美国西奈山伊坎医学院Marina Kremyanskaya团队研究了拟铁调素Rusfertide治疗真性红细胞增多症的疗效与安全性。该研究于2024年2月21日发表于《新英格兰医学杂志》。

真性红细胞增多症是一种以红细胞增多为特征的慢性骨髓增生性肿瘤。Rusfertide是一种模拟主铁调节激素铁调素的注射肽，限制了铁在红细胞生成中的可用性。Rusfertide治疗静脉切开依赖的真性红细胞增多症的安全性和有效性尚不清楚。

在国际2期REVIVE试验的第1部分中，研究组对患者进行了为期28周的rusfertide剂量发现评估。第2部分是一个双盲、随机的停药期，以1:1的比例将患者分为两组，分别接受rusfertide或安慰剂治疗，为期12周。主要疗效终点是缓解，由红细胞压积控制、未进行静脉切开和第2部分试验方案完成来定义。患者报告的结果通过改良的骨髓增生性肿瘤症状评估表（MPN-SAF）患者日志进行评估（评分范围从0到10，评分越高表示症状越严重）。

70名患者被纳入试验的第1部分，59名患者被分配接受第2部分中的rusfertide（30名患者）或安慰剂（29名患者）。在第一次rusfertide给药之前的28周内，每年静脉抽血的估计平均数（±SD）为8.7±2.9，在第1部分为0.6±1.0（估计差异为每年8.1次静脉抽血）。第1部分的平均最大红细胞压积为44.5±2.2%，而第一次给药前28周为50.0±5.8%。在第2部分中，60%接受rusfertide治疗的患者出现了缓解，而接受安慰剂治疗的患者只有17%（P=0.002）。

在基线和第1部分结束之间，在基线时有中度或重度症状的患者中，rusfertide治疗与MPN-SAF的个体症状评分下降有关。在第1部分和第2部分，13%的患者发生了3级不良事件，没有一名患者发生4级或5级不良事件。严重程度为1级或2级的注射部位反应很常见。

研究结果表明，在真性红细胞增多症患者中，在28周的剂量发现期内，Rusfertide治疗的平均红细胞压积低于45%，并且在12周的随机停药期内有缓解的患者百分比高于安慰剂。

附：英文原文

Title: Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera

Author: Marina Kremyanskaya, Andrew T. Kuykendall, Naveen Pemmaraju, Ellen K. Ritchie, Jason Gotlib, Aaron Gerds, Jeanne Palmer, Kristen Pettit, Uttam K. Nath, Abdulraheem Yacoub, Arturo Molina, Samuel R. Saks, Nishit B. Modi, Frank H. Valone, Sarita Khanna, Suneel Gupta, Srdan Verstovsek, Yelena Z. Ginzburg, Ronald Hoffman

Issue&Volume: 2024-02-21

Abstract:

Background

Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown.

Methods

In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms).

Results

Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P=0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common.

Conclusions

In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo.

DOI: 10.1056/NEJMoa2308809

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2308809