Data from a retrospective analysis showed that prolonged bridging therapy with a BTK inhibitor improved responses to CAR T-cell therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who had at least 1 high-risk prognostic feature.1
Findings published in Frontiers in Immunology demonstrated that patients in the overall population (n = 31) achieved an overall response rate (ORR) of 77.42% at 2 months following the infusion of CAR T-cell therapy, including a complete response (CR) rate of 58.06% and a partial response rate of 19.35%; the stable disease and progressive disease rates were 19.35% and 3.44%, respectively.
The ORR was 93.75% among patients who received at least 2 months of bridging therapy with a BTK inhibitor compared with 60.0% for those who received BTK inhibitor bridging therapy for less than 2 months (n = 15). No statistically significant difference in CR rate was reported between the 2 group (P = .2852).
At data cutoff, the median progression-free survival (PFS) and overall survival (OS) were not reached in the overall population; there were no significant difference in PFS (P = .3494) or OS (P = .3673) between the bridging therapy duration subgroups.
Regarding safety, the incidence of grade 2 or higher cytokine release syndrome (CRS) was higher among patients who received at least 2 months of bridging therapy with a BTK inhibitor (P = .0113); however, no significant difference in the rate of grade 1 or higher immune effector cell–associated neurotoxicity syndrome was observed between the groups (P = .0768). The incidences of grade 2 or higher neutropenia (P < .0001), grade 2 or higher anemia (P = .0155), and grade 1 or higher thrombocytopenia (P = .0000) were also higher in the subgroup of patients who received prolonged bridging therapy.
“Notably, the potential [adverse] effects of extending the duration of BTK inhibitor bridging therapy prior to anti-CD19 CAR T-cell therapy should be considered,” lead study author Jia Wang, MD, of the Department of Hematology of Tianjin First Central Hospital and the School of Medicine at Nankai University in China, and colleagues wrote in the publication. “Although none of the patients in our study succumbed to bacterial infections or invasive fungal diseases, implementing infection prevention measures throughout the course of BTK inhibitor bridging therapy before anti-CD19 CAR T-cell therapy is crucial for improving patient outcomes.”
What was the rationale for retrospectively analyzing outcomes based on BTK inhibitor bridging therapy duration in patients with DLBCL receiving CAR T-cell therapy?
BTK Inhibitor Bridging Duration and CAR T-Cell Therapy Outcomes in R/R DLBCL: Retrospective Findings
- Prolonged BTK inhibitor bridging therapy persisting at least 2 months was associated with improved responses to CD19-directed CAR T-cell therapy in patients with relapsed/refractory DLBCL.
- The ORR at 2 months following CAR T-cell therapy infusion was 93.75% for patients who received bridging therapy for at least 2 months (n = 16) compared with 60.00% for those who received BTK inhibitor bridging therapy for less than 2 months (n = 15).
- Prolonged BTK inhibitor exposure was associated with higher rates of grade 2 or higher CRS, grade 2 or higher neutropenia, grade 2 or higher anemia, and grade 1 or higher thrombocytopenia.
Within the United States, the CD19-directed CAR T-cell therapies axicabtagene ciloleucel (Yescarta), lisocabtagene maraleucel (Breyanzi), and tisagenlecleucel (Kymriah) have all been approved by the FDA for the treatment of select patients with relapsed/refractory DLBCL.2-4
Although CD19-targeted CAR T-cell therapies have become key treatment options for various subgroups of patients with non–Hodgkin lymphomas, improving durability of responses for these populations remains key, Wang and colleagues explained.1
Data from prior studies have demonstrated satisfactory clinical outcomes with the use of BTK inhibitors as bridging therapy ahead of CAR T-cell therapy, study authors noted, and this retrospective analysis sought to further evaluate the efficacy and safety of varying durations of BTK inhibitor bridging therapy.
The study featured a cohort of 33 patients with relapsed/refractory DLBCL who received BTK inhibitor bridging therapy prior to CD19-directed CAR T-cell therapy from July 2019 to March 2022. Patients were required to have at least 1 high-risk disease feature associated with poor prognosis, including high tumor burden (maximum diameter ≥7.5 cm), Richter transformation to LBCL, double-hit lymphoma or expression, TP53-mutated disease, or at least 2 extranodal lesions. Patients were followed from the day of CAR T-cell therapy infusion until death or the data cutoff of December 31, 2025.
Patients received bridging therapy with ibrutinib (Imbruvica) at 420 mg once per day or zanubrutinib (Brukinsa) at 160 mg twice per day, with treatment durations spanning from 1 to 4 months. Patients with severe hematologic toxicity or infectious complications during bridging therapy discontinued treatment with the BTK inhibitor. Notably, patients were assessed for response prior to receiving CAR T-cell therapy, and responders were permitted to forgo CAR T-cell therapy. Among the 33 patients included in the study, 31 received CAR T-cell therapy; the 2 patients who did not receive CAR T-cell therapy experienced disease progression during bridging therapy.
