Replacing chemotherapy with arsenic trioxide for the treatment of acute promyelocytic leukemia in the frontline setting: Is it cost‐effective?

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML). APL carries a hallmark biomolecular alteration that has significant implications for the clinical course and approach to management of patients with APL. The striking success of APL treatment using the differentiating agents has encouraged scientific research regarding a new approach to treating cancer. Before the introduction of all-trans retinoic acid (ATRA), APL was treated similarly to other subtypes of AML and carried a poor prognosis with early mortality, in particular due to coagulopathy. ATRA overcomes the maturation block that is introduced by the PML-RARA fusion gene that is characteristic of APL. This promotes physiologic myeloid differentiation and is effective in resolving the cardinal clinical manifestations of APL. Today, with the use of differentiating agents and improved supportive care, complete remission is expected in >90% of patients with APL along with a similar long-term event-free survival. The differentiating agents currently form the backbone of APL treatment and treatment with ATRA plus an anthracycline has become the standard for treating patients with APL within the last decade of the 20th century. Arsenic trioxide (ATO) was shown to provide a significant benefit to patients with recurrent/refractory APL, with complete remission rates comparable to those noted in the first-line setting. In recent years, medical data have been accumulating in favor of the use of ATO over anthracycline treatment in the first-line setting. Arsenic derivatives are among the oldest substances used as medication. Their use dates back to 400 BC and they were used to treat cancer, syphilis, and psoriasis along with other significant diseases until the 20th century. ATO has a complex mechanism of action, and is believed to interfere with multiple intracellular signaling pathways by binding cysteine-rich residues. The growing interest in ATO is due mainly to its potent activity against APL cells, in which it degrades the PML-RARA fusion protein and induces apoptosis in the malignant cells. A randomized, multicenter, open-label, phase 3 trial enrolled 162 patients with low-risk or intermediate-risk APL and demonstrated the noninferiority of the combination of ATRA and ATO compared with ATRA plus idarubicin treatment in the first-line setting. The 2-year overall survival rate was 99% in the patients treated with ATRA and ATO compared with 91% in those receiving ATRA and idarubicin (P = .02). The patients treated with ATRA and ATO were found to have an average of 7.4 fewer hospital days, 4.5 fewer units of blood product transfusions, and 10.7 fewer days of intravenous antibiotic use compared with patients receiving ATRA and idarubicin in the first 2 courses of treatment. The study strongly suggested that treatment with the combination of ATRA and ATO is noninferior to that with ATRA and idarubicin. In another multicenter, open-label, phase 3 trial that enrolled 235 patients with APL in which all risk groups were included, patients were randomized to receive either ATRA and ATO or ATRA and idarubicin. The percentages of patients who were alive at the end of 4 years were 93% and 89%, respectively, for the ATRA and ATO and ATRA and idarubicin groups (P = .25). A noticeable finding in this study was that the 4-year event-free survival rate in the patients treated with ATRA and ATO was 91% compared with a significantly lower rate of 70% in the group receiving ATRA and idarubicin (P = .002). Life-threatening adverse events were observed in 53 of 119 patients in the group treated with ATRA and idarubicin and in 46 of 116 patients in group receiving ATRA and ATO. The results of this trial were updated in 2018, and again confirmed earlier findings. The 5-year recurrence rate remained very low at 1% for the combination of ATRA and ATO, whereas the rate was 20% for patients receiving