Received: 15 December 2020 | Revised: 9 March 2021 | Accepted: 17 March 2021 DOI: 10.1002/cam4.3881 ORIGINAL RESEARCH Real-­world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-­cell lymphoma Gloria Iacoboni1,2,3 | Guillermo Villacampa4 | Nuria Martinez-­Cibrian5 | Rebeca Bailén6,7 | Lucia Lopez Corral8,9 | Jose M. Sanchez10 | Manuel Guerreiro11 | Ana Carolina Caballero12,13 | Alberto Mussetti14,15 | Juan-­Manuel Sancho16 | Rafael Hernani 17,18 | Pau Abrisqueta 1,2,3 | Carlos Solano17,18,19 | Anna Sureda14,15 | Javier Briones 12,13 | Alejandro Martin Garcia-­Sancho | Mi Kwon | 8,9 6,7 Juan Luis Reguera-­Ortega5 | Pere Barba1,2,3 | GETH, GELTAMO Spanish Groups 1 Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain 2 Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain 3 Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain 4 Oncology Data Science, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain 5 Department of Hematology, University Hospital Virgen del Rocio, Sevilla, Spain 6 Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain 7 Gregorio Marañón Health Research Institute (IiSGM), Madrid, Spain 8 Hematology Department, Hospital Clínico Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain 9 Centro de Investigación del Cáncer-­IBMCC, Salamanca, Spain 10 Hematology Department, Hospital 12 de Octubre, Madrid, Spain 11 Department of Hematology, Hospital La Fe, Valencia, Spain 12 Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 13 Josep Carreras Leukaemia Research Institute, Barcelona, Spain 14 Hematology Department, Institut Catala d'Oncologia, Hospital Duran i Reynals, L'Hospitalet De Llobregat, Spain 15 Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet De Llobregat, Barcelona, Spain 16 Hematology Department, ICO-­IJC Hospital Germans Trias i Pujol, Barcelona, Spain 17 Department of Hematology, Hospital Clínico Universitario de Valencia, Valencia, Spain 18 Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain 19 Department of Medicine, University of Valencia, Valencia, Spain Correspondence Gloria Iacoboni, Department of Abstract Hematology, Hospital Universitari Vall Tisagenlecleucel (tisa-­cel) is a second-­generation autologous CD19-­targeted chimeric d’Hebron. Universitat Autònoma de antigen receptor (CAR) T-­cell therapy approved for relapsed/refractory (R/R) large Barcelona, Pg. Vall Hebron 119, 08035. Barcelona, Spain. B-­cell lymphoma (LBCL). The approval was based on the results of phase II JULIET Email: giacoboni@vhio.net trial, with a best overall response rate (ORR) and complete response (CR) rate in in- fused patients of 52% and 40%, respectively. We report outcomes with tisa-­cel in the standard-­of-­care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. 3214 |  wileyonlinelibrary.com/journal/cam4 Cancer Medicine. 2021;10:3214–3223. IACOBONI et al.    | 3215 who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa-­cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa-­cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non-­relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow-­up of 14.1 months from CAR T-­cell infusion, median progression-­free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa-­cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses. KEYWORDS clinical cancer research, clinical observations, hematological cancer, non-­Hodgkin's lymphoma 1 | IN T RO D U C T IO N 2 | M ETHODS First-­line immunochemotherapy cures around 60% of pa- 2.1 | Data collection and analysis tients with large B-­cell lymphoma (LBCL).1,2 In the relapse/ refractory (R/R) setting, second-­line immunochemotherapy, Data were collected retrospectively on all consecutive pa- usually including autologous stem cell transplant consolida- tients with R/R LBCL who underwent leukapheresis with tion, salvages less than half of the patients,3-­6 whereas those the intent to manufacture commercial tisa-­cel at 10 Spanish in the third-­line setting have a dismal prognosis.7 