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.

尽管有免疫抑制治疗，但大约四分之一的患有严重性性贫血的患者仍然是全年的，而另一些患者至少有一种谱系的反应次数均高。我们已经开发了一个程序来询问使用刺激内源性激素血栓蛋白的C-MPL受体的药物是否可以在体内刺激人类造血干细胞。 鼠，我们自己的恒河猴和人类数据都表明，血小板蛋白可以刺激原始的造血干和祖细胞扩展。最初开发的小分子口服血栓形成蛋白模拟物Eltrombopag是为了使血小板产生从骨髓巨核细胞中过度刺激，以补偿免疫血小板破坏。 我们在1/2期临床试验中针对难治性严重性性障碍性贫血的患者开发了一种利用Eltrombopag的方案。我们最初报告说，Eltrombopag在这种情况下具有疗效，其中44％（11/25）具有临床上显着的血液学反应。在当前的报告期间，我们报告了另外18例患者的安全性和功效数据，并对43例患者的整个队列进行了长期随访。在3至4个月时，包括三 - 和双纤维反应的43例患者中的总体反应率为17例（40％）。在扩展研究（14/17）中仍留在Eltrombopag的大多数患者继续显示出改善，最终7名中性粒细胞，红细胞和血小板谱系的患者最终显着增加。五名血液计数的近差正函数患者的药物在进入后的中位数为28.5个月（范围为9-37个月），并且所有维持稳定的计数的中位数为13个月（范围为1-15个月）。八名患者，包括6名无反应者和2个响应者，在Eltrombopag上产生了新的细胞遗传学异常，其中5例具有7染色体损失或部分缺失。迄今为止，没有一个演变为急性髓样白血病。 我们发起了一项新的研究，询问是否会长时间延长Eltrombopag，而不是3个月而不是3个月，将提高反应率，并挽救更大的难治性患者。该方案正在进行中，并且已经累积了一半以上的目标患者（22）。 迄今为止，响应率似乎高于初始试验。 这些患者的样本被用于研究该患者人群中该药物的药代动力学，并与Neal Young博士和Andre Larochelle博士合作研究该治疗对骨髓衰竭遗传异常的影响，以及体内和体外干细胞的扩张。 该计划最近导致了FDA批准了一种新的标记的Eltrombopag标记指示，用于治疗难治性性障碍性贫血。这是数十年来批准性贫血的首款新药，也是专门用于难治性性障碍患者群体的第一种药物。如Neal Young博士的报告所述，这些试验现在也扩展到治疗许多其他骨髓衰竭患者人群。