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The Johns Hopkins Oncology Center [S. D. G., L-J. W., R. C. D., M. G., L. B. G., Y. Z., K. B., C. B. M.], Departments of Pediatrics [G. J. D.] and Pathology [C. A. G., A. L. H.], Johns Hopkins School of Medicine, Baltimore, Maryland 21205; Pharmacokinetic Section, National Cancer Institute [W. D. F., S. Z.], Bethesda, Maryland 20892; and the Institute for Drug Development, San Antonio, Texas 78229 [E. K. R.]
Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and differentiating activity against malignant myeloid cells (ID50, 1–2 mM). Higher doses induce apoptosis. Patients with myelodysplasia (n = 11) and acute myeloid leukemia (n = 16) were treated with PB as a 7-day continuous infusion repeated every 28 days in a Phase I dose escalation study. The maximum tolerated dose was 375 mg/kg/day; higher doses led to dose-limiting reversible neurocortical 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 achieved complete or partial remission, four patients achieved hematological improvement (neutrophils in three, platelet transfusion-independence in one). Other patients developed transient increases in neutrophils or platelets and 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. Hematological response was often associated with increases in both colony-forming units-granulocyte-macrophage and leukemic colony-forming units. PB administration was also associated with increases in fetal erythrocytes. These data document the safety of continuous infusion PB and provide preliminary evidence of clinical activity in patients with myeloid malignancies.
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