Reduced Relapse but No Quality-of-Life Benefit With ATRA/Arsenic Trioxide vs ATRA/Idarubicin in Acute Promyelocytic Leukemia


Key Points

  • No overall difference in quality of life was observed between groups.
  • ATRA/arsenic trioxide was associated with reduced risk of relapse and reduced need for supportive care but no significant improvement in overall survival.

In a UK-based phase III trial (AML17) reported in The Lancet Oncology, Burnett et al found that a chemotherapy-free regimen of arsenic trioxide plus all-trans retinoic acid (ATRA) did not improve quality of life, the primary endpoint, vs ATRA plus idarubicin in patients with acute promyelocytic leukemia in all risk groups. ATRA/arsenic trioxide was associated with reduced risk of relapse, but overall survival did not differ between groups.

Study Details

In this open-label trial, 235 patients aged ≥ 16 years with acute promyelocytic leukemia confirmed by the presence of the PML-RARA transcript from 81 sites in the UK, Denmark, and New Zealand were randomly assigned between May 2009 and October 2013 to ATRA/idarubicin (n = 119) or ATRA/arsenic trioxide (n = 116). Patients could not have significant cardiac or pulmonary comorbidities or active malignancy and could not be pregnant or breastfeeding.

ATRA was given in a daily divided oral dose of 45 mg/m2 until remission or until day 60 and then in a 2 weeks on/2 weeks off schedule. Idarubicin was given intravenously at 12 mg/m2 on days 2, 4, 6, and 8 of course 1 and then at 5 mg/m2 on days 1 to 4 of course 2, along with mitoxantrone at 10 mg/m2 on days 1 to 4 of course 3, and idarubicin at 12 mg/m2 on day 1 of the fourth (final) course. Arsenic trioxide was given intravenously at 0.3 mg/kg on days 1 to 5 of each course and at 0.25 mg/kg twice weekly in weeks 2 to 8 of course 1 and weeks 2 to 4 of courses 2 to 5.

High-risk patients (n = 57) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m2 IV). Patients did not receive maintenance treatment or CNS prophylaxis.

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 were by intention to treat. Participants had a median age of 47 years (range = 16–77 years), and 50% to 52% were male.

Quality of Life

There was no significant difference in QLQ-C30 global functioning (effect size = 2.17, 95% confidence interval = −2.79 to 7.12, P = .39), with the confidence intervals ruling out a minimally clinically significant disadvantage of 6 points for ATRA/arsenic trioxide vs ATRA/idarubicin. For other QLQ-C30 measures, point estimates tended to favor ATRA/arsenic trioxide, with significant benefit observed in cognitive and role functioning, although all benefits were modest.

Adverse Events

Grade 3 or 4 adverse events occurred in 48% of patients in the ATRA/idarubicin group and 34% of the ATRA/arsenic trioxide group. During course 1, the most common grade 3 or 4 adverse events in the ATRA/idarubicin group were alopecia (23% vs 5%), oral adverse events (19% vs 1%), and increased ALT (10% vs 25%); the most common in the ATRA/arsenic trioxide group was increased ALT. After two courses, the most common grade 3 or 4 adverse events in the ATRA/idarubicin group were alopecia (28% vs 3%) and increased AST (2% vs 2%) and the most common in the ATRA/arsenic trioxide group were cardiac events (3% vs 0%).

Patients in the ATRA/arsenic trioxide group had significantly reduced requirement for aspects of supportive care, including reduced use of blood and platelet units during courses 1 and 2, reduced days of antibiotics during course 1, and reduced days of hospitalization during courses 1 and 2.

Relapse and Survival

There was no significant difference between the ATRA/idarubicin and ATRA/arsenic trioxide groups in complete remission rates (89% vs 94%, P = .18) or confirmed molecular negativity (88% vs 91%, P = .43) and no difference in 4-year overall survival (89% vs 93%, P = .25.). Four-year event-free survival (91% vs 70%, P = .002), morphologic recurrence-free survival (97% vs 78%, P = .004), and molecular recurrence-free survival  (98% vs 70%, P < .001) were greater in the ATRA/arsenic trioxide group, and 4-year cumulative incidence of morphologica relapse (1% vs 18%, P = .0007) and molecular relapse (0% vs 27%, P < .0001) were lower.

The investigators concluded: “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.”

Alan K. Burnett, FMedSci, of Cardiff University School of Medicine, is the corresponding author for the Lancet Oncology article.

The study was funded by Cancer Research UK. For full disclosures of the study authors, visit

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