ARTICLE - Cell Therapy & Immunotherapy Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma Mi Kwon,1,2* Gloria Iacoboni,3,4* Juan Luis Reguera,5 Lucía López Corral,6 Rafael Hernani Morales,7 Valentín Ortiz-Maldonado,8 Manuel Guerreiro,9 Ana Carolina Caballero,10 María Luisa Correspondence: M. Kwon Guerra Domínguez,11 Jose Maria Sanchez Pina,12 Alberto Mussetti,13 Juan Manuel Sancho,14 mi.kwon@salud.madrid.org Mariana Bastos-Oreiro,1,2 Eva Catala,3,4 Javier Delgado,5 Hugo Luzardo Henriquez,11 Jaime Received: February 7, 2022. Sanz,9 María Calbacho,12 Rebeca Bailén,1,2 Cecilia Carpio,3,4 Jose Maria Ribera,14 Anna Sureda,13 Accepted: June 17, 2022. Javier Briones,10 Juan Carlos Hernandez-Boluda,7 Nuria Martínez Cebrián,8 Jose Luis Diez Prepublished: June 30, 2022. Martin,1,2,15 Alejandro Martín6 and Pere Barba3,4 on behalf of GETH-TC (Spanish Group of Stem Cell Transplantation and Cell Therapy) and GELTAMO (Spanish Group of Lymphoma and https://doi.org/10.3324/haematol.2022.280805 Autologous Stem Cell Transplantation) ©2023 Ferrata Storti Foundation Published under a CC BY-NC license 1 Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid; 2 Instituto de Investigación Sanitaria Gregorio Marañón, Madrid; 3Department of Hematology, Vall d’Hebron University Hospital, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona; 4Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra; 5Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Sevilla; 6 Department of Hematology, Hospital Clínico Universitario de Salamanca, IBSAL, Salamanca; 7 Department of Hematology, Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria INCLIVA, Valencia; 8Department of Hematology, Hospital Clínic, Barcelona; 9Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia; 10 Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona; 11Department of Hematology, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria; 12Department of Hematology, Hospital Universitario 12 de Octubre, Madrid; 13 Department of Hematology, Hospital Duran i Reynals, Instituto Catalán de Oncología, Barcelona; 14Department of Hematology, Hospital Universitari Germans Trias i Pujol, Instituto Catalán de Oncología, Josep Carreras Research Institute, Badalona and 15Universidad Complutense de Madrid, Madrid, Spain * MK and GI contributed equally as co-first authors. Abstract 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 com- mon 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 lympho- depletion. 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 re- ceiving tisa-cel. Efficacy was not significantly different between both products. Haematologica | 108 January 2023 110 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. esis (intention-to-treat analysis, ITT) and in patients who Introduction received a CAR T-cell infusion. All patients provided in- Patients with relapsed or refractory (R/R) large B-cell lym- formed consent for CAR T-cell therapy. The study was ap- phoma (LBCL) after two lines of therapy have a very poor proved by the ethical committee of the Hospital General outcome with currently available conventional therapies. Universitario Gregorio Marañón and conducted in accord- Only a small proportion of patients will eventually achieve ance with the Declaration of Helsinki. prolonged disease-free survival with subsequent treat- ments.1,2 Axicabtagene ciloleucel (axi-cel) and tisagenle- Patient management cleucel (tisa-cel) are CD19-targeted chimeric antigen Patients received lymphodepleting chemotherapy with receptors (CAR) T cells commercially available in Europe fludarabine (30 mg/m2 for axi-cel and 25 mg/m2 for tisa- for R/R LBCL after two or more lines of systemic therapy. cel) and cyclophosphamide (500 mg/m2 for axi-cel and In the registration ZUMA-1 trial, 58% of patients who re- 250 mg/m2 for tisa-cel) for 3 consecutive days. After 2 to ceived axi-cel achieved a complete response (CR), with a 4 days of washout, patients received the CAR T-cell infu- progression-free survival (PFS) at 24 months of 36%.3,4 The sion in a hospitalization regimen to guarantee a close pivotal JULIET trial with tisa-cel showed a CR rate of 40%, monitoring of adverse events. Grading of cytokine release with a PFS at 24 months of 33%.5,6 Several joint efforts syndrome (CRS) and immune effector cell-associated among United States’ centers have shown similar overall neurotoxicity syndrome (ICANS) followed the American real-world results to those obtained in the pivotal trials.7–9 