Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy
Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrel...
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| Veröffentlicht in: | Blood advances 2022-04, Vol.6 (7), p.1961-1968 |
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| creator | Fabrizio, Vanessa A. Boelens, Jaap Jan Mauguen, Audrey Baggott, Christina Prabhu, Snehit Egeler, Emily Mavroukakis, Sharon Pacenta, Holly Phillips, Christine L. Rossoff, Jenna Stefanski, Heather E. Talano, Julie-An Moskop, Amy Margossian, Steven P. Verneris, Michael R. Myers, Gary Douglas Karras, Nicole A. Brown, Patrick A. Qayed, Muna Hermiston, Michelle Satwani, Prakash Krupski, Christa Keating, Amy K. Wilcox, Rachel Rabik, Cara A. Chinnabhandar, Vasant Kunicki, Michael Goksenin, A. Yasemin Mackall, Crystal L. Laetsch, Theodore W. Schultz, Liora M. Curran, Kevin J. |
| description | Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, |
| doi_str_mv | 10.1182/bloodadvances.2021006418 |
| format | Article |
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•Optimal fludarabine exposure in those with relapsed/refractory B-cell ALL receiving CD19-specific CAR T-cell therapy was AUC ≥13.8 mg × h/L.•Suboptimal exposure led to a 2.5-fold higher risk of relapse and twofold higher risk of relapse/loss of B-cell aplasia.
[Display omitted]</description><identifier>ISSN: 2473-9529</identifier><identifier>ISSN: 2473-9537</identifier><identifier>EISSN: 2473-9537</identifier><identifier>DOI: 10.1182/bloodadvances.2021006418</identifier><identifier>PMID: 34788386</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Child ; Child, Preschool ; Clinical Trials and Observations ; Humans ; Immunotherapy, Adoptive - adverse effects ; Immunotherapy, Adoptive - methods ; Infant ; Prospective Studies ; Recurrence ; Retrospective Studies ; Vidarabine - analogs & derivatives ; Young Adult</subject><ispartof>Blood advances, 2022-04, Vol.6 (7), p.1961-1968</ispartof><rights>2022 The American Society of Hematology</rights><rights>2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.</rights><rights>2022 by The American Society of Hematology. Licensed under , permitting only noncommercial, nonderivative use with attribution. All other rights reserved. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c534t-e10a44f4f5dfa9d7818b1019f04dd2a6d851c341faa5a8cf809a9d0d858ccbe93</citedby><cites>FETCH-LOGICAL-c534t-e10a44f4f5dfa9d7818b1019f04dd2a6d851c341faa5a8cf809a9d0d858ccbe93</cites><orcidid>0000-0002-8653-1069 ; 0000-0003-0359-9023 ; 0000-0003-2232-6952 ; 0000-0002-8497-3138 ; 0000-0001-8589-3087 ; 0000-0002-7097-5917 ; 0000-0002-3337-9956 ; 0000-0003-0471-9883 ; 0000-0003-3236-6093</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006295/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006295/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34788386$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fabrizio, Vanessa A.</creatorcontrib><creatorcontrib>Boelens, Jaap Jan</creatorcontrib><creatorcontrib>Mauguen, Audrey</creatorcontrib><creatorcontrib>Baggott, Christina</creatorcontrib><creatorcontrib>Prabhu, Snehit</creatorcontrib><creatorcontrib>Egeler, Emily</creatorcontrib><creatorcontrib>Mavroukakis, Sharon</creatorcontrib><creatorcontrib>Pacenta, Holly</creatorcontrib><creatorcontrib>Phillips, Christine L.</creatorcontrib><creatorcontrib>Rossoff, Jenna</creatorcontrib><creatorcontrib>Stefanski, Heather E.</creatorcontrib><creatorcontrib>Talano, Julie-An</creatorcontrib><creatorcontrib>Moskop, Amy</creatorcontrib><creatorcontrib>Margossian, Steven P.</creatorcontrib><creatorcontrib>Verneris, Michael R.</creatorcontrib><creatorcontrib>Myers, Gary Douglas</creatorcontrib><creatorcontrib>Karras, Nicole A.</creatorcontrib><creatorcontrib>Brown, Patrick A.</creatorcontrib><creatorcontrib>Qayed, Muna</creatorcontrib><creatorcontrib>Hermiston, Michelle</creatorcontrib><creatorcontrib>Satwani, Prakash</creatorcontrib><creatorcontrib>Krupski, Christa</creatorcontrib><creatorcontrib>Keating, Amy K.</creatorcontrib><creatorcontrib>Wilcox, Rachel</creatorcontrib><creatorcontrib>Rabik, Cara A.</creatorcontrib><creatorcontrib>Chinnabhandar, Vasant</creatorcontrib><creatorcontrib>Kunicki, Michael</creatorcontrib><creatorcontrib>Goksenin, A. Yasemin</creatorcontrib><creatorcontrib>Mackall, Crystal L.</creatorcontrib><creatorcontrib>Laetsch, Theodore W.</creatorcontrib><creatorcontrib>Schultz, Liora M.</creatorcontrib><creatorcontrib>Curran, Kevin J.</creatorcontrib><title>Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy</title><title>Blood advances</title><addtitle>Blood Adv</addtitle><description>Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n = 131 of 152), 12-month OS of 75.1% (95% confidence interval [CI], 67.6% to 82.6%), and 12-month CIR of 36.4% (95% CI, 27.5% to 45.2%). Optimal fludarabine exposure was determined as AUC ≥13.8 mg × h/L. In multivariable analyses, patients with AUC <13.8 mg × h/L had a 2.5-fold higher CIR (hazard ratio [HR], 2.45; 95% CI, 1.34-4.48; P = .005) and twofold higher risk of relapse or loss of BCA (HR, 1.96; 95% CI, 1.19-3.23; P = .01) compared with those with optimal fludarabine exposure. High preinfusion disease burden was also associated with increased risk of relapse (HR, 2.66; 95% CI, 1.45-4.87; P = .001) and death (HR, 4.77; 95% CI, 2.10-10.9; P < .001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy.
