 We’ll move on to segment 2 of our discussion, where we’re going to talk about the evolving treatment landscape and specifically fixed-dose regimens for patients with CLL [chronic lymphocytic leukemia]. We already have 1 fixed-dose regimen, venetoclax [Venclexta] plus obinutuzumab [Gazyva], in frontline CLL, but there are other oral doublet regimens which have come along, namely the combination of ibrutinib [Imbruvica] plus venetoclax.

I want to talk about 2 trials. One is the CAPTIVATE study, which is a large international effort where patients with CLL who were previously untreated and needed treatment were given a combination of ibrutinib plus venetoclax. The design of these trials had patients given ibrutinib for 3 months and then venetoclax was added. Venetoclax was added for a combination duration of 1 year. At that time, there were 2 arms to the study. In 1 arm that was the only treatment given. That was a fixed-duration cohort. Then there’s another arm in the study where patients were randomized based on MRD [minimal residual disease] to subsequent therapies.

These data were updated more recently, and they will be updated at the upcoming ASH [American Society of Hematology Annual Meeting] as well. But what was clear from these data was that the combination of ibrutinib plus venetoclax leads to high rates of bone marrow MRD negativity, at about 65% to 70% at the 1-year mark for these patients. These data were consistent with other phase 2 data from other centers as well, where it was about 60% to 70% MRD negativity in the bone marrow. That was the large multicenter phase 2 CAPTIVATE study.

Importantly, at the EHA [European Hematology Association] meeting over the summer, the phase 3 data from the GLOW study was reported. In the GLOW study, the same regimen was taken: ibrutinib plus venetoclax for a total duration of 1 year. There’s 3 months of ibrutinib, then venetoclax starts, and then venetoclax plus ibrutinib goes on for 12 months. That’s a total of 15 months of the regimen. That regimen was compared with chlorambucil plus obinutuzumab.

Obviously, the comparator here isn’t the most optimal comparator for randomized studies. It’s probably the last study using that randomized arm. But the investigator showed that the progression-free survival was in favor of ibrutinib plus venetoclax as opposed to chlorambucil plus obinutuzumab. That’s not a total surprise. That was a phase 3 registrational study.

Based on those data, I expect that this regimen of ibrutinib plus venetoclax may eventually get approved by the FDA in the United States. Then we’ll have 2 different venetoclax-based regimens for time-limited approaches. We’ll have venetoclax plus obinutuzumab based on the CLL14 study, which is also a 1-year regimen, and we’ll also likely have the regimen of venetoclax plus ibrutinib, which is also about a year, and doesn’t have any IV [intravenous] drugs or infusions involved.

Strategy will change when that regimen becomes FDA approved. One of the important things at that time will be how we incorporate that regimen of ibrutinib plus venetoclax for our patients when we already have very effective regimens, including acalabrutinib [Calquence] and venetoclax plus obinutuzumab. That will be another regimen to add to the mix for our patients for discussion.

Richard, we talked about this combination, double oral strategy. How do you think that will play out for the patients if the FDA approves that regimen? In which patients would you think about using the doublet of ibrutinib plus venetoclax?

These are great treatment strategies. As an aside, the GLOW study had to be done for the purposes of approval, but it doesn’t tell us or teach us anything of relevance. It’s unfortunate that those types of studies need to be done. We always talk about CAPTIVATE as a phase 2, but CAPTIVATE is probably one of the most important studies we’ve recently done that’s really going to help us understand whether fixed-duration therapy is the best option for our patients. When people start receiving either 12 or 24 months of venetoclax as part of the CLL14 or the MURANO trial regimens, the treatment duration is relatively arbitrary. We don’t know whether we’re harming our patients and leaving efficacy on the table by discontinuing the therapies at these fixed durations.

