Abstract
CD34 positive cells from patients with trisomy 8 myelodysplastic syndrome (MDS) have pronounced expression of early apoptotic markers compared to normal hematopoietic cells. However, trisomy 8 clones persist in patients with bone marrow failure and expand following immunosuppression (Sloand EM et al; Blood2005; 106(3):841). We have demonstrated up-regulation of c-myc, survivin, and CD1 in CD34 cells of patients with trisomy 8 (Sloand et al; Blood2007; 109(6):2399). Employing siRNA mediated knockdown of the anti-apoptotic protein survivin, we demonstrated a decrease in trisomy 8 cell growth and postulated that increased Cyclin D1 caused the upregulation of survivin resulting in resistance of these cells to apoptosis.
Using fluorescent in situ hybridization (FISH) we showed that the novel styryl sulfone, ON 01910.Na (Vedula MS et al; European Journal of Medicinal Chemistry2003;38:811), inhibits cyclin D1 accumulation and is selectively toxic to trisomy 8 cells while promoting maturation of diploid cells. Flow cytometry of cultured cells demonstrated increased proportions of mature CD15 positive myeloid cells and decreased number of immature CD33+ cells or CD34+ blasts (Sloand EM et al; Blood2007;110:822).
These encouraging in vitro data led to a phase I/II trial of ON 01910.Na in MDS patients with refractory anemia with excess blasts who had IPSS =/> int-2. This study was designed to assess the safety, and activity of escalating doses of ON 01910.Na (800 mg/m2/day × 3 days, 800 mg/m2/day × 5 days, 1500 mg/m2/day × 5 days, 1800 mg/m2/day × 5 days every 2 weeks) in MDS patients. To date five MDS patients have been treated with ON 01910.Na for 4 to 16 weeks in the first two dose cohorts. Two patients had isolated trisomy 8, two had complex cytogenetic abnormalities including trisomy 8 in all aneuploid cells, and one had monosomy 7. Three and five day infusions were well tolerated. Pharmakokinetic analysis showed that the half life of the drug is 1.3 ± 0.5 hours without signs of drug accumulation. Four of five patients demonstrated a rapid and significant decrease in the number of peripheral blasts and aneuploid cells after 4 weeks of therapy (see below), concomitantly with increases in neutrophil and/or platelet counts in four patients. All four patients exhibiting a biological effect of drug treatment had trisomy 8 in their aneuploid clone prior to therapy. One monosomy 7 patient, previously refractory to EPO became responsive to Darbopoietin and another trisomy 8 patient became platelet-transfusion independent.
In this early safety trial, ON 01910.Na demonstrates efficacy at early timepoints with respect to improved cytopenias and decreased blast counts. Continued enrollment and long term follow-up will further detail clinical efficacy and impact on the long term prognosis of high risk MDS patients treat with this drug.
Figure Figure
Nuclear accumulation of cyclin D1 following long-term fractionated exposures to low-dose ionizing radiation in normal human diploid cells