title: Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.
abstract: BACKGROUND
  All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.
  
  
  METHODS
  We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.
  
  
  RESULTS
  Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.
  
  
  CONCLUSIONS
  ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).
authors.affiliation: Dipartimento di Biomedicina e Prevenzione, Università Tor Vergata, Rome, Italy. francesco.lo.coco@uniroma2.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Avvisati
authors.forename: Marco
authors.initials: M
authors.lastname: Vignetti
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Sonia Maria
authors.initials: SM
authors.lastname: Orlando
authors.forename: Simona
authors.initials: S
authors.lastname: Iacobelli
authors.forename: Felicetto
authors.initials: F
authors.lastname: Ferrara
authors.forename: Paola
authors.initials: P
authors.lastname: Fazi
authors.forename: Laura
authors.initials: L
authors.lastname: Cicconi
authors.forename: Eros
authors.initials: E
authors.lastname: Di Bona
authors.forename: Giorgina
authors.initials: G
authors.lastname: Specchia
authors.forename: Simona
authors.initials: S
authors.lastname: Sica
authors.forename: Mariadomenica
authors.initials: M
authors.lastname: Divona
authors.forename: Alessandro
authors.initials: A
authors.lastname: Levis
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Elisa
authors.initials: E
authors.lastname: Cerqui
authors.forename: Massimo
authors.initials: M
authors.lastname: Breccia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fioritoni
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Salih
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Lorella
authors.initials: L
authors.lastname: Melillo
authors.forename: Angelo M
authors.initials: AM
authors.lastname: Carella
authors.forename: Christian H
authors.initials: CH
authors.lastname: Brandts
authors.forename: Enrica
authors.initials: E
authors.lastname: Morra
authors.forename: Marie
authors.initials: M
authors.lastname: von Lilienfeld-Toal
authors.forename: Bernd
authors.initials: B
authors.lastname: Hertenstein
authors.forename: Mohammed
authors.initials: M
authors.lastname: Wattad
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.forename: Matthias
authors.initials: M
authors.lastname: Hänel
authors.forename: Norbert
authors.initials: N
authors.lastname: Schmitz
authors.forename: Hartmut
authors.initials: H
authors.lastname: Link
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Kropp
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.forename: Giorgio
authors.initials: G
authors.lastname: La Nasa
authors.forename: Mario
authors.initials: M
authors.lastname: Luppi
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Olimpia
authors.initials: O
authors.lastname: Finizio
authors.forename: Adriano
authors.initials: A
authors.lastname: Venditti
authors.forename: Francesco
authors.initials: F
authors.lastname: Fabbiano
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Michaela
authors.initials: M
authors.lastname: Sauer
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Franco
authors.initials: F
authors.lastname: Mandelli
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects / Q000627:therapeutic use*; D060830:Consolidation Chemotherapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010087:Oxides / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D014212:Tretinoin / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide