Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia

Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and di fferentiating activity against malignant myeloid cells (ID50, 1-2 mM). High er doses induce apoptosis. Patients with myelodysplasia (n = 11) and acute myeloid leukemia (n = 16) were treated with PB as a 7-day continuous infusi on repeated every 28 days in a Phase I dose escalation study. The maximum t olerated dose was 375 mg/kg/day; higher doses led to dose-limiting reversib le neuro-cortical toxicity. At the maximum tolerated dose, PB was extremely well tolerated, with no significant toxicities; median steady-state plasma concentration at this dose was 0.29 +/- 0.16 mm. Although no patients achi eved complete or partial remission, four patients achieved hematological im provement (neutrophils in three, platelet transfusion-independence in one). Other patients developed transient increases in neutrophils or platelets a nd decrements in circulating blasts. Monitoring of the percentage of clonal cells using centromere fluorescence in situ hybridization over the course of PB administration showed that hematopoiesis remained clonal. Hematologic al response was often associated with increases in both colony-forming unit s-granulocyte-macrophage and leukemic colony-forming units. PB administrati on was also associated with increases in fetal erythrocytes. These data doc ument the safety of continuous infusion PB and provide preliminary evidence of clinical activity in patients with myeloid malignancies.