An Entirely Oral Regimen of Oral-Arsenic Trioxide/All-Trans Retinoic Acid/Ascorbic Acid in Newly-Diagnosed Acute Promyelocytic Leukaemia (APL): Updated Results of an Ongoing Multicentre Trial

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Background: Pure oral arsenic trioxide (oral-ATO) solution (Arsenol ®) was first formulated in Hong Kong. It achieves a bioavailability comparable with that of intravenous ATO (i.v.-ATO). Oral-ATO combined with all-trans retinoic acid (ATRA) and ascorbic acid (the AAA regimen) combined with chemotherapy is highly efficacious in relapsed and newly-diagnosed APL. To reduce treatment-related toxicities and long-term risks of second primary cancers, a chemotherapy-free approach is increasingly favoured. Aims: The objectives of this prospective multicentre study in newly diagnosed APL patients were: 1. to evaluate the efficacy and safety of an entirely oral AAA-induction in a risk-adapted strategy; 2. to evaluate the molecular responses during oral-AAA-based induction/consolidation/maintenance. Methods: Newly-diagnosed APL patients were stratified by presentation leucocyte count into standard-risk (≤ 10 x 10 9/L) and high-risk (> 10 x 10 9/L) groups. Standard-risk patients and high-risk patients ≥ 65 years old received AAA induction comprising oral-ATO (Arsenol ®, Jacobson Pharma Corporation, Hong Kong) (10 mg/day, or 0.16 mg/kg in patients < 18 years old, days 1-42), ATRA (45 mg/m 2/day, or 25 mg/m 2/day in patients <18 years old, in 2 divided doses, days 1-42), and oral ascorbic acid (1 g/day, or 15mg/kg/day in patients <18 years old, days 1-42). High-risk patients < 65 years old received in addition daunorubicin (50 mg/m 2/day i.v. for 3 days). On reaching first complete remission (CR1), consolidation with AAA (days 1-14) every 28 days for 2 cycles was given, followed by maintenance with AAA (days 1-14) every 8 weeks for 12 cycles. Real-time quantitative polymerase chain reaction for PML:: RARA with a sensitivity of 10 -5 was performed (weekly during induction, every 4 weeks during consolidation, every 8 weeks during maintenance and thereafter every 12 weeks for 2 years). For molecular response, the normalized copy number ratio was defined as PML::RARA copy number/ ABL copy number. Primary outcomes were overall survival (OS, time from presentation to death or last follow-up), and relapse-free survival (RFS, time from CR1 to molecular or haematological relapse, death or last follow-up), and safety (according to the Common Toxicity Criteria for Adverse Events (AE) version 5.0). The secondary outcome was molecular response. Data were censored on July 22, 2023. Results: Between January 1, 2018 to July 22, 2023, 5 paediatric/adolescent patients (male, N=2; female, N=3) at a median age of 12 (3-15) years and 116 adult (> 18 years old) patients (male, N=47 ; female, N=69) at a median age of 49 (19-91) years were accrued (standard risk: paediatric/adolescent, N=3; adults, N=87; high-risk: paediatric/adolescent, N=2; adults, N=29). Seven patients (all high-risk adults) died at presentation before induction (intracranial haemorrhage, N=6; severe APL differentiation syndrome, DS, with leucocyte >100 x10 9/L, N=1). One-hundred and fourteen patients received oral-AAA-based induction (AAA alone, N=90; AAA+daunorubicin, N=24), all achieving CR1. For PML:: RARA normalized copy number, all treated patients at week 8 achieved a ratio of <0.01; and on completion of AAA maintenance, all evaluable patients (N=56) achieved a ratio of <0.0001. The median follow-up was 29 (IQR: 8-47) months, with 56 patients (49%) having completed 2 years of AAA maintenance. There was only one relapse, occurring in an adult patient 12 months after completion of AAA maintenance. Molecular analysis showed a PML B2 domain A216V mutation that conferred resistance to ATO. One adult patient died of an unrelated gastrointestinal bleeding while in CR1. The 3-year OS was 99.1% (paediatric/adolescent: 100%; adult: 99%). The 3-year RFS was 97.9% (paediatric/adolescent: 100%; adult: 97.9%). The most common non-haematological AEs (all grade 1-2) were transaminitis (N=54, 47.3%) and headache (N=32, 28%) Notably, no cardiotoxicity (arrhythmias/cardiac failure) was observed. APL-DS occurred in 67 patients (58.7%) after initiation of AAA, all responding fully to intravenous dexamethasone. There were no treatment discontinuations. 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 age groups. Early deaths remained an obstacle to realizing a cure-for-all in APL.

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