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Br J Haematol. 2010 Jul;150(2):189-95. doi: 10.1111/j.1365-2141.2010.08213.x. Epub 2010 Apr 29.

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.

Author information

1
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

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.

PMID:
20456354
PMCID:
PMC2917115
DOI:
10.1111/j.1365-2141.2010.08213.x
[Indexed for MEDLINE]
Free PMC Article

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