In Joseph Kesserling’s classic 1941 black comedy “Arsenic and Old Lace,” 2 well-meaning elderly sisters served elderberry wine laced with arsenic, strychnine, and a “pinch” of cyanide to lonely single elderly men who were subsequently buried in the basement by their delusional brother Teddy who believed he was Theodore Roosevelt digging the Panama Canal. In addition to this creative, albeit morbid, application, arsenic has been historically used in electronics, as a wood preservative, and in antisyphilitic medications.
The 1997 publication from the Shanghai Institute of Hematology that reported a nearly 100% complete response rate to arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL) was both startling and remarkable.1 The finding was confirmed by a group from Memorial Sloan Kettering Cancer Center2 and in a multicenter study.3 ATO was subsequently introduced into induction and consolidation treatments for patients with newly diagnosed APL (eg, Mathews et al4 and Gore et al5) and demonstrated improved overall survival when compared with therapies that did not include ATO.6 The impressive activity of ATO relates to its specificity for inducing the degradation of the PML-RARα (Promyelocytic Leukemia-Retinoic acid receptor alpha) oncoprotein in leukemic promyelocytes and in their stem cells (reviewed in a study by de Thé et al7).
The combination of ATO with all-trans retinoic acid (ATRA) proved to be superior to the contemporary standard of care ATRA-chemotherapy combinations8 in low- to intermediate-risk APL and was at least comparable in high-risk patients with improved quality of life.9 Based on these studies, ATRA-ATO represents the current standard of care for patients with newly diagnosed APL with estimated cure rates of 86% to 97%.10
Curing APL continues to require intensive resources. The successful mitigation of life-threatening coagulopathy and differentiation syndrome during induction remains challenging and continues to lead to induction deaths, particularly among patients who present with an elevated white blood cell count. From the patient perspective, after a prolonged and intensive inpatient induction hospitalization, 7 months of consolidation therapy with ATRA and ATO ensue. The ATO must be administered IV for 20 doses, 5 days a week, for 4 cycles during this period (a total of 80 doses). In other words, over 7 months of consolidation therapy, patients must come into the clinic daily during business hours for 4 months (80 infusion visits). Although most would agree that the goal of cure is highly worthwhile, the impact of this parenteral administration on the quality of life and productivity can easily be imagined.
An oral formulation of ATO has been in use in Hong Kong and China and is highly effective11; however, attempts to bring oral ATO into Western countries have met regulatory and pharmacoeconomic hurdles. A study that examined the pharmacokinetics of an oral formulation was criticized on methodological bases.12 The author of this commentary had an National Institutes of Health grant application that proposed to study oral ATO in APL rejected because the problem was merely a “patient convenience” issue and therefore apparently not worthy of government funds.
Thus, all leukemia physicians should welcome the publication of the Australasian Leukaemia and Lymphoma Group Acute Promyelocytic Leukemia (APML) 5 study of oral ATO in consolidation therapy for APL by Iland et al13 in this issue of Blood Advances. The Australian group, led by Iland and Wei, studied the bioavailability of an oral formulation produced by Eupharma in patients with APL in remission. The investigators wisely chose to study the bioavailability during consolidation therapy so that there would be no risk of compromising the management of patients with APL during induction. The well-designed study administered oral ATO in lieu of parenteral ATO for 1-week periods at various points during consolidation, with patients randomly assigned to receive the oral ATO before or after parenteral ATO. When compared with the earlier pharmacokinetic study, the Australian group treated more patients (31 vs 11) and used inductively coupled plasma mass spectrometry to quantify arsenic species. Unsurprisingly, there were no significant pharmacokinetic differences between the 2 formulations (after all, the elderberry wine was highly effective) with equivalence in terms of both the area under the curve and the maximum concentration (Cmax) in whole blood and plasma. The adverse event profile for both formulations were comparable, primarily featuring headache and nausea; both treatment-induced adverse events were predominantly grade 1. Importantly, there were no reports of QTc prolongation, which has complicated parenteral ATO induction regimens.
These data should allay the fears of physicians, pharmaceutical companies, and regulatory agencies reluctant to bring oral ATO into the consolidation treatment of patients with newly diagnosed APL. The availability of oral ATO for these patients would expedite the rehabilitation of patients in remission and their reintroduction into society many months before their ability to do so with current regimens using parenteral ATO. The potential reduction of 80 clinic visits for ATO infusion could have an enormous cost savings for the treatment of these patients. Oral ATO might even be used to complete induction on an outpatient basis for patients who have passed the time-window at risk for coagulopathy and differentiation syndrome. Such outpatient management would of course require careful monitoring. The authors should be commended for their long-standing commitment to the development of treatments for this subset of patients with acute leukemia who once had a mortality rate that approached 50%. With what is now curative therapy for most patients, the development of regimens that reduce the burden on patients and that is indeed more convenient (is there something wrong with that?) should be actively pursued by investigators and regulatory agencies. The patients deserve this.
Conflict-of-interest disclosure: S.D.G. declares no competing financial interests.
