Ibrutinib plus venetoclax for patients with relapsed or refractory mantle cell lymphoma: an editorial on the phase 3 SYMPATICO trial

The rationale for studying the combination of ibrutinib and venetoclax in patients with relapsed and refractory (r/r) mantle cell lymphoma (MCL) includes data on each drug used as monotherapy and preclinical data supporting the combination.

Covalent Bruton tyrosine kinase (BTK) inhibitors have become a critical component in the management of r/r MCL. However, disease progression is inevitable and is particularly rapid in high-risk subgroups, including those with TP53-mutated disease (1). Ibrutinib is the first-in-class covalent BTK inhibitor. Long-term follow-up of the phase 2 and 3 trials of ibrutinib in patients with r/r MCL demonstrated a complete response (CR) rate of 23% in both studies, median progression-free survival (PFS) 13–15.6 months, and median overall survival (OS) 22.5–30.3 months (2,3).

Venetoclax is the only Food and Drug Administration (FDA)-approved BCL2 inhibitor as of August 2025. Long-term follow-up of a phase 1 trial of venetoclax in patients with r/r B-cell non-Hodgkin lymphomas demonstrated a CR rate of 21% and median PFS of 11.3 months in the MCL cohort (4). Retrospective chart review data on the efficacy of venetoclax monotherapy in patients with r/r MCL, almost all of whom received prior BTK inhibitor, yielded a CR rate of 18% (5), median PFS of 2.8–3.2 months, and median OS of 9.4–9.5 months (5,6).

In vitro (7-9) and in vivo studies (9) of ibrutinib and venetoclax demonstrated synergistic anti-tumor activity, suggesting that the combination may be more efficacious than using each agent in sequence and providing a rationale for assessing the combination in human studies.

In 2018 Tam et al. published a single-arm open-label phase 2 study of ibrutinib-venetoclax in adults with MCL who either had r/r disease or who were treatment-naïve but deemed not to be candidates for cytotoxic chemotherapy (10). Twenty-four patients enrolled, including 23 with r/r disease, with half having a TP53 mutation and/or deletion. The week 16 CR rate without positron emission tomography (PET) (primary endpoint) was 42%, a statistically and clinically significant improvement over the 9% week 16 CR rate chosen as a benchmark based on results from the single-arm phase 2 trial of ibrutinib monotherapy (10). With PET, the week 16 CR rate was 62%. The 12- and 18-month PFS were 75% and 57% respectively, while the 18-month OS rate was 74%. Although these results were promising, a randomized trial was needed to demonstrate the benefit of ibrutinib-venetoclax over ibrutinib monotherapy more definitively.

In a recent issue of Lancet Oncology, Wang et al. published the randomized, double-blind, placebo-controlled, multicenter phase 3 SYMPATICO study comparing treatment with ibrutinib-venetoclax with ibrutinib-placebo in adults with r/r MCL after failure of at least one line of therapy containing an agent targeting CD20 (11). The combination was planned to be taken for 2 years followed by single-agent ibrutinib. Two hundred and sixty-seven patients enrolled—134 on the ibrutinib-venetoclax arm and 133 on the ibrutinib-placebo arm. The ibrutinib-venetoclax and ibrutinib-placebo arms included 30% and 28% patients with TP53 mutations, respectively.

At median follow-up of 51.2 months, the median PFS for ibrutinib-venetoclax was 31.9 vs. 22.1 months for the ibrutinib-placebo arm, and the PFS hazard ratio (HR) of 0.65 significantly favored ibrutinib-venetoclax. The 24-month PFS rates were 57% and 45% for ibrutinib-venetoclax and ibrutinib-placebo, respectively. The CR rates were 54% and 32% for ibrutinib-venetoclax and ibrutinib-placebo, again favoring the venetoclax-containing arm. Additionally, CRs in patients on the ibrutinib-venetoclax arm were more durable than those in patients on the ibrutinib-placebo arm. Only a small share of patients were evaluable for measurable residual disease (MRD) by 8-color flow cytometry (sensitivity 5×10⁻⁴) due to a high proportion with negative or unknown baseline MRD status, making results challenging to interpret. However, the available data demonstrate higher rates of undetectable MRD on the ibrutinib-venetoclax arm, again supporting the combination’s higher-quality responses. In future studies a more sensitive MRD assay such as one using next-generation sequencing could be considered (12).