institutions from December 1st, 2018, until June 1st, 2020. Chimeric antigen receptor (CAR) T-­cell therapy provides For the safety analysis, we included all patients who re- long-­term remissions in a proportion of patients with R/R ceived a tisa-­cel infusion and had a minimum follow-­up of LBCL with significant but manageable toxicity. The results 1 month. Efficacy-­evaluable patients included those who met of two pivotal phase 2 clinical trials led to the approval of axi- the prior criteria and had an imaging response assessment. cabtagene ciloleucel (axi-­cel) and tisagenlecleucel (tisa-­cel) Survival outcomes were assessed in all patients who un- by the Food and Drug Administration (FDA) and European derwent leukapheresis (intention-­to-­treat analysis, ITT) and Medicines Agency (EMA) for patients with R/R LBCL after in patients who received a CAR T-­cell infusion. The study 2 or more lines of systemic therapy. These trials had strict in- was approved by the ethics committee of the Vall d’Hebron clusion criteria and infused around 100 patients each, mainly Hospital Board. in United States (US).8-­10 Thus, evaluating the feasibility of this therapy outside the US, as well as gaining knowledge on the outcome of patients treated in the commercial setting is 2.2 | Patient management mandatory. Several single-­ center and registry-­ based studies have Patients were selected by hematologists around the coun- shown that treatment with axi-­cel is feasible outside the clin- try when they met technical data sheet criteria. A checklist ical trial setting with a similar safety and efficacy profile with the usual screening tests (PET scan, laboratory results, to the pivotal trial.11-­14 However, data regarding the use of echocardiogram, repeat biopsy if applicable) was forwarded tisa-­cel in patients with R/R LBCL outside clinical trials are to the Spanish Ministry of Health, who reviewed the pro- scarce.13-­15 posal. Once it received approval, apheresis was performed. To provide valuable information on patient outcomes Bridging treatment was usually carried out at the local with commercial tisa-­cel in LBCL, we performed a national, hospital. multicenter, retrospective study evaluating the safety and ef- Lymphodepleting (LD) chemotherapy included three ficacy of tisa-­cel in a European real-­life setting. consecutive days of fludarabine (25 mg/m2/day) and 3216 |    IACOBONI et al. cyclophosphamide (250 mg/m2/day) in all cases and started T-­cell infusion until death of any cause. The duration of re- once tisa-­cel had arrived on site; if the CAR T-­cell product sponse (DOR) was defined as the time from CR or PR to did not meet commercial release criteria according to EMA relapse, progression, or death from any cause, whichever oc- requirements (out-­of-­specification, OOS) but it was consid- curred first. ered acceptable by the physician, patients were offered treat- ment through an expanded access protocol and their results were included. After 2–­4 days of chemotherapy washout, pa- 2.4 | Statistical analyses tients received the CAR T-­cell infusion in a hospitalization regimen to guarantee a close monitoring of adverse events, A descriptive analysis of all included variables in the study such as cytokine release syndrome (CRS) and immune ef- was performed. Continuous variables were expressed as fector cell-­ associated neurotoxicity syndrome (ICANS). median and interquartile range (IQR), and categorical vari- Management of these adverse events was carried out accord- ables were expressed as absolute values and percentages. ing to the institutional guidelines in each center. Infectious Univariate logistic regression model was carried out to es- complications were managed homogenously according to the timate the association between ORR and baseline factors. Spanish consensus guidelines.16 Survival analysis (PFS and OS) was calculated using the For the efficacy analysis, all patients underwent a baseline Kaplan–­Meier