Piga Antonio, Longo Filomena, Gamberini Maria Rita, Voskaridou Ersi, Ricchi Paolo, Caruso Vincenzo, Pietrangelo Antonello, Zhang Xiaosha, Shetty Jeevan K, Attie Kenneth M, Tartaglione Immacolata
Department of Clinical and Biological Sciences, Turin University, Regione Gonzole, 10, Orbassano, 10043 Turin, Italy.
Department of Clinical and Biological Sciences, Turin University, Turin, Italy.
Ther Adv Hematol. 2022 Dec 5;13:20406207221134404. doi: 10.1177/20406207221134404. eCollection 2022.
β-thalassemia is a hereditary blood disorder resulting in ineffective erythropoiesis and anemia. Management of anemia with regular blood transfusions is associated with complications including iron overload. Here, we report long-term safety and efficacy results of the first clinical study of luspatercept in β-thalassemia, initiated in 2013, enrolling adults with both nontransfusion-dependent (NTD) and transfusion-dependent (TD) β-thalassemia.
The objective was to report long-term safety data, for up to 5 years of treatment, for 64 patients with TD or NTD β-thalassemia, and long-term efficacy data for a subset of 63 patients with β-thalassemia who received high-dose luspatercept (0.6-1.25 mg/kg): 31 NTD and 32 TD patients.
The study was a phase 2, noncontrolled, open-label trial comprising a dose-finding base phase and a 5-year extension phase.
Endpoints include safety; erythroid response over a continuous 12-week period [NTD: hemoglobin increase from baseline ⩾1.0 or ⩾1.5 g/dl; TD: red blood cell (RBC) transfusion burden reduction, ⩾20%, ⩾33%, or ⩾50%]; and changes in biomarkers of ineffective erythropoiesis, iron metabolism parameters, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, and 6-min walking distance.
Median duration of luspatercept exposure for NTD and TD patients was 910 days (range, 40-1850) and 433 days (range, 21-1790), respectively. Seventeen of 31 (54.8%) NTD patients achieved a mean hemoglobin increase of ⩾1.5 g/dl and 19 of 32 (59.4%) TD patients achieved ⩾50% reduction in RBC transfusion burden, during any continuous 12-week period. Median cumulative duration of response was 1126 days (range, 127-1790) for NTD patients and 909 days (range, 87-1734) for TD patients. The most common treatment-related adverse events of any grade were bone pain, headache, and myalgia.
Long-term assessment of patients with β-thalassemia showed luspatercept was associated with sustained increases in hemoglobin levels in NTD patients and sustained transfusion burden reductions in TD patients.
(ClinicalTrials.gov Identifiers: NCT01749540 and NCT02268409).
β-thalassemia is a genetic blood disorder caused by mutations in the β-globin gene, which encodes one of the proteins that comprise hemoglobin, a key constituent of red blood cells. Patients with β-thalassemia experience anemia, the main treatment for which is blood transfusions. Long-term repeated blood transfusions lower patients' quality of life, use hospital resources, and the resulting accumulation of excess iron can cause organ failure and decrease life expectancy. The severity of the anemia experienced by patients with β-thalassemia varies; patients with transfusion-dependent β-thalassemia require regular blood transfusions, compared with those with nontransfusion-dependent β-thalassemia who require infrequent transfusions, or even none at all, to manage their symptoms. Luspatercept (Reblozyl) is an agent that stimulates the production of red blood cells and is used to treat anemia caused by β-thalassemia. However, the long-term effects of luspatercept treatment on patients with β-thalassemia are not known. In this study, we report the long-term safety of luspatercept in 64 adult patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, and the long-term efficacy of high-dose luspatercept (0.6-1.25 mg/kg) in a subset of 63 patients. The average time period that patients were treated with luspatercept was 910 days for nontransfusion-dependent β-thalassemia and 433 days for transfusion-dependent β-thalassemia. We report that in patients with nontransfusion-dependent β-thalassemia, luspatercept treatment was associated with sustained increases, just over 3 years, in hemoglobin levels. Likewise, in transfusion-dependent β-thalassemia, luspatercept treatment was associated with a sustained reduction, 2.5 years, in the amount of blood transfusion required to manage their anemia. Long-term treatment with luspatercept was not associated with any new side effects compared with previous short-term treatment studies. The most common side effects were headache (27 patients), bone pain (20 patients), and muscle pain (14 patients) with more than 90% of these patients experiencing these side effects as mild severity. The results of this study show that in patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, luspatercept provides lasting reduction in anemia with mostly mild and predictable side effects.
