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Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy. Blood Adv 2022 04 12;6(7):1961-1968

Date

11/18/2021

Pubmed ID

34788386

Pubmed Central ID

PMC9006295

DOI

10.1182/bloodadvances.2021006418

Scopus ID

2-s2.0-85128537799   5 Citations

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 a?Y13.8 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.

Author List

Fabrizio VA, Boelens JJ, Mauguen A, Baggott C, Prabhu S, Egeler E, Mavroukakis S, Pacenta H, Phillips CL, Rossoff J, Stefanski HE, Talano JA, Moskop A, Margossian SP, Verneris MR, Myers GD, Karras NA, Brown PA, Qayed M, Hermiston M, Satwani P, Krupski C, Keating AK, Wilcox R, Rabik CA, Chinnabhandar V, Kunicki M, Goksenin AY, Mackall CL, Laetsch TW, Schultz LM, Curran KJ

Authors

Amy Moskop MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
Julie-An M. Talano MD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Child
Child, Preschool
Humans
Immunotherapy, Adoptive
Infant
Prospective Studies
Recurrence
Retrospective Studies
Vidarabine
Young Adult