RESEARCH LETTER TO THE EDITOR: Real-world evidence of brexucabtagene autoleucel for the treatment of relapsed or refractory mantle cell lymphoma Gloria Iacoboni,1,2 Kai Rejeski,3 Guillermo Villacampa,4-6 Jaap A. van Doesum,7 Annalisa Chiappella,8 Francesca Bonifazi,9 Lucia Lopez-Corral,10,11 Michiel van Aalderen,12 Mi Kwon,13,14 Nuria Martınez-Cibrian,15 Stefania Bramanti,16 Juan Luis Reguera-Ortega,17 Lina Camacho-Arteaga,18-20 Christian Schmidt,3 Ana Marın-Niebla,1,2 Marie Jos e Kersten,12 10 9,21 Alejandro Martin Garcia-Sancho, Pier Luigi Zinzani, Paolo Corradini, Tom van Meerten, Marion Subklewe,3 and 8 7 1,2 Pere Barba 1 Department of Hematology, Vall d’Hebron University Hospital, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 2Department of Medicine, Universitat Aut onoma de Barcelona, Bellaterra, Spain; 3Department of Medicine III, University Hospital, LMU Munich, Munich, Germany; 4Oncology Data Science, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; 5SOLTI Breast Cancer Research Group, Barcelona, Spain; 6The Institute of Cancer Research, London, United Kingdom; 7Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 8Division of Hematology and Stem Cell Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milano, Milano, Italy; 9IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seragnoli”, Bologna, Italy; 10Hematology Department, Hospital Clınico Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain; 11Centro de Investigaci on del Cancer-IBMCC, Salamanca, Spain; 12Department of Hematology, Amsterdam University Medical Centers, Cancer Center Amsterdam, LYMMCARE (Lymphoma and Myeloma Center Amsterdam), Amsterdam, The Netherlands; 13Department of Hematology, Hospital General Universitario Gregorio Mara~ n, Madrid, Spain; 14Gregorio Mara~ no non Health Research Institute, Madrid, Spain; Department of Hematology, Hospital Clinic, Barcelona, Spain; Istituto Clinico Humanitas IRCCS, Rozzano, Italy; 17Department of 15 16 Hematology, University Hospital Virgen del Rocio, Sevilla, Spain; 18Clinical Pharmacology Department, Vall d’Hebron University Hospital, Barcelona, Spain; 19Clinical Pharmacology, Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Barcelona, Spain; 20Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, Barcelona, Spain; and 21Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Universita di Bologna, Bologna, Italy Brexucabtagene autoleucel (brexu-cel) is a second-generation CD19-targeted chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory (R/R) mantle cell lymphoma (MCL) based on the results of the ZUMA-2 study.1 This phase 2 trial enrolled 74 patients and infused 68 patients, with an overall response rate (ORR) of 85% (complete response [CR], 59%) among all patients who under- went apheresis. Grade $3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 15% and 31% of patients, respectively. However, there are very limited published data regarding safety and efficacy outside the context of the ZUMA-2 trial.2 In our study, we report the results of patients with R/R MCL treated with brexu-cel in the European Early Access Program. All consecutive patients with R/R MCL who underwent apheresis for brexu-cel at 11 European sites in Spain, Italy, Germany, and the Netherlands, from start of the European Early Access Program (February 2020) until August 2021, were included in the study. Ethical approval was granted by the Vall d’Hebron Hospital Ethical Committee, and the study was identified with code EOM(AG)041/2021(5851). The study was performed in accordance with the Declaration of Helsinki. After ethics committee approval, data were collected retrospectively in an electronic database. Efficacy outcomes were calculated in patients who received brexu-cel and in all patients who underwent apheresis (intention-to-treat). Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and reported along with the associated 95% confidence interval (95% CI). Adverse events after infusion were graded according to the American Society for Transplantation and Cellular Therapy consensus,3 and efficacy outcomes were assessed with Lugano criteria.4 During the study period, 39 patients with R/R MCL underwent apheresis for brexu-cel. Three (8%) patients had an initial manufacturing failure, requiring a second (2) or third (1) apheresis to obtain an ade- quate product; 2 out of 3 patients were finally infused. Regarding all enrolled patients, 33 (85%) patients received an infusion, whereas 6 (15%) patients did not owing to progressive disease (PD; n 5 3), Submitted 28 December 2021; accepted 15 February 2022; prepublished online on The full-text version of this article contains a data supplement. Blood Advances First Edition 10 March 2022; final version published online 20 June 2022. © 2022 by The American Society of Hematology. Licensed under Creative DOI 10.1182/bloodadvances.2021006922. Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC- Poster presentation at the 63rd annual meeting of the American Society of Hematol- ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other ogy, 11-14 December 2021. rights reserved. Requests for data sharing may be submitted to Gloria Iacoboni (giacoboni@vhio.net). 3606 28 JUNE 2022 • VOLUME 6, NUMBER 12 Table 1. Baseline characteristics of the infused patients in the Table 1. (continued) present series and in the ZUMA-2 trial Infused (N533) ZUMA-2 (N568) Infused (N533) ZUMA-2 (N568) s-MIPI, n (%) Sex, n (%) Low 8 (24) 28 (41) Male 29 (88) 57 (84) Intermediate/high 23 (70) 38 (56) Female 4 (12) 11 (16) Not available 2 (6) 2 (3) Age, median y (range) 67 (47-79) 65 (38-79) Extranodal disease, n (%)‡ $65 23 (70) 39 (57) Yes 26 (79) 37 (62) ,65 10 (30) 29 (43) No 7 (21) 23 (38) Prior lines, median (range) 2 (1-8) 3 (1-5) Bone marrow infiltration, n (%) .2 prior lines 15 (45) 55 (81) Yes 10 (30) 37 (54) #2 prior lines 18 (55) 13 (19) No 23 (70) 31 (46) Primary refractory,* n (%) Peripheral blood involvement, n (%) Yes 7 (21) † Yes 6 (18) † No 26 (79) No 27 (82) Previous auto-HCT, n (%) LDH, n (%)‡ Yes 12 (36) 29 (43) .ULN 14 (42) 23 (38) No 21 (64) 39 (57) #ULN 19 (56) 35 (59) Previous allo-HCT, n (%) Not available 0 (0) 2 (3) Yes 5 (15) 0 (0) ECOG, n (%) No 28 (85) 68 (100) 0 15 (45) 44 (65) Best response to previous $1 18 (55) 24 (35) ibrutinib, n (%) Allo-HCT, allogeneic hematopoietic cell transplantation; auto-HCT, autologous CR 11 (34) † hematopoietic cell transplantation; ECOG, Eastern Cooperative Oncology Group; LDH, PR 10 (30) lactate dehydrogenase; MIPI, Mantle Cell Lymphoma International Prognostic Index; ULN, upper limit of normal. SD/PD 8 (24) *Information not available owing to different definitions or cutoffs between the ZUMA-2 Not available 4 (12) trial and this study. †Never achieving complete remission with any line of treatment. Prior bendamustine therapy, n (%) ‡Reported on the 60 patients of the primary efficacy analysis set. Yes 14 (42) 37 (54) No 19 (58) 31 (46) achieving CR after bridging (n 5 2) or infection (n 5 1). Among Prior rituximab maintenance, n (%) infused patients, median age was 67 years (interquartile range Yes 14 (42) † [IQR], 62-72). Most patients had a high-risk simplified MCL Interna- No 19 (58) tional Prognostic Index (s-MIPI) score at apheresis (55%), advanced Morphology, n (%) stage disease (88%), and 36% had received a prior autologous Classical 22 (67) 36 (53) hematopoietic cell transplantation (HCT). Eight (24%) patients had Blastoid/pleomorphic 9 (27) 21 (31) a blastoid morphology, and 4 (12%) patients had TP53 mutations. Not available 2 (6) 11 (16) Full baseline characteristics (compared with patients included in the ZUMA-2 trial) are summarized in Table 1. Median follow-up after TP53 status, n (%) CAR T-cell infusion was 10.1 months (95% CI, 7.9-11.5). Mutated 4 (12) 6 (9) Unmutated 11 (33) 30 (44) Thirty-two patients (82%) received one (n 5 26) or two (n 5 6) bridging regimens after apheresis. The most common bridging ther- Not available 18 (55) 32 (47) apy (BT) was chemotherapy (n 5 14) followed by ibrutinib (n 5 12) Ki67 index>30%, n (%) (supplemental Table 1). Best disease response after BT included PD Yes 16 (49) 40 (59) in 18 (56%) patients, stable disease (SD) in 7 (22%) patients, partial No 3 (9) 9 (13) response (PR) in 5 (16%) patients, and CR in 2 (6%) patients. Not available 14 (42) 19 (28) Median time from apheresis to brexu-cel delivery and infusion was 29 Stage, n (%)‡ days (IQR, 28-34) and 41 days (IQR, 35-49), respectively. I-II 4 (12) 2 (15) Among the 33 infused patients, 30 (91%) patients developed CRS, III-IV 29 (88) 58 (85) grade $2 in 18 (55%) patients and grade $3 in 1 (3%) patient. 28 JUNE 2022 • VOLUME 6, NUMBER 12 RESEARCH LETTER 3607 A B 1.00 1.00 Progression-free survival (PFS) 0.75 0.75 Overall survival (OS) 6-months OS 83.2% 6-months PFS 12-months OS 0.50 0.50 (70.7%–97.9%) 77.2% 12-months PFS 61.4% (63.6%–93.6%) 50.8% (40.9%–92%) 0.25 (31.1%–83%) 0.25 0.00 0.00 0 3 6 9 12 15 18 0 3 6 9 12 15 18 Time from infusion (months) Time from infusion (months) N. at risk N. at risk 33 26 18 12 3 1 1 33 27 19 14 4 1 1 C D Variable N Progression-free survival 6-months PFS (95% CI) Variable N Overall survival 6-months OS (95% CI) Overall 33 77.2 (63.6−93.6) Overall 33 83.2 (70.7−97.9) Age Age 65 years 10 67.5 (43−100) 65 years 10 88.9 (70.6−100) t65 years 23 81.5 (66.6−99.7) t65 years 23 81 (65.7−99.7) Prior lines Prior lines 1–2 18 82.5 (66.3−100) 1–2 18 81.4 (64.3−100) 3+ 15 71.4 (51.3−99.5) 3+ 15 85.1 (68−100) Previous ASCT Previous ASCT No 21 74.5 (57.4−96.6) No 21 78.7 (62.1−99.7) Yes 12 81.8 (61.9−100) Yes 12 90.9 (75.4−100) Morphology Morphology Classical 22 80.3 (64.6−99.7) Classical 22 79.4 (63.2−99.8) Blastoid/Pleomorphic 9 66.7 (42−100) Blastoid/Pleomorphic 9 87.5 (67.3−100) TP53 mutation TP53 mutation No mutation 11 100 (67.6−100) No mutation 11 100 (67.6−100) Mutation 4 66.7 (30−100) Mutation 4 66.7 (30−100) Simplified MIPI Simplified MIPI Low/Intermediate 13 100 (86.5−100) Low/Intermediate 13 100 (86.5−100) High 18 61.1 (42.3−88.3) High 18 70.5 (51.7−96.2) Extranodal disease Extranodal disease No 7 85.7 (63.3−100) No 7 100 (77.6−100) Yes 26 74.8 (59.1−94.5) Yes 26 78.4 (63.2−97.2) LDH LDH dULN 19 87.5 (72.7−100) dULN 19 93.3 (81.5−100) !ULN 14 64.3 (43.5−95) !ULN 14 70.7 (50.2−99.6) ECOG ECOG 0 15 85.7 (69.2−100) 0 15 100 (88.2−100) 1–2 18 69.6 (50.4−96) 1–2 18 68.2 (48.5−95.9) Prior bendamustine Prior bendamustine No 19 76.4 (58.5−99.8) No 19 76.4 (58.5−99.8) Yes 14 78.6 (59.8−100) Yes 14 92.9 (80.3−100) 0% 20% 40% 60% 80% 100% 0% 20% 40% 60% 80% 100% 6m progression-free survival (%) 6m overall survival (%) Figure 1. PFS and OS in patients with MCL treated with brexu-cel. PFS (A) and OS for infused patients (B). Forest plot of 6-month PFS (C) and 6-month OS (D) estimation along with 95% CI in key subgroups. ASCT, autologous stem cell transplant. Median time from infusion to CRS onset and median duration of stay was 5 days (IQR, 3-6). Five patients (15%) died of treatment- CRS were 5 days (IQR 2-6) and 4 days (IQR 3-6), respectively. related complications: 4 patients from infection (COVID-19, pneumo- Twenty-one (64%) patients developed NE, grade $2 in 16 (48%) nia, sepsis, and aspergillosis) and 1 patient from clinical deterioration patients and grade $3 in 12 (36%) patients. Median time from infu- in the context of prolonged steroid therapy. Four of these 5 patients sion to NE and median duration of neurological symptoms were had experienced previous grade 3-4 NE and were in CR at last evalu- 7 days (IQR, 5-9) and 8 days (IQR, 3-13), respectively. Tocilizumab ation (supplemental Tables 2 and 3). and steroids were administered to 28 (85%) and 21 (64%) patients, respectively. There were no reported cases of tumor lysis syndrome. Best response among infused patients included CR in 26 (79%) At 1-month post-infusion, 16 (50%) patients had grade $3 thrombo- patients and PR in 4 (12%) patients (ORR 5 91%). Median time to cytopenia and 15 (47%) patients had grade $3 neutropenia (supple- best response was 1-month post-infusion. SD and PD were the mental Figure 1). Nine (27%) patients were admitted to the intensive best response in 1 (3%) patient each. One (3%) patient died before care unit (ICU) for CRS (3 patients), NE (3 patients), sepsis the 1-month evaluation. Among patients achieving an initial PR (2 patients), and pneumonia (1 patient). The median duration of ICU (N 5 6), 1 converted to CR at 3 months, 3 maintained a PR at last 3608 RESEARCH LETTER 28 JUNE 2022 • VOLUME 6, NUMBER 12 follow-up (5, 9, and 14 months), and 2 progressed at the 3-month additional insight to physicians facing these patients in the real- evaluation. Of the 2 patients in SD at 1 month, 1 patient converted world setting. to CR and the other maintained an SD at last follow-up (5 months). In conclusion, brexu-cel is a very effective salvage regimen for MCL The 6- and 12-month postinfusion PFS were 77% (95% CI, 64-94) patients treated outside of clinical trials, including those with high- and 51% (95% CI, 31-83), respectively (Figure 1A). The 6- and risk features. However, the occurrence of severe adverse events 12-month OS were 83% (95% CI, 71-98) and 61% (95% CI, was significant and deserves further attention. 41-92), respectively (Figure 1B). Patients with low/intermediate s-MIPI had better PFS than those with high s-MIPI (HR: 0.1; 95% CI, Acknowledgments: The authors thank the patients and their 0.01-0.81). PFS and OS were consistent among other pretreatment families for their participation in this study. They would also like  to thank Angel Cedillo from the Spanish Group of Stem Cell variables, including previous bendamustine therapy (Figure 1C-D). In the intention-to-treat analysis (N 5 39), ORR was 77% Transplantation and Cell Therapy group for the technical support (CR 5 64%). The 6-month PFS and OS from apheresis were 68% provided with the electronic database. (95% CI, 55-85) and 76% (95% CI, 63-91), respectively (supple- Contribution: G.I. and P.B.: conceptualization, data curation, formal mental Figure 2). analysis, writing – original draft, review and editing; K.R., J.A.v.D., In this European, multicenter study, we have shown that safety and A.C., F.B., L.L.-C., M.v.A., M.K., N.M.-C., S.B., J.L., R.