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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; [...]

Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy

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  • Medientyp: E-Artikel
  • Titel: Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy
  • Beteiligte: 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; [...]
  • Erschienen: American Society of Hematology, 2022
  • Erschienen in: Blood Advances
  • Sprache: Englisch
  • DOI: 10.1182/bloodadvances.2021006418
  • ISSN: 2473-9529; 2473-9537
  • Schlagwörter: Hematology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>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, &amp;lt;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 &amp;lt;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 &amp;lt; .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.</jats:p>
  • Zugangsstatus: Freier Zugang