Key Takeaways

• Early trials of pirtobrutinib in chronic lymphocytic leukemia and mantle cell lymphoma have demonstrated efficacy in pretreated patients, including those who have received prior BTK inhibitors.
• Ongoing studies seek to determine the optimal venetoclax-based doublet therapy for frontline chronic lmphocytic leukemia treatment across a broad patient population and the optimal BTK inhibitor for pretreated patients with mantle cell lymphoma who are BTK inhibitor naive.

Treatment for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) is continually evolving. In this commentary, Matthew S. Davids, MD, MMSc, and Julie M. Vose, MD, MBA, discuss select studies with BTK inhibitors from the 2022 Pan Pacific Lymphoma Conference and their potential impact on the current standard of care in these hematologic malignancies.

Matthew S. Davids, MD, MMSc:
Pirtobrutinib is a highly specific BTK inhibitor that is noncovalent, which is different from the first-generation covalent BTK inhibitors that are currently approved. The phase I/II BRUIN study evaluated pirtobrutinib (formerly LOXO-305) in patients with CLL/small lymphocytic lymphoma (SLL) or B-cell non-Hodgkin lymphoma following treatment with at least 2 prior therapies, including a BTK inhibitor. Of the 618 patients included, 261 patients with CLL were evaluated. The group was representative of previously treated patients with CLL, with a median age of 69 years; all patients had received a prior BTK inhibitor; and 20% of patients had received a prior BTK inhibitor and the BCL2 inhibitor venetoclax, comprising the double-refractory population. Finally, this was a population also enriched for high-risk genetic disease markers such as del(17p) or TP53 mutation, which was seen in more than one third of patients.

A very impressive response was seen in this study, with an overall response rate (ORR) of 68%. This is remarkable considering there really isn’t a standard of care approach for these patients. Also presented was an impressive waterfall plot that highlighted the point that patients—whether they had discontinued their previous BTK inhibitor due to progression or toxicity—had an equal response to pirtobrutinib. The response was observed across different risk groups, including patients who have the classic BTK inhibitor resistance mutation BTK C481S. It is particularly interesting that these patients responded equally well to pirtobrutinib compared with patients who did not. This drug really has potential in either group of patients.

Finally, the safety profile of pirtobrutinib looks very good, and in patients with CLL, this was a well-tolerated drug. We did see some of the typical BTK inhibitor–related toxicities such as bruising, although typically low grade, with very low rates of more major bleeding and background incidence of atrial fibrillation and hypertension. There were no dose-limiting toxicities. They did not reach a maximum tolerated dose, so 200 mg was selected as the dose moving forward. I think it’s exciting, as we think about where the relapsed CLL field is heading, to know that phase III studies are now launching with pirtobrutinib compared with standards of care. Hopefully, this will eventually lead to an FDA approval for pirtobrutinib in relapsed/refractory CLL.

Julie M. Vose, MD, MBA:
The toxicity profile does look good for pirtobrutinib. Assuming the future phase III trials show similar outcomes and, in addition, demonstrate the ability to overcome some of the resistance issues, where do you think pirtobrutinib will sit in the future as far as therapy for our patients with CLL?

Matthew S. Davids, MD, MMSc:
That’s a crucial question, and they also are launching registrational trials for pirtobrutinib in the frontline setting. These studies, fortunately, will take a long time, as patients with CLL generally do well for a longer time. I think it is going to be difficult to supplant the covalent BTK inhibitors. We certainly know, right now, that the sequence of starting with a covalent BTK inhibitor and then moving to pirtobrutinib is successful, but it’s going to take several years before we have the opposite order, where we start with pirtobrutinib and then need to know whether covalent BTK inhibitors can be effective subsequently. From early reports, it does seem that a different pattern of resistance mutations is arising with the noncovalent inhibitors, and whether the covalent BTK inhibitors can overcome that remains an open question. But, to your point, because the toxicity profile of pirtobrutinib does look so good, if that really holds up in the phase III experience, it could be a best-in-class molecule and used in the frontline setting based on the safety and efficacy profile.

CLL: SEQUOIA

Matthew S. Davids, MD, MMSc:
SEQUOIA is a phase III study of zanubrutinib, another covalent BTK inhibitor that is not yet approved in CLL. SEQUOIA included multiple cohorts, but the one I think will be most impactful is cohort 1, the registrational cohort where patients were randomized to receive continuous zanubrutinib or a standard 6-month course of bendamustine and rituximab. This was an older CLL population with a median age of approximately 70 years and various risk markers. This cohort excluded high-risk patients with del(17p).

