“A single administration of Liso-Cel demonstrated rapid, deep, and durable responses in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma,” said Dr. Tanya Siddiqi, senior study author and medical director at the Department of Lymphoma at the City of Hope Orange County in Duarte, California, said.
Lisocabtagene maraleucel (liso-cel; Breyanzi) demonstrated a response in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) regardless of prior disease progression or the absence of venetoclax (Venclexta), as evidenced by the results of the phase 1/2 TRANSCEND CLL 004 study (NCT03331198) presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.1,2
With a median follow-up of 21.0 months (95% CI: 17.5-26.6), the Independent Review Committee (IRC)-assessed Complete Response (CR)/CR with Incomplete Hematologic Recovery (CRi) rate was 18% (95% CI). 11-28%) in the overall study population receiving Liso-Cel at dose level 2 (n=87). The IRC objective response rate (ORR) was 47% (95% CI, 36%-58%) and the rate of undetectable minimal residual disease (uMRD) in the blood was 64% (95% CI, 53%- 58%). 74%).
Additional results showed that the uMRD rate in the bone marrow was 59% (95% CI: 48%-69%). Best overall response consisted of CR/CRi (18%), partial response (PR)/unconfirmed PR (29%), stable disease (39%), and disease progression (7%). Six patients (7%) were not evaluable.
The median time to first response in the entire study population was 1.5 months (range: 0.8-17.4). The median time to first CR/CRi was 4.4 months (range: 1.1-17.9).
“A single administration of Liso-Cel demonstrated rapid, deep, and durable responses in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma,” said Dr. Tanya Siddiqi, senior study author and medical director at the Department of Lymphoma at the City of Hope Orange County in Duarte, California, said.
Patients with relapsed/refractory CLL/SLL after treatment with BTK inhibitors and venetoclax have poor outcomes and experience reduced treatment efficacy with any subsequent therapy. Liso-cel is a CD19-targeted CAR T cell therapy delivered at equal target doses to CD8+ and CD4+ CAR+ T cells.
The TRANSCEND CLL 004 study enrolled patients at least 18 years of age with relapsed/refractory CLL/SLL who had received prior BTK inhibition or were ineligible for BTK inhibition. Patients had to be at high risk or standard risk as defined by lack of efficacy from at least 2 or at least 3 prior lines of treatment. Additionally, an ECOG performance status of 0 or 1, adequate bone marrow, organ, and cardiac function, and the absence of Richter transformation and active central nervous system involvement from malignancy were required.
The primary endpoint of the study was CR/CRi according to the International Workshop on CLL 2018 criteria as per IRC assessment. Secondary endpoints included ORR, blood uMRD, duration of response (DOR), duration of CR, progression-free survival, time to response, time to CR, overall survival (OS), blood uMRD CR rate, and safety.
During the study, patients were followed for 24 to 48 months and up to 15 years after their last Liso-Cel treatment outside of the study.
The study design required patients to undergo screening, recruitment and leukapheresis, Liso-Cel fabrication allowing bridging therapy and reconfirmed eligibility criteria, followed by lymphodepletion and administration. Lymphodepletion consisted of 30 mg/m2 fludarabine and 300 mg/m2 cyclophosphamide for 3 days. Liso-cel was administered 2 to 7 days after lymphodepletion with 50 x 106 CAR+ T cells at dose level 1 (phase 1) and 100 x 106 CAR+ T cells at dose level 2 (phase 2).
For baseline characteristics in the overall study population, the mean age and number of prior lines of systemic therapy were 65.0 years (range 49-82) and 5 (range 2-12), respectively. Most patients had bulky lymph nodes (44%), high-risk cytogenetics (83%), BTK (88%) and venetoclax-refractory disease (76%), and prior bridge therapy (76%). Notably, 60% of patients experienced both BTK inhibitor progression and venetoclax failure.
In the overall study population, 137 patients underwent leukapheresis, 117 were treated, and 96 were evaluable for efficacy; 87 patients were treated at dose level 2. In the BTK/venetoclax-experienced population, 82 underwent leukapheresis, 70 received Liso-Cel, and 53 were evaluable for efficacy; 49 patients received Liso-Cel at dose level 2.
Response was also evaluated in the population of patients who received Liso-Cel at dose level 2 and whose disease progressed on BTK inhibition and who were non-responsive to venetoclax (n=49). Here, the CR/CRi rate determined by IRC was 18% (95% CI, 9%-32%; P=0.0006). The ORR and uMRD rates determined by IRC were 43% (95% CI, 29%-58%; P=0.3931) and 63% (95% CI, 48%-77%), respectively. Bone marrow uMRD occurred in 59% of patients (95% CI: 44%-73%).
The best responses in this population consisted of CR/CRi (18%), PR/unconfirmed PR (24%), stable disease (43%), and progressive disease (8%). Three patients were not evaluable. The median time to first response was 1.2 months (range: 0.8-17.4). The median time to first CR/CRi was 3.0 months (range: 1.1-6.1).
