Oral Arsenic Plus Retinoic Acid Versus Intravenous Arsenic Plus Retinoic Acid for Non-High Risk Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trials

Objective

Intravenous arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non high-risk acute promyelocytic leukemia (APL), resulting in cure rates exceeding 95%. Pilot study of treatment with oral arsenic named the Realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy has shown high efficacy, convenient and economical. This randomized, multicenter, phase 3 noninferiority trial was designed to test the efficacy and safety of an oral RIF and ATRA compared with intravenous ATO for newly diagnosed non high-risk APL patients.

Methods

We conducted a phase 3, multicenter trial comparing RIF plus ATRA with ATO plus ATRA in patients with non high-risk APL (white-cell count, ≤10×109 per liter) between 2014 and 2017. In all, 109 patients were randomly assigned (2:1) to oral RIF (60 mg/kg) plus ATRA (25 mg/m2) or ATO (0.16mg/kg) plus ATRA (25 mg/m2) as induction therapy until complete hematologic remission. Postremission therapy included RIF or ATO on a schedule of 4 weeks on and 4 weeks off and ATRA on a schedule of 2 weeks on and 2 weeks off for 7 months.

The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival (EFS) at 2 years in the two groups was not greater than 10%.

Results

Complete remission was achieved in all 69 patients in the RIF-ATRA group who could be evaluated (3 withdraw during the induction) and in 34 of 36 patients in the ATO-ATRA group (2 died and another one withdraw during the induction) (100% vs. 94.4%, p= 0.12).

The median follow-up was 32 months. Two-year EFS rates were 97.1% in the RIF-ATRA group (n=69) and 94.4% in the ATO-ATRA group (n=36). The EFS rate difference was 2.7% (95% CI,-5.8% to11.1%). The lower limit of the 95%CI for EFS rate difference was greater than-10% noninferiority margin, confirming noninferiority (noninferiority P=0.0017). There is no difference about relapse rate and overall survival between two groups (all p >0.05).

Conclusions

RIF plus ATRA is not inferior to ATO plus ATRA in the treatment of patients with non high-risk APL (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054).