Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-targeted chimeric antigen receptor (CAR) T cells approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We performed a retrospective study to evaluate safety and efficacy of axi-cel and tisa-cel outside the setting of a clinical trial. Data from consecutive patients with R/R LBCL who underwent apheresis for axi-cel or tisa-cel were retrospectively collected from 12 Spanish centers. A total of 307 patients underwent apheresis for axi-cel (n=152) and tisa-cel (n=155) from November 2018 to August 2021, of which 261 (85%) received a CAR T infusion (88% and 82%, respectively). Median time from apheresis to infusion was 41 days for axi-cel and 52 days for tisa-cel (P=0.006). None of the baseline characteristics were significantly different between both cohorts. Both cytokine release syndrome and neurologic events (NE) were more frequent in the axi-cel group (88% vs. 73%, P=0.003, and 42% vs. 16%, P<0.001, respectively). Infections in the first 6 months post-infusion were also more common in patients treated with axi-cel (38% vs. 25%, P=0.033). Non-relapse mortality was not significantly different between the axi-cel and tisa-cel groups (7% and 4%, respectively, P=0.298). With a median follow-up of 9.2 months, median PFS and OS were 5.9 and 3 months, and 13.9 and 11.2 months for axi-cel and tisa-cel, respectively. The 12-month PFS and OS for axi-cel and tisa-cel were 41% and 33% (P=0.195), 51% and 47% (P=0.191), respectively. Factors associated with lower OS in the multivariate analysis were increased lactate dehydrogenase, ECOG ≥2 and progressive disease before lymphodepletion. Safety and efficacy results in our real-world experience were comparable with those reported in the pivotal trials. Patients treated with axi-cel experienced more toxicity but similar non-relapse mortality compared with those receiving tisa-cel. Efficacy was not significantly different between both products.
Patients with relapsed or refractory (R/R) large B-cell lym-phoma (LBCL) after two lines of therapy have a very poor outcome with currently available conventional therapies. Only a small proportion of patients will eventually achieve prolonged disease-free survival with subsequent treat-ments.1,2 Axicabtagene ciloleucel (axi-cel) and tisagenle-cleucel (tisa-cel) are CD19-targeted chimeric antigen receptors (CAR) T cells commercially available in Europe for R/R LBCL after two or more lines of systemic therapy. In the registration ZUMA-1 trial, 58% of patients who received axi-cel achieved a complete response (CR), with a progression-free survival (PFS) at 24 months of 36%.3,4 The pivotal JULIET trial with tisa-cel showed a CR rate of 40%, with a PFS at 24 months of 33%.5,6 Several joint efforts among United States’ centers have shown similar overall real-world results to those obtained in the pivotal trials.7– 9 However, European data is heterogenous, with 3-month CR rates ranging from 37% to 21% for axi-cel and 29% to 17% for tisa-cel.10,11,12,13,14 These differences may be explained by multiple factors including patient selection, country-specific administrative issues and manufacturing turnaround time, among others. Taking into account the absence of randomized trials comparing both products and the significant differences in patient inclusion criteria and trial design that preclude direct comparisons between the ZUMA-1 and JULIET results, mainly regarding patient selection and bridging strategies, there is scarce data available to guide product selection.15,16 We performed a multicenter, retrospective study to compare efficacy and safety results of axi-cel and tisa-cel in the real-world setting.
Data from all consecutive patients who underwent apher-esis for axi-cel or tisa-cel between November 2018 and August 2021 were retrospectively collected from electronical medical records at 12 Spanish institutions. Three centers contributed with patients treated only with tisa-cel (n=13). All treatments were approved after review of patients’ diagnoses and medical charts by a national expert panel of the Ministry of Health. Primary mediastinal lymphoma cases were excluded from this study since they were treated exclusively with axi-cel. Selection of axi-cel or tisa-cel did not follow predefined uniform criteria and was performed according to each centers’ guidelines. Patients included for safety and response analysis had a minimum post-infusion follow-up of 30 days and at least one imaging response assessment. Survival outcomes were assessed in all patients who underwent leukapheresis (intention-to-treat analysis, ITT) and in patients who received a CAR T-cell infusion. All patients provided informed consent for CAR T-cell therapy. The study was approved by the ethical committee of the Hospital General Universitario Gregorio Marañón and conducted in accordance with the Declaration of Helsinki.
