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

  • Margaret T. Kasner
  • Rosemarie Mick
  • Grace R. Jeschke
  • Matthew Carabasi
  • Joanne Filicko-O’Hara
  • Neal Flomenberg
  • Noelle V. Frey
  • Elizabeth O. Hexner
  • Selina M. Luger
  • Alison W. Loren
  • James K. Mangan
  • John L. Wagner
  • Mark Weiss
  • Martin Carroll
  • Alexander E. Perl
PHASE II STUDIES

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.

Keywords

Acute myeloid leukemia mTOR mTORC1 Biomarker Phospho-flow cytometry 

Notes

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.

Compliance with ethical standards

Conflict of interest

All authors declare no conflicts 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.

Supplementary material

10637_2018_585_MOESM1_ESM.docx (102 kb)
ESM 1 (DOCX 102 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Margaret T. Kasner
    • 1
  • Rosemarie Mick
    • 2
  • Grace R. Jeschke
    • 3
    • 4
  • Matthew Carabasi
    • 1
  • Joanne Filicko-O’Hara
    • 1
  • Neal Flomenberg
    • 1
  • Noelle V. Frey
    • 3
    • 4
  • Elizabeth O. Hexner
    • 3
    • 4
  • Selina M. Luger
    • 3
    • 4
  • Alison W. Loren
    • 3
    • 4
  • James K. Mangan
    • 3
    • 4
  • John L. Wagner
    • 1
  • Mark Weiss
    • 1
  • Martin Carroll
    • 3
    • 4
  • Alexander E. Perl
    • 3
    • 4
  1. 1.Department of Medical Oncology, Sidney Kimmel Medical College and Cancer CenterThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Department of Biostatistics and Epidemiology, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Division of Hematology-Oncology, Department of Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  4. 4.Abramson Cancer CenterUniversity of PennsylvaniaPhiladelphiaUSA

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