BTK Inhibitors with CAR T-cell Therapy

The emergence of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has transformed the therapeutic approach in the management of relapsed/refractory (R/R) B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). Currently, there are 5 CD19-directed CAR T-cell therapies approved for B-cell lymphoma and leukemia: axicabtagene ciloleucel (axi-cel), brexucabtagene autoleuce (brexu-cel), tisagenlecleucel (tisa-cel), lisocabtagene maraleucel (liso-cel), and obecabtagene autoleucel (obe-cel).

Despite impressive response rates, CAR T-cell therapy faces challenges, including T-cell exhaustion, limited persistence, and toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity (ICANS). Bruton tyrosine kinase (BTK) inhibitors have also emerged as key therapies for B-cell malignancies, as they are highly effective in preventing the proliferation of malignant B-cells. The FDA-approved BTK inhibitors include ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib. There is evidence that combining CD-19-directed CAR T-cell therapy with a BTK inhibitor will improve CAR T-cell efficacy and outcomes by enhancing T-cell expansion, persistence, and tumor clearance. Additionally, the BTK inhibitors can penetrate the blood-brain barrier, making them particularly useful in the setting of central nervous system (CNS) involvement. This article reviews the clinical evidence, toxicity profiles, and future directions for combining BTK inhibitors with CAR T-cell therapy.

BTK Inhibitors
Ibrutinib

Ibrutinib, a first-generation covalent BTK inhibitor, has shown synergistic effects with CAR T-cell therapy by promoting T helper (TH)1 differentiation, increasing interferon-gamma, and thus sustaining CAR T-cell function and tumor clearance.¹

The phase II, prospective, TARMAC trial evaluated ibrutinib in combination with tisa-cel in patients with R/R MCL.² Patients started ibrutinib at least 7 days before leukapheresis and continued for at least six months after CAR T-cell administration. In this study of 20 patients, investigators reported an overall response rate (ORR) of 85%, with a complete response rate (CR) of 80%; 70% achieved minimal residual disease (MRD) negativity at month 4.² At a median follow-up of 13 months, median progression-free survival (PFS) was not reached.² These durable responses were also seen in high-risk subgroups, including those with prior BTK inhibitor exposure or TP53 mutation, and deep responses were associated with robust CAR T-cell expansion and less exhausted baseline T-cells.²

The phase 1/2 TRANSCEND CLL 004 trial evaluated the combination of ibrutinib and liso-cel in patients with relapsed/refractory CLL.³ Patients started or continued ibrutinib before leukapheresis and for up to 90 days after the liso-cel infusion.³ A total of 56 patients received combination therapy, and all had been previously treated with a BTK inhibitor.³ The ORR was 86% with 45% of patients achieving a complete remission rate.³ Patients had deep remissions with a median PFS of 31 months and an 86% undetectable measurable residual disease rate (uMRD) in the blood.³ In both the TARMAC and TRANSCEND CLL 004 studies, safety was comparable with expected CRS and ICANS rates.^2,3

In a pilot cohort from a phase I-II, open-label clinical trial of CD19 CAR T-cell therapy, 19 patients with R/R CLL were treated with concurrent ibrutinib.⁴ Patients initiated ibrutinib at least two weeks before leukapheresis and continued treatment for at least three months following CAR T-cell infusion.⁴ A retrospective analysis compared outcomes between the ibrutinib cohort and a non-ibrutinib cohort.⁴ The overall response rate at 4 weeks was 83% in the ibrutinib cohort versus 56% in the non-ibrutinib cohort (P=0.15).⁴ Any-grade cytokine release syndrome (CRS) occurred in 74% of patients receiving ibrutinib compared to 95% in the non-ibrutinib group, with grade ≥3 CRS observed in 0% versus 11%, respectively.⁴ Any-grade neurotoxicity was seen in 26% of the ibrutinib cohort and 42% of the non-ibrutinib cohort, while grade ≥3 neurotoxicity occurred in 26% and 37%, respectively.⁴ Importantly, responses to CD19 CAR T-cell therapy with concurrent ibrutinib were associated with enhanced CAR T-cell expansion.⁴

Acalabrutinib

Acalabrutinib is a second-generation covalent BTK inhibitor with improved specificity compared to ibrutinib, thereby reducing off-target toxicities. A phase 1/2 study investigated the combination of acalabrutinib and axi-cel for DLBCL, primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma (FL).⁵ Patients received acalabrutinib starting between 3 weeks and 24 hours prior to leukapheresis until up to one year post axi-cel infusion or until unacceptable toxicity or disease progression.⁵ Of the 16 patients that received axi-cel, 15 (94%) were successfully bridged from leukapheresis to lymphodepletion (LD) with single agent acalabrutinib.⁶ The ORR reached 93%, with 71% achieving CR at 30 days post-infusion.⁶ At a median follow-up of 15.8 months, 11 were progression free, suggesting durable remissions in this high-risk population.⁶ From a safety perspective, no patients experienced grade ≥3 CRS and only 3 patients had grade 3 ICANS which resolved with management.⁶ No patients had to discontinue acalabrutinib due to toxicity.⁶ 

