Eltrombopag for bone marrow failure

艾曲波帕治疗骨髓衰竭

• 批准号: 8939922
• 负责人: CYNTHIA E DUNBAR
• 金额: $ 4.61万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939922
• 关键词: Acute Myelocytic Leukemia; Antithymoglobulin; Aplastic Anemia; Binding; Blood; Blood Platelets; Cessation of life; Chromosome abnormality; Clinical Trials; Collaborations; Cyclosporine; Data; Drug Kinetics; Equus caballus; Erythrocytes; Failure; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Hormones; Human; Immune; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Iron Overload; Label; Laboratories; Macaca mulatta; Marrow; Megakaryocytes; Modality; Molecular Abnormality; Morbidity - disease rate; Mus; Oral; Pancytopenia; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Production; Protocols documentation; Refractory; Regimen; Reporting; Research; Risk; Safety; Sampling; Stem cells; Therapeutic immunosuppression; Thrombopoietin; Transplantation; base; bench to bedside; chromosome 7 loss; clinically significant; cohort; follow-up; human data; improved; in vivo; mimetics; neutrophil; patient population; programs; receptor; response; small molecule; stem

About a quarter of patients with severe aplastic anemia remain pancytopenic despite immunosuppressive therapy, and others have suboptimal responses in at least one lineage. We have developed a program to ask whether use of a drug stimulating the c-mpl receptor, which binds the endogenous hormone thrombopoietin, could stimulate human hematopoietic stem cells in vivo. Murine, our own rhesus, and human data all suggest that thrombopoietin can stimulate primitive hematopoietic stem and progenitor cells to expand. The small molecule oral thrombopoietin mimetic eltrombopag was initially developed to overstimulate platelet production from marrow megakaryocytes to compensate for immune platelet destruction. We developed a protocol utilizing eltrombopag in a phase 1/2 clinical trial for patients with refractory severe aplastic anemia. We initially reported that eltrombopag had efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses. During the current reporting period, we reported safety and efficacy data on a further 18 patients and long-term follow-up on the entire cohort of 43 patients. The overall response rate was 17 of 43 patients (40%) at 3 to 4 months, including tri- and bilineage responses. The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell, and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range, 9-37 months), and all maintained stable counts a median of 13 months (range, 1-15 months) off eltrombopag. Eight patients, including 6 nonresponders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. None evolved to acute myeloid leukemia to date. We initiated a new study, asking whether more prolonged administration of eltrombopag, for 6 months instead of 3 months, would improve response rate and rescue a larger fraction of refractory patients. This protocol is ongoing and has already accrued more than half of its target patients (22). To date, response rates appear higher than in the initial trial. Samples from these patients are being utilized to investigate pharmacokinetics of the drug in this patient population, and in collaboration with Dr. Neal Young's and Dr. Andre Larochelle's research groups, to investigate the impact of this treatment on genetic abnormalities in marrow failure, and on in vivo and in vitro stem cell expansion. This program recently resulted in FDA approval of a new labeled indication for eltrombopag, for treatment of refractory aplastic anemia. This is the first new drug approved for aplastic anemia in decades and the first drug approved specifically for the refractory aplastic anemia patient population. These trials have now also expanded to treating a number of other bone marrow failure patient populations, as detailed in Dr. Neal Young's report.

尽管接受了免疫抑制治疗，但大约四分之一的严重再生障碍性贫血患者仍然保持全血细胞减少，其他患者至少有一个谱系的反应不佳。我们已经开发了一个程序来询问使用一种刺激c-MPL受体的药物是否可以在体内刺激人类造血干细胞。小鼠、我们自己的恒河猴和人类的数据都表明，血小板生成素可以刺激原始的造血干和祖细胞扩张。小分子口服促血小板生成素模拟物ELMBOMBOPG最初是为了过度刺激骨髓巨核细胞产生血小板以补偿免疫血小板的破坏而开发的。我们在难治性重型再生障碍性贫血患者的1/2期临床试验中开发了一种使用eltrombopg的方案。我们最初报道，在这种情况下，eltrombopg有效，44%(11/25)的患者有临床显著的血液学反应。在本报告所述期间，我们报告了另外18名患者的安全性和有效性数据，并对整个43名患者进行了长期随访。43例患者3~4个月总有效率为17例(40%)，包括三联体和双联体反应。在一项扩展研究中，大多数继续服用伊波波普的患者(14/17)继续显示出改善，7名患者最终中性粒细胞、红细胞和血小板谱系显著增加。5名血细胞计数接近正常的患者在进入试验后停药的中位数为28.5个月(范围为9-37个月)，所有患者的血细胞计数均保持稳定，中位数为13个月(范围为1-15个月)。8名患者，包括6名无反应者和2名应答者，在ELTROMBOG上出现了新的细胞遗传学异常，包括5例7号染色体丢失或部分缺失。到目前为止，没有一例演变为急性髓系白血病。 我们发起了一项新的研究，询问是否更长时间地使用eltrombopg，6个月而不是3个月，是否会提高应答率并挽救更大比例的难治性患者。该方案正在进行中，已经积累了其目标患者的一半以上(22人)。到目前为止，应答率似乎高于最初的试验。这些患者的样本正被用于研究该药物在该患者群体中的药代动力学，并与尼尔·杨博士和安德烈·拉罗切尔博士的研究小组合作，调查这种治疗方法对骨髓衰竭的遗传异常以及对体内和体外干细胞扩增的影响。 这项计划最近导致FDA批准了一种新的标签适应症，用于治疗难治性再生障碍性贫血。这是几十年来批准的第一种治疗再生障碍性贫血的新药，也是第一种专门针对难治性再生障碍性贫血患者群体批准的药物。这些试验现在也扩展到治疗其他一些骨髓衰竭患者，尼尔·杨博士的报告中详细介绍了这一点。