Impact of the Putative Differentiating Agent Sodium Phenylbutyrate on Myelodysplastic Syndromes and Acute Myeloid Leukemia 1 Steven D. Gore, 2 Li-Jun Weng, Suoping Zhai, William D. Figg, Ross C. Donehower, George J. Dover, Michael Grever, Constance A. Griffin, Louise B. Grochow, Eric K. Rowinsky, Yelena Zabalena, Anita L. Hawkins, Kathleen Burks, and Carole B. Miller 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.] ABSTRACT Sodium phenylbutyrate (PB) is an aromatic fatty acid with cytostatic and differentiating activity against malignant myeloid cells (ID 50 , 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 contin- uous 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 neuro- cortical toxicity. At the maximum tolerated dose, PB was extremely well tolerated, with no significant toxicities; me- dian 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 im- provement (neutrophils in three, platelet transfusion-inde- pendence in one). Other patients developed transient in- creases 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 hemato- poiesis remained clonal. Hematological response was often associated with increases in both colony-forming units-gran- ulocyte-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. INTRODUCTION Current therapies offer limited benefit to patients with MDS 3 and resistant subsets of AML. Supportive care remains a standard of care for the majority of patients with MDS. Subsets of AML can be identified in which available therapies have been mainly palliative: the elderly, AML arising from MDS, AML with poor risk cytogenetic abnormalities, and therapy-induced AML (1– 4). In MDS and resistant AML, allogeneic bone mar- row transplantation represents the only potentially curative ther- apy for these patients (5). Unfortunately, transplantation is not a feasible treatment modality for many patients. Successful application of molecules that promote the ter- minal differentiation of malignant myeloid cells could have at least three potential roles in the treatment of myeloid neoplasms: terminal differentiation of a malignant clone to clonal extinc- tion, as in retinoic acid remission-induction of acute promyelo- cytic leukemia (6), enforced clonal differentiation leading to functional but clonal hematopoiesis, and prolongation of remis- sion duration in patients with AML or MDS with residual disease after chemotherapy through suppression of proliferation of the malignant clone. We have recently shown that the aromatic fatty acid com- pound PB induces differentiation and inhibits the growth of primary leukemic cells (7, 8) in vitro at concentrations similar to those achieved in patients receiving this drug for nonmalignant disorders (9, 10). PB inhibits CFU-L production from bone marrow specimens from patients with MDS (8). In the ML-1 myeloid leukemia cell line, PB-induced differentiation is asso- ciated with induction of p21 WAF1/CIP1 , hypophosphorylation of Rb protein, and arrest in the G 1 phase of the cell cycle (7). PB has been effectively used to induce fetal erythropoiesis in pa- tients with sickle cell anemia and -thalassemia (9 –11). Encouraged by the biological impact of PB on primary bone marrow samples from patients with MDS and AML stud- ied in vitro at doses similar to those achieved in patients treated for inborn errors of metabolism and hemoglobinopathies, we Received 7/27/00; revised 4/13/01; accepted 4/18/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This study was supported in part by Grants RO1 CA67803, CA 15396 from National Cancer Institute, and by NIH/National Center for Re- search Resources Grant RR00052 to Johns Hopkins University General Clinical Research Center. 2 To whom requests for reprints should be addressed, at The 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@jhu.edu. 3 The abbreviations used are: MDS, myelodysplastic syndromes; AML, acute myeloid leukemia; PB, sodium phenylbutyrate; CFU-L, leukemia colony-forming unit; CFU-GM, colony-forming units-granulocyte- macrophage; CNS, central nervous system; MTD, maximum tolerated dose; FISH, fluorescence in situ hybridization; HI, hematological im- provement; PAG, phenylacetylglutamine; PA, phenylacetylate; AUC, area under the curve; TUNEL, terminal deoxynucleotidyl transferase- mediated nick end labeling; RAEB, refractory anemia with excess blasts; RAEB-t, refractory anemia with excess blasts in transformation. 2330 Vol. 7, 2330 –2339, August 2001 Clinical Cancer Research Research. on April 8, 2016. © 2001 American Association for Cancer clincancerres.aacrjournals.org Downloaded from