Arsenic Trioxide (ATO) Is Safe and Effective in Combination with Low-Dose Ara-C (LDAC) for the Treatment of IPSS-2 Myelodysplastic Syndrome (MDS) and Poor-Prognosis Acute Myeloid Leukemia (AML) in Elderly Patients.

There is no adequate therapy for advanced MDS and elderly AML and treatment outcomes are generally poor. LDAC in elderly AML patients using a variety of dosing schedules results in a CR rate of approximately 20% and possibly improved morbidity and mortality compared to conventional chemotherapy or supportive care. In MDS patients, the CR rates with LDAC are lower, 10–20%, with short duration and no clear benefit over supportive care. On the basis of preclinical data suggesting a possible anti-angiogenic effect of ATO, as well as clinical data showing activity of ATO in MDS, a phase I/II trial of ATO in combination with LDAC was initiated in IPSS-2 MDS and newly-diagnosed, poor-prognosis AML patients. ATO was given at a dose of 0.25 mg/kg for days 1–5 and 8–12. LDAC was dose-escalated from 5 mg/m² SC BID to the target phase II dose of 10 mg/m² SC BID for days 1–14 (one treatment cycle). Patients who achieved CR after one treatment cycle were given a second, identical cycle, followed by maintenance treatment of 5 days of LDAC and 2 days of ATO every 28 days. Patients who did not achieve CR after one cycle were given a second cycle beginning between days 21–28, with the addition of ascorbic acid 1g IV within 30 minutes of the ATO infusion. Fifty-seven patients have been enrolled to date, 34 with AML and 23 with MDS. A total of 28 AML and 16 MDS patients are evaluable for response, 38 of whom were treated with the target dose of LDAC. There were no responses in patients treated with less than the target dose. Clinical characteristics of the 28 AML patients include: mean age 75 yrs (range 55–85 yrs; one patient < 60 yrs with AML and multiple medical comorbidities was included); 18 (64%) abnormal cytogenetics; 18 (64%) antecedent hematologic disorder; 4 (14%) secondary disease. CR was achieved in 11 patients (39%), with follow-up 1–8+ mos. Six patients (55%) required 2 treatment cycles to achieve CR. Of the total 34 AML patients, 4 (12%) died of progressive disease prior to day 30 and 1 (3%) died of neutropenic sepsis. Clinical characteristics of the 16 evaluable IPSS-2 MDS patients include: mean age 70 yrs (range 56–84 yrs); 11 (69%) abnormal cytogenetics; 2 (1%) prior therapy with 5-azacytidine. CR was achieved in 4 (25%) patients, follow-up 1–11+ mos. One patient required 2 treatment cycles to achieve CR; there were no therapy related deaths. The regimen was generally well-tolerated, with minimal grade 3/4 non-hematologic toxicity and no significant nausea, emesis, diarrhea or mucositis. Alopecia was not seen. Grade 4 hematologic toxicity was, as predicted, observed in all patients. Fluid retention occurred in 21/34 (62%) of patients. There were no clinically significant drug-related arrhythmias. For AML patients, the combination of ATO and LDAC resulted in a CR rate comparable to conventional chemotherapy, with improved tolerability and induction mortality. Further investigation of this regimen is warranted in both MDS and AML.