited about these combinations of therapies. We’re seeing great clinical synergy. We see the vast majority of patients—regardless of high-risk features—able to achieve MRD negativity, which we know translates to longer-term remission. I’m excited about that. I also echo Dr Burke a little in trying to get behind our thoughts of what is personalizing the treatments for our patients. But I really want to dive into the data and find cytogenetic abnormalities that may respond better to a certain approach.

We have a little evidence that that there may be something there with BTK inhibitors or 11q, and wecan start to tease out certain patient populations that might actually do better with a specific approach. It’s not going to be a discussion of only what the patient wants, which is what we do now, but rather we will tailor therapy to evidence-based practice guiding treatment, so we know this is going to be the best treatment for you. With maturation of all this data and larger numbers of patients being treated in uniform manners and similar populations, we’ll be able to start to tease that out and have meta-analyses type of studies. I’m excited to see research into those areas as well.

 In addition to what was just mentioned about combination therapy and using an MRD-guided approach, I’m excited that no matter how different high-risk disease, there are patients who are still in need of different types of treatment and novel treatment approaches. It’s good to see that immunotherapy specifically is still active for CLL. We definitely do have patients who need treatment beyond what we discussed today.

Maybe this is more hopeful than exciting, but with more treatment options, I certainly hope that translates to affordability and availability for patients around the world. Hopefully more treatment options will create some competition that eventually patients will benefit from. We shouldn’t forget that these drugs are not necessarily available for all CLL patients in different countries. With more agents, there will be a situation where we can help other patients have access too.

 Again, thank you all. To our viewing audience, we hope you found this 

® discussion to be useful and informative. Thank you.

Future Directions in CLL

 We have just a few more minutes. I think we will wrap things up with the new agents. I’m going to ask Dr Allan in a second about the reversible inhibitors of BTK [Bruton tyrosine kinase]. But John Burke, maybe you can comment on the cellular therapy and CAR T [chimeric antigen receptor T-cell therapy] and whether that represents promise for our patients with CLL [chronic lymphocytic leukemia].

 At the ASH [American Society of Hematology Annual Meeting], we saw data on the CD19-directed CAR T-cell product liso-cel, and they showed data on 23 patients, most of whom had failed ibrutinib and demonstrated an overall response rate of 81%, a complete response rate of 45%, and then an MRD [minimal residual disease] undetectable rate of 75% to 85%, depending on blood vs bone marrow. The toxicities were not trivial—74% of patients had some degree of cytokine release syndrome, although only 2 were rated as grade 3.

They saw tumor lysis syndrome in 17% of patients, suggesting clear activity. The data remain fairly early. That particular product would certainly appear active in this high-risk population, but it’s also pretty toxic. CAR T is not something I have referred many patients for, and right now I save it for last. We’ve also seen data that CAR T can be added to ibrutinib, but these data weren’t presented at the last ASH.

Patients who had been treated with ibrutinib for 6 months and failed to achieve a certain degree of remission, then had CAR T added. The CAR T helped clear the bone marrow, and patients achieved deeper remissions but at a fairly considerable toxicity cost and financial cost as well. I’m a little uncertain about where the final role of CAR T will be, but right now it remains a research tool.

 In terms of newer agents in development, there’s a lot of work going on with the next generation of BTK inhibitors, the reversible inhibitors. Dr Allan, I know you’ve done some work with the reversible inhibitors. Can you highlight some of the features of those new agents? How do they differ from what we have available with the irreversible inhibitors and what we’re seeing with the activity for those in compounds?

 Absolutely. It’s important to remember that the 3 big FDA-approved BTK inhibitors are all covalently bound to the protein BTK at the Cys481 amino acid, which is within the kinase pocket, prevents activation and phosphorylation, and inhibits and kills the enzyme irreversibly. Therefore, the only way for the cell to make more BTK is to transcribe it, translate it, and then repopulate the protein, which then is inhibited the next day when you take the new BTK inhibitor.

We know that the resistance mechanism is a mutation developed in BTK at that Cys481 residue, which is then turned from a cysteine to a serine, disrupting the irreversible binding and covalently binding to the protein. Therefore, the molecule gets kicked out. That’s the major mechanism of resistance we recognized in the vast majority of patients who progress that have been reported, a BTK mutation is typically present. These covalently bound molecules have short half-lives.

Therefore, the drug is in and out of the kinase pocket, gets washed out of the system based on its pharmacokinetics [PK], and the enzyme is then able to fire again, allowing the CLL to signal through the B-cell receptor. One way that has been devised to overcome that is to use what’s called a reversible BTK inhibitor, where the drug no longer binds into the pocket irreversibly but instead goes in, interacts with the pocket, inhibits activation, and throughout the day goes in and out of the pocket within that cell.

The PK is a little better on these reversible BTK inhibitors. These molecules have longer PKs. They’re hanging around the body. Therefore, they’re staying in the cell longer. They’re not getting broken down. By having a reversible inhibitor, you can have relatively prolonged inhibition of the protein and have high occupancy rate, even though the drug is not covalently bound. There are 3 reversible BTK inhibitors currently advancing in clinical stage and at least 1 or several others that are coming on board and trying to get into the clinic now.

The current studies are entering phase 2 populations and are emerging from their phase 1 data. Limited data have been demonstrated. These patients that are recommended for these studies are very high risk. They have BTK mutations. Most are 17p deletion, so it’s a really difficult patient population to treat. It’s hard to glean efficacy from this specific population.

We found that these inhibitors do have activity and different selectivity for their kinome. Some are rather specific, much like acalabrutinib and zanubrutinib, and don’t have a lot of other off-target inhibition. Others have similar kinase inhibition, like ibrutinib. Then there are other molecules that have a broader inhibition of other molecules. What we’re starting to tease out is if it all depends on BTK inhibition, or is it some other off-target effect based on these different molecules?

We’re starting to learn and see activity. As we start to expand in these phase 2 populations, that’s where we’re going to glean from our efficacy. We’re going to get less patients who have been pretreated. It remains unclear to me if these drugs will be in a niche in which we’re only going to be using them for patients who progress with BTK inhibitors and patients who have BTK mutations. Or will the reversible BTK inhibitors be able to potentially unseat covalently bound BTK inhibitors?

It is possible that you may be able to prevent the mutation by using reversible BTK inhibitors because that evolutionary pressure is not there, but that remains to be seen. What has been reported is that these drugs do appear safe. They don’t appear to have huge rates of atrial fibrillation. They don’t have huge rates of other toxicities that we sometimes attributed to our covalently bound BTK inhibitors, such as arthralgias and diarrhea. We’re learning here and we’re starting to target our resistant mechanism, and that’s where we are in the current state.

We’ll see at ASH, I think, the big 3 companies that have a molecule in advanced stages showing more results with larger patient populations, and we’ll start to glean if there are differences among the molecules. We don’t quite understand that yet. We don’t know if there’s a winner of the 3 that are currently far ahead, but we’ll start to understand that and the toxicities and to make sure that these patient populations are similar so we can understand why 1 is better. Is it a potency issue?

Is it a patient population issue? What patient factor might predict response? Or is it some other off-target effect that, as the science catches up, we would start to learn? We’re using these drugs. They’re coming down the pike, and I do think there will be some value in them, especially in this special resistance niche of patients. It remains to be seen if reversible BTK inhibitors can cross the threshold to be adopted broader.

Novel Therapies for CLL

 You mentioned PI3K inhibitors. Let’s touch briefly on PI3K inhibitors and their utility. Dr Shadman, what are your thoughts on PI3K inhibitors, and what has your experience been with them? How do they fit into what we’re doing today with therapeutic strategies in CLL [chronic lymphocytic leukemia]?

When we think about the novel agents that we have for CLL, the 3 big groups are basically BTK [Bruton tyrosine kinase] inhibitors—including the next generation, second generation, and now third generation—BCL2 inhibitors, and PI3K inhibitors. PI3K inhibitors are in the 2 large studies for CLL therapy. As John Allan just mentioned, they’re usually not the first or second choice most of the time.

Based on the initial experience, using these agents in the frontline setting usually comes with more toxicity. These are treatments we think about using in the relapse setting. You have 2 approved drugs for CLL, of course: idelalisib and duvelisib. Idelalisib was the first drug approved, and it’s a PI3K-delta inhibitor. A randomized study combined idelalisib with rituximab and the control arm was placebo and rituximab.

The study showed PFS [progression-free survival] and OS [overall survival] benefit based on a relatively short follow-up. I believe the PFS was 5 to 6 months for the control arm and not reached for idelalisib-rituximab. There was an OS benefit. The study population included patients with normal kidney function, significant myelosuppression, and patients with coexisting issues. Recently last year the long-term follow-up was published in the 

 It sounds as if they looked overall for patients who received the combination therapy idelalisib-rituximab.

