Background: Pure oral arsenic trioxide (oral-ATO) solution (Arsenol ®) was first formulated in Hong Kong. It achieves a bioavailability comparable to that of intravenous ATO (i.v.-ATO). Oral-ATO, used in combination with all trans retinoic acid (ATRA) and ascorbic acid (the AAA regimen) has been shown to highly effective in the frontline induction/consolidation of newly-diagnosed acute promyelocytic leukaemia (APL) in combination with chemotherapy.

Aims: The objectives of this ongoing multi-centre phase 2 study of newly-diagnosed APL patients were: 1. to evaluate the efficacy and safety of an entirely oral AAA-induction in a risk-adapted strategy with no chemotherapy and minimal chemotherapy in low-risk and high-risk (presentation leucocyte ≤ 10 x 10⁹/L and > 10 x 10⁹/L) cases; 2. to evaluate the molecular responses during treatment with oral-AAA-based induction/consolidation/maintenance.

Methods: Patients with newly-diagnosed APL received oral-AAA induction that comprised oral ATO (Arsenol ®, Jacobson Pharma, Hong Kong) (10mg/day, or 0.16mg/kg in patients < 18 years old, days 1-42), ATRA (45mg/m²/day, or 25mg/m²/day in patients <18 years old, in 2 divided doses, days 1-42), and oral ascorbic acid (1g/day, or 15mg/kg/day in patients <18 years old, days 1-42). Daunorubicin (50mg/m²/day intravenously for 3 days) was administered to patients < 65 years old with high-risk disease. On reaching first complete remission (CR1) consolidation treatment comprising oral-AAA (days 1-14) every 28 days for 2 cycles was given, followed by maintenance with oral-AAA (days 1-14) every 8 weeks for 12 cycles. Real-time quantitative polymerase chain reaction for PML:RARA was performed weekly during induction, every 4 weeks during consolidation, every 8 weeks during maintenance and every 12 weeks for 2 years thereafter. The primary outcomes were overall survival (OS, time from presentation to death), and relapse-free survival (RFS, time from CR1 to molecular/haematologic relapse or death), and safety. The secondary outcome was molecular response. Data were censored on February 28, 2023.

Results: Between January 1, 2018 to January 31, 2023, 41 men and 64 women with a median age of 49 years (range: 3-91 years) were accrued, with 77 patients (73.3%) and 28 patients (26.7%) belonging to the low-risk and high-risk groups. Seven patients (6.7%) died at presentation before induction (intracranial haemorrhage, N=6; differentiation syndrome, DS, N=1). Ninety-eight patients received oral-AAA-based induction (AAA alone, N=77; AAA+daunorubicin, N=21). All treated patients achieved CR1. At 8 weeks, all patients achieved a MRD ratio of <0.01. On completion of AAA maintenance, all evaluable patients achieved an MRD ratio of <0.0001. The median duration of follow-up was 27 months (interquartile range: 7-44 months), with 40 patients having completed 2 years of AAA maintenance at data censoring. During the study period, only one patient had molecular relapse 12 months after the completion of AAA maintenance, followed by haematologic relapse 2 weeks later and died from refractory APL. This patient harboured the A216V variant on the PML B2 domain conferring resistance to ATO. One patient died in remission due to gastrointestinal bleeding unrelated to treatment. The 3-year OS and RFS were 98.9% and 97.1% respectively. Cardiotoxicity and grade 3/4 hepatotoxicity related to oral-ATO were not observed. APL-DS occurred in 59 patients (60%) after initiation of AAA (all within the first 14 days), all responding fully to dexamethasone.

Summary/Conclusion: The use of an entirely oral AAA-based induction in a risk-adapted strategy that minimized chemotherapy was highly effective and safe in newly-diagnosed APL of all risk categories, and induced deep molecular responses.