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，但超过四分之一的严重再生障碍性贫血患者仍然保持全血细胞减少，其他患者至少有一个谱系的反应不佳。我们已经开发了一个程序来询问使用一种刺激c-MPL受体的药物是否可以在体内刺激人类造血干细胞。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的造血干和祖细胞在没有终末分化的情况下增殖。小分子口服促血小板生成素模拟物ELMBOPAG最初是为了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)中的血小板破坏而开发的。我们最初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eltrombopg的方案。我们报告了eltrombopg在这种情况下的疗效，44%(11/25)的患者有临床上显著的血液学反应(Olnes等人，《新英格兰医学杂志》2012)。然后，我们报告了43名扩大队列患者的额外安全性和有效性数据，证实了3至4个月治疗的总有效率或40%，包括三线性和双线性反应(Desmond等人，2014年)。在一项扩展研究中，大多数继续服用伊曲莫普的患者继续显示出改善，最终大多数患者的中性粒细胞、红细胞和血小板谱系显著增加。那些血细胞计数接近正常的患者在入选后停药的中位数为28.5个月，绝大多数患者的血细胞计数保持稳定。随后在难治性SAA(13-H-0133)中进行了一项试验，询问对于难治性SAA患者，更长时间地给予ELTROMBOPE 6个月而不是3个月是否会提高应答率并挽救更多的难治性患者。最初6个月终点的应答率为50%，与最初的试验相比没有明显改善。然而，25%(5/20)的患者在3个月时未达到有效标准，但在6个月时有效，因此通过更长时间的治疗得以挽救。我们结合了这两个队列进行分子分析，询问EPAG是否影响克隆进展，以及HPSC携带与髓系恶性肿瘤相关的特定基因突变或由新的体细胞突变定义的其他克隆是否受到EPAG治疗的特异性刺激。我们没有发现与EPAG治疗相关的特定体细胞突变克隆性扩张的证据。两项试验的细胞遗传学进展率加在一起现在是19%。值得注意的是，所有出现7号单体或其他有害的7号染色体异常的患者都是在最初的3-6个月内发生的，这表明可能是对先前存在的克隆的优先刺激。其他细胞遗传学异常出现较晚，无论用药或停药，通常都是一过性的，并且不伴有发育不良改变或白血病进展。这项研究最近发表(Winkler等人，布拉德，2019年)。 该计划导致FDA于2014年8月批准了eltrombopg的新标签适应症，并于2015年底批准了eltrombopg治疗难治性再生障碍性贫血。这是几十年来批准的第一种治疗再生障碍性贫血的新药，也是第一种专门针对难治性再生障碍性贫血患者群体批准的药物。此外，根据我们的研究，与尼尔·S·杨博士及其分支机构开展的一项合作试验证明，对于未经治疗的严重再生障碍性贫血，在标准免疫抑制的基础上加用EPAG可以改善预后(Townsley等，NEJM，2017年)，导致FDA/EHA第二次批准EPAG用于治疗再生障碍性贫血。 在本报告所述期间，我们完成了一项临床试验(11-H-0134)中登记的34名患者的分析，检查了eltrombopg对中度再生障碍性贫血或单纯性红细胞减少症患者的安全性和有效性。在4个月的主要终点，包括1例遗传性钻石-布莱克凡贫血(DBA)患者，应答率为50%。患者每天耐受剂量高达300毫克，没有明显毒性。我们注意到，在严重的难治性再生障碍性贫血中，细胞遗传学进展率(6%)低于先前的试验，并且没有7号染色体细胞遗传学进展率的患者。65%的患者能够停用EPAG以获得强大的多谱系反应，然而大多数患者需要重新开始药物以维持计数，这与我们之前在难治性重型再生障碍性贫血方面的经验形成了鲜明对比。这项工作发表在2020财年(Fan等人，血液进步，2020)。 根据所有三项试验中产生的数据，我们观察到，eltrombopg作为一种临床相关的铁络合剂，提高了血液中的铁水平，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质补充剂。我们推测，在遗传性核糖体病DBA中，EPAG逆转贫血的活性可能是由于EPAG强大的细胞内螯合活性，因为最近的实验室研究表明，由于红系祖细胞蛋白质合成放缓，DBA的红系发育受到抑制，导致全球链生产与血红素生物合成的失衡，导致游离的血红素/细胞内铁增加和活性氧的毒性积累。我们已经设计了一项临床试验来测试DBA中EPAG的活性，该试验已经获得批准，由于新冠肺炎对将患者带到NIH CC的限制，患者的应计延迟。