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

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BlankPhase 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.

KA Blum, Z Liu, DM Lucas, P Chen, Z Xie, R Baiocchi, DM Benson, SM Devine, J

, L Andritsos, J Flynn, C Plass, G Marcucci, KK Chan, MR Grever, and JC

Byrd

Br J Haematol, April 29, 2010; .

Division of Hematology-Oncology, Department of Internal Medicine, The Arthur G.

Comprehensive Cancer Center, Columbus OH, USA.

Summary 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