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FAQs: BTKis for R/R MCL
FAQs: Optimizing the Care of Patients With Relapsed/Refractory MCL

Released: April 05, 2023

Marco Ladetto
Marco Ladetto, MD
Max Topp
Max Topp, MD
Julie M. Vose
Julie M. Vose, MD, MBA
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Key Takeaways
  • Globally, the covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) are the second-line treatment of choice for most patients with mantle cell lymphoma.
  • Pirtobrutinib, a reversible, noncovalent BTK inhibitor, received accelerated FDA approval in January 2023 for relapsed/refractory mantle cell lymphoma after ≥2 lines of systemic therapy, including a BTK inhibitor.
  • Acalabrutinib and zanubrutinib are associated with lower rates of atrial fibrillation compared with ibrutinib, and trials comparing the safety and efficacy of pirtobrutinib with the 3 covalent BTK inhibitors are underway.

In this commentary adapted from a discussion among Julie M. Vose, MD, MBA; Marco Ladetto, MD; and Max Topp, MD, during a live roundtable webinar titled, “Experts Discuss Advances in the Use of BTK Inhibitors for the Treatment of Relapsed/Refractory MCL” on January 17, 2023, the experts address important clinical questions about how to optimize the use of BTK inhibitors (BTKis) in the management of patients with mantle cell lymphoma (MCL).

What is the optimal sequencing of treatments after resistance or intolerance to a prior BTKi?

Julie M. Vose, MD, MBA:
Pirtobrutinib is a noncovalent, third-generation, reversible BTKi. Based on the results of the single-arm phase I/II BRUIN trial, pirtobrutinib recently received FDA approval in the United States for the treatment of patients with relapsed/refractory MCL after ≥2 lines of systemic therapy, including a BTKi. So, for a patient with relapsed/refractory MCL with resistance or intolerance to a covalent BTKi, I would recommend pirtobrutinib.

Marco Ladetto, MD:
In this setting, pirtobrutinib is a very important BTKi to have access to. However, it is not yet available for use in Europe outside of a clinical trial setting. For older patients, especially those who are intolerant to a covalent BTKi, I would strongly consider pirtobrutinib. Of importance, the binding sites for covalent and noncovalent BTKis are different. Although this has not yet been tested, theoretically, it will be interesting to clinically investigate the reverse sequence of therapy. History has caused us to test pirtobrutinib following intolerance or resistance to a covalent BTKi. At present, therefore, it is unknown if the reverse order of a covalent BTKi after pirtobrutinib will be effective.

In Italy, I would recommend the CAR T-cell therapy brexucabtagene autoleucel for a patient with disease progression on a covalent BTKi. If the patient is not eligible for brexucabtagene autoleucel, I would strongly recommend enrollment on a clinical trial of a noncovalent BTKi, specifically pirtobrutinib.

Julie M. Vose, MD, MBA:
I agree that reversing the sequence to see if a noncovalent BTKi before a covalent BTKi would be effective is an interesting concept to investigate in future studies. 

What are your thoughts on the results of the phase III TRIANGLE trial of ibrutinib combined with chemoimmunotherapy presented at the 2022 American Society of Hematology Annual Meeting, and have these results changed your clinical practice?

Max Topp, MD:
The phase III TRIANGLE trial is investigating the efficacy and safety of adding ibrutinib to standard rituximab-containing chemotherapy with or without autologous stem cell transplant (ASCT) for previously untreated younger patients with MCL. The initial results of this trial showed that ibrutinib in combination with standard first-line therapy or as a substitute for ASCT is effective among younger patients with MCL. For younger, transplant-eligible patients with untreated MCL, the data from the TRIANGLE trial are not mature enough to skip ASCT. A median follow-up of 31 months is insufficient to fully inform about the benefits vs risks of omitting ASCT. So, I would definitely recommend ASCT following response to ibrutinib and standard first-line therapy, if the TRIANGLE regimen receives regulatory approval.

Marco Ladetto, MD: 
I agree with Dr Topp. The results from the TRIANGLE data are impressive, but in my opinion, it would be reasonable to still perform ASCT until we have longer-term follow-up data supporting the prolonged benefit of the regimen when ASCT is omitted in transplant-eligible patients.

Julie M. Vose, MD, MBA:
As of right now, the regimen used in the TRIANGLE trial has not yet received regulatory approval. However, even if upfront ibrutinib plus chemotherapy were to become available, I would continue to perform ASCT. This is primarily because I have patients who underwent transplant 30 years ago and are still faring well. 

Max Topp, MD:
Eventually, ibrutinib will be incorporated into the frontline MCL setting. The final results from the TRIANGLE trial will help to better determine how first-, second-, and next-generation BTKis should be sequenced. Obviously, the treatment landscape will continue to expand as more drug classes, such as the CAR T-cell therapies, are tested in earlier lines. With the continuous expansion of the MCL treatment landscape, the optimal sequence of these agents will be determined in clinical trials.