One of the things I appreciate about the CAPTIVATE study is the idea that in the MRD treatment arm, patients will be randomized to either stay on ibrutinib alone or go on placebo to see whether that makes a difference. When patients relapse on placebo, they’re going to be able to go back on ibrutinib to show that we didn’t breed any resistance. The patients in the fixed-duration trial are going to have the same options, and that will also show us that we’re able to intermittently treat our patients without the development of resistance. These being oral agents and the ibrutinib being able to debulk the tumors and avoid the tumor lysis from venetoclax make it such a great strategy that can really benefit the patients.

 Yes. That’s fantastic. There are more longer-term follow-up data with venetoclax/obinutuzumab, but taking 2 oral drugs together has some appeal to it without worrying about things like infusion reactions and chair time with obinutuzumab. There are ongoing randomized studies, including CLL17, which is comparing these regimens head-to-head. It’s ibrutinib alone vs ibrutinib plus venetoclax vs venetoclax plus obinutuzumab. There are other studies being planned as well. Eventually, in due course, we’ll know in a randomized fashion if one is better than the others in terms of the efficacy or safety profile. But for now, we’ll certainly have more options available for our patients. A lot of patients, at least in my practice, prefer time-limited approaches over taking the continuous daily therapy. That would appeal to them.

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Nitin Jain, MD, leads the discussion on the use of fixed-dose regimens for the treatment of CLL as seen in the phase 2 CAPTIVATE and phase 3 GLOW trials.

Role of Fixed-Dose Regimens in CLL

 Moving on to the next segment, we’ll talk about head-to-head BTK trials. I’ll pass it to Dr Furman.

 Thank you. I want to make some remarks on the prior discussion. When we talk about using a BTK inhibitor—ibrutinib, acalabrutinib, or zanubrutinib—or venetoclax and obinutuzumab, once a drug is approved, it can be used for any reason or indication and it’s important to tailor our therapies to what’s going to be the best data-driven treatment for our patients. As of now, we don’t have a lot of information on obinutuzumab or any anti-CD20 having a significant effect compared with the actual novel agent. It’s important to consider the role of the toxicities associated with obinutuzumab: the infusion reactions, tumor lysis, impact on COVID-19 immunity, or even just coming into the office and weighing that against everything else.

For the rest of the conversation, I’m going to focus on the BTK inhibitors that we have available. We have 2 trials that are designed to compare ibrutinib with acalabrutinib: the ELEVATE-RR on relapsed/refractory disease and the ALPINE study, which looked at zanubrutinib vs ibrutinib. I want to caution everyone that these trials were done in different populations and the data can’t be extrapolated from 1 trial to another. We fortunately have an embarrassment of riches in CLL [chronic lymphocytic leukemia], so we have a lot of good options. It affords us the opportunity to be a little choosy.

The first study looking at ibrutinib vs acalabrutinib was done in patients who had 17p deletion or 11q deletion and relapsed. The vast majority of these patients relapsed after chemoimmunotherapy. The original inclusion for 11q was based on early data suggesting that 11q deletion predicted a worse outcome compared with trisomy 12, 13q deletion, and no abnormality by interphase FISH [fluorescence in situ hybridization]. Of course, 17p deletion has always been the worse predictor of outcome with chemoimmunotherapy and BTK inhibitors. Interestingly, subsequent data showed that 11q deletion lost its poor prognostication with BTK inhibitors. But the study was designed to look at patients with 11q and 17p deletions who had relapsed. These represented the worst of the worst.

Patients were randomized 1:1 to acalabrutinib 100 mg twice a day or ibrutinib 420 mg daily, and we were following for progression-free survival. The overall response rate was an important evaluation as well. With the median follow-up of about 40 months, the median progression-free survival was equal for both arms at about 38 months, showing that there was noninferiority of acalabrutinib to ibrutinib.

The rest of the data generated were using a hierarchical assignment, where they were able to look at different criteria as long as there was statistical significance. Once they had criteria that didn’t meet statistical significance, they couldn’t comment statistically in the subsequent assessments. The first assessment was going to be based on the rate of atrial fibrillation [AFib]. If that proved statistically significant, then they could look at the risk of infections and then Richter transformation.

