Oral etoposide vs intravenous daunorubicin plus ATRA-RIF as induction therapy for low-risk acute promyelocytic leukemia: A phase II randomized controlled Trial Free

Introduction Despite all-trans retinoic acid (ATRA) -arsenical regimens achieve high cure rates in low-risk APL, relapse persists as a key challenge. Recent studies and our prior work suggest intravenous chemotherapy during induction may reduce relapses (Br J Haematol, 2021; Am J Hematol, 2019; Blood, 2010). Our clinical experience with oral etoposide in APL treatment indicated its efficacy, safety, and convenience as a cytoreductive agent during induction therapy (Zhu XL et al. J Cell Mol Med. 2024; Leuk Res Rep, 2021). Here we designed a randomized, phase II clinical trial (NCT05832320) comparing oral etoposide versus intravenous daunorubicin as cytoreductive therapy, both combined with ATRA and the realgar-indigo naturalis formula (RIF, an oral arsenic tetra-sulfide [As₄S₄] preparation), for induction therapy in low-risk APL patients.

Methods Newly diagnosed adult patients (aged 18-75 years) with low-risk APL were enrolled. Between January 1, 2023, and December 16, 2024, eligible patients were randomized 1:1 to receive double-induction therapy with either oral etoposide or intravenous daunorubicin.

ATRA plus RIF was administered following the 2018 Chinese APL management guidelines. When WBC exceeded 4.0×10⁹/L during induction , patients were given oral etoposide (50 mg QD to 50 mg TID) with a cumulative dosage ≤1500mg. Initiation of intravenous daunorubicin (20 to 40 mg per dose) was at the same situation and adjust the dose according to the patients' condition and WBC counts. The primary outcome were CR and the incidence of PML-RARA transcript levels of ≥6.5% at the end of induction, which was proved to be associated with a subsequent risk of relapse in our study. Secondary endpoints included early death (ED), 2-year cumulative incidence of relapse (CIR), 2-year disease-free survival rate (EFS) and safety.

Results Seventy-eight patients were randomized to cytoreductive therapy with intravenous daunorubicin (n = 39) or oral etoposide (n = 39). Median follow-up was 538 (range 196-880) days. During induction, mean cumulative doses were 180 (0-240) mg for daunorubicin and 1000 (250-1500) mg for etoposide.

All evaluable patients achieved hematological CR without any ED events. The median time to hematological CR was 47 (30-63) days. During the follow-up period, relapse events were observed in both treatment groups with distinct patterns. In the daunorubicin group (n=6), the median time to relapse was 451 (183-691) days, comprising one hematologic relapse (occurring in a patient without daunorubicin exposure) and five molecular relapses (including two cases with ≤100 mg cumulative daunorubicin exposure). The etoposide group (n = 3) showed a median time to relapse of 330 (189-570) days, with one hematologic relapse and two molecular relapses (both occurring in patients with ≤500 mg cumulative etoposide exposure). The 2-year cumulative incidence of hematologic relapse was 3.85% in the daunorubicin group and 7.14% in the etoposide group (P = 0.638). The 2-year EFS were 57.8% and 86.8%, respectively (P = 0.238). All molecular relapse cases (n = 7) achieved complete molecular remission after reinduction therapy.

One daunorubicin-treated patient developed hematological relapse with PML-RARA transcripts ≥6.5% post-induction, whereas no etoposide-treated patients achieved this transcript level at induction completion. Univariate analysis revealed statistically significant associations between relapse and both CD56 expression (P = 0.030) and FLT3-ITD positivity at diagnosis (P = 0.023). Variables with P <0.2 in univariate analysis (CD34/CD56 expression, FLT3-ITD positivity at diagnosis, and induction-phase differentiation syndrome) were included in multivariate modeling, though none achieved independent significance. Importantly, the incidence of treatment-related adverse events did not differ significantly between treatment groups.

Conclusions In summary, the combination of oral etoposide and RIF-ATRA as induction therapy demonstrates comparable efficacy in preventing relapse and offers superior convenience compared to intravenous daunorubicin in low-risk APL.The data suggest a potential link between reduced cytoreductive dosing and increased relapse risk, while maintaining a manageable safety profile. Ongoing studies with extended follow-up will further define long-term outcomes.