The median PFS was around 20 months. The take-home point from this paper is the toxicity data. One of the factors we consider when deciding whether to use PI3K inhibitors is the toxicity—namely, colitis, pneumonitis, and transaminitis. As I mentioned, these toxicities seem more common in patients who were previously untreated, maybe because their immune system is more intact.

When we looked at the long-term follow-up data, the longer exposure to idelalisib, the adverse effects like diarrhea, colitis, and pneumonitis become more common and more prevalent. For example, diarrhea grade 3 or more is in the range of 16% when you continue to take idelalisib, and grade 2 diarrhea is in the range of 17%. When you think about grade 2 diarrhea as having 4 to 6 stools per day, that is significant.

The same is true with colitis. For those of us who deal with colitis as a result of taking idelalisib, in my experience the patients who I treated early on treat graft-vs-host disease with the same type of approach: high-dose steroids and tapering. Some patients had to go back on the drug because at the time, there were not many other options. The drug had significant toxicities: pneumonitis, at 6% of grade 3 or more with longer use. We usually see hepatitis early on after starting therapy.

Usually hepatitis doesn’t come back, and the longer follow-up confirms that. Duvelisib is the other drug. It’s a PI3K-delta and PI3K-gamma inhibitor. Duvelisib is also approved as monotherapy for CLL based on the head-to-head randomized trial comparing duvelisib with ofatumumab. The median PFS was 13 months, 13.3 months vs 10 months in favor of duvelisib led to its approval.

I’m not sure how much duvelisib is used. To know more about the true rate of toxicity, we need to use the drug beyond the initial clinical trial. We need to get more real-world data, but it sounds like diarrhea and colitis are the common toxicities. These are recorded separately in the paper, so it’s hard to know the true rate. But to me, the drug seems to have the same toxicity profile with hepatitis occurring a little less. It’s not recorded.

The incidence of hepatitis was less than 10%. But again, we need to use duvelisib more, and the drug has more indications as being used in T-cell lymphomas, for example, more recently. We may get more toxicity information from different histologies. PI3K inhibitors as a group are extremely effective, but if we have to use them, we need to be mindful of the toxicity, mainly infections and autoimmune adverse effects, and prepare prophylaxis that needs to be used. There are strategies to make PI3K inhibitors better tolerated.

At ASCO [American Society of Clinical Oncology Annual Meeting], we have some strategies—maybe we should call them next-generation PI3K inhibitors—in terms of scheduling. We give PI3K inhibitors less frequently after an initial phase. In that approach we may have a PI3K inhibitor that has a different toxicity profile that may be available for CLL and other lymphomas. For umbralisib there are many studies in combination with a CD20 monoclonal antibody and other combinations. We have some work to do from a toxicity standpoint, but in patients who I had on these drugs, and even patients who are high risk, it is extremely effective medication as long as you control the adverse effects.

I see PI3K inhibitors as a third-line treatment in patients who either progress on both BTK inhibitors and venetoclax, or for some reason they can’t tolerate BTK inhibitors. There may be a future in combining PI3K inhibitors with other drugs. It sounds as if the future involves a venetoclax-based therapy. If a BTK inhibitor for any reason is not a good partner, maybe a safe PI3K inhibitor could be used.

Drug-drug interactions are significant with PI3K inhibitors and venetoclax. But there are studies that have shown safety for duvelisib and the newer generations of PI3K inhibitors.

PI3 Kinase Inhibitors in CLL

 We talked about first-line therapy and what drives selection of first-line therapy. Patients do well for many years, but some of them do relapse or progress on treatment. Therefore, therapeutic sequencing is an important concept. There are not a lot of data around therapeutic sequencing. I wonder, Dr Allan, if I could ask you to give us your thoughts on the major concepts regarding therapeutic sequencing. For example, if we start with a BTK [Bruton tyrosine kinase] inhibitor, what do we do next if a patient progresses, and where are we trying to get that patient for long-term disease control? If we start with a BCL2 small-molecule inhibitor, what is the sequencing strategy in that case?

 That’s a great topic and a hot topic, but we don’t quite know the answer to whether there is a best sequence for our patients. The only way to find the answer is to start patients on 1 therapy and have a long-term study that then follows patients switching to another therapy upon progression. Because these patients do so well and following that PFS [progression-free survival] too, depending on your sequence, a study with a long-term follow-up would be the only way to truly identify the best sequence. That’s never going to happen because it requires a large number of patients and long-term follow-up. Therefore, we’re left looking at studies that have been performed, where 1 of the inclusion criteria is exposure as a prior therapy to say a BTK inhibitor or a BCL2 inhibitor.

The only prospective clinical trial that’s been designed and reported and published in that manner is looking at true ibrutinib progressors in patients with a BTK inhibitor intolerance and salvaging them with venetoclax. This was a smaller phase 2 study that enrolled patients with true progression and/or intolerance. This study had close to 100 or so patients, of which the vast majority—close to 60%—had progression on BTK inhibitors.

Mind you, patients in this study are heavily pretreated with relapsed/refractory CLL [chronic lymphocytic leukemia] from the era of the earlier BTK use, which is where we’re hopefully emerging from, so we won’t be treating these types of patients anymore. But we found that venetoclax has great salvage abilities, and response rates were close to 70%. CR [complete response] rates were relatively high in the patient population with refractory CLL. Peripheral blood MRD [minimal residual disease] rates were in the 40% range, which didn’t necessarily translate to deep bone marrow disease negativity. Not a lot of patients had deep bone marrow disease negativity, so that’s a little unknown.

We found and have shown that if you can get patients in an MRD-negative state, those patients had a PFS that wasn’t met at the time—they had reported it and never had another follow-up. But overall, patients had a PFS of about 2 years when they get venetoclax-based salvage therapy. In this case, again, patients were highly refractory and had previous progression on BTK inhibitors, so that is typically the classic standard of care.

If you start a BTK inhibitor, we then flip to a venetoclax or a BCL2 inhibitor–based treatment. Whether you add an anti-CD20 monoclonal antibody or you do fixed-duration therapy is based on MURANO data. Though it is important to remember that in the MURANO study, only a small number of patients of the total patient population had prior BTK inhibitor exposure. Therefore, we didn’t get our answer from that study. Ultimately, though, you typically do some venetoclax-based treatment.

Based on some real-world evidence, personal experience, and cross-study comparisons, we know that switching to another B-cell receptor antagonist like a PI3K inhibitor after a BTK inhibitor, progression is probably not going to MRD negativity. If you come off a BTK inhibitor for intolerance, PI3K inhibitors can have some activity and get you to MRD negativity, but they have their own issues with intolerance and toxicities. As we said, venetoclax is a very well-tolerated drug. Patients do well on venetoclax. We can salvage these patients who are tough to treat because we know that if they’re progressing on a BTK inhibitor, disease biology is saying something.

That typically indicates 17p deletion. There is a small subset of patients who don’t have a 

 mutation, but they are common among patients who truly progress. They need a switch out of the treatment pathway, so to speak, and fortunately, we have venetoclax to do that. The flip side of this is now that the CLL14 study is around, and many people are adopting and are attracted to this fixed-duration therapy, we’re getting a new wave of patients who’ve been BTK inhibitor naïve. We don’t have current prospective clinical data of true patients being salvaged with BTK inhibitors post-venetoclax progression or relapse.

Fortunately with time, we’ve gotten some real-world data from collaborating groups around the world to be able to put enough patients in relapsed/refractory settings who had been BTK inhibitor naïve. We now have relatively significant numbers in real-world settings to where we can see response rates resemble what we see when you use a BTK inhibitor in a patient who is BTK inhibitor naïve even though they progress and relapse on venetoclax.

That data provide some encouragement from the community and from providers. It allows us to at least educate our patients that it doesn’t matter so much which drug you use first. You will be salvaged regardless of which drug you use, and it makes sense. These are completely different mechanisms of action. They don’t have cross-talk too much and the mechanisms of resistance with a venetoclax or BCL2 inhibitor are very different from the mechanisms of resistance we see with a BTK inhibitor–based treatment.

Fortunately, we know that the sequence doesn’t seem to matter too much. You can tailor therapy a little, but classically, you’re staying in a BTK pathway then a BCL2 pathway or the opposite. You’re not typically doing a B-cell receptor or a BTK inhibitor staying within the B-cell receptor antagonism and going to a PI3K and then to a venetoclax, because it is probably not going to get you to MRD negativity. That’s typically my practice. Depending on which class of drugs you use first, you use the other class second.

