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: Kristie A Blum, Zhongfa Liu, David M Lucas, Ping Chen, Zhiliang Xie, Robert Baiocchi, Donald M Benson, Steven M Devine, Jeffrey Jones, Leslie Andritsos, Joseph Flynn, Christoph Plass, Guido Marcucci, Kenneth K Chan, Michael R Grever, John C Byrd
• Journal: British journal of haematology (Br J Haematol) Vol. 150 Issue 2 Pg. 189-95 (Jul 2010) ISSN: 1365-2141 [Electronic] England
• PMID: 20456354 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• DNA, Neoplasm
• Decitabine
• Azacitidine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (administration & dosage, blood, therapeutic use, toxicity)
• Azacitidine (administration & dosage, analogs & derivatives, blood, therapeutic use, toxicity)
• DNA Methylation (drug effects)
• DNA, Neoplasm (drug effects)
• Decitabine
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (blood, drug therapy, genetics)
• Lymphoma, Non-Hodgkin (blood, drug therapy, genetics)
• Male
• Middle Aged
• Neutropenia (chemically induced)
• Thrombocytopenia (chemically induced)
• Treatment Outcome