CAR T-cell therapy for patients with relapsed or refractory marginal zone

# CAR T-cell therapy for patients with relapsed or refractory marginal zone lymphoma *The Lancet 2026* Comment obesity group with individuals who did not develop Whatever the explanations are of obesity–infection the above-mentioned features during the follow- associations, the study by Nyberg and colleagues up period. Such a group could have a lower risk of provides an impetus for more research and is a valuable infection irrespective of the presence of obesity. source of quantitative information on the burden of both Individuals possibly being in a healthy state at baseline obesity and communicable diseases. With the expected might have progressed to the unhealthy state during rapid development of the global pandemic of obesity,11 the observations period; therefore, the question the burden of obesity-related communicable diseases will remains whether such a safe state of excess fat mass be of increasing concern, both in public health settings exists, without an increased comorbidity risk, now also and in clinical management in either disease domain. including risk of infections. We declare no competing interests. Nyberg and colleagues carefully avoided interpreting *Thorkild I A Sørensen, Merete Osler the risk associations as based on causal effects of tias@sund.ku.dk obesity on the course of infections. Before interpreting Novo Nordisk Foundation Centre of Basic Metabolic Research, University of such risks as causal, various types of biases must be Copenhagen, Copenhagen, Denmark (TIAS); Department of Public Health, Section of Epidemiology, University of Copenhagen, Copenhagen DK-1353, considered. The cohorts represent selected parts of Denmark (TIAS, MO); Center for Clinical Research and Prevention, Bispebjerg– the populations, and probably do not include socially Frederiksberg Hospitals, Copenhagen, Denmark (MO) 1 Rubino F, Cummings DE, Eckel RH, et al. Definition and diagnostic criteria deprived groups and individuals with severe mental of clinical obesity. Lancet Diabetes Endocrinol 2025; 13: 221–62. illness.7 BMI and risk of infections might be related to 2 Pugliese G, Liccardi A, Graziadio C, Barrea L, Muscogiuri G, Colao A. Obesity and infectious diseases: pathophysiology and epidemiology of a double participation in both the study and the health services, pandemic condition. Int J Obes (Lond) 2022; 46: 449–65. which could introduce biases.8,9 Moreover, the authors 3 Yang W-S, Chang Y-C, Chang C-H, Wu L-C, Wang J-L, Lin H-H. The association between body mass index and the risk of hospitalization did not include individuals with the lowest BMI values, and mortality due to infection: a prospective cohort study. who might have lost weight and been at high risk. Open Forum Infect Dis 2020; 8: ofaa545. 4 Huang Y, Lu Y, Huang Y-M, et al. Obesity in patients with COVID-19: However, repeated waves of investigations in the a systematic review and meta-analysis. Metabolism 2020; 113: 154378. Finnish cohorts suggest that weight loss among people 5 Nyberg ST, Frank P, Ahmadi-Abhari S, et al. Adult obesity and risk of severe infections: a multicohort study with global burden estimates. Lancet 2026; with obesity is associated with lower risk of infections. published online Feb 9. https://doi.org/10.1016/S0140-6736(25)02474-2. 6 Muscogiuri G, Pugliese G, Laudisio D, et al. The impact of obesity on The important issue of a possible association of immune response to infection: plausible mechanisms and outcomes. obesity with exposure dose of the infectious agents Obes Rev 2021; 22: e13216. 7 Nilsson SF, Laursen TM, Osler M, et al. Adverse SARS-CoV-2-associated in explaining the risk of becoming infected with a outcomes among people experiencing social marginalisation and subsequent severe course remains unaddressed. psychiatric vulnerability: a population-based cohort study among 4·4 million people. Lancet Reg Health Eur 2022; 20: 100421. Enhanced exposure dose is a plausible contribution 8 Sonne-Holm S, Sørensen TI, Jensen G, Schnohr P. Influence of fatness, to the elevated risk of people with obesity during the intelligence, education and sociodemographic factors on response rate in a health survey. J Epidemiol Community Health 1989; 43: 369–74. COVID-19 pandemic, especially for those with co- 9 Hernán MA, Monge S. Selection bias due to conditioning on a collider. BMJ 2023; 381: 1135. morbidities or with crowded living conditions (which 10 Mølbak K, Sørensen TIA, Bhatt S, Lyngse FP, Simonsen L, Aaby P. Severity of might have implied a greater risk of high-dose exposure respiratory tract infections depends on the infectious dose. Perspectives for the next pandemic. Front Public Health 2024; 12: 1391719. to the virus). Such exposure might play a general role in 11 Ng M, Gakidou E, Lo J, et al. Global, regional, and national prevalence of the obesity association with other types of infections adult overweight and obesity, 1990–2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. Lancet and deserves further investigation.10 2025; 405: 813–38. CAR T-cell therapy for patients with relapsed