We don’t know if there is a frontline impact on long-term survival, so we don’t know if there is a best first-line treatment. Those head-to-head studies haven’t been done. We’re getting that, but the studies have all been combinations vs monotherapies. It is an exciting time, but using 1 pathway and then the other has typically been my practice. When talking to my colleagues and other people in the community, that’s the train of thought currently in therapeutic sequencing.

Therapeutic Sequencing in CLL

 Dr Burke, in terms of BTK [Bruton tyrosine kinase] inhibitor–based therapy, what can we expect in the relapsed setting in general? We talked about first-generation versus second-generation compounds. What can we expect if we put a patient who’s been previously treated, maybe with BR [bendamustine, rituximab], on a BTK inhibitor–based therapy? Most trials that have been done in the relapsed setting enrolled patients who’d had prior chemoimmunotherapy. In that setting, what can we expect with a BTK inhibitor–based therapy as relapsed treatment?

: If you look to the data, the original study that we have the longest follow-up with is RESONATE, which compared ibrutinib with ofatumumab in patients previously treated with chemoimmunotherapy. The long-term follow-up was published last year, and they reported a median PFS [progression-free survival] with ibrutinib of 44 months, just under 4 years. The median overall survival was a little over 5 years. I think the RESONATE study is the best long-term follow-up data we have with ibrutinib.

With acalabrutinib, we have the ASCEND trial that compared acalabrutinib with the control arm, which was a mix of either bendamustine-rituximab or idelalisib-rituximab. We saw improved PFS with acalabrutinib in that trial. For patients who have been treated previously with chemotherapy, a BTK inhibitor or the venetoclax-rituximab combination therapy is the way to go over salvage chemotherapy. I saw a patient not that long ago who had previously been treated with fludarabine-based chemotherapy and then relapsed and saw a doctor who recommended BR.

I cringed because we now have data that suggest that patient would be better served by either a BTK inhibitor or venetoclax-rituximab. That’s the key point practitioners need to know—those are the standard approaches now for second-line therapy after previous chemoimmunotherapy. Median PFSs are in the range of 4 years.

 In the relapse setting, what population of patients worry you? Are you still worried about 17p deletion, even though we know that the targeted therapies have activity in patients who are 17p deletion mutated?

 aberrancies still fare less well than those who do not have those in the relapsed setting. Most of the other gene mutations seem to have less prognostic importance, which is true in the untreated setting as well. In the previously untreated setting, there was a publication in 

 just 2 months ago based on the CLL14 study showing that venetoclax seems to overcome some of the adverse prognostic implications of, say, deletion 11q. The only FISH [fluorescence in situ hybridization] abnormality that conferred a less favorable prognosis with up-front therapy with venetoclax-bendamustine was 17p or 

It’s true that these targeted agents are overcoming a lot of the other adverse prognostic and genetic factors but not 100% overcoming the 17p problem.

BTK Inhibitors in Relapsed/Refractory CLL

 Dr Shadman, let’s switch gears now and move to relapsed disease. You spoke a lot about the CLL14 study, which analyzed venetoclax in the frontline setting. Let’s transition to the relapsed setting and the application of venetoclax in the relapsed setting. The MURANO trial led to approval for venetoclax-rituximab in the relapsed setting and has been updated recently. Can you highlight the information from that update?

 MURANO was the study that brought venetoclax-based therapy in combination with rituximab to the relapsed setting for CLL [chronic lymphocytic leukemia]. Patients were given a chemotherapy-free regimen that was time limited—in this case, 2 years. Patients were randomized in a 2-arm study to either venetoclax-rituximab—here venetoclax started first, and a patient received that treatment for 2 years—or bendamustine-rituximab. It was not an MRD-guided study. All participants stopped at 2 years if they could tolerate and if they were responsive to treatment.

The standard arm of the study was bendamustine-rituximab, a commonly used regimen. Around 40% of patients, distributed between the 2 arms, had an abnormal 

 deletion or mutation. The study showed both PFS [progression-free survival] and an overall survival advantage for venetoclax and rituximab, and I believe a PFS of around 86% vs 35% in the initial report. This is another situation in which achieving an MRD-negative state at the end of treatment is important for prognostic information and because that translates to a longer PFS.

At the last ASH [American Society of Hematology Annual Meeting] in 2019, Dr John Seymour presented the 4-year follow-up of the MURANO study, in which we continued to see improved PFS in the venetoclax-rituximab arm—57% vs 5%. The most important piece of that presentation, looking specifically at MURANO, was that we have clear numbers of PFS in patients who have an undetectable MRD, and that is uMRD4, with a median of 22 months being off therapy.

Eighty-six percent of patients who have uMRD at the end of treatment are PFS vs 60% in patients who are considered low MRD, which is 10-2 to 10-4 vs about 7% in patients who have more disease burden, defined as more than 10-2. The MRD achieved at the end of treatment gives valuable information on what to expect in terms of clinical progression.

The important data that came out of this long-term follow-up help us answer the question Dr Burke asked earlier, which is do we use MRD in clinical practice? In my case, my official answer would be no. I try to go with 1 or 2 years of therapy, but I have been looking at MRD because the MURANO long-term follow-up shows that the kinetic of the MRD matters. When they looked at the patients who had detectable MRD at the end of treatment, the patients had a rising MRD level before the end of therapy.

In a way, we can use MRD to predict if a patient will have relapsed CLL. If you start checking a little earlier and see the rate of the level of detectable CLL rising, you know that your patient won’t achieve an undetectable state at the end of 2 years and probably won’t achieve an undetectable state if you continue the current course of treatment. Not only will you not see improvement, but you will see more disease. Do I use that? I have. For a number of patients I started looking at their MRD a little before the end of therapy. If I see that their levels are going down, and if I can treat them for 26 months instead of 24 months and then stop and they achieved detectable MRD state, I do it. This is not based on any data, but I think most of us try to create some data for ourselves.

That’s my small project. But really, this is another discussion that I have with patients. I tell them that the whole idea of going on this therapy is to have a fixed-duration therapy. If I want to continue to chase an MRD, that may not be the smartest idea. But if I see that trend and if I feel that by treating 2 more months we can get an undetectable state, then I will. Some patients feel much more comfortable stopping treatment if they know they don’t have any detectable disease, using what we have in terms of the MRD assessment tools.

The longer follow-up of the MURANO study shows that a time-limited chemotherapy-free treatment using only 1 of the novel agents in the relapsed space is effective. We talked a lot about combinations, and it’s great to use our best drug up front and hopefully cure patients, but I also think about the situation in which a patient stops responding to both. Having a combination of venetoclax with a non–BTK [Bruton tyrosine kinase] therapy is reassuring because you know you have a very reliable drug as a backup plan. This was the MURANO summary and follow-up.

MURANO Trial Update in R/R CLL

 Before we move on to relapsed disease and management for relapsed disease, I want to touch on MRD [minimal residual disease] briefly because it’s been mentioned many times. I agree with you, Dr Allan. We are very focused on MRD in our clinical trial and our clinical trial design—MRD as an end point, MRD as a surrogate marker for depth of response, and prolonged progression-free survival [PFS] for patients with MRD negativity.

Dr Burke, what is the utility of MRD testing in the standard management of patients with CLL [chronic lymphocytic leukemia] in the community? Is MRD useful, or do we stick with fixed-duration and stopping treatment at fixed duration? For example, with venetoclax-based therapy at 1 year for frontline and 2 years in the relapsed setting.

 I’m somewhere in between. Bill, you and other experts who have been doing this for years have probably been doing MRD on your clinical trials for a long time. Right now, the average community practitioner is not doing MRD at all. I am in a phase where I have increased my use of MRD, even off study. That could be debated whether one should even do that. For me, MRD is a prognostic tool when a patient finishes venetoclax therapy.

MRD helps the patient and the physician understand the patient’s likelihood of relapsing within the next few years. As has been discussed, you have patients with MRD negativity who have a relatively favorable PFS and a low likelihood of relapsing, whereas patients with MRD positivity are much more likely to relapse quicker. MRD is a prognostic tool, but it doesn’t tell you what to do with the information. If a patient is MRD positive, should the patient continue the current course of therapy?

Should the patient go ahead and stop therapy at 1 or 2 years or whatever the defined plan was? Should the patient switch therapy or add a therapy? These are all options, and we don’t know the answer to that question. A trial like CAPTIVATE is going to start getting an answer to that, but these are unknowns. You’ll hear opinions, but you won’t really hear data-driven answers as to what is best for that patient. Likewise, I don’t think we know the best duration of therapy for patients who are MRD negative.

