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，但约四分之一的严重再生障碍性贫血患者仍呈全血细胞减少症，而其他患者至少在一个谱系中反应不佳。我们开发了一个程序来询问使用刺激 c-mpl 受体（与内源性激素血小板生成素结合）的药物是否可以刺激体内的人类造血干细胞。 小鼠、恒河猴和人类数据都表明，血小板生成素可以刺激原始造血干细胞和祖细胞增殖。小分子口服血小板生成素模拟物艾曲波帕最初被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。 我们在针对难治性严重再生障碍性贫血患者的 1/2 期临床试验中开发了一项利用艾曲波帕的方案。我们最初报道艾曲波帕在这种情况下有效，44% (11/25) 的患者出现临床显着的血液学反应。在本报告期内，我们报告了另外 18 名患者的安全性和有效性数据，以及对整个队列 43 名患者的长期随访。 3 至 4 个月时，43 名患者中有 17 名患者有总缓解率 (40%)，包括三系和双系缓解。在一项扩展研究中，大多数仍使用艾曲波帕的患者 (14/17) 继续表现出改善，其中 7 名患者的中性粒细胞、红细胞和血小板谱系最终显着增加。 5 名血细胞计数接近正常化的患者在入组后中位 28.5 个月（范围为 9-37 个月）时停药，并且在艾曲波帕治疗后中位 13 个月（范围为 1-15 个月）内血细胞计数均保持稳定。 8 名患者，包括 6 名无反应者和 2 名反应者，在艾曲波帕治疗后出现了新的细胞遗传学异常，其中 5 名患者出现 7 号染色体丢失或部分缺失。迄今为止，没有人进化为急性髓系白血病。 我们发起了一项新的研究，询问延长艾曲波帕给药时间（6 个月而不是 3 个月）是否会提高缓解率并挽救更多的难治性患者。该方案正在进行中，并且已经吸引了一半以上的目标患者 (22)。 迄今为止，响应率似乎高于最初的试验。 这些患者的样本被用来研究该药物在该患者群体中的药代动力学，并与 Neal Young 博士和 Andre Larochelle 博士的研究小组合作，研究该治疗对骨髓衰竭遗传异常以及体内和体外干细胞扩增的影响。 该计划最近导致 FDA 批准艾曲波帕的新标签适应症，用于治疗难治性再生障碍性贫血。这是数十年来第一个被批准用于再生障碍性贫血的新药，也是第一个专门针对难治性再生障碍性贫血患者群体而被批准的药物。正如 Neal Young 博士的报告中详细介绍的那样，这些试验现在还扩展到治疗许多其他骨髓衰竭患者群体。