Therapy Based on Attenuated Arsenic Trioxide Plus Low-Dose All-Trans-Retinoic Acid in Acute Promyelocytic Leukemia. Is Less More?

Introduction: the standard-of-care of acute promyelocytic leukemia (APL) is now chemotherapy-free. The use of lower doses of all-trans-retinoic acid (ATRA) have been shown to achieve effective plasma concentrations with doses of 25mg/m2/day. An attenuated regimen of arsenic trioxide (ATO) has been proven to be effective in inducing similar remission rates and prolonged disease-free survival, also demonstrating a reduction in associated toxicities. Therefore, in this study we aimed to demonstrate the effectiveness of combined therapy of low-dose ATRA plus attenuated dose ATO.

Methods: we designed a phase 2, non-randomized, single-center clinical trial (NCT05497310) in consecutive adults with diagnosis of APL, confirmed by the presence of t (15;17) by FISH or PCR from July 2022 to April 2024, combined induction therapy of low-dose ATRA (25 mg/m2/day, continuous at least 28 days) plus attenuated dose of intravenous (IV) ATO (0.3 mg/kg/day for days 1-5, then 6-10 doses of 0.25 mg/kg/day divided twice a week) until complete remission (CR). If high-risk (WBC >10 x10⁹/L at presentation) a mitoxantrone 10 mg/m2/day was added on day 1. Three cycles of consolidation therapy (low-dose ATRA every day and IV ATO 0.25 mg/kg/day twice a week for 4 weeks each). Differentiation syndrome (DS) prophylaxis with dexamethasone and hydroxyurea or anthracycline was used; supportive transfusion care as needed to reach goals. Adverse events and in-patient stay days were registered. The primary endpoint was CR at the end of induction; the secondary endpoints were molecular response (mCR), by RT-PCR PML-RARA, at the end of first and third consolidation cycle, early death (ED), hematological a non-hematological toxicities and overall survival (OS) and event-free survival (EFS), defined as no achievement CR after induction, including ED, relapse or death, by Kaplan Meier method. There was no maintenance therapy, instance active surveillance with molecular evaluations was established.

Results: we included 15 consecutive patients (pts) with newly diagnosed APL, 2 pts (13%) had secondary APL, 11 pts (73%) were women, median age was 33 years (IQR, 20-49). According to Sanz criteria 3 pts (20%) were high-risk, 12 pts were intermediate-risk (80%), none were low-risk. The median time of hospitalization was 19 days (IQR, 14-23), after discharge treatment continued as an outpatient. All pts developed leukocytosis with a peak of 36.9x10⁹/L (IQR, 21.9-58.7), with a median of 12 days (IQR, 9-17) during induction. None had DS or QT prolongation. None had CNS involvement at evaluation. Hematological CR was achieved in 13 pts (87%), 8 of them (61%) had hematological incomplete CR, the median time to CR was 37 days (IQR, 32-42). Two pts (13%) did not evaluate CR because of ED due to CNS bleeding both at day 7 and 12 of induction. All 13 pts (100%) achieved mCR after at least one cycle of consolidation, median follow-up of 9 months (IQR, 7.4-14.6). The 2-year EFS rate was 72%. CNS relapse was observed in 1 patient at 9.4 months after CR, none other relapses were observed. The 2-year OS rate was 87%. No deaths in CR were reported. Adverse events grade 2 or more during induction: hyperphosphatemia 8 pts (53%), headache 7 (46%), bleeding 6 (40%), edema 4 (27%), infections 4 (27%), hepatotoxicity 3 (20%), hypomagnesemia 2 (13%), heartburn 2 (13%), fever of unknown origin 2 (13%), acute kidney failure 1 (6%), pseudotumor cerebri 1 (6%).

Conclusion: low-dose ATRA plus ATO led to comparable CR and mCR rates and is an attractive alternative in limited resources settings. Despite ATO and ATRA ED remains the main problem in our context. This therapy was effective and safe, even for outpatient use after the late induction phase. This approach is promising, although further follow-up and validation studies are needed to confirm our results.

Gomez-Almaguer:Blueprint Medicines: Research Funding; Amgen: Consultancy, Other: Advisory board, Research Funding, Speakers Bureau; Incyte: Research Funding; Sanofi: Speakers Bureau; Seattle Genetics: Research Funding; Astex Pharmaceuticals: Research Funding; Kartos Therapeutics: Research Funding; Roche: Speakers Bureau; AbbVie: Research Funding, Speakers Bureau; Tevas: Speakers Bureau; BMS: Consultancy, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Other: Advisory board, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: Advisory board, Speakers Bureau; Janssen: Consultancy, Other: Advisory board, Speakers Bureau; Gilead/Forty Seven: Research Funding; ConstellationPharmaceuticals: Research Funding. Gomez-De Leon:Abbvie: Honoraria; Amgen: Honoraria; bms: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Sanofi: Honoraria, Other: Advisory board; Janssen: Other: Advisory board.