According to primary results from the phase 1/2 TRANSCEND CLL 004 study published in the Blood Journal by Wierda et al., combining lisocabtagene maraleucel (liso-cel; Breyanzi) and ibrutinib (Imbruvica) achieves high rates of complete response and undetectable minimal residual disease in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.
TRANSCEND CLL 004 Study Design and Patient Response Rates
The multicenter, open-label trial enrolled adults with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma who had prior Bruton tyrosine kinase inhibitor exposure, according to ClinicalTrials.gov records. Starting at enrollment, participants were administered ibrutinib at 420 mg daily through leukapheresis, which then continued for up to 90 days following a single infusion of liso-cel. Wierda et al. report that among 51 patients treated at the recommended dose level, the primary end point of complete response or complete response with incomplete marrow recovery reached 45%, with a 95% confidence interval ranging from 31% to 60%. The overall response rate hit 86%, with a 95% confidence interval of 74% to 94%.
Did you know? Out of the 23 patients who achieved a best response of complete response or complete response with incomplete marrow recovery, 12 initially presented with a partial response that deepened over time.
Progression-Free Survival and Undetectable MRD Data
At a median follow-up of 24.8 months, the median duration of response was not reached for patients achieving complete response or complete response with incomplete marrow recovery, while it stood at 41.4 months among all responders, according to Wierda et al. The median progression-free survival reached 31.4 months. Undetectable minimal residual disease at a sensitivity of 10⁻⁴ was achieved in 86% of treated patients in peripheral blood and 84% in bone marrow. For patients who reached complete response or complete response with incomplete marrow recovery, the undetectable minimal residual disease rate climbed to 96% in both peripheral blood and bone marrow compartments.
Safety Profile and Adverse Events in Combination Therapy
Safety findings matched the known profiles of chimeric antigen receptor T-cell therapy and ibrutinib without revealing new signals, according to the study authors. Within the full combination-treated group of 56 patients, grade 3 or higher treatment-emergent adverse events impacted 86% of participants. Neutropenia affected 52% and anemia affected 41%. Cytokine release syndrome of any grade developed in 80% of patients, though grade 3 events occurred in only 4%, and no grade 4 or grade 5 events were reported. Neurological events impacted 41% of patients, with grade 3 or 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 in 7% and atrial fibrillation in 2%. Wierda et al. confirmed that no treatment-related deaths occurred.
Exploratory Analyses and Mechanistic Insights
As reported by Wierda et al., evaluations within the TRANSCEND CLL 004 trial revealed that chimeric antigen receptor-positive T cells from participants who received the combination therapy exhibited significantly reduced T-cell exhaustion scores at peak expansion relative to those in a liso-cel monotherapy group, resulting in a P value of .016. These findings provide a biological rationale for why adding ibrutinib may enhance chimeric antigen receptor T-cell activity in chronic lymphocytic leukemia, a disease where T-cell dysfunction historically limits efficacy. Post hoc propensity score-matched comparisons between the combination and monotherapy cohorts favored the combination for complete response rate and overall response rate. However, progression-free survival and overall survival did not differ significantly, and the authors cautioned that these nonrandomized comparisons require careful interpretation.
Frequently Asked Questions
What was the primary end point of the TRANSCEND CLL 004 study?
According to Wierda et al., the primary end point was the investigator-assessed complete response or complete response with incomplete marrow recovery rate, which reached 45% among 51 patients treated at the recommended dose level.
What dose level of liso-cel was selected for the combination cohort?
Dose level 2, delivering 100×10⁶ chimeric antigen receptor-positive T cells following lymphodepleting chemotherapy, was selected as the recommended dose based on prior dose-escalation results, according to ClinicalTrials.gov data.
Were there any treatment-related deaths reported in the study?
No treatment-related deaths were reported in the combination-treated group, according to the findings published by Wierda et al.
How common was cytokine release syndrome in the trial?
Cytokine release syndrome of any grade occurred in 80% of patients, but grade 3 events were reported in only 4%, with no grade 4 or 5 events observed, according to the study.
What are your thoughts on these findings? Share your perspective in the comments below, or subscribe to our newsletter for ongoing updates on clinical hematology research.
Worth a look