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

Autor:	Fabrizio VA; Colorado Children's Hospital, Anschutz Medical Campus, University of Colorado, Aurora, CO., Boelens JJ; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.; Department of Pediatrics, Weill Cornell Medical College, New York, NY., Mauguen A; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY., Baggott C; Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA., Prabhu S; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA., Egeler E; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA., Mavroukakis S; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA., Pacenta H; Department of Pediatrics, University of Texas Southwestern Medical Center/Children's Health, Dallas, TX.; Division of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX., Phillips CL; Department of Pediatrics, University of Cincinnati, Cincinnati, OH.; Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH., Rossoff J; Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL., Stefanski HE; Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN., Talano JA; Department of Pediatric Hematology Oncology, Medical College of Wisconsin, Wauwatosa, WI., Moskop A; Department of Pediatric Hematology Oncology, Medical College of Wisconsin, Wauwatosa, WI., Margossian SP; Pediatric Hematology-Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA., Verneris MR; Colorado Children's Hospital, Anschutz Medical Campus, University of Colorado, Aurora, CO., Myers GD; Children's Mercy Hospital, Kansas City, MO., Karras NA; Department of Pediatrics, City of Hope National Medical Center, Duarte, CA., Brown PA; Department of Oncology, Sidney Kimmel Cancer Center, John Hopkins School of Medicine, Baltimore, MD., Qayed M; Children's Healthcare of Atlanta, Emory University, Atlanta, GA., Hermiston M; Benioff Children's Hospital, University of California San Francisco, San Francisco, CA., Satwani P; Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Medical Center, New York, NY., Krupski C; Department of Pediatrics, University of Cincinnati, Cincinnati, OH., Keating AK; Colorado Children's Hospital, Anschutz Medical Campus, University of Colorado, Aurora, CO., Wilcox R; Children's Mercy Hospital, Kansas City, MO., Rabik CA; Department of Oncology, Sidney Kimmel Cancer Center, John Hopkins School of Medicine, Baltimore, MD., Chinnabhandar V; Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN., Kunicki M; Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA., Goksenin AY; Benioff Children's Hospital, University of California San Francisco, San Francisco, CA., Mackall CL; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.; Division of Stem Cell Transplantation and Cell Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA., Laetsch TW; Department of Pediatrics, University of Texas Southwestern Medical Center/Children's Health, Dallas, TX.; Department of Pediatrics and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and.; Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA., Schultz LM; Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA., Curran KJ; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.; Department of Pediatrics, Weill Cornell Medical College, New York, NY.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2022 Apr 12; Vol. 6 (7), pp. 1961-1968.
DOI:	10.1182/bloodadvances.2021006418
Abstrakt:	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. (© 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.)
Databáze:	MEDLINE
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