title: 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.
abstract: BACKGROUND
  Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia.
  
  
  METHODS
  In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535.
  
  
  RESULTS
  Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group.
  
  
  CONCLUSIONS
  ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.
authors.affiliation: Department of Haematology Cardiff University School of Medicine, Cardiff, UK. Electronic address: akburnett719@gmail.com.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
authors.affiliation: Department of Haematology, Nottingham University Hospital NHS Trust, Nottingham, UK.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Russell
authors.affiliation: Department of Haematology Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hills
authors.affiliation: Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bowen
authors.affiliation: Department of Haematology, University Hospital of Wales, Cardiff, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kell
authors.affiliation: Department of Haematology Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Knapper
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, UK.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Morgan
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, UK.
authors.forename: Jennie
authors.initials: J
authors.lastname: Lok
authors.affiliation: Department of Haematology Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Grech
authors.affiliation: Department of Haematology, Newcastle Teaching Hospitals NHS Trust, Newcastle, UK.
authors.forename: Gail
authors.initials: G
authors.lastname: Jones
authors.affiliation: Department of Haematology, University College Hospitals, London, UK.
authors.forename: Asim
authors.initials: A
authors.lastname: Khwaja
authors.affiliation: Department of Haematology, Rigshospitalet, National University Hospital, Copenhagen, Denmark.
authors.forename: Lone
authors.initials: L
authors.lastname: Friis
authors.affiliation: Department of Haematology, Belfast City Hospital, Belfast, UK.
authors.forename: Mary Frances
authors.initials: MF
authors.lastname: McMullin
authors.affiliation: Department of Haematology, Leicester Royal Infirmary, Leicester, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Hunter
authors.affiliation: Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clark
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D003718:Denmark; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000009:adverse effects / Q000627:therapeutic use*; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D015473:Leukemia, Promyelocytic, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010087:Oxides / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome; D014212:Tretinoin / Q000009:adverse effects / Q000627:therapeutic use*; D006113:United Kingdom; D055815:Young Adult
chemical_list: D001152:Arsenicals; D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide; D015255:Idarubicin