Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: a Wisconsin Oncology Network study

Abstract

Arsenic trioxide (As 2 O 3 ) has established clinical activity in acute promyelocytic leukaemia and has pre-clinical data suggesting activity in lymphoid malignancies. Cell death from As 2 O 3 may be the result of oxidative stress. Agents which deplete intracellular glutathione, such as ascorbic acid (AA), may potentiate arsenic-mediated apoptosis. This multi-institution phase II study investigated a novel dosing schedule of As 2 O 3 and AA in patients with relapsed or refractory lymphoid malignancies. Patients received As 2 O 3 0.25 mg/kg IV and AA 1000 mg IV for five consecutive days during the first week of each cycle followed by twice weekly infusions during weeks 2-6. Cycles were repeated every 8 weeks. The primary end point was objective response. In a subset of patients, sequential levels of intracellular glutathione and measures of Bcl-2 and Bax gene expression were evaluated in peripheral blood mononuclear cells during treatment. Seventeen patients were enrolled between March 2002 and February 2004. The median age was 71, and the majority of enrolled patients had non-Hodgkin's lymphoma (12/17). Sixteen patients were evaluable, and one patient with mantle cell lymphoma achieved an unconfirmed complete response after five cycles of therapy for an overall response rate of 6%. The trial, which had been designed as a two-stage study, was closed after the first stage analysis due to lack of activity. Haematologic toxicities were the most commonly reported events in this heavily pre-treated population, and comprised the majority of grade 3 and 4 toxicities. Intracellular depletion of glutathione was not consistently observed during treatment. As 2 O 3 and AA in this novel dosing strategy was generally well tolerated but had limited activity in patients with relapsed and refractory lymphoid malignancies.

Is There a Role for Oral or Intravenous Ascorbate (Vitamin C) in Treating Patients With Cancer? A Systematic Review

“…One study used standard therapy alone as a comparator [29], one observational study compared patients who received i.v. ascorbate during their standard chemotherapy and radiation therapy for early stage breast cancer to patients who did not receive ascorbate therapy [30], and the other 14 studies had no comparator arm [31][32][33][34][35][36][37][38][39][40][41][42][43][44]. Median sample size for these studies was 17 (range, 1-153).There were 11 studies that enrolled patients diagnosed with advanced and metastatic disease [29, 31-38, 40, 43], whereas four studies did not define disease extent [39,41,42,44], and one study was in early stage breast cancer [30].…”

“…One study dosed by plasma levels of ascorbate [43], one study did not define the dose of ascorbate given [41], and five studies were dose finding or had a primary endpoint of safety/toxicity [31,32,36,37,43]. One study's primary endpoint was quality of life [30] (measured by symptom intensity score), and two studies used a primary endpoint of tumor response [33,34]. Six studies were case reports and had no defined primary endpoint.…”

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

“…However, ATO also has been found to be effective against many other hematologic malignancies and solid tumors. For example, together with imatinib it is a promising treatment for chronic myelocytic leukemia (3), and it has been used alone with some success to treat multiple myeloma (4), myelodysplasia syndrome (5), and non-Hodgkin lymphoma (6). ATO also is under clinical investigation as a possible medication for lung cancer, hepatocellular carcinoma, melanoma, renal cell carcinoma, and colorectal cancer (https://www.clinicaltrials.gov/).…”

Phase 2 study of imexon, a prooxidant molecule, in relapsed and refractory B-cell non-Hodgkin lymphoma

“…22 Although notable activity in acute promyelocytic leukemia has been observed with this agent, little benefit was demonstrated in relapsed lymphoid malignancies. 23 The proteasome inhibitor bortezomib, known to be active in mantle cell, lymphoplasmacytic, and to a lesser degree FL, may work in part by modulating the redox environment. 24 However, proteasome inhibition likely has several additional effects accounting for its cytotoxicity.…”