title: Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial.
abstract: BACKGROUND
  Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy.
  
  
  METHODS
  Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639.
  
  
  RESULTS
  124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4·2 years (IQR, 3·2-5·2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0·23 (95% CI 0·08-0·64, p=0·002) for freedom from relapse, 0·21 (0·07-0·59, p=0·001) for disease-free survival, 0·34 (0·16-0·69, p=0·002) for event-free survival, and 0·35 (0·14-0·91, p=0·02) for overall survival.
  
  
  CONCLUSIONS
  Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival.
  
  
  BACKGROUND
  Phebra.
authors.affiliation: Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; University of Sydney, Sydney, NSW, Australia. Electronic address: harryiland@gmail.com.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Iland
authors.affiliation: Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, VIC, Australia.
authors.forename: Marnie
authors.initials: M
authors.lastname: Collins
authors.affiliation: University of Sydney, Sydney, NSW, Australia; Haematology, Westmead Hospital, Westmead, NSW, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Bradstock
authors.affiliation: Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Shane G
authors.initials: SG
authors.lastname: Supple
authors.affiliation: Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Alberto
authors.initials: A
authors.lastname: Catalano
authors.affiliation: University of Sydney, Sydney, NSW, Australia; Haematology, Westmead Hospital, Westmead, NSW, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Hertzberg
authors.affiliation: University of Auckland, Auckland, New Zealand.
authors.forename: Peter
authors.initials: P
authors.lastname: Browett
authors.affiliation: Haematology, Royal Melbourne Hospital, Parkville, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Grigg
authors.affiliation: University of Melbourne, Melbourne, VIC, Australia; Haematology, St Vincent's Hospital, Fitzroy, VIC, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Firkin
authors.affiliation: University of Melbourne, Melbourne, VIC, Australia; Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy, VIC, Australia.
authors.forename: Lynda J
authors.initials: LJ
authors.lastname: Campbell
authors.affiliation: Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Hugman
authors.affiliation: Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, VIC, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, VIC, Australia.
authors.forename: Juliana
authors.initials: J
authors.lastname: Di Iulio
authors.affiliation: Haematology, Gosford Hospital, Gosford, NSW, Australia; University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Campbell
authors.initials: C
authors.lastname: Tiley
authors.affiliation: Haematology, Mater Medical Centre, South Brisbane, QLD, Australia.
authors.forename: Kerry
authors.initials: K
authors.lastname: Taylor
authors.affiliation: University of Melbourne, Melbourne, VIC, Australia; Haematology, St Vincent's Hospital, Fitzroy, VIC, Australia.
authors.forename: Robin
authors.initials: R
authors.lastname: Filshie
authors.affiliation: University of Newcastle, Callaghan, NSW, Australia; Haematology, Calvary Mater Hospital, Newcastle, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Seldon
authors.affiliation: Haematology, Nepean Hospital, Kingswood, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Taper
authors.affiliation: Haematology, Royal Melbourne Hospital, Parkville, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Jeff
authors.initials: J
authors.lastname: Szer
authors.affiliation: Haematology, St Vincent's Hospital, Darlinghurst, NSW, Australia; University of New South Wales, Kensington, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Moore
authors.affiliation: Haematology, Wesley Medical Centre, Auchenflower, QLD, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Bashford
authors.affiliation: Haematology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D001315:Australia; D060830:Consolidation Chemotherapy; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D010087:Oxides / Q000627:therapeutic use*; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide