title: Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation.
abstract: Targeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B-cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL (n = 4). Patients received 1-3 cycles of decitabine. Dose-limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m(2) per d days 1-10, consisting of grade 3-4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m(2) per d days 1-10 without DLT; however, re-expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5-day decitabine schedule was examined. With 15 mg/m(2) per d decitabine days 1-5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3-4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome-wide methylation or in target gene re-expression. In conclusion, dose-limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in CLL and NHL.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, The Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. kristie.blum@osumc.edu
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Liu
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Xie
authors.forename: Robert
authors.initials: R
authors.lastname: Baiocchi
authors.forename: Donald M
authors.initials: DM
authors.lastname: Benson
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.forename: Leslie
authors.initials: L
authors.lastname: Andritsos
authors.forename: Joseph
authors.initials: J
authors.lastname: Flynn
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D019175:DNA Methylation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D000077209:Decitabine; D001374:Azacitidine
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