Impact of Prolonged Infusions of the Putative Differentiating Agent Sodium Phenylbutyrate on Myelodysplastic Syndromes and Acute Myeloid Leukemia

Impact of Prolonged Infusions of the Putative Differentiating Agent Sodium Phenylbutyrate on Myelodysplastic Syndromes and Acute Myeloid Leukemia1

The Johns Hopkins Oncology Center [S. D. G., L-J. W., R. C. D., M. R. G., C. G., A. H., K. B., and C. B. M.], Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21231 [G. D], and Clinical Pharmacokinetic Section, National Cancer Institute, Bethesda, Maryland 20892 [W. D. F., L. B G., and S. Z.]

Abstract

The aromatic fatty acid sodium phenylbutyrate (PB) promotescytostasis and differentiation in a wide variety of tumor types; among several molecular activities, inhibition of histone deacetylase (HDAC) may account for many of its pharmacodynamic effects. A Phase I study demonstrated promising preliminary evidence of clinical activity in acute myeloid leukemia and myelodysplastic syndrome; however, plasma concentrations achieved at the maximum tolerated dose were less than those targeted based on in vitro studies. Because prolonged exposure to suboptimal concentrations of PB in vitro led to pharmacodynamic changes similar to a more brief exposure to higher concentrations, a study of the feasibility of prolonged administration of sodium PB was performed. Selected patients with acute myeloid leukemia and myelodysplastic syndrome were treated with sodium PB as a continuous i.v. infusion via ambulatory infusion pump. Sequential cohorts were treated for 7 consecutive days out of 14 or with 21 consecutive days out of 28. Prolonged infusions were well tolerated; dose-limiting central nervous system toxicity developed in 1 of 23 patients treated. End-of-infusion plasma concentrations were maintained within a range sufficient to inhibit HDAC. Two patients on the 21/28 schedule developed hematological improvement. Prolonged infusions of PB are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition.

Footnotes

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↵1 Supported in part by Grants RO1 CA67803 and CA 15396. S. D. G. is the recipient of a Scholar Award for Clinical Research from The Leukemia and Lymphoma Society of America. Targon Pharmaceuticals provided support for data management. Presented in part at the annual meeting of The American Society of Hematology, December 1998.
↵2 To whom requests for reprints should be addressed, at Johns Hopkins Oncology Center, 1650 Orleans Street, Room 288, Baltimore, MD 21231-1000. Phone: (410) 955-8781; Fax: (410) 614-1005; E-mail: Steven.Gore{at}jhu.edu
↵3 The abbreviations used are: MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; PB, phenylbutyrate; MTD, maximum tolerated dose; PA, phenylacetate; CNS, central nervous system; FISH, fluorescence in situ hybridization; HI, hematological improvement; PAG, phenylacetylglutamine; CFU-L, leukemia colony-forming unit; CFU-GM, colony-forming unit, granulocyte-macrophage; G-CSF, granulocyte colony-stimulating factor; HDAC, histone deacetylase.
- Accepted November 16, 1901.
- Received May 17, 1901.
- Revision received November 8, 1901.