Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes Journal Article

  

Authors:	Klimek, V. M.; Fircanis, S.; Maslak, P.; Guernah, I.; Baum, M.; Wu, N.; Panageas, K.; Wright, J. J.; Pandolfi, P. P.; Nimer, S. D.
Article Title:	Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes
Abstract:	Purpose: Epigenetic modulation of gene expression plays an important role in cancer, including leukemia. Furthermore, histone deacetylase inhibitors may induce the reexpression or repression of genes critical for normal hematopoiesis. The purpose of this study was to evaluate the toxicity, pharmacokinetic profile, and selected pharmacodynamic properties of the histone deacetylase inhibitor depsipeptide in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). Experimental Design: Depsipeptide was administered to MDS or AML patients at a (solid tumor) phase I dose of 18 mg/m2 i.v. on days 1 and 5 every 3 weeks. Toxicities and clinical activity were monitored and pharmacokinetic and pharmacodynamic studies were done. Results: Twelve patients (nine with AML, three with MDS) received one to five cycles of depsipeptide. The most common grade 3/4 toxicities were febrile neutropenia/infection (five patients), neutropenia/thrombocytopenia (nine patients), nausea (nine patients), and asymptomatic hypophosphatemia (three patients). No clinically significant cardiac toxicity was observed. The best response of 11 assessed patients was one complete remission in a patient with AML, stable disease in six patients, and progression of disease in four patients. Exploratory laboratory studies showed modest but rapid increases in apoptosis and changes in myeloid maturation marker expression. Histone H3 and H4 acetylation levels were evaluated in five patients; no consistent changes were observed. Conclusion: Depsipeptide therapy can be administered with acceptable short-term toxicity. However, gastrointestinal symptoms and fatigue seem to be treatment-limiting after multiple cycles. Depsipeptide monotherapy has limited clinical activity in unselected AML/MDS patients. © 2008 American Association for Cancer Research.
Keywords:	adult; clinical article; controlled study; aged; middle aged; unclassified drug; acute granulocytic leukemia; human cell; leukemia, myeloid, acute; polymorphism, single nucleotide; histone deacetylase inhibitor; clinical trial; constipation; disease course; drug activity; drug tolerability; fatigue; neutropenia; drug safety; hypophosphatemia; side effect; antineoplastic agents; cytarabine; drug megadose; anorexia; treatment indication; apoptosis; controlled clinical trial; infection; multiple cycle treatment; cell maturation; bleeding; gastrointestinal symptom; leukopenia; nausea; randomized controlled trial; thrombocytopenia; vomiting; dehydration; myalgia; weight reduction; creatinine blood level; drug effect; hematuria; asthenia; backache; chill; dyspnea; febrile neutropenia; hypomagnesemia; purpura; tumor lysis syndrome; gene expression regulation; hypoalbuminemia; hypokalemia; hyponatremia; hypotension; myelodysplastic syndrome; rigor; epigenetics; salsalate; cardiotoxicity; histone h3; mitoxantrone; daunorubicin; taste disorder; xerostomia; remission; 5 aza 2' deoxycytidine; receptor, erbb-2; alkaline phosphatase blood level; headache; bone marrow cell; phase 1 clinical trial; idarubicin; bilirubin blood level; romidepsin; depsipeptides; myelodysplastic syndromes; acetylation; aromatase; hypocalcemia; ecg abnormality; sinus tachycardia; histone h4; cd135 antigen; petechia; microsomal aminopeptidase; midostaurin; bismuth 213; monoclonal antibody m 195; 4 [6 methoxy 7 [3 (1 piperidinyl)propoxy] 4 quinazolinyl] 1 piperazinecarboxylic acid (4 isopropoxyphenyl)amide; fibroblast growth factor receptor 4; monoclonal antibody m 195 bi 213
Journal Title:	Clinical Cancer Research
Volume:	14
Issue:	3
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2008-02-01
Start Page:	826
End Page:	832
Language:	English
DOI:	10.1158/1078-0432.ccr-07-0318
PUBMED:	18245545
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-38949144400&partnerID=40&md5=bd1d84923b3417cb6d5bf9eafc7500b4
Notes:	--- - "Cited By (since 1996): 54" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"

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