-O., L.C.-A., efficacy of commercial brexu-cel are similar to the results obtained C.S., A.M.-N., M.J.K., A.M.G.-S., P.L.Z., P.C., T.v.M., and M.S.: in the pivotal ZUMA-2 trial. To the best of our knowledge, this is the data curation, writing – review and editing; G.V.: formal analysis, first paper focused on patients with MCL receiving this treatment writing – review and editing; collection and assembly of data were outside of the clinical trial setting. performed by all authors; and all authors contributed to manuscript writing and final approval of the manuscript and are accountable for Considering patients’ and disease characteristics, our study had all aspects of the work. a higher-risk population compared with the ZUMA-2 trial, includ- ing a higher s-MIPI score, worse Eastern Cooperative Oncology Conflict-of-interest disclosure: G.I. declares having received Group performance status, and previous allogeneic HCT (5 vs 0 honoraria from BMS/Celgene, Gilead, Novartis, Janssen, and patients). Also, the turnaround period from apheresis to CAR-T Roche. K.R. declares having received research funding and travel delivery was significantly longer than in the ZUMA-2 trial (29 vs support from Kite/Gilead and honoraria from Novartis. G.V. reported 16 days; P , .01). Finally, BT was more frequently used in our receiving honoraria for speaker activities from Merck Sharp & study as opposed to the registration trial (82% vs 37%; P , Dohme and served in an advisory role for Astrazeneca. A.C. .01), where only steroids or Bruton tyrosine kinase inhibitors declares having participated in advisory boards for BMS, Clinigen/ were allowed. SecuraBIO, Gilead-Sciences, Janssen, Roche, and Takeda; receiv- ing honoraria for lectures from Astrazeneca, BMS, Clinigen/Secura- When comparing the toxicity profile to the pivotal trial, grade $3 BIO, Gilead-Sciences, Incyte, Janssen, Novartis, Roche, and CRS was less frequent and had a delayed onset in our study, Takeda. F.B. declares having received honoraria from Jazz Pharma- whereas the frequency and onset of grade $3 NE were similar ceuticals, NEOVII Biothech, MSD, Novartis, Pfizer, Amgen, and Cel- (supplemental Table 4). In contrast to observations in other dis- gene. C.S. declares having received travel support from Kite/Gilead. eases,5-8 the utilization of tocilizumab and dexamethasone was simi- MJ.K. reports honoraria from Kite, Novartis, Miltenyi Biotech, Roche, lar in our real-world data compared with the pivotal trial. Importantly, and Bristol Myers Squibb/Celgene; serves in a consultancy or advi- fatal events occurred more frequently in our study (15% vs 3%). sory role for Kite, Roche, Bristol Myers Squibb/Celgene, Novartis, This could be related to the selection bias of patients included in and Miltenyi Biotech; received research funding from Kite, Roche, clinical trials and the longer turnaround time observed in the real- Takeda, and Celgene; and travel support from Kite, Roche, Novartis, world setting, which may have led to an increased tumor burden and Miltenyi Biotech. A.M.G.