In the entire study population, the mean DOR was not reached (NR), namely 24.0 months (95% CI, 12.3 NR) and 35.5 months (95% CI, 19.8 NR) in patients , the CR/CRi, PR/ unconfirmed PR or derived response to Liso-Cel. In the BTK/venetoclax-experienced population, the mean DOR NR, 23.8 months (95% CI, 8.4 NR) and 35.3 months (95% CI, 11.0 NR), were respectively a median follow-up of 19.7 months (95% CI: 16.5-27.2).
Best response OS, which resulted in a median follow-up of 24.2 months (95% CI: 23.3-29.7) in the overall study population and 20.8 months (95% CI: 17.8-25, 2) evaluated in the BTK/venetoclax-experienced population also showed improved outcomes in patients who achieved CR/CRi. In the overall study population, mean OS NR, NR, was 10.7 months (95% CI, 6.4-27.1) and 43.2 months (95% CI, 26.9-NR) in patients that achieved CR/CRi, PR/unconfirmed PR. No answer, or altogether. In the novel agent-experienced population, the medians were NR, NR (95% CI, 20.9 NR), 10.7 months (95% CI, 7.3-30.3), and 30.3, respectively months (95% CI, 11.2 NR). .
PFS by best response and blood MRD status by next-generation sequencing with a sensitivity of 10-4 showed similar trends, with the best outcomes being seen in patients who achieved CR/CRi and uMRD. Specifically, the mean PFS was NR (95% CI, 30.1 NR), 26.9 months (95% CI, 18.0 NR), 6.3 months (95% CI, 4.6– 12.0) and 3.0 months (95% CI, 1.9 NR). ) and 1.0 months (95% CI, 0.8-NR) in patients who achieved CR/CRi uMRD, PR/unconfirmed PR uMRD, stable disease uMRD, stable disease-detectable MRD, and progressive disease-detectable MRD, respectively.
In the novel agent-experienced population, median NRs were 26.2 months (95% CI 9.4 NR), 6.4 months (95% CI 3.7-12.0), 2.8 months (95% CI, 1.9 NR) and 0.9 months (95% CI, 0.8 NR).
“Higher Liso-Cel expansion with an area under the curve from 0 to 28 days was observed in responders compared to non-responders and in patients with uMRD compared to those without uMRD,” said Siddiqi.
In addition, Siddiqi indicated that Liso-Cel expansion was associated with a reduction in CD19+ cells in responders and patients with stable disease and uMRD. In addition, less Liso-Cel expansion was associated with the best response to stable disease and detectable MRD; This population was unable to clear CD19+ cells over time.
Liso-cel also showed “rapid expansion” with a median time to maximum expansion of 14 days (interquartile range: 10.0-14.0) after Liso-cel administration. In addition, “Liso-Cel transgene persistence was detected in at least one in four evaluable patients up to 36 months after Liso-Cel infusion,” Siddiqi said.
Regarding safety, the most common treatment-emergent adverse reactions (AEs) were Grade 3 or greater, neutropenia (61%), anemia (52%), and thrombocytopenia (41%).
Cytokine release syndrome (CRS) occurred in 85% of patients (Grade 1: 37%; Grade 2: 39%; Grade 3: 9%). The mean time to onset and resolution of CRS was 4.0 (range: 1-18) and 6.0 (range: 2-37) days, respectively. Neurotoxicity occurred in 45% of patients (Grade 1: 11%; Grade 2: 15%; Grade 3: 18%; Grade 4: 1%). The median time to onset and resolution was 7.0 days (range: 1-21 and range: 1-83, respectively). A total of 69% of patients received tocilizumab (Actemra) and/or corticosteroids.
Other adverse reactions of particular interest were persistent cytopenia (54%), grade 3 or greater infection (17%), hypogammaglobulinemia (15%), tumor lysis syndrome (11%), second primary malignancy (9%), and macrophage activation syndrome (3%).
There were five treatment-related AE-related deaths, four of which were classified as non-treatment-related.
“Taken together, these results support Liso-Cel as a potential new treatment option for relapsed/refractory CLL/SLL,” said Siddiqi, who is also Director of the Chronic Lymphocytic Leukemia Program at the Toni Stephenson Lymphoma Center and Associate Professor in the Department of Lymphoma, Department of Hematology and hematopoietic cell transplantation, completed.
ReferencesSiddiqi T, Maloney DG, Kenderian S, et al. Lisocabtagene maraleucel (liso-cel) in R/R Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): Primary Analysis of TRANSCEND CLL 004. J Clin Oncol. 2023;41(suppl 16):7501. doi:10.1200/JCO.2023.41.16_suppl.7501Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene Maraleucel in chronic lymphocytic leukemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a phase 1-2, multicenter, open-label, single-arm study. The lancet. Published online June 6, 2023. doi:10.1016/S0140-6736(23)01052-8
