Dr Gill on the Evaluation of Oral Arsenic Trioxide Plus ATRA/Ascorbic Acid in APL

Harry Gill, MD, FRCP, FRCPath, clinical assistant professor, Department of Medicine, Li Ka Shing Faculty of Medicine, Hong Kong University of Medicine, discusses the investigation of an all-oral combination of arsenic trioxide, all trans retinoic acid (ATRA), and ascorbic acid (the AAA regimen) in patients with newly diagnosed acute promyelocytic leukemia (APL).

Data from the phase 2 APL003 trial (NCT04687176) presented at the 2023 EHA Congress showed that all 98 patients evaluable for efficacy experienced a complete remission, according to Gill. Through the study and follow-up period, only 1 patient relapsed and later died from refractory APL. Gill says this relapse was due to a PML-B2 A216V mutation, which conferred resistance to arsenic trioxide.

Additional data showed that the 3-year relapse-free survival (RFS) rate was 97.1%, and the 3-year overall survival (OS) rate was 98.9%. 

Regarding safety, the most common non-hematologic adverse effects (AEs) included transaminitis (55%) and headache (33%), and those toxicities were all grade 1/2. Notably, no cardiotoxicity or grade 3/4 hepatoxicity related to oral arsenic trioxide were reported. Additionally, no treatment-related deaths occurred, and arsenic trioxide did not lead to any treatment discontinuations. APL differentiation syndrome was reported in 60% of patients within 14 days of the initiation of AAA; all of these patients fully responded to dexamethasone.

The ongoing single-arm study is enrolling patients with newly diagnosed APL with t(15;17)(q24;q21) or acute myeloid leukemia harboring variant RARA translocation, per 2022 World Health Organization Classification. During induction, patients received 10 mg of arsenic trioxide per day plus 45mg/m² of ATRA in 2 divided doses and 1 g of ascorbic acid per day for 42 days. In patients under 18 years of age, the doses were 0.16 mg/kg per day for arsenic trioxide, 25 mg/m² per day of ATRA, and 15 mg/kg per day for ascorbic acid.

Consolidation therapy consisted of AAA daily for 14 days every 28 days for 2 cycles, and AAA was then given as maintenance therapy for 2 weeks every 8 weeks for up to 2 years, totaling 12 cycles. RFS and event-free survival serve as the trial’s co-primary end points. OS and toxicities are secondary end points. Recruitment in a multicenter setting in Asia is ongoing.