Patients received lymphodepleting chemotherapy with fludarabine (30 mg/m2 for axi-cel and 25 mg/m2 for tisa-cel) and cyclophosphamide (500 mg/m2 for axi-cel and 250 mg/m2 for tisa-cel) for 3 consecutive days. After 2 to 4 days of washout, patients received the CAR T-cell infusion in a hospitalization regimen to guarantee a close monitoring of adverse events. Grading of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) followed the American Society for Transplantation and Cellular Therapy (ASTCT) recommendations.17 Management of CRS and ICANS followed local institutional guidelines, based on national guidelines.18 Briefly, tocilizumab was used for the treatment of CRS grade ≥2, but considered in cases of persistent CRS grade 1. Steroids were the second line for CRS if two to three doses of tocilizumab were unsuccessful. For ICANS, steroids were the first line of treatment (dexa-methasone 10 mg 4 times each day [QID]), started at grade ≥2 and considered for cases of persistent grade 1. Severe ICANS was treated with anakinra or siltuximab as per local protocol. Tocilizumab was only considered in cases of concurrent CRS. For the reporting of other adverse events, Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used. Infectious complications were treated following the Spanish consensus guidelines.19 Infection severity was classified as mild, moderate, severe, life-threatening, or fatal as previously established.20 All reported cytopenias were recorded from salvage therapy-naïve patients. All patients underwent a baseline positron emission tomography and computed tomography (PET/CT) scan immediately before the start of LD chemotherapy (after the last bridging regimen). Response assessment after CAR T-cell therapy was performed at 1, 3, 6, 12 and 18 months post-infusion and graded according to the 2014 Lugano recommendations.21
Definition and endpoints
Overall response rate (ORR) was defined as the percentage of patients who achieved a partial response (PR) or CR after CAR T-cell therapy. Progression-free survival (PFS) was defined as the time from apheresis (ITT population) or CAR T-cell infusion until relapse, progression or death from any cause. Overall survival (OS) was defined as the time from apheresis (ITT) or CAR T-cell infusion until death of any cause. Duration of response (DOR) was defined as the time from CR or PR to relapse, progression or death from any cause, whichever occurred first. Non-relapse mortality (NRM) was defined as any death event not associated to relapse/progression since leukapheresis to last follow-up and computed as time-to-event outcome.
Descriptive statistics included mean, standard deviation, median, range and interquartile range (IQR) for continuous variables, and percentages for categorical variables. Fisher’s exact test or Chi-squared test was used to evaluate the association between two categorical variables. Comparability of the two groups (axi-cel and tisa-cel) for the main prognostic features was tested with t test or Mann-Whitney test. Kaplan-Meier method was used to estimate PFS and OS rates, including 95% confidence interval (95% CI), and log-rank test was used to evaluate the difference in PFS or OS between patient groups. Cox proportional hazards regression models were used for uni-variable and multivariable analysis to include significant covariates. Variables with at least marginal association with PFS/OS from the univariable analysis (P<0.2) were included in the initial multivariable model. A univariable and multivariable logistic regression model was performed to study the association with CRS and ICANS grade ≥3. A P value <0.05 was considered statistically significant. The data analyses were carried out using SPSS (IBM, SPSS Statistics for Windows, Version 25.0. Armonk, NY, USA).
