Encouraging results with the compassionate use of hydralazine/valproate (TRANSKRIP™) as epigenetic treatment for myelodysplastic syndrome (MDS)

Abstract

The hypomethylating agents azacytidine and decitabine are unaffordable for many patients with MDS. The combination of the DNA methyltransferase inhibitor hydralazine and the histone deacetylase inhibitor valproate has shown preliminary efficacy in MDS. The aim of this study is to evaluate the clinical efficacy and safety of hydralazine/valproate in a case series of MDS patients treated in a compassionate manner. Hydralazine was dosed according to the acetylation genotype of patients (slow acetylators 83 mg daily; fast acetylators 182 mg daily), and valproate was dosed at 30 mg/kg/day. Both drugs were given daily until disease progression. Response and toxicity were evaluated with the International Working Group criteria and CTCAE, version 4, respectively. Survival parameters were estimated with the Kaplan-Meier method. From 2009 to 2012, 14 patients were treated. The median age ± SD was 55.2 ± 19.52 (range 23-87) years. According to the IPSS, cases were graded as intermediate-1 (n = 8/14; 57.2%) or intermediate-2 (n = 6/14; 42.8%). Responses were as follows: five (35.7%) complete response, one (7.1%) partial response, and two (14.28%) became transfusion independent. The mean duration of response ± SD was 60 ± 35.28 months (range 5-94). Three patients progressed to AML. At a median follow-up of 57 months (range 1-106), the median OS was 27 months. At that point, five patients remained on the treatment, one with partial response and four with complete response. The median OS was not reached in the eight patients who saw a clinical benefit from the treatment, in comparison to an OS of 7 months in the six patients who had no treatment. The combination of hydralazine and valproate is safe and effective in MDS, and its further testing is highly desirable.

Epigenetics-Associated Risk Reduction of Hematologic Neoplasms in a Nationwide Cohort Study: The Chemopreventive and Therapeutic Efficacy of Hydralazine

“…A therapeutic significance of HDZ on B-cells as suggested in this retrospective cohort study is conceivable. In addition, with the support by the role of DNMT1 in MDS and myeloid leukemia as reported in a previous review (40) and reports indicating a reduction in mRNA level of DNMTs by HDZ (37) and an abnormally high expression level of DNMTs in cell lines of MDS and myeloid leukemia including AML and CML (41), we suggest that HDZ alone may have enough efficacy to inhibit MDS or myeloid leukemia while previous trials selected a combination of HDZ and VAL (23,24,27,28).…”

“…Over the last decade, several clinical trials have revealed that a combination of HDZ and VAL is a promising therapy for the several hematological malignancies, including mycosis fungoides (22), MDS (23,24), CTCL (25,26), AML (27), chronic myeloid leukemia (CML) (28). However, there has been no integral analysis targeting all the HNs as outcomes based on a large health insurance database.…”

HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia

“…There are several possible reasons behind this failure. For example, HDACi exert different outcomes depending on timing of administration and differentiation stage of the tumor (Kuendgen et al, 2011;Garcia-Manero et al, 2012;Novotny-Diermayr et al, 2012;Romanski et al, 2012;Xie et al, 2012;Candelaria et al, 2017;Huang and Zong, 2017;Young et al, 2017). In addition, the vast majority of preclinical and clinical studies deploying HDACi for anti-cancer treatment involved unselective inhibitors targeting all HDACs (pan-HDACi) with broad spectrum of side effects and toxicity, thus calling for exploitation of agents that specifically block individual HDACs.…”

Effect of epigenetic treatment on SST2 expression in neuroendocrine tumour patients

“…The importance of choice and dosage of the epidrugs was shown by the effect of the DNMT inhibitor hydralazine, exhibiting only mild effects in pharmacologically unreachable dosages despite good efficiency observed in other tumours. 7 , 8 A possible future limitation for epigenetic treatment in NETs could also be the observed non‐specific effect of increased renal uptake in our patients. Although changes in uptake measures of up to 25% SUV max between two scans have been described, 9 the increase in renal uptake was seen in 78% of our patients in the second PET/CT.…”