Society for Transplantation and Cellular Therapy (ASTCT) However, European data is heterogenous, with 3-month recommendations.17 Management of CRS and ICANS fol- CR rates ranging from 37% to 21% for axi-cel and 29% to lowed local institutional guidelines, based on national 17% for tisa-cel.10,11,12,13,14 These differences may be explained guidelines.18 Briefly, tocilizumab was used for the treat- by multiple factors including patient selection, country- ment of CRS grade ≥2, but considered in cases of persist- specific administrative issues and manufacturing turn- ent CRS grade 1. Steroids were the second line for CRS if around time, among others. Taking into account the two to three doses of tocilizumab were unsuccessful. For absence of randomized trials comparing both products ICANS, steroids were the first line of treatment (dexa- and the significant differences in patient inclusion criteria methasone 10 mg 4 times each day [QID]), started at grade and trial design that preclude direct comparisons be- ≥2 and considered for cases of persistent grade 1. Severe tween the ZUMA-1 and JULIET results, mainly regarding ICANS was treated with anakinra or siltuximab as per local patient selection and bridging strategies, there is scarce protocol. Tocilizumab was only considered in cases of data available to guide product selection.15,16 We performed concurrent CRS. For the reporting of other adverse events, a multicenter, retrospective study to compare efficacy and Common Terminology Criteria for Adverse Events (CTCAE) safety results of axi-cel and tisa-cel in the real-world set- version 5.0 was used. Infectious complications were ting. treated following the Spanish consensus guidelines.19 In- fection severity was classified as mild, moderate, severe, life-threatening, or fatal as previously established.20 All re- ported cytopenias were recorded from salvage therapy- Methods naïve patients. All patients underwent a baseline positron Study design emission tomography and computed tomography (PET/CT) Data from all consecutive patients who underwent apher- scan immediately before the start of LD chemotherapy esis for axi-cel or tisa-cel between November 2018 and (after the last bridging regimen). Response assessment August 2021 were retrospectively collected from elec- after CAR T-cell therapy was performed at 1, 3, 6, 12 and tronical medical records at 12 Spanish institutions. Three 18 months post-infusion and graded according to the 2014 centers contributed with patients treated only with tisa- Lugano recommendations.21 cel (n=13). All treatments were approved after review of patients’ diagnoses and medical charts by a national ex- Definition and endpoints pert panel of the Ministry of Health. Primary mediastinal Overall response rate (ORR) was defined as the percen- lymphoma cases were excluded from this study since they tage of patients who achieved a partial response (PR) or were treated exclusively with axi-cel. Selection of axi-cel CR after CAR T-cell therapy. Progression-free survival or tisa-cel did not follow predefined uniform criteria and (PFS) was defined as the time from apheresis (ITT popu- was performed according to each centers’ guidelines. Pa- lation) or CAR T-cell infusion until relapse, progression or tients included for safety and response analysis had a death from any cause. Overall survival (OS) was defined minimum post-infusion follow-up of 30 days and at least as the time from apheresis (ITT) or CAR T-cell infusion one imaging response assessment. Survival outcomes until death of any cause. Duration of response (DOR) was were assessed in all patients who underwent leukapher- defined as the time from CR or PR to relapse, progression Haematologica | 108 January 2023 111 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. or death from any cause, whichever occurred first. Non- The proportion of patients who received BT before axi-cel relapse mortality (NRM) was defined as any death event and tisa-cel was similar (78% vs. 83%, respectively). Thirty not associated to relapse/progression since leukapheresis (14%) patients achieved a response to BT (21 PR, 9 CR), to last follow-up and computed as time-to-event out- most of them after chemotherapy (Online Supplementary come. Table S2B). Baseline characteristics at the time of lym- phodepletion (LD) therapy were similar between patients Statistical methods treated with axi-cel and tisa-cel (Online Supplementary Descriptive statistics included mean, standard