A Phase II Trial of Hydroxyurea and Pulse Arginine Butyrate

已经确定，胎儿血红蛋白（Hb F）的诱导可以改善镰状细胞病的临床并发症，Hb F的任何增加都提供一些临床益处，但通常需要等于或> 20%的高Hb F水平来防止器官损伤。化疗药物羟基脲（HU）诱导成人患者的Hb F平均水平为8.6%，并降低疼痛危象和急性胸部综合征的发生率， 有一半的成年患者有反应。镰状细胞病的最终治疗仍然需要诱导Hb F达到高水平的其他治疗剂。在初步研究中，精氨酸丁酸盐（AB）的脉冲方案在9/11例成人患者中诱导Hb F达到21%的平均水平。当AB加入到HU中时，在5/5例患者中观察到Hb F的进一步诱导，平均比单独HU的Hb F水平高14.8%。虽然HU被认为是通过影响Hb F， 在红系细胞动力学中，丁酸盐在报告基因测定中转录激活γ珠蛋白基因启动子。在一些对AB具有快速高Hb F反应的患者中，多核糖体分析表明γ珠蛋白mRNA翻译的效率增加。因此，HU和AB似乎通过不同的机制诱导Hb F。基于这些发现，我们假设1）HU +脉冲AB联合治疗将诱导比HU单独治疗更高水平的Hb F，2）进一步研究AB诱导Hb F的翻译机制将为设计更有效的丁酸盐给药方案提供基础。拟开展HU + AB治疗镰状细胞病患者的多中心II期临床试验 来验证这些假设

It is well-established that induction of fetal hemoglobin (Hb F) can ameliorate the clinical complications of sickle cell disease, that any increment in-Hb F provides some clinical benefit, but high Hb F levels equal to or > 20% are usually required to prevent organ damage. The chemotherapeutic agent Hydroxyurea (HU) induces Hb F to a mean level of 8.6% in adult patients, and reduces the incidence of painful crises and acute chest syndrome, with half of adult patients responding. Additional therapeutics which induce Hb F to high levels are still needed for definitive treatment of sickle cell disease. In pilot studies, a Pulsed regimen of Arginine Butyrate (AB) induced Hb F in 9/11 adult patients to a mean level of 21%. When AB was added to HU, further induction of Hb F, by a mean 14.8% above the Hb F levels on HU alone was observed in 5/5 patients. While HU is considered to stimulate Hb F through effects on erythroid cell kinetics, Butyrate transcriptionally activates the gamma globin gene promoter in reporter assays. In some patients who have rapid high Hb F responses to AB, polysome analysis demonstrates increased efficiency of gamma globin mRNA translation. HU and AB, therefore, appear to induce Hb F through different mechanisms. Based on these findings, we hypothesize that 1) combined therapy with HU + Pulsed AB will induce higher levels of Hb F than the levels achieved with HU alone, and 2) further investigation of translational mechanisms of Hb F induction by AB will provide a basis for designing more effective regimens of administration of Butyrate. A multi-center Phase II clinical trial of HU + AB in sickle cell patients is proposed to test these hypotheses.