Prior to receiving CAR T-cell therapy, eligible patients underwent lymphodepleting chemotherapy comprising fludarabine at 30 mg/m2 per day and cyclophosphamide at 400 mg/m2 per day on days –4 to –2. Anti-CD19 CAR T-cell therapy was administered on day 0 at a dose of 2 x 106 cells/kg. Patients also received a BTK inhibitor as maintenance, with the treatment continued for 6 to 12 months for those in CR. BTK inhibitor maintenance was stopped upon disease progression, irrespective of CAR T-cell therapy response status.
Among patients who underwent CAR T-cell therapy, the mean age was 53.69 years (standard deviation [SD], 12.98) in those who received BTK inhibitor bridging therapy for at least 2 months and 54.47 years (SD, 14.08) for those who received bridging therapy for less than 2 months. Most patients in both groups were male (≥2 months, 81.3%; <2 months, 60.0%). Included patients had high tumor load (50.0%; 46.7%), double-hit lymphoma/expression (68.8%; 20.0%), TP53 deletions or mutations (31.3%; 33.3%), Richter transformation (56.3%; 40.0%), and more than 1 extranodal lesion (62.5%; 13.3%).
In patients who received bridging therapy for at least 2 months, International Prognostic Index (IPI) scores included 5 (25.0%), 4 (62.5%), 3 (12.5%), and 2 (0%); in the less than 2 months group, these respective rates were 0%, 13.3%, 46.7%, and 40.0%. Ann Arbor disease stages included 4 (≥2 months, 43.8%; <2 months, 40.0%), 3 (43.8%; 60.0%), and 2 (12.5%; 0%). Patients had either relapsed (25.0%; 46.7%) or refractory (75.0%; 53.3%) disease. Ibrutinib was used as bridging therapy for 43.8% of patients who underwent bridging for at least 2 months and 73.3% of patients who received bridging for less than 2 months. The remainder in each group received zanubrutinib.
What additional efficacy and safety outcomes were reported among study subgroups?
Findings also showed that in the overall population, patients with Richter transformation achieved an ORR of 86.67% compared with 68.75% for patients with DLBCL (P = .3944). Those with Richter transformation who underwent at least 2 months of bridging therapy experienced an ORR of 88.89% compared with 44.4% for those with DLBCL who received less than 2 months of bridging therapy (P = .1312). No statistically significant differences were reported regarding CR rate for patients with Richter transformation vs DLBCL (P = .1489) and those with Richter transformation treated with at least 2 months of bridging therapy vs those with DLBCL treated with bridging therapy for less than 2 months (P = .1534).
Regarding safety, an increased incidence of grade 2 or higher CRS was reported for patients with Richter transformation who received bridging therapy for at least 2 months vs those who had DLBCL and received less than 2 months of bridging therapy (P = .0498). No statistically significant difference was reported between the overall Richter transformation and DLBCL subgroups (P = .4795).
Grade 2 or higher neutropenia also occurred at higher rates in patients who had Richter transformation and received 2-plus months of bridging therapy vs those with DLBCL who received less than 2 months of bridging therapy (P = .0034); this difference was not statistically significant between the Richter transformation and DLBCL subgroups (P = .4795). Although differences in grade 2 or higher anemia were reported based on bridging therapy duration for the overall population, this difference was not statistically significant among the Richter transformation vs DLBCL subgroups (P = .7043) or the 2-plus months plus Richter transformation vs less than 2 months plus DLBCL subgroups (P = .1312).
“Our study revealed that extending the duration of BTK inhibitor bridging therapy prior to anti-CD19 CAR T-cell therapy has the potential to enhance outcomes in patients with relapsed/refractory DLBCL with unfavorable baseline characteristics, such as higher IPI, double hit/expression, and multiple extranodal lesions,” Wang and coauthors concluded. “Validation of these findings requires further expansion of the clinical sample size. Moreover, maintaining vigilance against hematological toxicity resulting from the extension of BTK inhibitor bridging therapy before anti-CD19 CAR T-cell therapy is essential.”
References
- Wang J, Cui R, Qi Y, et al. Predictors and responses to varying durations of BTK inhibitor bridging therapy before anti-CD19 CAR-T cell therapy in patients with relapsed/refractory DLBCL. Front Immunol. 2026;17:1674235. doi:10.3389/fimmu.2026.1674235
- Yescarta. Prescribing information. Updated February 2026. Accessed March 16, 2026. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/yescarta/yescarta-pi.pdf
- Breyanzi. Prescribing information. Updated February 2026. Accessed March 16, 2026. https://packageinserts.bms.com/pi/pi_breyanzi.pdf
- Kymriah. Prescribing information. Updated December 2025. Accessed March 16, 2025. https://www.novartis.com/us-en/sites/novartis_us/files/kymriah.pdf
