Eltrombopag for bone marrow failure

艾曲波帕治疗骨髓衰竭

• 批准号: 10253883
• 负责人: CYNTHIA E DUNBAR
• 金额: $ 38.48万
• 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/10253883
• 关键词: Agonist; Anemia; Annual Reports; Aplastic Anemia; Back; Binding; Blood; Blood Platelets; Bone Marrow; COVID-19; Chelating Activity; Chromosome 7; Chromosome abnormality; Clinical; Clinical Trials; Clonal Evolution; Clonal Expansion; Collaborations; Cyclosporine; Cytogenetics; Data; Diamond-Blackfan anemia; Disease; Dose; Enrollment; Equus caballus; Erythrocytes; Erythroid; Erythropoiesis; European; Genes; Hematology; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heme; Hormones; Human; Immune; Immunosuppression; In Vitro; Inherited; Iron; Iron Chelating Agents; Iron Chelation; Label; Laboratories; Laboratory Study; Link; Marrow; Megakaryocytes; Modality; Molecular Analysis; Monosomy 7; Morbidity - disease rate; Mus; Mutate; Mutation; Myeloproliferative disease; Oral; Outcome; Pancytopenia; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I/II Clinical Trial; Production; Proliferating; Property; Protein Biosynthesis; Protocols documentation; Publishing; Purpura; Reactive Oxygen Species; Refractory; Refractory anemias; Regimen; Report (document); Reporting; Rhesus; Safety; Somatic Mutation; Testing; Therapeutic immunosuppression; Thrombocytopenia; Thrombopoietin; Time; Toxic effect; United States National Institutes of Health; Work; base; bench to bedside; clinically relevant; clinically significant; cohort; collaborative trial; cytopenia; design; experience; heme biosynthesis; human data; improved; improved outcome; in vivo; iron supplementation; leukemia; mimetics; neutrophil; novel therapeutics; patient population; primary endpoint; progenitor; programs; receptor; response; small molecule; stem cells

More than 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 proliferate without terminal differentiation. The small molecule oral thrombopoietin mimetic eltrombopag was initially developed to overstimulate platelet production from marrow megakaryocytes to compensate for platelet destruction in immune thrombocytopenia purpura ITP). We originally developed a protocol utilizing eltrombopag in a phase 1/2 clinical trial for patients with refractory severe aplastic anemia. We reported that eltrombopag had efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses (Olnes et al, NEJM 2012). We then reported additional safety and efficacy data on an expanded cohort of 43 patients, confirming an overall response rate or 40% with 3 to 4 months of treatment, including tri- and bilinear responses (Desmond et al, Blood, 2014). The majority of patients who remained on eltrombopag in an extension study continued to show improvement, and most eventually had significant increases in neutrophil, red cell, and platelet lineages. Those with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry and the vast majority maintained stable counts off eltrombopag. A subsequent trial in refractory SAA (13-H-0133) asking whether more prolonged administration of eltrombopag to patients with refractory SAA, for 6 months instead of 3 months, would improve response rate and rescue a larger fraction of refractory patients. The response rate at the primary 6 month end point was 50%, not significantly improved over the initial trial. However, 25% of patients (5/20) did not reach response criteria at 3 months but were responders at 6 months, and thus were salvaged by the more prolonged treatment. We combined both cohorts for molecular analyses asking whether EPAG impacts on clonal progression, and whether HPSC carrying mutations in specific genes linked to myeloid malignancies or other clones defined by new somatic mutations are specifically stimulated by EPAG treatment. We found no evidence for specific somatically-mutated clonal expansions related to EPAG treatment. The cytogenetic progression rate in both trials combined is now 19%. Of note, all patients that developed monosomy 7 or other deleterious chromosome 7 abnormalities did so within the first 3-6 months, suggesting potential preferential stimulation of a pre-existing clone. Other cytogenetic abnormalities appeared later, were often transient whether on or off drug, and were not accompanied by dysplastic changes or leukemic progression. This study was published recently (Winkler et al, Blood, 2019). This program resulted in FDA approval of a new labeled indication for eltrombopag in August 2014, and European commission approval in late 2015 for eltrombopag 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. In addition, a collaborative trial carried out with Dr Neal S Young and his Branch documented that EPAG added to standard immunosuppression for untreated severe AA resulted in improved outcomes (Townsley et al, NEJM, 2017), leading to a 2nd FDA/EHA approval for EPAG in AA based on our studies. During the current reporting period, we completed analyses of 34 patients enrolled in a clinical trial (11-H-0134) examining safety and efficacy of eltrombopag in patients with moderate aplastic anemia or unilineage cytopenias. The response rate was 50% at the primary endpoint of 4 months, including in a patient with the inherited Diamond-Blackfan Anemia (DBA). Patients tolerated doses up to 300mg/day without significant toxicity. We noted a lower rate of cytogenetic progression (6%) than in the prior trials in severe refractory aplastic anemia, and no patients with chromosome 7 cytogenetic progression. 65% of patients were able to have EPAG discontinued for a robust multi lineage response, however the majority needed to have the drug restarted to maintain counts, in contrast to our prior experience in refractory severe aplastic anemia. This work was published in FY2020 (Fan et al, Blood Advances, 2020). Based on data generated in all three trials, we made the observation that eltrombopag acts as a clinically-relevant iron chelator, raising blood levels of iron and resulting net iron loss in patients on the drug long term. Several patients have required oral iron supplementation. We hypothesize that the activity of EPAG in reversing anemia in the inherited ribosomopathy DBA may be due to the potent intracellular chelating activity of EPAG, because recent laboratory studies suggest that erythroid development is inhibited in DBA due to slowed protein synthesis in erythroid progenitors, with a resulting imbalance in global chain production versus heme biosynthesis, leading to free heme/increased intracellular iron and toxic accumulation of reactive oxygen species. We have designed a clinical trial to test the activity of EPAG in DBA and this has been approved, with a delay in patient accrual due to COVID-19 restrictions on bringing patients to the NIH CC.

