Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy

Takuto Takahashi, Aileen Scheibner, Qing Cao, Rachael Pearson, Kinjal Sanghavi, Daniel J. Weisdorf, Claudio G. Brunstein, John Rogosheske, Veronika Bachanova, Erica D. Warlick, Anthony Wiseman, Pamala A. Jacobson

Research output: Contribution to journalArticlepeer-review

Abstract

Reduced-intensity conditioning regimens using fludarabine (Flu) and cyclophosphamide (Cy) have been widely used in hematopoietic cell transplantation (HCT) recipients. The optimal exposure of these agents remains to be determined. We aimed to delineate the exposure-outcome associations of Flu and Cy separately and then both combined on HCT outcomes. This is a single-center, observational, pharmacokinetic (PK)-pharmacodynamic (PD) study of Flu and Cy in HCT recipients age ≥18 years who received Cy (50 mg/kg in a single dose), Flu (150 to 200 mg/m 2 given as 5 daily doses), and total body irradiation (TBI; 200 cGy). We measured trough concentrations of 9-β-D-arabinosyl-2-fluoradenine (F-ara-A), an active metabolite of Flu, on days -5 and -4 (F-ara-A Day-5 and F-ara-A Day-4, respectively), and measured phosphoramide mustard (PM), the final active metabolite of Cy, and estimated the area under the curve (AUC). The 89 enrolled patients had a nonrelapse mortality (NRM) of 9% (95% confidence interval [CI], 3% to 15%) at day +100 and 15% (95% CI, 7% to 22%) at day +180, and an overall survival (OS) of 73% (95% CI, 63% to 81%) at day +180. In multivariate analysis, higher PM area under the curve (AUC) for 0 to 8 hours (PM AUC 0-8 hr) was an independent predictor of worse NRM (P < .01 at both day +100 and day +180) and worse day +180 OS (P < .01), but no associations were identified for F-ara-A trough levels. We observed lower day +100 NRM in those with both high F-ara-A Day-4 trough levels (≥40 ng/mL; >25th percentile) and low PM AUC 0-8 hr (<34,235 hr ng/mL; <75th percentile), compared with high exposures to both agents (hazard ratio, 0.06; 95% CI, 0.01 to 0.48). No patients with low F-ara-A Day-4 (<40 ng/mL; <25th percentile) had NRM by day +100, regardless of PM AUC. The interpatient PK variability was large in F-ara-A Day-4 trough and PM AUC 0-8 hr (29-fold and 5.0-fold, respectively). Flu exposure alone was not strongly associated with NRM or OS in this reduced Flu dose regimen; however, high exposure to both Flu and Cy was associated with a >16-fold higher NRM. These results warrant further investigation to optimize reduced-intensity regimens based on better PK-PD understanding and possible adaptation to predictable factors influencing drug clearance.

Original languageEnglish (US)
JournalTransplantation and Cellular Therapy
Volume27
Issue number9
Early online dateMay 24 2021
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
Financial disclosure: This work was supported in part by National Institutes of Health Grant P30 CA77598 utilizing the Masonic Cancer Center, University of Minnesota Biostatistics shared resource.

Funding Information:
The expert technical assistance of Jim Fisher is gratefully acknowledged. Financial disclosure: This work was supported in part by National Institutes of Health Grant P30 CA77598 utilizing the Masonic Cancer Center, University of Minnesota Biostatistics shared resource. Conflict of interest statement: C.B. has received research funding from Nant, Fate Therapeutics, and GamidaCell and has served as a consultant for AlloVir (Data Safety and Monitoring Board) and BlueRock Bio. Financial disclosure: See Acknowledgments on page XXX.

Publisher Copyright:
© 2021 The American Society for Transplantation and Cellular Therapy

Keywords

  • Noncompartmental analysis
  • Pharmacodynamic
  • Pharmacokinetic
  • Phosphoramide mustard
  • Reduced-intensity conditioning

PubMed: MeSH publication types

  • Journal Article

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