Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies.
Decitabine (5-aza-2'-deoxycytidine) inhibits DNA methylation and has dual effects on neoplastic cells, including the reactivation of silenced genes and differentiation at low doses and cytotoxicity at high doses. We evaluated, in a phase 1 study, low-dose prolonged exposure schedules of decitabine in relapsed/refractory leukemias. Patient cohorts received decitabine at 5, 10, 15, or 20 mg/m2 intravenously over one hour daily, 5 days a week for 2 consecutive weeks, doses 5- to approximately 30-fold lower than the maximum tolerated dose (MTD). There were 2 groups that also received 15 mg/m2 daily for 15 or 20 days. A total of 50 patients were treated (44 with acute myelogenous leukemia [AML]/myelodysplasia [MDS], 5 with chronic myelogenous leukemia [CML], and 1 with acute lymphocytic leukemia [ALL]), and the drug was well tolerated at all dose levels, with myelosuppression being the major side effect. Responses were seen at all dose levels. However, the dose of 15 mg/m2 for 10 days appeared to induce the most responses (11 of 17 or 65%), with fewer responses seen when the dose was escalated or prolonged (2 of 19 or 11%). There was no correlation between P15 methylation at baseline or after therapy and response to decitabine. We conclude that decitabine is effective in myeloid malignancies, and low doses are as or more effective than higher doses.
Issa
Jean-Pierre J
JP
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. jpissa@mdanderson.org
Garcia-Manero
Guillermo
G
Giles
Francis J
FJ
Mannari
Rajan
R
Thomas
Deborah
D
Faderl
Stefan
S
Bayar
Emel
E
Lyons
John
J
Rosenfeld
Craig S
CS
Cortes
Jorge
J
Kantarjian
Hagop M
HM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D005260:Female; D020868:Gene Silencing; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D007621:Karyotyping; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine