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Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsed/refractory acute lymphoblastic leukemia


Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) patients suffer risk of chemotherapy-associated toxicities and poor outcomes. We evaluated tisagenlecleucel in 16 patients with DS-ALL in two phase 2 trials (ELIANA [NCT02435849], ENSIGN [NCT02228096]) and a phase 3b, managed access protocol (B2001X [NCT03123939]). Patients were 5–22 years old, had a median of two prior lines of therapy (range, 1–4), and four (25%) had prior stem cell transplants. Fourteen of 16 patients (88%) achieved complete remission (CR) or CR with incomplete blood count recovery (CRi); 12 of 14 (86%) with CR/CRi were minimal residual disease-negative. With a median follow-up of 13.2 months (range, 0.5–49.3 months), six patients (43%) relapsed after CR (three, CD19-negative; three, unknown) between 80–721 days post-infusion. Ongoing remissions in nine patients ranged from 6–48 months. Any-grade and grade 3/4 AEs occurred in 16 and 14 patients, respectively; 44% experienced grade 3/4 cytokine release syndrome and 13% experienced grade 3/4 neurological events. Grade 3/4 prolonged cytopenias occurred in 44% of patients. No grade 3/4 infections were observed. Tisagenlecleucel expansion and long-term persistence were consistent with previous reports. Comparable to ALL patients without DS, tisagenlecleucel produced high remission rates, manageable side-effects, and promising long-term outcomes in pediatric/young adult patients with DS-ALL.

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Fig. 1: Patients with DS-ALL were treated with tisagenlecleucel in three clinical studies.
Fig. 2: Relapse-free survival and overall survival by best overall response in patients with DS-ALL treated with tisagenlecleucel.
Fig. 3: Duration of response (A) and overall survival (B) of patients with DS.

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Medical writing support was provided by Michael Hobert, PhD, CMPP (Healthcare Consultancy Group) and was funded by Novartis Pharmaceuticals Corporation. This study was sponsored by Novartis Pharmaceuticals Corporation.

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All authors have contributed to the acquisition, analysis, or interpretation of data for this article; contributed to drafts of the article; revised the manuscript critically for important intellectual content; approved the final version to be published; and agreed to be accountable for all aspects of the article.

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Correspondence to Theodore W. Laetsch.

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Competing interests

TWL has received personal fees and nonfinancial support from Novartis, Cellectis, Bayer, Loxo Oncology, Eli Lilly, Deciphera, Jumo Health, and Y-mAbs Therapeutics; and research funding to his institution from Novartis, Pfizer, and Bayer. SLM has received clinical trial support from Novartis; and has served as a consultant or on advisory boards or study steering committees for Novartis, Kite, and Wugen. AB has received travel reimbursement and meeting support from Neovii and Medac; advisory board honorarium, speaker fees, and travel support from Novartis; and advisory board and speaker fees from Amgen. SR has received clinical trial support: consulting, advisory boards, travel reimbursement, and meeting support from Novartis, Shire/Servier, Cellectis, JazzPharma, Celgene, Kite/Gilead, and Amgen; and has served on a study steering committee for Novartis. HB has received consulting fees from Novartis Oncology, and personal fees and nonfinancial support from Jazz (outside the submitted work). MWB has received honoraria from Novartis. JB has received personal fees, advisory board/steering committee honoraria, and nonfinancial support from Novartis (during the conduct of the study); and advisory board honoraria from Pfizer, Kite, and Janssen (outside the submitted work). BDM has participated in an advisory board for Novartis; has received nonfinancial support from Articulate Science (during the conduct of the study); and has received nonfinancial support from Jazz Pharmaceuticals (outside the submitted work). MQ has received honoraria from Medexus, Jazz Pharmaceuticals, and Mesoblast, and has served as a consultant for Novartis. CLP has served as a member on the Board of Directors or Advisory Committees for Novartis and Incyte. MAP has received grants from Miltenyi and Adaptive; personal fees from Novartis, Adaptive, Mesoblast, Medexus, and Equillium. HH has received clinical trials support from Novartis. RT is an employee of Novartis. SAG has received grants and personal fees from Novartis, Jazz Pharmaceuticals, and CRISPR/Vertex; personal fees from Adaptimmune, TCR2 Therapeutics, Eureka Therapeutics, Cellectis, Roche, and Juno Therapeutics; and grants from Servier and Kite; and has been issued a patent for toxicity management for anti-tumor activity of CARs managed by the University of Pennsylvania.

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Laetsch, T.W., Maude, S.L., Balduzzi, A. et al. Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsed/refractory acute lymphoblastic leukemia. Leukemia 36, 1508–1515 (2022).

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