Original Article | Published:

Acute myeloid leukemia

PML–RARα kinetics and impact of FLT3–ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy

Leukemia volume 30, pages 19871992 (2016) | Download Citation

Abstract

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low–intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia–retinoic acid receptor-α (PML–RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3–internal tandem duplication (FLT3–ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML–RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA–ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML–RARα transcripts was detected in the ATRA–ATO as compared with the ATRA–CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3–ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA–ATO, whereas a trend for inferior EFS was observed in FLT3–ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA–ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA–CHT in low–intermediaterisk APL. The data also suggest that ATRA–ATO may abrogate the negative prognostic impact of FLT3–ITD.

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Acknowledgements

We thank all participants and research staff of all centers within GIMEMA. This study was supported by grants from Associazione Italiana contro le Leucemie (AIL) and Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 5916, to Dr Lo-Coco).

Author contributions

LC, MD and FL-C. designed the study and wrote the paper; MD, CC, AF TO, LC, SL and VA performed the experiments; MD, FL-C, LC, MTV, FP, AL, SS and AP analysed data; MV, PF, GA, FF, PF, EDB, GS, MB, EC, MS, MGK, AS, SA, MTV and FM revised the paper.

Author information

Author notes

    • L Cicconi
    •  & M Divona

    These authors contributed equally to this work.

Affiliations

  1. Dipartimento di Biomedicina e Prevenzione, Università degli studi Tor Vergata, Roma, Italy

    • L Cicconi
    • , C Ciardi
    • , T Ottone
    • , A Ferrantini
    • , S Lavorgna
    • , V Alfonso
    • , S Amadori
    • , M T Voso
    •  & F Lo-Coco
  2. Laboratorio di Oncoematologia, Policlinico Tor Vergata, Roma, Italy

    • M Divona
  3. Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) Data Center, Rome, Italy

    • F Paoloni
    • , A Piciocchi
    •  & F Mandelli
  4. Dipartimento di Ematologia, Università Campus Biomedico, Rome, Italy

    • G Avvisati
  5. Dipartimento di Ematologia e Trapianto di Cellule Staminali, Ospedale Cardarelli, Napoli, Italy

    • F Ferrara
  6. Dipartimento di Terapie cellulari ed Ematologia, Unità Operativa di Ematologia, Vicenza, Italy

    • E Di Bona
  7. Dipartimento di Ematologia, Università di Bari, Bari, Italy

    • F Albano
  8. Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Roma, Italy

    • M Breccia
  9. Dipartimento di Ematologia, Spedali Civili, Brescia, Italy

    • E Cerqui
  10. Dipartimento di Ematologia, Ospedale Civile, Pescara, Italy

    • M Sborgia
  11. Azienda Ospedaliera Pugliese Ciaccio, Catanzaro, Italy

    • M G Kropp
  12. Divisione di Ematologia e Unità di Trapianti di Midollo Osseo, Ospedale Riuniti Villa Sofia-Cervello, Palermo, Italy

    • A Santoro
  13. Dipartimento di Oncoematologia, Sopedale SS Antonio e Biagio, Alessandria, Italy

    • A Levis
  14. Università Cattolica Sacro Cuore, Roma

    • S Sica
  15. Santa Lucia Foundation, Roma, Italy

    • F Lo-Coco

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Competing interests

FL-C received honoraria from Lundbeck and Teva. The remaining authors declare no conflict of interest.

Corresponding author

Correspondence to F Lo-Coco.

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DOI

https://doi.org/10.1038/leu.2016.122

Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)

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