or refractory marginal zone lymphoma Marginal zone lymphoma (MZL) is an indolent B-cell nodal, splenic, and extranodal or mucosa-associated See Articles page 963 malignancy that accounts for approximately 7% of lymphoid tissue subtypes.2 For relapsed or refractory mature non-Hodgkin lymphomas.1 It is characterised MZL, standard options include anti-CD20-based by varied anatomical and clinical features across regimens, lenalidomide–rituximab, and Bruton Comment The overall response rate as the primary endpoint evaluated by independent review committee was 95% (95% CI 87·3–99·1). The complete response rate was 62% (95% CI 49·3–73·8). With a median follow- up of 24·1 months, median duration of response, progression-free survival, and overall survival were not reached, with 24-month rates of 89%, 86%, and 90%, respectively. Subgroup analyses showed consistent responses across subtypes and high-risk features, including POD24 and refractory disease. Patient- reported outcomes indicated an initial transient decline followed by improvements in quality of life, with sustained or enhanced scores in domains such as global health status, physical functioning, and pain. The safety profile was manageable, with 4% of patients having grade 3 cytokine release syndrome and neurological tyrosine kinase inhibitors (BTKis).3 However, the events, and no grade 4–5 events. All cytokine release achievement of deep and durable remissions remains syndrome and neurological events were resolved by use challenging. Against this backdrop, anti-CD19 chimeric of tocilizumab and corticosteroids. Grade 3 or higher antigen receptor (CAR) T-cell therapies, which have infections occurred in 16% of patients with transient proven transformative in the treatment of aggressive cytopenias. lymphomas,4 have gradually expanded into indolent These findings contribute to the dynamic landscape histology, but disease-specific data for MZL have lagged of relapsed or refractory MZL management. Current behind follicular lymphoma.5 standard options include BTKis, such as zanubrutinib In The Lancet, M Lia Palomba and colleagues6 approved from the MAGNOLIA study, which reported an report the phase 2 results from the MZL cohort of overall response rate of 68% and 2-year progression-free the TRANSCEND FL study, which evaluated an anti- survival of 71%.7 The lenalidomide plus rituximab-based CD19 CAR T-cell product, lisocabtagene maraleucel, option had overall response rates of 64–65%, complete in a global, multicentre, open-label, single-arm trial in response rates of 29–39%, and median progression- patients with relapsed or refractory indolent B-cell non- free survival of 20·2–41·2 months in the AUGMENT and Hodgkin lymphoma. This cohort enrolled 77 patients MAGNIFY studies.8,9 Despite the limitations of cross-trial with relapsed or refractory MZL across 30 sites from comparisons, the high overall response rate and sustained the USA, Canada, Europe, and Japan. Of these patients remissions observed in patients with relapsed or who were leukapheresed, 67 received lisocabtagene refractory MZL treated with lisocabtagene maraleucel are maraleucel at a dose of 100 × 10 CAR+ T cells and noteworthy. Additionally, 39% of patients had previous 66 were evaluable for efficacy. The median age was BTKi exposure, and 22% had received lenalidomide 62 years, 42% were female, and 58% were male. These plus rituximab treatment, highlighting the efficacy of patients were heavily pretreated (median number of lisocabtagene maraleucel in patients who had developed previous lines of systemic therapy was three), with resistance to BTKis or lenalidomide–rituximad regimens. 79% classified as high risk by the MZL International The comparisons with other anti-CD19 CAR T-cell Prognostic Index (MZL-IPI) and 36% having progression products provide valuable insights but must be within 24 months of first-line therapy (POD24). All approached with caution. Axicabtagene ciloleucel MZL subtypes were also included. These patients were showed an overall response rate of 77% and complete predominantly White (57%), with low representation response rate of 65% in 31 patients with nodal or of Asian (6%) and Black (1%) participants and extranodal MZL, with 18-month progression-free 36% unknown race data, limiting generalisability to survival of 43% in the ZUMA-5 study.10 However, under-represented groups. ZUMA-5 excluded splenic MZL and reported higher rates 918 segamI ytteG aiv yrarbiL otohP ecneicS/olzsaL semeN Comment of grade 3 or higher cytokine release syndrome (8%) T-cell efficacy, such as circulating tumour DNA levels and neurological events (38%).10 Notably, the inclusion or tumour microenvironment factors, to refine patient of all MZL subtypes and the lower severe toxicity rates selection and optimise outcomes. The effect on CAR represented practical advantages in applicability and T-cell outcomes in MZL of genetic alterations—such safety in the TRANSCEND FL study. Additionally, as TP53 mutations, which might drive histological lisocabtagene maraleucel has received accelerated transformation, and glycoprotein receptor CD58 loss, approval for