Chemotherapy-Free Regimen of ATRA Plus Arsenic Trioxide Improves Survival in APL

Updated results from the APL0406 study suggest that the combination of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) was associated with greater long-term event-free survival (EFS) and disease-free survival (DFS) in patients with low- and intermediate-risk acute promyelocytic leukemia (APL), compared with ATRA plus chemotherapy (ATRA-CHT). The research letter was published in Leukemia by Laura Cicconi, MD, from University Tor Vergata in Rome.

“This recent analysis confirms the significant advantage of the ATRA-ATO combination for all outcome measures, including its associated survival rate, which constantly exceeded 95%,” corresponding author Maria Teresa Voso, MD, also from the University Tor Vergata, told ASH Clinical News. “The specific sensitivity of APL to ATRA-ATO was shown by the absence of primary resistance to this treatment, with all patients achieving molecular remission.”

The prospective, randomized, phase III APL0406 trial enrolled 276 patients with newly diagnosed low- to intermediate-risk APL (age range = 18-71 years). After patients who did not have confirmation of the disease-defining PML/RARA fusion gene and who did not start allocated treatment per study protocol were excluded, there were 266 patients in the long-term, intention-to-treat analysis.

Participants were randomized to receive either:

  • ATRA-ATO combination for induction and consolidation therapy (n=129)
  • ATRA plus chemotherapy (idarubicin) induction therapy, followed by three cycles of ATRA plus chemotherapy consolidation therapy cycles, then maintenance therapy with low-dose chemotherapy plus ATRA (n=137)

During a median follow-up of 66.4 months (range = 0.9-116.7 months), 263 patients were evaluable for EFS, the study’s primary endpoint.

The EFS rate at 72 months was significantly greater in the ATRA-ATO group compared with the ATRA-CHT group: 96.6% versus 77.4% (hazard ratio [HR] = 0.14; 95% CI 0.05–0.39; p=0.0002).

Rates of the secondary efficacy endpoint, 72-month DFS, were greater in the ATRA-ATO group (96.6% vs. 79.8%; HR=0.16 [95% CI 0.05-0.45; p=0.0006]).

Patients in the ATRA-ATO group also had a lower cumulative incidence of relapse compared with the ATRA-CHT group (HR=0.102; 95% CI 0.024-0.434; p=0.020):

  • ATRA-ATO: 1.7% (95% CI 0.0-4.0)
  • ATRA-CHT: 15.5% (95% CI 9.0-22.0)

Moreover, the benefit of ATRA-ATO appeared to grow over time, the researchers reported, noting that “no additional relapses were reported in the ATRA-ATO group [since the earlier published reports from APL0406], while the relapse rate in the ATRA-chemotherapy arm has increased over time, with two additional late relapses (50 and 55 months) being recorded after the last report.” In addition, two patients in the ATRA-CHT group developed secondary leukemias, while no cases have been observed in patients randomized to ATRA-ATO.

The investigators noted that the ATRA-ATO combination had “a relatively safe profile in the short term,” but, in this long-term report, ATRA-ATO was consistently associated with a higher incidence of transient AST/ALT increase, QTc prolongation, and leukocytosis compared with ATRA-CHT.

“These long-term outcome data suggest that the ATRA-ATO regimen can now be considered standard of care in patients with low-risk to intermediate-risk APL, which is the first acute leukemia considered curable by a chemotherapy-free regimen,” Dr. Voso said.

Despite their findings, the researchers added that some “burning” issues on this topic are still open and ready to be explored. “Early death, prior to treatment start, often due to central nervous system or lung bleeding, remains a problem affecting 10% to 30% of patients,” Dr. Voso explained. “These figures strongly affect the survival probability of APL but are not properly depicted by survival curves, since most deaths occur prior to diagnosis and/or enrollment in clinical trials.” She noted that more extensive real-life registries are required to fully understand this issue, and the present analysis did not include information about overall survival.

Dr. Voso added that the potential for the development of differentiation syndrome in this patient population requires intensified monitoring and more targeted treatments.

The authors report no relevant conflicts of interest.

Reference

Cicconi L, Platzbecker U, Avvisati G, et al. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2019 October 14. [Epub ahead of print]