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Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial

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Abstract

Decitabine and azacitidine, two DNA methyltransferase (DNMT) inhibitors, are the current standard of treatment for myelodysplastic syndrome (MDS). Histone deacetylase (HDAC) inhibitors are also being tested against MDS. Both drug classes synergize in their gene reactivating and anticancer activities. The combination of hydralazine and valproate (Transkrip®), a DNMT and HDAC inhibitor, respectively), has been developed as epigenetic therapy under the drug repositioning concept. To evaluate the clinical efficacy and safety of hydralazine and valproate against MDS, an open phase-II study for previously treated patients with MDS was conducted. The hydralazine dose was given according with the acetylator phenotype, and valproate was dosed at 30 mg/kg/day. Response was graded with International Working Group criteria. Toxicity was evaluated by the Common Toxemia Criteria-National Cancer Institute version 3 scale. From November 2007 to January 2010, 12 patients were included. Median age ± SD was 53 ± 19.78 years (range, 23–79 years); median time from diagnosis to inclusion in the study was 7.9 months (range 2.6–36.1 months). Median of previous treatment was 2 (range, 1–6). Refractory cytopenia with multilineage dysplasia was diagnosed in ten cases, and refractory anemia with excess of blasts in two. Overall response was documented in six (50%) of 12 cases, including one CR, one PR, and four hematological improvements of the erythroid series. Two patients (16.6%) progressed to acute myeloid leukemia. Hemoglobin increased from 7.4 to 10.3 g/dL (in 13 weeks), neutrophils, from 1.1 to 2.0 (in 3 weeks), and platelets, from 66 × 109 to 72 × 109/L (in 2 weeks). Transfusional requirements decreased from 2.3 to 0 U bi-monthly for red blood cells and from 0.5 to 0 U bi-monthly for platelets in responding patients. Main toxicities were mild, including somnolence and nausea. Preliminary results of this phase-II study suggest that the combination of hydralazine and valproate is a promising non-toxic and effective therapy for MDS.

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Competing interests

The authors have declared that no competing interests exist.

Funding

This work was supported by CONACyT grants SALUD-2002-C01-6579, 60517, AVANCE C01-294, and by Psicofarma, S.A. de C.V., Mexico. Sponsors did not participate in study design; collection, analysis, and interpretation of data; writing of the paper; nor decision to submit it for publication.

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Authors and Affiliations

  1. Division de Investigación Clínica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico

    Myrna Candelaria, Juan Labardini, Daymi Arias-Bofill & Silvia Vidal

  2. Departamento de Hematología, INCan, Mexico City, Mexico

    Aquileo Herrera

  3. División de Investigación Básica, INCan, Mexico City, Mexico

    Aurora González-Fierro, Catalina Trejo-Becerril, Lucía Taja-Chayeb, Enrique Pérez-Cárdenas, Erick de la Cruz-Hernández & Eduardo Cervera

  4. Unidad de Investigación Biomédica en Cáncer (UIBC), Instituto de Investigaciones Biomédicas (IIB), Universidad Nacional Autonóma de Mexico (UNAM), Mexico City, Mexico

    Alfonso Dueñas-Gonzalez

  5. Instituto Nacional de Cancerología, Av. San Fernando 22, Tlalpan, 14080, Mexico, D.F., Mexico

    Alfonso Dueñas-Gonzalez

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  1. Myrna Candelaria
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Correspondence to Alfonso Dueñas-Gonzalez.

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Candelaria, M., Herrera, A., Labardini, J. et al. Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial. Ann Hematol 90, 379–387 (2011). https://doi.org/10.1007/s00277-010-1090-2

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  • DOI: https://doi.org/10.1007/s00277-010-1090-2

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