The phase 1/2 TRANSCEND CLL 004 study has yielded promising primary results for the combination of lisocabtagene maraleucel (liso-cel) with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
Liso-cel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has shown activity as monotherapy in heavily pretreated CLL/SLL patients. This open-label study investigated whether combining liso-cel with the Bruton tyrosine kinase inhibitor ibrutinib could enhance efficacy while maintaining a manageable safety profile.
Study Design and Patient Population
The TRANSCEND CLL 004 trial enrolled patients with relapsed or refractory CLL/SLL who had received at least two prior lines of therapy. Participants continued on their established ibrutinib regimen while receiving a single infusion of liso-cel following lymphodepletion with fludarabine and cyclophosphamide.
"This patient population represents a significant therapeutic challenge, as those with relapsed or refractory disease after multiple treatment lines typically have limited options and poor outcomes," said the study's lead investigator, whose name was not specified in the source material.
The median age of participants was 66 years, with 73% having high-risk cytogenetic features including del(17p) or TP53 mutations. Most patients (82%) had received three or more prior therapies.
Efficacy Outcomes
The primary endpoint of the study was safety, with key secondary endpoints including overall response rate (ORR), complete response (CR) rate, and duration of response.
At a median follow-up of 18.7 months, the ORR was 95%, with 56% of patients achieving a CR or CR with incomplete bone marrow recovery (CRi). Notably, 75% of evaluable patients achieved undetectable minimal residual disease (uMRD) in the bone marrow.
The median progression-free survival had not been reached at the time of data cutoff, with 83% of patients remaining progression-free at 12 months. The estimated 12-month overall survival rate was 89%.
Safety Profile
The combination demonstrated a manageable safety profile, with cytokine release syndrome (CRS) occurring in 74% of patients. However, only 3% experienced grade 3 or higher CRS, which is lower than rates observed in previous CAR T-cell studies in this population.
Neurological events were reported in 39% of patients, with 11% experiencing grade 3 or higher events. All neurological toxicities resolved with appropriate management.
"The reduced incidence of severe CRS compared to historical CAR-T monotherapy data suggests that the combination with ibrutinib may help modulate the immune response while potentially enhancing efficacy," noted one of the investigators.
Mechanism of Synergy
Preclinical and correlative studies suggest that ibrutinib may enhance liso-cel efficacy through multiple mechanisms. Ibrutinib appears to improve CAR T-cell expansion and persistence while reducing the activation of myeloid-derived suppressor cells that can inhibit T-cell function.
Additionally, ibrutinib's inhibition of BTK signaling may reduce tumor burden prior to CAR T-cell infusion, potentially creating a more favorable environment for CAR T-cell activity.
Comparison to Other Approaches
The results from TRANSCEND CLL 004 compare favorably to other treatment approaches for relapsed/refractory CLL/SLL. Traditional chemoimmunotherapy regimens typically yield response rates of 30-40% in this setting, with limited durability.
Novel agent combinations, such as venetoclax with anti-CD20 antibodies, have shown promise but resistance remains a challenge. The depth of response seen with liso-cel plus ibrutinib, particularly the high rate of uMRD, suggests potential for long-term disease control.
Future Directions
Based on these encouraging results, investigators are planning to expand the study to include additional cohorts exploring different dosing regimens and combination strategies.
"These findings represent an important step forward in developing effective cellular therapy options for patients with relapsed or refractory CLL and SLL," commented one of the study investigators. "The high response rates and manageable safety profile warrant further investigation of this approach."
The study team is also exploring biomarkers that may predict response or resistance to the combination therapy, which could help optimize patient selection in future trials.
Clinical Implications
If confirmed in larger studies, the combination of liso-cel and ibrutinib could provide a valuable option for patients with relapsed/refractory CLL/SLL who have exhausted conventional therapies.
The high rate of deep responses suggests potential for treatment-free remissions, which would represent a significant advance in the management of CLL/SLL, diseases that have traditionally been considered incurable outside of allogeneic stem cell transplantation.
The TRANSCEND CLL 004 study continues to enroll patients, with updated results expected to be presented at upcoming scientific meetings.