Right now, we have this defined period and we can reassure patients that they’re likely to do relatively well when they stop therapy if they are MRD negative. But would they be better off continuing therapy for a longer period of time with venetoclax, as you do with a BTK [Bruton tyrosine kinase] inhibitor? I don’t think we know the answer to that question. These are a lot of unknowns that we are facing in the field. Should a community practice center check MRD at the end of a venetoclax regimen—1 year, 2 years? I offer that as an option to my patients if they want to know the prognostic information.

If they want to know their likelihood of recurrence within the next couple of years, then we can do that test. If they’re not that interested and they’re worried about cost, MRD is certainly optional and can be omitted for routine clinical practice. There’s my perspective.

Utility of MRD Testing in CLL Management

I’m going to ask Dr Allan in a second about the new and novel combinations of targeted therapies, but maybe Dr Burke can give us an idea of his experience with venetoclax tolerability and safety. What are the things you’re thinking about when you’re planning patients on venetoclax? What’s been your experience with tolerability and safety?

 I would add a few comments. As an oncologist, I think it’s amazing when patients come in and tell me they have no adverse effects and I hear that a lot with venetoclax. I use it quite a bit. I don’t mean to say that it has no adverse effects, but patients come in after 6, 9, 12 months of therapy and they say they feel fine. That’s not everyone, but it’s a lot of patients. I find venetoclax to be a well-tolerated drug. One issue I’ve had with patients’ tolerance of venetoclax is neutropenia. In order to try to maintain them on a full dose, I give a fair amount of growth factor, particularly during the first 6 months when they’re on obinutuzumab.

I’ve had 1 patient for whom I had to stop therapy because of thrombocytopenia. He went into the teens and didn’t come out of it, but I think his underlying liver disease was the cause. Rarely have I had to stop therapy, and so in general I think venetoclax is a well-tolerated drug. I found that giving GCSF helps me maintain dose intensity without having too many pauses. I’ve had to admit 1 patient with a neutropenic fever, but that is rare.

In the frontline setting, as we heard from Dr Shadman, you can debulk patients with obinutuzumab and reduce their tumor burden. I have never had to admit a patient for tumor lysis syndrome [TLS] prevention in the frontline setting because I’m in no rush to start venetoclax. I don’t feel the need to follow the label to start venetoclax on day 22 of cycle 1 all the time. You can give patients a couple of extra doses of obinutuzumab if you need and debulk them further before starting venetoclax to make sure it’s safe.

I’ll repeat a CT scan. With this method, I’ve been able to keep every patient as an outpatient. By doing that, following the label, and checking the TLS labs on schedule on day 2 and on day 3, it’s been very safe. I had really no problems with venetoclax.

 Dr Allan, tell us about the combinations BTK [Bruton tyrosine kinase] inhibitor plus BCL2 inhibitor, the interest in the combinations, and the results.

 I should give credit to The University of Texas MD Anderson Cancer Center for publishing data that show for the first time the preclinical synergy between BTK inhibitors and BCL2 inhibitors. We are seeing this now translate to clinical efficacy as well, not just additive properties between these drugs. We can utilize the modulation of different pathways and then hit them hard with both of these drugs. A lot of work has been done.

There have now been a few clinical trials. Nitin Jain from MD Anderson has published some of the first frontline data with combination BCL2 inhibitors, venetoclax, and ibrutinib and showed MRD [minimal residual disease] rates that rival or were better than what we used to see with chemoimmunotherapy, especially in high-risk patients. We are seeing that clinically. There has now been transition where the industry has started to turn out larger-phase studies with more patients.

We’re starting to introduce MRD-based thoughts and response adaptive therapies vs fixed duration. One of the major studies we will watch for updates is the CAPTIVATE study, which is a study by Pharmacyclics looking at a combination of ibrutinib-venetoclax in treatment-naïve frontline patient all comers. This study is special in that it has 2 cohorts.

The first cohort is an MRD-response adapted cohort, where the patients are debulked with ibrutinib for 3 months and then treated with an additional 12 months of venetoclax plus ibrutinib, so 12 months of combination but 15 months of total treatment. At the end of that time in the first cohort, MRD assessments are made in the bone marrow. At previous congresses, the groups have published MRD rates in the bone marrow showing up to 72% of patients are MRD negative in the bone marrow with the combination of ibrutinib and venetoclax.

Let me remind you, there are no anti-CD20 monoclonal antibodies in this treatment regimen. This is all completely oral, which makes the study unique and special, and we’re seeing impressive results. The CAPTIVATE study is randomizing the MRD-negative patients. Remember, 72% of over 160, 170 patients were MRD negative. They were randomized in a placebo double-blind fashion to placebo or continual maintenance ibrutinib. For the first time, we’re going to see if we need maintenance.

We will find out if a patient population seems to benefit from maintenance. We are putting MRD into a response-adapted thought where we’re not measuring MRD, not knowing what to do with it. We’re going to start to learn what to do with it. The 25% of patients who don’t achieve MRD are randomized to monotherapy ibrutinib vs continuing the doublet venetoclax-ibrutinib and then a period of continual ibrutinib after that. That will be an interesting group to see who is not reaching MRD and then how well they do.

In that group, we’ll be also able to see if their MRD is deepening over time, because that is the big question. Right now, a lot of the data show that patients either reach MRD negativity or don’t within the first year or 2. After the second year, MRD doesn’t seem to deepen. There is something about the biology of CLL [chronic lymphocytic leukemia] that keeps MRD from deepening. The study also has a fixed-duration cohort where they enrolled another several hundred—150, 160, 170—patients who are receiving the same regimen and stopping regardless of their MRD status.

Because of the power of these 2 cohorts, they will be able to do a cross-study comparison to understand the value of stopping and the value of continual maintenance therapy in the patients who do achieve MRD. There’s a lot of power in the study. Now there are many other studies that are looking at combinations of triplet and stopping therapies, and we can go through a whole list of them. A few studies were conducted by cooperative groups.

Alliance has a study, A041702, in older patients with a triplet obinutuzumab-ibrutinib-venetoclax vs ibrutinib-obinutuzumab, where those patients are going to have a response-adapted therapy and at the end of that a combination therapy. There is an ECOG study as well, EA9161, which is for patients younger than 70 years old, where patients have a fixed-duration for the triplet regimen vs continual therapy of ibrutinib-obinutuzumab. A limitation of the study is that there isn’t a monotherapy ibrutinib arm or a fourth arm without anti-CD20 monoclonal antibodies plus the combination therapy.

We are limited in terms of understanding the benefit of that anti-CD20, whether it is going to help or not. We’ll start to see MRD rates, and these are all very similar patient populations, so we will be able to make comparisons across studies to see if these MRD rates are any different or can have an additive effect. Can we push people into the 80% bone marrow disease negative state with anti-CD20 plus the doublet?

These are exciting times, and over the next 2 or 3 years we’re going to start to see answers to those questions as the data continue to mature. These studies have an ability to impact how we might treat patients in the future. Right now, we use monotherapy sequencing treatments.

In the future, we will likely—as we did with fludarabine in adding cyclophosphamide and then rituximab—start to add all our treatments, putting our best foot forward, getting the vast majority of people to MRD-negative states. We’ll pick and choose the high-risk patient who we’ll be able to leave on a continual maintenance therapy vs the low-risk patient who might be able to receive 15-month stop and then maybe go 6, 7, 8 years and then receive the regimen again as a second treatment for a fixed-duration. Over the course of 15 years, they may have 2 or 3 years of total treatment.

That’s where it’s moving. A lot of these questions that are up in the air may be moot and obsolete in a few years as we transition to combination therapy. I’m not saying combination therapy is going to be right for every patient. There might be a patient who is older and frail and may not be right for combination therapy. We have found from these studies that there do seem to be increased toxicities. Nothing new, but things like diarrhea might be a little more severe with a combination therapy.

There are also some cytopenia issues that we start to see with combination therapy. Therefore, some of our frailer patients who are older and have low-risk disease, they’re in their late 70s or early 80s and might do beautifully with a BTK inhibitor and never need another treatment in their lifetime. Treatment is not going to be 1 size fits all. For our younger patients who are more fit or older patients, combination therapy is an exciting opportunity for them to achieve the MRD-negative state, which we do believe is important, especially if we’re going to try to stop therapy.

That’s where some of the combination data are initially starting to come out. Some studies are being done with acalabrutinib. They’re being done with PI3K inhibitors in combination with venetoclax. As long as it’s a B-cell receptor antagonist PI3K or BTK, this synergy that you get with the BCL2 in modulation of that BCL2-protein population, you definitely see this synergy along with B-cell receptor antagonists.

