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Multicenter Study
. 2025 Aug 12;9(15):3955-3966.
doi: 10.1182/bloodadvances.2024015719.

Outcomes of bispecific antibody therapy after CAR T-cell failure in relapsed/refractory large B-cell lymphoma

Evgenii Shumilov  1 , Julia Katharina Scholz  2 , Maximilian Seib  1 , Paolo Mazzeo  3   4 , Rebecca Wurm-Kuczera  5 , Vladan Vucinic  6 , Udo Holtick  7 , Hristo Boyadzhiev  8   9 , Thomas Melchardt  10   11   12   13 , Alexander Hölscher  14 , Christian Schultze-Florey  15 , Atef Abdelhafez  5 , Giuliano Filippini Velazquez  16 , Anna Ossami Saidy  17 , Vadim Lesan  18 , Ulf Schnetzke  19 , Andrea Kerkhoff  1 , Ulrike Bacher  20 , Susanne Ghandili  21 , Enver Aydilek  3 , Niklas Gebauer  22 , Thomas Weber  23 , Gerald Wulf  3 , Bertram Glass  17 , Lorenz Thurner  18 , Florian H Heidel  15   24 , Christoph Schmid  16 , Andreas Viardot  25 , Mathias Hänel  26 , Sascha Dietrich  14 , Thomas Pabst  8 , Francis Ayuk  27 , Bastian von Tresckow  28 , Björn Chapuy  5 , Christiane Pott  29 , Fabian Müller  2 , Georg Lenz  1
Affiliations
Multicenter Study

Outcomes of bispecific antibody therapy after CAR T-cell failure in relapsed/refractory large B-cell lymphoma

Evgenii Shumilov et al. Blood Adv. .

Abstract

Patients with large B-cell lymphoma (LBCL) who experience relapsed disease after CD19-directed chimeric antigen receptor (CAR) T-cell (CAR-T) therapy have a poor prognosis. Bispecific antibodies (BsAbs) induce complete remissions in ∼35% of these cases. Hypothesizing overlapping LBCL-intrinsic resistance mechanisms as well as common poor prognosis predictors to CAR-T and BsAb therapy, we conducted a multicenter retrospective analysis including 92 patients with relapsed/refractory (R/R) LBCL treated with BsAbs after CAR-T failure. Overall response rate (ORR) was 43%, with a progression-free survival (PFS) of 2.8 months. Patients receiving BsAbs during early relapse (≤3 months) achieved a significantly worse outcome (ORR, 29%; PFS, 2.2 months) compared with patients with an intermediate (4-6 months; ORR, 54%; PFS, 3.7 months) or a late relapse (>6 months; ORR, 60%; PFS, 10.5 months). The benefit of later relapse was particularly notable in patients receiving BsAbs as first salvage therapy compared with those receiving a BsAb in subsequent lines (PFS not reached vs 2.7 months; overall survival not reached vs 9.1 months, respectively). In addition to early R/R state before BsAbs, elevated lactate dehydrogenase and higher International Prognostic Index score were significant predictors of poor outcomes to BsAb in multivariate Cox regression analyses. The finding that patients with early relapse after CAR-T respond particularly poorly to BsAb highlights the necessity for alternative treatment options in this high-risk patient cohort.

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Conflict of interest statement