Between November 2018 and August 2021, 307 patients with R/R LBCL underwent apheresis for axi-cel (n=152) and tisa-cel (n=155) in 12 centers, of which 261 (85%) received a CAR T-cell infusion (n=134, 88% and n=127, 82%, respectively). The main reason for not receiving an infusion was progressive disease in both groups (n=12, 66% in axi-cel and n=25, 89% in tisa-cel) (Online Supplementary Figure S1). Median time from apheresis to infusion was 41 days (interquartile range [IQR], 36-56) for axi-cel and 52 days (IQR, 46-63) for tisa-cel (P=0.006).
Patient and disease characteristics at apheresis are shown in Table 1. Median age was 61 years (range, 23-79). The most frequent subtype was diffuse LBCL NOS (70%), followed by high grade B-cell lymphoma (15%) and transformed follicular lymphoma (14%). Patient and disease characteristics at apheresis were similar for the axi-cel and tisa-cel cohorts (Table 1). Infused patients´ characteristics are detailed in the Online Supplementray Table S1. Of the 261 infused patients, 210 (80%) received bridging therapy (BT) before infusion, chemotherapy-based in most cases (n=127, 60%; Online Supplementary Table S2A).
The proportion of patients who received BT before axi-cel and tisa-cel was similar (78% vs. 83%, respectively). Thirty (14%) patients achieved a response to BT (21 PR, 9 CR), most of them after chemotherapy (Online Supplementary Table S2B). Baseline characteristics at the time of lym-phodepletion (LD) therapy were similar between patients treated with axi-cel and tisa-cel (Online Supplementary Table S1). Median follow-up from infusion for patients receiving axi-cel and tisa-cel was 8.2 months (IQR, 6-13.7) and 12.4 months (IQR, 6-20), respectively.
Cytokine release syndrome and immune efector cell-associated neurotoxicity syndrome
For all infused patients, any grade of CRS and ICANS occurred in 211 (81%) and 78 (30%) patients. Median time to onset was 2 days for CRS (range, 0-10) and 7 days for ICANS (range, 2-65) (Table 2).
When comparing axi-cel and tisa-cel toxicity, frequency of all grade CRS but not severe (grade ≥3) CRS was higher in the axi-cel group (88% vs. 73%, P=0.003), (8% vs. 6%, P=0.637). Use of tocilizumab and corticosteroids for CRS was more common in axi-cel treated patients (Table 2). Any grade and grade ≥3 ICANS were significantly more frequent in the axi-cel group (42% vs. 16%, P<0.001, and 18% vs. 5%, P=0.001, respectively). Corticosteroids, siltuximab and tocilizumab for ICANS were also used more often in the axi-cel group (Table 2). There were no differences in times of onset and duration of CRS and ICANS between axi-cel ant tisa-cel (Table 2; Online Supplementary Figure S2). Macrophage activation syndrome (MAS) occurred in four patients, one treated with axi-cel and three with tisa-cel (one of them fatal).22
In the multivariable analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≥2 at start of LD was the only factor associated with an increased risk of CRS grade ≥3 (P=0.046). The use of axi-cel (P=0.027) and having received >2 prior lines of therapy (P=0.015) were associated with an increased risk of ICANS grade ≥3 (Table 3; Online Supplementary Table S3).
Hematological toxicity and infections
Among the 220 evaluable patients, neutropenia and thrombocytopenia grade 3-4 at 1 month after infusion were reported in 53 (24%) and 95 (43%) patients, respectively. At 3 months post-infusion, of the 123 evaluable patients, these cytopenias persisted in 12 (10%) and 18 (15%), respectively. There were no significant differences in the rate of persistent cytopenias between patients treated with axi-cel and tisa-cel (Table 2).
Eighty-three (32%) infused patients presented 91 infectious episodes during the first 6 months after CAR T-cell infusion, mainly bacterial (n=54, 59%) followed by viral (n=31, 34%) and fungal (n=6, 7%). Six patients presented human herpes virus 6 reactivation, all of them after axi-cel infusion. Two patients presented a SARS-CoV-2 infection during the first 6 months post-infusion, one of them fatal. Of note, three additional patients died from SARS-CoV-2 infection after 6 months (Online Supplementary Table S4). In general, infections in the first 6 months post-infusion were more frequent in patients treated with axi-cel than with tisa-cel (Table 2; Online Supplementary Table S4).
