TY - JOUR
T1 - Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy
AU - Fabrizio, Vanessa A.
AU - Boelens, Jaap Jan
AU - Mauguen, Audrey
AU - Baggott, Christina
AU - Prabhu, Snehit
AU - Egeler, Emily
AU - Mavroukakis, Sharon
AU - Pacenta, Holly
AU - Phillips, Christine L.
AU - Rossoff, Jenna
AU - Stefanski, Heather E.
AU - Talano, Julie An
AU - Moskop, Amy
AU - Margossian, Steven P.
AU - Verneris, Michael R.
AU - Myers, Gary Douglas
AU - Karras, Nicole A.
AU - Brown, Patrick A.
AU - Qayed, Muna
AU - Hermiston, Michelle
AU - Satwani, Prakash
AU - Krupski, Christa
AU - Keating, Amy K.
AU - Wilcox, Rachel
AU - Rabik, Cara A.
AU - Chinnabhandar, Vasant
AU - Kunicki, Michael
AU - Goksenin, A. Yasemin
AU - Mackall, Crystal L.
AU - Laetsch, Theodore W.
AU - Schultz, Liora M.
AU - Curran, Kevin J.
N1 - Publisher Copyright:
© 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.
PY - 2022/4/12
Y1 - 2022/4/12
N2 - 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 5 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n 5 131 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%).
AB - 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 5 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n 5 131 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%).
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U2 - 10.1182/bloodadvances.2021006418
DO - 10.1182/bloodadvances.2021006418
M3 - Article
C2 - 34788386
AN - SCOPUS:85128537799
SN - 2473-9529
VL - 6
SP - 1961
EP - 1968
JO - Blood Advances
JF - Blood Advances
IS - 7
ER -