indolent lymphomas of another subtype, which impairs CAR T-cell function by disrupting the namely, follicular lymphomas, on the basis of the immune synapse—remains unclear and warrants further TRANSCEND FL study.11 With a median follow-up of study. Finally, the superiority of CAR T-cell therapy approximately 30 months, patients with relapsed compared with emerging therapies such as bispecific or refractory follicular lymphoma treated with antibodies and antibody–drug conjugates remains to be lisocabtagene maraleucel in the third line or later elucidated in MZL. (n=103) achieved an overall response rate of 97·1% SZ, HZ, and XW report support from the National Natural Science Foundation of (95% CI 91·7–99·4) and a complete response rate China (W2412122, 82570229, and 82470195), Tianjin Natural Science Foundation—Science and Technology Project (24JCYBJC00780 and of 94·2% (95% CI 87·8–97·8), per Lugano criteria with 24ZXZSSS00050), and Tianjin Key Medical Discipline Construction PET–CT.12 Responses in the MZL cohort were evaluated Project (TJYXZDXK-3-003A). SZ, HZ, and XW declare no competing interests. by CT, showing a complete response rate of 62%, which Sicong Zhang, Huilai Zhang, *Xianhuo Wang is numerically lower compared with the 94·2% complete tjzlyy_xianhuow@163.com response rate assessed by PET–CT in follicular lymphoma. State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Department of Lymphoma, Tianjin Medical University Cancer Institute However, in the post-hoc analysis of patients with MZL and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical with PET-avid disease at baseline (n=56), the complete Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China (SZ, HZ, XW) response rate was 91% with PET–CT, suggesting similar 1 Rossi D, Bertoni F, Zucca E. Marginal-aone lymphomas. N Engl J Med 2022; complete response rates when assessed using the same 386: 568–81. 2 Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the imaging modality. Differences in baseline prognostic World Health Organization Classification of Haematolymphoid Tumours: risk might also have contributed, with 79% high risk by lymphoid neoplasms. Leukemia 2022; 36: 1720–48. 3 Alderuccio JP, Noy A. The treatment of marginal zone lymphoma. Blood MZL-IPI compared with 57% by Follicular Lymphoma 2025; 147: 115–26. International Prognostic Index. Despite these 4 Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017; differences, the similar overall response rate 377: 2531–44. (95% in MZL vs 97% in follicular lymphoma) and durable 5 Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. 24-month rates of duration of response (89% vs 74·6%), Nat Med 2022; 28: 325–32. progression-free survival (86% vs 72·5%), and overall 6 Palomba ML, Schuster SJ, Karmali R, et al. Lisocabtagene maraleucel in patients with relapsed or refractory marginal zone lymphoma survival (90% vs 88·2%) indicate the consistent long- (TRANSCEND FL): primary analysis results from the global, multicohort, single-arm, phase 2 study. Lancet 2026; 407: 963–75. term efficacy of lisocabtagene maraleucel across 7 Opat S, Tedeschi A, Hu B, et al. Safety and efficacy of zanubrutinib in indolent subtypes. relapsed/refractory marginal zone lymphoma: final analysis of the MAGNOLIA study. Blood Adv 2023; 7: 6801–11. Notably, on the basis of the TRANSCEND FL study, 8 Leonard JP, Trneny M, Izutsu K, et al, and the AUGMENT Trial Investigators. lisocabtagene maraleucel has recently received US Food AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol and Drug Administration approval for adults with relapsed 2019; 37: 1188–99. 9 Lansigan F, Andorsky DJ, Coleman M, et al. P1156: MAGNIFY phase 3b or refractory MZL after at least two previous lines of study of lenalidomide+ rituximab (R2) followed by maintenance in systemic therapy. This broadens the application of anti- relapsed/refractory indolent non-Hodgkin lymphoma: complete induction phase analysis. HemaSphere 2022; 6: 1043–44. CD19 CAR T-cell therapy to MZL, especially for those 10 Neelapu SS, Chavez JC, Sehgal AR, et al. Three-year follow-up analysis of with POD24 or progression on BTKi or lenalidomide– axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Blood 2024; 143: 496–506. rituximab regimens. Although these phase 2 results 11 Britton K, Mahat U, Richardson NC, et al. FDA approval summary: are encouraging, larger sample sizes in confirmatory lisocabtagene maraleucel for relapsed or refractory follicular lymphoma. Clin Cancer Res 2025; 31: 3830–33. phase 3 trials are warranted to validate durability and 12 Nastoupil L, Dahiya S, Palomba ML, et al. Lisocabtagene maraleucel (liso-cel) in patients (pts) with relapsed or refractory (R/R) follicular generalisability. Simultaneously, translational studies lymphoma (FL): TRANSCEND FL 2-year follow-up. Blood 2024; should prioritise identification of predictors of CAR 144 (suppl 1): 4387. --- [PDF原文](https://sci-net.xyz/storage/7932541/06181e62c483e5372c60aad3c3555df84e6ee7392ae81704035a0b1e4f4b26a9/CAR-T-cell-therapy-for-patients-with-relapsed-or-refractory-marginal-zone-lymphoma.pdf) DOI: 10.1016/S0140-6736(26)00094-2