{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:36:11Z","timestamp":1785213371348,"version":"3.55.0"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:00:00Z","timestamp":1718323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg\/m<jats:sup>2<\/jats:sup> and cyclophosphamide 500 mg\/m<jats:sup>2<\/jats:sup> for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg\/m<jats:sup>2<\/jats:sup> and cyclophosphamide 500 mg\/m<jats:sup>2<\/jats:sup> for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>From June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin\u2019s lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2\u20134 cytokine release syndrome (55% vs 50%, p=0.82), grade 2\u20134 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>As the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1403145","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T14:42:36Z","timestamp":1721400156000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Comparing 2-day vs 3-day flu-CY lymphodepleting regimens for CD19 CAR T-cell therapy in patients with non-hodgkin\u2019s lymphoma"],"prefix":"10.3389","volume":"15","author":[{"given":"David G.","family":"Frame","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Geer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salena","family":"Kasha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Markstrom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Scappaticci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tate","family":"Feeney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Hayduk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary M.","family":"Mansoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avery","family":"Oberfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"D\u2019Antonio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Anand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Won","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Maciejewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attaphol","family":"Pawarode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Mansour","family":"Riwes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muneesh","family":"Tewari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Magenau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monalisa","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1303935","article-title":"Lymphodepletion \u2013 an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle","volume":"14","author":"Lickefett","year":"2023","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2013021-00476\u20132","article-title":"Immunogenicity of CAR T cells in cancer therapy","volume":"18","author":"Wagner","year":"2021","journal-title":"Nat Rev Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.09.009","article-title":"In vivo fate and activity of second- versus third-generation CD19-specific CAR-T cells in B cell non-Hodgkin\u2019s lymphomas","volume":"26","author":"Ramos","year":"2018","journal-title":"Mol Ther"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707447","article-title":"Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma","volume":"377","author":"Neelapu","year":"2017","journal-title":"New Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20136736(22)00662\u20136","article-title":"Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial","volume":"399","author":"Kamdar","year":"2022","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20136736(20)31366\u20130","article-title":"Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study","volume":"396","author":"Abramson","year":"2020","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2013021-01622\u20130","article-title":"Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial","volume":"28","author":"Fowler","year":"2022","journal-title":"Nat Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709866","article-title":"Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia","volume":"378","author":"Maude","year":"2018","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023010302","article-title":"Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma","volume":"7","author":"Scordo","year":"2023","journal-title":"Blood Adv"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021006418","article-title":"Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy","volume":"6","author":"Fabrizio","year":"2022","journal-title":"Blood Adv"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V110.11.1192.1192","article-title":"In vitro toxicity of fludarabine on normal bone marrow (BM) progenitors suggests its involvement in the impairment of hematopoietic progenitor (HP) mobilization","volume":"110","author":"Richard","year":"2007","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.54.8800","article-title":"Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification","volume":"32","author":"Cheson","year":"2014","journal-title":"J Clin Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2013018-0715\u20139","article-title":"Population pharmacokinetics of fludarabine in children and adults during conditioning prior to allogeneic hematopoietic cell transplantation","volume":"58","author":"Langenhorst","year":"2019","journal-title":"Clin Pharmacokinet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"355ra116","DOI":"10.1126\/scitranslmed.aaf8621","article-title":"Immunotherapy of non-Hodgkin lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells","volume":"8","author":"Turtle","year":"2016","journal-title":"Sci Transl Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.12.758","article-title":"ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells","volume":"25","author":"Lee","year":"2019","journal-title":"Biol Blood marrow Transplant"},{"key":"B16","doi-asserted-by":"publisher","first-page":"4821","DOI":"10.1182\/blood-2021\u2013153457","article-title":"Successful development of an outpatient chimeric antigen receptor (CAR) T cell therapy program","volume":"138","author":"Borogovac","year":"2021","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","first-page":"4828","DOI":"10.1182\/blood-2021\u2013146283","article-title":"Feasibility of outpatient CAR T cell therapy: experience of a single institution","volume":"138","author":"Shao","year":"2021","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022\u2013159645","article-title":"Lisocabtagene maraleucel (Liso-cel) in patients with relapsed or refractory (R\/R) large B-cell lymphoma (LBCL) treated as outpatients or inpatients in the community\/nonuniversity setting: patient-reported outcomes\/health-related quality of life from the outreach study","volume":"140","author":"Linhares","year":"2022","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2020\u2013141415","article-title":"Costs of postinfusion monitoring by site of care for patients with relapsed\/refractory (R\/R) large B-cell lymphoma (LBCL) who received third-line or later treatment with lisocabtagene maraleucel (liso-cel) in the transcend NHL 001 and outreach trials","volume":"136","author":"Palomba","year":"2020","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.02104","article-title":"Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US lymphoma CAR T consortium","volume":"38","author":"Nastoupil","year":"2020","journal-title":"J Clin Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020001837","article-title":"Bridging therapy prior to axicabtagene ciloleucel for relapsed\/refractory large B-cell lymphoma","volume":"4","author":"Pinnix","year":"2020","journal-title":"Blood Adv"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.05.521","article-title":"Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas","volume":"33","author":"Ghilardi","year":"2022","journal-title":"Ann Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023011492","article-title":"Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and associates with reduced inflammatory cytokines","volume":"8","author":"Ghilardi","year":"2024","journal-title":"Blood Adv"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1403145\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T14:42:39Z","timestamp":1721400159000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1403145\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,14]]},"references-count":23,"alternative-id":["10.3389\/fimmu.2024.1403145"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1403145","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,14]]},"article-number":"1403145"}}