We’re going to have a lot of options for patients. We are going to be able to tailor treatment, and we should keep an eye out for how these studies mature and when they start to report out, definitely with PFS [progression-free survival] rate as we start to get 3, 4 years out on some of these studies.

Venetoclax Combinations, Safety and Efficacy

 I’m struck when I sit with a patient and I talk about them going on a BTK [Bruton tyrosine kinase] inhibitor–based therapy as their frontline therapy. They’ll ask me how long this is going to work. In the frontline setting, I have to answer that I don’t know because even the long-term data we have, we don’t know what the median is in terms of progression-free survival [PFS]. We’ve never been in that situation before. But let’s switch gears and talk about a BCL2 inhibitor–based therapy, venetoclax.

Venetoclax is approved in the frontline setting, and that was based on the CLL14 trial. We have seen some recent updates regarding CLL14. Maybe Dr Shadman can summarize what we know in the frontline long-term follow-up from CLL14, the trial design, and what it showed.

 The CLL14 study, in my opinion, is 1 of the most important studies for CLL [chronic lymphocytic leukemia]. It brought time limits and nonchemotherapy, or chemotherapy-free treatment, into the first-line setting. That’s very important for our patients. The study was done by the German CLL Study Group. Patients with comorbidities, defined as CIRS [cumulative illness rating scale] score of more than 6 or kidney function with the creatinine clearance of less than 70 mL/min, were randomized to receive either venetoclax and obinutuzumab as a combination therapy for a fixed 1-year duration without any role from MRD [minimal residual disease] in terms of stopping the treatment.

Every participant received 1 year of treatment, starting with obinutuzumab, and then venetoclax was added. The control arm was chlorambucil and obinutuzumab. The primary end point of the study was progression-free survival with MRD, overall survival, and response rates as other end points. It’s important to mention that roughly 12% of patients had abnormal 

, either mutation or deletion, and 60% of patients overall had an unmutated 

 gene without much difference between the 2 arms.

The initial report we had from this study showed that the study met the primary end point with a 3-year PFS of greater than 80%: 82% in the VenG [venetoclax-obinutuzumab] arm and 50% in the chlorambucil-obinutuzumab arm. The benefit was seeing all the known risk groups for CLL, including 

 gene. Because we are talking about the fixed-duration therapy, the depth of response becomes very important. Therefore, the rate of MRD eliminations is a particularly important end point.

So in peripheral blood, the percentage of patients who received VenG [venetoclax-obinutuzumab] had 76% undetectable MRD with the sensitivity of 10-4, and then the percentage of patients with MRD negativity in bone marrow was 57%. This is very impressive because what we know from venetoclax-based therapies and from this study is that the duration of response and PFS is directly correlated with the depth of response, meaning that if you achieve that undetectable MRD, the PFS would be longer. In the recent ASCO [American Society of Clinical Oncology] Annual Meeting, we saw that 18 months after finishing therapy, 47% of patients on the VenG [venetoclax-obinutuzumab] arm were still in the undetectable MRD status, which is very impressive.

For the CLL14 study, we don’t have the actual estimates as we do for MURANO, such as the exact PFS for each category of undetectable or low MRD or high MRD, but we know that they are significantly different. Unlike the discussion we had about BTK inhibitors, achieving an MRD or adding a second agent really doesn’t help the overall benefit. I agree that the benefit is not necessarily PFS. Here with a venetoclax-based therapy, we are in a very different situation because the goal is to give a fixed-duration therapy and stop.

Therefore, it does matter how good that response is. The most recent follow-up at ASCO showed that undetectable status could be durable. We’re still not seeing any new safety signals with the current follow-up, which is important. There was some report of secondary malignancies, which the numbers I believe are in the 17% range for the treatment arm versus 10%, but they are mainly skin cancers. I don’t believe there were any concerns, from what I reviewed, that there is a specific type of secondary malignancy that is more prevalent in the treatment arm.

Overall, as I mentioned, this study gives us an opportunity to offer a treatment that finishes at some point, and it’s not chemotherapy. As part of the conversation that you mentioned earlier about the decision between BTK inhibitors or venetoclax-based therapy, 1 of the factors to consider is that while venetoclax-based therapy is a great treatment and we talked about the benefits, it’s not as easy to start as BTK inhibitor–based therapy. As we discussed in regard to the coronavirus pandemic, you can start patients on treatment without even seeing them.

Hopefully that won’t happen, but it’s not impossible. You can follow patients’ labs and start them on treatment. With venetoclax, you need teamwork. You need a lot of coordination. There is a risk of tumor lysis syndrome [TLS], and there are strategies that you must follow to decrease that risk. One would be choosing the right patient for treatment. If you have a patient who’s not able to follow the recommendations in terms of coming to the clinic and following the ramp-up protocol, or they have unstable kidney function, maybe venetoclax-based therapy is not the best treatment option for them. Most important, involve the patient.

One of the differences in CLL14, which is a frontline study, and MURANO, which is a relapse study—we’ll talk about it later, I believe—is that CLL14 starts patients with obinutuzumab. With this approach, from the lymphocyte count standpoint, we’re able to downgrade these patients in terms of TLS risk. In the real practice, this approach may not be adequate in patients who have significant bulky disease, so in those cases, you add more time to that antibody or use other strategies.

In general, it is important to follow the CLL14 schedule and regimen—I follow it religiously—until we have more data. As great of a drug venetoclax is, we don’t want a situation where a patient develops TLS when it was preventable. Venetoclax is a new option for us and is that initial phase of debulking and ramp-up that we have as part of the conversation with patients.

Venetoclax and Obinutuzumab in CLL

 We’re always looking for other therapies in our relapsed CLL [chronic lymphocytic leukemia] patients, and it would be neglectful not to mention CAR [chimeric antigen receptor] T-cell therapy and, of course, allogeneic stem cell transplantation. Of course, allogeneic stem cell transplantation has also decreased in our CLL population remarkably over the years because of the advent of novel agents. Those were typically the patients who had high-risk disease, 17p, 

, complex karyotypes, and failed chemoimmunotherapy or other therapies, or those who may have transformed. We would be taking those young, fit, high-risk patients to transplantation, but they were still a minority of patients that we were seeing.

We’ve made a lot of strides in CAR T-cell therapy. You see improvements in the response and efficacy but also a decrease in the adverse-effect profile of CAR T-cell therapy. It’s a modality that’s including more clinical trials. It’s obviously approved in our relapsed diffuse large cell patients as well as ALL [acute lymphocytic leukemia], but ongoing clinical trials in CLL look very promising. Of course, whether we use that modality after many subsequent lines of therapy is always an argument. If you save things like transplant and CAR T-cell until the patient is refractory, those are harder patients to salvage with these types of modalities. Clearly, depending how that data go, if the efficacy and the adverse-effect profile continues to improve, clearly there’s a potential that those modalities, or CAR T cells, might move up. It typically tends to be patients who are multiple relapsed, where we’re still using CAR T cell. Again, transplant seems to be further pushed down the line given the plethora of combinations and these novel agents that are approaching. As I said, there are many second-generation and other BTK [Bruton tyrosine kinase] inhibitors that we’re evaluating to salvage our patients; these modalities tend to be pushed off further.

We’re looking at other B-cell receptor pathway agents that are being studied, and there are lots of novel agents in the B-cell receptor pathway that we’re looking at as well. There are a ton of new agents, like CDK9 inhibitors, and there are a ton of new agents that are in phase 1 and phase 2 trials that are constantly being evaluated for CLL and refractory CLL patients.

In terms of groundbreaking transformation of CLL therapies, the BTK inhibitors and venetoclax-based treatments really have changed how we approach our CLL patients. They’ve improved the overall survival and the progression-free survival of our patients. There have been dramatic improvements to the therapy of our patients. These are going to be the mainstays of our treatments. Monotherapy versus combination therapy are still being worked out, but clearly these are drugs that are here to stay.

Hopefully we’ll find newer therapies to salvage even those players who have relapsed after BTKs or after venetoclax-based combinations because we’ll always be looking for newer therapies that are curative. Hopefully 1 of these will be a curative therapy for all. Given that the disease is so complex—and it’s probably not 1 disease; there are multiple subtypes—it may not necessarily be 1 agent by itself. It might be a combination of agents that will achieve such a cure or certainly a long disease-free survival, as did in that subgroup of those 13q-mutated patients. Some of them have gone over 20 years without needing therapy. That would be the best thing that we could do for all our patients with CLL.

