Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: Interim results of the SCCLG-APL clinical study

Abstract

Intravenous arsenic trioxide (ATO) has been adopted as the first-line treatment for acute promyelocytic leukemia (APL). Another arsenic compound named the Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine containing As₄ S₄ , has been shown to be highly effective in treating adult APL. In the treatment of pediatric APL, the safety and efficacy of RIF remains to be confirmed. This randomized, multicenter, and noninferiority trial was conducted to determine whether intravenous ATO can be substituted by oral RIF in the treatment of pediatric APL. From September 2011 to January 2017, among 92 patients who were 16 years old or younger with newly diagnosed PML-RARa positive APL, 82 met eligible criteria and were randomly assigned to ATO (n = 42) or RIF (n = 40) group. The remaining 10 patients did not fulfilled eligible criteria because five did not accept randomization, four died and one had hemiplegia prior to arsenic randomization due to intracranial hemorrhage or cerebral thrombosis. Induction and consolidation treatment contained ATO or RIF, all-trans-retinoic acid and low intensity chemotherapy. End points included event-free survival (EFS), adverse events and hospital days. After a median 3-year follow-up, the estimated 5-year EFS was 100% in both groups, and adverse events were mild. However, patients in the RIF group had significantly less hospital stay than those in the ATO group. This interim analysis shows that oral RIF is as effective and safe as intravenous ATO for the treatment of pediatric APL, with the advantage of reducing hospital stay. Final trial analysis will reveal mature outcome data.

Figure 1

The SCCLG‐APL regimen. Abbreviations: ATRA, all‐trans retinoic acid; MA, mitoxantrone; R, randomization; ATO, arsenic trioxide; RIF, Realgar‐Indigo naturalis formula; HCR, haematologic complete remission; HCRp, HCR with incomplete platelet recovery; AC, cytarabine; MRD, minimal residual disease; IT, intrathecal injection of cytarabine and dexamethasone; MTX, methotrexate; 6MP, 6‐mercaptopurine. *Patients received ATRA if morphologically diagnosed with APL. ^#Bone marrow examination is considered for evaluating the achievement of HCR or HCRp when no leukemic cell was found in peripheral blood. ^□Patients were randomly assigned to ATO or RIF group when the diagnosis was genetically confirmed (5‐6 days later), and then ATO or RIF was started and ATRA was continued until HCR/HCRp or for a maximum of 42 days. ^▵The doses of 6MP and MTX were adjusted to maintain the WBC of patients between 2 and 3.5 × 10⁹/L

Figure 2

CONSORT diagram of enrolled patients. ATO, arsenic trioxide; RIF, Realgar‐Indigo naturalis formula