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MCL Care Today
European Perspective on Today’s Approaches to Optimize the Care of Patients With Mantle Cell Lymphoma

Released: February 02, 2026

Mats Jerkeman
Mats Jerkeman, MD, PhD
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Key Takeaways
  • BTK inhibitors are now a central component of frontline MCL therapy. They improve disease control and reduce reliance on intensive chemotherapy and ASCT across different age groups.
  • Chemotherapy-free BTKi-based combinations are increasingly being employed in the frontline MCL setting and multiple targeted and immune-directed options are now available in the relapsed/refractory disease setting.
  • Effective management of adverse events is critical, particularly to mitigate and prevent cardiovascular, infectious, and immune-related toxicities associated with the long-term use of BTKis and cell-based therapies.

Covalent BTKi Plus Chemoimmunotherapy in the Frontline Treatment of MCL
Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin lymphoma, and its clinical presentation varies from indolent to very aggressive forms. Primarily, MCL is an aggressive incurable B-cell lymphoma that is typically diagnosed in the advanced stage. The treatment landscape for patients with MCL has evolved substantially with the recent advent of covalent BTK inhibitors (BTKis) in the frontline setting. Currently, there are 3 approved covalent BTKis in the frontline MCL setting—ibrutinib, acalabrutinib and zanubrutinib—and 1 approved noncovalent BTKi—pirtobrutinib—in the relapsed/refractory setting. Until fairly recently, dose-intensified chemoimmunotherapy (CIT), often incorporating high-dose cytarabine, followed by autologous stem cell transplant (ASCT), was the standard first-line treatment for younger, fit patients, whereas for older patients, conventional CIT with regimens such as bendamustine/rituximab (BR) or rituximab plus cyclophosphamide/doxorubicin/vincritine (R-CHOP) followed by rituximab maintenance was the upfront standard of care.

Evidence from multiple randomized phase III trials provided significant support for the incorporation of covalent BTKis into the first-line treatment of patients with MCL, particularly younger, fit patients. As such, covalent BTKi-containing approaches have become the new benchmark for the frontline treatment of these patients. For transplant-eligible or biologically fit patients with MCL (aged 65 years or younger), the phase III TRIANGLE trial demonstrated that the addition of ibrutinib to CIT induction significantly improves failure-free survival and overall survival (OS). Of importance, the omission of ASCT while incorporating ibrutinib into the CIT regimen as induction therapy followed by ibrutinib with or without rituximab maintenance led to survival outcomes that were comparable to ibrutinib plus CIT and ASCT. CIT plus ibrutinib without ASCT followed by ibrutinib with or without rituximab maintenance was associated with substantially reduced incidence of hematologic toxicity as well as infections compared with CIT plus ibrutinib and ASCT followed by ibrutinib with or without rituximab maintenance.

These findings positioned covalent BTKi-containing induction therapy followed by the covalent BTKi and rituximab maintenance as the current gold standard for transplant-eligible, younger, fit patients with untreated stage II-IV MCL. Although the addition of ASCT may still be considered in select patients with high-risk disease such as those with blastoid morphology, high Ki-67 score, and/or TP53 mutation–positive disease, the role of ASCT in the routine care of patients is diminishing.

For older, transplant-ineligible patients aged 65 years or older with previously untreated MCL, the addition of a covalent BTKi to BR has also shown benefit. The randomized phase III SHINE trial evaluated BR with or without ibrutinib induction followed by rituximab with or without ibrutinib maintenance, and the randomized phase III ECHO trial investigated BR with or without acalabrutinib induction followed by rituximab with or without acalabrutinib maintenance. Both trials demonstrated statistically significant improvements in progression-free survival (PFS) with the addition of the covalent BTKi compared with BR alone. In the SHINE trial, however, the addition of ibrutinib was associated with increased toxicity compared with the placebo arm. On the other hand, acalabrutinib was associated with a more favorable tolerability profile in the ECHO trial. Of note, however, neither the SHINE trial nor the ECHO trial demonstrated a statistically significant OS advantage with the addition of a covalent BTKi to induction and maintenance therapy, underscoring the need to balance efficacy gains against associated toxicity, preexisting comorbidities and patient preference before selecting the covalent BTKi for transplant-ineligible, older patients with newly diagnosed MCL requiring treatment. Based on the results of the ECHO trial, acalabrutinib plus BR received European Medicines Agency and FDA approval for adult patients with previously untreated MCL who are ineligible for autologous hematopoietic stem cell transplantation.