Stay tuned. There are lots of clinical trials, lots of exciting things, but we still have a lot to learn from the agents that are even approved. If we can decrease the adverse effects of those agents for our patients so nobody has a problem, that would be best for all.

Novel Therapies for Relapsed/Refractory CLL

 In the relapsed setting, what do we do with our patients? This is a little trickier because it depends on what they might have received in frontline therapy. Have their disease characteristics changed? Of course, our patient population certainly will be older by the time they hit relapse. Are there different comorbidities that we’re facing? One needs to take into account all these factors, just as you do in the front line, but certainly you have to consider what they’ve gotten and how their disease might have changed with regard to their frontline therapy. I think that’s very important.

Clearly, we have data, and some of it may not be data-driven either. We have more data for our patients who got BTK [Bruton tyrosine kinase] inhibitors in the front line, that certainly patients can then be salvaged by venetoclax-based combinations such as venetoclax-rituximab in the relapsed setting. We have a lot more data on that. Because many patients have received venetoclax-obinutuzumab frontline, we’re accruing data and getting more data about salvaging those individuals with a BTK inhibitor. One option, obviously, when we talk about the relapse data, is looking at venetoclax-rituximab or the MURANO study. Those individuals who received venetoclax-rituximab for 2 years were able to discontinue therapy and be monitored. If their disease came back, a small number of patients were rechallenged with venetoclax-based therapy, and some of them went back into remission. Can you rechallenge your patients with venetoclax-based therapy as well? Certainly, we’re waiting to accrue more data to show how you can salvage or sequence if you started with a BTK or BCL2 inhibitor up front and then in the relapsed setting. Many of us feel comfortable doing those alternatives because we know that. You’re going to have to consider what that patient has been through, has their disease changed, and what you might do depending on what has occurred prior. It’s a little trickier for sure.

We don’t see necessarily that the chemoimmunotherapy use has increased because of that in the relapsed setting. If a patient has gotten a BTK or a venetoclax-based frontline therapy, do we see then a lot more chemoimmunotherapy? I don’t necessarily see that in practice from referrals. Most people are just alternating 1 versus the other if they’ve gotten that in frontline.

Let’s talk a little about PI3 kinase inhibitors. There have been many data. Remember, ibrutinib was first to market, but the second was idelalisib-rituximab. Those were the first approvals of B-cell receptor agents in our CLL [chronic lymphocytic leukemia] patient population before venetoclax became available. Certainly, there was a lot of transitioning. If somebody had an adverse effect on ibrutinib, they would go to a PI3 kinase inhibitor, and idelalisib was used more frequently in that setting. Now there’s no PI3 kinase inhibitor that’s been approved in frontline. You have idelalisib that’s been approved with rituximab in relapse, and you also have duvelisib. That’s also been approved in relapsed CLL patients. Recent data that were presented looked at acalabrutinib versus idelalisib and rituximab versus bendamustine and rituximab in relapsed/refractory CLL patients, and the data favored acalabrutinib over idelalisib-rituximab or bendamustine-rituximab. Many of us tend to use a BTK before we use a PI3 kinase inhibitor.

What can you glean about what happens if your patient got ibrutinib or acalabrutinib in frontline therapy and then they relapse? Many of us would probably go to a venetoclax-based regimen. What about PI3 kinases? Can you use that then? There were data—most of this is retrospective data that came out, and some of that from the real-world data setting that many of my colleagues published—in multiple publications looking at that initial ibrutinib data, what happens to patients if they discontinued for adverse events versus whether they had progressive disease.

There’s no doubt that there are data for if you have a patient who is intolerant to a BTK inhibitor. Could you then salvage them with a PI3 kinase inhibitor? I think that’s absolutely correct. If you have a patient who is intolerant, whether it’s to ibrutinib, acalabrutinib, or other BTKs, can you then use idelalisib in the relapsed setting or duvelisib in the relapsed setting to salvage that individual? Yes, I think you can. Certainly, there are other adverse effects of those agents that you have to take into consideration if your patient is appropriate for them as well, but that’s certainly an option, using a PI3 kinase inhibitor.

What about patients, though, who had ibrutinib or acalabrutinib or a BTK inhibitor front line and then failed that agent? Can you use a PI3 kinase inhibitor in that situation? That’s trickier. The data from the retrospective and pooled data from real world suggests that obviously those individuals don’t do as well. Intolerance is 1 issue, where a PI3 kinase can be attractive. If they’re really refractory to a BTK inhibitor, then they won’t get much mileage out of a PI3 kinase inhibitor. A venetoclax-based combination would have more appeal.

Unfortunately, because of the plethora of agents that have now become available, the usage of PI3 kinase inhibitors has declined in CLL given the ibrutinib and now the second-generation BTK inhibitors, such as acalabrutinib or zanubrutinib. There are data even for patients who are intolerant to ibrutinib. they could possibly be tolerant to acalabrutinib. There are data showing that in a cohort of patients, not all of them had those adverse events occur again. You have multiple options about your patients who may have an adverse effect. Can you transition to another BTK inhibitor? We have covalent and noncovalent BTK inhibitors. There are more clinical trials running on different BTK inhibitors and whether there are patients you might be salvaging with other BTK inhibitors.

The role of PI3 kinase inhibitors has decreased, but there’s certainly still a role for them. We know that depending on the age of our patient and how long they’re living with CLL, some of these patients go from 1 regimen to another over a period of time, and you do need alternative strategies for those individuals. I think PI3 kinase inhibitors are still an important modality, but you need to self-select who those patients are depending on if they had intolerance versus real resistant disease.

Relapsed/Refractory CLL: Treatment Selection

 Dr Allan, let’s talk a little about CD20-targeted monoclonal antibodies. We heard a little about the 3-arm randomized trial with ibrutinib plus rituximab or ibrutinib monotherapy versus BR [bendamustine, rituximab]. What are your thoughts around the utility of a CD20 antibody in the setting of a first-generation BTK [Bruton tyrosine kinase] inhibitor–based therapy and particularly a comparison of rituximab versus obinutuzumab as a partner choice.

 Absolutely. It’s a great question, and it is something I don’t know if we’ve answered fully yet. To give some context to some of the viewers and physicians and/or patients who may be watching, there’s been a head-to-head study called CLL11 from the German CLL [chronic lymphocytic leukemia] Study Group, where they looked at obinutuzumab-chlorambucil versus rituximab-chlorambucil versus chlorambucil. It’s a 3-arm study in older patients with comorbidities.

CLL11 showed that obinutuzumab seems to be the superior anti-CD20 antibody in terms of its efficacy, with improved response rates as well as progression-free survival and a trend in a very modest potential overall survival benefit in this older, very sick patient population. Obinutuzumab is a glycoengineered antibody with enhanced ADCP [antibody-dependent cell-mediated phagocytosis] and a mechanism of cell kill. In my own anecdotal experience, obinutuzumab appears to be an extraordinarily effective agent.

That brings some context to what I’ll lead into. You mentioned the ALLIANCE A041202 study, where we looked at ibrutinib and ibrutinib-rituximab versus BR [bendamustine, rituximab]. There was no difference with adding rituximab to ibrutinib in terms of response rates, MRD [minimal residual disease] rates, or progression-free survival. Literally, the lines were overlapping, so I still use monotherapy BTK inhibitors, and I’m not using anti-CD20.

That brings us into the fact of the matter: We’ve never seen obinutuzumab-ibrutinib versus ibrutinib alone. There is a study iLLUMINATE, which looked at ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab. We see a little higher response rates at the first data cut, and we’ve seen that’s a better agent, but we don’t have single-agent data. As we know with monotherapy, you continue to deepen the response.

Is it that patients may get to a deeper response faster? Will that mean anything later on, 3 to 4 years later? Or will everyone plateau and get there and you got to that response faster with the better anti-CD20? It remains unknown because we don’t have that monotherapy arm. With that said, the ELEVATE-TN study, which was acalabrutinib-obinutuzumab versus acalabrutinib versus chlorambucil-obinutuzumab, does have that monotherapy arm. We see the response rates are better or deeper and CR [complete response] rates are a little higher.

MRD rates are a little higher in the acalabrutinib-obinutuzumab arm than what we saw with a rituximab-based agent. That study showed, as Dr Burke mentioned, this potential superior progression-free survival. It is very modest, with an absolute difference of only about 6%. The study wasn’t powered to be able to show that statistically, so you can’t really state that’s a true difference. Frankly speaking, follow these patients out another 3 to 4 years, those lines may come together because the anti-CD20 is only 6 months of the overall treatment.

