Authors Compare Bridging Therapy Strategies Prior to Brexu-Cel in MCL

Patients with mantle cell lymphoma (MCL) now have options in chimeric antigen receptor (CAR) T-cell therapy, with brexucabtagene autoleucel (brexu-cel; Tecartus; Kite Pharma) and lisocabtagene maraleucel (liso-cel; Breyanzi; Bristol Myers Squibb) approved in the United States for later lines of treatment.^1,2

Brexu-cel has been used to treat MCL longer, having been approved in 2020 for patients with prior treatments, including a Bruton tyrosine kinase (BTK) inhibitor.¹ Although the pivotal ZUMA-2 trial (NCT02601313) restricted bridging therapy to BTK inhibitors and/or steroids in just 37% of patients,³ real-world practice sees 68% to 90% of patients receiving bridging therapy, prompting authors in the United Kingdom to study patients from 15 cancer centers to evaluate best practices in bridging therapy to yield good outcomes with brexu-cel in patients with MCL. Results were published online this month in the British Journal of Haematology.⁴

The UK study involved 176 patients, of whom 90% (158/176) received bridging therapy, with the majority receiving standard chemotherapy with or without radiotherapy (53%) or targeted therapy alone (23%).

Preferred Bridging Therapy Choices

The 2 dominant strategies were standard chemotherapy with or without radiotherapy (chemo +/– RT), given to 53% of patients, and targeted therapy (TT) alone, given to 23% of patients; these were primarily BTK or BCL-2 inhibitors. Clinicians tended to favor chemo +/− RT in higher-risk patients, specifically those with an ECOG performance status of 1, blastoid disease morphology, bulky disease exceeding 5 cm, and elevated lactate dehydrogenase levels. In the multivariable analysis, an ECOG performance status of 1 was the only factor independently associated with selection of chemo +/− RT over TT alone.

Response to Bridging Therapy

Bridging therapy response was available for 154 patients (97%). Investigators reported that the overall response rate (ORR) to bridging therapy was 46% (71/154), with a complete response rate of just 12% (19/154), highlighting the limited efficacy of current strategies for bridging therapy.

Patients receiving chemo +/− RT achieved the highest ORR (58%) and were nearly 4 times more likely to respond than those receiving other modalities, after adjustment for performance status and disease burden. The chemoimmunotherapy regimen of rituximab, bendamustine, and cytarabine (R-BAC) was the standout performer, with an ORR of 64%. TT alone yielded the lowest ORR at 23%, though patients who switched to an alternative targeted agent after approval achieved a more encouraging 58% response rate. Notably, the authors found that no disease-specific features, including TP53 mutation status, BTK inhibitor refractoriness, or tumor bulk, independently predicted response. The only significant predictor was the use of chemo +/− RT.

Impact on CAR T-Cell Therapy Outcomes

The study portrays the variability of whether patients selected for CAR T-cell therapy ultimately make it to infusion.

“Of 176 apheresed patients, 147 [84%] received their infusion,” the investigators reported. “Infusion rates did not differ by [bridging therapy] modality…. Likewise, [bridging therapy] choice had no impact on time from harvest to cell infusion…. Median time from harvest to infusion for all was 38 days [range 26-271].”

The best ORR to CAR T was 87%. Neither bridging therapy modality nor response significantly affected progression-free survival or overall survival post infusion.

However, patients who progressed despite bridging therapy had a meaningfully lower ORR to CAR T-cell therapy (77% vs 91%; P = .03) and were more than 3 times more likely to develop immune effector cell–associated neurotoxicity syndrome of grade 3 or higher (OR, 3.43; P = .01), which the authors said was of particular concern given the older median age of patients with MCL.

Toxicity and Nonrelapse Mortality

Chemo +/− RT was associated with significantly higher rates of neutropenia of grade 3 or higher in the first month and thrombocytopenia of grade 3 or higher in the first and third months after infusion. Patients receiving TT alone were comparatively protected from these cytopenias. Early nonrelapse mortality (NRM) within 90 days was strikingly higher in those who received chemo +/− RT (13%) vs those who received TT (0%), with 80% of early NRM events occurring in patients who had not recovered adequate neutrophil counts. Sepsis contributed to most of these deaths, the authors reported.

The authors concluded that although chemo +/− RT, particularly R-BAC, delivers superior response rates in bridging therapy, this does not translate into improved survival post infusion. The goal should be disease control with the least toxic regimen possible, they noted.

With 90% of UK patients receiving bridging therapy, the authors wrote, “it was not possible to determine which factors influenced the decision to administer bridging therapy [vs watch and wait]. Bridging therapy was highly heterogeneous and likely guided by disease burden and pace, prior therapy/sensitivity, physician preference, patient fitness, hematopoietic reserve, and access to novel therapies.”

Clinicians preferred chemo +/− RT in higher-risk cases, with an ECOG performance status of 1 being the apparent main driver, they said.

Of note, they wrote, decisions on whether to administer bridging therapy and/or more intensive therapy in poorer-risk candidates have been demonstrated in MCL and large B-cell lymphoma and may confound outcome assessment. “Therefore, comparisons of…chemo +/− RT vs other modalities in our analysis should be interpreted with caution.”

They wrote that pirtobrutinib (Jaypirca; Eli Lilly and Company), a third-generation noncovalent BTK inhibitor, could be an attractive option.

Careful assessment of hematopoietic reserve before selecting bridging therapy, rigorous postinfusion supportive care for delayed cytopenias, and the development of more effective, better-tolerated bridging strategies should be clinical priorities going forward.

References

1. CAR T-cell therapy approved by FDA for mantle cell lymphoma. National Cancer Institute. August 24, 2020. Accessed March 21, 2026. https://www.cancer.gov/news-events/cancer-currents-blog/2020/fda-brexucabtagene-mantle-cell-lymphoma
2. Caffrey M. FDA approves liso-cel to treat R/R mantel cell lymphoma. AJMC. May 30, 2024. Accessed March 21, 2026. https://www.ajmc.com/view/fda-approves-liso-cel-to-treat-r-r-mantle-cell-lymphoma
3. 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
4. O'Reilly MA, Wilson W, Maybury B, et al. Bridging practices prior to brexucabtagene autoleucel for mantle cell lymphoma in the United Kingdom: an analysis of modality, response, toxicity and survival. Br J Haematol. 2026;208(4):1347-1358. doi:10.1111/bjh.70357