At 24 months, the data look very good for zanubrutinib. It is a relatively early look for a frontline CLL study, but nonetheless at 24 months there was an 85% progression-free survival (PFS) rate with zanubrutinib compared with approximately 70% with bendamustine/rituximab (BR). This benefit was observed across different risk groups based on genetics and various clinical characteristics. The one group without a significant improvement in PFS was patients with mutated IGHV CLL, where there was a numerical but not yet statistically significant advantage for zanubrutinib. That’s to be expected with short follow-up, and these patients can do well with BR.

The safety profile continues to look very good for zanubrutinib, with very few patients needing to discontinue due to toxicity, but there are some risks around neutropenia and hypertension with zanubrutinib. Looking at the adverse event data, in a randomized comparison of zanubrutinib and BR, most striking was that the rates of atrial fibrillation were equivalent between the 2 arms—in the range of approximately 3%—and that has not been observed with the other BTK inhibitors, including ibrutinib or acalabrutinib, where we typically see a higher rate of atrial fibrillation in these randomized comparisons with chemoimmunotherapy. Again, this is a short follow-up, and it will be interesting to see if any differences emerge over time, but it is very encouraging from a safety perspective.

I think one question that will arise is: How are we going to use zanubrutinib in CLL once it is approved by the FDA? We’ll have 3 great options in the frontline setting—acalabrutinib, ibrutinib, and zanubrutinib—and these also will be options in the relapsed setting. The bottom line is that it’s good for patients to have choices. All of these drugs have somewhat different adverse event profiles, and we’ll probably be using all three in clinical practice.

Julie M. Vose, MD, MBA:
Yes, that’s a good point. In what particular patient profile would you tend to shy away from ibrutinib and go toward some of these newer BTK inhibitors?

Matthew S. Davids, MD, MMSc:
For me, the older patients—particularly those with comorbidities that involve cardiovascular disease—are the ones where I’m avoiding ibrutinib now, because we have head-to-head phase III data comparing acalabrutinib vs ibrutinib and zanubrutinib vs ibrutinib, and to me the takeaways from those studies are that, particularly for patients with cardiovascular comorbidities, this next generation of covalent BTK inhibitors is better tolerated. I think there are still young, fit patients who can tolerate ibrutinib well—and it is once-daily dosing, and there’s a very long track record with the drug and a lot of experience—so there is an opportunity for those patients. For the decision between acalabrutinib and zanubrutinib, we do have patients, for example, who suffer from headaches. That is a known risk with acalabrutinib, so that might be a patient for whom you’d prioritize zanubrutinib. We may have patients who have issues with hypertension, and it seems like the rates are a little higher with zanubrutinib, so maybe we start that patient on acalabrutinib. Various other nuances between these drugs might push us one way or the other.

Julie M. Vose, MD, MBA:
Yes, absolutely. I think the other issue to bring up is that hypertension with ibrutinib happens sometimes very late, and you have to continue to monitor patients carefully. I’ve seen the hypertension happen years later, and it can sneak up on you, and you have to be careful about that. So that’s another patient population where you may want to change to a different BTK inhibitor.

Editor’s Note: An online interactive tool is available with guidance on managing BTK inhibitor–associated adverse events in hematologic malignancies and can be found here.

CLL: MAJIC

Matthew S. Davids, MD, MMSc:
Lastly, I want to mention the MAJIC trial, which is trying to answer the question of: What is the optimal venetoclax-based doublet for frontline CLL treatment across all-comers, all ages, and all genetic risk groups? This trial has not yet activated but is a comparison of the standard comparator arm of venetoclax and obinutuzumab with a combination of acalabrutinib and venetoclax. This is a noninferiority study with a primary endpoint of 3-year PFS.

One thing that is unique about this study is that both arms have minimal residual disease (MRD)-guided treatment duration. Typically, the venetoclax plus obinutuzumab approved regimen is 1 year for all patients regardless of their MRD status at the end of that year. To make this a fairer comparison, both arms are allowing a measurement of MRD at the end of 1 year of venetoclax. Those patients who are undetectable for MRD would stop treatment, and those who still have detectable MRD would go on to receive a second year of venetoclax. Of importance, as we move toward more time-limited therapies in CLL, all patients in the MAJIC study will stop treatment after 2 years of venetoclax-based therapy regardless of their MRD status at that time.

Another unique aspect of this study is that we’re using the next-generation sequencing–based approach clonoSEQ for our MRD testing. This is allowing us to get down to a level of 10^-5 detection consistently rather than 10^-4 by flow cytometry, which has traditionally been used in trials. The hope is that this will allow for more accurate risk stratification and identification of patients who can safely discontinue therapy and enjoy a long PFS.

