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Latest Updates in Treatment Sequencing for R/R MCL After Covalent BTK Inhibitors

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Released: November 09, 2026

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In this commentary, experts discuss the evolving treatment landscape of R/R mantle cell lymphoma as the use of covalent BTK inhibitors further expands into the first-line setting. The discussion highlights the similarities and differences between the approved small molecule inhibitors pirtobrutinib and sonrotoclax, including patient selection, step-up dosing requirements, TLS monitoring, efficacy post covalent BTKi, sequencing, and the feasibility of implementing treatment in community practices. They also examine the efficacy and safety of CAR T-cell therapy and bispecific antibodies, describing their current and possible future roles in R/R mantle cell lymphoma.

Toby A. Eyre
Toby A. Eyre, MBChB, MD
Tycel J. Phillips
Tycel J. Phillips, MD, FASCO
Treatment Sequencing MCL Post cBTKi

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The treatment landscape of relapsed/refractory (R/R) mantle cell lymphoma (MCL) is evolving as new therapies are being developed and the use of covalent BTK inhibitors further expands into the first-line setting. In a recent podcast titled “Hematologist On Call: Relapsed/Refractory Mantle Cell Lymphoma Post cBTKi”, Toby A. Eyre, MD, MBChB, and Tycel J. Phillips, MD, FASCO, discussed how the field is changing and how they are incorporating the latest agents into their clinical practice. In this commentary, the expert faculty highlight similarities and differences between the approved small molecule inhibitors pirtobrutinib and sonrotoclax, including patient selection, step-up dosing requirements, tumor lysis syndrome monitoring, efficacy after covalent BTK inhibitor, sequencing, and the feasibility of implementing treatment in community practices. They also examine the efficacy and safety of CAR T-cell therapy and bispecific antibodies, describing their current and possible future roles in R/R MCL.

Are Covalent BTK Inhibitors Being Used for All Patients in the First-line Setting?
Tycel J. Phillips, MD, FASCO: There is substantial momentum toward incorporating covalent BTK inhibitors into first-line treatment in patients diagnosed with MCL. Unless a patient has a contraindication, healthcare professionals are increasingly choosing the TRIANGLE, ENRICH, BOVen, and ECHO regimens in the front line. However, this momentum may be overshadowing discussion about which patients benefit most from combination treatment that includes a covalent BTK inhibitor and which patients might be better served by sequencing therapies. Ultimately, treatment selection should remain nuanced.

Toby A. Eyre, MD, MBChB: The TRIANGLE evidence is particularly compelling in younger patients, demonstrating an overall survival benefit with incorporating ibrutinib into chemotherapy and the option to omit autologous transplant. For older patients, I am more selective about using covalent BTK inhibitors. For example, adding acalabrutinib to bendamustine and rituximab and subsequent maintenance therapy makes the regimen more immunosuppressive. Some lower-risk patients may still be suited to chemoimmunotherapy followed by a covalent BTK inhibitor at disease relapse.

With more patients receiving a covalent BTK inhibitor in the first line, the population requiring treatment after exposure to these agents is growing. These first-line regimens are not necessarily curative, making subsequent treatment selection increasingly important.

Current Treatment Practices in R/R MCL
Tycel J. Phillips, MD, FASCO: In the second-line setting, it is important to distinguish whether the patient stopped a covalent BTK inhibitor because of intolerance or progressed during treatment. Pirtobrutinib can be a particularly useful alternative after intolerance, with the potential for a durable response when other covalent BTK inhibitors would not be appropriate. After progression, I am more cautious about the durability of another BTK-directed therapy. Resistance in MCL differs from that in chronic lymphocytic leukemia, and we cannot assume that moving from one BTK inhibitor, regardless of mechanism of action, to another will provide prolonged disease control.

For patients followed at our center, when feasible, we generally obtain another biopsy and repeat molecular testing. We often do not identify a mutation that explains covalent BTK inhibitor resistance, so treatment selection also depends on fitness and clinical trial availability. Currently, many community referrals to us have already started pirtobrutinib. At that point, the discussion centers on whether it is controlling the disease and whether we should proceed toward CAR T-cell therapy or consider another treatment.

Toby A. Eyre, MD, MBChB: Progression on treatment also needs to be distinguished from relapse after planned treatment completion. The TRIANGLE regimen includes 2 years of fixed-duration ibrutinib, and some patients relapsing after a treatment-free interval may eventually be candidates for covalent BTK inhibitor retreatment. Additional follow-up data will be needed to establish if this is an effective strategy.

For patients unsuitable for CAR T-cell therapy in subsequent lines of therapy, pirtobrutinib and sonrotoclax are oral therapy options often with a palliative treatment goal. However, we should not assume that every patient will have only short-term benefit. Although many responses are not prolonged, a subset of patients receiving pirtobrutinib can benefit for 2 or 3 years.

Sonrotoclax and Pirtobrutinib Post Covalent BTK Inhibitor
Toby A. Eyre, MD, MBChB: We have long recognized the activity of BCL2 inhibitors in MCL, but much of the data on venetoclax after BTK inhibitor exposure has come from retrospective studies. The second-generation BCL2 inhibitor sonrotoclax gives us an opportunity to evaluate this strategy more directly and as monotherapy. Sonrotoclax was recently approved by the FDA for the treatment of adult patients with R/R MCL after ≥2 lines of systemic therapy including a BTK inhibitor, but it is not yet approved in the UK or EU. The pivotal phase I/II study enrolled 125 patients and demonstrated an overall response rate (52%), complete response rate (16%), and median progression-free survival (6.5 months) that appeared broadly similar to those reported with pirtobrutinib. These findings leave us with an important sequencing question rather than a clear answer about which agent should come first.

