FDA Approves Arsenic Trioxide for Promyelocytic Leukemia

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

The approval was based on published findings and a review of a global safety database for arsenic trioxide, according to Teva Pharmaceuticals, the company developing the combination. In findings published in the New England Journal of Medicine (NEJM), arsenic trioxide plus ATRA led to a 2-year event-free survival (EFS) rate of 97% compared with 86% for ATRA plus chemotherapy, for an overall difference of 11% (95% CI, 2%-22%). The EFS P value was <.001 for noninferiority and P = .02 for superiority for the novel combination versus ATRA and chemotherapy.

“Today’s approval to expand the indication of Trisenox is a testament to Teva’s commitment to providing solutions to advance cancer care,” Paul Rittman, Senior Vice President and General Manager, Teva Oncology, said in a statement. “This label expansion represents an important benefit as Trisenox is now an FDA-approved first-line treatment option for patients with acute promyelocytic leukemia.”

The phase III study randomized 156 patients between October 2007 and September 2010 to receive ATRA plus arsenic trioxide (n = 77) or chemotherapy (n = 79). The median age of patients in the arsenic trioxide arm was 44.6 years, and the median white cell count was 1.49 x 10^-9/liter. The median platelet count was 31 x 10^-9/liter and the risk levels were low (43%) and intermediate (57%). The PML-RARA isoform was long for 58% and 22% of patients had FLT3-ITD mutations.

In the induction phase, ATRA was administered at 45 mg/m² per day and arsenic trioxide was given intravenously at a dose of 0.15 mg/kg daily until bone marrow remission. Following induction therapy, arsenic trioxide was given in a consolidation phase at 0.15 mg/kg per for 5 days followed by 2 days of rest and ATRA the same induction dose for 15 days in each 28-day cycle. In the comparator arm, ATRA was given with idarubicin for induction followed by ATRA and chemotherapy in the consolidation and maintenance setting.

In the induction phase, 100% of patients treated in the arsenic trioxide group experienced a hematologic complete remission (CR) compared with 95% of those in the comparator arm (P = .012). The median time to hematologic CR was 32 versus 35 days in the arsenic trioxide and chemotherapy arms, respectively (P = .61). The rates of differentiation syndrome were similar between the two arms (19% with arsenic trioxide and 16% with chemotherapy; P = .62).

Of those achieving hematologic CR in the induction phase, 146 went on to receive consolidation therapy. All evaluable patients in this setting achieved molecular remission, which accounted for 75 in the arsenic trioxide arm and 70 in the chemotherapy group. Sixty-seven patients in the control arm proceeded to maintenance therapy.

After a median follow-up of 34.4 months, the 2-year overall survival rate was 99% (95% CI, 96%-100%) in the arsenic trioxide arm compared with 91% (95% CI, 85%-97%) for the chemotherapy group (P = .02). The 2-year disease-free survival rate was 97% (95% CI, 94%-100%) with arsenic trioxide versus 90% (95% CI, 84%-97%) in the control arm (P = .11). The cumulative incidence of relapse at 2 years was 1% versus 6% in the investigational and control arms, respectively (P = .24).

Grade 3/4 thrombocytopenia and neutropenia lasting for >15 days was significantly more common in the chemotherapy group versus the arsenic trioxide arm. Grade 3/4 hepatic toxicity was more common with arsenic trioxide (63%) versus chemotherapy (6%). QTc interval prolongation was experienced by 16% of patients in the arsenic trioxide compared with none for chemotherapy.

In the induction phase, grade 3/4 thrombocytopenia for >15 days occurred for 88% of patients in the chemotherapy group versus 59% in the arsenic trioxide arm. Additionally, in the induction phase, 79% of patients in the chemotherapy group had grade 3/4 neutropenia lasting >15% compared with 46% in the arsenic trioxide group. In the consolidation period, few patients in the investigational arm experienced these events compared with similar rates for the chemotherapy arm.

Arsenic trioxide was initially approved in 2000 as a treatment for patients with APL who are refractory or have relapsed on retinoid and anthracycline chemotherapy. The agent was approved as a frontline therapy for patients with low- and intermediate-risk APL in the European Union in November 2016. This indication was based more exclusively on the data published in NEJM.

"This decision is a very positive endorsement by the European Commission, as it was made based solely on published academic research and studies," the phase III lead investigator Francesco Lo-Coco, MD, hematology, University Tor Vergata, said in a statement when the drug was approved in Europe. "From now on, APL patients with non-high risk disease will have access to this chemotherapy-free regimen of Trisenox plus retinoic acid at diagnosis, which has the potential to increase survival rates while minimizing side effects associated with chemotherapy.”

Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia. N Engl J Med. 2013;369:111-121. DOI: 10.1056/NEJMoa1300874.

Prophylactic prednisone was given at 0.5 mg/kg on day 1 until the end of induction therapy to avoid differentiation syndrome. If signs of the syndrome were noted, ATRA, arsenic trioxide, or both were temporarily discontinued and intravenous dexamethasone was administered at 10 mg every 12 hours for a minimum of 3 days.