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A pilot pharmacologic biomarker study in HLA-haploidentical hematopoietic cell transplant recipients

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Abstract

Purpose

Eleven patients diagnosed with various hematologic malignancies receiving an HLA-haploidentical hematopoietic cell transplant (HCT) participated in an ancillary biomarker trial. The goal of the trial was to evaluate potential pharmacologic biomarkers pertinent to the conditioning regimen [fludarabine monophosphate (fludarabine) and cyclophosphamide (CY)] or postgrafting immunosuppression [CY and mycophenolate mofetil (MMF)] in these patients.

Methods

We characterized the interpatient variability of nine pharmacologic biomarkers. The biomarkers evaluated were relevant to fludarabine (i.e., area under the curve (AUC) of 2-fluoro-ara-A or F-ara-A), CY (i.e., AUCs of CY and four of its metabolites), and MMF (i.e., total mycophenolic acid (MPA) AUC, unbound MPA AUC, and inosine monophosphate dehydrogenase (IMPDH) activity).

Results

Interpatient variability in the pharmacologic biomarkers was high. Among those related to HCT conditioning, the interpatient variability ranged from 1.5-fold (CY AUC) to 4.0-fold (AUC of carboxyethylphosphoramide mustard, a metabolite of CY). Among biomarkers evaluated as part of postgrafting immunosuppression, the interpatient variability ranged from 1.7-fold (CY AUC) to 4.9-fold (IMPDH area under the effect curve). There was a moderate correlation (R 2 = 0.441) of within-patient 4-hydroxycyclophosphamide formation clearance.

Conclusions

Considerable interpatient variability exists in the pharmacokinetic and drug-specific biomarkers potentially relevant to clinical outcomes in HLA-haploidentical HCT recipients. Pharmacodynamic studies are warranted to optimize the conditioning regimen and postgrafting immunosuppression administered to HLA-haploidentical HCT recipients.

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Acknowledgments

The authors would like to thank the participants and their caregivers for their time and cooperation, as well as the patient care staff for their support of this project. We would also like to acknowledge Ms. Megan Kelton-Rehkopf for her contributions to study coordination, Dr. David Blough for his statistical expertise, and Ms. Linda Risler and Mr. Brian Phillips for their analytical expertise. This study was supported by grants from the National Institutes of Health (HL91744S1, CA78902).

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Authors and Affiliations

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

    Meagan J. Bemer, Mohamed Sorror, Brenda M. Sandmaier, Paul V. O’Donnell & Jeannine S. McCune

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

    Mohamed Sorror, Brenda M. Sandmaier & Paul V. O’Donnell

  3. Department of Pharmacy, University of Washington, Box 357630, Seattle, WA, 98195-7630, USA

    Jeannine S. McCune

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  1. Meagan J. Bemer
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  2. Mohamed Sorror
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  3. Brenda M. Sandmaier
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  4. Paul V. O’Donnell
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  5. Jeannine S. McCune
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Correspondence to Jeannine S. McCune.

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Bemer, M.J., Sorror, M., Sandmaier, B.M. et al. A pilot pharmacologic biomarker study in HLA-haploidentical hematopoietic cell transplant recipients. Cancer Chemother Pharmacol 72, 607–618 (2013). https://doi.org/10.1007/s00280-013-2232-8

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