Among the prespecified subgroup analyses for PFS, it is worth highlighting the similar HRs for TP53-mutated (0.57) and unmutated (0.52) disease, suggesting that the combination regimen may abrogate the negative prognostic impact of TP53-mutated disease. However, 25% of patients had missing TP53 mutation status, a degree of missingness which could have had an impact on results’ statistical significance (https://rpubs.com/dkr2109/1337257) (13-15). Other subgroups, including those for blastoid and blastoid/pleomorphic variant, were small which limits interpretation of their PFS HRs. In addition, Ki-67, an important prognostic factor for MCL (16), was not assessed due to limitations in tissue availability, as tissue was appropriately prioritized for TP53 testing. Since all patients were treated in the second line or later, it would have also been helpful for the authors to have conducted a subgroup analysis for progression of disease within 24 months (POD24), a known adverse prognostic indicator (17,18).

The median OS for the ibrutinib-venetoclax group was 44.9 months whereas that for the ibrutinib-placebo group was 38.6 months (HR 0.85). Although the OS HR was not statistically significant, at the data cutoff 31% of those in the ibrutinib-venetoclax group and 45% of those in the ibrutinib-placebo group had gone on to a subsequent line of therapy and continued follow-up was planned.

In the SYMPATICO study, the most common grade 3–4 adverse events (AEs) were neutropenia (ibrutinib-venetoclax 31% vs. ibrutinib-placebo 11%), thrombocytopenia (13% vs. 8%), and pneumonia (12% vs. 11%). There was a higher rate of myeloid growth factor use in the combination arm (27%) vs. the placebo arm (11%). Rates of atrial fibrillation were equal between arms. Including worsening of MCL not meeting protocol criteria for progressive disease as an AE, the rates of grade 5 AEs were 16% vs. 14%. Rates of death due to COVID-19 were 7% vs. 8%. However, on the ibrutinib-venetoclax arm 4 individuals (3%) had grade 5 cardiac AEs and 2 (1%) had grade 5 hemorrhagic AEs, whereas no subjects on the ibrutinib-placebo arm had grade 5 cardiac or hemorrhagic AEs. Although the numbers are small, this may indicate a slight increase in the risk associated with drug-related cardiac and hemorrhagic AEs with the combination and suggests caution in using the combination in those with known cardiac disease or who are predisposed to bleeding. This is in line with a similar trend of serious AEs related to ibrutinib in each group of 34% vs. 27%. As expected, there was a higher rate of grade 1–2 gastrointestinal AEs in the ibrutinib-venetoclax arm than in the ibrutinib-placebo arm.

The results of the SYMPATICO study demonstrate that ibrutinib-venetoclax improves PFS over ibrutinib monotherapy in patients with r/r MCL, including those with TP53-mutated disease. The study’s inclusion of a high proportion of patients with TP53-mutated disease and appropriately not including subjects with lower-risk TP53 aberrations (e.g., TP53 deletions) (19) in the TP53 mutation subgroup analysis is a key strength. There are few randomized studies in r/r MCL and, among these, this study is the first to demonstrate improved PFS in r/r TP53-mutated disease; the authors should be commended on this effort. Although the PFS subgroup analysis for TP53 mutation status was prespecified, we note that a separate trial in patients with TP53-mutated disease would be required for definitive conclusions about the impact of adding venetoclax to ibrutinib in this subgroup. The ibrutinib-venetoclax combination is feasible to deliver based on the reported AE profile and the once daily oral dosing of both agents is also convenient for patients.

