Phase III trial of oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukemia

In a recent issue of The Lancet Oncology, Hong-Hu Zhu from Peking University People’s Hospital, Beijing, China, published the results of a multicenter, non-inferiority, open-label, randomized, controlled phase III trial (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054), evaluating the efficacy and safety of oral arsenic realgar-Indigo naturalis formula (RIF) in combination with all-trans retinoic acid (ATRA) compared with intravenous arsenic trioxide (ATO) plus ATRA therapy in patients with newly diagnosed non high-risk acute promyelocytic leukemia (APL).

Between February 2014 and August 2015, 109 patients were enrolled and randomly assigned 2:1 to receive either oral RIF plus ATRA (n = 72) or ATO plus ATRA (n = 37) as induction therapy until complete hematologic remission. As post-remission therapy, RIF or ATO was given on a schedule of 4 weeks’ on and 4 weeks’ off, furthermore, ATRA was administered on a schedule of 2 weeks’ on and 2 weeks’ off for 7 months. The primary endpoint of the study was event-free survival (EFS) at two years. The secondary endpoints included complete remission (CR), overall survival (OS), and safety.  

Key findings:

• Efficacy

  • CR in the RIF-ATRA and ATO-ATRA cohorts: 100% (69/69) vs 94.4% (34/36) respectively, P = 0.12
  • 2-year EFS rate in the RIF-ATRA and ATO-ATRA cohorts: 97% vs 94%, P = 0.49
  • 2-year overall survival in the RIF-ATRA and ATO-ATRA cohorts: 100% vs 94%, P = 0.049
  • There was no significant difference in relapse between the RIF-ATRA and the ATO-ATRA arm, P = 0.32

• Safety

  • Most common grade 3/4 non-hematological and hematological adverse events during induction treatment:
    • RIF-ATRA group: neutropenia, anemia, thrombocytopenia, infection, increased liver ALT/AST levels
    • Arsenic trioxide-ATRA group: neutropenia, anemia, thrombocytopenia, infection, increased liver ALT/AST levels, hemorrhage
  • Liver damage during induction in the RIF-ATRA vs ATO-ATRA arms: 58% vs 78%, P = 0.05

In summary, these results indicate that RIF plus ATRA is not inferior to ATO plus ATRA as first-line treatment of patients with non-high-risk APL. The authors further added that “nonhigh-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy. Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

References

1. Zhu H. et al. Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial. Lancet Oncol. 2018 June 5. DOI: 1016/S1470-2045(18)30295-X.