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Pharmacokinetics of alemtuzumab in pediatric patients undergoing ex vivo T-cell-depleted haploidentical hematopoietic cell transplantation

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Abstract

Purpose

Alemtuzumab is a humanized monoclonal antibody against CD52 which is predominantly present on T and B lymphocytes. Alemtuzumab has been used as part of conditioning regimens for prophylaxis against rejection and GVHD. While the mechanism of action is well understood, the pharmacokinetics of this drug in children needed to be studied in more detail especially in the setting of ex vivo T-cell-depleted hematopoietic cell transplantation (HCT).

Methods

Serum alemtuzumab levels were measured at various time points in 13 patients who underwent haploidentical HCT utilizing ex vivo donor T-cell depletion. Alemtuzumab was administered subcutaneously at a cumulative dose of 45 mg/m2 from days − 13 to − 11. A one-compartmental model was used to fit the data using non-linear mixed effects modeling.

Results

We determined the median half-life to be 11 days. Alemtuzumab clearance increased with increasing baseline lymphocyte count (p = 0.008). Additionally, clearance increased with weight and age (p ≤ 0.035). AUC of alemtuzumab did not have any significant relationship with type of leukemia, overall survival, engraftment, immune reconstitution, mixed chimerism or GVHD, although the number of subjects in this pilot study was limited.

Conclusion

Absolute lymphocyte count and body weight affect alemtuzumab clearance. We also demonstrate feasibility of body-surface area-based dosing of alemtuzumab in pediatric HCT patients. Further studies are needed to evaluate the role of monitoring alemtuzumab serum concentrations to balance the prevention of graft rejection and GVHD with the promotion of rapid donor immune reconstitution.

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Availability of data and transplarency

Data are available at request.

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Acknowledgements

This work is supported, in part, by the National Cancer Institute Cancer Center Support (CORE) grant P30 CA021765 and the American Lebanese Syrian Associated Charities (ALSAC).

Funding

This work is supported, in part, by the National Cancer Institute Cancer Center Support (CORE) grant P30 CA021765 and the American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Senthil Velan Bhoopalan

  2. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Shane J. Cross & John C. Panetta

  3. Department of Bone Marrow Transplantation and Cell Therapy, St. Jude Children’s Research Hospital, MS 1130, Room I3305, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Brandon M. Triplett

Authors
  1. Senthil Velan Bhoopalan
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  2. Shane J. Cross
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  3. John C. Panetta
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  4. Brandon M. Triplett
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Contributions

SVB, SC, and JCP analyzed data. BMT designed clinical trial and supervised the project. All authors wrote the manuscript.

Corresponding author

Correspondence to Brandon M. Triplett.

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Conflict of interest

B.M.T. received travel support for EBMT 2018 Annual Meeting from Miltenyi Biotec Inc to present published data. The remaining authors declare no competing financial interests.

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This work was approved by IRB and Ethics Committee of our institution.

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Supplementary file1 (DOCX 31 kb)

280_2020_4160_MOESM2_ESM.pdf

Supplemental Figure S1. Goodness-of-Fit plots. Black dots: measured concentrations/residuals; Red dots: simulated concentrations below the LLOQ (141 ng/mL); Panel A: individual predicted vs actual concentration; Panel B: population predicted vs actual concentration; Panel C: individual weighted residuals vs time; Panel D: population weighted residual vs time. (PDF 334 kb)

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Bhoopalan, S.V., Cross, S.J., Panetta, J.C. et al. Pharmacokinetics of alemtuzumab in pediatric patients undergoing ex vivo T-cell-depleted haploidentical hematopoietic cell transplantation. Cancer Chemother Pharmacol 86, 711–717 (2020). https://doi.org/10.1007/s00280-020-04160-7

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  • DOI: https://doi.org/10.1007/s00280-020-04160-7

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