bone marrow Alisertib blasts . Thirteen patients had good risk cytogenetics, and seven had poor risk. IPSS risk score was low in six patients, intermediate 1 in eight patients, intermediate 2 in six patients, and high in one patient. Prior therapy included growth factors, azacytidine , and chemotherapy Nilotinib molecular weight . Patients were treated with median of four cycles of belinostat. Most of the 79 cycles administered were delivered on time, at full dose. Three patients had treatment delays for grade 3 hyperglycemia, recovery from surgery, and unavailability of study drug. Three patients Response to belinostat There was one confirmed response to belinostat, hematologic improvement in neutrophils in a patient with RAEB 1 , for an overall response rate of 5% . The duration of the response was 2.1 months.
Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual after 21 patients. At a median follow up of 12 months , nine patients progressed, and 14 patients died. Median time to progression was 14.9 months , and median overall survival was 17.9 months . Twelve month time to progression ZD6474 price was 66% , and 12 month overall survival was 71% . Toxicity Belinostat was generally well tolerated in this patient population, although hematologic adverse events were common. Grade 3 or 4 hematologic toxicity occurred in 19 and 15 patients, respectively, regardless of attribution. Grade 3 or 4 hematologic toxicities attributed to belinostat occurred in 13 and 11 patients, respectively, including neutropenia , thrombocytopenia , and anemia , although for many patients, the cytopenias were not changed from baseline .
In general, cytopenias persisted, but did not worsen, when patients received subsequent cycles. Grade 3 or 4 nonhematologic toxicities considered at least possibly related to belinostat occurred in five Etoposide ic50 and one patients, respectively, and included fatigue , febrile neutropenia , headache , and QTc prolongation . Two patients had grade 2 cytokine release syndrome during belinostat infusion, which was managed with administration of steroids and reduction of the infusion rate. Discussion The aberrant acetylation of histones is a feature of malignant cells, and the inhibition of HDAC enzymes can change histone acetylation patterns in ways that lead to increased expression of genes involved in differentiation and apoptosis .
The use of HDAC inhibitors in MDS has been carbohydrates approached with enthusiasm, given the preclinical evidence that HDAC inhibitors promote differentiation in malignant myeloid cell lines and the fact that hypomethylating agents, which also act via epigenetic mechanisms, have established efficacy in MDS . However, in phase I and II clinical trials, single agent activity of HDAC inhibitors in MDS and AML has been modest, with response rates ranging from 0% to 17% in trials that enrolled primarily patients with AML . In contrast, Kuendgen et al. reported a superior response rate in MDS patients treated with the HDAC inhibitor valproic acid, with or without all trans retinoic acid . In their trial, the subset of 23 patients with MDS and a normal blast count had an overall response rate of 52% .Belinostat, a member of the hydroxamate class of HDAC inhibitors, induces a concentration dependent acetylation .