Administration of ibrutinib (Imbruvica) prior to leukapheresis and infusion of tisagenlecleucel (Kymriah) may help improve the quality of chimeric antigen receptor (CAR) T-cell therapy and outcomes for patients with relapsed/refractory large B-cell lymphoma (LBCL), according to data from a phase 1 trial (NCT03876028) published in Blood Neoplasia.1
Findings showed that patients treated with ibrutinib prior to apheresis (n = 4) achieved a best overall response rate (ORR) of 100%. Notably, patients who started ibrutinib following apheresis (n = 6) experienced a best ORR of 50%. At 3 and 6 months, the ORRs were 75% in the pre-apheresis arm and 33% in the postapheresis arm. The complete response (CR) rates were 75% and 33%, respectively; 1 patient in each arm achieved CR with ibrutinib prior to treatment with tisagenlecleucel.
Notably, in evaluable responders in the pre-apheresis arm (n = 3), the maximum plasma concentration following tisagenlecleucel was 590 (117.8%) copies/µg compared with 3980 (160.2%) copies/µg in evaluable responders in the post-apheresis arm (n = 3). Additionally, administration of ibrutinib prior to apheresis was associated with lower percentages of senescent CD4-positive and CD8-positive T cells in both apheresis and the final CAR T-cell therapy product compared with the post-apheresis arm. Final products in the pre-apheresis arm had higher CAR-positive cell counts and higher viability percentages than those in the postapheresis arm.
“Despite the small number of patients, individual patient cellular kinetics over time were consistent with the interpatient variability seen in the expansion profiles observed in the [phase 2] JULIET clinical trial [NCT02445248] of tisagenlecleucel in relapsed/refractory LBCL,” lead study author Julio C. Chavez, MD, MS, and colleagues wrote in the publication. “Although data from this study indicate that patients in the postapheresis arm had greater CAR T-cell expansion in vivo than patients in the pre-apheresis arm, such comparisons should be interpreted with caution because of the small sample size and high interindividual variability.”
Chavez is an associate member in the Lymphoma Section of the Department of Malignant Hematology and the medical director of the ICE-T Clinical Research for Hematologic Malignancies at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida.
In May 2018, the FDA approved tisagenlecleucel for the treatment of adult patients with relapsed/refractory LBCL—including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy, based on data from the JULIET trial.2
Takeaways for Ibrutinib Plus Tisagenlecleucel in R/R LBCL
- Ibrutinib administered prior to leukapheresis was associated with higher ORR and CR rates than postapheresis initiation in patients receiving tisagenlecleucel.
- Pre-apheresis ibrutinib exposure correlated with more favorable CAR T-cell product characteristics, including reduced T-cell senescence and improved viability.
- Lower rates of CRS were observed with pre-apheresis ibrutinib, although findings are hypothesis generating given the small sample size.
What was the design of the phase 1 trial evaluating ibrutinib plus tisagenlecleucel in R/R LBCL?
The multicenter, open-label, nonrandomized exploratory study enrolled patients aged 18 or older with confirmed LBCL who had received at least 2 prior lines of systemic therapy, including an anti-CD20 agent and an anthracycline-based chemotherapy.1 Progression or relapse following autologous stem cell transplant or ineligibility/lack of consent for transplant was also required. Patients also needed to have an ECOG performance status of 0 or 1.
Patients with Richter transformation, Burkitt lymphoma, or primary central nervous system LBCL were excluded.
In the pre-apheresis arm, patients received ibrutinib at 560 mg per day for at least 21 days prior to apheresis and at least 21 days following apheresis until CAR T-cell therapy infusion. In the postapheresis arm, ibrutinib was initiated after leukapheresis and continued for at least 21 days before tisagenlecleucel administration. In both groups, ibrutinib was given continuously during lymphodepletion, during the CAR T-cell therapy infusion, and after the infusion. Tisagenlecleucel was given at 0.6 x 108 to 6.0 x 108 CAR-positive T cells as a single infusion.
Safety and tolerability served as the trial’s primary end point. Secondary end points included ORR, duration of response (DOR) in patients who achieved CR, progression-free survival (PFS), overall survival (OS), cellular kinetics, and cellular and humoral immunogenicity.
This study was ended early due to changes in the treatment landscape for relapsed/refractory LBCL; this decision was unrelated to safety or efficacy findings.
In the overall trial population (n = 10), patients had a median age of 61 years (range, 31-76), and 20% were female. Most patients had an ECOG performance status of 0 at screening (60%), stage IV disease (60%), no bone marrow involvement (90%), and no extralymphatic sites involved (60%). The number of prior lines of therapy included 2 (60%), 3 (20%), and 5 (20%).
What additional efficacy and safety data were reported?
Efficacy data also demonstrated that the median DOR, PFS, and OS were all not reached in the pre-apheresis arm. In the postapheresis arm, the median DOR was 17.2 months, the median PFS was 1.40 months, and the median OS was 8.4 months. One patient in the pre-apheresis arm and 4 patients in the postapheresis arm died during the study, with all deaths attributed to progressive disease.
“The combination of tisagenlecleucel and ibrutinib was well tolerated across ibrutinib pre-apheresis and postapheresis arms,” the study authors wrote. At least 1 adverse effect (AE) was reported in all patients following CAR T-cell therapy infusion, and 90% were treatment-related AEs (TRAEs) attributed to ibrutinib or tisagenlecleucel. The rates of grade 3 or higher AEs and grade 3 or higher TRAEs were 80% and 50%, respectively. AEs led to treatment discontinuation in 1 patient (10%) in the pre-apheresis arm. AEs also led to dose adjustment or interruption in 1 patient in the postapheresis arm.
The overall incidence of any-grade cytokine release syndrome (CRS) was 60% in the total population; however, this rate was 25% in the pre-apheresis arm vs 83% in the postapheresis arm. Grade 3 or higher CRS was not reported in either group. One patient in the postapheresis group experienced grade 1 immune effector cell–associated neurotoxicity syndrome.
“Overall, the pre-apheresis arm had lower rates of CRS…along with higher response rates than the postapheresis arm,” the study authors wrote. “However, the differences in outcomes between the pre-apheresis and postapheresis arms should be interpreted with caution and used primarily for hypothesis generation due to the low number of patients in each cohort and heterogeneous disease characteristics in the 2 treatment arms.”
References
- Chavez JC, Napier E, Bondanza A, et al. Tisagenlecleucel in combination with ibrutinib in adults with relapsed and/or refractory large B-cell lymphomas. Blood Neoplasia. 2025;3(1):100176. doi:10.1016/j.bneo.2025.100176
- FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. FDA. May 1, 2018. Accessed April 10, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-adults-relapsed-or-refractory-large-b-cell-lymphoma