-S. declares having received honoraria and worse performance status at infusion. Of note, deaths were from Roche, BMS/Celgene, Janssen, Servier, Gilead, Takeda, Eusa mainly attributed to infections in both studies. Pharma, and Novartis; consulting fees from Roche, BMS/Celgene, Regarding efficacy, the CR and ORR were similar to the registration Kyowa Kirin, Clinigen, Eusa Pharma, Novartis, Gilead, Servier, and trial. However, 12-month PFS and OS were slightly lower in our Incyte; and research funding from Janssen. P.B. declares having study, probably influenced by the increased nonrelapse mortality. In received honoraria from Amgen, Celgene, Gilead, Incyte, Jazz Phar- our series, patients with low/intermediate s-MIPI score had longer maceuticals, MSD, Novartis, Pfizer, and Roche; funding from the PFS compared with high s-MIPI score. Bone marrow or peripheral Carlos III FIS16/01433 Health Institute, Asociaci on Espa~ nola Con- blood involvement did not seem to have an impact on safety or effi- tra el Cancer (Ideas Semilla 2019) and a PERIS 2018-2020 grant cacy, although the low number of events could limit this conclusion from the Generalitat de Catalunya (BDNS357800). None of the (details not shown). No other potential risk factors for PFS and OS mentioned conflicts of interest were related to financing of the con- were identified. tent of this manuscript. The remaining authors declare no competing financial interests. Our findings are limited by their retrospective nature, small sample size, and relatively short follow-up, although the latter was compara- ORCID profiles: G.I., 0000-0003-0805-9288; G.V., 0000- ble to the ZUMA-2 trial (10.1 vs 12.3 months, respectively). How- 0003-4868-6585; J.A.v.D., 0000-0003-0214-3219; A.C., 0000- ever, our series of patients receiving commercial brexu-cel in 4 0002-2977-0098; L.L.-C., 0000-0003-1908-5596; L.C.-A., different countries, with a larger use of BT, might be more represen- 0000-0001-9609-0394; A.M.G.-S., 0000-0001-6330-1028; tative than the population included in the ZUMA-2 trial, providing P.L.Z., 0000-0002-2112-2651; M.S., 0000-0003-3905-0251. 28 JUNE 2022 • VOLUME 6, NUMBER 12 RESEARCH LETTER 3609 Correspondence: Gloria Iacoboni, Department of Hematology, 4. Cheson BD, Fisher RI, Barrington SF, et al; United Kingdom Hospital Universitari Vall d’Hebron, Passeig Vall Hebron 119, National Cancer Research Institute. Recommendations for initial 08035 Barcelona, Spain; e-mail: giacoboni@vhio.net. evaluation, staging, and response assessment of Hodgkin and non- Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014; 32(27):3059-3068. 5. Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene References ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2020; 38(27):3119-3128. 1. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in 6. Jacobson CA, Hunter BD, Redd R, et al. Axicabtagene ciloleucel in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020; the non-trial setting: outcomes and correlates of response, resis- 382(14):1331-1342. tance, and toxicity. J Clin Oncol. 2020;38(27):3095-3106. 2. Khurana A, Dalland JC, Young JR, Inwards DJ, Paludo J. 7. Pasquini MC, Hu ZH, Curran K, et al. Real-world evidence of Brexucabtagene autoleucel therapy induces complete remission in a tisagenlecleucel for pediatric acute lymphoblastic leukemia and non- primary refractory blastoid mantle cell lymphoma with Hodgkin lymphoma [published correction appears in Blood Adv. neurolymphomatosis. Am J Hematol. 2021;96(8):E298-E301. 2021;4(4):1136]. Blood Adv. 2020;4(21):5414-5424. 3. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus 8. Iacoboni G, Villacampa G, Martinez-Cibrian N, et al; GETH, grading for cytokine release syndrome and neurologic toxicity GELTAMO Spanish Groups. Real-world evidence of associated with immune effector cells. Biol Blood Marrow tisagenlecleucel for the treatment of relapsed or refractory large Transplant. 2019;25(4):625-638. B-cell lymphoma. Cancer Med. 2021;10(10):3214-3223. 3610 RESEARCH LETTER 28 JUNE 2022 • VOLUME 6, NUMBER 12