Outcome after chimeric antigen receptor (CAR) T-cell therapy failure in large B-cell lymphomas

Anna Dodero, Stefania Bramanti, Martina Di Trani, Martina Pennisi, Silva Ljevar, Annalisa Chiappella, Magagnoli Massimo, Anna Guidetti, Francesco Corrado, Paulina Maria Nierychlewska, Alice Di Rocco, Daniele Lorenzini, Rahal Daoud, Chiara De Philippis, Armando Santoro, Carmelo Carlo-Stella, Paolo Corradini, Anna Dodero, Stefania Bramanti, Martina Di Trani, Martina Pennisi, Silva Ljevar, Annalisa Chiappella, Magagnoli Massimo, Anna Guidetti, Francesco Corrado, Paulina Maria Nierychlewska, Alice Di Rocco, Daniele Lorenzini, Rahal Daoud, Chiara De Philippis, Armando Santoro, Carmelo Carlo-Stella, Paolo Corradini

Abstract

This study retrospectively evaluated the outcome of salvage therapy in 51 patients who failed axicabtagene ciloleucel or tisagenlecleucel for relapsed/refractory large B-cell lymphomas. Of these patients, 22 (43%) were enrolled in clinical trials (glofitamab or loncastuximab tesirine + ibrutinib), whereas 29 received standard therapies (lenalidomide [Len], checkpoint inhibitors [CPIs], ibrutinib [I], chemoimmunotherapy and radiotherapy) or supportive care. Overall, 26 of 39 (67%) treated patients received a treatment based on immunotherapy (glofitamab, CPI, Len) that was mainly represented by bispecific antibody (n = 18). In this subgroup, plasma samples were collected and analysed for circulating tumour DNA (ctDNA) using cancer-personalized profiling by deep sequencing (CAPP-seq). The study found that patients with high ctDNA had poor outcomes. At a median follow-up of 11.7 months, the estimated 12-month overall survival (OS) was 35%. Factors adversely affecting the prognosis in the multivariable model were the absence of response to CAR T-cell therapy (HR: 3.08; p = 0.0109) and a diagnosis other than PMBCL and t-FL (HR: 4.54; p = 0.0069). The outcome of patients failing CAR T cells is poor and requires further investigation.

Keywords: CAR T cells; bispecific antibodies; immunotherapy; refractory large B-cell lymphoma.

© 2023 British Society for Haematology and John Wiley & Sons Ltd.

References

REFERENCES

    1. Crump M, Neelapu SS, Farooq U, van den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808.
    1. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.
    1. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56.
    1. Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852.
    1. Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, et al. Axicabtagene ciloleucel as second- line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654.
    1. Abramson JS, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, 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.
    1. Lemoine J, Ruella M, Houot R. Overcoming intrinsic resistance of cancer cells to CAR T-cell killing. Clin Cancer Res. 2021;27(23):6298-6306.
    1. Monfrini C, Stella F, Aragona V, Magni M, Ljevar S, Vella C, et al. Phenotypic composition of commercial anti-CD19 CAR T cells affects in vivo expansion and disease response in patients with large B-cell lymphoma. Clin Cancer Res. 2022;28(15):3378-3386.
    1. Spiegel JY, Dahiya S, Jain MD, Tamaresis JS, Nastoupil L, Jacobs MT, et al. Outcomes of patients with large B-cell lymphoma progressing after axicabtagene ciloleucel. Blood. 2021;137(13):1832-1835.
    1. Alarcon Tomas A, Fein JA, Fried S, Flynn JR, Devlin SM, Fingrut WB, et al. Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma. Leukemia. 2023;37(1):154-163.
    1. Di Blasi R, Le Gouill S, Bachy E, Cartron G, Beauvais D, Le Bras F, et al. Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis. Blood. 2022;140(24):2584-2593.
    1. Gouni S, Rosenthal AC, Crombie JL, Ip A, Kamdar MK, Hess B, et al. A multicenter retrospective study of polatuzumab vedotin in patients with large B-cell lymphoma after CAR T-cell therapy. Blood Adv. 2022;6(9):2757-2762.
    1. Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800.
    1. Crombie JL, Nastoupil LJ, Redd RA, Tang K, Shouse G, Herrera AF, et al. Real-world outcomes of axicabtagene ciloleucel in adult patients with primary mediastinal B-cell lymphoma. Blood Adv. 2021;5(18):3563-3567.
    1. Chong EA, Alanio C, Svoboda J, Nasta SD, Landsburg DJ, Lacey SF, et al. Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy. Blood. 2022;139(7):1026-1038.
    1. Hutchings M, Morschhauser F, Iacoboni G, Carlo-Stella C, Offner FC, Sureda A, et al. Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase I trial. J Clin Oncol. 2021;39(18):1959-1970.
    1. Dickinson MJ, Carlo-Stella C, Morschhauser F, Bachy E, Corradini P, Iacoboni G, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231.
    1. Hutchings M, Mous R, Clausen MR, Johnson P, Linton KM, Chamuleau MED, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021;398(10306):1157-1169.
    1. Thieblemont C, Phillips T, Ghesquieres H, Cheah CY, Clausen MR, Cunningham D, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II trial. J Clin Oncol. 2023;41(12):2238-2247.
    1. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3067.
    1. Spina V, Bruscaggin A, Cuccaro A, Martini M, di Trani M, Forestieri G, et al. Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood. 2018;131(22):2413-2425.
    1. Freeman GH, Halton JH. Note on an exact treatment of contingency, goodness of fit and other problems of significance. Biometrika. 1951;38(1/2):141.
    1. Kruskal WH, Wallis WA. Use of ranks in one-criterion variance analysis. J Am Stat Assoc. 1952;47:583-621.
    1. Roschewski M, Rossi D, Kurtz DM, Alizadeh AA, Wilson WH. Circulating tumor DNA in lymphoma: principles and future directions. Blood Cancer Discov. 2022;3(1):5-15.
    1. Kurtz DM, Scherer F, Jin MC, Soo J, Craig AFM, Esfahani MS, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma. J Clin Oncol. 2018;36(28):2845-2853.
    1. Frank MJ, Hossain NM, Bukhari A, Dean E, Spiegel JY, Claire GK, et al. Monitoring of circulating tumor DNA improves early relapse detection after axicabtagene ciloleucel infusion in large B-cell lymphoma: results of a prospective multi-institutional trial. J Clin Oncol. 2021;39(27):3034-3043.
    1. Zurko J, Ramdial J, Shadman M, Ahmed S, Szabo A, Iovino L, et al. Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma. Haematologica. 2023;108(1):98-109.
    1. Neelapu SS, Dickinson M, Munoz J, Ulrickson ML, Thieblemont C, Oluwole OO, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022;28(4):735-742.
    1. Wudhikarn K, Palomba ML, Pennisi M, Garcia-Recio M, Flynn JR, Devlin SM, et al. Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma. Blood Cancer J. 2020;10(8):79.

Source: PubMed

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