The real-world utilization of axicabtagene ciloleucel demonstrated favorable outcomes and less frequent toxicity events compared with those reported in the pivotal ZUMA-1 trial and other real-world studies.
Mi Kwon, MD, PhD
The real-world utilization of axicabtagene ciloleucel (axi-cel; Yescarta) demonstrated favorable outcomes and less frequent toxicity events compared with those reported in the pivotal ZUMA-1 trial and other real-world studies, according to findings of a Spanish, multicenter, retrospective analysis presented during the Virtual 47th Annual Meeting of the EBMT.1
Of 80 evaluable patients on day 30 after axi-cel infusion, 40% had a complete response (CR) and 38% had a partial response (PR). On day 100 after infusion, 48% of 58 evaluable patients had a CR and 18% had a PR. On day 180 after infusion, 65% of 23 evaluable patients had a CR and 22% had a PR. Moreover, 23% of 39 patients who showed a PR or stable disease at day 30 converted to a CR.
The median estimated event-free survival (EFS) was 6.6 months (95% CI, 4.6-8.5) with axi-cel in the intention-to-treat (ITT) population (n = 106). The 6-month EFS rate was 55.5% with a 7.3-month median estimated EFS in the patient population who underwent axi-cel infusion per protocol (n = 92). The median EFS among patients who did not undergo infusion (n = 14) was 1.6 months (P < .001).
Finally, the median overall survival (OS) was 12.3 months (95% CI, 8.9-15.7) in the ITT population. In the infused population, the 6-month OS rate was 78%, and the median estimated OS was 13.1 months. In the non-infused population, the median estimated OS was 1.6 months (P < .001).
“This [study] showed encouraging results with axi-cel treatment in patients with relapsed/refractory aggressive B-cell lymphoma in the real-world setting,” said Mi Kwon, MD, PhD, head of the Bone Marrow Transplant Unit and CAR T-Cell Clinical Program in the Department of Hematology at the Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón in Madrid, Spain, during a virtual presentation of the data. “With [current] follow-up, response outcomes [were] favorable.”
Comparatively, findings from the ZUMA-1 trial demonstrated an 83% best overall response rate (ORR) and a 58% CR rate among 101 patients treated with axi-cel.2 Updated findings revealed that 47% of patients were alive at 3 years, and the median OS was 25.8 months (95% CI, 12.8-not estimable).3
Furthermore, other real-world analyses reported about a 70% best ORR and CR rates ranging from 40% to 66% with axi-cel.4-9
Data for the Spanish analysis were collected retrospectively from 6 centers designated for commercial CAR T-cell therapy administration in Spain.1 Patients had to have undergone apheresis for axi-cel treatment between June 2019 and November 2020.
Overall, 106 patients underwent leukapheresis for planned axi-cel administration. Of these patients, 14 were not infused because of progression-related death (n = 12; 86%), tumor lysis syndrome (n = 1; 7%), and a CR after bridging therapy (n = 1; 7%).
Of the infused patients, 85 underwent standard axi-cel administration; 7 patients were included as part of the expanded access program. The median follow-up was 6.5 months (range, 1-17.5).
Patients in the infused population were a median age of 57 (range, 19-79) and the majority were male (n = 48; 52%). Most patients (n = 89; 97%) had an ECOG performance status of 0 or 1, stage III to IV disease (n = 69; 75%), and CD19-positive disease (n = 40; 44%).
Over half of patients (n = 58; 63%) had diffuse large B-cell lymphoma not otherwise specified, 10% (n = 9) had double- or triple-hit high-grade B-cell lymphoma, 17% (n = 16) had primary mediastinal B-cell lymphoma, and 10% (n = 9) had transformed follicular lymphoma. Additionally, 36% (n = 33) of patients had bulky disease.
Patients had median of 2 prior lines of therapy (range, 2-7); 26% (n = 24) underwent prior autologous stem cell transplant (ASCT), 48% (n = 44) had primary refractory disease, and 85% (n = 78) underwent bridging therapy.
Most patients (70%) underwent chemotherapy as their first bridging therapy, whereas 15% of patients received radiotherapy and 15% did not receive bridging therapy. Other regimens for bridging therapy included rituximab (Rituxan), ifosfamide, carboplatin, and etoposide or mitoguazone, ifosfamide, vinorelbine, and etoposide (n = 9), steroids (n = 6), rituximab/bendamustine (n = 6), brentuximab vedotin (Adcetris; n = 3), lenalidomide (Revlimid; n = 3), polatuzumab vedotin-piiq (Polivy)/bendamustine (n = 2), checkpoint inhibitors (n = 2), ibrutinib (Imbruvica; n = 2), and high-dose methotrexate (n = 1). Fifteen percent of patients received a second line of bridging therapy.
Finally, at the time of lymphodepletion, 69% (n = 64) of patients had progressive disease, 22% (n = 20) had stable disease, and 9% (n = 8) had a PR.
The median time between approval for CAR T-cell therapy and infusion was 54 days, and the median time between apheresis and lymphodepletion was 29 days. After apheresis, the median time to infusion was 39 days, and the median time to discharge was 55 days.
Regarding safety, 83% of patients had any-grade cytokine release syndrome (CRS), 18% had grade 2 CRS, and 6.5% had grade 3 or 4 CRS. The median time to CRS onset was 3 days (range, 0-10), and the median duration of CRS was 5 days (range, 1-17). Over half of patients (58%) with CRS were treated with tocilizumab (Actemra) and 19% were treated with corticosteroids.
Additionally, 42.5% of patients experienced any-grade immune effector cell–associated neurotoxicity syndrome (ICANS), 10% had grade 2 ICANS, and 15% had grade 3 or 4 ICANS. Patients with ICANS were treated with corticosteroids (78%), tocilizumab (31%), anakinra (Kineret; 21%), or siltuximab (Sylvant; 15%).
Moreover, 22% of patients were admitted to the intensive care unit (ICU) because of CRS or ICANS.
Additionally, 62% of the 79 patients evaluable after day 28 presented with cytopenias; 15% had grade 3 or 4 anemia, 24% had grade 3 or 4 thrombocytopenia, and 60% had grade 3 or 4 neutropenia.
Six patients (6.5%) died from toxicity, including sepsis during ICU admission for ICANS (n = 1), ICANS plus haemophagocytic lymphohistiocytosis/macrophage activation syndrome (n = 1), cerebral edema (n = 2), refractory CRS (n = 1), and sepsis (n = 1). An additional 27 patients (29%) died because of relapse during the study time period.
In the ZUMA-1 trial, grade 3 or greater CRS or ICANS were reported in 11% and 32% of patients, respectively.2
The other real-world studies of axi-cel reported that 80% to 90% of patients experienced any-grade CRS, with approximately 8% being grade 3 or greater; approximately 65% of patients reported any-grade ICANS, with 20% to 40% being grade 3 or greater.4-9
“Significant toxicity events were less frequent than those reported in the pivotal trial and previous real-world studies; however, deaths associated with toxicity occurred,” Kwon said.
Findings from a univariate analysis of the data showed that bulky disease was associated with a lower CR rate on days 30 (P = .029) and 90 (P = .039).1 Other factors, including histology subgroup, disease stage, International Prognostic Index risk score, number of prior lines of therapy, prior ASCT, primary refractory disease, status at lymphodepletion, and prior bridging therapy, were not associated with a lower CR rate.
“Further analysis is needed to identify prognostic factors [to inform the likelihood of CRs],” concluded Kwon.