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Noncovalent BTKis in MCL
Noncovalent BTK Inhibitors in Mantle Cell Lymphoma: What You Should Know

Released: October 20, 2022

Expiration: October 19, 2023

Julie M Vose
Julie M Vose, MD, MBA
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Key Takeaways:

  • Approved covalent BTK inhibitors are the second-line treatment of choice for most patients with mantle cell lymphoma.
  • Most patients acquire resistance to covalent BTK inhibitors through BTK C481 mutations, which disrupt the binding of these agents.
  • The next-generation noncovalent BTK inhibitors do not bind to C481 and are an effective treatment option for patients with mantle cell lymphoma and acquired resistance to covalent BTK inhibitors.

Overview
Mantle-cell lymphoma (MCL) is a type of B-cell non-Hodgkin lymphoma. There are several variant forms of MCL, including aggressive blastoid and pleomorphic variants and indolent variants such as the classical and small-cell histologic subtypes. In general, MCL is typically aggressive. MCL is a rare disease that represents approximately 6% to 9% of all non-Hodgkin lymphoma cases in the United States, approximately 3% to 6% of cases in Western countries, and approximately 2% to 6% of cases in Asia. The National Comprehensive Cancer Network guidelines include several first-line treatment options for patients with MCL. For patients who are eligible for autologous stem cell transplant (ASCT), aggressive chemotherapy regimens containing high-dose cytarabine followed by rituximab maintenance after ASCT have been found to be effective. For those who are ineligible for ASCT, less aggressive regimens such as bendamustine plus rituximab (BR) can be administered in the first-line setting. 

Covalent vs Noncovalent BTK Inhibitors: Clinical Pearls
The first- and second-generation BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib are approved by the FDA in the relapsed/refractory (R/R) setting after ≥1 prior therapy. Ibrutinib, acalabrutinib, and zanubrutinib are covalent irreversible BTK inhibitors that act by binding to the C481 residue of the kinase domain of BTK. They block the ATP-binding pocket, prevent the catalytic activity of BTK, and suppress the growth and proliferation of malignant B-cells, thereby causing tumor cell death. Because these covalent BTK inhibitors are very effective in many patients with R/R MCL, they are typically the second-line treatment choice. However, under certain circumstances in the R/R setting, a covalent BTK inhibitor can be combined with an anti-CD20 monoclonal antibody, particularly if the patient has a high tumor burden or lots of circulating tumor cells. This approach rapidly decreases the number of circulating tumor cells and gets the disease symptoms under control.

Unfortunately, some patients who receive treatment with these covalent BTK inhibitors develop mutations and acquire resistance to these agents. The major mechanism of resistance to covalent BTK inhibitors is the emergence of C481 mutations, which disrupt binding. Unlike the covalent BTK inhibitors, reversible noncovalent BTK inhibitors such as pirtobrutinib, nemtabrutinib, fenebrutinib, or vecabrutinib do not bind to C481 and therefore have the ability to overcome mutations in C481. They offer a potentially effective treatment alternative for patients with acquired resistance to covalent BTK inhibitors due to C481 mutations. Of note, in the phase I/II BRUIN trial, pirtobrutinib, an investigational noncovalent BTK inhibitor, demonstrated a high response rate of 51% with a complete response rate of 25% in patients with MCL who had previously received a covalent BTK inhibitor. The response rate among BTK inhibitor–naive patients was higher at 82%. Pirtobrutinib currently is being investigated in the large phase III BRUIN-MCL-321 trial vs investigator’s choice of ibrutinib, acalabrutinib, or zanubrutinib for patients with previously treated BTK inhibitor–naive MCL (NCT04662255). 

Before recommending the use of a BTK inhibitor, it is important to consider the patient’s disease characteristics, current medications, and medical history. The first-generation covalent BTK inhibitor ibrutinib is associated with a higher incidence of atrial fibrillation, bleeding events, and hypertension. For older patients with preexisting hypertension or atrial fibrillation, I tend to shy away from ibrutinib. The second-generation covalent BTK inhibitors acalabrutinib and zanubrutinib are associated with fewer of these adverse events. However, acalabrutinib is known to cause headaches. So, in a patient who is prone to headaches, I would avoid acalabrutinib. Pirtobrutinib is not yet approved by the FDA but is associated with fewer atrial fibrillation, bleeding, and hypertension events. It appears that pirtobrutinib may be a good choice for patients with progression on or intolerance to one of the approved covalent BTK inhibitors if it receives FDA approval. However, we will have to wait and see what the data show. Of note, regardless of the mechanism of action, all BTK inhibitors seem to cause arthralgias and myalgias. In summary, patients receiving BTK inhibitors, whether covalent or noncovalent, need to be closely monitored for toxicities, some of which may develop later in the course of treatment. 

Future Directions With Noncovalent BTK Inhibitors
An unmet clinical need is in finding the optimal treatment for patients with MCL harboring TP53 mutations or those with highly aggressive MCL. Typically, these patients do not respond well to initial induction chemotherapy. Perhaps the next-generation noncovalent BTK inhibitors will be able to fill this gap in the second-line setting, whether as monotherapy or in combination with conventional therapies, in the near future. In the phase III SHINE trial, the combination of the first-generation covalent BTK inhibitor ibrutinib with BR demonstrated a significant progression-free survival improvement compared with BR alone among older patients with untreated MCL. I think we will see an evolving MCL treatment algorithm with respect to the earlier use of noncovalent BTK inhibitors, particularly in patients with a higher potential to quickly develop resistance to the covalent BTK inhibitors. This approach will expand the use of this class of agents to a larger patient population. Finally, I think the use of covalent vs noncovalent BTK inhibitors will become individualized with respect to the specific mutations harbored by the patient’s disease or the patient’s preexisting medical conditions. 

Your Thoughts?
What are the challenges you experience in your practice when it comes to treating patients with MCL with acquired resistance to covalent BTK inhibitors? Answer the polling question and join the conversation in the discussion box below.

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In your current practice, how often do you discuss potential participation in clinical trials of noncovalent BTK inhibitors with your patients with MCL and progression on a currently approved covalent BTK inhibitor?
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