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.
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.
Blum
Kristie A
KA
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
Liu
Zhongfa
Z
Lucas
David M
DM
Chen
Ping
P
Xie
Zhiliang
Z
Baiocchi
Robert
R
Benson
Donald M
DM
Devine
Steven M
SM
Jones
Jeffrey
J
Andritsos
Leslie
L
Flynn
Joseph
J
Plass
Christoph
C
Marcucci
Guido
G
Chan
Kenneth K
KK
Grever
Michael R
MR
Byrd
John C
JC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D019175:DNA Methylation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D000077209:Decitabine; D001374:Azacitidine
Cell. 2007 Jun 1;129(5):879-90
17540169
J Clin Oncol. 2005 Jun 10;23(17):3948-56
15883410
J Clin Oncol. 2005 Jun 10;23(17):3877-85
15809452
Haematologica. 2006 Jul;91(7):895-902
16818276
Nat Genet. 2005 Mar;37(3):265-74
15723065
Cancer Res. 2006 Jan 15;66(2):653-8
16423993
Rapid Commun Mass Spectrom. 2006;20(7):1117-26
16523529
Nucleic Acids Res. 2007;35(5):e31
17264127
Biochem Pharmacol. 2008 Feb 15;75(4):857-65
18078872
Br J Cancer. 2005 Dec 12;93(12):1388-94
16333246
Blood. 1996 Jun 15;87(12):4990-7
8652811
Blood. 2007 Jan 1;109(1):52-7
16882708
Blood. 1999 Jun 15;93(12):4347-53
10361133
Blood. 2004 Mar 1;103(5):1635-40
14604977
Cancer Sci. 2003 Jan;94(1):87-91
12708480
Clin Cancer Res. 2009 Jun 1;15(11):3881-8
19470736
Blood. 2009 Jan 15;113(3):659-67
18931345
Clin Cancer Res. 2004 May 1;10(9):2928-35
15131027
J Clin Oncol. 1999 Dec;17(12):3835-49
10577857
J Clin Oncol. 1999 Apr;17(4):1244
10561185
Cancer Res. 2004 Apr 1;64(7):2424-33
15059895
J Clin Oncol. 2007 Sep 1;25(25):3884-91
17679729