Phase II Multicenter Study of Association of Arsenic Trioxide (ATO) and Ascorbic Acid in Myelodysplastic Syndrome.

Arsenic trioxide (ATO) inhibits angiogenesis, induces apoptosis and differentiation in variety of malignant cells. Two multicenter phase II studies have documented that ATO has as a moderate activity both in low and high risk myelodysplasia with 19-21% haematological improvement. Ascorbic acid in “vitro” increases in tumor cells the activity of ATO by depleting GSH and inhibiting NF-kb. High EVI-1 levels have been reported to predicted the response to arsenic trioxide and thalidomide combination therapy. We report the results of a multicenter phase II study with combination of arsenic trioxide and acid ascorbic in myelodysplastic patients. Patient eligibility included:a) pts with 3q26 rearrangement or high EVI-1 levels; b) non-RAEB pts at low-intermediate/1 risk who failed a previous therapy; c) RAEB or high-intermediate-2 risk patients not elegible to chemotherapy and/or bone marrow transplant.

Arsenic trioxide was administrated intravenously over 1 hour at the loading dose of 0.30 mg/kg/day for 5 consecutive days, followed by 0.25 mg/kg/day twice weekly for 15 weeks. Ascorbic acid 1000 mg was given IV within 30 minutes after each arsenic trioxide infusion. Response evaluation was scheduled after two and four months of treatment according to the IWG criteria (Cheson 2000)

44 pts were enrolled .Median age was 71 years (range 47–80). WHO categories were non-RAEB (15 pts), RAEB-1 (12 pts), RAEB-2 (17 pts). 23 patients had a low/intermediate-1 IPSS score; 18 had a high/intermediate-2 risk. Risk category, could not be assessed in 3 pts lacking of cytogenetic data. Before starting therapy EVI-1 was highly expressed in 13 out of 34 evaluated pts (38%); high WT-1 levels was documented in 25 out of 35 pts (71%). 31 pts (57%) were transfusion dependent at baseline.

Ten out of 44 evaluable patients obtained a response (23%). They included 1 complete remission, 2 major erythroid hematologic improvement (HI-E major), 3 minor HI-E, 2 major neutrophil improvemet (HI-N) and 2 major trilineage responses. Response rate was 35% in lower risk IPSS patients and 6% in higher risk pts (p 0.05).Only 3 pts with high EVI-1 expression achieved a response. In 8 out of ten responders, the response was evident within the first 8 weeks of treatment. Twenty three (52%) patients discontinued treatment because disease progression (11%), severe adverse events (32%), drug unrelated adverse events (5%), withdrawal of consent (5%). Severe neutropenia and thrombocytopenia were observed respectively in 45% and 23% pts. The other G3-4 adverse events observed were: ATRA-like syndrome (9%), cardiotoxicity (11%) infection (11%), hepatotoxicity (9%). No toxic death was observed.

The combination of ATO and ascorbic acid is tolerable and it is active in about 25% of MDS patients. The addition of ascorbic acid to ATO does not increase neither the toxicity nor the response rate to ATO. The tolerability of this regimen is reduced in elderly and high risk patients. In our study high EVI-1 transcript levels were not confirmed to predict the response to ATO.

Off Label Use: Arsenic trioxide is yet approved for the treatment of MDS, even if its efficacy has been shown in other phase II studies.