Chemotherapy-Free Frontline Treatment of MCL
Chemotherapy-free frontline approaches are also gaining traction across the MCL disease spectrum, particularly for patients with indolent disease, older patients or those with significant preexisting comorbidities. For patients with indolent or low-risk MCL, observation after diagnosis remains appropriate, with no detriment to long-term survival. For those requiring therapy, nonchemotherapeutic regimens combining a covalent BTKi with an anti-CD20 monoclonal antibody have shown excellent disease control in single-arm phase II and randomized phase III trials.

These chemotherapy-free approaches are especially attractive in older patients for whom the avoidance of cytotoxic chemotherapy reduces hematologic toxicity and preserves immune function. The randomized phase II/III ENRICH trial compared the chemotherapy-free regimen of ibrutinib plus rituximab vs rituximab plus chemotherapy (CHOP or bendamustine) as induction therapy for transplant-ineligible patients aged 60 years or older with previously untreated MCL in need of treatment. Patients received rituximab with or without ibrutinib as maintenance therapy. Ibrutinib plus rituximab demonstrated a statistically significant improvement in PFS compared with CIT. The PFS advantage with ibrutinib plus rituximab was more evident when compared with R-CHOP vs BR. Also, BR was associated with less hematologic toxicity and better quality of life vs R-CHOP. Although the ENRICH regimen is yet to be broadly approved, this study provides proof of concept that chemotherapy-free frontline management is feasible in selected patients with MCL.

The treatment of patients with high-risk MCL, particularly those with disease harboring TP53 mutations, is an unmet clinical need. In this subgroup of patients, treatment outcomes with conventional CIT remain dismal, and even the use of covalent BTKi-based doublets has shown limited durability of response. The phase II BOVen trial investigated the efficacy and safety of zanubrutinib in combination with obinutuzumab, and venetoclax as frontline therapy for older patients aged 65 years or older with TP53 mutation–positive MCL (NCT03824483). In the relatively small study of 25 patients, the overall response rate was 96% with a complete response rate of 88%. These results suggest that chemotherapy-free triplet regimens combining an anti-CD20 antibody with a covalent BTKi and venetoclax, a BCL2 inhibitor, have the potential to improve outcomes in patients with TP53 mutation–positive MCL. Therefore, the efficacy and safety of such triplet regimens are increasingly being explored in clinical trials, as it is clear that the future direction of frontline therapy should tend more toward rational, disease biology-driven combinations. The single-arm phase II TrAVeRse trial is investigating acalabrutinib in combination with venetoclax and rituximab for patients with previously untreated MCL (NCT05951959). The ongoing single-arm phase II GATE1 trial is investigating the noncovalent BTKi pirtobrutinib in combination with rituximab and venetoclax for patients with previously untreated MCL (NCT06522386).

Chemotherapy-Free Options After Intolerance to or Disease Progression on a Covalent BTKi 
The use of single-agent covalent BTKi therapy has become the standard of care following CIT failure. Ibrutinib, acalabrutinib, and zanubrutinib induce high responses, and for patients who achieve a complete response, the responses are durable. Compared with ibrutinib, acalabrutinib and zanubrutinib are more selective covalent BTKi and are associated with lower rates of atrial fibrillation, hypertension, and bleeding events. Switching from one covalent BTKi to another may be considered to manage intolerance while maintaining disease control. Of note, the approval for ibrutinib was voluntarily withdrawn in the United States for patients with MCL who have received ≥1 prior therapy.

To improve outcomes beyond single-agent covalent BTKi in the second-line setting, chemotherapy-free approaches such as single-agent pirtobrutinib, ibrutinib plus venetoclax, lenalidomide plus rituximab, venetoclax-based combinations, CAR T-cell therapy and bispecific antibodies have been explored. The phase II AIM trial of ibrutinib plus venetoclax demonstrated long-term durable responses in patients with relapsed or refractory (R/R) MCL. In the randomized phase III SYMPATICO trial of ibrutinib with or without venetoclax for patients with MCL who have received 1-5 prior lines of therapy, the combination demonstrated superior PFS compared with ibrutinib, albeit with increased toxicity and no clear OS benefit to date. Lenalidomide plus rituximab is effective in patients with R/R MCL; however, a lower Ki-67 level (<50%) and fewer lines of previous therapy (<2) are associated with better PFS outcomes. Venetoclax-based combinations also provide additional chemotherapy-free options for patients previously treated with a covalent BTKi, although treatment of TP53 mutation–positive disease remains challenging.