Any patient with CLL in need of frontline treatment who is a candidate for venetoclax should be eligible for this study. One situation where they may not be a great candidate is in the setting of significant renal dysfunction. But this trial has broad eligibility, and we anticipate it will recruit relatively quickly.

Over time, we will see if differences emerge. Another key question that this study will help address is: Is it worth it to use the BTK inhibitor early on, or is it better to save it for later?

Editor’s Note: An online interactive tool is available with guidance on selecting treatment for CLL and can be found here.

Julie M. Vose, MD, MBA:
Yes, I think using the clonoSEQ assay is a really important discussion point. I’m not sure it’s being used very much in the community now, even though it was used in the original venetoclax trials, but do you find it difficult to use the clonoSEQ assay?

Matthew S. Davids, MD, MMSc:
We’ve found it very easy to send and have been doing so mostly for prognostic purposes in our patients receiving venetoclax-based regimens, particularly venetoclax/obinutuzumab in the frontline setting. You’re right that it’s not being widely ordered right now, particularly outside of academic medical centers. I think that makes sense because, so far, we haven’t really demonstrated a benefit for patients of using MRD-guided therapy, at least in any kind of definitive way in CLL. That’s why this is being built into the MAJIC trial—to try to generate a large dataset to show that it is feasible to get long remissions after an MRD-guided treatment discontinuation strategy. This is just one of many different studies looking at this now in CLL, including some studies comparing MRD-guided therapy with fixed-duration therapy. Hopefully, during the next few years, we’ll accumulate enough data so that MRD will be very impactful in terms of therapy duration in patients with CLL. But I think the burden of proof is on us, as clinical investigators, to demonstrate that it is useful before it will be taken up widely.

MCL: BRUIN

Julie M. Vose, MD, MBA :
Moving on to MCL, I will revisit the phase I/II BRUIN study of pirtobrutinib, which had a mantle cell component that included 134 patents—quite a large number. The average age was 70 years, which is fairly common for patients with MCL. For the most part, patients had classical MCL, with blastoid or pleomorphic histology in approximately 20% of patients. The patients were fairly heavily pretreated, with a median of 3 prior systemic therapies; 90% had received prior BTK inhibitors, almost all had prior anti-CD20 therapy, approximately one quarter had prior transplant, and some had received CAR T-cell therapy.

Just like in CLL, the responses were very important and very interesting in this heavily pretreated population. The ORR was 51%, and 25% of patients had complete remissions, which again would be very difficult in this heavily pretreated population. The efficacy in patients who were BTK inhibitor naive was fairly high, with an ORR of 82%. The median follow-up was approximately 8 months, and responses were ongoing in 60% of patients. Again, for these very heavily pretreated patients, I think these are really interesting and important results. Presumably, when this is moved up closer to first, second, or third line, the responses will be even higher.

The safety profile was very similar to that observed in the CLL subset—very well tolerated with hardly any grade 3 or 4 toxicities. There was some low-grade (grade 1) bruising, rash, and arthralgia—the usual BTK inhibitor–type symptoms—but hardly any even grade 2 toxicities in that range, so it was very well tolerated, including with regard to hypertension.

In addition to the CLL data, this shows that the tolerability of pirtobrutinib is really excellent. It’s very useful in patients for whom a different BTK inhibitor has failed or multiple therapies have failed. The next studies are looking at pirtobrutinib in a less heavily pretreated population and I think will be able to show some of these important outcomes and the tolerability we want to see.

Matthew S. Davids, MD, MMSc:
I think it’s likely that pirtobrutinib is going to get a label first in MCL, even before CLL, potentially based on an accelerated approval. If that were to happen, how would it work in your practice? Which patients would you consider for pirtobrutinib now?

Julie M. Vose, MD, MBA:
That’s going to be tough, because then we have so many choices in MCL, with 3 BTK inhibitors already approved—this would be the fourth. Again, looking at the toxicity profile for the patients and trying to see what their premorbid conditions are as far as hypertension or atrial fibrillation, clotting or bleeding issues would be one aspect to consider. We may want to look at outcomes with pirtobrutinib for patients with blastic MCL or TP53 abnormalities, but that of course is not yet known because we don’t have enough patients with those abnormalities. So, there’s a lot that is unknown, but hopefully we’ll be able to answer that in future studies.

Editor’s Note: An online interactive tool is available with guidance on selecting treatment for MCL and can be found here.

Matthew S. Davids, MD, MMSc:
Right. As we look to the future of pirtobrutinib in MCL, are there particular combinations that you’re excited about potentially being explored in future studies?

