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The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has been demonstrated to be at least equally effective to ATRA and chemotherapy (CHT) in non-high-risk acute promyelocytic leukemia (APL). However, the efficacy of ATRA-ATO compared to ATRA-ATO plus CHT in high-risk APL remains unknown. Here we performed a multi-center non-inferiority phase III study to compare the efficacy of ATRA-ATO and ATRA-ATO plus CHT in newly diagnosed all-risk APL to address this question. Patients were assigned to receive ATRA-ATO for induction, consolidation and maintenance or ATRA-ATO plus CHT for induction followed by three cycles of consolidation therapy, and maintenance therapy with ATRA-ATO. In the non-CHT group, hydroxyurea was used to control leukocytosis. A total of 128 patients were treated. The complete remission rate was 97% in both groups. The 2-year disease-free, event-free survival rates were 98% v 97% and 95% v 92% in the non-CHT group and CHT group in all-risk patients (P=0.62 and P=0.39, respectively). And they were 94% v 87% and 85% v 78% in the high-risk patients (P=0.52 and P=0.44, respectively). This study demonstrated that ATRA-ATO had the same efficacy as the ATRA-ATO plus CHT in the treatment of patients with all-risk APL.

Acute promyelocytic leukemia (APL) has become a highly curable disease with all-trans retinoic acid-based regimens. However, following the administration of arsenic trioxide (ATO), the relapse rate remains at 1-10%. It is not known whether the dosage of ATO is associated with the relapse rate in real-world settings. According to 2019 National Comprehensive Cancer Network guidelines, the recommended cumulative ATO dosage in post-remission therapy is 7.95-12 mg/kg in APL. In the current study, 112 patients with newly diagnosed APL receiving a combination of all-trans retinoic acid, anthracycline-based chemotherapy and different dosages of ATO for variable courses, were divided into the high-dose (ATO dosage, ≥12 mg/kg) and low-dose groups (ATO dosage, <12 mg/kg). Relapse risk factors were analyzed by multiple factor analysis. The relationship between relapse rate and ATO dosage in post-remission was elucidated by determining the 4-year cumulative incidence of relapse (CIR). Based on the ATO dosage in post-remission therapy, 72 (64.3%) patients were in the low-dose group and 40 (35.7%) were in the high-dose group. An increased ATO dosage was demonstrated to be an independent protective factor in terms of probability of relapse (P=0.004). With a median follow-up time of 53 months, the 4-year CIR was 16.7% in the low-dose group and 0% in the high-dose group, respectively (P=0.008). No patient relapsed when administered an ATO dosage >6 mg/kg. In conclusion, the relapse rate of APL was significantly associated with ATO dosage in post-remission therapy. An increased ATO dosage may serve as a protective factor of relapse. ATO dosage should therefore reach up to 12 mg/kg, with consideration to reduce the dosage in the future.

BackgroundAcute promyelocytic leukemia (APL) is a highly curable disease when treated with all-trans retinoid acid (ATRA) and arsenic trioxide (ATO). The combination of ATO and ATRA has become the standard therapeutic protocol for induction therapy in non-high-risk APL. An oral arsenic realgar-indigo naturalis formula (RIF) has also showed high efficacy and it has a more convenient route of administration than the standard intravenous regimen. Unlike in previous trials, the arsenical agent was used simultaneously with ATRA during post-remission therapy in this trial.MethodsThis study was designed as a multicenter, randomized controlled trial. The trial has a non-inferiority design with superiority being explored if non-inferiority is identified. All patients receive ATRA-ATO during the induction therapy. After achieving hematologic complete remission (HCR), patients were randomly assigned (1:1) to receive treatment with ATRA-RIF (experimental group) or ATRA-ATO (control group) as the consolidation therapy. During the consolidation therapy, the two groups receive ATRA plus RIF or intravenous ATO 2 weeks on and 2 to ~ 4 weeks off until molecular complete remission (MCR), then ATRA and oral RIF 2 weeks on and 2 to ~ 4 weeks off giving a total of six courses.DiscussionThis trial aims to compare the efficacy of ATRA-ATO versus ATRA-RIF in non-high-risk patients with APL, to demonstrate that oral RIF application reduces the total hospitalization days and medical costs. The simple schedule was studied in this trial.Trial registrationClinicalTrials.gov, NCT02899169. Registered on 14 September 2016.

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