Arsenic Trioxide and All-Trans Retinoic Acid Combination Therapy for the Treatment of High-Risk Acute Promyelocytic Leukemia: Results From the APOLLO Trial
Uwe Platzbecker, Lionel Adès, Pau Montesinos, Emanuele Ammatuna, Pierre Fenaux, Claudia D. Baldus, Massimo Bernardi, Céline Berthon, Monica Bocchia, Caroline Bonmati, Erika Borlenghi, Martin Bornhäuser, Diana Carp, Sylvain Chantepie, Enrico Crea, Mariadomenica Divona, Hartmut Döhner, Gerhard Ehninger, Jordi Esteve, Jamilé Frayfer, Ana Garrido Diaz, Cristina Gil, Luca Guarnera, Anna Franziska Hamm, Maël Heiblig, Daniela Heidenreich, Alwin Krämer, Marie‐Pierre Ledoux, Monia Lunghi, Valentina Mancini, Klaus H. Metzeler, Maria Cristina Miggiano, Carsten Müller‐Tidow, Pierre Péterlin, Alfonso Piciocchi, Kathrin Rieger, Christoph Röllig, Giovanni Rossi, Miguel Á. Sanz, Hubert Serve, Maaike Söhne, Karsten Spiekermann, Emmanuelle Tavernier, Christian Thiede, Susana Vives Polo, Wichard Vogel, Patrizia Zappasodi, Pauline Ziller-Walter, Maria Teresa Voso, on behalf of the SAL, AMCL-CG, AML-SG, OSHO, PETHEMA, HOVON and GIMEMA study groups, Fatiha Chermat, Livia Gorreo Renzulli, Madlen Jentzsch, Dietger Niederwieser, Michaela Weier, Sven Zukunft
Abstract
PURPOSE The phase III APOLLO trial prospectively compared the efficacy of arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) regimen (ATRA and ATO [ATRA-ATO]) plus low-dose idarubicin versus standard ATRA plus anthracycline-based chemotherapy (ATRA-CHT) regimen (ie, ATRA and idarubicin regimen) in patients with high-risk acute promyelocytic leukemia (APL; EudraCT 2015-01151-68; ClinicalTrials.gov identifier: NCT02688140 ). METHODS Adult patients with newly diagnosed high-risk APL in the ATRA-ATO arm received ATO 0.15 mg/kg once daily and ATRA 45 mg/m 2 twice daily until complete remission (CR), with two doses of idarubicin 12 mg/m 2 on days 1 and 3, followed by consolidation therapy (four ATRA-ATO cycles). Patients in the ATRA-CHT arm received induction with ATRA 45 mg/m 2 twice daily and idarubicin 12 mg/m 2 once daily on days 1, 3, 5, and 7, followed by three cycles of chemotherapy-based consolidation and 2 years of maintenance therapy. The primary study end point was event-free survival (EFS) at 2 years. RESULTS As of July 2022, 133 eligible patients had received either ATRA-ATO (n = 68) or ATRA-CHT (n = 65). The study was discontinued prematurely because of slow accrual during the COVID-19 pandemic. After a median follow-up of 37 months (range, 1.7-88.6 months), 2-year EFS was 88% in the ATRA-ATO arm and 71% in the ATRA-CHT arm (HR, 0.4 [95% CI, 0.17 to 0.92]; log-rank test P = .02). At a median of 7.8 and 12.1 months from achievement of CR, molecular relapse occurred in one (1.5%) ATRA-ATO patient versus eight (12.3%) ATRA-CHT patients ( P = .014). Overall, 32% and 68% of patients receiving ATRA-ATO and ATRA-CHT, respectively, reported serious treatment-emergent adverse events ( P < .01). CONCLUSION The results of the APOLLO trial support the use of ATO and ATRA for the treatment of newly diagnosed patients with high-risk APL.