If a BTK Inhibitor Comes First in MCL, What Comes Next?

Advances in the treatment of mantle cell lymphoma (MCL), a rare form of non-Hodgkin lymphoma, have brought significant improvements in survival. While this disease remains incurable, an analysis of the SEER database showed 5-year survival rates increased from 45.2% in 2000-2004 to 57.1% in 2015-2019.¹

Treatment approaches have shifted with the introduction of targeted agents, notably Bruton tyrosine kinase (BTK) inhibitors, as well as the emerging role of immunotherapy, according to a new review article by Jean M. Clement, MD, MSc, and Craig A. Portell, MD, both of the Division of Hematology/Oncology at the University of Virginia.²

In their review, Clement and Portell address the key question physicians face following an initial relapse in MCL: With so many patients receiving covalent BTK inhibitors in first-line treatment, what should come next?

BTK Inhibitors as First-Line Therapy in MCL

The authors explain that BTK inhibitors have emerged as the go-to therapies in first-line treatment in MCL based on 2 landmark studies. The TRIANGLE trial (NCT02858258) demonstrated that adding the covalent BTK inhibitor ibrutinib (Imbruvica; Pharmacyclics/Janssen) to chemoimmunotherapy (CIT) and maintenance therapy produced a meaningful event-free survival (EFS) benefit, while showing that high-dose therapy with autologous stem cell rescue adds no benefit when a BTK inhibitor is already included.³ Similarly, the SHINE study (NCT01776840) confirmed an EFS benefit when ibrutinib is added to CIT, in this case bendamustine and rituximab.⁴

The result, Clement and Portell write, is that “covalent BTK [inhibitor] in addition to CIT and maintenance therapy without high dose therapy consolidation has become the new standard in the first-line setting given improvement in progression-free survival noted in patients who receive first-line BTK [inhibitor].”

The authors explain the underlying biology of MCL and how this improved understanding of the disease has transformed treatment: The disease is driven by the t(11;14) translocation and cyclin D1 overexpression, along with aberrant SOX11 expression, BCL2-mediated anti-apoptosis, constitutive NF-kB activation, and TP53 dysregulation. These factors affect B-cell receptor signaling, the primary target of BTK inhibitors. There have been advances in predicting which patients are high risk; these factors include high Ki-67, early relapse within 24 months, TP53 alterations, and a high score on the Mantle Cell Lymphoma International Prognostic Index (MIPI).²

Treatment Decisions at the First Relapse

Expanded use of BTK inhibitors in the frontline setting raises pressing questions about what to prescribe at relapse. The authors draw a distinction between patients who have never been treated with BTK inhibitors vs those already exposed—and between those who progress while on active treatment with a BTK inhibitor vs those who progress after stopping therapy, which is becoming more common due to increased use of fixed-duration protocols.⁵

For BTK inhibitor–naive patients who relapse following their first treatment, covalent BTK inhibitors are the standard; pooled data confirm that earlier use of ibrutinib (second line vs later) yields dramatically better outcomes, with median overall survival (OS) of 61.6 months vs 22.5 months. Next-generation BTK inhibitors are acalabrutinib, sold as Calquence (AstraZeneca), with 81% overall response rate (ORR) and median progression-free survival (PFS) of 20 months, and zanubrutinib, sold as Brukinsa (BeOne Medicines), with 83.7% ORR and a 77.9% complete response (CR) rate at 35 months’ follow-up.² The authors highlighted these therapies’ improved selectivity and safety over ibrutinib, which was voluntarily withdrawn from the US market for treatment of relapsed/refractory MCL in 2023. For patients intolerant of BTK inhibitors, lenalidomide plus rituximab or bortezomib plus rituximab remain viable alternatives, they wrote.

The aggressive nature of MCL calls for urgent treatment when patients progress on a covalent BTK inhibitor; the authors write that patients “who do not receive immediate salvage treatment have a short median overall survival, suggesting a more aggressive disease biology.” Real-world OS following progression on a BTK inhibitor is only 9.7 months, they note.⁶ In contrast with chronic lymphocytic leukemia, BTK mutations are not the dominant resistance mechanism in MCL, which the authors say complicates decisions about whether to abandon BTK inhibitors. They recommend testing for BTK and PLC-gamma mutations to guide this choice, favoring use of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca; Eli Lilly) or possibly chimeric antigen receptor (CAR) T-cell therapy.

The SYMPATICO trial (NCT03112174) evaluated ibrutinib plus the BCL2 inhibitor venetoclax (Venclexta; AbbVie/Genentech), which shows a PFS benefit (31.9 vs 22.1 months) compared with ibrutinib alone, but no OS advantage,⁷ leading the authors to conclude that "combination therapy may not be better than single agent sequential therapy." Venetoclax alone has limited durability in MCL, although the authors wrote that they commonly use it as a bridge to CAR T-cell therapy.

CAR T-Cell Therapy: Transformative but Nuanced

Two CAR T products are FDA-approved for R/R MCL: brexucabtagene autoleucel (brexu-cel/Tecartus; Gilead) and lisocabtagene maraleucel (liso-cel/Breyanzi; Bristol Myers Squibb). Brexu-cel was evaluated in the ZUMA-2 trial (NCT02601313), which demonstrated an 85% objective response and 67% CR in heavily pretreated patients, with 3-year follow-up confirming durability (68% CR; median duration of response [mDOR], 28.2 months).⁸ For liso-cel, the MCL cohort of TRANSCEND-NHL (NCT02631044) showed 83.1% ORR and 72.3% CR with mDOR of 15.7 months.⁹ While no direct comparisons exist, the toxicity profiles differ markedly. Brexu-cel carries high rates of cytokine release syndrome (CRS; any-grade, 89%; grade 3 or higher, 11%) and immune effector cell–associated neurotoxicity syndrome (ICANS; any-grade, 62%; grade 3 or higher, 30%), whereas liso-cel shows substantially lower rates (CRS: any-grade, 49%-54%; grade 3 or higher, 1%-2%; ICANS: any-grade, 27%-31%; grade 3 or higher, 4%-8%). The authors conclude that "Liso-cel appears to have superior safety profile with respect to the unique toxicities of CRS and ICANS associated with CAR T-cell therapy."

The Pipeline: Novel Therapies on the Horizon

The authors outlined a host of therapies and combinations in the pipeline, some of which have approvals in other types of lymphoma. Bispecific T-cell engagers, or BiTEs, targeting CD20xCD3 have shown promising early results. Glofitamab (Columvi; Genetech) achieved a CR rate of 78.3% and ORR of 85% in a phase 1/2 study, which included 71% CR in patients with prior treatment with BTK inhibitors. A pivotal phase 3 trial vs investigator's choice is enrolling (NCT06084936). Mosunetuzumab (Lunsumio; Roche) combined with polatuzumab vedotin (Polivy; Genentech) showed 88% best ORR and 79% CR in patients following treatment with BTK inhibitors. Epcoritamab (Epkinly; Genmab) and odronextamab (Regeneron) are also under study. Multiple combination trials pairing glofitamab with pirtobrutinib, acalabrutinib, zanubrutinib, venetoclax, or lenalidomide are actively recruiting.²

BTK degraders are an emerging class designed to overcome resistance mutations by physically eliminating the BTK protein rather than merely inhibiting its activity. These agents have demonstrated in vitro activity against BTK inhibitor-resistant MCL cell lines. Bexobrutideg (NX-5948) has FDA orphan drug designation and is under study in R/R MCL (NCT05131022); BGB-16673 has shown early promise. Some of the most watched results will come from a phase 3 trial of the next-generation BCL2 inhibitor sonrotoclax plus zanubrutinib versus zanubrutinib alone (NCT06742996).

Antibody-drug conjugates, which have seen recent success in classic Hodgkin lymphoma and even hard-to-treat cancers such as acute myeloid leukemia, are also being evaluated in MCL. Zilovertamab vedotin targeting ROR1 achieved 40% ORR in multiply relapsed patients, improving to 64% combined with the noncovalent BTK inhibitor nemtabrutinib. Loncastuximab tesirine targeting CD19 showed 46.7% ORR in a small MCL cohort, with venetoclax combinations under investigation. PI3K inhibitors such as parsaclisib have early activity data, but as yet there is no phase 3 trial.

MCL therapy is at an inflection point, the authors conclude. The integration of covalent BTK inhibitors into frontline therapy has meaningfully extended PFS, but this has also upended traditional sequencing algorithms for subsequent lines and created the need for more options. High-risk patients should receive early consultation for allogeneic stem cell transplant if they achieve remission, the authors recommend, and all patients should consider a clinical trial.

“Newer therapies, such as non-covalent BTK [inhibitors], BTK degraders and bispecific antibodies, will further advance the care of patients,” Clement and Portell write. “Much is yet to be studied as far as sequence, combinations, and maintenance therapies, and clinical trial enrollment should be encouraged.”

References

1. Arora R, Lefante J, Saba S. Updated trends in incidence and survival of mantle cell lymphoma from 2000 to 2020. Blood 2023;142(suppl 1):5160. doi:10.1182/blood-2023-190022
2. Clement JM, Portell CA. SOHO state of the art updates and next questions: sequencing therapies in relapsed/refractory mantle cell lymphoma. Clin Lymph Myleoma Leuk. Published online January 13, 2026. doi:10.1016/j.clml.2026.01.008
3. Dreyling M, Doorduijn J, Gine E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a 3-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306. doi:10.1016/S0140-6736(24)00184-3
4. Wang ML, Jurczak W, Jerkeman M et al. Ibrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma. N Engl J Med. 2022;386(26):2482-2494. DOI: 10.1056/NEJMoa2201817
5. Caffrey M. Time-limited regimens gain notice, offering a break for patients with blood cancer and savings for payers. Am J Manag Care. 2026;32(Spec. No. 1):SP12.
6. Hess G, Dreyling M, Oberic L, et al. Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: the SCHOLAR-2 retrospective chart review Study. Br J Haematol. 2023;202(4):749-759. doi: 10.1111/bjh.18519
7. Wang M, Jurczak W, Trneny M, et al.Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma (SYMPATICO): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2026;26(2):200-213. doi:10.1016/S1470-2045(24)00682-X
8. Wang M. Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347
9. Wang M, Siddiqi T, Gordon LI, et al. Lisocabtagene maraleucel in relapsed/refractory mantle cell lymphoma: primary analysis of the mantle cell lymphoma cohort from TRANSCEND NHL 001, a phase I multicenter seamless design study. J Clin Oncol. 2024;42(10):1146-1157. doi:10.1200/JCO.23.02214