method and the log-­rank test was used for Positron Emission Tomography and Computed Tomography statistical comparison. Cox proportional hazard models were (PET/CT) scan immediately before the start of LD chemo- used to obtain hazard ratios (HRs) with 95% CIs. For variable therapy (after the last bridging regimen) at the infusing center. selection in multivariate analysis, we used the least absolute Disease evaluation after CAR T-­cell therapy was scheduled shrinkage and selection operator (LASSO) method to con- at 1, 3, 6, 12, 18, and 24 months after infusion. The imaging struct the most parsimonious model.22 To assess the impor- reports were based on the Lugano recommendation for re- tance of the type of response at first evaluation, a landmark sponse assessment,17 and PET images were graded according analysis using the date of first evaluation in non-­progressor to the 5-­point Deauville score. patients was performed.23 The data analyses were carried out using R statistical soft- ware version 3.6.2. 2.3 | Definitions and endpoints Disease status at leukapheresis was defined as one of three 3 | RESULTS possibilities: (a) primary refractory if never achieving end-­ of-­treatment CR; (b) refractory to last therapy if not pri- 3.1 | Patients and product characteristics mary refractory but not achieving a complete response to the most recent therapy, (c) or relapsed. Bridging therapy Ninety-­one patients with R/R LBCL underwent leukaphere- was defined as any lymphoma-­specific treatment admin- sis for tisa-­cel. Seventy-­five (82%) patients received the CAR istered after leukapheresis and before lymphodepleting T-­cell infusion, whereas 16 (18%) did not. Reasons to not chemotherapy. receive the infusion were: progressive disease (n = 11, 69%), Grading of CRS and ICANS was performed following the manufacturing failure (n = 4, 25%), and psychiatric disorder American Society for Transplantation and Cellular Therapy (n = 1, 6%). All 75 patients had at least the first disease re- (ASTCT) criteria.18 Patients who were infused before April sponse evaluation at 1-­month post-­infusion. 2019 were graded according to the Lee criteria19 and then Baseline characteristics of the infused patients are sum- re-­assessed retrospectively to meet the 2019 criteria. Severe marized in Table 1. The median age was 60 years (IQR 52–­ CRS and/or ICANS were defined as grade 3 or higher 67) and 59% were male patients. Most had an International events. For the reporting of other adverse events, Common Prognostic Index score >2 (62%), an advanced stage (92%) Terminology Criteria for Adverse Events (CTCAE) version and were primary refractory (52%). Sixty-­five patients (87%) 5.0 was used.20 Tumor lysis syndrome was defined according received bridging therapy before infusion, including chemo- to Cairo-­Bishop criteria.21 therapy in most cases (n = 56, 86%). The median time from Objective response rate (ORR) was defined as the per- apheresis to infusion was 53 days (IQR 49–­56). Median in- centage of patients who achieved a partial remission (PR) fused cell dose was 3.5 × 108 CAR positive viable T-­cells or complete remission (CR) after CAR T-­ cell infusion. (IQR 1.5–­4.2). Eight products were considered OOS accord- Progression-­free survival (PFS) was defined as the time from ing to EMA requirements and four could not be manufactured. apheresis (ITT population) or CAR T-­cell infusion until re- Reasons for OOS were low cellularity (n = 6, 75%) and low lapse, progression, or death from any cause. Overall survival viability (n = 2, 25%). Six of the eight OOS products were in- (OS) was defined as the time from apheresis (ITT) or CAR fused (Table S1), the other two patients were not infused due IACOBONI et al.    | 3217 TABLE 1 Baseline characteristics of infused patients TABLE 1 (Continued) Baseline characteristics of infused patientsa N = 75 Baseline characteristics of infused patientsa N = 75 Median age (IQR) -­years 60 (52–­67) Rituximab-­CHOPe 3 (5) Age ≥65 y–­n (%) 23 (31) Steroids 2 (3) Gender –­n (%) Radiotherapy 2 (3) Male 44 (59) Rituximab-­Lenalidomide 2 (3) f Female 31 (41) Other chemotherapy 3 (5) ECOG score, median (IQR) 1 (0–­1) Data not available 3 (5) 0–­n (%) 25 (33) Abbreviations: ASCT, Autologous Stem Cell Transplant; DH/TH, Double Hit/ 1–­n (%) 41 (55) Triple Hit; ECOG, Eastern Cooperative Oncology Group; GCB, Germinal Center B-­cell; IPI, International Prognostic Index; IQR, Interquartile range; LDH, Lactate 2–­n (%) 5 (7) Dehydrogenase; NOS, Not Otherwise Specified; ULN, Upper Limit of Normal. Missing data –­n (%) 4 (5) a ECOG score was missing in four patients, IPI missing in four patients; Bulky Histology –­n (%) data missing in two patients, extranodal missing in one patient. b CVP, Cyclophosphamide, vincristine, and prednisolone. Diffuse large B-­cell lymphoma, NOS 44 (58) c Platinum-­based strategies included R-­GEMOX (12), R-­GDP (3) and R-­ESHAP (1). High grade B-­cell lymphoma DH/TH 11 (15) d Bendamustine based included Rituximab-­Bendamustine with (2) or without (3) Transformed from follicular lymphoma 17 (23) Polatuzumab. e Transformed from other indolent histology 3 (4) CHOP, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone. f Cell of origin –­n (%) Other chemotherapy included MINE (Mesna, Ifosfamide, Mitoxantrone, Etoposide), R-­IE (rituximab, ifosfamide, and etoposide) and R-­hyperCVAD GCB 44 (59) (Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone). Non-­GCB 24 (32) Missing data 7 (9) Disease stage-­n (%) to rapid disease progression. Median follow-­up from CAR Stage I-­II 6 (8) T-­cell infusion was 14.1 months (95%CI 13.1–­17.4). Stage III-­IV 69 (92) Extranodal disease (≥1 site)–­n (%) Bulky disease (>7 cm)–­n (%) 60 (80) 30 (42) 3.2 | Safety analysis LDH levels before treatment Among the infused patients, 53 (71%) developed any grade <2xULN 51 (68) of CRS; 21 (28%) and four (5%) patients developed grade ≥2xULN 24 (32) ≥2 and grade ≥3 CRS, respectively. Eleven (15%) patients IPI prognostic score –­n (%) developed any grade of ICANS, whereas five (7%) and one 0–­2 25 (33) (1%) developed grade ≥2 and grade ≥3 ICANS, respectively. 3–­5 46 (62) The median time from infusion to the onset of symptoms of Missing data 4 (5) CRS and ICANS was 2 days (IQR 1–­4) and 7 days (IQR 5–­9), respectively. Tocilizumab and steroids were administered to Number of previous lines of treatment, median 3 (2–­4) (IQR) 24 (32%) and 16 (21%) patients, respectively. Ten (13%) pa- tients required admission to the Intensive Care Unit. By day 2–­3 54 (72) 90 post-­infusion, three (4%) patients experienced treatment-­ >3 21 (28) related mortality: two from bacterial infection, specifically Previous ASCT –­n (%) 29 (39) one case of Klebsiella pneumoniae BLEE sepsis and another Response to previous therapy –­n (%) of multiresistant Pseudomonas aeruginosa soft tissue infec- Primary refractory 39 (52) tion (at 26 and 30 days from infusion, respectively) and one Refractory to last therapy 22 (29) from macrophage activation syndrome (MAS)24 (at 36 days Relapsed 14 (19) from infusion), despite treatment with tocilizumab, steroids, Bridging treatment -­n (%) 65 (87) anakinra, and siltuximab. There were two other cases of Cyclophosphamide-­Prednisone/CVPb 29 (44) MAS: one resolved with dexamethasone and the other with- c out specific treatment. Other adverse events including infec- Platinum-­based 16 (24) tion and tumor lysis syndrome are summarized in Table 2. Bendamustine-­basedd 5 (8) The univariate analysis of risk factors for the development of adverse events is summarized in Table S2. The baseline (Continues) characteristics associated with an increased risk of grade ≥2 3218 |    IACOBONI et al. TABLE 2 Safety analysis of infused patients ORR of 60%. In the ITT analysis, the best response achieved Safety profile of infused patients N = 75 was CR in 26% (24/91) with an ORR of 49% (45/91). Patients CRS who achieved a response (CR or PR) had