Abstract
Tisagenlecleucel (tisa-cel), an autologous anti-CD19 CAR T-cell therapy, has significantly improved outcomes in pediatric, adolescents and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). However, 30–50% experience early failure or relapse. We retrospectively analyzed 52 cases of early failures (n = 13) or relapses (n = 39), evaluating post-tisa-cel outcomes and prognostic factors. CD19 antigen loss was the only factor associated with a lower complete remission rate after salvage therapy (OR = 0.16, 95%CI [0.03–0.90], p = 0.04). Median overall survival (OS) was 14.5 months, with a 2-year OS of 37.4% (95%CI [24.4–50.4]), similar between early failure (38.5%) and relapse (37.0%) groups (p = 0.78). Patients with measurable residual disease only at salvage initiation had significantly improved 2-year OS (61.9%, (95%CI [38.1–78.8])) compared to those with overt disease (20.7%, (95%CI [8.4–36.7], p = 0.008)). Factors associated with inferior OS included high pre-infusion tumor burden (HR = 3.57, p < 0.01), and prior inotuzumab ozogamicin exposure (HR = 3.81, p < 0.01). Although salvage therapies and hematopoietic stem cell transplantation benefit some patients, 5 of 18 transplanted patients died from treatment-related toxicity, underscoring the significant associated risks. These findings highlight the poor prognosis of tisa-cel failures and the urgent need for novel strategies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout
Data availability
The datasets generated during the current study are included in this published article and its supplementary information files.
References
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.
Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.
Pasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4:5414–24.
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18.
Laetsch TW, Myers GD, Baruchel A, Dietz AC, Pulsipher MA, Bittencourt H, et al. Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial. Lancet Oncol. 2019;20:1710–8.
Schultz LM, Baggott C, Prabhu S, Pacenta HL, Phillips CL, Rossoff J, et al. Disease burden affects outcomes in pediatric and young adult B-cell lymphoblastic leukemia after commercial tisagenlecleucel: a pediatric real-world chimeric antigen receptor consortium report. JCO. 2022;40:945–55.
Dourthe ME, Rabian F, Yakouben K, Chevillon F, Cabannes-Hamy A, Méchinaud F, et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia. 2021;35:3383–93.
Lamble AJ, Myers RM, Taraseviciute A, John S, Yates B, Steinberg SM, et al. Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells. Blood Adv. 2023;7:575–85.
Myers RM, Li Y, Barz Leahy A, Barrett DM, Teachey DT, Callahan C, et al. Humanized CD19-targeted chimeric antigen receptor (CAR) T cells in CAR-Naive and CAR-exposed children and young adults with relapsed or refractory acute lymphoblastic leukemia. JCO. 2021;39:3044–55.
Pan J, Niu Q, Deng B, Liu S, Wu T, Gao Z, et al. CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia. 2019;33:2854–66.
Kamitori T, Umeda K, Akazawa R, Iwai A, Obu S, Isobe K, et al. Inotuzumab ozogamicin following allogeneic hematopoietic stem cell transplantation successfully rescued relapse of CD19-negative acute lymphoblastic leukemia after CAR-T cell therapy. Pediatr Blood Cancer. 2021;68:e28980.
Wudhikarn K, Flynn JR, Rivière I, Gönen M, Wang X, Senechal B, et al. Interventions and outcomes of adult patients with B-ALL progressing after CD19 chimeric antigen receptor T-cell therapy. Blood. 2021;138:531–43.
Schultz LM, Eaton A, Baggott C, Rossoff J, Prabhu S, Keating AK, et al. Outcomes after nonresponse and relapse post-tisagenlecleucel in children, adolescents, and young adults with B-cell acute lymphoblastic leukemia. JCO. 2023;41:354–63.
Oporto, Espuelas M, Burridge S, Kirkwood AA, Bonney D, Watts K, Shenton G, et al. Intention-to-treat outcomes utilising a stringent event definition in children and young people treated with tisagenlecleucel for r/r ALL through a national access scheme. Blood Cancer J. 2024;14:66.
