An oral tetra-arsenic tetra-sulfide formula may be a promising alternative to intravenous arsenic trioxide in the first-line treatment of acute promyelocytic leukemia.
The oral realgar–Indigo naturalis formula (RIF) plus all-trans-retinoic acid (ATRA) produced a similar 2-year disease-free survival rate as intravenous arsenic trioxide (ATO) plus ATRA (98.1% vs. 95.5%, respectively; P < .001 for noninferiority) in a multicenter, randomized phase III trial.
This is the first study to demonstrate noninferiority for the RIF/ATRA combination in the first-line treatment of acute promyelocytic leukemia (APL). Toxicity, which is a concern with any arsenic-containing agent, was also similar with both treatments.
"The results may indicate that oral RIF may be used in place of ATO as a first-line treatment in newly diagnosed APL," Dr. Hong-Hu Zhu reported in the Journal of Clinical Oncology (2013;31:4215-21).
RIF is commercially available in China and contains realgar (a tetra-arsenic tetra-sulfide mineral), Indigo naturalis, Radix salviae miltiorrhizae, and Radix pseudostellariae. Indigo naturalis and Radix salviae miltiorrhizae promote intracellular transport of arsenics and have shown synergistic effects with tetra-arsenic tetra-sulfide on the differentiation and apoptosis of APL cells, explained Dr. Zhu, of Peking University People’s Hospital, Beijing.
In a prior phase II trial, RIF demonstrated a reasonable safety profile and a 96.7% complete response (CR) rate (Chin. J. Hematol. 2006;27:801-4).
The current trial, designed by the Chinese APL Cooperative Group, randomly assigned 242 patients, aged 15-60 years, with APL to induction ATRA 25 mg/m2 plus oral RIF 60 mg/kg or ATO 0.16 mg/kg. Mitoxantrone 1.4 mg/m2 daily was added for 5 days on the fourth day or on the first day for patients with a white blood cell (WBC) count higher than 10 x 109/L.
After achieving a CR, patients received three courses of consolidation chemotherapy (homoharringtonine, cytarabine, daunorubicin, and mitoxantrone), and eight cycles of maintenance therapy consisting of ATRA 25 mg/m2 for 15 days for the first month followed by either RIF 60 mg/kg for RIF induction patients or ATO 0.16 mg/kg for ATO induction patients for 15 days for the second and third months, and continued for 2 years.
All patients received seven intrathecal injections of cytarabine 50 mg/methotrexate 10 mg/dexamethasone 5 mg for central nervous system (CNS) leukemia prophylaxis. Eleven patients were excluded from the final analysis for various reasons, including failure to meet entry criteria. All patients had a WHO (World Health Organization) performance status of 2 or lower; their median age was 36 years.
After a median follow-up of 39 months (range, 21-64 months), 98.3% of patients achieved a CR. The CR rate was similar between the RIF and ATO groups (99.1% vs. 97.4%, respectively; P = .62), as was the median time to CR of 29 days. CR rates were comparable or slightly higher than in previous studies using ATRA and chemotherapy or an arsenic-based first-line treatment, Dr. Zhu observed.
Of the 227 patients receiving consolidation chemotherapy and maintenance therapy, 1 patient in each arm relapsed, but achieved a second CR after reinduction with tamibarotene and ATO, and remained alive at last follow-up.
Three-year overall survival was similar in the RIF and ATO groups (99.1% vs. 96.6%; P = .18). Survival was also higher than observed in previous reports (64% to 92%), possibly due to the 2-year induction/maintenance treatment period, exclusion of patients with a high risk of relapse (WBC greater than 50 x 109/L), and use of CNS prophylaxis, he said.
Grade 3/4 nonhematologic adverse events, including liver events, were similar between the two groups.
Both RIF and ATO achieved arsenic concentrations within a range (0.1-2.0 mmol/L) previously shown by the authors to induce apoptosis of APL cells, "which may explain why both drugs had comparable efficacies," the authors noted. No significant accumulation of arsenic was observed in the study (cumulative dose, about 2,500 mg), despite the 2 years of treatment.
Dr. Zhu reported having no financial disclosures; a coauthor reported consulting for and receiving honoraria from Novartis and Bristol-Myers Squibb.