Therefore, it does bring up this question of if you combine the better anti-CD20 agent with the BTK inhibitor, you may be able to impact a longer-term outcome, although I’m a little skeptical of that. There are some issues with it. Anti-obinutuzumab does have infusion reactions and requires an IV [intravenous] administration. There are cytopenias that we have to deal with that can be very problematic for some of our patients. Patients are getting growth factor. They’re getting very thrombocytopenic. They’re on a drug that may enhance bleeding.

We may see more bruising. All these kinds of things that you have to be worried about are the real-world practice of some of these patients who aren’t quite eligible for potential clinical trials that we’re treating in the real world. There’s potential benefit for it. But honestly—and we mentioned this—with a drug like a BTK inhibitor that you’re using for years, I find it hard to believe that 6 months of treatment with an anti-CD20 up front will significantly impact that longer-term outcome.

The longer-term outcome remains to be seen with obinutuzumab. But as the ELEVATE-TN study continues to mature, maybe that slight difference in MRD rate will matter in terms of a longer-term treatment if there is a significant number of patients who achieve MRD. We do know those patients typically do better. If you’re remaining on a treatment and you’re MRD and remain MRD, that line may start to differentiate based on those patients who were able to achieve it.

There are a lot of interesting aspects about that specific anti-CD20. It is a superior drug. I think it is the anti-CD20 we should use when we’re using an agent for CLL, although this does not hold across other histologies. We have not seen obinutuzumab and proved outcomes against rituximab in DLBCL [diffuse large B-cell lymphoma]. We have seen obinutuzumab have some impact in follicular lymphoma, so there are some properties about it that are special, that are unique. It does have some other issues, but I think there’s some value to it.

However, when I am using a BTK inhibitor, I am still typically using it as monotherapy for a lot of reasons, such as infusion reactions and cytopenias. The fact is, a long-term outcome may not actually be impacted by doing this when I’m using a drug that’s continuous. That may change a little if we talk about a BCL2 inhibitor in fixed duration, but I know we’ll be getting to that a little later. Those are my thoughts on that situation in terms of anti-CD20 and BTK.

 Dr Burke, are you using CD20 with your BTK inhibitor–based therapy in the frontline setting?

 No, I agree 100% with everything Dr Allan just said. I echo his skepticism that adding the anti-CD20 is going to really impact long-term outcomes. Even if there is a small difference in PFS [progression-free survival] that holds or may become a little significant over time, I certainly question whether that will translate to OS [overall survival] benefit. The equation is complicated. It’s not all about PFS. It’s about overall survival. It’s about toxicities. It’s about cost. We say what statement is better, and the definition of better has to do with a lot more than PFS. The short answer to your question is, no, I’m not adding new CD20 to my BTK inhibitors right now as initial therapy.

BTK inhibitor With vs Without a CD20-Targeted Antibody

 Following on those thoughts about BTK [Bruton tyrosine kinase] inhibitor–based therapy, there are second-generation BTK inhibitors that have been developed. The acalabrutinib was relatively recently approved for patients with CLL [chronic lymphocytic leukemia], and the data that supported the approval was recently published with the ELEVATE-TN trial. John Burke, maybe you can comment on—particularly if you’ve had any experience using acalabrutinib—what your experience has been in terms of efficacy, activity, and tolerability of the second generation, particularly acalabrutinib.

There’s another 1, zanubrutinib, which is not approved for CLL but is approved by the FDA for mantle cell lymphoma. We also may have zanubrutinib available for CLL eventually. What are your thoughts on the second-generation molecules?

 If you want, I cansummarize ELEVATE-TN data. These were presented by Jeff Sharman at the ASH [American Society of Hematology] Annual Meeting and then published in April of this year in 

. This is a phase 3 trial that had 3 arms. The control arm was chlorambucil-obinutuzumab, and the 2 investigational arms were acalabrutinib alone and acalabrutinib plus obinutuzumab. The patients were those similar to iLLUMINATE and CLL14. These were patients who were either older or had higher CIRS [cumulative illness rating scale] scores and thought not to be candidates for more aggressive therapy.

The primary end point was PFS [progression-free survival]. The median follow-up is just over 2 years. The data show that PFS with either acalabrutinib arm was superior to PFS with chlorambucil-obinutuzumab. There was a numerical improvement in PFS in the combo acalabrutinib-obinutuzumab arm compared with single-agent acalabrutinib. The authors were careful to state that they could not comment on the statistical significance because that was a post hoc analysis and not part of the primary end point.

In terms of toxicity, they reported the rate of atrial fibrillation [AF] at 3% to 4%, which as I just mentioned, is similar to what we saw in the earlier follow-up with ibrutinib trials. There’s a lot of talk about how AF rate may be lower with some of the second-generation agents and we’ve seen documentation of that in the phase 3 ASPEN trial of zanubrutinib in Waldenström macroglobulinemia as compared with ibrutinib. Those are the only randomized data I’m aware of, and we’re waiting on acalabrutinib-versus-ibrutinib randomized data to see if that difference in AF rate holds up.

I hear experts talk about how acalabrutinib is likely to cause less AF and less cardiac toxicity. I’m a little cautious in drawing that conclusion myself and a bit agnostic on that. The bleeding rate in the ELEVATE-TN trial was in the 35%-to-45% range. The grade 3 bleeding rate was 2%, similar to what we heard early on with ibrutinib. The 1 comment on the acalabrutinib toxicity that is a little unique, but practitioners should know, is headaches. If you haven’t heard this before, headaches are relatively commonly reported with acalabrutinib.

The data that I saw early on was that it was about a third of patients. There is probably more attention paid to that now. In the studies coming out now, we’re seeing about two-thirds of patients reporting headaches. How many of those are actually because of acalabrutinib versus the fact that people get headaches and they get reported, I’m not sure. It certainly seems that there’s a headache signal. The headaches are usually manageable. I tell my patients to try caffeine and Tylenol and those types of things.


Usually it will help manage the headaches, and most patients are not having to stop the drug because of intolerable headaches. In my hands, acalabrutinib has been well tolerated. I haven’t used as much of it as I have ibrutinib. So far, I haven’t had any major problems. However, I did have 1 bleed in a patient who I was forced to use acalabrutinib concurrently with an anticoagulant, so there you go. I’d be cautious about that.

Second-Generation BTK Inhibitors in CLL

 When we talk about the future of CLL [chronic lymphocytic leukemia] and we talk about these combinations, there are many studies that are looking at multiple combinations as I alluded to earlier, looking at a Bruton tyrosine kinase [BTK] plus a BCL2 inhibitor, even triplet combinations, looking at a BTK, and venetoclax, and a monoclonal antibody. There are chemotherapy novel agent combinations with reduced-intensity chemotherapy plus a novel agent like a BTK or venetoclax. There are multiple strategies looking at whether these other options might be better for disease. As I alluded to earlier, I think it would be naïve for any of us to think that these combinations wouldn’t have great efficacy in our patients; they do. Those combinations are often time-limited, which I think is an advantage and appeal for many of us and our patients, that they’re not on chronic, continuous daily therapy.

However, I think we have to figure out whether that’s appropriate for all. We see these high response rates; one thing we need to learn about is how long that will last, how do we salvage those patients who have gotten a doublet or a triplet, what they will be sensitive to, and have we changed the resistance pattern or the milieu of their CLL, or complications that they may incur by those doublets or triplets. I think there’s a lot to learn. I don’t think we have the right answer just yet. That’s why that discussion of do you do frontline monotherapy versus a venetoclax/anti-CD20 antibody combination with your patient is relevant because it’s a preference, and there are many factors to consider. Unless there’s something that really stands out, I don’t think we have the answer that one is better than another just yet. And again, there are many trials looking to address this issue of if they start this combination, whether they continue one of the agents versus stopping.

There will be many randomized studies that hopefully…it will take us time to figure out. Given how well patients are doing, these data got presented recently at ASCO [the American Society of Clinical Oncology annual meeting], the updated data of long-term ibrutinib or acalabrutinib as monotherapy in front line. There were really great PFS [progression-free survival] curves in the frontline untreated population, albeit those patients are continuing on oral therapy. You can see that patients are doing really well with these novel agents. Figuring out whether there is one strategy better than another is going to take us some time to do. Obviously there’s a great appeal to get people off of therapy for many reasons, financial considerations, long-term toxicity issues because they’re on chronic, continuous therapy; there are many advantages to looking at time-limited durations of therapy. Of course, we have to look at the adverse effect issues, change of resistance patterns, how do we salvage those patients after, things like that because then our patient population only gets older, and are you going to go back to chemoimmunotherapy? There are a lot of factors to consider.