deviation, Table S1). Median follow-up from infusion for patients re- median, range and interquartile range (IQR) for continuous ceiving axi-cel and tisa-cel was 8.2 months (IQR, 6-13.7) variables, and percentages for categorical variables. and 12.4 months (IQR, 6-20), respectively. Fisher’s exact test or Chi-squared test was used to evalu- ate the association between two categorical variables. Safety Comparability of the two groups (axi-cel and tisa-cel) for Cytokine release syndrome and immune effector cell- the main prognostic features was tested with t test or associated neurotoxicity syndrome Mann-Whitney test. Kaplan-Meier method was used to es- For all infused patients, any grade of CRS and ICANS oc- timate PFS and OS rates, including 95% confidence inter- curred in 211 (81%) and 78 (30%) patients. Median time to val (95% CI), and log-rank test was used to evaluate the onset was 2 days for CRS (range, 0-10) and 7 days for difference in PFS or OS between patient groups. Cox pro- ICANS (range, 2-65) (Table 2). portional hazards regression models were used for uni- When comparing axi-cel and tisa-cel toxicity, frequency variable and multivariable analysis to include significant of all grade CRS but not severe (grade ≥3) CRS was higher covariates. Variables with at least marginal association in the axi-cel group (88% vs. 73%, P=0.003), (8% vs. 6%, with PFS/OS from the univariable analysis (P<0.2) were in- P=0.637). Use of tocilizumab and corticosteroids for CRS cluded in the initial multivariable model. A univariable and was more common in axi-cel treated patients (Table 2). multivariable logistic regression model was performed to Any grade and grade ≥3 ICANS were significantly more fre- study the association with CRS and ICANS grade ≥3. A P quent in the axi-cel group (42% vs. 16%, P<0.001, and 18% value <0.05 was considered statistically significant. The vs. 5%, P=0.001, respectively). Corticosteroids, siltuximab data analyses were carried out using SPSS (IBM, SPSS and tocilizumab for ICANS were also used more often in Statistics for Windows, Version 25.0. Armonk, NY, USA). 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 Results four patients, one treated with axi-cel and three with tisa- Patient characteristics cel (one of them fatal).22 Between November 2018 and August 2021, 307 patients In the multivariable analysis, Eastern Cooperative Oncol- with R/R LBCL underwent apheresis for axi-cel (n=152) ogy Group (ECOG) performance status (PS) score ≥2 at and tisa-cel (n=155) in 12 centers, of which 261 (85%) re- start of LD was the only factor associated with an in- ceived a CAR T-cell infusion (n=134, 88% and n=127, 82%, creased risk of CRS grade ≥3 (P=0.046). The use of axi-cel respectively). The main reason for not receiving an infu- (P=0.027) and having received >2 prior lines of therapy sion was progressive disease in both groups (n=12, 66% in (P=0.015) were associated with an increased risk of ICANS axi-cel and n=25, 89% in tisa-cel) (Online Supplementary grade ≥3 (Table 3; Online Supplementary Table S3). Figure S1). Median time from apheresis to infusion was 41 days (interquartile range [IQR], 36-56) for axi-cel and 52 Hematological toxicity and infections days (IQR, 46-63) for tisa-cel (P=0.006). Among the 220 evaluable patients, neutropenia and Patient and disease characteristics at apheresis are thrombocytopenia grade 3-4 at 1 month after infusion shown in Table 1. Median age was 61 years (range, 23-79). were reported in 53 (24%) and 95 (43%) patients, respect- The most frequent subtype was diffuse LBCL NOS (70%), ively. At 3 months post-infusion, of the 123 evaluable pa- followed by high grade B-cell lymphoma (15%) and trans- tients, these cytopenias persisted in 12 (10%) and 18 (15%), formed follicular lymphoma (14%). Patient and disease respectively. There were no significant differences in the characteristics at apheresis were similar for the axi-cel rate of persistent cytopenias between patients treated and tisa-cel cohorts (Table 1). Infused patients´ character- with axi-cel and tisa-cel (Table 2). istics are detailed in the Online Supplementray Table S1. Eighty-three (32%) infused patients presented 91 infec- Of the 261 infused patients, 210 (80%) received bridging tious episodes during the first 6 months after CAR T-cell therapy (BT) before infusion, chemotherapy-based in infusion, mainly bacterial (n=54, 59%) followed by viral most cases (n=127, 60%; Online Supplementary Table S2A). (n=31, 34%) and fungal (n=6, 7%). Six patients presented Haematologica | 108 January 2023 112 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. human herpes virus 6 reactivation, all of them after axi- fatal. Of note, three additional patients died from SARS- cel infusion. Two patients presented a SARS-CoV-2 infec- CoV-2 infection after 6 months (Online Supplementary tion during the first 6 months post-infusion, one of them Table S4). In general, infections in the first 6 months post- Table 1. Baseline patients and disease characteristics at apheresis. Total ITT Axi-cel ITT Tisa-cel ITT P N=307 N=152 N=155 Age in years, median (range) 61 (23-79) 59 (29-79) 62 (23-76) 0.078 Sex, N (%) 186 (61) 89 (59) 97 (63) 0.486 Male HCT-CI, N (%) 0-2 236 (77) 121 (80) 115 (74) 0.486 3 or more 66 (21) 30 (19) 36 (23) Not available 5 (2) 1 (1) 4 (3) ECOG, N (%) 0-1 288 (94) 144 (95) 144 (93) 0.637 2-3 19 (6) 8 (5) 11 (7) Histology, N (%) DLBCL, NOS 214 (70) 114 (75) 100 (64) DH/TH HGBCL 45 (15) 20 (13) 25 (16) 0.178 Transformed FL 43 (14) 17 (11) 26 (17) Transformed from other indolent 5 (1) 1 (1) 4 (3) Cell of origin, N (%) GCB 173 (57) 84 (55) 89 (57) 0.697 Non-GCB 90 (29) 41 (27) 49 (32) Unknown 44 (14) 27 (18) 17 (11) Disease stage, N (%) I-II 73 (24) 35 (23) 38 (25) 0.789 III-IV 234 (76) 117 (77) 117 (75) R-IPI score, N (%) 0-2 143 (46) 73 (48) 70 (45) 0.648 3-5 150 (49) 76 (50) 74 (48) 0.732 NA 14 (5) 3 (2) 11 (7) Bulky disease*, N (%) 75 (24) 40 (26) 35 (23) 0.688 Primary refractory, N (%) 178 (58) 90 (59) 88 (57) 0.729 Previous lines, median (range) 2 (2-7) 2 (2-6) 2 (2-7) 0.124 Prior ASCT, N (%) 88 (29) 45 (30) 43 (28) 0.801 Prior Allo-SCT, N (%) 3 (1) 1 (1) 2 (1) 1.000 Disease status, N (%) Progressive disease 276 (90) 138 (91) 138 (89) Stable disease 21 (6) 10 (7) 11 (7) 1.000 Partial response 9 (3) 4 (3) 5 (3) Complete response 1 (1) 0 (0) 1 (1) LDH >ULN, N (%) 185 (60) 84 (54) 101 (66) 0.385 CRP >ULN, N (%) 154 (50) 62 (41) 92 (59) 0.105 Lymphocytes x103/μL, median (range) 0.9 (0.1-11) 0.88 (0.1-6.3) 0.9 (0.1-11.0) 0.711 Platelets x103/μL, median (range) 157 (11-1,000) 165 (27-1,000) 146 (11-523) 0.119 ITT: intention-to-treat; HCT-CI: hematopoietic cell transplantation-comorbidity index; DLBCL NOS: diffuse large B-cell lymphoma not otherwise specified; HGBCL: high grade B-cell lymphoma; FL: follicular lymphoma; GCB: germinal center B-cell like; R-IPI: revised international prognostic index; NA: not available; ASCT: autologous stem cell transplantation; LDH: lactate dehydrogenase; CRP: c-reactive protein; >ULN: upper limit of normal. *Bulky disease (>7 cm). Haematologica | 108 January 2023 113 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. infusion were more frequent in patients treated with axi- Non-relapse mortality for all infused patients was 5% cel than with tisa-cel (Table 2; Online Supplementary Table (Table 2) and similar between both groups (P=0.298). In S4). the axi-cel cohort, nine patients (7%) died due to infection (2 bacterial, 1 SARS-CoV-2, 1 fungal, 1 not specified), ICANS Hospitalization, intensive care unit admission and non- (2), CRS (1) and tumor lysis syndrome (1). In the tisa-cel relapse mortality group, five patients (4%) died due to SARS-CoV-2 infection Median length of hospitalization was 22 days (IQR, 20-29) (2), CRS (1), ICANS (1) and MAS (1) (Online Supplementary for the axi-cel cohort and 18 days (IQR, 14-22) for the tisa- Figure S3). cel cohort (P<0.001). Admission to the intensive care unit (ICU) was needed in 22% of patients in the axi-cel group Efficacy and 15% in the tisa-cel group (P=0.154) with a median stay Disease response of 4 days (IQR, 2-7) and 3 days (IQR, 1-5), respectively Among all infused patients, the ORR was 57% (38% CR, (P<0.001). 19% PR) (Online Supplementary Figure S4). Thirteen (17%) Table 2. Safety analysis of infused patients. All infused patients Axi-cel infused Tisa-cel infused P N=261 N=134 N=127 CRS, N (%) 211 (81) 118 (88) 93 (73) 0.003 CRS grade ≥3, N (%) 19 (7) 11 (8) 8 (6) 0.637 CRS onset day, median (range) 2 (0-10) 3 (0-10) 2 (0-10) 0.154 CRS duration days, median (range) 5 (1-35) 5 (1-15) 5 (1-35) 0.574 CRS treatment, N (%) Tocilizumab 120 (46) 81 (60) 39 (31) <0.001 Steroids 52 (20) 41 (31) 11 (9) <0.001 ICANS, N (%) 78 (30) 57 (42) 21 (16) <0.001 ICANS grade ≥3, N (%) 30 (11) 24 (18) 6 (5) 0.001 ICANS onset day, median (range) 7 (2-65) 7 (2-65) 6 (2-35) 0.214 ICANS duration days, median (range) 4.5 (1-83) 4 (1-44) 7 (1-83) 0.119 ICANS treatment, N (%) Tocilizumab 2 (1) 2 (1) 0 (0) <0.001 Steroids 65 (25) 48 (36) 17 (13) <0.001 Anakinra 15 (6) 12 (9) 3 (2) <0.001 Siltuximab 14 (5) 11 (8) 3 (2) <0.001 Hospitalization days, median (IQR) 20 (17-27) 22 (20-29) 18 (14-22) <0.001 ICU admission, N (%) 49 (18) 30 (22) 19 (15) 0.154 median stay, days (IQR) 3 (2-7) 4 (2-7) 3 (1-5) <0.001 Infections during first 6 months, N (%) 83 (32) 51 (38) 32 (25) 0.033 Persistent cytopenias by day 28, N (%)* Neutropenia grade 3-4 53 (24) 31 (28) 22 (19) 0.082 Thrombocytopenia grade 3-4 95 (43) 49 (47) 46 (40) 0.278 Persistent cytopenias by day 90, N (%)* Neutropenia grade 3-4 12 (10) 6 (10) 6 (10) 1.000 Thrombocytopenia grade 3-4 18 (15) 10 (16) 8 (13) 0.799 Persistent cytopenias by day 180, N (%)* Neutropenia grade 3-4 2 (3) 1 (3) 1 (3) 1.000 Thrombocytopenia grade 3-4 4 (6) 3 (8) 1 (3) 0.625 Non-relapse mortality, N (%) 13 (5) 9 (7) 4 (3) 0.298 CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; ICU: intensive care unit: *Evaluable patients: 220 at day 28, 123 at day 90, 66 at day 180. Haematologica | 108 January 2023 114 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. patients in PR at 1 month converted to CR (10 at day 90 47% (P=0.191), respectively. and 3 at day 180) and four (13%) patients in stable disease Regarding factors with an impact on efficacy, an increased at 1 month achieved CR (3 at day 180 and 1 at 1 year). lactate dehydrogenase (LDH) before apheresis (P=0.003), Median duration of response was 14.1 months (95% CI: 5.8 ECOG PS ≥2 before LD therapy (P<0.001) and progressive to not reached) for all infused patients and was not disease before LD therapy (P=0.018) were associated with reached for those who achieved CR. In the axi-cel cohort, a worse PFS in the multivariable analysis (Table 4; Figure ORR was 60% (CR 42% and PR 18%) with a median DOR of 2; Online Supplementary Table S3). Factors independently 12.5 months (95% CI: 5.7 to not reached). In the tisa-cel associated with a worse OS included high LDH at apher- group, ORR was 54% (n=68) (34% CR and 19% PR), with a esis, (P=0.023), ECOG PS ≥2 at apheresis (P=0.021), pro- median DOR of 14.1 months (95% CI: 2.5 to not reached). gressive disease at apheresis (P=0.018) and ECOG PS ≥2 Median DOR was not significantly different between both before LD therapy (P=0.001). Patients with very high LDH cohorts (P=0.494). elevation (>2x upper limit of normal [ULN]) showed worse PFS (hazard ration [HR] 2.5, P<0.001) and OS (HR 2.1, Progression-free survival and overall survival P<0.001) than patients with mild (1-2x ULN) increase. In the ITT analysis, with a median follow-up of 9.2 months Noteworthy, 15 of the 19 patients with EOCG PS > or =2 at (IQR, 5-15), median PFS and OS were 4.8 months (95% CI: the time of apheresis died, 13 due to disease progression 4.5-5.6) and 11.7 months (95% CI: 10.2-14.3), respectively. (8 of them did not receive the CAR T infusion) and two The estimated 12-month PFS and OS were 34% (95% CI: due to toxicity. 27-39) and 48% (95% CI: 41-54), respectively (Figure 1). Re- garding each cohort, the 12-month PFS and OS for pa- tients intended to be treated with axi-cel and tisa-cel were 41% and 27% (P=0.091), 50% and 45% (P=0.07) (On- Discussion line Supplementary Figure S5), respectively. We report herein one of the largest European cohort of Focusing on infused patients with axi-cel or tisa-cel, patients with R/R aggressive B-cell lymphoma treated median PFS was 5.9 months and 3 months, respectively, with commercial CAR T cells, including a detailed com- and median OS was 13.9 months and 11.2 months, re- parison between axi-cel and tisa-cel, which has been very spectively (Figure 1). The estimated 12-month PFS was little addressed in previous real-world studies.23,24,25,26 41% and 33% (P=0.195), and 12-month OS was 51% and In our study, patient and disease characteristics at apher- Table 3. Factors significantly associated with cytokine release syndrome grade ≥3 and immune effector cell-associated neurotoxicity syndrome grade ≥3 in the logistic regression analysis of axicabtagene ciloleucel and tisagenlecleucel–treated patients. CRS grade 3 OR (95% CI) P ECOG PS at LD, 2-3 vs. 0-1 3.528 (1.021-12.186) 0.046 R-IPI at LD, 0-2 vs. >2 1.530 (0.419-5.590) 0.520 LDH at LD, >UNL vs. normal 2.978 (0.580-15.284) 0.191 ICANS grade 3 OR (95% CI) P CAR T type axi-cel vs. tisa-cel 3.545 (1.156-10.870) 0.027 Number prior lines, >2 vs. 2 2.000 (1.150-3.503) 0.015 ECOG PS at LD, 2-3 vs. 0-1 1.812 (0.418-7.878) 0.427 R-IPI