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Acute Leukemias

A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse

Leukemia volume 27, pages 1479–1486 (2013)Cite this article

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Abstract

The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10–70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.

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Acknowledgements

We thank all the GOELAMS investigators, the molecular biologists, Laurence Lode, Olivier Kosmider, Odile Blanchet, Marie–Pierre Gaub and clinical trial office staff in Tours and Novartis.

Author contributions

Conception and design: Sophie Park, Didier Bouscary, Christian Recher, Annabelle Merlat. Administrative support: Roselyne Delepine, François Dreyfus, Catherine Lacombe and Patrick Mayeux. Provision of study materials or patients: Sophie Park, Christian Recher, Norbert Vey, Thomas Prebet, Patrice Chevallier, Jean-Yves Cahn, Thibault Leguay, Pierre Boris, Francis Witz, Thierry Lamy, Jérôme Tamburini, Annabelle Merlat, Marie-Christine Béné, Norbert Ifrah and Didier Bouscary. Collection and assembly of data: Roselyne Delepine. Data analysis and interpretation: Sophie Park, Nicolas Chapuis, Franck Saint Marcoux, Christian Recher, Norbert Vey, Thomas Prebet, Patrice Chevallier,Jean-Yves Cahn, Thibault Leguay, Pierre Boris, Francis Witz, Thierry Lamy, Annabelle Merlat, Roselyne Delepine, Francois Dreyfus, Marie-Christine Béné, Norbert Ifrah and Didier Bouscary.

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Authors and Affiliations

  1. Service d'Hématologie, INSERM U1016, Institut Cochin, Hôpital Cochin, AP-HP, Paris, France

    S Park, J Tamburini, F Dreyfus & D Bouscary

  2. Département d’Immuno-Hématologie, CNRS UMR8104, INSERM U1016, Institut Cochin, Paris, France

    S Park, N Chapuis, P Mayeux, C Lacombe, J Tamburini, F Dreyfus & D Bouscary

  3. Service d’hématologie biologique, Hôpital Cochin, AP-HP, Paris, France

    N Chapuis & C Lacombe

  4. Service de Pharmacologie, Toxicologie et Pharmacovigilance, Hôpital Dupuytren—CHU de Limoges, Limoges, France

    F Saint Marcoux

  5. Hôpital Purpan, Université Toulouse, Toulouse, France

    C Recher & C Demur

  6. Hôpital Paoli-Calmettes, Marseille, France

    T Prebet & N Vey

  7. Service d’hématologie, Centre Hospitalo-Universitaire, Nantes, France

    P Chevallier

  8. Onco-Hematologie, UMR5525 CNRS-UJF, CHU-Grenoble, Grenoble, France

    J-Y Cahn

  9. CHU Bordeaux, Hematology, Pessac, France

    T Leguay

  10. CHU Strasbourg, Strasbourg, France

    P Bories

  11. Service d’Hématologie, CHU de Nancy, Nancy, France

    F Witz & M C Béné

  12. Service d’Hématologie, CHU de Rennes, Rennes, France

    T Lamy

  13. BU oncologie Novartis Pharma SAS, Novartis, France

    A Merlat

  14. Hématologie et thérapie cellulaire, CHU Bretonneau, Tours, France

    R Delepine

  15. Service d'Hématologie, CHU Angers, Angers, France

    N Ifrah

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GOELAMS (Groupe Ouest Est d’Etude des Leucémies aiguës et Autres Maladies du Sang)

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Correspondence to S Park.

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Competing interests

AM is employed at BU oncologie Novartis Pharma SAS, Novartis, Rueil-Malmaison, France. The rest of the authors declare no conflict of interest.

Additional information

Oral communication at the 53th Annual Meeting of the American Society of Hematology, San Diego, 2011, Blood, 118: Abstract 945. Oral communication at the Annual Meeting of the Société Française d’Hématologie, Paris, 2012. Oral communication at the Annual Meeting of the European Society of Hematology, Amsterdam, 2012, Haematologica, 2012, 97 s1: 469, Abstract 1136.

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Park, S., Chapuis, N., Saint Marcoux, F. et al. A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse. Leukemia 27, 1479–1486 (2013). https://doi.org/10.1038/leu.2013.17

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