Julie M. Vose, MD, MBA:
I agree. Already, there are several ongoing studies of BTKis in untreated MCL. We have to wait to see what the results from these studies show to make optimal treatment decisions.

What are some of the challenges you face regarding patient adherence to BTKis? 

Max Topp, MD:
Diarrhea is a real issue for patients who are receiving BTKis, particularly because treatment continues until disease progression. A large proportion of my patients request treatment holidays because of diarrhea. Without any dataset supporting treatment breaks from BTKis, it is very challenging.

Julie M. Vose, MD, MBA:
I agree. However, during the COVID-19 pandemic, I inadvertently was forced to test the treatment break approach because some of my patients had to stop treatment for an extended period of time due to a COVID-19 infection. During this period, I had at least 2 patients who were off treatment for 6 months without disease recurrence. So, treatment breaks from BTKis may be possible in a select group of patients.

Marco Ladetto, MD: 
I totally agree. It is becoming important to find fixed-duration treatment approaches for BTKis, even if only for a select group of patients. I believe that finding a fixed duration for BTKis will be a step in the right direction, as it is every patient’s desire.

Julie M. Vose, MD, MBA:
For numerous reasons—including toxicity, associated treatment costs, and because most patients do not want to have to take a pill every day indefinitely—it will be reasonable to look into finding a fixed-duration period for BTKis.

For patients who are about to undergo a major surgical procedure, can BTKis be withheld? 

Julie M. Vose, MD, MBA:
It depends on what is being referred to as major surgery.

Max Topp, MD:
I agree. For a patient who is about to undergo hip replacement, for example, I would recommend withholding the BTKi for at least 2 weeks prior to and 4 weeks after the surgery.

Julie M. Vose, MD, MBA:
Sometimes, what the patient may consider a minor surgical procedure may be major when taking a BTKi. Patients sometimes neglect to inform their oncologists about all surgical procedures, such as having a tooth removed. I would recommend holding a BTKi for several days before and after extensive dental procedures.

In your experience, what are the major differences in the adverse events you see among the covalent and noncovalent BTKis? 

Julie M. Vose, MD, MBA:
In the United States, ibrutinib, acalabrutinib, and zanubrutinib are approved by the FDA as second-line therapy. In my experience, acalabrutinib and zanubrutinib are well tolerated, and both have a lower incidence of atrial fibrillation compared with ibrutinib. Acalabrutinib causes headache, which in my experience can be pretty significant. Sometimes, taking caffeinated drinks reduces the headaches, which seem to resolve after a month or two of receiving acalabrutinib.

Max Topp, MD:
In Europe, neither acalabrutinib, zanubrutinib, nor pirtobrutinib is approved for use in patients with MCL, except on clinical trials. Once these agents become available in Europe, I definitely will start using zanubrutinib and acalabrutinib in the approved setting.

Marco Ladetto, MD: 
Both acalabrutinib and zanubrutinib seem to be well tolerated. However, headaches are typical adverse events with acalabrutinib, and zanubrutinib seems to be associated with infections. Besides these, both agents seem to have similar toxicity profiles.

Julie M. Vose, MD, MBA:
Pirtobrutinib, which is now approved in the United States after ≥2 lines of previous therapy, including a BTKi, may be associated with less atrial fibrillation than the covalent BTKis ibrutinib, acalabrutinib, and zanubrutinib. However, this is yet to be clearly demonstrated in head-to-head clinical trials. The ongoing randomized phase III BRUIN-MCL-321 trial of pirtobrutinib vs investigator’s choice of ibrutinib, acalabrutinib, or zanubrutinib for previously treated patients with MCL who have not received any prior BTKi will shed more light on the relative tolerability profiles of these agents.

Max Topp, MD:
Of importance, the ongoing BRUIN-MCL-321 trial also will inform on the benefits of using pirtobrutinib in earlier lines of therapy, before covalent BTKis. We are eagerly awaiting the results of this trial.

Marco Ladetto, MD:
In addition, other covalent and noncovalent BTKis, such as tirabrutinib and nemtabrutinib, are under investigation in lymphomas. However, these agents are still in early phases of development. We shall be waiting for the results of these trials as the MCL treatment landscape continues to expand.

Your Thoughts?

What are the challenges you experience in your clinical practice when it comes to patient adherence to continuous BTKi therapy? Answer the polling question and join the conversation in the discussion box below.

Check back in the next few months for 2 new Interactive Decision Support Tools in MCL. The first will be an update of the current MCL tool, with treatment recommendations for many clinical scenarios from 5 experts practicing in the United States. This will be followed by a separate global version of the MCL tool with recommendations from 5 international experts from Brazil, France, Italy, Germany, and Spain.

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In your current practice, how often do your patients with MCL who are receiving BTKi therapy request a treatment break?

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