Epigenetic Therapy With Hydralazine and Magnesium Valproate Reverses Imatinib Resistance in Patients With Chronic Myeloid Leukemia

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• 作者：Eduardo Cervera¹ ; Myrna Candelaria¹ ; ² ; Omar Ló ; pez-Navarro¹ ; Juan Labardini¹ ; Aurora Gonzalez-Fierro³ ; Lucia Taja-Chayeb³ ; Jorge Cortes⁴ ; Daniela Gordillo-Bastidas¹ ; Alfonso Dueñ ; as-Gonzá ; lez⁵ ; ^{alfonso_duenasg@yahoo.com}
• 关键词：Chronic myeloid leukemia ; Epigenetic therapy ; Imatinib resistance
• 刊名：Clinical Lymphoma Myeloma and Leukemia
• 出版年：2012
• 期刊代码：pca95_21522650
• 类别：med
• 出版时间：June, 2012
• 卷：12
• 期：3
• 页码：207-212
• 文件大小：294 K

摘要

<h4 class="h4">Backgroundh4>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.<h4 class="h4">Patient and Methodsh4>

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.<h4 class="h4">Resultsh4>

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.<h4 class="h4">Conclusionsh4>

Our results suggest that the epigenetic drugs hydralazine and valproate revert the resistance to imatinib in patients with CML.