The combination of all-trans­-retinoic acid (ATRA) and arsenic trioxide continues to show advantages over ATRA and chemotherapy as first-line therapy for patients with low- or intermediate-risk acute promyelocytic leukemia (APL), investigators report.

The final analysis of the APL046 study , a noninferiority trial of ATRA plus arsenic trioxide (ATRA-ATO) vs. ATRA and standard chemotherapy, showed that event-free survival (EFS) and overall survival (OS) were significantly better among patients assigned to ATRA-ATO. Patients in this group also had a significantly lower cumulative incidence of relapse, reported Francesco Lo-Coco, MD, of University Tor Vergata in Rome and colleagues.

“Our results support the use of ATRA-ATO in patients with newly diagnosed APL and point to this strategy as the new standard of care for low- or intermediate-risk patients. Studies exploring the role of ATRA-ATO are warranted in other APL subsets including high-risk, pediatric, and elderly patients,” they wrote (J Clin Oncol. 2016 July 11. doi: 10.1200/JCO.2016.67.1982 ).

In the trial, 276 patients with newly diagnosed APL were randomly assigned to receive either ATRA-ATO or ATRA plus chemotherapy with idarubicin, mercaptopurine, and methotrexate.

A total of 263 patients were evaluable for response to induction, including 127 assigned to ATRA-ATO and 136 assigned to ATRA-chemotherapy. Following induction, all patients assigned to ATRA-ATO and 127 assigned to chemotherapy (97%) achieved a complete remission (CR).

After a median follow-up of 40.6 months, the rate of EFS, the primary outcome, was 97.3% for ATRA-ATO vs. 80% for ATRA-chemotherapy (P less than .001). The cumulative incidences of relapse were 1.9% and 13.9%, respectively (P = .0013), and overall survival rates at 50 months were 99.2% vs. 92.6% (P = . 0073).

Hematologic toxicities were more frequent among patients assigned to chemotherapy, while liver function abnormalities occurred more often among those assigned to ATO.

One patient assigned to ATRA-ATO died while in CR, from bronchopneumonia caused by the H1N1 (influenza) virus. Five patients assigned to chemotherapy died in CR, from hemorrhagic shock, pulmonary embolism, bronchopneumonia (two patients) and secondary myelodysplastic syndrome.

Of the 17 patients who experienced relapses during follow-up, 2 assigned to ATRA-ATO had relapses at 22 and 27 months. The remaining 15 relapses were among patients assigned to ATRA-chemotherapy, occurring at a median of 14 months.

The authors noted that the superior EFS and cumulative incidence of relapse with ATRA-ATO emerged only after longer follow-up, indicating that the advantage of ATRA-ATO over ATRA-chemotherapy increases over time and that “the inclusion of ATO in the treatment of low- or intermediate-risk APL not only reduces mortality and hematologic toxicity, but also results in improved and sustained antileukemic activity.”

The study was supported by the Gruppo Italiano Malattie Ematologiche dell’Adulto Foundation; the Associazione Italiana Contro le Leucemie, Linfomi e Mieloma, Associazione Italiana per la Ricerca sul Cancro, and the German Federal Ministry of Education and Research. Dr. Lo-Coco disclosed honoraria, consulting, and speakers’ bureau activities with Teva Pharmaceutical, Lundbeck, Novartis, Baxalta, and Pfizer. Several other coauthors disclosed similar relationships.