General AML

Long-term results from the phase III randomized study of attenuated arsenic trioxide and ATRA for patients with acute promyelocytic leukemia

The randomized NCRI AML17 Trial compared a standard chemotherapy-based regimen of all-trans retinoic acid (ATRA) plus anthracycline (AIDA) to a chemotherapy-free approach consisting of attenuated schedule of arsenic trioxide (ATO) plus ATRA in patients with acute promyelocytic leukemia (APL). In this study, 235 patients (median age = 47 years, range, 16–77) with APL were randomized 1:1 to receive either ATRA plus idarubicin (n = 119) or ATRA plus ATO (n = 116). Previously published data from this study showed that ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with APL, with a high cure rate and less relapse than ATRA and idarubicin, with a low incidence of liver toxicity. However, there was no significant difference in overall survival (OS) between the ATO plus ATRA and AIDA arms.1

In a Letter to the Editor of Blood, a group of researchers from the UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group reported the long-term results for randomized patients and for 32 patients who received the same schedule of ATO + ATRA after relapsing from the AIDA arm in the NCRI AML 17 trial. The primary objective of this updated analysis was to ascertain whether an overall survival benefit for the ATO+ATRA over the chemotherapy-based regimen has emerged.2

Treatment
  • AIDA arm:
    • Course 1: idarubicin (12 mg/m2) on day 2, 4, 6, 8 plus ATRA (45 mg/m2/d in two divided doses) to day -60
    • Course 2: Idarubicin 5 mg/m2 on day 1–4 plus ATRA on day 1–15
    • Course 3: Mitoxantrone 10 mg/m2 on day 1–5 plus ATRA on day 1–15
    • Course 4: Idarubicin 12 mg/m2 dl plus ATRA on day 1–15
  • ATO plus ATRA arm:
    • ATO: 8-week induction 0.3 mg/kg, day 1–5 on week 1, 0.25 mg/kg x 2/w on week 2–8, followed by 4 consolidation courses of 0.3 mg/kg on day 1–5 on week 1, 0.25mg/kg x 2/w, on week 2–4 (63 ATO doses)
    • ATRA: 45 mg/m2 in two divided doses
Key findings for randomized patients:
  • Median follow-up time: 67.4 months
  • 5-year OS in the ATO plus ATRA and AIDA arm: 92% vs 86%, HR = 0.71 (0.21–1.34), P = 0.4
  • 5-year Molecular relapse-free survival among patients who became MRD negative after consolidation therapy in the ATO plus ATRA and AIDA arm: 97% vs 78%, HR = 0.25 (0.12–0.52), P = 0.0002
  • No molecularly negative patients treated in the ATO plus ATRA arm relapsed
  • 5-year cumulative incidence of relapse in patients in the ATO plus ATRA and AIDA arm: 1% vs 10%, HR = 0.43 (0.18–1.03), P = 0.005
  • 5-year relapse-free survival (RFS) in the ATO plus ATRA and AIDA arm: 96% vs 86%, HR = 0.43 (0.18–1.03), P = 0.06
Key findings for 32 patients who relapsed following AIDA therapy and treated with attenuated ATO schedule:
  • Median follow-up: 44.9 months
  • 5-year OS: 88%
  • All patients achieved molecular complete remission

In summary, the combination of ATO and ATRA continues to show a very low risk of relapse irrespective of risk group with a significantly superior RFS, however, no OS benefit emerged over AIDA.

References
  1. Burnett A. K. et al. 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. Lancet Oncol. 2015; 16: 1295-305. DOI: 10.1016/S1470-2045(15)00193-X. Epub 2015 Sep 14.
  2. Russell N. H. et al. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood. 2018 Aug 10. DOI: 10.1182/blood-2018-05-851824. [Epub ahead of print].
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