at LD, 0-2 vs. >2 2.414 (0.868-6.711) 0.091 OR: odds ratio; CRS: cytokine release syndrome; ECOG PS: Eastern Cooperative Group performance status; LD: lymphodepletion; R-IPI: revised international prognostic index; LDH: lactate dehydrogenase; ULN: upper limit of normal; ICANS: Immune effector cell-associated neurotoxicity syndrome; CI: confidence interval. Haematologica | 108 January 2023 115 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. esis were similar between both cohorts, suggesting that with axi-cel compared with tisa-cel. Accordingly, the use CAR T selection was likely driven by other factors includ- of tocilizumab, corticosteroids, and siltuximab was also ing logistical aspects, manufacturing slot availability and more common in the former group. Patients who received expected turnaround time. More patients in the axi-cel axi-cel presented a longer median hospitalization, an in- group received the CAR T infusion, probably influenced by creased infection rate and a higher likelihood of being the shorter turnaround time. Although other possible un- transferred to the ICU. Since prolonged neutropenia was intended bias in product selection are yet to be identified, similar in both cohorts, potential reasons which could jus- the fact that both populations were comparable, provides tify the increased infection rate observed with axi-cel the opportunity to compare outcomes after treatment could be the rate of CRS, ICANS and the higher use of im- with axi-cel and tisa-cel from patients with similar fea- munosuppressive therapies for these adverse events.27 tures. Non-relapse mortality was similar to previous real-world In terms of toxicity, rates of CRS and ICANS were lower studies in patients with R/R LBCL.7–9 Noteworthy, four pa- than the pivotal trials and in line with other contemporary tients died of SARS-CoV-2 infection, mostly in the early real-world studies.3,5,7,9 A better understanding of these ad- months of the pandemic and before the wide implemen- verse events together with an earlier administration of tation of vaccines.27,28 Despite these relatively low specific treatments (i.e., tocilizumab, steroids) could ex- numbers, our study highlights the significant morbidity plain these lower rates. Notably, CRS and, especially, burden of CAR T-cell therapies and the potential associ- ICANS were more frequent and severe in patients treated ated costs derived from health resource utilization which A B C D Figure 1. Progression-free survival and overal survival of patients treated with axicabtagene ciloleucel and tisagenlecleucel. (A) Progression-free survival (PFS) from apheresis for the intention-to-treat (ITT) population. (B) Overall survival (OS) from apheresis for the ITT population. (C) PFS from infusion according to product infused. (D) OS from infusion according to product infused. Haematologica | 108 January 2023 116 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. Table 4. Characteristics significantly associated with progression-free survival and overall survival in the multivariable analysis of axicabtagene ciloleucel and tisagenlecleucel–treated patients. Progression-free survival HR (95% CI) P CAR T type, axi-cel vs. tisa-cel 0.888 (0.576-1.370) 0.592 Cell of origin, CGB vs. non-CGB 0.726 (0.460-1.147) 0.170 Primary Refractory, yes vs. no 1.371 (0.806-2.331) 0.244 Prior ASCT, yes vs. no 0.957 (0.550-1.666) 0.877 Disease status, PD vs. other 1.804 (1.096-3.507) 0.018 ECOG at apheresis, 2-3 vs. 0-1 0.731 (0.208-2.572) 0.626 Disease stage, III-IV vs. I-II 0.494 (0.159-1.539) 0.244 R-IPI at apheresis 1.156 (0.824-1.621) 0.402 Bulky size at apheresis, yes vs. no 0.770 (0.401-1.477) 0.431 LDH at apheresis, >UNL vs. normal 2.181 (1.303-3.651) 0.003 CRP at apheresis, >UNL vs. normal 1.489 (0.925-2.398) 0.101 Platelets at apheresis, x109 0.998 (0.995-1.001) 0.130 ECOG at LD, 2-3 vs. 0-1 5.446 (2.354-12.597) <0.001 Overall survival HR (95% CI) P ECOG at apheresis, 2-3 vs. 0-1 2.113 (1.122-3.980) 0.021 LDH at apheresis, >UNL vs. normal 1.809 (1.084-3.021) 0.023 Bridging therapy, yes vs. no 1.791 (0.817-3.930) 0.146 Disease status at LD, PD vs. other 2.561 (1.812-3.999) 0.018 Bulky (>7 cm) prior to LD, yes vs.no 1.495 (0.794-2.816) 0.212 Extranodal at LD >2 sites, yes vs. no 1.158 (0.951-1.411) 0.145 ECOG at LD, 2-3 vs. 0-1 4.306 (1.841-10.071) 0.001 R-IPI at LD 0.827 (0.476-1.437) 0.500 LDH at LD, >UNL vs. normal 1.304 (0.565-3.013) 0.581 CRP at LD, >UNL vs. normal 1.235 (0.455-3.353) 0.679 LDH at