Having those patients appropriately enrolled on these clinical trials I think is paramount. It’s very important as we study these exciting combinations to figure out, long term, what might be the best strategy. Again, it may not be one-size-fits-all unless there’s a home run entirely. I think there are many patients who are completely appropriate, happy, and content to be on monotherapy. Just stay tuned, we’ll have to see, but many exciting combinations are being evaluated.

Therapies in the Pipeline for Frontline CLL

 Given the recent pandemic, of course, a lot of us are doing a lot more telemedicine these days. This was already starting to brew in many of the medicine departments for other reasons prior to the pandemic, but the pandemic definitely pushed this out to the forefront. I think there are many patients you can do this for, and a good proportion of my patients now are on telemedicine, although it’s actually a little less than previously during the height of the pandemic in New York. I assume this will be evolving across the country depending upon their incidence of COVID-19 [coronavirus disease 2019] around them. Where it was mostly telemedicine then, now probably it’s changed back, in my practice it is maybe 60/40 right now. But I think that’s evolving because patients are coming back to clinic.

There are a proportion of our patients who are on active observation, for example, who certainly can be on telemedicine. They can have local laboratory tests; there are services that some patients use that can have labs drawn at home depending upon their insurance or capabilities, or they can go to a local lab and then have a telemedicine visit because they’ve been stable for years; they’re doing well otherwise. The thing that I always stress to patients, even during the pandemic, is that their health needs are more important. If somebody is sick and they need to be evaluated, I think that’s a no-brainer. They need to come in and see their physician or their care provider because otherwise their medical issues are not being attended to because they’re so fearful of the virus.

Many medical centers and practices are providing PPE [personal protective equipment], or patients have PPE when they walk through the door. They are cleaning facilities, providing masks and gloves, and doing what they need to appropriately try to control the environment, to try to reduce the risk of infection from COVID-19. I think if patients need to be seen, they need to be seen. It’s a crime not to have those individuals who are sick be seen because then they wind up coming to the emergency department really sick. For some of our patients with chronic lymphocytic leukemia [CLL], that can be really life-threatening depending upon the circumstance.

There are many patients, though, for whom I think even continuing telemedicine is completely appropriate, and then if there’s something that seems alarming on that telemedicine visit, then you can convert them to coming into the office. I think this will stay. There are many patients who appreciate this. I think it makes it easier even for patients who come long distances, or don’t have the social support in which they could otherwise. Depending upon where they’re visiting, there may not be visitors allowed into the center and they need their social support, their spouse, their family member, their friend to come with them, unless that changes depending upon the pandemic. I think that doing telemedicine makes it very easy to have access to their physician or their providers, and they very much appreciate it. We, as physicians, just need to have a heightened level of escalating that visit if there seems like there’s something that’s not OK with that patient.

Many of our patients converted to telemedicine. I think that’s changing now that patients are feeling more comfortable, depending on where they are in the country. Each of us will need to find the right balance for our patients with CLL to figure out that some of them can continue telemedicine and decrease the frequency of their in-person visits, and other patients, if they’re active, will be coming in routinely.

Telemedicine for Patients With CLL

 Let's focus a little bit on BTK [Bruton tyrosine kinase] inhibitor-based therapy and have some discussion around that. Dr Shadman, we’ll start with you and maybe you can give us a summary. Ibrutinib has been around the longest, it was the initial BTK inhibitor that was available and studied. What are the data that we have available to review with ibrutinib in the frontline setting? Who does it work for? What are the expected responses that we see with ibrutinib-based therapy?

: The current era really started with ibrutinib, as you mentioned. As oncologists or hematologists, we're very interested in long-term data regarding how effective these drugs are and how safe they are. For example, we now have the phase 1b/2 study, PCYC-1102, for the initial study where ibrutinib was used in both frontline and relapsed settings. An 8-year follow-up of that specific study was recently published in 2020. There are a lot of studies using ibrutinib in combination or as monotherapy.

To briefly mention some of the take-home points from those studies, the 7-year progression-free survival rate in the first-line setting is 83% and the median was not reached. This is outstanding for a drug that has been around for that long. There are still patients taking it with such a great efficacy. Of course, as you mentioned, the numbers are lower, as expected, in the relapsed setting. For frontline, we are looking at an overall survival rate of more than 80%.

Interestingly, we are also getting more information about some of the adverse effects of ibrutinib. For example, the 5-year follow-up of the RESONATE-2 study, which was published last year, is telling us that most of the adverse effects of ibrutinib decline over time, with an exception of hypertension. So, the more we use ibrutinib, the adverse effects that will lead to drug discontinuation would basically disappear with the exception of hypertension.

More importantly, based on the long-term follow-up of the RESONATE-2 study, we are seeing that the quality of response improved over time. With the initial report of RESONATE-2, the CR [complete remission] rate was reported to be around 11% with 18-month follow-up, and 30% with 5-year follow-up. That, again, is an important message. What I gather from these 2 studies, and long-term follow-up of these studies, is that this is an effective drug. Ibrutinib works and if you take it longer, it works better and the quality of response improves.

Of the adverse events that patients may have issues with initially, most will go away, or there are interventions that may help with those symptoms, such as dose reduction or supportive care. More importantly, we're not seeing signals that the biology of the disease is changing in terms of transformation to more high-risk histology, as we’ve seen with other malignancies. I think it's important to continue to have follow-up studies from those initial studies, but this is really promising.

This is our first drug that really changed the landscape, and it's very reassuring to see that it remains to be effective and also safe, meaning no new safety signals or concerns. Of course, we then have a randomized study, the Alliance A041202 study, which was a very important 3-arm study that targeted patients who we would consider bendamustine or rituximab-type patients. In the study the patients either received bendamustine or rituximab or ibrutinib, or a combination of ibrutinib and rituximab.

The study tried to answer 2 important questions: ibrutinib-based therapy vs BR [bendamustine, rituximab], which is a very popular regimen for the frontline setting, or was at the time, and whether rituximab specifically added to ibrutinib would be beneficial. Now the study, as we know, was positive in terms of the end point in favor of ibrutinib-based therapy, and the primary end point being progression-free survival [PFS], with a 2-year PFS based on the original publication of 88%, which is outstanding.

With a longer follow-up of those patients, it sounds like this continues to be the case. What I mean by longer follow-up, we don't have a follow-up publication, but later in the course of treatment, it sounds like the benefit of ibrutinib-based therapy was seen in both mutated and unmutated

 for the primary end point of PFS, and I think that's very important. As Dr Burke mentioned, there is no overall survival [OS] benefit yet in favor of ibrutinib-based therapy.

So, if somebody really wants to go with BR, in my opinion, there are other reasons to convince them not to do it. From the OS standpoint, this study hasn't shown that ibrutinib-based therapy is better than bendamustine, rituximab. Again, a very important finding from this study was that rituximab really didn't add anything to ibrutinib therapy, so ibrutinib is used as monotherapy. Now, we can talk about other CD20 monoclonal antibodies and whether those could be beneficial, and other BTK inhibitors, but specific to rituximab and ibrutinib, there's really no point of using the combination.

Of course, the CLL [chronic lymphocytic leukemia] community became a little bit concerned when there were 7 sudden deaths reported on this study on the ibrutinib-based arms. That makes us look a little more closely at the other studies that use ibrutinib to see if this is something that is consistent. That’s basically the 3 major studies that use ibrutinib for the elderly and less fit population in the frontline setting.

: There are a couple of interesting things that emerged from the longer-term follow-up that we didn't really know. Early on, it was getting good responses, but with the long-term follow-up data, you really see that the PFS is excellent. Even though the MRD [minimal residual disease] rates are not high and the CR rates are not high, the progression-free survival rate is outstanding. You can feel comfortable and your patients can feel comfortable, that when they start this drug, they are likely to have good control of their CLL for a long time.

The second point is we talked about initially when these drugs were coming out that they never achieved a CR. That’s not quite true. In fact, as you pointed out, with longer follow-up they are achieving CR in a higher percentage of patients. The third point is that the toxicities are a little higher than first reported. When we first heard about atrial fibrillation [AF] with ibrutinib in some of these studies, it was at that 3% to 5% range, and the grade 3 bleeding was at a 2% to 3% range. We are seeing with the longer follow-ups that they’re starting to parallel the real-world data. When I heard the 3% to 5% AF number, I said, that seems to be lower than what I see in my practice. Now, with the longer follow-up on these trials, it’s more like a 10% to 15% to 20% range of folks who are getting AF, and the actual grade 3 bleeding rate is about 10%, often in conjunction with other anticoagulants. I think the toxicities are a little higher than we heard about early on when these data were coming out.

Mazyar Shadman, MD, MPH, Fred Hutchinson Cancer Research Center

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