Topline results from the phase 2 TRANSCEND CLL 004 trial hint that lisocabtagene maraleucel may be active in relapsed or refractory chronic lymphocytic leukemia.
Lisocabtagene maraleucel (liso-cel; Breyanzi) has induced a significant rate of complete responses (CRs) in adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), which is higher than historic CR rates. With this result, the primary end point of the phase 2 TRANSCEND CLL 004 trial has been met.1
The historic control used was a prespecified subset of patients with R/R CLL, which included patients who were refractory to a Bruton’s tyrosine kinase (BTK) inhibitor and pretreated with a BCL-2 inhibitor. A BTK inhibitor combined with venetoclax (Venclexta) is the current standard of care for R/R CLL and SLL.
"The rationale for the study was that it is a one-time treatment that has the promise of durable/long-term remission after patients had been on continuous therapy [including BTK inhibitors and venetoclax] up until that point. These were also patients that didn’t have a lot of other good options left," explained Tanya Siddiqi, MD, director of the Chronic Lymphocytic Leukemia Program at City of Hope’s Toni Stephenson Lymphoma Center, and associate professor, in the Division of Lymphoma at City of Hope Department of Hematology & Hematopoietic Cell Transplantation, in a statement to Targeted OncologyTM.
Previously in the phase 1 portion of TRANSCEND CLL 004, 25 patients with R/R CLL/SLL with standard- or high-risk disease that was treated with ≥3 or ≥2 prior therapies were enrolled. Patients were initially dosed with 50 × 106 or 100 × 106 CAR+ T cells. Of the patients enrolled, 23 were treated with liso-cel, and these patients were evaluable for the primary end point of safety and tolerability and determining the recommended phase 2 dose (RP2D) of liso-cel. The study also evaluated minimal residual disease (MRD) in the blood and bone marrow. Twenty-two of the 25 patients were evaluable for response, and 20 patients were evaluable for MRD.2
At a median follow-up of 24 months (range, 17.9-24.4 months), the objective response rate (ORR) was 82% (95% CI, 59.7%-94.8%). The CR rate or CR with incomplete recovery (CRi) rate was 45%, consisting of 6 CRs and 4 CRis. Notably, the responses occurred rapidly and were durable. The median time to response was 1 month (range 1-6), and the median time to CR or Cri was 2 months (range, 1-12). The median duration of response was not reached (NR), and at the time of data cutoff, 11 patients had more than 18 months of follow-up.
The median progression-free survival shown during phase 1 was 18 months (95% CI, 3.0-NR).
Liso-cel treatment did not cause any dose-limiting toxicities (DLTs) in patients treated at dose level 1. Of those administered dose level 2, there were DLTs observed in 2 patients. The first patient with a DLT had grade 4 hypertension, and the other had grade 3 encephalopathy, grade 3 muscle weakness, and grade 4 tumor lysis syndrome. All DLTs were completely resolved, and the RP2D was determined to be 100 x 106 CAR T cells.
All patients experienced treatment-emergent adverse events (TEAEs). The most frequently occurring TEAEs of any grade were anemia (83%), cytokine release syndrome (74%), thrombocytopenia (74%), and neutropenia or neutrophil count decrease (70%). The most common grade 3 or 4 TEAEs were anemia (74%), thrombocytopenia (70%), neutropenia/neutrophil count decrease (70%), leukopenia (43%), febrile neutropenia (26%), and lymphopenia (26%). Fifty-seven percent of patients experienced serious TEAEs.
Overall, 9 patients died during the study, 7 of which were a result of disease progression (PD). For the 2 patients without PD, 1 died after developing grade 3 pneumonia, and the other had cute kidney injury and pneumonia.
In terms of cytokine release syndrome, the was a median onset was 3 days (range, 1-10). Grade 3 cytokine release syndrome occurred in 2 patients, both of whom received dose level 2.
The phase 2 topline analysis of TRANSCEND CLL 004 did not reveal any new safety signals for liso-cel. The data will be presented during an upcoming medical meeting and shared with regulatory authorities.1
"This is a strong treatment in the armamentarium against CLL for a growing population of patients whose disease is refractory after treatment with BTK inhibitors and venetoclax. A lot of my patients are very happy to have had years of remission with this CAR T therapy because no other maintenance/treatments are needed and they can live normal lives with a good quality of life," Siddiqi added.
1. Bristol Myers Squibb announces TRANSCEND CLL 004 trial of Breyanzi® (lisocabtagene maraleucel) met primary endpoint of complete response rate in patients with relapsed or refractory chronic lymphocytic leukemia. News release. Bristol Myers Squibb. January 26, 2023. Accessed January 26, 2023. https://bit.ly/3XxsouZ
2. Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood. 2022; 139 (12): 1794-1806. doi:10.1182/blood.2021011895