title: A pilot study of subcutaneous decitabine in β-thalassemia intermedia.
abstract: Ineffective erythropoiesis, the hallmark of β-thalassemia, is a result of α/non-α globin chain imbalance. One strategy to redress globin-chain imbalance is to induce γ-globin gene (HBG) expression. Repression of HBG in adult erythroid cells involves DNA methylation and other epigenetic changes. Therefore, the cytosine analog decitabine, which can deplete DNA methyltransferase 1 (DNMT1), can potentially activate HBG. In 5 patients with β-thalassemia intermedia, a dose and schedule of decitabine intended to deplete DNMT1 without causing significant cytotoxicity (0.2 mg/kg subcutaneous 2 times per week for 12 weeks) increased total hemoglobin from 7.88 ± 0.88 g/dL to 9.04 ± 0.77 g/dL (P = .004) and absolute fetal hemoglobin from 3.64 ± 1.13 g/dL to 4.29 ± 1.13 g/dL (P = .003). Significant favorable changes also occurred in indices of hemolysis and red blood cell densitometry. Consistent with a noncytotoxic, differentiation altering mechanism of action, the major side effect was an asymptomatic increase in platelet counts without erythrocyte micronucleus or VDJ recombination assay evidence of genotoxicity. This study was registered at www.clinicaltrials.gov as #NCT00661726.
authors.affiliation: Hemoglobinopathy Research, University Health Network, University of Toronto, Toronto, ON.
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Olivieri
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.forename: Vivek
authors.initials: V
authors.lastname: Thayalasuthan
authors.forename: Janet
authors.initials: J
authors.lastname: Kwiatkowski
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ware
authors.forename: Frans A
authors.initials: FA
authors.lastname: Kuypers
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Felicia L
authors.initials: FL
authors.lastname: Trachtenberg
authors.forename: Elliott P
authors.initials: EP
authors.lastname: Vichinsky
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002454:Cell Differentiation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011379:Prognosis; D055815:Young Adult; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000235:genetics; D055545:gamma-Globins / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D006454:Hemoglobins; D055545:gamma-Globins; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D001374:Azacitidine