Back Back
Frontline BTK inhibitors for MCL
Optimizing Frontline Therapy for Mantle Cell Lymphoma: The Evolving Role of BTK Inhibitors

Released: January 24, 2025

Expiration: January 23, 2026

Brad Kahl
Brad Kahl, MD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • FDA recently approved acalabrutinib in combination with bendamustine/rituximab for adults with previously untreated mantle cell lymphoma who are ineligible for autologous stem cell transplant (ASCT).
  • BTK inhibitors like acalabrutinib and zanubrutinib are being integrated into aggressive regimens for younger, fit patients, based on the European TRIANGLE study.
  • Both acalabrutinib and zanubrutinib are effective options with unique features, but there are no head-to-head comparisons between these agents, leaving the choice of BTK inhibitor therapy largely dependent on healthcare professional preference and patient-specific factors.

Mantle cell lymphoma (MCL) remains one of the more challenging non-Hodgkin lymphoma subtypes to treat, with a spectrum of clinical behavior ranging from indolent to aggressive disease. Recent data have reshaped how we approach frontline therapy for both younger, fit patients and older, less fit individuals. The addition of BTK inhibitors to the treatment landscape has offered new options, but these choices come with important considerations. 

BTK Inhibition in MCL: A Game-changer With Nuance
BTK inhibitors disrupt the B-cell receptor signaling pathway, inducing cell death in MCL. Ibrutinib, the first BTK inhibitor approved, was groundbreaking when introduced but faced limitations because of off-target toxicities, including atrial fibrillation and bleeding. The second-generation BTK inhibitors acalabrutinib and zanubrutinib were designed to improve tolerability without compromising efficacy. Ibrutinib was voluntarily withdrawn from the US market after initial accelerated approvals in patients with MCL after ≥1 previous line of therapy and in patients with marginal zone lymphoma after ≥1 previous anti-CD20−based therapy, based on data from the phase III SHINE and SELENE trials.

Older Patients With MCL: Balancing Efficacy and Tolerability
Older patients with MCL often cannot tolerate aggressive regimens like autologous stem cell transplant (ASCT) or cytarabine-based chemotherapy. In this group of patients, bendamustine/rituximab (BR) followed by rituximab maintenance has been a standard of care, but BTK inhibitors may offer a less toxic, more targeted alternative. 

The phase III SHINE trial in patients aged 65 years or older with no planned ASCT reported a notable progression-free survival (PFS) improvement with the addition of ibrutinib to BR plus rituximab maintenance. However, there was an increase in the rates of some adverse event (AEs), including atrial fibrillation (13.9% vs 6.5%) and major bleeding (5.8% vs 4.2%), with no improvement in overall survival (OS). These data led to the withdrawal of ibrutinib for frontline use in MCL.

The phase III ECHO trial, also in patients aged 65 years or older, reported an approximately 17-month improvement in PFS with the addition of acalabrutinib to BR plus rituximab maintenance. Of importance, in this trial, the addition of acalabrutinib did not significantly increase the rates of AEs such as atrial fibrillation (6.1% vs 4.4%) and major bleeding (2.4% vs 5.4%). OS differences were not observed with the addition of acalabrutinib. This trial largely occurred in the midst of the COVID-19 pandemic and there were more COVID-19–related deaths on the acalabrutinib arm. Sensitivity analyses of OS accounting for COVID-19–related deaths suggested a possible trend favoring acalabrutinib. These data show that adding acalabrutinib to BR is an option for older patients with MCL. Based on these data, the FDA recently approved acalabrutinib in combination with BR for adults with previously untreated MCL who are ineligible for ASCT.

Current National Comprehensive Cancer Network guidelines also recommend acalabrutinib plus rituximab as an option for less aggressive therapy. At ASH 2024, data from the phase II ALTAMIRA trial with risk- and response-adapted treatment with acalabrutinib plus rituximab in patients aged 60 years or older with MCL reported a 24-month PFS rate of 75% and a 24-month OS rate of 94%. Patients with low-risk disease had better 24-month PFS rates than those with high-risk disease (TP53 mutation with blastoid histology) (91% vs 32%, respectively). Although these data are preliminary, these data suggested that acalabrutinib plus rituximab may be a reasonable treatment regimen for low-risk, older patients, but it may not be ideal for patients with higher-risk MCL.

Younger, Fit Patients with MCL: A Role for BTK Inhibitors in Aggressive Therapy
For younger patients with MCL who are eligible for high-dose chemotherapy and ASCT, BTK inhibitors may complement or even replace some components of traditional regimens. Currently, preferred regimens include LyMA (R-DHA + platinum followed by R-CHOP), NORDIC (maxi-CHOP/R-HDAC), BR followed by R-HDAC, and TRIANGLE. These regimens are generally followed by consolidation with ASCT followed by rituximab maintenance. 

The phase III TRIANGLE trial in patients aged 65 years or younger with previously untreated MCL who were suitable for high-dose cytarabine and ASCT showed that adding ibrutinib to a chemoimmunotherapy backbone improved failure-free survival, particularly in high-risk patients such as those with TP53 mutations. However, with ibrutinib no longer widely used in MCL, second-generation BTK inhibitors such as acalabrutinib and zanubrutinib may offer similar benefits with better safety and are included as options for this regimen in most guidelines. Updated data for the TRIANGLE trial were presented at the 2024 ASH meeting. With longer follow up, an OS benefit has emerged for the patients receiving the BTK inhibitor in this setting.

At ASH 2024, data from the phase III EA4151/BMT CTN 1601 trial reported that patients achieving measurable residual disease (MRD) negativity after aggressive induction may forgo the added ASCT without compromising efficacy. These data, along with additional follow-up from the TRIANGLE trial, suggest that maintenance treatment without ASCT may suffice for patients who achieve MRD-negative status after induction therapy, sparing them from the risks and adverse effects associated with high-dose chemotherapy and ASCT. 

The phase II ECOG-ACRIN EA4181 trial compared treatment with either BR plus acalabrutinib, BR with high-dose cytarabine and acalabrutinib, or BR with high-dose cytarabine as frontline treatment for patients aged 70 years or younger and showed similar efficacy between arms, but fewer AEs with BR plus acalabrutinib. These findings suggest that the addition of acalabrutinib to BR can maintain efficacy while minimizing AEs associated with more intensive therapy like cytarabine.

Practical Considerations in the Clinic
Both acalabrutinib and zanubrutinib are second-generation BTK inhibitors with high efficacy and improved tolerability compared with ibrutinib. Trials like ECHO have spotlighted the efficacy and safety of acalabrutinib in combination with chemoimmunotherapy. Trials with zanubrutinib also suggest unique advantages with this BTK inhibitor, including the option for once-daily dosing and lower rates of atrial fibrillation. There are no head-to-head comparisons between acalabrutinib and zanubrutinib, leaving the choice largely dependent on healthcare professional preference and patient-specific factors. For example, acalabrutinib may be preferred in patients who can tolerate twice-daily dosing and want to avoid hypertension or higher cardiovascular risks, whereas zanubrutinib offers flexibility in dosing schedules and less risk for headache.

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

Continue

Poll

1.

In your current practice, when are you considering a frontline BTK inhibitor–based regimen for your patients with MCL?

Submit