Pilatrino Chiara, Cilloni Daniela, Messa Emanuela, Morotti Alessandro, Giugliano Emilia, Pautasso Marisa, Familiari Ubaldo, Cappia Susanna, Pelicci Pier Giuseppe, Lo Coco Francesco, Saglio Giuseppe, Guerrasio Angelo
Department of Clinical and Biological Science, University of Turin, Turin, Italy.
Cancer. 2005 Jul 1;104(1):101-9. doi: 10.1002/cncr.21132.
The authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all-trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor-risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
Twenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45-100 microg/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for > or = 2 months were considered evaluable.
Hematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63-550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone.
Differentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life.
作者研究了组蛋白去乙酰化酶抑制剂丙戊酸（VPA）和全反式维甲酸（ATRA）作为分化剂在一组老年、高危急性髓系白血病（AML）或骨髓增生异常综合征（MDS）患者中的疗效和安全性。
20例复发或难治性AML或MDS老年患者按照II期方案接受序贯VPA和ATRA治疗。VPA起始剂量为每日10mg/kg，然后逐渐增加剂量以达到血清浓度45 - 100μg/mL。当VPA达到目标血清浓度时，添加ATRA，剂量为每日45mg/平方米（sm）。仅连续治疗≥2个月的患者被视为可评估对象。
根据世界卫生组织标准，在纳入该方案的20例患者中有6例出现血液学改善，但在11例被视为可评估的患者中有6例出现改善。5例患者出现主要血小板反应，实现了血小板输注独立。这5例患者中有3例还表现出轻微红系反应。第6例患者既表现出轻微红系反应又有血小板反应。反应的中位持续时间为189天（范围63 - 550天）。未观察到原始细胞计数有显著降低。4例患者出现3级神经皮质毒性。4例患者（2例4级和2例3级）经历了严重骨痛，且与外周原始细胞计数增加有关。ATRA治疗并未改变单独使用VPA时观察到的反应。
VPA分化疗法对约30%具有不良预后特征的难治性贫血伴原始细胞增多型老年AML和MDS患者具有临床益处。部分患者可能获得持续数月的显著血小板输注独立，减轻姑息治疗负担并改善生活质量。
