Improved OutcomesWith Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial

被引：301

作者：

Platzbecker, Uwe ^{[1
,2
]}

Avvisati, Giuseppe ^{[14
]}

Cicconi, Laura ^{[15
]}

Thiede, Christian ^{[1
]}

Paoloni, Francesca ^{[16
]}

Vignetti, Marco ^{[16
,17
]}

Ferrara, Felicetto ^{[18
]}

Divona, Mariadomenica ^{[15
]}

Albano, Francesco ^{[19
]}

Efficace, Fabio ^{[16
]}

Fazi, Paola ^{[16
]}

Sborgia, Marco ^{[20
]}

Di Bona, Eros ^{[21
]}

Breccia, Massimo ^{[17
]}

Borlenghi, Erika ^{[22
]}

Cairoli, Roberto ^{[23
]}

Rambaldi, Alessandro ^{[26
]}

Melillo, Lorella ^{[27
]}

La Nasa, Giorgio ^{[28
]}

Fiedler, Walter ^{[3
]}

Brossart, Peter

Hertenstein, Bernd ^{[5
]}

Salih, Helmut R. ^{[6
]}

Wattad, Mohammed ^{[7
]}

Luebbert, Michael ^{[8
]}

Brandts, Christian H. ^{[9
]}

Haenel, Mathias ^{[10
]}

Roellig, Christoph ^{[1
]}

Schmitz, Norbert ^{[4
]}

Link, Hartmut ^{[11
]}

Frairia, Chiara ^{[29
]}

Pogliani, Enrico Maria

Fozza, Claudio ^{[30
]}

D'Arco, Alfonso Maria ^{[31
]}

Di Renzo, Nicola ^{[32
]}

Cortelezzi, Agostino ^{[24
,25
]}

Fabbiano, Francesco ^{[33
]}

Doehner, Konstanze

Ganser, Arnold ^{[13
]}

Doehner, Hartmut

Amadori, Sergio ^{[15
]}

Mandelli, Franco ^{[16
]}

Ehninger, Gerhard ^{[1
,2
]}

Schlenk, Richard F. ^{[12
]}

Lo-Coco, Francesco ^{[15
]}

机构：

[1] Tech Univ Dresden, Univ Klinikum Carl Gustav Carus, Dresden, Germany

[2] Study Alliance Leukemia, Dresden, Germany

[3] Univ Hosp Hamburg Eppendorf, Hamburg, Germany

[4] Asklepios Klin St Georg Hamburg, Hamburg, Germany

[5] Klinikum Bremen Mitte, Bremen, Germany

[6] Univ Hosp Tubingen, Essen, Germany

[7] Kliniken Essen Sud, Essen, Germany

[8] Univ Med Ctr, Freiburg, Germany

[9] Goethe Univ Frankfurt, Frankfurt, Germany

[10] Klinikum Chemnitz gGmbH, Chemnitz, Germany

[11] Westpfalz Klinikum, Klin Innere Med 1, Kaiserslautern, Germany

[12] Univ Hosp Ulm, Ulm, Germany

[13] Hannover Med Sch, Hannover, Germany

[14] Univ Campus Biomed, Rome, Italy

[15] Univ Tor Vergata, Rome, Italy

[16] Grp Italiano Malattie Ematol, Adulto Cent Off, Rome, Italy

[17] Sapienza Univ, Rome, Italy

[18] Cardarelli Hosp, Naples, Italy

[19] Univ Bari, Bari, Italy

[20] UO Ematol Clin, Pescara, Italy

[21] San Bortolo Hosp, Vicenza, Italy

[22] UO Ematol, Spedali Civili, Brescia, Italy

[23] Osped Niguarda Ca Granda, SC Ematol, Milan, Italy

[24] Osped Maggiore Policlin, Fdn Ist Ricovero Cura Carattere Sci Ca Granda, Milan, Italy

[25] Univ Milan, Milan, Italy

[26] Azienda Opsed Papa Giovanni XXIII, Bergamo, Italy

[27] IRCCS, Casa Sollievo Sofferenza Hosp, San Giovanni Rotondo, Italy

[28] Univ Cagliari, Osped R Binaghi, Ctr Trapianti Midollo Osseo, Cagliari, Italy

[29] Citta Salute & Sci, Hematol, Turin, Italy

[30] Univ Sassari, Sassari, Italy

[31] UO Med Interna & Oncoematol PO Umberto I, Nocera Inferiore, Nocera Inferior, Italy

[32] Osped Vito Fazzi, Lecce, Italy

[33] Osped Riuniti Villa Sofia Cervello, Palermo, Italy

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2017年 / 35卷 / 06期

关键词：

FRONT-LINE THERAPY; CONSOLIDATION THERAPY; ANTHRACYCLINE; MANAGEMENT;

D O I：

10.1200/JCO.2016.67.1982

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose The initial results of the APL0406 trial showed that the combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in firstline therapy of low-or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low-or intermediate-risk APL (WBC at diagnosis # 10 3 109/ L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively (P =.12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively (P<.001, P =.0013, and P =.0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances ofmolecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRACHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low-and intermediate-risk APL. (C) 2016 by American Society of Clinical Oncology

引用

页码：605 / +

页数：14

共 26 条

[1] Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience [J].

