{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T06:30:23Z","timestamp":1793773823259,"version":"4.6.1"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In the absence of randomized controlled trials comparing tisagenlecleucel vs. standard of care (SOC) in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (r\/r ALL), the objective was to compare the efficacy of tisagenlecleucel with historical controls from multiple disease registries using patient-level adjustment of the historical controls. The analysis is based on patient-level data of three tisagenlecleucel studies (ELIANA, ENSIGN and CCTL019B2001X) vs. three registries in Germany\/Austria. Statistical analyses were fully pre-specified and propensity score weighting of the historical controls by fine stratification weights was used to adjust for relevant confounders identified by systematic literature review. Results showed high comparability of cohorts after adjustment with absolute SMD\u2009\u2264\u20090.1 for all pre-specified confounders and favorable outcomes for tisagenlecleucel compared to SOC for all examined endpoints. Hazard ratios for OS<jats:sub>(Intention to treat)ITT,adjusted<\/jats:sub>, EFS<jats:sub>(Full analysis set)FAS,na\u00efve<\/jats:sub> and RFS<jats:sub>FAS,na\u00efve<\/jats:sub> were 0.54 (95% CI: 0.41\u20130.71, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), 0.67 (0.52\u20130.86, <jats:italic>p<\/jats:italic>\u2009=\u20090.001) and 0.77 (0.51\u20131.18, <jats:italic>p<\/jats:italic>\u2009=\u20090.233). The OS<jats:sub>ITT, adjusted<\/jats:sub>, EFS<jats:sub>FAS,na\u00efve<\/jats:sub> and RFS<jats:sub>FAS,naive<\/jats:sub> survival probability at 2 years was 59.49% for tisagenlecleucel vs. 36.16% for SOC population, 42.31% vs. 30.23% and 59.60% vs. 54.57%, respectively. Odds ratio for ORR<jats:sub>ITT,adjusted<\/jats:sub> was 1.99 (1.33\u20132.97, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Results for OS and ORR were statistically significant after adjustment for confounders and provide evidence supporting a superiority of tisagenlecleucel in r\/r ALL given the good comparability of cohorts after adjustment for confounders.<\/jats:p>","DOI":"10.1038\/s41375-023-02042-4","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T15:03:09Z","timestamp":1698246189000},"page":"2346-2355","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Tisagenlecleucel vs. historical standard of care in children and young adult patients with relapsed\/refractory B-cell precursor acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8103-2631","authenticated-orcid":false,"given":"Arend","family":"v. 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Akute lymphatische Leuk\u00e4mie (ALL); 2022 [cited 2022 Jul 6]. Available from: https:\/\/www.onkopedia.com\/de\/onkopedia\/guidelines\/akute-lymphatische-leukaemie-all\/@@guideline\/html\/index.html."},{"key":"2042_CR2","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1007\/s00761-017-0249-z","volume":"23","author":"K Kraywinkel","year":"2017","unstructured":"Kraywinkel K, Spix C. Epidemiologie akuter Leuk\u00e4mien in Deutschland. Der Onkol. 2017;23:499\u2013503.","journal-title":"Der Onkol"},{"key":"2042_CR3","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1007\/s00108-014-3595-6","volume":"56","author":"N G\u00f6kbuget","year":"2015","unstructured":"G\u00f6kbuget N. Aktuelle Therapie der akuten lymphatischen Leuk\u00e4mie des Erwachsenen. Der Internist. 2015;56:344\u201353.","journal-title":"Der Internist"},{"key":"2042_CR4","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1200\/JCO.20.02529","volume":"39","author":"C Peters","year":"2021","unstructured":"Peters C, Dalle J-H, Locatelli F, Poetschger U, Sedlacek P, Buechner J, et al. Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. J Clin Oncol: Off J Am Soc Clin Oncol. 2021;39:295\u2013307.","journal-title":"J Clin Oncol: Off J Am Soc Clin Oncol"},{"key":"2042_CR5","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1200\/JCO.2014.58.9747","volume":"33","author":"C Peters","year":"2015","unstructured":"Peters C, Schrappe M, Stackelberg AV, Schrauder A, Bader P, Ebell W, et al. Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol: Off J Am Soc Clin Oncol. 2015;33:1265\u201374.","journal-title":"J Clin Oncol: Off J Am Soc Clin Oncol"},{"key":"2042_CR6","doi-asserted-by":"publisher","first-page":"2807","DOI":"10.1182\/blood-2012-02-265884","volume":"120","author":"F Locatelli","year":"2012","unstructured":"Locatelli F, Schrappe M, Bernardo ME, Rutella S. How I treat relapsed childhood acute lymphoblastic leukemia. Blood. 2012;120:2807\u201316.","journal-title":"Blood"},{"key":"2042_CR7","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-016-0519-8","volume":"18","author":"A Ronson","year":"2016","unstructured":"Ronson A, Tvito A, Rowe JM. Treatment of Relapsed\/Refractory Acute Lymphoblastic Leukemia in Adults. 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Medical writing was provided by Daniela Skalt, Stephanie Sussmann and Fabian Berkemeier. Statistical analyses were provided by Heidi Kulas and Guido Schiffhorst. These are employed by IGES Institut GmbH, which received financial support from Novartis Pharma GmbH for this research project. Katja\u00a0J\u00e4schke, Corinna\u00a0Templin, Ulli\u00a0Jeratsch and Daniela\u00a0Kosmides are employees from Novartis GmbH and Etienne Jousseaume from Novartis Pharma AG which sponsored the studies ELIANA, ENSIGN and CCTL019B2001X.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The current manuscript describes analyses using patient-level data from the ELIANA (NCT02435849), ENSIGN (NCT02228096) and CCTL019B2001X (NCT03123939) single arm studies, which have been previously published. This manuscript also uses data from the registries ALL-REZ BFM (Berlin), ALL-SCT BFM (Vienna) and GMALL (Frankfurt). This study was approved by the institutional review board of each participating institution.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Written informed consent was obtained by the patients\/guardians participating in the registries for participation in research projects. The data from the registries have been shared with the involved institute conducting the analyses for this study in a fully anonymized form.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}