Adding Ibrutinib to Liso-Cel Drives Deep Remissions in R/R CLL/SLL

Primary results from the phase 1/2 TRANSCEND CLL 004 study (NCT03331198) indicate high rates of complete response and undetectable minimal residual disease (MRD) with the combination of lisocabtagene maraleucel (liso-cel; Breyanzi) and ibrutinib (Imbruvica) in heavily pretreated patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹

Among 51 patients treated at the recommended dose level, the complete response/remission (CR) or CR with incomplete marrow recovery (CRi) rate—the study's primary end point—was 45% (95% CI, 31%-60%), and the overall response rate (ORR) was 86% (95% CI, 74%-94%). At a median follow-up of 24.8 months, median duration of response was not reached for patients achieving CR/CRi and was 41.4 months (95% CI, 23.3-not reached [NR]) among all responders. Median progression-free survival (PFS) was 31.4 months (95% CI, 20.1-NR).

Undetectable MRD at a sensitivity of 10⁻⁴ (uMRD4) was achieved in 86% of treated patients in peripheral blood and 84% in bone marrow. Among patients who reached CR/CRi, the uMRD4 rate rose to 96% in both peripheral blood and bone marrow. Median time to first response was 1.0 month, and median time to first CR/CRi was 3.1 months; of the 23 patients with best response of CR/CRi, 12 had an initial partial response that deepened over time.

“In conclusion, the combination of liso-cel plus ibrutinib treatment was efficacious and feasible in this cohort of patients with R/R CLL/SLL and induced deep and durable responses,” authors Wierda et al concluded in the publication.

TRANSCEND CLL 004 Study Design

TRANSCEND CLL 004 is a multicenter, open-label, phase 1/2 study that enrolled adults with relapsed/refractory CLL/SLL and prior Bruton tyrosine kinase (BTK) inhibitor exposure.² In the combination cohort, patients received ibrutinib 420 mg daily starting at enrollment through leukapheresis and continuing for up to 90 days after a single liso-cel infusion, given at a target dose of 50×10⁶ (dose level 1 or 100×10⁶ (dose level 2) chimeric antigen receptor (CAR)-positive T cells following lymphodepleting chemotherapy; dose level 2 was selected as the recommended dose based on prior dose-escalation results. The primary end point was investigator-assessed CR/CRi rate.

Safety Findings

Safety findings were consistent with the known profiles of CAR T-cell therapy and ibrutinib, with no new signals identified. In the full combination-treated group (n = 56), grade 3 or higher treatment-emergent adverse events occurred in 86% of patients, most commonly neutropenia (52%) and anemia (41%). Cytokine release syndrome (CRS) of any grade occurred in 80% of patients, though grade 3 events were reported in only 4%, with no grade 4 or 5 events. Neurological events occurred in 41% of patients, with grade 3/4 events in 11% and no grade 5 events.

Ibrutinib-related adverse events of grade 3 or higher occurred in 43% of patients, including hypertension (7%) and atrial fibrillation (2%). No treatment-related deaths were reported.

Exploratory Findings and Clinical Context

In TRANSCEND CLL 004, exploratory analyses showed that CAR-positive T cells from patients treated with the combination had significantly lower T-cell exhaustion scores at maximum expansion than those from a liso-cel monotherapy cohort (P =.016), offering a possible biological rationale for the efficacy signal. These findings offer a possible mechanistic explanation for why adding ibrutinib may enhance CAR T-cell activity in CLL, a disease in which T-cell dysfunction has historically limited CAR T-cell efficacy.

Additionally, post hoc propensity score–matched comparisons between the combination and monotherapy cohorts favored the combination for CR/CRi rate and ORR, though PFS and overall survival did not differ significantly, and the authors cautioned that these nonrandomized comparisons should be interpreted with care.

REFERENCES

1. Wierda WG, Dorritie KA, Gauthier J, et al. Lisocabtagene maraleucel combined with ibrutinib in R/R CLL or SLL: primary results from TRANSCEND CLL 004. Blood Journal. Published online July 28, 2026. doi:10.1182/blood.2026033565

2. Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). ClinicalTrials.gov. Updated July 6, 2026. Accessed August 6, 2026. https://clinicaltrials.gov/study/NCT03331198