They didn’t see a statistically significant increase in atrial fibrillation with ibrutinib as compared with acalabrutinib. This rate was about 16% vs 9%. It’s hard to compare across trials because these were also patients who were beaten up by prior chemoimmunotherapy and likely had significant comorbidities, so we might see the atrial fibrillation rate a little higher in this patient population. The subsequent analysis showed that there was no difference in infection risk, so that was the last assessment made.

The second trial, ALPINE, is looking at zanubrutinib vs ibrutinib. It used overall response rate as a primary end point and showed an improved overall response rate by iwCLL [International Workshop on Chronic Lymphocytic Leukemia] indication for zanubrutinib compared with ibrutinib. But there’s an important caveat: the overall response rate determination only used CR [complete response] and PR [partial response] and excluded PR with lymphocytosis. Using just the CR and PR criteria, we see an improvement in overall response rate for zanubrutinib compared with ibrutinib. This wasn’t statistically assessed, but when using PR with lymphocytosis, the difference becomes numerically much smaller.

Subsequently, the data were looking at adverse events, and there was also a significant reduction in cardiovascular and atrial fibrillation with zanubrutinib compared with ibrutinib. We have these 2 studies showing at least equivalency among the 3 BTK inhibitors in terms of efficacy, but with diminished cardiovascular adverse events for acalabrutinib and zanubrutinib compared with ibrutinib.

 That’s a very nice summary. One thing to point out, which you highlighted, is that the median follow-up of these 2 trials was quite different.

 There’s almost 4 years for acalabrutinib and just over 1 year for the zanubrutinib ALPINE study. If you look at a cross section of the atrial fibrillation rate and the cross-trial comparison, you may think that 9.4% AFib with acalabrutinib seems much higher than 2.5% with zanubrutinib. But you have to take into consideration the time these patients were followed. There was much longer follow-up for the acalabrutinib trial, so more patients had time to get those events. With the ALPINE study with the longer follow-up, the rate of atrial fibrillation also increased with time. We’ll have to see with a longer follow-up how the AFib rate plays out, but it should hopefully stay significantly less compared with ibrutinib.

 One aspect of atrial fibrillation that’s very relevant to discussion is it looks like the rate of atrial fibrillation has a dramatic increase during the first 2 years and then levels off. The slope from 2 years beyond for acalabrutinib, ibrutinib, and zanubrutinib all look to be the same and probably equal to what might be considered age-related rates of developing AFib. The first 2 years are so critical in trying to assess the effect of the BTK inhibitor on the development of atrial fibrillation.

 I have a question for you about these head-to-head trials. In your practice or in general rounds, are you using second-generation BTK inhibitors for your patients based on these data in the relapsed and frontline settings?

 I am exclusively. It’s nice to have at least the acalabrutinib and zanubrutinib to avoid the adverse events that are likely going to be most problematic for the individual patient.

 Right. That has been the practice of our group, moving to the second-generation BTK inhibitors as opposed to ibrutinib after these data. Plus the early phase data were also indicated toward better tolerability of second-generation agents compared with ibrutinib.

Richard R. Furman, MD, leads the discussion on clinical implications from head-to-head trials of BTK inhibitors in the relapsed setting for patients with CLL.

ELEVATE-RR and ALPINE Trials in Relapsed CLL

 program titled “Updates in CLL: What’s on the Horizon in CLL?” I’m Nitin Jain. I’m an associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas. Tonight, I’m joined by Dr Richard Furman from Weill Cornell Medicine. Dr Furman, do you want to introduce yourself?

 I’m Richard Furman from Weill Cornell Medicine in New York City.

 The treatment of CLL [chronic lymphocytic leukemia] has evolved and continues to evolve as we’re incorporating new agents in the therapy of CLL. Through our discussion, we hope to review the head-to-head data of BTK inhibitors in the treatment of patients with CLL, discuss new and novel therapies on the horizon, and take an in-depth look at where new therapies and regimens will fit into the already evolving treatment paradigm for patients. Please submit questions for our Q&A portion of the program, and we’ll take as many as possible toward the end of the session. This program will be led by myself and Dr Furman. Let’s get started.

