A Proof of Principle Clinical Trial in Myelodysplastic Syndromes of Non-Cytotoxic Differentiation Therapy with Decitabine

Autor: Eric D. Hsi, Ricki Englehaupt, Lisa Durkin, Matt Kalaycio, Edward A. Copelan, Manual Afable, Yogen Saunthararajah, Joy Juersivich, Kathleen Cooper, Jaroslaw P. Maciejewski, Anjali S. Advani, Mikkael A. Sekeres, Ronald Sobecks, Tomas Radivoyevitch, Reda Z. Mahfouz, Robert M. Dean
Rok vydání: 2011
Předmět:
Zdroj: Blood. 118:3830-3830
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v118.21.3830.3830
Popis: Abstract 3830 In myeloid malignancies, genetic abnormalities in key apoptosis pathway genes (eg., p53) are associated with poor responses to conventional cytotoxic therapy. In pre-clinical models, non-cytotoxic, DNA methyltransferase 1 (DNMT1) depleting regimens of the deoxycytidine analogue decitabine relieve aberrant epigenetic repression of key late-differentiation genes and induce cell cycle exit by p53-independent differentiation pathways (CEBPE, MXD1, p27/CDKN1B) (Ng et al, Leukemia 2011). To translate these observations into practice, a clinical trial is being conducted in MDS, using decitabine at minimum doses required to deplete DNMT1 (0.1–0.2 mg/kg [5–10 mg/m2]), administered by the subcutaneous (SC) route to avoid high peak levels that cause apoptosis, and using a metronomic schedule (1-3X/week for ≥1y) to increase exposure time for S-phase specific depletion of DNMT1. To evaluate mechanism of action, correlative studies include quantification of pH2AX (DNA damage marker) and DNMT1 levels in bone marrow by flow-cytometry, and immunohistochemical evaluation by ImageQuant of p27/CDKN1B and KI67 expression, expected to vary directly and inversely respectively with terminal differentiation. A two-stage Simon design was used, and results from the first stage (n=15, patient characteristics table 1) are reported (median follow-up 330 days, range 142–180). Anti-emetics were not required, and there were no administration related adverse events. Neutropenic fever (NF) occurred in 11 patients, 7 of whom did not have NF prior to therapy (median time to nadir 40 days). By IWG criteria, complete hematologic and cytogenetic remissions (CR) with persistent dysplasia occurred in 2 subjects, hematologic improvement (HI) occurred in 4 subjects (overall response rate, ORR=40%), and stable disease in 7. Median response duration for HI/CR is 243 days, with 5 of 6 responses ongoing (range 74–292). Complete cytogenetic responses occurred even in patients with highly complex chromosome abnormalities (table 1). Bone marrow cell pH2AX expression decreased non-significantly from pre-treatment to week 6 to week 12 (median values 1.2, 0.5 and 0.4% respectively, p=0.27 Wilcoxon test), with a >3-fold reduction in mean percentage of cells expressing DNMT1 in the same period (Turkey-Kramer test p All subjects: baseline and response characteristics BM blasts: Disclosures: No relevant conflicts of interest to declare.
Databáze: OpenAIRE
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