a median duration Any grade; n (%) 53 (71) of response of 8.9 months (95%CI 2.2–­NA). Stable disease and progressive disease were the best response in 6 (8%) and Grade ≥2; n (%) 21 (28) 24 (32%) patients, respectively. Of the six infused OOS prod- Grade ≥3; n (%) 4 (5) ucts, two patients achieved a CR, one patient achieved a sta- Time from infusion to start of CRS; median days 2 (1–­4) ble disease and eventually progressed, whereas three patients (IQR) progressed at the first disease assessment (Table S1). Duration CRS; median days (IQR) 4 (4–­6) Regarding the patients who achieved an initial PR at the ICANS 1-­month disease assessment, five (5/25, 20%) converted to Any grade; n (%) 11 (15) CR at 3 (2 patients), 6, 12, and 18 months, respectively; the Grade ≥2; n (%) 6 (8) other patients in PR progressed in the following 3 to 6 months Grade ≥3; n (%) 1 (1) (18/25, 72%), or were in a maintained PR at data cutoff (2/25, Time from infusion to start of ICANS; median days 7 (5–­9) 8%). Regarding the nine patients who achieved an initial SD, (IQR) two patients converted to a CR at 6-­and 18-­months post-­ Duration ICANS; median days (IQR) 9 (3–­14) infusion, respectively, and one patient improved to a PR ICU, n (%) 10 (13) at 3 months post-­infusion; one patient remained in SD at Tocilizumab 6 months post-­infusion and the remaining five patients had progressed at data cutoff. Patients; n (%) 24 (32) In the subgroup analysis, ORR was consistent across all Median number doses tocilizumab (IQR) 1 (1–­5) baseline characteristics except for the International Prognostic Corticosteroids Index (IPI) score (a high IPI [3–­5] showed a lower ORR [OR Patients; n (%) 16 (21) 0.35, p = 0.05]) and a history of previous indolent lymphoma Duration steroids; median days (IQR) 11 (8–­ (OR 3.59, p = 0.04) (Figure 1). In the subgroup analysis for 15) CR, patients with an ECOG of 0, an LDH <2xULN and a low Macrophage activation syndrome, n (%) 3 (4) IPI score had a significantly increased probability of achiev- Infections in the first month after infusion ing a CR (Figure S1). There was no significant difference Patients, n (%) 21 (28) in any of the efficacy endpoints for patients with high-­grade Infectious events 31 B-­cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 Bacterial 19 rearrangements. Patients who developed grade 2 or higher CRS or ICANS Viral 8 had a similar ORR (65% vs. 58%, p = 0.54) and OS in com- Fungal 3 parison to patients who did not develop grade 2 or higher ad- Not identified 1 verse events. There was no significant impact of tocilizumab Tumor Lysis Syndrome, n (%) 2 (3) or steroid use on the ORR (69% and 81%, respectively, p-­ Treatment-­related mortality, n (%) 3 (4) values >0.1). Abbreviations: Cytokine Release Syndrome (CRS); Immune Effector Associated Neurotoxicity Syndrome (ICANS); Intensive Care Unit (ICU); Interquartile range (IQR). 3.3.2 | Survival analysis CRS and/or ICANS were ECOG (≥1 vs. 0), primary refrac- Median PFS and OS for all infused patients were 3 months tory disease, lactate dehydrogenase (LDH) levels (>2xULN (95%CI 2.6–­4.7) and 10.7 months (95%CI 7.4–­NA), respec- [(Upper Limit of Normal)] vs. <2xULN), and the infused cell tively (Figure 2). The overall 6-­month and 12-­month PFS dose per kg of body weight (0.01-­units increase). was 33.3% and 31.7%, respectively. Patients in CR and PR at first disease evaluation had a PFS at 12 months of 87% and 20% (p < 0.001) and OS of 93% and 39% (p < 0.001), 3.3 | Efficacy analysis respectively (Figure S2). In the ITT analysis, median PFS and OS from apheresis 3.3.1 | Disease response were 4.6 months (95%CI 4.1–­6.9) and 11.1 months (95%CI 7.9–­NA), respectively (Figure S3). Among the 75 infused patients, the best response achieved In terms of PFS, patients who were primary refractory, was CR in 24 (32%) patients and PR in 21 (28%), with an had an ECOG of 1 or higher, a non-­GCB cell of origin, IACOBONI et al.    | 3219 F I G U R E 1 Subgroup analysis according to ORR for infused patients. Note: Overall response rate according to baseline patient and disease characteristics high IPI score and high LDH levels (>2xULN) had a sig- received an infusion. The median time from apheresis to nificantly lower PFS in the univariate analysis (Table 3 and infusion was similar to the registration trial9 (54 days vs. Figure 3). Primary refractory disease [HR: 2.24 (95%CI 53 days) and in both studies most patients received bridg- 1.20–­4.18), p = 0.01] and high LDH levels [HR: 2.18 ing therapy (92% vs. 87%). This turnaround time is longer (95%CI 1.19–­3.99), p = 0.01] maintained the independent than the published real-­world data with axi-­cel and tisa-­cel statistical significance in the multivariate model (Table 3). in the US11,12,15 but similar to previous tisa-­cel reports from For OS, patients who were primary refractory, had an European centers.13,14 Reasons behind this delay would in- ECOG of 1 or higher, high IPI score and high LDH levels clude limited referral experience, reduced number of man- were associated with a lower OS in the univariate analysis ufacturing slots, and few European facilities; this could (Table 3 and Figure 3). In the multivariate analysis, ECOG have certainly played a role in the number of patients who [HR: 2.80 (95%CI 1.10–­7.11), p = 0.03] and LDH levels dropped out due to disease progression and, even, in the final [HR: 2.33 (95%CI 1.14–­4.76), p = 0.02] remained signifi- outcome of the infused patients. This bridging period has cantly associated with OS (Table 3). gradually improved with the increasing experience of refer- ral sites and a growing number of European manufacturing facilities. 4 | D IS C U SS ION Eight products were considered OOS in our study, mainly due to low cellularity. Low viability, a larger prob- This is the largest study to date focused exclusively on pa- lem in the US, was not as frequent, probably due to the tients with R/R LBCL treated with tisa-­cel in the real-­world lower EMA limit in comparison with the FDA (70% vs. setting. We have shown that CAR T-­cell therapy with tisa-­cel 80% respectively).15 In our study, 82% of the patients who is feasible outside the US and has a similar safety and effi- underwent apheresis received an infusion; in the pivotal cacy profile to the pivotal clinical trial.9 trial9 only 67% of enrolled patients received an infusion, In our study, 91 patients with R/R LBCL underwent leu- possibly related to the stricter criteria and the different kapheresis for commercial tisa-­cel and 75 (82%) patients baseline characteristics, which included a smaller number 3220 |    IACOBONI et al. F I G U R E 2 PFS (a) and OS (b) for all infused patients and for patients achieving CR at first disease assessment. Note: PFS and OS in infused patients and in patients achieving CR after CAR T-­cell infusion of transformed patients in comparison to our cohort (19% in our study than in the pivotal trial9 (20% vs. 54%). We also vs. 27%, respectively). observed that patients with a SD or PD as the best response Focusing on the safety analysis, the incidence of severe after CAR T-­cell therapy represent a high-­risk subgroup: the adverse events, including both CRS (5%) and ICANS (1%), 12-­month OS was 14% for patients with PD/SD, in compar- was lower than the JULIET trial (22% and 12%, respec- ison to 28% for patients with PR and 95% for patients with tively), taking into account the usual caveats derived from CR. Therefore, patients in CR after tisa-­cel therapy seem to different grading systems.25,26 Noteworthy, our results were have a very good prognosis, with durable remissions in most similar to a recent real-­world registry-­based study includ- cases; patients who achieve a PR should be closely monitored ing patients with LBCL and acute lymphoblastic leukemia during the first 3 months, the highest-­risk period, to look out treated with tisa-­cel in the US.15 Reasons behind this trend for early signs of