In the first segment, we’ll talk about the role of BTK management in the context of CLL. We have at least 2 BTK inhibitors approved for CLL in the frontline and relapsed settings. These include ibrutinib, which was the original BTK inhibitor approved in 2014 for patients with CLL based on the RESONATE study, which was in relapsed/refractory CLL. Subsequently, we have RESONATE-2 data, which led to the approval of ibrutinib in the frontline setting. Then we have acalabrutinib, a second-generation BTK inhibitor that was approved a couple of years ago. It has fewer off-target effects than ibrutinib.

Several phase 3 studies have been reported with this agent. The first, in the relapsed/refractory setting, was the ASCEND trial, which was acalabrutinib vs BR [bendamustine, rituximab] or idelalisib. In the frontline setting was the ELEVATE-TN trial, which was focused on acalabrutinib vs acalabrutinib plus obinutuzumab vs chlorambucil-obinutuzumab. More recently was the ELEVATE-RR trial, which compared 2 BTK inhibitors head-to-head. The therapy options for CLL with these agents have evolved, and both agents are approved in the frontline and relapsed settings for CLL. The other agent I didn’t mention is venetoclax, a BCL2 inhibitor that’s approved in combination with obinutuzumab in the frontline setting for CLL and in combination with rituximab for relapsed/refractory CLL.

In terms of the strategy recommended by the NCCN [National Comprehensive Cancer Network] Guidelines, the role for chemotherapy is very limited in the context of CLL. An argument could be made for a certain subgroup of patients who are young and fit and have 

 mutations, where chemotherapy such as FCR [fludarabine, cyclophosphamide, rituximab] could be used. But I’d argue that with the data we’re seeing and will see at the upcoming ASH [American Society of Hematology Annual Meeting], the use of FCR [fludarabine, cyclophosphamide, rituximab] has gone away, and the role of chemotherapy has declined for these patients. In the frontline setting, we have 3 FDA-approved agents: the 2 BTK inhibitors I already mentioned, which are to be given continuously indefinitely, and a time-limited approach of venetoclax plus obinutuzumab for patients with CLL, which is to be given for 1 year.

There are pros and cons for these approaches. I’ll let Dr Furman share his thought process for when he’s thinking about these frontline FDA-approved approaches for patients with CLL. Richard?

 Thank you, Nitin. I appreciate the opportunity. This is an amazing time in CLL treatment because for the first time, we have the ability to treat our patients with very effective agents that don’t appear to have significant long-term toxicities. The most worrisome toxicity, as you alluded to, is the chemoimmunotherapy affecting not just the immune system function but also bone marrow survival. Patients who have mutated immunoglobulin genes and achieve a long-term remission with FCR [fludarabine, cyclophosphamide, rituximab] chemotherapy have to worry about secondary MDS [myelodysplastic syndromes and AML [acute myeloid leukemia], as well as infections. With COVID-19, it should be ever-present. We have the opportunity to control the disease with therapies that are extremely well tolerated, and taking advantage of them is in the best interest of our patients.

 One of the questions that comes up is how to select between the 3 FDA-approved therapies. There’s the BTK inhibitor vs the combination of BCL2 plus obinutuzumab. There are pros and cons to these approaches. In terms of the data, we have the longest track record with ibrutinib. It has the longest follow-up data available. But patients on ibrutinib have risk of atrial fibrillation, ventricular arrhythmias, and other adverse effects, which can be quite problematic, including arthralgias and hypertension.

With acalabrutinib, all the same adverse effects could occur but at a lower frequency, and it has the adverse effect of headaches, which can occur during the first month of therapy. Then we have venetoclax-obinutuzumab, which has the advantage of being a time-limited therapy. There’s no risk of atrial fibrillation, but it requires the logistics of TLS [tumor lysis syndrome] monitoring. Patients have to come to the clinic quite often. Obviously obinutuzumab is given IV [intravenously], so that requires chair time in the infusion unit. There’s also neutropenia. Almost 50% of patients will develop grade 3 or 4 neutropenia. You have to watch them closely and give them G-CSF [granulocyte colony-stimulating factor] support. Many times, there are dose reductions for these patients. For the usual patients, these are the options I discuss in the clinic with them to come up with the right plan of what they want to do.

