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.

尽管有免疫抑制治疗，但超过四分之一的患有严重性贫血的患者仍然是全年的，而另一些患者至少有一种谱系的反应。我们已经开发了一个程序来询问使用刺激内源性激素血栓蛋白的C-MPL受体的药物是否可以在体内刺激人类造血干细胞。 鼠，我们自己的恒河猴和人类数据都表明，血小板素可以刺激原始的造血干和祖细胞，而无需终极分化而增殖。最初开发了小分子口服血栓形成蛋白模仿eltrombopag，以使血小板产生从骨髓巨核细胞中产生，以补偿免疫血小板细胞减少紫菜ITP的血小板破坏）。我们最初在1/2期临床试验中针对难治性严重性性贫血患者开发了一种利用Eltrombopag的方案。我们报道说，Eltrombopag在这种情况下具有疗效，其中44％（11/25）的患者具有临床上显着的血液学反应（Olnes等，NEJM 2012）。然后，我们报告了43例患者的增加的同类人群的其他安全性和疗效数据，确认了总体缓解率，或40％的治疗方法，包括三线和双线性反应（Desmond等，Blood，2014）。在一项扩展研究中，大多数留在Eltrombopag的患者继续表现出改善，大多数患者最终在中性粒细胞，红细胞和血小板谱系中显着增加。那些血液计数近差异化的人的药物在进入后的中位数为28.5个月，而绝大多数人保持稳定的计数。 随后在难治性SAA（13-h-0133）中进行的试验询问是否会延长对难治性SAA患者的延长Eltrombopag，持续6个月而不是3个月，将提高应答率，并挽救更大的耐味患者的一部分。主要6个月终点的响应率为50％，在初始试验中没有显着提高。但是，25％的患者（5/20）在3个月时没有达到反应标准，而是在6个月时为反应者，因此被延长的治疗方法挽救了。我们将两个队列组合在一起进行分子分析，询问EPAG对克隆进展的影响，以及与髓样恶性肿瘤相关的特定基因中携带突变还是由新体细胞突变定义的其他克隆（EPAG治疗）特异性刺激。我们没有发现与EPAG治疗相关的特定体体突变的特异性克隆扩张的证据。现在，这两个试验中的细胞遗传学进展速率现在为19％。值得注意的是，所有开发单肌第7或其他有害染色体异常的患者在最初的3-6个月内都这样做，这表明潜在的优先刺激了先前存在的克隆。 其他细胞遗传学异常出现后来，通常是瞬时的，无论是开或关闭药物，都不伴有发育不良的变化或白血病进展。这项研究最近发表（Winkler等，Blood，2019）。 该计划在2014年8月获得了FDA批准Eltrombopag的新标记指示，并于2015年底批准了Eltrombopag治疗难治性型性贫血的治疗。这是数十年来批准性贫血的首款新药，也是专门用于难治性性障碍患者群体的第一种药物。此外，与Neal S Young博士进行的一项合作试验记录，EPAG在未经治疗的严重AA中增加了标准的免疫抑制作用，从而改善了结果（Townsley等，NEJM，2017年），导致基于我们的AA基于AA中EPAG的第二次FDA/EHA批准。 在当前报告期间，我们完成了34例临床试验（11-H-0134）患者的分析，检查了Eltrombopag对中等性性障碍性贫血或单位性细胞质的患者的安全性和功效。在4个月的主要终点，应答率为50％，其中包括遗传性钻石黑色贫血（DBA）的患者。患者耐受剂量高达300毫克/天，没有明显的毒性。 我们注意到，在严重难治性性障碍性贫血中，细胞遗传学进展率（6％）低，没有7个细胞遗传学进展的患者。 65％的患者能够以鲁棒的多谱系反应中停止EPAG，但是与我们先前在难治性严重的严重性性贫血方面的经验相反，大多数人需要重新启动该药物才能维持计数。这项工作发表在2020财年（Fan等，《血液进展》，2020年）。 根据在所有三项试验中产生的数据，我们观察到，Eltrombopag充当临床上与铁螯合剂相关，从而增加了铁的血液水平并长期导致药物患者的净铁损失。几个患者需要补充口服铁。 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活性氧的细胞内铁和毒性积累。我们设计了一项临床试验来测试EPAG在DBA中的活性，并且已批准了这一试验，并且由于COVID-19将患者带入NIH CC而导致患者应计的延迟。