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Acute myeloid leukemia

Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial

Leukemia volume 34, pages 914–918 (2020)Cite this article

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The combination of All-trans retinoic acid (ATRA) and chemotherapy has long since represented the standard of care for newly diagnosed acute promyelocytic leukemia (APL). This approach showed long-term cure rates exceeding 80% [1, 2] but was associated with the risk of severe infections, deaths in remission and to the development of therapy-related leukemias and myelodysplastic syndromes [3,4,5].

More recently, based on the results of two randomized trials, the combination of arsenic trioxide (ATO) and ATRA has been established as the new standard of care for front-line therapy of non-high-risk APL patients. The APL0406 study was designed by the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) as a prospective, randomized, multicenter, phase III noninferiority trial comparing ATRA–ATO, and ATRA-chemotherapy (AIDA) regimens in patients with a low-intermediate risk APL [6]. The study was conducted by the GIMEMA together with the German Acute Myeloid Leukemia Study Group (AMLSG) and Study Alliance Leukemia group (SAL). This study has first shown that the chemotherapy-free approach with ATRA–ATO is at least equally effective to ATRA and chemotherapy-based regimens [6]. The toxicity profile of ATRA–ATO combination appeared to be mild, with considerably reduced myelosuppression and infections as compared with ATRA-chemotherapy, and was associated with frequent but manageable side-effects (i.e., leukocytosis, QTc prolongation, liver enzyme increase). The superior antileukemic efficacy of ATRA–ATO was later shown in an independent randomized trial (AML17) conducted in the UK by the National Cancer Research Institute [7]. Albeit adopting a different ATO schedule as compared with the Italian-German study, Burnett et al. reported superior event-free survival (EFS), relapse-free survival, and lower cumulative incidence of relapse (CIR) rates in ATRA–ATO treated patients as compared with those receiving ATRA–chemotherapy [7], supporting the feasibility and benefit of this chemotherapy-free strategy in APL all risk categories (including high-risk patients).

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Acknowledgements

Authors would like to acknowledge the patients who participated in this study, and their families. This study has been supported by AIRC IG 5916 to FLC, and by an AIRC research fellowship to LC.

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Author notes

  1. These authors contributed equally: Laura Cicconi, Uwe Platzbecker

Authors and Affiliations

  1. Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy

    Laura Cicconi, Maria Teresa Voso & Francesco Lo-Coco

  2. Universitätsklinikum Leipzig, Leipzig, Germany

    Uwe Platzbecker

  3. Ematologia e Trapianto di cellule staminali, Università Campus Bio-Medico, Rome, Italy

    Giuseppe Avvisati & Ombretta Annibali

  4. GIMEMA Data Center, Rome, Italy

    Francesca Paoloni, Marco Vignetti, Paola Fazi, Fabio Efficace, Sergio Amadori & Franco Mandelli

  5. Universitätsklinikum Carl Gustav Carus der Technischen Universität, Dresden, Germany

    Christian Thiede, Christoph Rollig & Gerhard Ehninger

  6. Dipartimento di Ematologia e Trapianto di Cellule Staminali, Ospedale Cardarelli, Napoli, Italy

    Felicetto Ferrara

  7. Laboratorio di Oncoematologia, Policlinico Tor Vergata, Rome, Italy

    Mariadomenica Divona

  8. Dipartimento di Ematologia, Università di Bari, Bari, Italy

    Francesco Albano

  9. U.O. di Ematologia Clinica, Pescara, Italy

    Marco Sborgia

  10. Dipartimento di Terapie cellulari ed Ematologia, Unità Operativa di Ematologia, Ospedale S. Bortolo, Vicenza, Italy

    Eros Di Bona

  11. Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy

    Massimo Breccia

  12. Dipartimento di Ematologia, Spedali Civili, Brescia, Italy

    Erika Borlenghi

  13. Grande Ospedale Metropolitano Niguarda, SC Ematologia, Milan, Italy

    Roberto Cairoli

  14. Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

    Alessandro Rambaldi

  15. Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy

    Lorella Melillo

  16. Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Università di Cagliari, Cagliari, Italy

    Giorgio La Nasa

  17. University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Walter Fiedler

  18. Department of Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, CIO Bonn, Bonn, Germany

    Peter Brossart

  19. Klinikum Bremen Mitte, Bremen, Germany

    Bernd Hertenstein

  20. University Hospital Tubingen, Tubingen, Germany

    Helmut R. Salih

  21. Kliniken Essen Süd, Essen, Germany

    Mohammed Wattad

  22. University Medical Center, Freiburg, Germany

    Michael Lubbert

  23. Goethe University Frankfurt, Frankfurt, Germany

    Christian H. Brandts

  24. Klinikum Chemnitz gGmbH, Chemnitz, Germany

    Mathias Hanel

  25. Asklepios Klinik St Georg Hamburg, Hamburg, Germany

    Norbert Schmitz

  26. Klinik für Innere Medizin I, Westpfalz-Klinikum, Kaiserslautern, Germany

    Hartmut Link

  27. Città della Salute e della Scienza, Hematology, Torino, Italy

    Chiara Frairia

  28. University of Sassari, Sassari, Italy

    Claudio Fozza

  29. U.O. Medicina Interna e Onco-Ematologica P.O. Umberto I, Nocera Inferiore, Nocera Inferiore, Italy

    Alfonso Maria D’Arco

  30. Ospedale Vito Fazzi, Lecce, Italy

    Nicola Di Renzo

  31. Foundation Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy

    Agostino Cortelezzi

  32. Divisione di Ematologia e Unità di Trapianti di Midollo Osseo, Ospedale Riuniti Villa Sofia-Cervello, Palermo, Italy

    Francesco Fabbiano

  33. University Hospital Ulm, Ulm, Germany

    Konstanze Dohner & Hartmut Dohner

  34. Hannover Medical School, Hannover, Germany

    Arnold Ganser

  35. Fondazione Santa Lucia, Laboratorio di Neuro-Oncoematologia, Roma, Italy

    Maria Teresa Voso & Francesco Lo-Coco

  36. NCT Trial Center, National Center for Tumor Diseases Heidelberg, Heidelberg, Germany

    Richard F. Schlenk

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  1. Laura Cicconi
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Corresponding author

Correspondence to Maria Teresa Voso.

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Conflict of interest

LC, Speakers’ Bureau: Teva Pharmaceutical Industries; UP, Honoraria and Research Funding: Teva Pharmaceutical Industries; CT, Employment: AgenDix; FE, Advisory Role: Teva Pharmaceutical Industries, Research Funding: Lundbeck (Inst); HL, Honoraria and Research Funding: Teva Pharmaceutical Industries; RFS, Honoraria and Research Funding: Teva Pharmaceutical Industries; FL-C, Honoraria: Teva Pharmaceutical Industries, Lundbeck, Consulting or Advisory Role: Teva Pharmaceutical Industries, Lundbeck. Other authors declared that they have no conflict of interest.

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Cicconi, L., Platzbecker, U., Avvisati, G. et al. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia 34, 914–918 (2020). https://doi.org/10.1038/s41375-019-0589-3

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