Julie M. Vose, MD, MBA:
Yes. Definitely looking at pirtobrutinib with anti-CD20 antibodies, because they work so well in MCL, as well. And then trying to look at long-term outcomes perhaps after transplant and using BTK inhibitors with or without anti-CD20 antibodies. I think we’re going to see all kinds of combinations both up front and in the relapsed setting and be able to improve outcomes for patients with MCL because, unfortunately, they do relapse again and again, just like patients with CLL, and we need multiple therapies.

MCL: BRUIN MCL-321

Julie M. Vose, MD, MBA:
BRUIN MCL-321 is large, international phase III trial of approximately 500 patients in a 1:1 randomization of pirtobrutinib vs choice of the other BTK inhibitors—acalabrutinib, ibrutinib, or zanubrutinib—in patients with previously treated MCL who have not received a prior BTK inhibitor. Basically, it is evaluating the first BTK inhibitor for this patient population. This is a very important study for seeing if pirtobrutinib is better as far as outcomes and toxicity and then, of course, for looking at the mutations of MCL to see if there’s a particular patient population for which pirtobrutinib would be better. This trial just started, and although it’s going to be a long time before we get answers to these questions, it is an important one to discuss with our patients.

Matthew S. Davids, MD, MMSc:
Do you think they’re looking at the right endpoints on this trial? Is it going to give us meaningful data?

Julie M. Vose, MD, MBA:
It is. They’re looking at response rates, PFS, and overall survival (OS). It’s going to be unlikely, at least in the short term, that there will be an OS advantage; these patients would likely need to be followed for a very long time to see that. But certainly, response rates and PFS are important endpoints, and then of course tolerability, as well. And then looking at the time of relapse—if they do get mutations, too. So, yes, I think there are good endpoints. This is an important study, and I’ll be interested to see the results.

Matthew S. Davids, MD, MMSc:
Yes, certainly I will, as well. Also, the safety comparison is going to be interesting because we don’t have randomized data comparing pirtobrutinib with other BTK inhibitors, and I wonder whether we’ll extrapolate from this MCL study into CLL if we do see meaningful safety differences among the different drugs.

MCL: BRIDGE

Julie M. Vose, MD, MBA:
The BRIDGE trial is an interesting study. This study includes patients with MCL with no central nervous system involvement and no prior stem cell transplant who receive induction with R-CHOP for 3 cycles, alternating with R-DHAP or similar regimens for 3 cycles every 21 days, and also receive zanubrutinib on cycles 1, 3, and 5 with the R-CHOP regimen. Then, if the patients have partial response or better they can go on to autologous stem cell transplant per standard of care. As part of the study, they receive zanubrutinib maintenance for 2 years after the transplant. The primary endpoint is MRD negativity, and secondary endpoints are PFS and OS.

A small initial subset of this study was presented at the 2022 Pan Pacific Lymphoma Conference. It included 7 patients with a median age of 52 years and mostly advanced-stage disease, as would be expected. All patients had peripheral blood and bone marrow involvement, as well as some with gastrointestinal and other involvement, which is typical for MCL. This is a short follow-up—a median of only 35 weeks—but they were able to complete MRD testing in the majority of patients and found that, in 5 of the 7 who had completed at least 1 MRD test, all had achieved MRD negativity in the peripheral blood and bone marrow. One patient had gone on to stem cell transplant.

As far as safety, the majority of patients tolerated zanubrutinib very well without any major adverse events or complications. Grade 3/4 neutropenia was found in only 2 of the 7 patients with zanubrutinib.

Although these data are very early, it is a really interesting analysis and design. I think this is something we’re going to see a lot more of—the different combinations of chemotherapy, immunotherapy, and BTK inhibitors together.

Matthew S. Davids, MD, MMSc:
Yes, for sure. One of the things that seems appealing to me about this design is that it’s a time-limited amount of a BTK inhibitor after those 2 years of maintenance.

Julie M. Vose, MD, MBA:
Yes, the study design is a 2-year, time-limited BTK inhibitor, which again I think is an important aspect because, unfortunately, the BTK inhibitors are expensive, and to receive these agents for an unlimited number of years can be difficult for patients, including from a toxicity standpoint. So, the time-limited aspect is very important.

Matthew S. Davids, MD, MMSc:
Yes, I agree. It also might open up using the BTK inhibitor again as another line of therapy if they have several years of remission. So, there are lots of potential advantages there.

Julie M. Vose, MD, MBA:
Yes, to have the ability to somewhat mix and match our different treatments. To have time off therapy may mean the lymphoma becomes sensitive again to that particular agent or a similar agent. So, particularly with the BTK inhibitors, that’s an important concept.

Your Thoughts?
What are your thoughts and questions on new management approaches with BTK inhibitors for patients with CLL and MCL? Please answer the polling question and join the conversation by posting a comment in the discussion section below.