Combining BTK and BCL2 Inhibitors in Mantle Cell Lymphoma: Eyre Weighs in on Where the Field Goes Next

When the phase 3 SYMPATICO study (NCT03112174) was designed to study the combination of ibrutinib (Imbruvica; Janssen) and venetoclax (AbbVie), in mantle cell lymphoma (MCL), the end goal was a global approval.

But much can happen along the way, and as Toby Eyre, MD, of Oxford University Hospitals writes in a commentary for the British Journal of Haematology.¹ Eyre explains how the landscape for pairing a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL2) inhibitor in MCL has shifted markedly, as the journal simultaneously published the 5-year update of SYMPATICO.²

Ibrutinib and venetoclax have each demonstrated substantial single-agent activity in relapsed/refractory (R/R) MCL, Eyre explained, and preclinical and early clinical work established their synergistic potential. SYMPATICO sought to capitalize on results seen in the AIM trial,³ which provided proof of concept that the combination improved complete remission (CR) rates over ibrutinib alone and allowed some patients to achieve MRD-negative CR and subsequently stop therapy.

As Eyre and those in the multiple myeloma field know, US regulatory approval for the ibrutinib-venetoclax combination was not to be, despite the early signal. “No overall survival benefit has been seen with long-term follow- up,” he wrote, noting an HR 0.837 (95% CI, 0.60–1.15); P = .2669. “Despite the success of aspects of the trial, ibrutinib–venetoclax ultimately failed to receive regulatory approval by major bodies such as the FDA, European Medicines Agency and Medicines and Healthcare products Regulatory Agency.”

In the US, ibrutinib is no longer on the market for MCL, following a voluntary withdrawal of the production this indication.³

The final SYMPATICO analysis confirms the efficacy advantage seen at primary analysis. Among patients with naïve to covalent BTK inhibitors in R/R MCL, ibrutinib–venetoclax produced a median progression-free survival (PFS) of 31.9 months vs 22.1 months for ibrutinib plus placebo (HR 0.63; P = .0024), and a CR rate of 54% vs 32% (P = .0004).^1,2 Patients with high-risk features, including TP53 mutations, derived meaningful PFS benefit from the combination.

Despite the regulatory failures, the combination is included as a treatment option in guidelines from the European Hematology Association, the European Society of Medical Oncology, and the National Comprehensive Cancer Network. Eyre anticipates some off-label use, but he said it will vary widely by geography.

“Where available, the data to date suggest that younger/fitter patients with higher biological risk have potentially more to gain from the off-label use of the combination, and such patients may be able to manage the additional toxicities and monitoring noted in more robust fashion,” Eyre writes.¹

Looking forward, Eyre identifies 2 forces reshaping the relevance of ibrutinib–venetoclax. First, the field is rapidly incorporating covalent BTK inhibition into frontline MCL regimens, which will progressively shrink the pool of patients naïve to these drugs who can be studied in the R/R setting. Whether patients who received fixed-duration covalent BTK inhibition in the first-line setting could later be rechallenged with ibrutinib–venetoclax remains an open and unanswered question. Second, the OASIS II trial (NCT04802590) has demonstrated that a triplet with a BTK inhibitor, a BCL2 inhibitor, and an anti-CD20 therapy produces deep MRD-negative responses in previously untreated MCL, signaling growing interest in chemotherapy-free frontline approaches.⁴

The most consequential development, Eyre argues, is the emergence of next-generation agents. Sonrotoclax (Beqalzi; BeOne Medicines), a second-generation BCL2 inhibitor with greater potency and selectivity than venetoclax and a shorter half-life, showed a 52% ORR as monotherapy in heavily pretreated, R/R MCL patients previously treated with BTK inhibitors. In combination with zanubrutinib, early-phase data in patients naïve to covalent BTK inhibition in R/R MCL yielded a 79% ORR and 66% CR rate. On May 13, sonrtoclax received FDA approval for patients with R/R MCL who have received at least 2 lines of systemic therapy, including a BTK inhibitor.⁵

The ongoing phase 3 CELESTIAL-RR MCL trial (NCT06742996) is now testing zanubrutinib–sonrotoclax against zanubrutinib–placebo in a 300-patient global study—a direct attempt to achieve where SYMPATICO fell short.⁶

If combinations with BTK and BCL2 inhibitors are to be used in the future, Eyre concludes, “It will be critical for the field to generate robust evidence of the efficacy of the BTK [inhibitor]–BCL2 [inhibitor] combination in patients exposed to a [covalent] BTK [inhibitor] as a fixed-duration therapy (or due to intolerance) in the first-line setting.”

References

1. Eyre TA. Where next for BTKi–BCL2i combinations in mantle cell lymphoma? Br J Haematol. 2026;00:1–2. https://doi.org/10.1111/ bjh.70621
2. Wang M, Jurczak W, Trneny M, et al. Ibrutinib plus venetoclax for relapsed/refractory mantle cell lymphoma: final analysis of the phase 3 SYMPATICO study. Br J Haematol. 2026.
3. Caffrey M. If a BTK inhibitor comes first in MCL, what comes next? AJMC. February 19, 2026. Accessed June 29, 2026. https://www.ajmc.com/view/if-a-btk-inhibitor-comes-first-in-mcl-what-comes-next-
4. Le Gouill S, Morschhauser F, Chiron D, et al. Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Blood. 2021;137(7):877-887. doi: 10.1182/blood.2020008727.
5. FDA grants accelerated approval to sonrtoclax for relapsed or refractory mantle cell lymphoma. News release. FDA newsroom. May 13, 2026. Accessed June 29, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sonrotoclax-relapsed-or-refractory-mantle-cell-lymphoma
6. Barrett D. Sonrotoclax + zanubrutinib for patients with R/R MCL: Results from the phase I BGB-11417-101 trial. LymphomaHub. July 24, 2025. Accessed June 29, 2026. https://lymphomahub.com/medical-information/sonrotoclax-zanubrutinib-for-patients-with-rr-mcl-results-from-the-phase-i-bgb-11417-101-trial