Expert: Assessing the Role of Second-Generation BTK Inhibitors in Frontline Mantle Cell Lymphoma Treatment

In an interview with Pharmacy Times®, Lynnette Henshaw, PharmD, BCOP, lymphoma clinical pharmacy specialist at Memorial Sloan Kettering (MSK), focused on a real-world study at MSK evaluating the Triangle regimen for mantle cell lymphoma, incorporating first- and second-generation Bruton tyrosine kinase (BTK) inhibitors. She noted that investigators found strong efficacy outcomes, including a 100% overall response rate, 97% 12-month progression-free survival (PFS), and no new safety concerns, with adverse effects remaining manageable. Henshaw highlighted that these results support the use of second-generation BTK inhibitors in frontline therapy and may help shape future NCCN guideline considerations.

Pharmacy Times: Can you describe the design of your real-world research project and the role your team played in guiding it?

Lynnette Henshaw, PharmD, BCOP: The idea for the research study initially came about after the phase 3 Triangle study was published, which changed the treatment landscape of mantle cell lymphoma, specifically looking at ibrutinib in the frontline setting for mantle cell lymphoma patients in combination with chemoimmunotherapy for those fit to tolerate an intensive induction regimen. Real-world evidence evaluating the Triangle regimen is lacking, especially when utilizing second-generation BTK inhibitors such as acalabrutinib or zanubrutinib. The Triangle study specifically looked at the first-generation BTK inhibitor, ibrutinib, but we know in practice it is common to substitute with second-generation BTK inhibitors.

Our team set out to evaluate the efficacy and safety outcomes within our patient population at MSK using the Triangle regimen with any of the three BTK inhibitors: acalabrutinib, zanubrutinib, or ibrutinib. My role on the team was to present my initial research proposal to our research subcommittee at MSK, which was accepted for the 2024–2025 residency year. I was the research mentor on the team, along with our pharmacy resident, Dr. Kelly Chung, PharmD, who was the lead on this project. I also worked with other pharmacy members on the team—Drs. Amanda Chron, PharmD, Lisa Modelevsky, PharmD, Ashley Joseph, and Dr. Anita Kumar, MD—who were all vital in facilitating the project.

Pharmacy Times: What were the key outcomes and findings from the study?

Henshaw: Overall, we retrospectively looked at 32 patients, so a relatively small patient population. The initial results for the Triangle regimen were published in December 2022, and we evaluated patients from that date until our cutoff in September 2024. All patients had to complete six cycles of induction therapy. When we evaluated the patients, we saw an equal distribution among all of the BTK inhibitors: 17 on ibrutinib and 15 on second-generation BTK inhibitors. All patients who completed induction went on to receive maintenance therapy with a BTK inhibitor and rituximab. None of the patients received consolidation with autologous stem cell transplant.

For efficacy outcomes, we looked at overall response rates. Post-induction, overall response rates were 100% across all arms, with a 100% CR rate. Twelve-month PFS was 97%, and overall survival was 100% at the 12-month mark.

For safety, we evaluated cytopenias, infection rates, diarrhea and GI toxicities, as well as cardiovascular events such as hypertension and atrial fibrillation. Overall, we saw low-grade diarrhea and arrhythmias, most of which were grade 1–2, with only one arrhythmia event. In terms of hypertension, only three patients required an intervention and change to their antihypertensive therapy. We did not see differences in hypertension among BTK inhibitors, though second-generation BTK inhibitors were more often used in patients who already had higher baseline hypertension, which could have confounded the results.

Pharmacy Times: How might these results influence future treatment decisions for patients receiving the Triangle regimen?

Henshaw: Our efficacy and safety results were similar to those of the original Triangle study. These results are very promising, with high overall response rates and no new safety signals. To my knowledge, this is one of the only studies to date that has evaluated second-generation BTK inhibitors in combination with the Triangle regimen.

Currently, NCCN recognizes ibrutinib, the BTK inhibitor used in the original trial, as a category 2A recommendation. Zanubrutinib and acalabrutinib, the second-generation BTK inhibitors, are only listed as category 2B. With the results of our study, we believe this affirms the use of second-generation BTK inhibitors in the frontline setting in combination with the Triangle regimen. We hope these findings will be applicable to other institutions and reaffirm the practices we are already implementing.

Our resident, Dr. Kelly Chung, PharmD, presented these results at the HOPA conference in 2025, and we hope to publish the full results soon.