Phase II Study of Arsenic Trioxide Plus Ascorbic Acid for Relapsed and Refractory Lymphoid Malignancies: A Wisconsin Oncology Network Study.

Introduction: Arsenic trioxide (AT) has impressive single agent activity in relapsed acute promyelocytic leukemia. It also has activity in myelodysplastic syndromes and multiple myeloma. In vitro data has suggested increased cytotoxicity when combined with agents that deplete intracellular glutathione, forming the rationale for combination studies. Ascorbic acid (AA) can deplete intracellular glutathione and may potentiate the cytotoxicity of AT. Upon this basis, we initiated a phase II study of arsenic trioxide plus ascorbic acid for relapsed/refracory lymphoid malignancies. Arsenic trioxide was administered at a dose of 0.25 mg/kg IV over one hour M-F for one week and then 2X/week for 5 weeks. Each arsenic infusion was followed by an infusion of 1000 mg ascorbic acid over 15 minutes. Each 6-week cycle was followed by a two-week rest period before repeating the cycle. Treatment was continued until best response plus two cycles or progressive disease.

Patient characteristics: Median age 70.5 (37–88). Gender 10M, 6F. Histologies CLL/SLL (4), Follicular (3), Mantle Cell (3), DLBCL (2), Burkitt (2), Marginal Zone (1), Hairy Cell (1). Median # Prior therapies 4 (2–13). Refractory to prior treatment 13/16. Median ECOG PS 1 (0–2). B symptoms 3/16. Elevated LDH 8/16. Elevated B2M 13/16.

Results: Median number of completed cycles 1 (0–4). Eight patients did not complete cycle #1, six due to progressive disease (PD) and 2 due to toxicity. Of the 2 patients coming off for toxicity, one patient with known coronary artery disease suffered a myocardial infarction on the 4^th day of treatment and expired from congestive heart failure and the other experienced repeated grade 4 hyperglycemia. Six patients completed one cycle of therapy and were removed for PD. One patient completed 3 cycles of therapy before experiencing PD. One patient with mantle cell lymphoma received 4 cycles of therapy and achieved a CRu. The overall response rate was 6% (1/16). The responding patient’s treatment was stopped after 4 cycles for MD/patient preference and she experienced PD 5 months after completion of therapy. Grade 3 toxicities included thrombocytopenia (2 patients), anemia (3), neutropenia (1), stomatitis (1), anorexia (1), and elevated LFTs (1). Grade 4 toxicities included neutropenia (2) and hyperglycemia (1).

Conclusions: AT plus AA in this dosing schedule had modest toxicity but limited antitumor activity. The data should be interpreted in the context of our heavily treated, essentially refractory patient population. Our trial had a two-stage design, and was closed due to lack of activity at the first stage analysis. Other doses and schedules may prove to be more efficacious.