In general, relapse after continuous covalent BTKi therapy represents a critical inflection point that has been transformed by cellular and novel targeted therapies. Anti-CD19 CAR T-cell therapy induces deep and durable remissions in heavily pretreated patients, including those with prior exposure to a covalent BTKi, albeit associated with significant acute toxicities. Pirtobrutinib offers an effective and well tolerated oral option for patients who have previously received a covalent BTK inhibitor, especially those patients who are ineligible to receive CAR T-cell therapy, and it can also be considered for use as a bridge to cellular therapy. Finally, bispecific antibodies, such as glofitamab, and BTK degraders, such as bexobrutideg, are currently under investigation in MCL and have the potential to further expand the chemotherapy-free armamentarium in the R/R MCL space. These evolving drug classes are very likely to further reshape the R/R MCL landscape.

Management of Treatment-Related Adverse Events 
All cancer treatments are associated with adverse events (AEs), with some being more toxic than others. Even as the treatment landscape continues to shift away from cytotoxic chemotherapy and more toward targeted therapies and immune-directed treatments, proactive toxicity management continues to remain essential. Regarding the covalent BTKis, cardiac toxicities (atrial fibrillation, hypertension), bleeding risk, infections, and gastrointestinal AEs are key concerns. Therefore, baseline cardiovascular assessment, careful review of concomitant anticoagulation or antiplatelet therapy, and regular monitoring are recommended. Dose interruption, reduction, or switching from the first-generation covalent BTKi ibrutinib to a second-generation covalent BTKi (acalabrutinib or zanubrutinib) can help to mitigate most AEs without compromising efficacy. The risk of infection warrants vaccination, antiviral prophylaxis where appropriate, and vigilance in patients previously exposed to bendamustine or prolonged BTKi therapy. Venetoclax-containing regimens require attention to the risk of tumor lysis syndrome, particularly in patients with a high disease burden. Venetoclax administration necessitates dose ramp-up, laboratory monitoring, and prophylactic measures. Lenalidomide-based therapies require thromboprophylaxis and careful monitoring for cytopenias and rash. CAR T-cell therapy introduces distinct acute toxicities, of note, cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome, as well as prolonged cytopenias and hypogammaglobulinemia. Management of these AEs requires the involvement of specialized centers, standardized grading, early intervention with tocilizumab and/or corticosteroids, and long-term infection prophylaxis with immunoglobulin replacement when indicated. Across all treatment settings in MCL, supportive care—including growth factor support, antimicrobial prophylaxis, vaccination, and structured long-term follow-up—is crucial to optimize treatment outcomes and quality of life in an increasingly chronic treatment paradigm.

Overall Conclusions
In summary, BTKi-based strategies have become the backbone for MCL treatment in the frontline and R/R settings, as they offer more effective and less chemotherapy-dependent options across different age groups and fitness levels. Chemotherapy-free regimens are increasingly feasible, particularly for older patients and after progression on first-line therapy. Even for patients with high-risk disease, BTKi-based combinations with agents targeting complementary signaling pathways offer promising outcomes. As survival outcomes improve and more targeted chemotherapy-free options become available, the proactive and meticulous management of treatment-related AEs and quality-of-life issues have taken center stage in the provision of high-quality MCL care.

Your Thoughts
What are your questions and challenges with the use of covalent BTKis in the management of your patients with previously untreated or R/R MCL? Take our poll and leave a comment or question.

Also, with the increasing evolution and complexity of treatment options for patients with MCL, 4 of my expert colleagues and I from across Europe are updating an Interactive Decision Support Tool for MCL that allows you to enter specific characteristics for your patients with MCL and see our treatment recommendations for the same combination of characteristics considering the currently available evidence. Be sure to come back and visit the site and take advantage of this tool to gain insights for treating your patients with MCL.

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How often do you recommend acalabrutinib plus BR for your older, transplant-ineligible patients with previously untreated MCL since the combination received approval?

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