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Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients

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Abstract

Purpose

Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine’s metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4+ and CD8+ cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients.

Methods

Participants with hematologic diseases were conditioned with fludarabine and low-dose total body irradiation (TBI) followed by allogeneic HCT and post-grafting immunosuppression. After fludarabine administration, we evaluated pharmacological biomarkers for fludarabine—F-ara-A area under the curve (AUC) and the ratio of circulating CD4+ and CD8+ cells (CD4+/CD8+ ratio) after fludarabine administration—in 102 patients; F-ara-ATP accumulation rate in enriched CD4+ and CD8+ cells was evaluated in 36 and 34 patients, respectively.

Results

Interpatient variability in the pharmacological biomarkers was high, ranging from 3.7-fold (F-ara-A AUC) to 39-fold (F-ara-ATP in CD8+ cells). Circulating CD8+ cells were more sensitive to fludarabine administration. A population pharmacokinetic-based sampling schedule successfully allowed for estimation of F-ara-A AUC in this outpatient population. There was a poor correlation between the F-ara-AUC and the F-ara-ATP accumulation rate in CD4+ (R 2 = 0.01) and CD8+ cells (R 2 = 0.00). No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality).

Conclusions

Considerable interpatient variability exists in pharmacokinetic and fludarabine-based biomarkers, but these biomarkers are not associated with clinical outcomes in fludarabine/TBI-conditioned patients.

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Acknowledgments

The authors are very grateful to the patients who participated in this study. The authors also wish to thank all physicians, nurses, and support personnel for their care of patients on this study. The efforts of Ms. Linda Risler and Mr. Brian Phillips for F-ara-A and F-ara-ATP quantification are acknowledged, as are the efforts of Dr. Brent Wood and the University of Washington Hematopathology Laboratory for the quantitation of circulating CD4+ and CD8+ cells. This work was supported by the following Grants from the National Institutes of Health: NHLBI (HL91744, HL36444), NCI (CA15704 (core), CA18029, CA78902), NIBIB (EB001975), and NIDDK (DK56465).

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Jeannine S. McCune, Brenda M. Sandmaier, Barry E. Storer & Shelly Heimfeld

  2. School of Pharmacy, University of Washington, Seattle, WA, USA

    Jeannine S. McCune & Meagan J. Bemer

  3. School of Medicine, University of Washington, Seattle, WA, USA

    Brenda M. Sandmaier

  4. Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA

    Donald E. Mager

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  1. Jeannine S. McCune
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  2. Donald E. Mager
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  4. Brenda M. Sandmaier
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  5. Barry E. Storer
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Correspondence to Jeannine S. McCune.

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McCune, J.S., Mager, D.E., Bemer, M.J. et al. Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. Cancer Chemother Pharmacol 76, 85–96 (2015). https://doi.org/10.1007/s00280-015-2768-x

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  • DOI: https://doi.org/10.1007/s00280-015-2768-x

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