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Clinical Trial
. 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

Kristie A Blum  1 , 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
Affiliations
Clinical Trial

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

Kristie A Blum et al. Br J Haematol. 2010 Jul.

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.

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Conflict of interest statement

Conflict of Interest Disclosure: There are no relevant financial conflicts of interest to disclose for any of the investigators participating in this trial.

Figures

Figure 1
Figure 1
Pharmacokinetics of decitabine. Plasma decitabine concentration versus time in a representative patient treated with 15 mg/m2 decitabine (blue line), in a patient with CLL treated with 10 mg/m2 decitabine (pink line), and in a patient with diffuse large cell lymphoma treated with 15 mg/m2 decitabine.
Figure 2
Figure 2
Global DNA hypomethylation changes (mean ± SD). Changes are assessed by LC-MS immediately prior to decitabine (pre-dose, clear) and days 3, 5, 15, and 22 of cycle 1 (post-dose, grey) in CD-19 selected CLL/NHL cells in patients treated with 10 mg/m2 decitabine x 10 days (n=6 CLL patients), 15 mg/m2 decitabine x 10 days (n=4 CLL patients), and 15 mg/m2 x 5 days (n=6 CLL patients and 1 NHL patient).
See this image and copyright information in PMC

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