infusion, >UNL vs. normal 1.235 (0.520-2.938) 0.632 CRP at infusion, >UNL vs. normal 1.501 (0.487-4.629) 0.479 CRS grade 3-4, yes vs. no 1.939 (0.726-5.177) 0.186 CRS tocilizumab, yes vs. no 0.914 (0.539-1.548) 0.737 ICANS grade 3-4, yes vs. no 1.066 (0.316-3.589) 0.918 ICANS tocilizumab, yes vs. no 1.148 (0.462-2.852) 0.766 ICANS steroids, yes vs. no 1.090 (0.503-2.362) 0.827 HR: hazard ratio; GCB: germinal center B-cell like; ASTC: autologous stem cell transplantation; PD: progressive disease; ECOG PS: Eastern Cooperative Group performance status; R-IPI: revised international prognostic index; LD: lymphodepletion; LDH: lactate dehydrogenase; NA: not applicable (characteristic not a part of the multivariable-adjusted model for the listed outcome); ULN: upper limit of normal; CRP: c-re- active protein. need to be studied in more depth.29 Efforts should be turnaround time in our study.3,5 Our results were also made to decrease toxicity in future trials, including design similar to other real-world data, albeit some differences of CAR T cells with an improved safety profile together in patients characteristics and logistical country-specific with prophylactic or preemptive strategies for CRS and aspects.7–9,13,23 Both for the ITT and the infused population, ICANS.30,31 Moreover, real-world studies like ours might PFS and OS were similar between axi-cel and tisa-cel. help identify patients at high risk of developing severe ad- Noteworthy, there was a trend towards a higher PFS and verse events, improving patient selection and manage- OS in the ITT analysis in favor of the axi-cel cohort (PFS ment. Several models for predicting CAR T-cell related at 9 months 41% and 27%, P=0.091, and OS 67% vs. 54%, toxicity have been proposed. External validation of these P=0.07). These trends could be explained by a shorter models in independent cohorts is warranted to assess turnaround time in patients receiving axi-cel which could their implementation in routine clinical practice.32,33 have led to slightly fitter population at the time of CAR T Regarding efficacy, median PFS and OS in the ITT analysis infusion. Also, the number of apheresed patients who fi- were comparable to the pivotal trials, despite a longer nally did not receive the infusion was higher in the tisa- Haematologica | 108 January 2023 117 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. cel group. Finally, complete responses were more fre- different efficacy of each product, as suggested by differ- quently seen in patients treated with axi-cel. Whether ences on the results of the phase III clinical trials in sec- these trends towards higher PFS and OS are driven by a ond-line therapy,34,35 or by patient selection and/or logistic A B C D E Figure 2. Progression-free survival and overall survival from CAR T-cell infusion stratified by prognostic factors. (A) Progression-free survival (PFS) by disease status at lym- phodepletion. (B) PFS by lactate dehydrogenase (LDH) at leukapheresis. (C) PFS by LDH at lymphodepletion. (D) Overall survival (OS) by LDH at leukapheresis. (E) OS by Eastern Cooperative Group performance status (ECOG PS) at lymphodepletion. Haematologica | 108 January 2023 118 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. reasons warrants further studies. Outstanding prognostic Disclosures factors included LDH and ECOG PS, in line with previous MK has received honoraria from Gilead, Novartis, BMS and reports.8,13,36,37 Even though the use of BT has been associ- Pfizer. GI has received honoraria from BMS/Celgene, Gi- ated with worse outcomes, especially the use of systemic lead, Novartis, Janssen, AstraZeneca, Abbvie and Roche. therapy,38 there is scarce data regarding the impact of dis- LLC has received honoraria from Gilead and Novartis, and ease status at time of LD therapy. In our study, progress- research funding from Gilead. JB has received honoraria ive disease as best response to BT was associated with a from Roche, Takeda, Celgene, Novartis, Gilead, and re- worse PFS. Noteworthy, more than half of our patients, search funding from Celgene, Roche. JS has received hon- without significant differences between both cohorts, had oraria from Kite and Novartis. MBO has received honoraria PD as best response to BT. Given the availability of novel from Roche, Takeda, Kite, Novartis, Janssen, Incyte, and therapies for LBCL, future studies should address the op- research funding from Roche. AM has received honoraria timal bridging strategy for patients