Epigenetic therapy with hydralazine and magnesium valproate reverses imatinib resistance in patients with chronic myeloid leukemia

Eduardo Cervera, Myrna Candelaria, Omar López-Navarro, Juan Labardini, Aurora Gonzalez-Fierro, Lucia Taja-Chayeb, Jorge Cortes, Daniela Gordillo-Bastidas, Alfonso Dueñas-González

Research output: Contribution to journalArticle

Abstract

Background: Epigenetic alterations participate in the development of acquired resistance to imatinib, hence, the DNA methylation, and histone deacetylase inhibitors hydralazine and valproate, respectively, has the potential to overcome it. Patient and Methods: A series of 8 patients with chronic myeloid leukemia (CML) refractory to imatinib mesylate with no access to second-generation tyrosine kinase inhibitors were treated with hydralazine and valproate in a compassionate manner. Clinical efficacy and safety of these drugs added to imatinib mesylate were evaluated. Results: Two patients were in the blast phase, 5 were in the accelerated phase, and 1 was in the chronic phase. All the patients continued with the same dose of imatinib that they had been receiving at the time of development of resistance, with a median dose of 600 mg daily (range, 400-800 mg). The median time from diagnosis of CML to the start of hydralazine and valproate was 53.6 months (range, 19-84 months). Two (25%) patients had a complete hematologic response, one (12.5%) had an major cytogenetic response, and one (12.5%) had a complete cytogenetic response. Three (37.5%) patients had stable disease, and only one (12.5%) patient failed to respond. At a median follow-up time of 18 months (range, 3-18 months), the median survival had not been reached, and the projected overall survival was 63%. All the patients had mild neurologic toxicity, including distal tremor and somnolence. No grade 3 or 4 toxicity was observed. Conclusions: Our results suggest that the epigenetic drugs hydralazine and valproate revert the resistance to imatinib in patients with CML.

Original languageEnglish (US)
Pages (from-to)207-212
Number of pages6
JournalClinical Lymphoma, Myeloma and Leukemia
Volume12
Issue number3
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

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Hydralazine
Valproic Acid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Epigenomics
Therapeutics
Cytogenetics
Blast Crisis
Imatinib Mesylate
Histone Deacetylase Inhibitors
Survival
Tremor
DNA Methylation
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Nervous System
Safety

Keywords

  • Chronic myeloid leukemia
  • Epigenetic therapy
  • Imatinib resistance

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Cervera, E., Candelaria, M., López-Navarro, O., Labardini, J., Gonzalez-Fierro, A., Taja-Chayeb, L., ... Dueñas-González, A. (2012). Epigenetic therapy with hydralazine and magnesium valproate reverses imatinib resistance in patients with chronic myeloid leukemia. Clinical Lymphoma, Myeloma and Leukemia, 12(3), 207-212. https://doi.org/10.1016/j.clml.2012.01.005

Epigenetic therapy with hydralazine and magnesium valproate reverses imatinib resistance in patients with chronic myeloid leukemia. / Cervera, Eduardo; Candelaria, Myrna; López-Navarro, Omar; Labardini, Juan; Gonzalez-Fierro, Aurora; Taja-Chayeb, Lucia; Cortes, Jorge; Gordillo-Bastidas, Daniela; Dueñas-González, Alfonso.

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 12, No. 3, 01.06.2012, p. 207-212.

Research output: Contribution to journalArticle

Cervera, E, Candelaria, M, López-Navarro, O, Labardini, J, Gonzalez-Fierro, A, Taja-Chayeb, L, Cortes, J, Gordillo-Bastidas, D & Dueñas-González, A 2012, 'Epigenetic therapy with hydralazine and magnesium valproate reverses imatinib resistance in patients with chronic myeloid leukemia', Clinical Lymphoma, Myeloma and Leukemia, vol. 12, no. 3, pp. 207-212. https://doi.org/10.1016/j.clml.2012.01.005
Cervera, Eduardo ; Candelaria, Myrna ; López-Navarro, Omar ; Labardini, Juan ; Gonzalez-Fierro, Aurora ; Taja-Chayeb, Lucia ; Cortes, Jorge ; Gordillo-Bastidas, Daniela ; Dueñas-González, Alfonso. / Epigenetic therapy with hydralazine and magnesium valproate reverses imatinib resistance in patients with chronic myeloid leukemia. In: Clinical Lymphoma, Myeloma and Leukemia. 2012 ; Vol. 12, No. 3. pp. 207-212.
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AU - Cervera, Eduardo

AU - Candelaria, Myrna

AU - López-Navarro, Omar

AU - Labardini, Juan

AU - Gonzalez-Fierro, Aurora

AU - Taja-Chayeb, Lucia

AU - Cortes, Jorge

AU - Gordillo-Bastidas, Daniela

AU - Dueñas-González, Alfonso

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N2 - Background: Epigenetic alterations participate in the development of acquired resistance to imatinib, hence, the DNA methylation, and histone deacetylase inhibitors hydralazine and valproate, respectively, has the potential to overcome it. Patient and Methods: A series of 8 patients with chronic myeloid leukemia (CML) refractory to imatinib mesylate with no access to second-generation tyrosine kinase inhibitors were treated with hydralazine and valproate in a compassionate manner. Clinical efficacy and safety of these drugs added to imatinib mesylate were evaluated. Results: Two patients were in the blast phase, 5 were in the accelerated phase, and 1 was in the chronic phase. All the patients continued with the same dose of imatinib that they had been receiving at the time of development of resistance, with a median dose of 600 mg daily (range, 400-800 mg). The median time from diagnosis of CML to the start of hydralazine and valproate was 53.6 months (range, 19-84 months). Two (25%) patients had a complete hematologic response, one (12.5%) had an major cytogenetic response, and one (12.5%) had a complete cytogenetic response. Three (37.5%) patients had stable disease, and only one (12.5%) patient failed to respond. At a median follow-up time of 18 months (range, 3-18 months), the median survival had not been reached, and the projected overall survival was 63%. All the patients had mild neurologic toxicity, including distal tremor and somnolence. No grade 3 or 4 toxicity was observed. Conclusions: Our results suggest that the epigenetic drugs hydralazine and valproate revert the resistance to imatinib in patients with CML.

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