Axicabtagene Ciloleucel As Second-Line Therapy for Large B-Cell Lymphoma in Transplant-Ineligible Patients: Primary Analysis of Alycante, a Phase 2 Lysa Study

Abstract

Background Patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after first-line treatment who are unable to undergo high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) have poor outcomes and limited treatment options. Axicabtagene ciloleucel (axi-cel) has recently demonstrated superiority over standard of care (SOC; salvage chemotherapy followed by HDCT/HSCT in responders) as second-line therapy in patients intended for transplant in the phase 3, ZUMA-7 study (Locke et al, NEJM 2022). The objective of the open-label, phase 2, ALYCANTE study (NCT04531046) was to evaluate the efficacy and safety of axi-cel in patients with R/R LBCL after 1 prior line of therapy not intended for HDCT/HSCT owing to age and/or comorbidities. Methods Eligible patients were adults with R/R LBCL that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy and who were not deemed candidates for HDCT/HSCT based on physician's assessment and at least one of the following criteria: age ≥ 65 years; age ≥ 18 years and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score ≥3; or age ≥ 18 years and prior ASCT (as 1st line consolidation). Patients received lymphodepletion with cyclophosphamide and fludarabine, followed 2 days later by axi-cel infusion at a target dose of 2 × 10^6 CAR T-cells/kg. Cytokine release syndrome (CRS) and neurological events (ICANS) were graded using the ASTCT grading system. The primary endpoint was the complete metabolic response (CMR) at 3 months from axi-cel infusion based on investigator disease assessment. Results Of 43 patients who underwent leukapheresis, 40 received axi-cel. Median age was 68 years (range, 49-81; 45% ≥ 70 years), 30% had HCT-CI score ≥ 3, and 52.5% were refractory to first-line treatment. Overall, 37 patients (92.5%) received bridging chemotherapy (R-GEMOX for all patients but one). Twenty-seven patients (67.5%) were refractory to bridging therapy, including 15 patients (37.5%) who experienced disease progression upon bridging therapy. Median on-study follow-up was 6.7 months. The study met its primary endpoint with a CMR at 3 months of 67.5% versus 12% expected with SOC based on historical controls (Cazelles et al, Leukemia & Lymphoma 2021). Objective response (OR) rate at 3 months was 75%. Best OR and CR rates were 92.5% and 77.5%, respectively. CRS were seen in 90% of patients, including 10% of grade 3-4. ICANS were seen in 55% of patients, including 17.5% of grade 3-4. Twelve patients (30%) patients were admitted to ICU. Six patients died: 2 due to lymphoma and 4 due to fatal adverse events (COVID-19, mucormycosis, perineal infection, and sepsis). Grade ≥ 3 prolonged cytopenias (i.e. not resolved on Day 29 after axi-cel infusion) occurred in 14 patients (35%). Conclusions In the ALYCANTE study, axi-cel as second-line treatment in patients with LBCL who were not deemed candidates for HDCT/HSCT appears feasible and induces high response rates. Additional exploratory analyses are ongoing, including early PET-CT at Day 14 post-infusion and ctDNA monitoring, which will be presented at the meeting. Finally, the protocol was amended to allow an expansion of 20 additional patients (for a total of 60 patients) to achieve sufficient power to compare 2 subgroups of patients based on age (≥ 70 vs < 70 years).