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


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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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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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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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).

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