•Optimal fludarabine exposure in those with relapsed/refractory B-cell ALL receiving CD19-specific CAR T-cell therapy was AUC ≥13.8 mg × h/L.•Suboptimal exposure led to a 2.5-fold higher risk of relapse and twofold higher risk of relapse/loss of B-cell aplasia.
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Yasemin</creatorcontrib><creatorcontrib>Mackall, Crystal L.</creatorcontrib><creatorcontrib>Laetsch, Theodore W.</creatorcontrib><creatorcontrib>Schultz, Liora M.</creatorcontrib><creatorcontrib>Curran, Kevin J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fabrizio, Vanessa A.</au><au>Boelens, Jaap Jan</au><au>Mauguen, Audrey</au><au>Baggott, Christina</au><au>Prabhu, Snehit</au><au>Egeler, Emily</au><au>Mavroukakis, Sharon</au><au>Pacenta, Holly</au><au>Phillips, Christine L.</au><au>Rossoff, Jenna</au><au>Stefanski, Heather E.</au><au>Talano, Julie-An</au><au>Moskop, Amy</au><au>Margossian, Steven P.</au><au>Verneris, Michael R.</au><au>Myers, Gary Douglas</au><au>Karras, Nicole A.</au><au>Brown, Patrick A.</au><au>Qayed, Muna</au><au>Hermiston, Michelle</au><au>Satwani, Prakash</au><au>Krupski, Christa</au><au>Keating, Amy K.</au><au>Wilcox, Rachel</au><au>Rabik, Cara A.</au><au>Chinnabhandar, Vasant</au><au>Kunicki, Michael</au><au>Goksenin, A. Yasemin</au><au>Mackall, Crystal L.</au><au>Laetsch, Theodore W.</au><au>Schultz, Liora M.</au><au>Curran, Kevin J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy</atitle><jtitle>Blood advances</jtitle><addtitle>Blood Adv</addtitle><date>2022-04-12</date><risdate>2022</risdate><volume>6</volume><issue>7</issue><spage>1961</spage><epage>1968</epage><pages>1961-1968</pages><issn>2473-9529</issn><issn>2473-9537</issn><eissn>2473-9537</eissn><abstract>Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n = 131 of 152), 12-month OS of 75.1% (95% confidence interval [CI], 67.6% to 82.6%), and 12-month CIR of 36.4% (95% CI, 27.5% to 45.2%). Optimal fludarabine exposure was determined as AUC ≥13.8 mg × h/L. In multivariable analyses, patients with AUC <13.8 mg × h/L had a 2.5-fold higher CIR (hazard ratio [HR], 2.45; 95% CI, 1.34-4.48; P = .005) and twofold higher risk of relapse or loss of BCA (HR, 1.96; 95% CI, 1.19-3.23; P = .01) compared with those with optimal fludarabine exposure. High preinfusion disease burden was also associated with increased risk of relapse (HR, 2.66; 95% CI, 1.45-4.87; P = .001) and death (HR, 4.77; 95% CI, 2.10-10.9; P < .001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy.
•Optimal fludarabine exposure in those with relapsed/refractory B-cell ALL receiving CD19-specific CAR T-cell therapy was AUC ≥13.8 mg × h/L.•Suboptimal exposure led to a 2.5-fold higher risk of relapse and twofold higher risk of relapse/loss of B-cell aplasia.
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>34788386</pmid><doi>10.1182/bloodadvances.2021006418</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-8653-1069</orcidid><orcidid>https://orcid.org/0000-0003-0359-9023</orcidid><orcidid>https://orcid.org/0000-0003-2232-6952</orcidid><orcidid>https://orcid.org/0000-0002-8497-3138</orcidid><orcidid>https://orcid.org/0000-0001-8589-3087</orcidid><orcidid>https://orcid.org/0000-0002-7097-5917</orcidid><orcidid>https://orcid.org/0000-0002-3337-9956</orcidid><orcidid>https://orcid.org/0000-0003-0471-9883</orcidid><orcidid>https://orcid.org/0000-0003-3236-6093</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2473-9529 |
| ispartof | Blood advances, 2022-04, Vol.6 (7), p.1961-1968 |
| issn | 2473-9529 2473-9537 2473-9537 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9006295 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Adolescent Adult Child Child, Preschool Clinical Trials and Observations Humans Immunotherapy, Adoptive - adverse effects Immunotherapy, Adoptive - methods Infant Prospective Studies Recurrence Retrospective Studies Vidarabine - analogs & derivatives Young Adult |
| title | Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-04T06%3A52%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Optimal%20fludarabine%20lymphodepletion%20is%20associated%20with%20improved%20outcomes%20after%20CAR%20T-cell%20therapy&rft.jtitle=Blood%20advances&rft.au=Fabrizio,%20Vanessa%20A.&rft.date=2022-04-12&rft.volume=6&rft.issue=7&rft.spage=1961&rft.epage=1968&rft.pages=1961-1968&rft.issn=2473-9529&rft.eissn=2473-9537&rft_id=info:doi/10.1182/bloodadvances.2021006418&rft_dat=%3Cproquest_pubme%3E2599070678%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2599070678&rft_id=info:pmid/34788386&rft_els_id=S2473952921008089&rfr_iscdi=true |