Another phase 1 trial combining acalabrutinib and CAR T-cell therapy, conducted by Baird et al., evaluated acalabrutinib alongside a naive/stem-memory phenotype-enriched CD19-CAR T-cell product in 8 patients with R/R MCL.⁷ Patients began acalabrutinib treatment 3 to 7 months before study enrollment and continued it until day 180 post-CAR T-cell infusion.⁷ The median duration of acalabrutinib treatment before enrollment was 6 months.⁷ The best ORR was 88%, with 75% of patients achieving a CR. OS rates at 1 year PFS were 70% and 100%, respectively.⁷ Grade 1-2 CRS occurred in 63% of patients, with no cases of grade 3-4 CRS or ICANS.⁷ There were no serious adverse events or treatment discontinuations reported.⁷ Although these studies have small sample sizes, the combination of acalabrutinib with CAR T-cell shows promising early results.

Zanubrutinib

Like acalabrutinib, zanubrutinib is a second-generation covalent BTK inhibitor with improved selectivity to BTK when compared to ibrutinib. A small study by Wang et al. was the first to report the use of sequential zanubrutinib therapy and CAR T-cell therapy.⁸ The study included 6 patients with relapsed/refractory DLBCL who received zanubrutinib 1-month post-axi-cel infusion.⁸ One month after the CAR T-cell infusion and before initiation of zanubrutinib, there was an ORR of 100%.⁸ Three patients achieved a CR (50%), and the remaining 3 patients achieved a PR (50%).⁸ All patients with PR achieved CR within 6 months following zanubrutinib initiation.⁸ A median follow-up of 19.6 months, all patients remained in CR.⁸ In the safety analysis, 5 patients (83%) experienced grade 2 CRS, while 2 patients (33.3%) developed grade ICANs.⁸ There was no grade ≥3 CRS cases reported. Other safety signals related to zanubrutinib toxicity were not reported.⁸ The authors concluded that the sequential zanubrutinib therapy strategy following CD19 CAR T-cell therapy is effective with acceptable toxicity.⁸ While not reported in the study, the sequential strategy may have been implemented to mitigate overlapping toxicities between zanubrutinib and CAR T-cell therapy, as most patients are anticipated to recover from CRS and/or ICANS one month following CAR T-cell therapy.

A retrospective study published in 2025 included 17 patients with relapsed/refractory DBLCL who received zanubrutinib in combination with an anti-CD19 CAR T-cell therapy.⁹ Patients received zanubrutinib for at least 2 months before CAR T-cell therapy.⁹ The ORR was 88.2% with 70.5% achieving CR.⁹ At 24 months, PFS was 59% and OS was 65%.⁹ One patient experienced grade 3 CRS, and no severe neurotoxicity was reported.⁹ Early expansion (<13 days) was associated with improved PFS and OS.⁹

Pirtobrutinib

The first and only FDA-approved non-covalent (reversible) BTK inhibitor is pirtobrutinib. Its unique binding is especially useful in the setting of covalent BTK inhibitor-resistant disease. A retrospective analysis of patients who received pirtobrutinib in combination with an investigational bispecific anti-CD19 and anti-CD20 CAR T-cell therapy (LV20.19) has been reported.¹⁰ There were 11 patients with either MCL, Richter’s Transformation (RT), CLL, Marginal Zone Lymphoma (MZL), or DLBCL who received pirtobrutinib within 4 weeks before apheresis.¹⁰ Patients were on pirtobrutinib for a median of 12 days before apheresis, and the median duration of pirtobrutinib was 4 months.¹⁰ The ORR reached 82%, with 64% achieving CR at 28 days post-infusion.¹⁰ The median PFS and OS were both 30.8 months, with 1-year PFS and OS rates of 9 and 15 months, respectively.¹⁰ Of note, there were no differences in the number of naïve or more differentiated CD4+ and CD8+ T-cells observed between groups. Still, there was a potential trend toward improved CAR T-cell function, as measured by polyfunctionality (PFA) and the polyfunctional strength index (PSI).¹⁰ Based on these results, there is an ongoing (as of the writing of this article) phase 1 clinical trial assessing the safety of pirtobrutinib as bridging and maintenance therapy with LV20.19 (NCT05990465).¹¹

Toxicity Consideration: CAR T-cell Therapy and BTK Inhibitor

While the combination of BTK inhibitors and CAR T-cell therapy has shown synergistic effects, it is important to consider their toxicity profiles. Notable toxicities seen with BTK inhibitors include cytopenias, arrhythmias, hypertension, bleeding, and infections. CAR T-cell therapy is associated with CRS and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), neurotoxicity, cytopenias, and infections. The incidence of these events varies by the specific BTK inhibitor and CAR T-cell product (Tables 1 and 2). With the combination of CAR T-cell therapy and BTK inhibitors, there is concern for overlapping toxicities.

