BREYANZI, a CD19-directed CAR T cell therapy incorporating a 4-1BB costimulatory domain, has demonstrated successful expansion and long-lasting presence of CAR T cells. It is created from the patient's own T cells, which are genetically modified to become CAR T cells and administered via infusion as a single treatment. The primary results from the Phase I/II TRANSCEND CLL 004 trial, presented at ASCO 2023, confirmed the achievement of primary trial objectives.
The TRANSCEND CLL 004 trial recruited patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL) who had experienced disease progression while on or were not suitable for BTK inhibition. The patients were categorized as high risk or standard risk based on their lack of response to at least 2 or at least 3 prior treatment regimens, respectively.
The main objective of the study was to determine the complete response (CR) or complete response with incomplete marrow recovery (CRi) according to the International Workshop on CLL 2018 criteria, as assessed by an independent review committee (IRC). Secondary objectives included evaluating the overall response rate (ORR), achieving undetectable minimal residual disease (uMRD) in blood, measuring the duration of response (DOR), duration of CR, progression-free survival, time to response, time to CR, overall survival (OS), uMRD CR rate in blood, and assessing the safety of the treatment.
Out of the total number of participants in the study, which consisted of 137 patients, leukapheresis was performed on 137 individuals. Among them, 117 patients received the treatment, and efficacy was evaluated in 96 patients. Specifically, in the subgroup of patients who had previously received BTK inhibitors or venetoclax treatment, leukapheresis was conducted on 82 patients. Among them, 70 patients were administered liso-cel, and efficacy was assessed in 53 patients. Among the patients in this subgroup, liso-cel at dose level 2 was given to 49 individuals. Efficacy outcomes are as follows:
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In the entire study population, the median duration of response (DOR) was not reached (NR) for patients who achieved CR/CRi, 24 months for patients with PR/non-confirmed PR, and 35.5 months for patients who demonstrated any response to liso-cel. In the subgroup of patients who had prior treatment with BTK inhibitors or venetoclax, the median DOR was NR for those who achieved CR/CRi, 23.8 months for patients with PR/non-confirmed PR, and 35.3 months for those who had any response. These results were observed at a median follow-up of 19.7 months.
The evaluation of overall survival (OS) based on the best response showed improved outcomes in patients who achieved CR/CRi in both the full study population and the subgroup of patients pretreated with BTK inhibitors or venetoclax. In the full study population, the median OS was not reached (NR) for patients who achieved CR/CRi, NR for patients with PR/non-confirmed PR, 10.7 months for patients who showed no response, and 43.2 months for the overall population. Among the novel agent-pretreated population, the medians were NR for patients who achieved CR/CRi, NR for PR/non-confirmed PR, 10.7 months for patients with no response, and 30.3 months for the overall population.
Progression-free survival (PFS) based on the best response and minimal residual disease (MRD) status in blood, assessed using next-generation sequencing at a sensitivity of 10-4, showed similar patterns, with the most favorable outcomes observed in patients who achieved complete response/complete response with incomplete marrow recovery (CR/CRi) and undetectable MRD (uMRD). Specifically, the median PFS was not reached (NR) for patients who achieved CR/CRi with uMRD, 26.9 months for patients with PR/non-confirmed PR and uMRD, 6.3 months for patients with stable disease and uMRD, 3 months for patients with stable disease and detectable MRD, and 1 month for patients with progressive disease and detectable MRD.
Regarding safety, the most frequent Grade 3 or higher treatment-emergent adverse effects (AEs) included neutropenia (61%), anemia (52%), and thrombocytopenia (41%). Cytokine release syndrome (CRS) occurred in 85% of patients, while neurotoxicity was experienced in 45% of patients. Other notable AEs included prolonged cytopenia (54%), hypogammaglobulinemia (15%), tumor lysis syndrome (11%), second primary malignancy (9%), and macrophage activation syndrome (3%). Five treatment-emergent AE-related deaths occurred, with four of them determined to be unrelated to the treatment.
KOL insights
“A single administration of liso-cel demonstrated rapid, deep, and durable responses in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.” –Expert Opinion.
“Overall, these results support liso-cel as a potential new treatment option for relapsed/refractory CLL/SLL” –Expert Opinion.
Conclusion
The expansion of liso-cel, the CAR T cell therapy, showed a significant reduction in CD19-positive cells among patients who responded positively or had stable disease with undetectable minimal residual disease (uMRD). This suggests that liso-cel effectively targets and eliminates CD19-positive cells, contributing to the positive outcomes observed. Interestingly, patients with stable disease and detectable MRD exhibited lower liso-cel expansion, indicating their inability to effectively clear CD19-positive cells over time. These findings highlight the potential of liso-cel as an exciting new treatment option for patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). By targeting and reducing CD19-positive cells, liso-cel offers promising prospects for improving patient outcomes in this challenging disease