Despite this trial’s promising results, there are some caveats in its application to real-world practice due to shifting treatment paradigms in r/r MCL since the initiation of the protocol. Crucially, ibrutinib is no longer approved for use in MCL in the US (20), with the second-generation covalent BTK inhibitors zanubrutinib and acalabrutinib primarily taking its place. Many clinicians have extrapolated data from studies using ibrutinib to these agents and trial data have been published supporting their use as monotherapy in r/r MCL (21,22). However, additional trials are needed to provide evidence for the use of second-generation covalent BTK inhibitors in combination with other agents. One advantage of second-generation covalent BTK inhibitors is their improved toxicity profile (23), so the possibility of better tolerability with combination therapies using second-generation covalent BTK inhibitors should be investigated in clinical trials.

The most compelling indication for ibrutinib-venetoclax is r/r TP53-mutated MCL. TP53 mutation has been associated with worse prognosis, particularly with standard chemoimmunotherapy (19) and even with BTK inhibitors alone (24). Given promising results with the combination of a BTK inhibitor and venetoclax in patients with r/r TP53-mutated MCL, there has been interest in moving this combination to frontline in this high-risk population. The combination of zanubrutinib, obinutuzumab, and venetoclax (BOVen) was assessed in a single-arm phase 2 trial in patients with treatment-naïve TP53-mutated MCL with promising results, including CR rate of 88% and 2-year PFS and OS 72% and 76% respectively (25). The most common treatment-related AEs included diarrhea, coronavirus disease 2019 (COVID-19) infection, neutropenia, and infusion-related reactions. Additionally, acalabrutinib with rituximab and venetoclax is being assessed in part of a phase 1b trial in patients with treatment-naïve MCL (NCT02717624). Trials combining a noncovalent BTK inhibitor with a BCL2 inhibitor in patients with TP53-mutated MCL could also be considered. A phase 2 trial of pirtobrutinib with venetoclax in patients with r/r MCL, including those with TP53-mutated disease, is currently recruiting (NCT05529069). The SYMPATICO trial provides more support for the benefit of a BTK inhibitor with venetoclax in high-risk patient populations, particularly TP53-mutated MCL, and for studying this combination in the frontline setting.

Sequencing of therapies in MCL is changing with the results of the TRIANGLE study suggesting benefit of BTK inhibitor in frontline therapy and maintenance (26). Therefore, more patients with r/r MCL may no longer be naïve to BTK inhibitors. Depending on timing of relapse, a combination of BTK inhibitor and venetoclax may still be relevant, but more data on BTK inhibitor retreatment in this setting will be needed.

Finally, in addition to second-generation covalent BTK inhibitors and noncovalent BTK inhibitors, there are also next-generation BCL-2 inhibitors being investigated (e.g., NCT05471843, NCT06742996, NCT06839053). This may lead to future combinations with further benefit in efficacy and potentially reduced toxicity.

The SYMPATICO study provides evidence for a valuable treatment option for patients with MCL, particularly those with TP53-mutated disease. Although this regimen will not likely be used often in clinical practice, the results of this study provide support for further investigations and development of BTK and BCL-2 inhibitor combinations in MCL.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-72/prf

Funding: This work was supported by the National Institutes of Health (UNC-Integrated Translational Oncology, Award No. T32-CA244125; to D.K.R.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-72/coif). D.K.R. reports receiving a grant from National Institutes of Health (UNC-Chapel Hill, Award No. T32-CA244125); travel grants from UNC-Chapel Hill and International Conference on Malignant Lymphoma; and stock ownership in Regeneron Pharmaceuticals, Intellia Therapeutics, Beam Therapeutics, and Summit Therapeutics. N.G. reports receiving grants from Regeneron and BMS; consulting fees from Genentech, OnoPharma, Janssen, Seagen, ADC Therapeutics, and Kite; and serving on Data Safety Monitoring Boards or Advisory Boards for BMS, Regeneron, and Novartis. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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