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 |
| |
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 |
| |
Institution: | 1. Division of Hematology‐Oncology, Department of Internal Medicine, The Arthur G. James Comprehensive Cancer Center;2. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus OH, USA;3. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University;4. Division of Epigenomics and Cancer Risk, German Cancer Research Centre (DKFZ), Heidelberg, Germany |
| |
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/m2 per d days 1–10, consisting of grade 3–4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m2 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/m2 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. |
| |
Keywords: | decitabine methylation chronic lymphocytic leukaemia non‐Hodgkin lymphoma |
|
|