β地中海贫血是一种遗传性血液疾病，会导致无效造血和贫血。通过定期输血治疗贫血会引发包括铁过载在内的并发症。在此，我们报告了2013年启动的第一项关于罗特西普治疗β地中海贫血的临床研究的长期安全性和有效性结果，该研究纳入了非输血依赖型（NTD）和输血依赖型（TD）β地中海贫血的成年患者。
目的是报告64例TD或NTDβ地中海贫血患者长达5年治疗期的长期安全性数据，以及63例接受高剂量罗特西普（0.6 - 1.25mg/kg）治疗的β地中海贫血患者亚组的长期有效性数据：31例NTD患者和32例TD患者。
该研究是一项2期非对照、开放标签试验，包括剂量探索基础阶段和5年延长期。
终点包括安全性；连续12周的红系反应[NTD：血红蛋白从基线水平增加⩾1.0或⩾1.5g/dl；TD：红细胞（RBC）输血负担降低⩾20%、⩾33%或⩾50%]；以及无效造血生物标志物、铁代谢参数、慢性病治疗功能评估 - 疲劳（FACIT - F）评分和6分钟步行距离的变化。
NTD和TD患者罗特西普暴露的中位持续时间分别为910天（范围40 - 1850天）和433天（范围21 - 1790天）。在任何连续12周期间，31例NTD患者中有17例（54.8%）血红蛋白平均增加⩾1.5g/dl，32例TD患者中有19例（59.4%）RBC输血负担降低⩾50%。NTD患者反应的中位累积持续时间为1126天（范围127 - 1790天），TD患者为909天（范围87 - 1734天）。任何级别的最常见治疗相关不良事件为骨痛、头痛和肌痛。
对β地中海贫血患者的长期评估表明，罗特西普与NTD患者血红蛋白水平持续升高以及TD患者输血负担持续降低相关。
（ClinicalTrials.gov标识符：NCT01749540和NCT02268409）。
β地中海贫血是一种由β珠蛋白基因突变引起的遗传性血液疾病，β珠蛋白基因编码构成血红蛋白的蛋白质之一，血红蛋白是红细胞的关键成分。β地中海贫血患者会出现贫血，主要治疗方法是输血。长期反复输血会降低患者生活质量、占用医院资源，并且由此导致的过量铁积累会引发器官衰竭并缩短预期寿命。β地中海贫血患者所经历贫血的严重程度各不相同；输血依赖型β地中海贫血患者需要定期输血，而非输血依赖型β地中海贫血患者则只需偶尔输血，甚至无需输血就能控制症状。罗特西普（Reblozyl）是一种刺激红细胞生成的药物，用于治疗β地中海贫血引起的贫血。然而，罗特西普治疗对β地中海贫血患者的长期影响尚不清楚。在本研究中，我们报告了罗特西普在64例输血依赖型或非输血依赖型β地中海贫血成年患者中的长期安全性，以及在63例患者亚组中高剂量罗特西普（0.6 - 1.25mg/kg）的长期有效性。非输血依赖型β地中海贫血患者接受罗特西普治疗的平均时间为910天，输血依赖型β地中海贫血患者为433天。我们报告称，在非输血依赖型β地中海贫血患者中，罗特西普治疗与血红蛋白水平在三年多时间里持续升高相关。同样，在输血依赖型β地中海贫血患者中，罗特西普治疗与管理贫血所需输血量在2.5年时间里持续减少相关。与之前的短期治疗研究相比，罗特西普长期治疗未出现任何新的副作用。最常见的副作用是头痛（27例患者）、骨痛（20例患者）和肌肉疼痛（14例患者），超过90%的这些患者经历的这些副作用为轻度。本研究结果表明，在输血依赖型或非输血依赖型β地中海贫血患者中，罗特西普能持续减轻贫血，且副作用大多轻微且可预测。
