“Boldness be my friend” (Shakespeare; Cymbeline)

Au et al report in this issue of Blood that oral arsenic trioxide (ATO) may be safely used in maintenance therapy in acute promyelocytic leukemia (APL).¹  This is a major improvement in convenience given that intravenous (IV) ATO requires daily administration for weeks at a time. In addition, the oral formulation may be less toxic. The time seems right to carefully explore the introduction of oral ATO earlier in treatment of the disease.

With all-trans retinoic acid (ATRA), intensive blood product support, and anthracycline-based chemotherapy, APL has become the most curable of the adult leukemias. Now that the outcome with current treatment is so favorable, an emerging goal is to improve convenience while maintaining excellent results. Population-based studies demonstrate that the early death rate (EDR) remains a substantial problem.^2,3  With earlier recognition of the disease and prompt administration of ATRA and blood product support,⁴  the EDR may well decrease. Concurrent with minimizing the EDR, the goals of modern studies have been to reduce the relapse rate and decrease the toxicities of treatment, prompting risk-adapted therapies.^5,6  ATO is the most effective single agent in the treatment of patients with APL and widely used for the treatment of relapsed and refractory disease. However, the current schedule of administration intravenously on a daily basis for 5 consecutive weeks is cumbersome. Initial studies have suggested that the use of ATO early in therapy (rather than reserving it for relapse), has further improved the response rate and minimized toxicities. As demonstrated by the North American intergroup study, the addition of ATO in early consolidation increased the event-free survival.⁷  Arsenic trioxide in consolidation may permit a reduction in the amount of anthracycline chemotherapy.⁸  Several randomized clinical trials are under way to evaluate the benefits of ATO given with ATRA as initial therapy. In all of these studies, ATO is administered as an IV formulation. The Hong Kong group developed an oral formulation of ATO and has previously studied it in patients with relapsed APL demonstrating good bioavailability, minimal prolongation of the QT interval, and safety in the outpatient setting.^1,9 

Here, Au and colleagues report the outcome of 76 patients with APL in first complete remission (CR1) after induction and consolidation therapy with daunorubicin and cytarabine regimens who received oral ATO maintenance.¹  During the study, the specific maintenance regimen changed from single-agent oral ATO, to oral ATO with ATRA, and finally to oral ATO with ATRA and ascorbic acid; each given for 2 weeks every 2 months for 2 years. Between 2001 and 2010, all patients with APL in CR1 were registered on this study and treated with oral ATO. At a median follow-up of 24 months, there were 8 relapses. The 3-year leukemia-free-survival (LFS) was 88% and overall survival (OS) was 91%. While adverse prognostic factors included male sex for LFS and unrelated cancers for OS, age, presenting white blood cell count and platelet count, and the type of oral ATO maintenance regimen used had no impact on OS. Importantly, QT prolongation and arrhythmias were not problematic. It appears that ATO can be administered in a convenient and safe oral formulation as maintenance therapy.

Several limitations prevent making a determination as to the contribution of oral ATO to the excellent outcome. First, it is not possible to directly compare these results to those of the GIMEMA, PETHEMA, or North American Intergroup studies because patients reported here were all in first complete remission at the time of ATO maintenance therapy. Second, the induction and consolidation regimens varied as did the maintenance therapy. Third, recent studies suggest that maintenance therapy may not be required for patients in molecular CR1 after induction and consolidation with standard ATRA plus anthracycline-based chemotherapy.^7,10  Furthermore, no data are available to address the question of whether patients treated with ATRA plus ATO for induction and consolidation receive benefit from ATO or any other maintenance. Finally, there were concerns about the development of secondary malignancies in this series.¹  Thus, what is most compelling about Au et al's work is the ability to use ATO orally. If bioavailability and tolerability are satisfactory, the road is paved to use oral ATO earlier in the treatment of the disease, namely in consolidation and induction. Oral ATO in induction and consolidation would be much more convenient and cost effective. Furthermore, it is predicted that cardiac toxicity would be less with oral absorption as opposed to potentially cardiotoxic peak concentration after IV infusion.¹¹  It is time to take the next bold step and evaluate oral ATO earlier in the natural history of the disease in carefully designed studies. We will certainly need continued vigilance for the development of secondary malignancies, as ATO is used more and earlier in the disease. Shakespeare would be proud as we urge the study of oral ATO in consolidation and even in induction. This would substantially improve quality of life and would likely allow more patients to benefit from ATO therapy. Boldness, be my friend.