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ACUTE LYMPHOBLASTIC LEUKEMIA

Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia

Leukemia volume 35, pages 3383–3393 (2021)Cite this article

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Abstract

Tisagenlecleucel therapy has shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, relapses occur in 30–50% of patients. Determinants for CD19pos versus CD19neg relapses are poorly characterized. We report on 51 patients with R/R BCP-ALL (median age 17 years) infused with tisagenlecleucel after lymphodepletion. Complete remission rate at D28 was 96%. Prior blinatumomab increased the risk of early failure at D28. The 18-month cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 51%, 44%, and 74%, respectively, at a median follow-up of 15.5 months. Factors associated with a high tumor burden (occurrence of cytokine release syndrome) and prior blinatumomab were associated with an increased CIR, and a shorter EFS and OS. Pre-lymphodepletion high disease burden (MRD ≥ 10–2, SHR 10.4, p = 0.03) and detectable MRD at D28 (SHR 7.2, p = 0.006) correlated with an increased risk of CD19neg relapse. Low disease burden (SHR 5.3, p = 0.03) and loss of B-cell aplasia (BCA) (SHR 21.7, p = 0.004) predicted an increased risk of CD19pos relapses. These data highlight the impact of prior therapy on patient outcome. Finally, detectable MRD at D28 and loss of BCA both define patients at high risk of relapse for whom additional interventions are needed.

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Fig. 1: Overall outcome of the cohort.
Fig. 2: Outcome according to prior blinatumomab exposure.
Fig. 3: Impact of loss of B-cell aplasia and prior tisagenlecleucel MRD on relapse CD19 phenotype.
Fig. 4: Impact of prior tisagenlecleucel tumor burden on the loss of B-cell aplasia (L-BCA).

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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 B Gruson from Amiens University Hospital; Dr JF Brasme from Angers University Hospital; Dr A Berceanun, Dr N Cheikh from Besancon University Hospital; Dr S Ducassou and Dr C Jubert from Bordeaux University Hospital; Dr G Guillerm from Brest University Hospital; Pr Justyna Kanold from Clermont-Ferrand University Hospital; Dr M Leclerc from Créteil University Hospital; Dr Y Hatchuel from Fort de France University Hospital; Dr Y Reguerre from La Réunion University Hospital; Dr C Berthon, Dr B Bruno, Dr E Deberranger, and Dr V Coiteux from Lille University Hospital; Dr MV Larcher from Lyon University Hospital; Dr Curtillet, Dr C Galambrun, Dr A Stérin, and Pr G Michel from Marseille University Hospital; Dr C Pochon and Dr C Schmitt from Nancy University Hospital; Dr L Legros from Nice University Hospital; Dr M Uzunov from La Pitié Salpétrière University Hospital, Paris; Dr N Maillard from Poitiers University Hospital; Pr V Gandemer and Pr T Lamy de la Chapelle from Rennes University Hospital; Dr N Buchbinder, Pr P Schneider, Dr F Jardin, and Dr AL Menard from Rouen University Hospital; Pr C Paillard from Strasbourg University Hospital; Dr F Huguet and Dr G Plat from Toulouse University Hospital; Pr E Gyan from Tours University Hospital; Dr H Boutroux, Dr C Dollfus, Dr J Donadieu, Dr M Simonin, Pr Petit, and Pr Leverger from Armand-Trousseau University Hospital, Paris; Dr U Overgaard from University Hospital of Copenhagen.

