Impact of Prolonged Infusions of the Putative Differentiating Agent Sodium Phenylbutyrate on Myelodysplastic Syndromes and Acute Myeloid Leukemia1
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Vol. 8, 963–970, April 2002 Clinical Cancer Research 963 Advances in Brief Impact of Prolonged Infusions of the Putative Differentiating Agent Sodium Phenylbutyrate on Myelodysplastic Syndromes and Acute Myeloid Leukemia1 Steven D. Gore,2 Li-Jun Weng, William D. Figg, ule developed hematological improvement. Prolonged infu- Suoping Zhai, Ross C. Donehower, George Dover, sions of PB are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition. Michael R. Grever, Constance Griffin, Louise B. Grochow, Anita Hawkins, Introduction Kathleen Burks, Yelena Zabelena, and The paucity of effective therapies for the treatment of Carole B. Miller MDS3 and resistant subsets of AML mandates the development The Johns Hopkins Oncology Center [S. D. G., L-J. W., R. C. D., of new therapeutic strategies for these disorders. The impetus to M. R. G., C. G., A. H., K. B., and C. B. M.], Department of use “differentiating” agents in MDS arises from the clinical Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21231 [G. D], and Clinical Pharmacokinetic Section, National Cancer observation that bone marrows in MDS are hypercellular, with Institute, Bethesda, Maryland 20892 [W. D. F., L. B G., and S. Z.] aberrant differentiation and concomitant bone marrow failure. Similarly, in resistant AML, agents that promote functional hematopoiesis might enable patients to survive with their dis- Abstract ease. Differentiating agents have at least three potential roles in The aromatic fatty acid sodium phenylbutyrate (PB) the treatment of myeloid neoplasms: (a) terminal differentiation promotes cytostasis and differentiation in a wide variety of of a malignant clone to clonal extinction, as in retinoic acid tumor types; among several molecular activities, inhibition induction of acute promyelocytic leukemia (1); (b) enforced of histone deacetylase (HDAC) may account for many of its clonal differentiation leading to functional but clonal hemato- pharmacodynamic effects. A Phase I study demonstrated poiesis; and (c) prolongation of remission duration in patients promising preliminary evidence of clinical activity in acute with AML or MDS with residual disease after chemotherapy myeloid leukemia and myelodysplastic syndrome; however, through suppression of proliferation of the malignant clone. plasma concentrations achieved at the maximum tolerated We recently completed a Phase I study of 7-day continuous dose were less than those targeted based on in vitro studies. infusions of the aromatic fatty acid PB in patients with MDS and Because prolonged exposure to suboptimal concentrations of selected patients with AML. (2) In vitro, PB induces differen- PB in vitro led to pharmacodynamic changes similar to a tiation, inhibits proliferation of AML cell lines and primary more brief exposure to higher concentrations, a study of the leukemic cells (3, 4), and inhibits CFU-L production from bone feasibility of prolonged administration of sodium PB was marrow specimens from patients with MDS (4). In the ML-1 performed. Selected patients with acute myeloid leukemia myeloid leukemia cell line, PB-induced differentiation is asso- and myelodysplastic syndrome were treated with sodium PB ciated with induction of p21WAF1/CIP1 expression, hypophos- as a continuous i.v. infusion via ambulatory infusion pump. phorylation of retinoblastoma protein, and arrest in the G1 phase Sequential cohorts were treated for 7 consecutive days out of of the cell cycle (3). At least some of the pharmacodynamic 14 or with 21 consecutive days out of 28. Prolonged infusions effects of PB appear to be because of its ability to inhibit HDAC were well tolerated; dose-limiting central nervous system (5); histone acetylation contributes importantly to regulation of toxicity developed in 1 of 23 patients treated. End-of-infu- gene transcription (6). The MTD of PB administered as a 7-day sion plasma concentrations were maintained within a range continuous infusion was 375 mg/kg/day; higher doses were sufficient to inhibit HDAC. Two patients on the 21/28 sched- associated with encephalopathy because of nonlinear accumu- lation of its metabolite PA (2). At the MTD, median steady state concentration of PB was 0.3 mM, less than the ED50 for differ- entiation and cytostasis in vitro (1–2 mM; Ref. 3) but well within the concentration range which induces acetylation of histones (5). Received 5/17/01; revised 11/8/01; accepted 11/16/01. Although steady-state concentrations achieved in this study The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked were lower than we had targeted, sustained HI in neutrophils advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 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 3 The abbreviations used are: MDS, myelodysplastic syndrome; AML, provided support for data management. Presented in part at the annual acute myeloid leukemia; PB, phenylbutyrate; MTD, maximum tolerated meeting of The American Society of Hematology, December 1998. dose; PA, phenylacetate; CNS, central nervous system; FISH, fluores- 2 To whom requests for reprints should be addressed, at Johns Hopkins cence in situ hybridization; HI, hematological improvement; PAG, Oncology Center, 1650 Orleans Street, Room 288, Baltimore, MD phenylacetylglutamine; CFU-L, leukemia colony-forming unit; CFU- 21231-1000. Phone: (410) 955-8781; Fax: (410) 614-1005; E-mail: Ste- GM, colony-forming unit, granulocyte-macrophage; G-CSF, granulo- ven.Gore @jhu.edu. cyte colony-stimulating factor; HDAC, histone deacetylase. Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2002 American Association for Cancer Research. 964 Prolonged Infusions of Sodium Phenylbutyrate and platelet counts were documented in several patients, and supplies of PB were distributed to patients. Patients or their transient improvement in hemograms were frequent (2). In family members changed the liter bag of PB daily; all of the addition, peripheral blood blasts were cleared in several patients used bags were returned to the pharmacy for verification of treated on this study. In vitro, prolonged exposure to lower administration. PB was administered through an indwelling concentrations of PB led to pharmacodynamic effects compara- central venous catheter (Hickman, Groshong, or port). Twelve ble with briefer exposures to higher concentrations (3). In acute weeks of therapy was planned; patients responding to PB could promyelocytic leukemia, the best clinical model of successful continue to receive the drug as long as they continued to show differentiation therapy, prolonged exposure to all-trans-retinoic improvement. acid is required to effect remission (1). Therefore, we studied All of the patients received 375 mg/kg/day of PB, the MTD the feasibility and efficacy of prolonged exposure to continuous defined previously. Two dosing schedules were studied. In the i.v. infusion of PB in a cohort of patients with resistant myeloid first schedule (7/14), patients received 7 days of PB, followed neoplasms. by 7 days of drug holiday. This schedule was repeated for a total of 12 weeks (total of 6 weeks of PB infusion alternating with 6 Patients and Methods weeks of drug holiday). In the second schedule (21/28), patients received 21 consecutive days of PB infusion followed by a Patients 7-day drug holiday. This schedule was repeated for a total of Patients were recruited from referrals to the Division of three cycles (12 weeks). Accrual was planned at each schedule Hematological Malignancy at The Johns Hopkins Oncology until 6 patients were evaluable for a full 12-week period of Ն Center. Previously treated or untreated patients age 18 years observation for toxicity at each schedule. with any French-American-Beinsh subset of MDS were eligible; An infusional schedule was considered tolerable if no more however, patients in whom blasts were not increased were than 1 of 6 evaluable patients had grade 3 or 4 nonhematological required to have some hematological abnormality potentially toxicity. As in the previous study, dose-limiting hematological benefiting from therapy: transfusion-dependence, granulocyte toxicity for MDS was defined as severe aplasia (neutrophils Ͻ Ͻ count 1,000/ l, or platelet count 50,000/ l. Most recent Ͻ500/l; platelets Ͻ25000/l if they were higher pretreat- Ն chemotherapy administration was required to be 1 month ment), which lasted Ͼ21 days. Dose-limiting hematological before enrollment. toxicity for relapsed AML was defined as prolonged aplasia in Patients with AML were eligible if they had relapsed or if the absence of disease progression if the neutrophil and platelet they were untreated but were deemed to be poor candidates counts were sufficiently higher before therapy, as defined medically for AML induction chemotherapy because of age, above. comorbidity, poor-risk cytogenetics, or because they had re- Despite the observation of asymptomatic alterations in uric fused chemotherapy. Patients with AML were required to have acid metabolism in the previous Phase I trial of a 7-day PB Ͻ WBC count 30,000/ l, stable for at least 2 weeks, and be infusion, allopurinol was not administered. Administration of deemed unlikely to require cytotoxic therapy during the duration hematopoietic growth factors was