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Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia

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Abstract

Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 μmol/L in patients with relapsed or refractory (R/R) AML. Five patients were enrolled before the study was halted due to issues with Erwinaze manufacturing supply. All patients received Erwinaze at a dose of 25,000 IU/m2 intravenously three times weekly for 2 weeks. Median trough plasma Gln level at 48 h after initial Erwinaze administration was 27.6 μmol/L, and 80% (lower limit of 1-sided 95% CI 34%) of patients achieved at least one undetectable plasma Gln value (< 12.5 μmol/L), with the fold reduction (FR) in Gln level at 3 days, relative to baseline, being 0.16 (p < 0.001 for rejecting FR = 1). No dose-limiting toxicities were identified. Two patients responded, one achieved partial remission and one achieved hematologic improvement after six doses of Erwinaze monotherapy. These data suggest asparaginase-induced Gln depletion may have an important role in the management of patients with AML, and support more pharmacologic and clinical studies on the mechanistically designed asparaginase combinations in AML.

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Authors and Affiliations

  1. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA

    Ashkan Emadi, Jennie Y. Law, Rena G. Lapidus, Myounghee Lee, Brandon A. Carter-Cooper, Isabella Van Der Merwe, Sunita Philip, Mohammad Imran, Stephen L. Yu, Hongxia Li, Vu H. Duong, Edward A. Sausville, Maria R. Baer & Søren M. Bentzen

  2. Department of Medicine, University of Maryland, Baltimore, USA

    Ashkan Emadi, Jennie Y. Law, Rena G. Lapidus, Linda J. B. Jeng, Danielle Sewell, Vu H. Duong, Edward A. Sausville & Maria R. Baer

  3. Department of Pharmacology, University of Maryland, Baltimore, USA

    Ashkan Emadi & Edward A. Sausville

  4. Department of Pediatrics, University of Maryland, Baltimore, USA

    Erin T. Strovel, Linda J. B. Jeng & Miriam G. Blitzer

  5. Department of Pathology, University of Maryland, Baltimore, USA

    Linda J. B. Jeng & Zeba Singh

  6. Massachusetts General Hospital Harvard Medical School, Boston, USA

    Philip C. Amrein & Amir T. Fathi

  7. Epidemiology and Public Health, University of Maryland, Baltimore, USA

    Søren M. Bentzen

Authors
  1. Ashkan Emadi
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  2. Jennie Y. Law
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  3. Erin T. Strovel
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  4. Rena G. Lapidus
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  5. Linda J. B. Jeng
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  6. Myounghee Lee
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  7. Miriam G. Blitzer
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  8. Brandon A. Carter-Cooper
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  9. Danielle Sewell
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  10. Isabella Van Der Merwe
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  11. Sunita Philip
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  12. Mohammad Imran
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  13. Stephen L. Yu
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  14. Hongxia Li
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  15. Philip C. Amrein
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  16. Vu H. Duong
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  17. Edward A. Sausville
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  18. Maria R. Baer
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  19. Amir T. Fathi
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  20. Zeba Singh
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  21. Søren M. Bentzen
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Contributions

AE developed the study design, performed data collection, management, and analysis, managed all regulatory aspects of conducting the trial, and wrote the manuscript; JYL developed the first draft of the manuscript under the direction of AE and helped with data analysis; ETS and MGB performed plasma amino acid (glutamine, asparagine and glutamate) concentration analysis; RGL and BACC performed asparaginase activity analysis; LJBJ and D.S. performed mutational analysis; IvDM, SP, MI, SLY, HL, and ML enrolled and monitored patients on study and helped with sample and data collection; ATF and PCA provided positive controls and helped in the performing and reporting of 2-HG assay and helped edit the manuscript; VHD, EAS, and MRB contributed to the study design and patient enrollment and helped edit the manuscript; ZS performed analysis of bone marrow aspirates and biopsies; SMB developed the statistical design and performed statistical analysis.

Corresponding author

Correspondence to Ashkan Emadi.

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Funding

This investigator-initiated clinical trial was funded by Jazz Pharmaceuticals.

Conflict of interest

A.E. has received research grant from Jazz Pharmaceuticals for this clinical trial and for pre-clinical studies to University of Maryland. The remaining authors declare no conflict of interest.

Ethical approval

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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Emadi, A., Law, J.Y., Strovel, E.T. et al. Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia. Cancer Chemother Pharmacol 81, 217–222 (2018). https://doi.org/10.1007/s00280-017-3459-6

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  • DOI: https://doi.org/10.1007/s00280-017-3459-6

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