Hospitalization, intensive care unit admission and non-relapse mortality
Median length of hospitalization was 22 days (IQR, 20-29) for the axi-cel cohort and 18 days (IQR, 14-22) for the tisa-cel cohort (P<0.001). Admission to the intensive care unit (ICU) was needed in 22% of patients in the axi-cel group and 15% in the tisa-cel group (P=0.154) with a median stay of 4 days (IQR, 2-7) and 3 days (IQR, 1-5), respectively (P<0.001).
Non-relapse mortality for all infused patients was 5% (Table 2) and similar between both groups (P=0.298). In the axi-cel cohort, nine patients (7%) died due to infection (2 bacterial, 1 SARS-CoV-2, 1 fungal, 1 not specified), ICANS (2), CRS (1) and tumor lysis syndrome (1). In the tisa-cel group, five patients (4%) died due to SARS-CoV-2 infection (2), CRS (1), ICANS (1) and MAS (1) (Online Supplementary Figure S3).
Among all infused patients, the ORR was 57% (38% CR, 19% PR) (Online Supplementary Figure S4). Thirteen (17%) patients in PR at 1 month converted to CR (10 at day 90 and 3 at day 180) and four (13%) patients in stable disease at 1 month achieved CR (3 at day 180 and 1 at 1 year). Median duration of response was 14.1 months (95% CI: 5.8 to not reached) for all infused patients and was not reached for those who achieved CR. In the axi-cel cohort, ORR was 60% (CR 42% and PR 18%) with a median DOR of 12.5 months (95% CI: 5.7 to not reached). In the tisa-cel group, ORR was 54% (n=68) (34% CR and 19% PR), with a median DOR of 14.1 months (95% CI: 2.5 to not reached). Median DOR was not significantly different between both cohorts (P=0.494).
Progression-free survival and overall survival
In the ITT analysis, with a median follow-up of 9.2 months (IQR, 5-15), median PFS and OS were 4.8 months (95% CI: 4.5-5.6) and 11.7 months (95% CI: 10.2-14.3), respectively. The estimated 12-month PFS and OS were 34% (95% CI: 27-39) and 48% (95% CI: 41-54), respectively (Figure 1). Regarding each cohort, the 12-month PFS and OS for patients intended to be treated with axi-cel and tisa-cel were 41% and 27% (P=0.091), 50% and 45% (P=0.07) (Online Supplementary Figure S5), respectively.
Focusing on infused patients with axi-cel or tisa-cel, median PFS was 5.9 months and 3 months, respectively, and median OS was 13.9 months and 11.2 months, respectively (Figure 1). The estimated 12-month PFS was 41% and 33% (P=0.195), and 12-month OS was 51% and 47% (P=0.191), respectively.
Regarding factors with an impact on efficacy, an increased lactate dehydrogenase (LDH) before apheresis (P=0.003), ECOG PS ≥2 before LD therapy (P<0.001) and progressive disease before LD therapy (P=0.018) were associated with a worse PFS in the multivariable analysis (Table 4; Figure 2; Online Supplementary Table S3). Factors independently associated with a worse OS included high LDH at apher-esis, (P=0.023), ECOG PS ≥2 at apheresis (P=0.021), progressive disease at apheresis (P=0.018) and ECOG PS ≥2 before LD therapy (P=0.001). Patients with very high LDH elevation (>2x upper limit of normal [ULN]) showed worse PFS (hazard ration [HR] 2.5, P<0.001) and OS (HR 2.1, P<0.001) than patients with mild (1-2x ULN) increase. Noteworthy, 15 of the 19 patients with EOCG PS > or =2 at the time of apheresis died, 13 due to disease progression (8 of them did not receive the CAR T infusion) and two due to toxicity.
