Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma

Abstract

Background Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor T-cell based anti-CD19 therapy. The ZUMA-1 study, multicenter, single-arm, registrational Phase 1/2 study of axi-cel demonstrated high objective response rate in patients with relapsed/refractory large B-cell lymphoma. Here, we present the results of the bridging study to evaluate the efficacy and safety of axi-cel in Japanese patients (JapicCTI-183914). Methods This study was the phase 2, multicenter, open-label, single-arm trial. Following leukapheresis, axi-cel manufacturing and lymphodepleting chemotherapy, patients received a single infusion of axi-cel (2.0 × 106 cells/kg). Bridging therapy between leukapheresis and conditioning chemotherapy was not allowed. The primary endpoint was objective response rate. Results Among 17 enrolled patients, 16 received axi-cel infusion. In the 15 efficacy evaluable patients, objective response rate was 86.7% (95% confidence interval: 59.5–98.3%); complete response/partial response were observed in 4 (26.7%)/9 (60.0%) patients, respectively. No dose-limiting toxicities were observed. Grade ≥ 3 treatment-emergent adverse events occurred in 16 (100%) patients—most commonly neutropenia (81.3%), lymphopenia (81.3%) and thrombocytopenia (62.5%). Cytokine release syndrome occurred in 13 (81.3%) patients (12 cases of grade 1 or 2 and 1 case of grade 4). No neurologic events occurred. Two patients died due to disease progression, but no treatment-related death was observed by the data-cutoff date (October 23, 2019). Conclusion The efficacy and safety of axi-cel was confirmed in Japanese patients with relapsed/refractory large B-cell lymphoma who have otherwise limited treatment options. Trial registration JapicCTI-183914.

Case Report: Cardiac Tamponade in Association With Cytokine Release Syndrome Following CAR-T Cell Therapy

“…Part of the lesions in the mediastinum was adjacent to the right side of the pericardium ( Figure 1 ). The patient was referred to our hospital for anti-CD19 CAR-T cell therapy with axicabtagene ciloleucel as part of a phase 2 clinical trial (JapicCTI-183914; https://rctportal.niph.go.jp/en/detail?trial_id=JapicCTI-183914 ) ( 6 ). He had a history of a duodenal ulcer but not cardiovascular disease.…”

Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B‐cell non‐Hodgkin lymphoma

“…Three second-generation anti-CD19 CAR T-cell therapies have demonstrated efficacy and safety in Japan for patients with R/R aggressive B-cell NHL: tisagenlecleucel, 10 axicabtagene ciloleucel, 9 and, with this report, liso-cel. Other CAR T-cell therapies did not permit enrollment of patients with secondary CNS lymphoma in their respective pivotal trials, but independent, retrospective, investigator-led studies have demonstrated that these patients can be successfully treated with CAR T-cell therapy.…”

“…The Japanese subgroup analysis of tisagenlecleucel reported an ORR of 78%, grade 3 or 4 CRS per the Penn grading system in two of nine patients (22%), and grade 3 NEs in one of nine patients (11%) 10 . In a study of axicabtagene ciloleucel in Japanese patients reporting an ORR of 87%, grade 4 CRS per the Lee 2014 criteria occurred in one patient (6%); no NEs were reported 9 …”

“…Several novel agents have been developed for patients with R/R large B‐cell lymphoma (LBCL), including DLBCL. Among them, anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapies are considered one of the most promising treatment options for this population 6–15 . The CD19‐directed autologous CAR T‐cell product, lisocabtagene maraleucel (liso‐cel), is administered as a sequential infusion of equal target doses of CD8 + and CD4 + CAR + T cells.…”

“…Among them, anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapies are considered one of the most promising treatment options for this population. 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 The CD19‐directed autologous CAR T‐cell product, lisocabtagene maraleucel (liso‐cel), is administered as a sequential infusion of equal target doses of CD8 + and CD4 + CAR + T cells. Liso‐cel production involves purifying CD8 + and CD4 + cells separately before activation and transduction followed by T‐cell‐specific activation and expansion, which reduces the variability of CD3 T‐cell frequencies, relative to leukapheresis.…”