Zhu HH, et al. - Given that high efficacy of oral arsenic realgar-Indigo naturalis formula (RIF) plus arsenic trioxide plus all-trans retinoic acid (ATRA) without chemotherapy in non-high-risk acute promyelocytic leukaemia (white blood cell count ≤10 × 10⁹ per L), compared with the standard intravenous regimen (intravenous arsenic trioxide plus ATRA without chemotherapy) has been shown in a pilot study, researchers compared these treatment regimens in this study. They found non-inferiority of oral RIF plus ATRA in comparison with intravenous arsenic trioxide plus ATRA for the treatment of patients with non-high-risk acute promyelocytic leukaemia. These findings indicate that for patients with non-high-risk acute promyelocytic leukaemia, a completely oral, chemotherapy-free model might be an alternative to the standard intravenous treatment.

Methods

• Researchers performed this multicentre, non-inferiority, open-label, randomised, controlled phase 3 trial at 14 centres in China including patients aged 18–70 years with newly diagnosed (within 7 days) non-high-risk acute promyelocytic leukaemia, and a WHO performance status of 2 or less.
• As the induction and consolidation therapy, patients were randomly administered (2:1) RIF-ATRA or arsenic trioxide-ATRA.
• They carried out randomisation centrally with permuted blocks and stratification according to trial centre and via an interactive web response system, implementation was done.
• Until complete remission, use of RIF (60 mg/kg bodyweight daily in an oral divided dose) or arsenic trioxide (0·15 mg/kg daily in an intravenous dose) and ATRA (25 mg/m² daily in an oral divided dose) was continued.
• The regimen of home-based consolidation therapy was: RIF (60 mg/kg daily in an oral divided dose) or intravenous arsenic trioxide (0·15 mg/kg daily in an intravenous dose) in a 4-week on 4-week off regimen for four cycles and ATRA (25 mg/m² daily in an oral divided dose) in a 2-week on 2-week off regimen for seven cycles.
• Patients and treating physicians were not masked to treatment allocation.
• Event-free survival at 2 years was the primary outcome.
• Non-inferiority assessment using a non-inferiority margin of -10% was performed.
• They carried out primary analyses in a modified intention-to-treat population of all patients who received at least one dose of their assigned treatment and the per-protocol population.

Results

• Enrollment and assignment to RIF-ATRA (n=72) or arsenic trioxide-ATRA (n=37) of 109 patients was done between Feb 13, 2014, and Aug 31, 2015.
• The assigned treatment was not received by 3 patients in the RIF-ATRA and 1 in the arsenic trioxide-ATRA.
• A median follow-up of 32 months (IQR 27–36) revealed that in the modified intention-to-treat population, 2-year event-free survival was achieved by 67 (97%) of 69 patients in the RIF-ATRA group and 34 (94%) of 36 in the arsenic trioxide-ATRA group.
• The reported percentage difference in event-free survival was 2·7% (95% CI, -5·8 to 11·1).
• Non-inferiority (p=0·0017) was confirmed by the observation that the lower limit of the 95% CI for the difference in event-free survival was greater than the -10% non-inferiority margin.
• Data showed non-inferiority was also confirmed in the per-protocol population.
• During induction therapy, six (9%) of 69 patients in the RIF-ATRA group vs five (14%) of 36 patients in the arsenic trioxide-ATRA group experienced grade 3–4 hepatic toxic impacts (ie, increased liver aspartate aminotransferase or alanine transaminase concentrations); grade 3–4 infection was reported in 15 (23%) of 64 vs 15 (42%) of 36 patients.
• They also reported death of 2 patients in the arsenic trioxide-ATRA group during induction therapy (one from haemorrhage and one from thrombocytopenia).