We report herein one of the largest European cohort of patients with R/R aggressive B-cell lymphoma treated with commercial CAR T cells, including a detailed comparison between axi-cel and tisa-cel, which has been very little addressed in previous real-world studies.23,24,25,26 In our study, patient and disease characteristics at apheresis were similar between both cohorts, suggesting that CAR T selection was likely driven by other factors including logistical aspects, manufacturing slot availability and expected turnaround time. More patients in the axi-cel group received the CAR T infusion, probably influenced by the shorter turnaround time. Although other possible unintended bias in product selection are yet to be identified, the fact that both populations were comparable, provides the opportunity to compare outcomes after treatment with axi-cel and tisa-cel from patients with similar features.
In terms of toxicity, rates of CRS and ICANS were lower than the pivotal trials and in line with other contemporary real-world studies.3,5,7,9 A better understanding of these adverse events together with an earlier administration of specific treatments (i.e., tocilizumab, steroids) could explain these lower rates. Notably, CRS and, especially, ICANS were more frequent and severe in patients treated with axi-cel compared with tisa-cel. Accordingly, the use of tocilizumab, corticosteroids, and siltuximab was also more common in the former group. Patients who received axi-cel presented a longer median hospitalization, an increased infection rate and a higher likelihood of being transferred to the ICU. Since prolonged neutropenia was similar in both cohorts, potential reasons which could justify the increased infection rate observed with axi-cel could be the rate of CRS, ICANS and the higher use of im-munosuppressive therapies for these adverse events.27 Non-relapse mortality was similar to previous real-world studies in patients with R/R LBCL.7– 9 Noteworthy, four patients died of SARS-CoV-2 infection, mostly in the early months of the pandemic and before the wide implementation of vaccines.27,28 Despite these relatively low numbers, our study highlights the significant morbidity burden of CAR T-cell therapies and the potential associated costs derived from health resource utilization which need to be studied in more depth.29 Efforts should be made to decrease toxicity in future trials, including design of CAR T cells with an improved safety profile together with prophylactic or preemptive strategies for CRS and ICANS.30,31 Moreover, real-world studies like ours might help identify patients at high risk of developing severe adverse events, improving patient selection and management. Several models for predicting CAR T-cell related toxicity have been proposed. External validation of these models in independent cohorts is warranted to assess their implementation in routine clinical practice.32,33
Regarding efficacy, median PFS and OS in the ITT analysis were comparable to the pivotal trials, despite a longer turnaround time in our study.3,5 Our results were also similar to other real-world data, albeit some differences in patients characteristics and logistical country-specific aspects.7–9,13,23 Both for the ITT and the infused population, PFS and OS were similar between axi-cel and tisa-cel. Noteworthy, there was a trend towards a higher PFS and OS in the ITT analysis in favor of the axi-cel cohort (PFS at 9 months 41% and 27%, P=0.091, and OS 67% vs. 54%, P=0.07). These trends could be explained by a shorter turnaround time in patients receiving axi-cel which could have led to slightly fitter population at the time of CAR T infusion. Also, the number of apheresed patients who finally did not receive the infusion was higher in the tisacel group. Finally, complete responses were more frequently seen in patients treated with axi-cel. Whether these trends towards higher PFS and OS are driven by a different efficacy of each product, as suggested by differences on the results of the phase III clinical trials in second-line therapy,34,35 or by patient selection and/or logistic reasons warrants further studies. Outstanding prognostic factors included LDH and ECOG PS, in line with previous reports.8,13,36,37 Even though the use of BT has been associated with worse outcomes, especially the use of systemic therapy,38 there is scarce data regarding the impact of disease status at time of LD therapy. In our study, progressive disease as best response to BT was associated with a worse PFS. Noteworthy, more than half of our patients, without significant differences between both cohorts, had PD as best response to BT. Given the availability of novel therapies for LBCL, future studies should address the optimal bridging strategy for patients intending to receive a CAR T-cell infusion. Although patients with high LDH and progressive disease showed worse PFS, whether these cases should not be eligible for CAR T-cell therapy is arguable, since these high-risk populations still performed better than with standard therapies.1,2 However, very few patients with very high LDH and ECOG PS score seemed to benefit from the therapy, highlighting the need of careful selection of patients harboring adverse prognostic factors. In all, our findings support the inclusion of selected patients with such baseline characteristics in prospective studies that would not only improve access but also better characterize the risk factors for safety and efficacy.
