FDA Approves Firstline Arsenic Trioxide for Acute Promyelocytic Leukemia

The FDA approved arsenic trioxide in combination with the all-trans retinoic acid (ATRA) tretinoin for firstline treatment of adults with newly diagnosed, low-risk acute promyelocytic leukemia (APL) and t(15;17) or PML-RARA gene expression.

The decision was based on a global safety database for arsenic trioxide, as well as results from a randomized, phase III trial that enrolled 156 patients between October 2007 and September 2010. Participants received ATRA plus arsenic trioxide (n=77; median age = 44.6 years; range = 19.1-70.2 years) or ATRA plus chemotherapy (n=79; median age = 46.6 years; range = 18.7-70.2 years). The study, published in The New England Journal of Medicine, found that arsenic trioxide plus ATRA resulted in a two-year event-free survival rate of 97 percent, compared with 86 percent for ATRA plus chemotherapy (overall difference = 11%; 95% CI 2-22; p<0.001 for non-inferiority; p=0.02 for superiority).

After a median follow-up of 34.4 months (range = 0.5 to 55.8 months), the two-year OS rate was 99 percent with ATRA plus arsenic trioxide (95% CI 96-100) and 91 percent with ATRA plus chemotherapy (95% CI 85-97; p=0.02). The two-year disease-free survival rate was 97 percent (95% CI 94-100) and 90 percent (95% CI 84-97), respectively (p=0.11). The cumulative incidence of relapse at two years was 1 percent with arsenic trioxide and 6 percent with chemotherapy (p=0.24).

In the induction phase, patients received daily ATRA 45 mg/m2 and arsenic trioxide 0.15 mg/kg administered intravenously daily until bone marrow remission. In the comparator arm, patients received ATRA with idarubicin for induction, followed by ATRA and chemotherapy in the consolidation and maintenance setting. All patients treated with arsenic trioxide experienced a hematologic complete remission (CR), compared with 95 percent of those in the comparator arm (p=0.012). The median time to CR was 32 days (range = 22-68 days) and 35 days (range = 26-63 days), respectively (p=0.61). Among those who achieved CR in this phase, 146 went on to receive consolidation therapy, and all evaluable patients achieved molecular remission (n=75 in the arsenic trioxide arm and n=70 in the chemotherapy group).

Grade 3/4 thrombocytopenia and neutropenia lasting more than 15 days occurred more often in the chemotherapy group, while grade 3/4 hepatic toxicity was more common with arsenic trioxide (63% vs. 6%; p value not provided).

Arsenic trioxide was approved in 2000 for patients with refractory or relapsed APL following retinoid and anthracycline chemotherapy. The drug carries a boxed warning for differentiation syndrome and cardiac conduction abnormalities.

Sources: Teva press release, January 15, 2018; Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111-21.