Conflict-of-interest disclosure: E.S. received honoraria (not related to this study) from Amgen, Bristol Myers Squibb (BMS), Sanofi, Oncopeptides, Gilead, Incyte, Eli Lilly, and Takeda. B.C. is inventor on patent applications related to molecular subtyping of diffuse large B-cell lymphoma, including DLBclass; has received research funding from Gilead in 2021, not related to this study; served on advisory boards (not related to this study) for AbbVie, ADC, BMS, Incyte, Janssen, Regeneron, Roche, and Sobi; received honoraria for talks from AbbVie, Ars Tempi, AstraZeneca, BMS, Incyte, Janssen, Gilead, KML, Roche, Sandoz, Sobi, and Ono Pharmaceutical (not related to this study); received travel support from Sobi and Roche (not related to this study); and is lead investigator on the R-Pola-Glo clinical trial, which is indirectly funded by Roche. M.H. received travel support from AbbVie and served on advisory boards (unrelated to this study) for Sobi, Novartis, Gilead, BMS, Pfizer, Incyte, Sanofi, Roche, Janssen, and Amgen. U.H. has served on advisory boards (not related to this study) for BMS, Johnson & Johnson, Kite Pharma (a Gilead company), and Roche, and received honoraria (unrelated to this study) for talks from AbbVie, BeiGene, BMS, Johnson & Johnson, Kite Pharma (a Gilead company), and Miltenyi Biotec. T.M. received honoraria from AbbVie, BMS, Incyte, Janssen, Regeneron, and Roche, not related to this study. B.v.T. is an adviser or consultant (unrelated to this study) for Allogene, Amgen, BMS/Celgene, Cerus, Kite Pharma (a Gilead company), Incyte, IQVIA, Janssen-Cilag GmbH, Eli Lilly, Merck Sharp & Dohme, Miltenyi Biotec, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, QualWorld, Regeneron, Roche, Sobi, and Takeda; has received honoraria (not related to this study) from AbbVie, AstraZeneca, BMS/Celgene, Kite Pharma (a Gilead company), Incyte, Eli Lilly, Merck Sharp & Dohme, Novartis, Roche Pharma AG, and Takeda; reports research funding (unrelated to this study) from Esteve (institutional), Merck Sharp & Dohme (institutional), Novartis (institutional), and Takeda (institutional); and reports travel support (not related to this study) from AbbVie, AstraZeneca, Kite Pharma (a Gilead company), Eli Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis. V.V. received honoraria for consultancy or advisory roles from AbbVie, Novartis, Gilead, BMS, Janssen, Sobi, Incyte, AstraZeneca, Amgen, and MSD, unrelated to this study G.L. received research grants (not related to this study) from Agios, Aquinox, AstraZeneca, Bayer, Celgene, Gilead, Janssen, MorphoSys, Novartis, Roche, and Verastem Oncology, and received honoraria (not related to this study) from ADC Therapeutics, AbbVie, Amgen, AstraZeneca, Bayer, BMS, Celgene, Constellation, Genase, Genmab, Gilead, Hexal-Sandoz, Inmagene, Incyte, Janssen, Karyopharm, Eli Lilly, Miltenyi Biotec, MorphoSys, NanoString, Novartis, Pentixapharm, Roche, Sobi, and Takeda. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Survival outcomes of BsAbs after CAR-T failure in all patients (Pts). (A) PFS for all Pts; (B) OS for all Pts. The P values are obtained using a log-rank test, and Pts at risk are highlighted below the Kaplan-Meier plot.
Figure 2.
Figure 2.
Survival outcomes of BsAb after CAR-T failure depending on the time point of CAR-T failure (early vs intermediate vs late). (A) PFS; (B) OS. The P values are obtained using a log-rank test. Pts at risk are highlighted below the Kaplan-Meier plot.
Figure 3.
Figure 3.
Survival outcomes of BsAbs after CAR-T failure depending on BsAb administration as either first or later salvage. (A) PFS; (B) OS. The P values are obtained using a log-rank test. Pts at risk are highlighted below the Kaplan-Meier plot.
Figure 4.
Figure 4.
Outcomes of BsAbs after CAR-T failure depending on the time point of CAR-T failure (early vs intermediate/late) and BsAb administration (first vs later salvage). (A) PFS in Pts with early relapse after CAR-Ts; (B) OS rates in Pts with early relapse after CAR-Ts; (C) PFS in Pts with intermediate/late relapse after CAR-Ts; and (D) OS rates in Pts with intermediate/late relapse after CAR-Ts; Pts at risk are highlighted below the Kaplan-Meier plot.
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References

    1. 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;377(26):2531–2544. - PMC - PubMed
    1. Abramson JS, Palomba ML, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel) treatment of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) and secondary CNS lymphoma: initial results from TRANSCEND NHL 001. J Clin Oncol. 2019;37(suppl 15):7515.
    1. Locke FL, Miklos DB, Jacobson CA, et al. All ZUMA-7 Investigators and Contributing Kite Members Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640–654. - PubMed
    1. Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023;141(14):1675–1684. - PMC - PubMed
    1. Schuster SJ, Bishop MR, Tam CS, et al. JULIET Investigators Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56. - PubMed

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