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Author notes

  1. These authors contributed equally: Marie-Emilie Dourthe, Florence Rabian

  2. These authors contributed equally: Nicolas Boissel, André Baruchel

Authors and Affiliations

  1. Department of Pediatric Hematology and Immunology, AP-HP, Hôpital Universitaire Robert Debré, Paris, France

    Marie-Emilie Dourthe, Karima Yakouben, Françoise Méchinaud, Audrey Grain, Delphine Chaillou, Julie Roupret-Serzec, Jean Hugues Dalle & André Baruchel

  2. Laboratory of Onco-Hematology, AP-HP, Hôpital Necker Enfants-Malades, Université de Paris, Institut Necker-Enfants Malades (INEM), INSERM U1151, Paris, France

    Marie-Emilie Dourthe

  3. Unité d’Hématologie Adolescents et Jeunes Adultes, AP-HP, Hôpital Saint Louis, Paris, France

    Florence Rabian, Florian Chevillon, Nathalie Dhédin & Nicolas Boissel

  4. Hematology Unit, Versailles Hospital, Versailles, France

    Aurélie Cabannes-Hamy

  5. Hematology Unit, AP-HP, Hôpital Necker Enfants-Malades, Paris, France

    Ilhem Rahal

  6. Laboratory of Immunology, AP-HP, Hôpital Saint Louis, INSERM UMR1149, Université de Paris, Paris, France

    Sophie Caillat-Zucman

  7. Etablissement Français du Sang, AP-HP, Hôpital Universitaire Robert Debré, Paris, France

    Emmanuelle Lesprit

  8. Pediatric Intensive Care Unit, AP-HP, Hôpital Universitaire Robert Debré, Paris, France

    Jérôme Naudin

  9. Therapeutic Apheresis Unit, AP-HP, Hôpital Saint Louis, Paris, France

    Nathalie Parquet & Anne Brignier

  10. Laboratory of Immunology, AP-HP, Hôpital Universitaire Robert Debré, Université de Paris, Paris, France

    Valérie Guérin-El Khourouj

  11. Laboratory of Hematology, AP-HP, Hôpital Universitaire Robert Debré, Université de Paris, Paris, France

    Elodie Lainey

  12. Department of Genetics, AP-HP, Hôpital Universitaire Robert Debré, Université de Paris, Paris, France

    Aurélie Caye-Eude & Hélène Cavé

  13. UMRS 1131, Institut de Recherche Saint-Louis, INSERM, Université de Paris, Paris, France

    Hélène Cavé

  14. Hematology Laboratory, AP-HP, Hôpital Saint Louis, Paris, France

    Emmanuelle Clappier & Stéphanie Mathis

  15. INSERM U944/CNRS UMR7212, Institut de Recherche Saint-Louis, Université de Paris, Paris, France

    Emmanuelle Clappier

  16. Intensive Care Unit, AP-HP, Hôpital Saint Louis, Université de Paris, Paris, France

    Elie Azoulay

  17. Pharmacy Department, AP-HP, Hôpital Saint Louis, Paris, France

    Isabelle Madelaine

  18. Unité de Thérapie Cellulaire et Centre MEARY de Thérapie Cellulaire et Génique, Université de Paris, AP-HP, Hôpital Saint-Louis, U976 et CICBT, INSERM, Paris, France

    Jérôme Larghero

  19. EA3518, Institut de Recherche Saint-Louis, Université de Paris, Paris, France

    Nicolas Boissel & André Baruchel

Authors
  1. Marie-Emilie Dourthe
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Contributions

M-ED, FR, NB, and ABaruchel conceived the study and oversaw the project; M-ED, FR, KY, FC, AC-H, IR, ND, DC, EL, JN, JR-S, NP, ABrignier, VG-EK, EA, JHD, IM, JL, NB, and ABaruchel provided patients or materials; SC-Z, EL AC-E, HC, EC, and SM provided biological analysis; M-ED, FR, and AC-H collected and assembled data; NB performed statistical analysis, M-ED, FR, NB, and ABaruchel analyzed and interpreted data; M-ED, FR, NB, and ABaruchel wrote the manuscript. All authors approved the manuscript.

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Correspondence to André Baruchel.

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Conflict of interest

NB receives honoraria from Novartis, Amgen, and Pfizer. ABaruchel receives honoraria from Novartis, Celgene, Servier, Jazz, and Astra-Zeneca.

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Dourthe, ME., Rabian, F., Yakouben, K. et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia 35, 3383–3393 (2021). https://doi.org/10.1038/s41375-021-01281-7

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