Cardiovascular Toxicity

CRS can be associated with cardiovascular complications, including arrhythmias, posing a risk for patients continuing BTK inhibitor therapy.¹² In the TARMAC study, ibrutinib was withheld in patients who experienced grade ≥2 CRS (2 patients).² This is due to a report of a fatal arrhythmia during grade 2 CRS in a separate trial studying ibrutinib combined with CAR T-cells.⁴ In contrast, a study combining acalabrutinib with axi-cel reported no tachyarrhythmias or treatment discontinuations due to toxicity.^5,6 This suggests that later-generation BTK inhibitors, which have a lower incidence of arrhythmias (Table 1), may be better tolerated from a cardiac standpoint in the combination setting.

Hematologic Toxicity

Cytopenias are a common feature of both CAR T-cell therapy and lymphodepleting chemotherapy, and their severity may be exacerbated by concurrent BTK inhibitor use. In the TARMAC study, holding criteria for ibrutinib included grade 4 neutropenia lasting for at least 7 days, grade 3 neutropenia associated with infection, grade 4 thrombocytopenia, or grade 3 thrombocytopenia associated with bleeding.² Despite a high incidence of grade 3-4 neutropenia (15%) and thrombocytopenia (25%), only two patients required holding ibrutinib due to cytopenias.² These two patients had grade 3 neutropenia associated with infection and grade 4 thrombocytopenia.² In another study with concurrent ibrutinib and CAR T-cell therapy, the rates of grade ≥ 3 neutropenia, anemia, and thrombocytopenia were observed in 100%, 79%, and 68% of patients, respectively.⁴ However, most patients achieved transfusion and growth factor support independence within 1 month of CAR T-cell therapy.⁴ Notably, all patients had pre-existing grade 2-4 cytopenias before enrollment.⁴

Infections

Along with cytopenias, there is a risk of infections with both BTK inhibitors and CAR T-cell therapy. Prophylaxis against viral infections (herpes simplex and varicella zoster) and Pneumocystis jirovecci pneumonia (PJP) are universally recommended for patients who have received CAR T-cell therapy.¹³ Such patients are also at risk for bacterial and fungal infections, particularly when high-dose or prolonged courses of steroids are required. The incidence of infections does not vary significantly among BTK inhibitors. Grade ≥ 3 infections were reported in 21% of patients treated with ibrutinib, 19% with acalabrutinib, 24% with zanubrutinib, and 24% with pirtobrutinib (Table 1). In the TARMAC study, 4 patients (20%) were reported to have an infection within the first month of cell infusion, mostly low-grade.²

Clinical Management Recommendations

Overall, patients should undergo baseline cardiac evaluation and be monitored closely for any cardiac abnormalities during treatment. Furthermore, there is a risk of cytopenias following CAR T-cell infusion and BTK inhibitor therapy in patients requiring frequent transfusions, especially within the first month post CAR T-cell therapy. Monitoring for infection is also crucial when implementing prophylactic measures against viral and PJP infections. Bacterial and fungal infections should also be closely monitored, particularly in the context of prolonged neutropenia or steroid use. To mitigate overlapping toxicities, some studies have delayed the initiation of BTK inhibitor therapy or implemented strict holding parameters for holding BTK inhibitors. Although no standardized guidelines currently exist regarding the continuation or interruption of BTK inhibitors in this context, careful assessment of patient-specific risk factors and disease status is crucial to determine the safety of ongoing BTK inhibitor use before CAR T-cell therapy.

Conclusion and Future Directions

The combination of BTK inhibitors with anti-CD19 CAR T-cell therapy is a promising strategy to improve outcomes in relapsed/refractory B-cell malignancies. The trials reviewed here suggest that BTK inhibitor administration may enhance efficacy by promoting CAR T-cell expansion and reducing T-cell exhaustion, while maintaining an acceptable safety profile. However, larger randomized controlled trials are needed to validate these findings.

A key question regarding the use of BTK inhibitors with CAR T-cell therapy is the optimal timing and duration of BTK inhibitor administration relative to CAR T-cell infusion. In most trials, such as TARMAC, TRANSCEND CLL 004, and Gauthier et al., the BTK inhibitor was initiated days to weeks before leukapheresis and continued through the peri-infusion period. Conversely, Wang et al. demonstrated that sequential administration, starting Zanubrutinib 1 month post-CAR T infusion, may be a feasible approach to minimize overlapping toxicities.

Another unresolved question concerns the optimal duration of BTK inhibitor therapy after CAR T-cell infusion. Some studies continued BTK inhibitors for a fixed period (e.g., 3-6 months), while others extended treatment up to 1 year or until disease progression. Prolonged BTK inhibitor therapy could support sustained CAR T-cell persistence and reduce the risk of relapse, but robust data are lacking. Longer treatment courses must be carefully balanced against potential toxicities and financial considerations. Long-term follow-up from trials such as TRANSCEND CLL 004 will help determine whether extended BTK inhibitor maintenance improves progression-free or overall survival.

Overall, the use of BTK inhibitors with CAR T-cell therapy holds substantial promise for enhancing clinical responses in B-cell malignancies. While preliminary evidence supports both concomitant and sequential approaches, the optimal timing, sequencing, and duration of BTK inhibitor therapy remain key areas for further research. Future studies, especially those involving next-generation BTK inhibitors and extended follow-up, will be essential to establish evidence-based guidelines.

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