Candelaria Myrna, Burgos Sebastian, Ponce Mayra, Espinoza Ramiro, Dueñas-Gonzalez Alfonso
Division de Investigación Clínica, Instituto Nacional de Cancerología, Av. San Fernando 22, Tlalpan, 14080, México, D.F., Mexico.
Departamento de Hematología, Instituto Nacional de Cancerologia, Mexico, Mexico.
Ann Hematol. 2017 Nov;96(11):1825-1832. doi: 10.1007/s00277-017-3103-x. Epub 2017 Aug 23.
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.
对于许多骨髓增生异常综合征（MDS）患者来说，低甲基化药物阿扎胞苷和地西他滨难以承受。DNA甲基转移酶抑制剂肼屈嗪和组蛋白去乙酰化酶抑制剂丙戊酸盐联合用药已在MDS中显示出初步疗效。本研究旨在评估以同情用药方式治疗的一系列MDS患者中肼屈嗪/丙戊酸盐的临床疗效和安全性。根据患者的乙酰化基因型确定肼屈嗪的剂量（慢乙酰化者每日83毫克；快乙酰化者每日182毫克），丙戊酸盐的剂量为30毫克/千克/天。两种药物均每日给药，直至疾病进展。分别采用国际工作组标准和美国国立癌症研究所不良事件通用术语标准第4版评估反应和毒性。采用Kaplan-Meier方法估计生存参数。2009年至2012年，14例患者接受了治疗。年龄中位数±标准差为55.2±19.52（范围23 - 87）岁。根据国际预后评分系统（IPSS），病例分级为中危-1（n = 8/14；57.2%）或中危-2（n = 6/14；42.8%）。反应情况如下：5例（35.7%）完全缓解，1例（7.1%）部分缓解，2例（14.28%）不再依赖输血。反应的平均持续时间±标准差为60±35.28个月（范围5 - 94）。3例患者进展为急性髓系白血病（AML）。在中位随访57个月（范围1 - 106）时，中位总生存期（OS）为27个月。此时，5例患者仍在接受治疗，1例部分缓解，4例完全缓解。与6例未接受治疗患者的7个月OS相比，8例从治疗中获得临床益处患者的中位OS未达到。肼屈嗪和丙戊酸盐联合用药在MDS中安全有效，非常需要进一步进行试验。
