Abstract 1767

Poster Board I-793


DNMT inhibitors decitabine and azacitidine are the current standard of MDS treatment. On the other hand, HDACs inhibitors are also being tested against this condition. These two drug classes synergize on their gene reactivating and anticancer activities. The combination of hydralazine and valproate (TRANSKRIP R/L), a DNMTs and HDACs inhibitors respectively is being developed as epigenetic therapy under the “Drug Repositioning” concept against common solid tumors in combination with chemo or radiation, as single agent against cutaneous lymphoma and against MDS.


To evaluate the clinical efficacy and safety of TRANSKRIP R/L against MDS.


Patients with previously treated MDS and having with normal hepatic and renal function were included. After signing informed consent the acetylator phenotype was determined to prescribe hydralazine dose (slow acetylators 82 mg, daily; fast acetylators 183 mg, daily). Valproate was dosed at 30 mg/kg/day. Both drugs were given daily until progression. Clinical and laboratory evaluations were done weekly. Response was graded with the International Working Group criteria. Toxicity was evaluated by OMS criteria. Bone marrow aspiration was performed every six weeks to evaluate global and gene specific DNA demethylation and histone acetylation.


From November 2007 to November 2008, twelve patients were included (5 female, 7 male). Median age ± SD was 59.5 ± 19.78 (range 23-79) years; median time from diagnosis to inclusion was 11.57 months (range 3- 23). Median of previous treatment was 3 (range 1-5). RCMD was diagnosed in 10 cases, and RAEB in two. Many (33 %) had a normal initial caryotype, followed by multiple, complex changes (25 %), two cases had -7 and isolated cases with -5q syndrome, +8, and 11q 23 were documented. According with IPSS, they were graded as intermedial-1 (58 %) or intermedial- two (42 %). Response was evaluated in nine cases: Global response was documented in 55.5 %, including one CR [lasting 10 w], one PR [lasting 6 w], four with an hematological improvement [with a mean time of duration of 25 w]; and one SD. Only two patients (22%) progressed to acute leukemia after 75 and 105 weeks of treatment. The mean increase of blood parameters is summarized in the following table:

Parameter Basal After treatment Weeks to response 
Hemoglobine (g/dL) 7.4 10.3 13 
Neutrophiles 1.1 2.0 
Platelets 66 72 
Parameter Basal After treatment Weeks to response 
Hemoglobine (g/dL) 7.4 10.3 13 
Neutrophiles 1.1 2.0 
Platelets 66 72 

Transfusional requirements decreased from 3 units monthly to 0.3 for RBC and from 1 to 0.16 monthly for platelets. The main toxicity was grade 1 & 2 somnolence in 70 % of pts, followed by grade 1 nausea in 57 % of them. None severe toxicity was documented. Mean ± SD valproate and hydralazine serum levels were: 68.2 ± 24.45 ug/mL and 211.59 ± 66.45 ng/mL, respectively. The results of pharmacokinetics, DNA methylation and histone acetylation will be presented at the meeting.


An hematological improvement was documented in most of the patients. These preliminary results are encouraging, since actually approved demethylating agents for MDS have shown a clearly decrease of hematological derivates transfusion, but not CR o PR. TRANSKRIP R/L administered to previously treated MDS patients is safe and shows promising clinical activity


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.