Ades, Lionel ;

Guerci, Agnes ;

Raffoux, Emmanuel ;

Sanz, Miguel ;

Chevallier, Patrice ;

Lapusan, Simona ;

Recher, Christian ;

Thomas, Xavier ;

Rayon, Consuelo ;

Castaigne, Sylvie ;

Tournilhac, Olivier ;

de Botton, Stephane ;

Ifrah, Norbert ;

Cahn, Jean-Yves ;

Solary, Eric ;

Gardin, Claude ;

Fegeux, Nathalie ;

Bordessoule, Dominique ;

Ferrant, Augustin ;

Meyer-Monard, Sandrine ;

Vey, Norbert ;

Dombret, Herve ;

Degos, Laurent ;

Chevret, Sylvie ;

Fenaux, Pierre .

BLOOD, 2010, 115 (09) :1690-1696

[2] A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARα transcript after consolidation therapy:: The Japan Adult Leukemia Study Group (JALSG) APL97 study [J].

Asou, Norio ;

Kishimoto, Yuji ;

Kiyoi, Hitoshi ;

Okada, Masaya ;

Kawai, Yasukazu ;

Tsuzuki, Motohiro ;

Horikawa, Kentaro ;

Matsuda, Mitsuhiro ;

Shinagawa, Katsuji ;

Kobayashi, Tohru ;

Ohtake, Shigeki ;

Nishimura, Miki ;

Takahashi, Masatomo ;

Yagasaki, Fumiharu ;

Takeshita, Akihiro ;

Kimura, Yukihiko ;

Lwanaga, Masako ;

Naoe, Tomoki ;

Ohno, Ryuzo .

BLOOD, 2007, 110 (01) :59-66

[3] AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance [J].

Avvisati, Giuseppe ;

Lo-Coco, Francesco ;

Paoloni, Francesca Paola ;

Petti, Maria Concetta ;

Diverio, Daniela ;

Vignetti, Marco ;

Latagliata, Roberto ;

Specchia, Giorgina ;

Baccarani, Michele ;

Di Bona, Eros ;

Fioritoni, Giuseppe ;

Marmont, Filippo ;

Rambaldi, Alessandro ;

Di Raimondo, Francesco ;

Kropp, Maria Grazia ;

Pizzolo, Giovanni ;

Pogliani, Enrico M. ;

Rossi, Giuseppe ;

Cantore, Nicola ;

Nobile, Francesco ;

Gabbas, Attilio ;

Ferrara, Felicetto ;

Fazi, Paola ;

Amadori, Sergio ;

Mandelli, Franco .

BLOOD, 2011, 117 (18) :4716-4725

[4] Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease [J].

Breccia, Massimo ;

Lo-Coco, Francesco .

EXPERT OPINION ON PHARMACOTHERAPY, 2012, 13 (07) :1031-1043

[5] Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial [J].

Burnett, A. K. ;

Hills, R. K. ;

Grimwade, D. ;

Jovanovic, J. V. ;

Craig, J. ;

McMullin, M. F. ;

Kell, J. ;

Wheatley, K. ;

Yin, J. A. L. ;

Hunter, A. ;

Milligan, D. ;

Russell, N. H. .

LEUKEMIA, 2013, 27 (04) :843-851

[6] Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial [J].

Burnett, Alan K. ;

Russell, Nigel H. ;

Hills, Robert K. ;

Bowen, David ;

Kell, Jonathan ;

Knapper, Steve ;

Morgan, Yvonne G. ;

Lok, Jennie ;

Grech, Angela ;

Jones, Gail ;

Khwaja, Asim ;

Friis, Lone ;

McMullin, Mary Frances ;

Hunter, Ann ;

Clark, Richard E. ;

Grimwade, David .

LANCET ONCOLOGY, 2015, 16 (13) :1295-1305

[7] Acute promyelocytic leukemia, arsenic, and PML bodies [J].

de The, Hugues ;

Le Bras, Morgane ;

Lallemand-Breitenbach, Valerie .

JOURNAL OF CELL BIOLOGY, 2012, 198 (01) :11-21

[8] Randomized Phase III Trial of Retinoic Acid and Arsenic Trioxide Versus Retinoic Acid and Chemotherapy in Patients With Acute Promyelocytic Leukemia: Health-Related Quality-of-Life Outcomes [J].

Efficace, Fabio ;

Mandelli, Franco ;

Avvisati, Giuseppe ;

Cottone, Francesco ;

Ferrara, Felicetto ;

Di Bona, Eros ;

Specchia, Giorgina ;

Breccia, Massimo ;

Levis, Alessandro ;

Sica, Simona ;

Finizio, Olimpia ;

Kropp, Maria Grazia ;

Fioritoni, Giuseppe ;

Cerqui, Elisa ;

Vignetti, Marco ;

Amadori, Sergio ;

Schlenk, Richard F. ;

Platzbecker, Uwe ;

Lo-Coco, Francesco .

JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (30) :3406-U239

[9] Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia [J].

Estey, E ;

Garcia-Manero, G ;

Ferrajoli, A ;

Faderl, S ;

Verstovsek, S ;

Jones, D ;

Kantarjian, H .

BLOOD, 2006, 107 (09) :3469-3473

[10] THE RETINOIC ACID SYNDROME IN ACUTE PROMYELOCYTIC LEUKEMIA [J].

FRANKEL, SR ;

EARDLEY, A ;

LAUWERS, G ;

WEISS, M ;

WARRELL, RP .

ANNALS OF INTERNAL MEDICINE, 1992, 117 (04) :292-296

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