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ACUTE MYELOID LEUKEMIA

A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML

Leukemia volume 38, pages 58–66 (2024)Cite this article

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Abstract

Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18–60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.)

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Data availability

The datasets analyzed for the current study will be available through the NCTN data archive within 6 months of publication: https://nctn-data-archive.nci.nih.gov.

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Acknowledgements

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers CA180888, CA180819, CA18020, CA180821, CA180863, CA077202, CA180816, CA180855, CA180846, CA189848, CA189957, CA180858, CA189860, CA180798, CA189953, CA189856, CA180835, CA189822, CA189971, CA189858, CA189830, CA180801, CA189853, CA189872, CA180826, CA11083, CA46282, CA46368, CA46136, CA46113, CA16385, CA12644, CA04919, CA13612, CA35119, CA73590, CA58723, CA016672, and CCSRI #021039. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the patients who participated in this trial and their families, the team members from each treating institution, and the support staff of the SWOG Operations Office and Statistics and Data Management Center.

Author information

Author notes

  1. Guido Marcucci

    Present address: City of Hope, Duarte, CA, USA

  2. Stephen A. Strickland & Sanjay R. Mohan

    Present address: Sarah Cannon, Nashville, TN, USA

  3. Mikkael A. Sekeres

    Present address: University of Miami, Maiami, FL, USA

  4. These authors contributed equally: Guillermo Garcia-Manero, Nikolai A. Podoltsev.

Authors and Affiliations

  1. Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA

    Guillermo Garcia-Manero

  2. Yale School of Medicine, New Haven, CT, USA

    Nikolai A. Podoltsev

  3. SWOG Statistics and Data Management Center, Seattle, WA, USA

    Megan Othus & Anna Moseley

  4. Swedish Cancer Institute, Seattle, WA, USA

    John M. Pagel

  5. Fred Hutchinson Cancer Center, Seattle, WA, USA

    Jerald P. Radich, Min Fang & Frederick R. Appelbaum

  6. Duke University Medical Center, Durham, NC, USA

    David A. Rizzieri

  7. Ohio State University (Alliance), Columbus, OH, USA

    Guido Marcucci

  8. Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

    Stephen A. Strickland & Sanjay R. Mohan

  9. Mayo Clinic, Rochester, MN, USA

    Mark R. Litzow

  10. Tom Baker Cancer Centre, Calgary, AB, Canada

    M. Lynn Savoie

  11. Stanford University, Stanford, CA, USA

    Bruno C. Medeiros

  12. Cleveland Clinic, Cleveland, OH, USA

    Mikkael A. Sekeres

  13. University of Kansas Medical Center, Kansas City, KS, USA

    Tara L. Lin

  14. Washington University School of Medicine, St. Louis, USA

    Geoffrey L. Uy

  15. Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA

    Bayard L. Powell

  16. North Shore University Hospital, Manhasset, NY, USA

    Jonathan E. Kolitz

  17. University of Chicago, Chicago, IL, USA

    Richard A. Larson

  18. Dana Farber Cancer Institute, Boston, MA, USA

    Richard M. Stone

  19. Pennsylvania State Milton S Hershey Medical Center, Hummelstown, USA

    David Claxton

  20. Jewish Hospital, Cincinnati, OH, USA

    James Essell

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

    Selina M. Luger

  22. Duke University Cancer Center, Durham, NC, USA

    Harry P. Erba

Authors
  1. Guillermo Garcia-Manero
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  2. Nikolai A. Podoltsev
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  25. Frederick R. Appelbaum
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Contributions

GGM, HPE, MO, JMP, JPR, and FRA designed the study and wrote the protocol. NAP, DAR, GM, SAS, MRL, MLS, BCM, MAS, TLL, GLU, BLP, JEK, RAL, RMS, DC, JE, SML, SRM, AM, HPE conducted the study. MF did cytogenetics review. MO and AM conducted all statistical analyses. GGM, HPE, and MO wrote the first draft of the manuscript. All authors reviewed the results of statistical analysis, participated in the interpretation of the results, and critically revised the manuscript.

Corresponding author

Correspondence to Nikolai A. Podoltsev.

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Garcia-Manero, G., Podoltsev, N.A., Othus, M. et al. A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML. Leukemia 38, 58–66 (2024). https://doi.org/10.1038/s41375-023-02073-x

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