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625–38.
Dourthe ME, Yakouben K, David A, Thouvenin S, Chaillou D, Caillat-Zucman S, et al. Success of donor-derived CAR-T cells after failure of autologous CD19 CAR-T cells (tisagenlecleucel) in B-cell acute lymphoblastic leukaemia. Br J Haematol. 2024;205:373–7.
Pulsipher MA, Han X, Maude SL, Laetsch TW, Qayed M, Rives S, et al. Next-generation sequencing of minimal residual disease for predicting relapse after tisagenlecleucel in children and young adults with acute lymphoblastic leukemia. Blood Cancer Discov. 2022;3:66–81.
Orlando EJ, Han X, Tribouley C, Wood PA, Leary RJ, Riester M, et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med. 2018;24:1504–6.
Ruella M, Xu J, Barrett DM, Fraietta JA, Reich TJ, Ambrose DE, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018;24:1499–503.
Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5:1282–95.
Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127:2406–10.
Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24:20–8.
Shah NN, Highfill SL, Shalabi H, Yates B, Jin J, Wolters PL, et al. CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase I anti-CD22 CAR T-cell trial. JCO. 2020;38:1938–50.
Acknowledgements
The authors would like to thank all the clinicians who referred patients to Robert Debré and Saint Louis University Hospitals (AP-HP) for apheresis and tisagenlecleucel treatment: Dr JF Brasme from Angers University Hospital; Dr S Ducassou, and Dr M Angoso from Bordeaux University Hospital; Dr G Guillerm from Brest University Hospital; Pr J Kanold-Lastawiecka from Clermont-Ferrand University Hospital; Dr M Leclerc from Créteil University Hospital; Dr Y Hatchuel from Fort de France University Hospital; Dr F Larcher from Grenoble University Hospital; Dr Y Reguerre from La Réunion University Hospital; Dr B Bruno, Dr E Deberranger, and Dr V Coiteux from Lille University Hospital; Dr N Garnier from Lyon University Hospital; Dr A Stérin, and Pr G Michel from Marseille University Hospital; Dr A Sirvent from Montpellier University Hospital; Dr C Pochon from Nancy University Hospital; Dr M Uzunov from La Pitié Salpétrière University Hospital, Paris; Dr N Maillard from Poitiers University Hospital; Pr V Gandemer from Rennes University Hospital; Pr P Schneider, and Dr F Jardin from Rouen University Hospital; Dr A David from Saint-Etienne University Hospital; Pr C Paillard from Strasbourg University Hospital; Dr G Plat from Toulouse University Hospital; Dr B Yvert, and Pr E Gyan from Tours University Hospital; Dr H Boutroux, Dr C Dollfus, Pr J Landman-Parker, Pr A Petit, and Dr P Tessaro from Armand-Trousseau University Hospital, Paris; Dr U Overgaard from University Hospital of Copenhagen.
Author information
Authors and Affiliations
Contributions
NL, ABaruchel, and NB conceived the study and oversaw the project; NL, FR, M-ED, KY, FC, IR, ND, DC, EL, JN, JR-S, NP, ABrignier, VG-EK, EA, JHD, IM, JL, ABaruchel and NB provided patients or materials; SC-Z, EL AC-E, HC, EC, and SM provided biological analysis; NL, FR and M-ED collected and assembled data; NB performed statistical analysis; NL, ABaruchel and NB analyzed, interpreted data and wrote the manuscript. All authors approved the manuscript.
Corresponding author
Ethics declarations
Competing interests
NB received honoraria from Novartis, Amgen, ARIAD, Astellas, Servier and Pfizer. ABaruchel received honoraria from Novartis, Servier, Jazz, and Astra-Zeneca.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lecornec, N., Rabian, F., Dourthe, ME. et al. Characteristics and outcome determinants in children, adolescents and young adults who failed tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia (2026). https://doi.org/10.1038/s41375-026-02867-9
Received:
Revised:
Accepted:
Published:
Version of record:
DOI: https://doi.org/10.1038/s41375-026-02867-9
