Introduction: Arsenic trioxide (ATO) is an exceptionally active drug in acute promyelocytic leukemia (APL), inducing complete remissions (CR) in 85% of relapsed patients. ATO also has clinical activity in myelodysplastic syndromes (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
). 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 administered ATO plus AA to patients with non-APL AML.

Methods: ATO 0.25 mg/kg was administrated intravenously over 1-4 hours with 1 gram of intravenous AA given 30 minutes after ATO 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 (

Bahlis et al Clin Cancer Res 8:3658, 2002
)). Responding patients received an additional consolidation cycle of 25 doses followed by maintenance including ATO + AA two weeks of every month for 4 cycles. Patients who failed to respond after two cycles were considered treatment failures.

Results: Nine patients aged 36–84 years (median: 66 years) were treated: 5 pts. had refractory AML or relapsed after chemotherapy; 4 elderly pts,. aged 66–84, with antecedent MDS were previously untreated. Activity was seen in 5 (56%) patients, including all 4 of the previously untreated pts: CR in 1 pt. (patient with an early relapse), CRp in 1 pt., decrease in bone marrow blasts to <5% with reduced transfusion requirements in 1 pt, and drop in peripheral blood blasts from 84% and 51% to <5% in 2 patients. Responses were observed after the first treatment cycle. Duration of responses were 6 months in the CR and CRp pts., and 1 week, 2 months. and 4 months in the other responders. Four pts had progressive disease; one patient died on study from progressive disease and infection. Grade 3 /4 toxicity included: infection in 8 pts., and anorexia, sensory neuropathy, elevated bilirubin in 1 pt. each. One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone.

Conclusions: ATO + AA has anti-leukemic activity in non-APL AML patients. Despite the high doses of ATO, higher than used in APL and MDS, toxicity was tolerable. This combination could be a less toxic alternative front-line approach to intensive chemotherapy in elderly patients with non-APL AML. Further study of ATO + AA is warranted either alone or in combination with other agents in an attempt to further improve the results.

Topics:
arsenic trioxide, ascorbic acid, bilirubin level, increased, leukemia, myelocytic, acute, brachial plexus neuritis, chemotherapy regimen, c-reactive protein, cyclic amp receptor protein, epley maneuver, infections

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2005, The American Society of Hematology
2005
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