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.

约四分之一的重型再生障碍性贫血患者尽管接受了免疫抑制治疗，但仍保持全血细胞减少，其他患者至少在一个谱系中有次优反应。我们已经开发了一个程序，以询问是否使用一种刺激c-mpl受体的药物，该受体与内源性激素血小板生成素结合，可以刺激体内的人类造血干细胞。 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造血干细胞和祖细胞扩增。小分子口服血小板生成素模拟物艾曲泊帕最初开发用于过度刺激骨髓巨核细胞产生血小板，以补偿免疫血小板破坏。 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艾曲泊帕的方案。我们最初报告艾曲泊帕在这种情况下有效，44%（11/25）的患者出现具有临床意义的血液学应答。在本报告期内，我们报告了另外18例患者的安全性和疗效数据，并对整个队列的43例患者进行了长期随访。在3至4个月时，43例患者中有17例（40%）的总体缓解率，包括三线和双线缓解。在一项扩展研究中，大多数继续接受艾曲泊帕治疗的患者（14/17）继续显示出改善，7例最终出现中性粒细胞、红细胞和血小板谱系显著增加。5例血细胞计数稳健接近正常化的患者在入组后中位28.5个月（范围，9-37个月）停药，所有患者在停用艾曲泊帕后中位13个月（范围，1-15个月）维持稳定计数。8例患者（包括6例无应答者和2例应答者）在艾曲泊帕治疗后发生了新的细胞遗传学异常，包括5例7号染色体缺失或部分缺失。迄今为止，没有人发展为急性髓性白血病。 我们启动了一项新的研究，探讨艾曲泊帕更长时间给药（6个月而不是3个月）是否会提高缓解率并挽救更大比例的难治性患者。该方案正在进行中，已经招募了一半以上的目标患者（22）。 迄今为止，反应率似乎高于最初的试验。 来自这些患者的样本被用于研究药物在该患者人群中的药代动力学，并与Neal Young博士和Andre Larochelle博士的研究小组合作，研究这种治疗对骨髓衰竭中遗传异常的影响，以及对体内和体外干细胞扩增的影响。 该项目最近导致FDA批准艾曲泊帕的新标签适应症，用于治疗难治性再生障碍性贫血。这是几十年来第一个批准用于再生障碍性贫血的新药，也是第一个专门批准用于难治性再生障碍性贫血患者人群的药物。这些试验现在也扩展到治疗其他一些骨髓衰竭患者群体，如Neal Young博士的报告所述。