progression and start additional therapies as for a better safety profile in the standard-­of-­care setting soon as needed. compared with the clinical trial includes an increased use of Patients with high LDH levels had a worse outcome after tocilizumab and steroids13,15 and more experience in CAR treatment with tisa-­cel. Other studies also identified LDH11 T-­cell management.27 Preliminary data from European cen- and high tumor volume, measured on CT29 or PET scan,14,30 ters seem to confirm this lower rate of severe adverse events as clear prognostic factors for disease response after CAR in the commercial setting.13,28 The median time to onset of T-­cell therapy. Patients with primary refractory disease also CRS and ICANS was similar between our study and the reg- had a lower PFS and OS. In line with previous publications, istration trial (2 vs. 3 days and 7 vs. 6 days, respectively). we found no significant efficacy difference for HGBL pa- Patients with primary refractory disease, a higher infused tients. Taking all this into account, patients progressing after cell dose per kg of body weight, an ECOG ≥1 and elevated second-­line therapy with low tumor burden, a good perfor- LDH levels showed an increased risk of developing grade 2 mance status, and low LDH could potentially benefit most or higher adverse events. In line with the pivotal CAR T-­cell from this treatment. trials,8,9 older age was not associated with an increased risk There are some limitations to this study. The data were of grade ≥2 toxicity, suggesting this is a feasible treatment collected retrospectively and many of the baseline char- modality for elderly patients with R/R LBCL. There was acteristics were captured before apheresis. Also, disease a 4% of treatment-­related mortality in this study; however, evaluation was only available previous to lymphodepleting all three patients were in progressive disease at the time of chemotherapy; thus, it was not possible to assess the impact these events so this could have played a role in the final of disease response to bridging treatment as a prognostic fac- outcome. tor for the efficacy of CAR T-­cell therapy. Longer follow-­up Efficacy results in our study were similar to the pivotal is needed to confirm the long-­term duration of complete re- trial. Interestingly, 12-­month PFS for patients who achieved missions and safety after tisa-­cel therapy. a CR at first disease assessment was 87%, confirming that To the best of our knowledge, this is the largest standard-­ most patients in this subgroup will maintain their response of-­care cohort of patients reported to date with tisa-­cel for over time. However, the PR to CR conversion rate was lower R/R LBCL in a European country. Our results confirm that IACOBONI et al.    | 3221 TABLE 3 Univariate and multivariate analysis of risk factors for PFS and OS Progression-­free survival (n = 75, events = 51) Overall survival (n = 75, events = 39) Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value Age (10-­years 0.82 (0.65–­1.04) 0.10 —­ —­ 0.78 (0.59–­1.02) 0.07 —­ —­ increase) Sex (male vs. 1.30 (0.73–­2.29) 0.37 —­ —­ 1.37 (0.71–­2.64) 0.34 —­ —­ female) ECOG (1+ vs. 0) 1.97 (1.06–­3.68) 0.03 —­ —­ 4.23 (1.75–­10.2) <0.01 2.83 (1.12–­7.11) 0.03 Stage (III-­IV vs. 1.54 (0.55–­4.28) 0.41 —­ —­ 2.24 (0.54–­9.29) 0.27 —­ —­ I-­II) Prev. indolent 0.89 (0.47–­1.67) 0.71 —­ —­ 0.90 (0.44–­1.85) 0.78 —­ —­ lymphoma (yes vs. no) Primary 2.19 (1.24–­3.87) <0.01 1.99 (1.12–­3.55) 0.02 2.00 (1.04–­3.86) 0.04 1.79 (0.90–­3.56) 0.09 refractory (yes vs. no) Bulky (>7 cm vs. 1.56 (0.88–­2.75) 0.13 —­ —­ 1.86 (0.96–­3.58) 0.06 —­ —­ <7 cm) Cell of origin 1.70 (0.93–­3.09) 0.08 —­ —­ 1.81 (0.92–­3.57) 0.09 —­ —­ (Non-­GCB vs. GCB) HGBL (yes vs. 0.99 (0.45–­2.19) 0.98 —­ —­ 1.31 (0.58–­2.96) 0.52 —­ —­ no) Previous lines 1.05 (0.83–­1.33) 0.69 —­ —­ 1.17 (0.88–­1.54) 0.28 —­ —­ IPI score 1.74 (1.30–­2.31) <0.001 * * 1.79 (1.28–­2.51) <0.001 * * CAR T-­cell dose 0.81 (0.58–­1.12) 0.21 —­ —­ 0.69 (0.46–­1.02) 0.07 —­ —­ CAR T-­cell dose/ 0.86 (0.68–­1.07) 0.18 —­ —­ 0.81 (0.62–­1.06) 0.12 —­ —­ kg (0.01-­units increase) LDH (>2xULN 2.70 (1.53–­4.86) <0.001 2.48 (1.40–­4.40) <0.01 3.92 (2.08–­7.40) <0.001 2.75 (1.38–­5.46) <0.01 vs. <2xULN) *IPI score was not included in the multivariate analysis because of the high multicollinearity with other covariates. IPI score and CAR T-­cell dose were analyzed as continuous variables. Abbreviations: CART, Chimeric Antigen Receptor T-­cell; ECOG, Eastern Cooperative Oncology Group; GCB, Germinal Center B-­cell; HGBL, High-­grade B-­cell lymphoma; IPI, International Prognostic Index; LDH, Lactate Dehydrogenase; ULN, Upper Limit of Normal. treatment with tisa-­cel in Europe is feasible and has similar ACKNOWLEDGMENT results to the pivotal trial. The authors thank the patients and their families for their par- ticipation in this study. CO M P LIA NCE WIT H E T HICA L CONFLICTS OF INTEREST STA N DA R D S G.I. declares having received honoraria from BMS/Celgene, Gilead, Novartis, Janssen, and Roche, not related with this Ethical approval: All procedures performed in this study in- article. G.V. reported receiving honoraria for speaker activi- volving human participants were in accordance with the ethi- ties from Merck Sharp & Dohme and an advisory role from cal standards of the institutional research committee and with Astrazeneca. A.M. declares having received Gilead research the 1964 Helsinki declaration and its later amendments or fundings and honoraria from Novartis and Takeda. JM. S. comparable ethical standards. declares having received honoraria from Roche, Novartis, Ethical approval was granted by the Vall d’Hebron Hospital Gilead, Celgene, Janssen, Takeda, and Incyte; also consult- Ethical Committee, study identified with code PR(AG)404/2020. ing for Roche, Novartis, Gilead, Celgene, Janssen, Incyte, 3222 |    IACOBONI et al. F I G U R E 3 Impact of LDH levels and primary refractory disease on PFS and OS of infused patients. Note: Impact of LDH levels on PFS (a) and OS (c); impact of primary refractory disease on PFS (b) and OS (d) Celltrion, and Sandoz. P.A. has received honorarium for ad- authors. All authors contributed to manuscript writing and final visory and speaker faculty from Janssen, Roche, Celgene, approval of the manuscript, and are accountable for all aspects Abbvie, Gilead, and Astrazeneca. A.M.G-­S. declares hav- of the work (ensuring questions related to accuracy or integrity ing received honoraria from Roche, Celgene, Janssen, of the work are appropriately investigated and resolved. Servier, Gilead; consulting fees from Roche, Celgene/BMS, Morphosys, Kyowa Kirin, Clinigen, Eusa Pharma, Novartis, DATA AVAILABILIT Y STATEMENT Gilead, Servier; research funding from Janssen. JL. R-­O. de- Data available on request from the authors. clares having received honoraria from Novartis, Kite/Gilead, BMS/Celgene. P.B. declares having received honoraria from ORCID Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, Gloria Iacoboni https://orcid.org/0000-0003-0805-9288 MSD, Novartis, Pfizer, and Roche, not related with this arti- Juan-­Manuel Sancho https://orcid.org/0000-0001-7168-6538 cle. P.B. received funding from the Carlos III FIS16/01433 Pere Barba https://orcid.org/0000-0001-7076-7969 Health Institute, Asociación Española contra el Cáncer (Ideas Semilla 2019) and a PERIS 2018–­2020 grant from R E F E R E NC E S the Generalitat de Catalunya (BDNS357800), not related to 1. Pfreundschuh M, Trümper L, Österborg A, et al. CHOP-­like che- this study. motherapy plus rituximab versus CHOP-­like chemotherapy alone in young patients with good-­prognosis diffuse large-­B-­cell lym- phoma: a randomised controlled trial by the MabThera International AUTHORS’ CONTRIBUTIONS Trial (MInT) Group. Lancet Oncol. 2006;7(5):379-­391. Concept and design were undertaken by PB and GI. Data 2. 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