The Impact of GM-CSF on Arsenic Trioxide (As2O3, Trisenox) Therapy in Patients with Myelodysplastic Syndrome (MDS): Preliminary Results of a Phase II Study.

Background: Arsenic trioxide(As2O3) has proven clinical efficacy in relapsed acute promyelocytic leukemia, and is currently being studied in the upfront setting. At micromolar doses, As2O3 induces apoptosis and cellular differentiation, promotes histone acetylation, and inhibits tumor angiogenesis. In preclinical MDS studies, As2O3 inhibits proliferation of malignant hematopoietic cells, and increases rates of apoptosis in short term cultures. Notably, pre-treatment with GM-CSF increases sensitivity of cells to the effect of As2O3. Single agent clinical activity has also been demonstrated in MDS and multiple myeloma. Methods: As2O3 was combined with GM-CSF in pts with MDS in a phase II trial. Eligible patients included those with Low/Int-1 and Int-2/High risk disease. Pts received treatment with As2O3 0.25 mg/Kg d1–d5 the first week, then twice a week for 9 weeks, then 2 weeks off. The cycle was repeated if a response was observed. GM-CSF was administered twice a week for the entire cycle. Pt characteristics are summarized in the table below. Toxicity: Grade 3 and 4 study related AEs included peripheral neuropathic pain (1/7), febrile neutropenia (2/7), infection (4/7), abdominal pain (2/7), thrombocytopenia (2/7), hypoxia (1/7), chills associated with infusion (1/7), VT despite normal electrolytes (1/7), AV block (1/7). Results. 7 pts were enrolled (5M/2F), RA (1), RARS (3) and RAEB (3). A minor hematologic response was seen in one patient with RARS. One patient with RAEB2 showed a reduction of marrow blast count from 15% to Conclusion: The data suggest that As2O3 with GM-CSF is active in MDS, however with significant side effects. The study of As2O3 with the newer approved agents such as 5-azacitidine or lenalidomide should be undertaken, but done sequentially in order to minimize any overlapping toxicities.