尽管接受了免疫抑制治疗，超过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、我们自己的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，而无需终末分化。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，以补偿免疫性血小板减少性紫癜（ITP）中血小板的破坏。我们最初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（Olnes 等，NEJM 2012）。然后，我们报告了由 43 名患者组成的扩大队列的额外安全性和有效性数据，确认了 3 至 4 个月治疗的总体缓解率为 40%，包括三线性和双线性缓解（Desmond 等人，Blood，2014）。在一项扩展研究中，大多数继续使用艾曲波帕的患者继续表现出改善，并且大多数患者最终中性粒细胞、红细胞和血小板谱系显着增加。血细胞计数接近正常化的患者在入组后中位 28.5 个月时停药，绝大多数人在艾曲波帕停药后血细胞计数保持稳定。 随后一项针对难治性 SAA 的试验 (13-H-0133) 询问，对难治性 SAA 患者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难治性患者。主要 6 个月终点的反应率为 50%，与初始试验相比没有显着改善。然而，25% 的患者 (5/20) 在 3 个月时未达到缓解标准，但在 6 个月时出现缓解，因此通过更长时间的治疗得以挽救。我们将两个队列结合起来进行分子分析，询问 EPAG 是否会影响克隆进展，以及携带与骨髓恶性肿瘤相关的特定基因突变的 HPSC 或新体细胞突变定义的其他克隆是否会受到 EPAG 治疗的特异性刺激。我们没有发现与 EPAG 治疗相关的特定体细胞突变克隆扩增的证据。目前两项试验的细胞遗传学进展率合计为 19%。值得注意的是，所有出现 7 号单体或其他有害 7 号染色体异常的患者都是在前 3-6 个月内出现的，这表明可能优先刺激预先存在的克隆。 其他细胞遗传学异常出现较晚，无论用药还是停药，通常都是短暂的，并且不伴有发育不良变化或白血病进展。这项研究最近发表（Winkler 等人，Blood，2019）。 该计划导致 FDA 于 2014 年 8 月批准了艾曲波帕的新标签适应症，欧盟委员会于 2015 年底批准了艾曲波帕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。此外，与 Neal S Young 博士及其分支机构进行的一项合作试验表明，对于未经治疗的严重 AA，将 EPAG 添加到标准免疫抑制中可改善预后（Townsley 等人，NEJM，2017），根据我们的研究，FDA/EHA 第二次批准 EPAG 用于 AA。 在本报告期内，我们完成了对参加临床试验 (11-H-0134) 的 34 名患者的分析，该试验检查了艾曲波帕对中度再生障碍性贫血或单系血细胞减少症患者的安全性和有效性。 4 个月主要终点的缓解率为 50%，其中包括患有遗传性 Diamond-Blackfan 贫血 (DBA) 的患者。患者耐受剂量高达 300 毫克/天，且没有明显毒性。 我们注意到，与之前的严重难治性再生障碍性贫血试验相比，细胞遗传学进展率 (6%) 较低，并且没有患者出现 7 号染色体细胞遗传学进展。 65% 的患者能够停用 EPAG 以获得强大的多谱系反应，但大多数患者需要重新启动药物以维持计数，这与我们之前在难治性严重再生障碍性贫血方面的经验形成鲜明对比。这项工作于 2020 财年发表（Fan et al, Blood Advances, 2020）。 根据所有三项试验中产生的数据，我们观察到艾曲波帕作为临床相关的铁螯合剂，可提高长期服用该药物的患者的血液铁水平并导致净铁损失。一些患者需要口服铁补充剂。 我们推测 EPAG 在逆转遗传性核糖体病 DBA 贫血中的活性可能是由于 EPAG 强大的细胞内螯合活性，因为最近的实验室研究表明，由于红系祖细胞中蛋白质合成减慢，DBA 中红系发育受到抑制，从而导致全链生产与血红素生物合成不平衡，导致游离血红素/增加 细胞内铁和活性氧的有毒积累。我们设计了一项临床试验来测试 EPAG 在 DBA 中的活性，该试验已获得批准，但由于 COVID-19 对将患者带到 NIH CC 的限制，患者的招募有所延迟。