Treatment of Acute Myelogenous Leukemia (non-APL) with Intravenous Trisenox® (Arsenic Trioxide) and Ascorbic Acid: Preliminary Results.

Abstract

Introduction: Arsenic trioxide (ATO) is an exceptionally active drug in acute promyelocytic leukemia (APL), inducing complete remissions in 85% of relapsed patients. ATO also has clinical activity in myelodysplastic syndrome (MDS). In non-APL AML cells lines, ATO induces apoptosis in vitro; however, in a small study of 11 non-APL AML patients, ATO showed no activity (Parmer et al Leuk Res 28:090, 2004). In some types of cancer cells, ATO-induced apoptosis has been shown to correlate inversely with the level of intracellular reduced glutathione (GSH) via generation of reactive oxygen species; cells with high concentrations of GSH are more resistant to ATO. Ascorbic acid (AA) increases apoptosis and overcomes resistance to ATO in multiple myeloma, non-APL AML and other cell lines by reducing intracellular GSH levels. AA alone has no activity in these cells. We therefore conducted a clinical trial in patients with non-APL AML combining ATO and AA.Methods: ATO at a dose of 0.25 mg/kg is administrated intravenously over 1–3 hour with 1 gram of intravenous AA given within 30 minutes daily for five days a week (five days on/2 days off) for five weeks (25 doses - one cycle). These doses were based on a phase I/II trial of ATO+AA in patients with multiple myeloma (Behalis et al Clin Cancer Res 8:3658, 2002)). Responding patients receive an additional consolidation cycle of 25 doses followed by maintenance of two weeks of every month of ATO+ AA for 4 cycles. Patients who fail to respond after two cycles are considered treatment failures.Results: Seven patients have so far enrolled: three (aged 36,52,59) had relapsed after chemotherapy, and four aged 66–84 (median 70), never received chemotherapy. For these untreated patients ATO+AA was given as front line treatment. In three of the four previously untreated patients the number of bone marrow blasts dropped from > 40% to < 5% (2 pts. after 1 cycle; 1 pt. after 2 cycles) At the time of this report only one of the responding patients received more than one cycle and had improvement in the peripheral blood counts. The three patients, who failed chemotherapy, did not respond to ATO+AA (one patient received only one cycle). Despite the high doses of ATO, higher than used in APL and MDS, the combination was very well tolerated with grade 3 toxicity in one patient only (sensory neuropathy). One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone.Conclusion: These preliminary results in patients with non-APL AML suggest that: (1) AA +ATO has anti-leukemia activity in untreated non-APL AML patients with minimal toxicity; (2) more than one cycle is probably needed to achieve a response in the peripheral blood counts; (3) in non-APL AML, ATO can cause the so called “differentiation syndrome” which should be anticipated and treated early. If confirmed in additional patients, ATO+AA might be a less toxic alternative upfront approach to intensive chemotherapy in elderly patients with non-APL AML.