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Evaluating the efficacy and toxicity of dose adjusted pegylated L-asparaginase in combination with therapeutic drug monitoring

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Abstract

The incorporation of pediatric-inspired regimens in the adolescent-young-adult (AYA) and adult populations have resulted improved survival outcomes (Stock et al. Blood 133(14):1548–1559 2019; Dunsmore et al. J Clin Oncol 38(28):3282–3293 2020; DeAngelo et al. Leukemia 29(3):526-534 2015). Nonetheless incorporation of such regimens is limited by increased toxicity to asparaginase. Dosing strategies that reduce the weight-based dose of pegylated-L-asparaginase (PEG-asparaginase) utilizing activity monitoring have been shown to result in better tolerability of these regimens. The purpose of this study was to analyze the efficacy and safety of treating adults with Philadelphia chromosome negative (Ph−) ALL with pediatric-inspired regimens that incorporate PEG-asparaginase dose adjustments and asparaginase activity level monitoring. Patients aged 18–65 years initiated on pediatric-inspired regimens utilizing dose-reduced PEG-asparaginase with therapeutic drug monitoring-guided adjustments were included. The screening of 122 patients treated between 2015 and 2021 resulted in the inclusion of 54 patients. The median age of the cohort was 35 years (16–65 years), and median body mass index (BMI) was 30 kg/m2 (18.3–53.4 kg/m2). The 36-month survival estimate was 62.1% (95% CI 48.1–77.7%), and the median overall survival (OS) was 62.2 months (95% CI 35.1–89.3 months). In the AYA cohort, the 36-month survival was 71.2% (95% CI 55.8–91%) and the median overall survival was not reached. Survival was not significantly affected by immunophenotype or BMI. Discontinuation due to toxicity or hypersensitivity reactions was low at 11% and 9% respectively. The encouraging survival outcomes and favorable tolerability of this older population in the real-world setting support the use of individualized PEG-asparaginase dosing with PharmD-guided therapeutic drug monitoring.

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Acknowledgements

The study group would like to acknowledge Vincent Marshall for his assistance with the statistical analysis.

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Authors and Affiliations

  1. Michigan Medicine, Ann Arbor, MI, USA

    Taylor D. Coe-Eisenberg, Anthony J. Perissinotti, Bernard L. Marini, Kristen M. Pettit, Dale L. Bixby, Patrick W. Burke & Lydia Benitez

  2. Department of Pharmacy Services Michigan Medicine, University of Michigan College of Pharmacy, 1540 E. Hospital Dr, Ann Arbor, MI, 48109, USA

    Bernard L. Marini & Lydia Benitez

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  1. Taylor D. Coe-Eisenberg
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  2. Anthony J. Perissinotti
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  3. Bernard L. Marini
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  7. Lydia Benitez
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Taylor Coe-Eisenberg, PharmD, and Lydia Benitez, PharmD, with collaboration from Vince Marshall, statistician with University of Michigan College of Pharmacy. The first draft of the manuscript was written by Taylor Coe-Eisenberg, Lydia Benitez, PharmD, and Anthony Perissinotti, PharmD. All authors contributed to all versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Lydia Benitez.

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This article does not contain any studies with human participants performed by any of the authors.

Conflict of interest

Taylor Coe-Eisenberg, PharmD, declares no conflict of interest. Anthony J. Perissinotti, PharmD, has consulted or Servier, Amgen, and Pfizer pharmaceuticals. Bernard L. Marini, PharmD, has consulted for Servier. Kristen M. Pettit, MD, provides advising for the following companies: Kura Oncology, PharmaEssentia, CTI Biopharma. Dale L. Bixby, MD, Ph.D., declares no conflict of interest. Patrick W. Burke, MD, declares no conflict of interest. Lydia L. Benitez, PharmD, declares no conflict of interest.

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Coe-Eisenberg, T.D., Perissinotti, A.J., Marini, B.L. et al. Evaluating the efficacy and toxicity of dose adjusted pegylated L-asparaginase in combination with therapeutic drug monitoring. Ann Hematol 102, 3133–3141 (2023). https://doi.org/10.1007/s00277-023-05373-5

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