Nitin Jain, MD, and Richard R. Furman, MD, review available treatment options for the treatment of CLL and discuss the safety and tolerability of these therapies.

BTK Inhibitors in the Management of CLL

Nitin Jain, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses the combination of venetoclax (Venclexta) and ibrutinib (Imbruvica) in chronic lymphocytic leukemia (CLL).

Outcomes of patients with CLL have improved remarkably over the past few years, says Jain. Two of the current FDA-approved agents, venetoclax and ibrutinib, are effective, but they generally lead to partial remissions.

In a phase II trial of patients with previously untreated high-risk CLL and relapsed/refractory CLL, the combination of venetoclax and ibrutinib was evaluated. Patients received ibrutinib for 3 months as monotherapy, and then venetoclax was added. Those eligible for the trial were patients with high-risk features, age 65 or older, and relapsed or refractory.

Preliminary results for the first 77 patients were presented at the 2017 ASH Annual Meeting, demonstrating that this combination was safe and active in patients with CLL. Jain reports that the majority of patients were in partial remission after the first 3 months on ibrutinib, and a high rate of complete remission (CR) was seen within 3 months of adding venetoclax. The CR increased to 61%, and continued to improve over time, Jain adds.

Dr. Jain on the Combination of Venetoclax and Ibrutinib in CLL

Nitin Jain, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses the treatment of patients with chronic lymphocytic leukemia (CLL) who have developed Richter’s transformation.

Richter’s transformation remains an unmet medical need, says Jain. Most of the targeted therapies for CLL have not been successful in patients with Richter’s transformation.

Checkpoint blockade is a valid concept, Jain says, as well as chimeric antigen receptor (CAR) T-cell therapies—studies of which will come out in the next few years.

Nitin Jain, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses the treatment of patients with chronic lymphocytic leukemia who have developed Richter’s transformation.

Dr. Jain Discusses Treatment of Richter's Transformation in CLL

Nitin Jain, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses PD-1 expression in patients with chronic lymphocytic leukemia (CLL) who were treated with the combination of nivolumab (Opdivo) and ibrutinib (Imbruvica).

In the ongoing phase II trial, there were encouraging results of safety and activity. The overall response rate was 80% for patients with relapse/refractory CLL, and PD-1 expression on large cells appeared to predict greater activity in this cohort.

Prior research revealed increased expression of PD-1, PD-L1, and PD-L2 on CLL cells, which suggests that blocking these targets could aid in T-cell activation.

Dr. Jain on PD-1 Expression in Nivolumab/Ibrutinib Combination in CLL

Nitin Jain, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses the efficacy and safety of the combination of idelalisib and rituximab for older patients with chronic lymphocytic leukemia.

In a trial at The University of Texas MD Anderson Cancer Center, patients over age 65 were treated with frontline idelalisib and rituximab. Significant efficacy was observed with the combination — 97% of patients responded.

After an average of 9 months after starting treatment, patients experienced colitis, including some grade 3 colitis (10/64).

Jain says there is activity with the combination, but that physicians need to be watchful of colitis in older patients.

Dr. Jain on the Combination of Idelalisib and Rituximab for Older Patients With CLL

Nitin Jain, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses lymphocytosis following treatment with a B-cell receptor inhibitor for patients with chronic lymphocytic leukemia.

The initial pattern of response following treatment with a b-cell receptor inhibitor is rapid reduction in lymphadenopathy associated with increased lymphocytosis. When patients start idelalisib and this reaction occurs, a treating oncologist should not regard this as progression — it may take 6-9 months for the white blood cell count to normalize.

View more from the 2014 Chemotherapy Foundation Symposium

Nitin Jain, MD, assistant professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses lymphocytosis following treatment with a B-cell receptor inhibitor.

Nitin Jain, MD

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