Tycel J. Phillips, MD, FASCO: I agree. The optimal sequence of sonrotoclax and pirtobrutinib remains uncertain. For older patients who are unsuitable for CAR T-cell therapy and may receive both continuous oral agents sequentially, the order likely does not matter. However, I am excited about the possibility that changing targets could help patients with covalent BTK inhibitor–refractory disease.

Regarding ease of initiation, pirtobrutinib is straightforward, and we often obtain an early indication of whether it is effective. Sonrotoclax begins with a twice-weekly dose ramp-up over 4 weeks, reaching the full dose in Week 5. The protocol included 1-hour predose and/or 4- to 8-hour postdose blood tests at each dose increase for tumor lysis syndrome monitoring. This protocol was less burdensome than the monitoring required for venetoclax initiation in chronic lymphocytic leukemia, which includes increased monitoring for patients with moderate or high tumor burden. For suitable patients, sonrotoclax dosing at home with nearby laboratory testing is feasible; however, bulky disease, leukemic involvement, and poor renal function may warrant additional prophylaxis, monitoring, and hospitalization. When counseling patients about the 2 treatment options, I would explain why a different mechanism might be attractive despite additional monitoring, rather than allowing convenience alone to be the single determining factor.

Role of CAR T-Cell Therapy in R/R MCL
Toby A. Eyre, MD, MBChB: In my UK practice, a central question when a patient’s disease is relapsed or refractory is whether the patient can tolerate brexucabtagene autoleucel (brexu-cel), the only approved CAR T-cell therapy for R/R MCL. Brexu-cel offers substantial efficacy, but its treatment burden makes patient selection essential. That assessment includes the potential for prolonged hospitalization, severe immune effector cell–associated neurotoxicity syndrome, intensive care admission, and substantial immunosuppression. There is no absolute age cutoff in our practice, although patients older than approximately 70-75 years of age need to be particularly fit. For patients who are unsuitable, I consider pirtobrutinib, sonrotoclax, and clinical trial access to bispecific antibodies.

Tycel J. Phillips, MD, FASCO: In my practice, pirtobrutinib is often used as a bridge while we try to promptly move suitable patients toward CAR T-cell therapy. Sonrotoclax could also be used as a bridging option.

In the US, brexu-cel is approved by the FDA for the treatment of R/R MCL, and lisocabtagene maraleucel (liso-cel) is also approved for R/R MCL after ≥2 prior lines of systemic therapy, including a BTK inhibitor. However, liso-cel has appeared to possibly be less efficacious than pirtobrutinib in the post covalent BTK inhibitor setting. Further long-term real-world data will help clarify its place in MCL. I remain cautious about assuming that liso-cel is as efficacious as brexu-cel, which is quite different to large B-cell lymphoma where liso-cel is comparable to axicabtagene ciloleucel (a brexu-cel equivalent).

Role of Bispecific Antibodies in R/R MCL
Tycel J. Phillips, MD, FASCO: Bispecific antibodies offer another potential route to durable remission in R/R MCL. Updated glofitamab follow-up has shown that some patients remain in remission for several years after completing treatment, which is encouraging in a setting where sustained responses have been difficult to achieve.

However, glofitamab step-up dosing can be challenging. Grade 2 or 3 cytokine release syndrome can occur with the initial 2.5-mg dose, and the early treatment period can require substantial support. In MCL, I currently expect much of this treatment to occur at centers with experience managing these toxicities and access to hospitalization, like with CAR T-cell therapy.

Reducing the incidence of cytokine release syndrome could extend the reach of bispecific antibodies into community practice. It could also make treatment before CAR T-cell therapy more attractive, potentially preserving brexu-cel and liso-cel for later in treatment sequencing. For now, access, physician experience, and the ability to manage early toxicity strongly influence where bispecific antibodies fit.

Toby A. Eyre, MD, MBChB: Mosunetuzumab plus polatuzumab vedotin is particularly interesting because the early findings suggest promising efficacy alongside a strategy that may reduce T-cell–activating toxicity. I am curious to see the long-term durability and whether the combination will undergo further development in MCL.

Randomized evidence from studies such as the phase III GLOBRYTE trial(NCT06084936) of glofitamab vs bendamustine/rituximab or rituximab plus lenalidomide will also be valuable. We now have several active approaches with markedly different treatment burdens and potential benefits. The remaining challenge is determining which patients are best served by each strategy and how to sequence them.

Tools for Expert Treatment Recommendations and Adverse Event Management
Are you interested in seeing recommendations from multiple experts for your patients with R/R MCL? Take a look at our Interactive Decision Support Tools for R/R MCL and managing BTK inhibitor–associated adverse events.

Your Thoughts
Are you using covalent BTK inhibitors in the first line for most of your patients? How are you approaching treatment sequencing with options like pirtobrutinib, sonrotoclax, bispecific antibodies, and CAR T-cell therapy? Tell us in the comments about your biggest challenges or needs when it comes to using these newer therapies for your patients with R/R MCL.

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