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Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition

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Summary

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1’s kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33–61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.

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Acknowledgements

The authors wish to acknowledge contributions of Joy Cannon, Amanda Cloud, Kristin Coffan, Martina DiMeglio, Cesary Swider, and Doris Shank for their contribution to this research. We also wish to thank the nurses involved for their excellent care of enrolled subjects.

Funding

Supported in part by the Abramson Cancer Center Support Grant P30-CA016520 (RM), the National Cancer Institute (K23 CA141054), the When Everyone Survives Foundation and the American Cancer Society (IRG-78-002-30) to AEP. AEP is a fellow of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania, which supported this research.

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Authors and Affiliations

  1. Department of Medical Oncology, Sidney Kimmel Medical College and Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Margaret T. Kasner, Matthew Carabasi, Joanne Filicko-O’Hara, Neal Flomenberg, John L. Wagner & Mark Weiss

  2. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Rosemarie Mick

  3. Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Grace R. Jeschke, Noelle V. Frey, Elizabeth O. Hexner, Selina M. Luger, Alison W. Loren, James K. Mangan, Martin Carroll & Alexander E. Perl

  4. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    Grace R. Jeschke, Noelle V. Frey, Elizabeth O. Hexner, Selina M. Luger, Alison W. Loren, James K. Mangan, Martin Carroll & Alexander E. Perl

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  1. Margaret T. Kasner
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  2. Rosemarie Mick
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  3. Grace R. Jeschke
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  9. Selina M. Luger
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  10. Alison W. Loren
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  13. Mark Weiss
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  14. Martin Carroll
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  15. Alexander E. Perl
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Correspondence to Alexander E. Perl.

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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.

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

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Kasner, M.T., Mick, R., Jeschke, G.R. et al. Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition. Invest New Drugs 36, 657–666 (2018). https://doi.org/10.1007/s10637-018-0585-x

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  • DOI: https://doi.org/10.1007/s10637-018-0585-x

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