Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma

Michael Scordo*, Jessica R. Flynn, Mithat Gonen, Sean M. Devlin, Allison Parascondola, Ana Alarcon Tomas, Roni Shouval, Jamie Brower, David L. Porter, Stephen J. Schuster, Veronika Bachanova, Joseph Maakaron, Richard T. Maziarz, Andy I. Chen, Loretta J. Nastoupil, Joseph P. McGuirk, Olalekan O. Oluwole, Andrew Ip, Lori A. Leslie, Michael R. BishopPeter A. Riedell, Miguel Angel Perales

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Fludarabine is one of the most common agents given for lymphodepletion before CD19 chimeric antigen receptor T cells, but its optimal therapeutic intensity is unknown. Using data from a multicenter consortium, we estimated fludarabine exposure (area under the curve [AUC]) using a population pharmacokinetic (PK) model in 199 adult patients with aggressive B-cell non-Hodgkin lymphomas who received commercial axicabtagene ciloleucel (Axi-cel). We evaluated the association of estimated fludarabine AUC with key outcomes, aiming to find an AUC that optimized efficacy and tolerability. We identified low (<18 mg × hour/L [mgh/L]), optimal (18-20 mgh/L), and high (>20 mgh/L) AUC groups for analyses; the 6-month cumulative incidences of relapse/progression of disease (relapse/ POD) by AUC groups were 54% (45%-62%), 28% (15%-44%), and 30% (14%-47%), respectively; and the 1-year progression-free survival (PFS) rates were 39% (31%-48%), 66% (52%-84%), and 46% (30%-70%) and the overall survival (OS) rates were 58% (50%-67%), 77% (64%-92%), and 66% (50%-87%), respectively. In multivariable analyses compared with low AUC, an optimal AUC was associated with the highest PFS (hazard ratio [HR], 0.52; 0.3-0.91; P = .02) and lowest risk of relapse/POD (HR, 0.46; 0.25-0.84; P = .01) without an increased risk of any-grade cytokine release syndrome (HR, 1.1; 0.7-1.6; P = .8) or and immune effector cell–associated neurotoxicity syndrome (ICANS) (HR, 1.36; 0.83-2.3; P = .2). A high AUC was associated with the greatest risk of any-grade ICANS (HR, 1.9; 1.1-3.2; P = .02). Although the main cause of death in all groups was relapse/POD, nonrelapse-related deaths, including 3 deaths from ICANS, were more frequent in the high AUC group. These findings suggest that PK–directed fludarabine dosing to achieve an optimal AUC may result in improved outcomes for patients receiving axi-cel.

Original languageEnglish
Pages (from-to)5579-5585
Number of pages7
JournalBlood advances
Volume7
Issue number18
DOIs
StatePublished - 26 Sep 2023
Externally publishedYes

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