intending to receive a from Takeda, Novartis, BMS, MSD, and research funding CAR T-cell infusion. Although patients with high LDH and from GILEAD. MG has received honoraria from Gilead and progressive disease showed worse PFS, whether these Novartis. AS has received honoraria from Takeda, BMS, cases should not be eligible for CAR T-cell therapy is ar- MSD, Sanofi, Roche, Novartis, Gilead Kite, Janssen, Sanofi, guable, since these high-risk populations still performed consultancy fees from Takeda, BMS, MSD, Novartis, better than with standard therapies.1,2 However, very few Janssen, Gilead Kite and speaker’s bureau for Takeda. patients with very high LDH and ECOG PS score seemed to JMS has received honoraria from Roche, Janssen, Gilead- benefit from the therapy, highlighting the need of careful Kite, Novartis, BMS-Celgene, Takeda, Incyte, Lilly, Beigene. selection of patients harboring adverse prognostic factors. PB has received honoraria from Amgen, BMS, Gilead, In- In all, our findings support the inclusion of selected pa- cyte, Jazz Pharmaceuticals, Miltenyi biotech, Novartis and tients with such baseline characteristics in prospective Pfizer. studies that would not only improve access but also better characterize the risk factors for safety and efficacy. Contributions There are some limitations to this study. The data was col- MK, GI and PB developed the concept, designed the study lected retrospectively and some previously reported prog- and wrote the manuscript. MK, GI, RB and PB collected and nostic factors were not collected in this dataset including assembled data. All authors provided study materials or albumin levels, total metabolic tumor volume and CAR T- patients, analyzed and interpreted data, and approved the cell kinetics.13,36,37 The patient population treated includes a final version of the manuscript. relatively small proportion of high-risk patients in terms of comorbidity and performance status scores. Previous real- Acknowledgments world reports showed superior results with axi-cel for pa- The authors thank the patients and their families for their tients who would had met eligibility criteria for the ZUMA-1 participation in this study, and staff and nurses of all the trial than those individuals that would have been ineligible.7 hematology and transplant units for their care and con- Further analysis to confirm our observations in patient tributions to making this work possible. They thank Jose populations with greater comorbidities are granted. In Maria Bellón from the Gregorio Marañón Institute of Health contrast, patients were infused in a small number of Research for data analysis. They thank Angel Cedillo from centers and treatment-related complications were man- GETH-TC and GELTAMO for coordination and data collec- aged homogenously.19 Also, the CAR T therapy approval pro- tion support. cess was carried out by a single national Expert Committee, ensuring uniform selection criteria of the patients.39 Given Funding the lack of direct comparisons between CAR T-cell prod- PS has received funding funding from the Carlos III (FIS) ucts within prospective randomized clinical trials, we con- Health Institute PI16/01433 and PI21/00197, Asociación Es- sider that retrospective comparisons can provide clinically pañola contra el Cáncer (Ideas Semilla 2019) and a PERIS meaningful insight to physicians managing these patients. 2018-2020 grant from the Generalitat de Catalunya In conclusion, safety and efficacy results in our real-world (BDNS357800). experience were comparable with those reported in the pivotal clinical trials. Patients treated with axi-cel experi- Data-sharing statement enced more toxicity but similar non-relapse mortality The data that support the findings of this study are avail- compared with those receiving tisa-cel while efficacy was able from the corresponding author upon reasonable re- similar between both products. quest. Haematologica | 108 January 2023 119 ARTICLE - Axi-cel versus tisa-cel for R/R large B-cell lymphoma M. Kwon et al. References 1. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory 18. https://www.sanidad.gob.es/profesionales/farmacia/ diffuse large B-cell lymphoma: results from the international pdf/20190508_Protocolo_manejo_efectos_adversos_CAR_T.pdf. SCHOLAR-1 study. Blood. 2017;130(16):1800-1808. 19. Los-Arcos I, Iacoboni G, Aguilar-Guisado M, et al. 2. Van Den Neste E, Schmitz N, Mounier N, et al. 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