There are some limitations to this study. The data was collected retrospectively and some previously reported prognostic factors were not collected in this dataset including albumin levels, total metabolic tumor volume and CAR T-cell kinetics.13,36,37 The patient population treated includes a relatively small proportion of high-risk patients in terms of comorbidity and performance status scores. Previous real-world reports showed superior results with axi-cel for patients who would had met eligibility criteria for the ZUMA-1 trial than those individuals that would have been ineligible.7 Further analysis to confirm our observations in patient populations with greater comorbidities are granted. In contrast, patients were infused in a small number of centers and treatment-related complications were managed homogenously.19 Also, the CAR T therapy approval process was carried out by a single national Expert Committee, ensuring uniform selection criteria of the patients.39 Given the lack of direct comparisons between CAR T-cell products within prospective randomized clinical trials, we consider that retrospective comparisons can provide clinically meaningful insight to physicians managing these patients. In conclusion, safety and efficacy results in our real-world experience were comparable with those reported in the pivotal clinical trials. Patients treated with axi-cel experienced more toxicity but similar non-relapse mortality compared with those receiving tisa-cel while efficacy was similar between both products.
- Received February 7, 2022
- Accepted June 17, 2022
MK has received honoraria from Gilead, Novartis, BMS and Pfizer. GI has received honoraria from BMS/Celgene, Gi-lead, Novartis, Janssen, AstraZeneca, Abbvie and Roche. LLC has received honoraria from Gilead and Novartis, and research funding from Gilead. JB has received honoraria from Roche, Takeda, Celgene, Novartis, Gilead, and research funding from Celgene, Roche. JS has received honoraria from Kite and Novartis. MBO has received honoraria from Roche, Takeda, Kite, Novartis, Janssen, Incyte, and research funding from Roche. AM has received honoraria from Takeda, Novartis, BMS, MSD, and research funding from GILEAD. MG has received honoraria from Gilead and Novartis. AS has received honoraria from Takeda, BMS, MSD, Sanofi, Roche, Novartis, Gilead Kite, Janssen, Sanofi, consultancy fees from Takeda, BMS, MSD, Novartis, Janssen, Gilead Kite and speaker’s bureau for Takeda. JMS has received honoraria from Roche, Janssen, Gilead-Kite, Novartis, BMS-Celgene, Takeda, Incyte, Lilly, Beigene. PB has received honoraria from Amgen, BMS, Gilead, In-cyte, Jazz Pharmaceuticals, Miltenyi biotech, Novartis and Pfizer.
MK, GI and PB developed the concept, designed the study and wrote the manuscript. MK, GI, RB and PB collected and assembled data. All authors provided study materials or patients, analyzed and interpreted data, and approved the final version of the manuscript.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
PS has received funding funding from the Carlos III (FIS) Health Institute PI16/01433 and PI21/00197, Asociación Es-pañola contra el Cáncer (Ideas Semilla 2019) and a PERIS 2018-2020 grant from the Generalitat de Catalunya (BDNS357800) .
The authors thank the patients and their families for their participation in this study, and staf and nurses of all the hematology and transplant units for their care and contributions to making this work possible. They thank Jose Maria Bellón from the Gregorio Marañón Institute of Health Research for data analysis. They thank Angel Cedillo from GETH-TC and GELTAMO for coordination and data collection support.
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