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Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy.
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.
Afiliação
  • 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.
  • Mauguen A; Department of Pediatrics, Weill Cornell Medical College, New York, NY.
  • Baggott C; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Prabhu S; Division of Hematology and Oncology, Department of Pediatrics, 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; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
  • Phillips CL; Department of Pediatrics, University of Texas Southwestern Medical Center/Children's Health, Dallas, TX.
  • Rossoff J; Division of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX.
  • Stefanski HE; Department of Pediatrics, University of Cincinnati, Cincinnati, OH.
  • Talano JA; Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
  • Moskop A; Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
  • Margossian SP; Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN.
  • Verneris MR; Department of Pediatric Hematology Oncology, Medical College of Wisconsin, Wauwatosa, WI.
  • Myers GD; Department of Pediatric Hematology Oncology, Medical College of Wisconsin, Wauwatosa, WI.
  • Karras NA; Pediatric Hematology-Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA.
  • Brown PA; Colorado Children's Hospital, Anschutz Medical Campus, University of Colorado, Aurora, CO.
  • Qayed M; Children's Mercy Hospital, Kansas City, MO.
  • Hermiston M; Department of Pediatrics, City of Hope National Medical Center, Duarte, CA.
  • Satwani P; Department of Oncology, Sidney Kimmel Cancer Center, John Hopkins School of Medicine, Baltimore, MD.
  • Krupski C; Children's Healthcare of Atlanta, Emory University, Atlanta, GA.
  • Keating AK; Benioff Children's Hospital, University of California San Francisco, San Francisco, CA.
  • Wilcox R; Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Medical Center, New York, NY.
  • Rabik CA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH.
  • Chinnabhandar V; Colorado Children's Hospital, Anschutz Medical Campus, University of Colorado, Aurora, CO.
  • Kunicki M; Children's Mercy Hospital, Kansas City, MO.
  • Goksenin AY; Department of Oncology, Sidney Kimmel Cancer Center, John Hopkins School of Medicine, Baltimore, MD.
  • Mackall CL; Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN.
  • Laetsch TW; Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
  • Schultz LM; Benioff Children's Hospital, University of California San Francisco, San Francisco, CA.
  • Curran KJ; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
Blood Adv ; 6(7): 1961-1968, 2022 04 12.
Article em En | MEDLINE | ID: mdl-34788386
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Imunoterapia Adotiva Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adolescent / Adult / Child / Child, preschool / Humans / Infant Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Imunoterapia Adotiva Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adolescent / Adult / Child / Child, preschool / Humans / Infant Idioma: En Ano de publicação: 2022 Tipo de documento: Article