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.

超过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，以补偿免疫性血小板减少性紫癜（ITP）中的血小板破坏。我们最初在难治性重度再生障碍性贫血患者的1/2期临床试验中开发了一项使用艾曲泊帕的方案。我们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缓解（Olnes et al，NEJM 2012）。然后，我们报告了43例患者的扩展队列的额外安全性和疗效数据，证实了3至4个月治疗的总体缓解率或40%，包括三线性和双线性缓解（Desmond et al，Blood，2014）。在扩展研究中，大多数继续接受艾曲泊帕治疗的患者继续显示出改善，并且大多数最终出现中性粒细胞、红细胞和血小板谱系的显著增加。血细胞计数接近正常的患者在入组后中位数28.5个月时停药，绝大多数患者在停用艾曲泊帕后血细胞计数保持稳定。 随后在难治性SAA中进行的一项试验（13-H-0133）询问难治性SAA患者更长时间的艾曲泊帕给药（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。主要6个月终点的应答率为50%，与初始试验相比没有显著改善。然而，25%的患者（5/20）在3个月时未达到缓解标准，但在6个月时为缓解者，因此通过更长时间的治疗得以挽救。我们结合两个队列进行分子分析，询问EPAG是否影响克隆进展，以及携带与骨髓恶性肿瘤相关的特定基因突变或由新体细胞突变定义的其他克隆的HPSC是否受到EPAG治疗的特异性刺激。我们没有发现与EPAG治疗相关的特异性体细胞突变克隆扩增的证据。两项试验合并的细胞遗传学进展率现在为19%。值得注意的是，所有发生7号单体性或其他有害的7号染色体异常的患者都是在最初的3-6个月内发生的，这表明对预先存在的克隆的潜在优先刺激。 其他细胞遗传学异常出现较晚，通常是短暂的，无论是药物治疗还是停药，并且不伴有发育异常变化或白血病进展。这项研究最近发表（Winkler et al，Blood，2019）。 该项目导致FDA于2014年8月批准了艾曲泊帕的新标签适应症，欧盟委员会于2015年底批准艾曲泊帕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。此外，与Neal S Young博士及其分支进行的一项合作试验证明，EPAG添加到未经治疗的重度AA的标准免疫抑制中可改善结局（Townsley et al，NEJM，2017），基于我们的研究，导致EPAG在AA中的第二次FDA/EHA批准。 在本报告期内，我们完成了对入组临床试验（11-H-0134）的34例患者的分析，该试验旨在检查艾曲泊帕在中度再生障碍性贫血或单系血细胞减少症患者中的安全性和疗效。在4个月的主要终点时，应答率为50%，包括1例遗传性Diamond-Blackfan贫血（DBA）患者。患者耐受剂量高达300 mg/天，无明显毒性。 我们注意到，在重度难治性再生障碍性贫血患者中，细胞遗传学进展率（6%）低于既往试验，且无患者出现7号染色体细胞遗传学进展。65%的患者能够停用EPAG以获得稳健的多谱系应答，但大多数患者需要重新开始药物治疗以维持计数，这与我们之前在难治性重度再生障碍性贫血中的经验相反。这项工作发表于2020财年（Fan et al，Blood Advances，2020）。 基于所有三项试验中生成的数据，我们观察到艾曲泊帕作为临床相关的铁螯合剂，可提高血液铁水平，并导致长期服用该药物的患者的铁净损失。一些患者需要口服铁补充剂。 我们假设EPAG逆转遗传性核糖体病DBA贫血的活性可能是由于EPAG的有效细胞内螯合活性，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，导致全球链生产与血红素生物合成失衡，导致游离血红素/增加的细胞内铁和活性氧物质的毒性积累。我们设计了一项临床试验，以测试EPAG在DBA中的活性，该试验已获得批准，由于COVID-19限制将患者带到NIH CC，因此患者招募延迟。