Siebenhaar Frank, Altrichter Sabine, Bonnekoh Hanna, Hawro Tomasz, Hawro Marlena, Michaelis Edward G, Kantor Andrea M, Chang Alan T, Youngblood Bradford A, Singh Bhupinder, Rasmussen Henrik S, Maurer Marcus
Institute of Allergology.
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Berlin, Germany.
Br J Dermatol. 2023 Oct 25;189(5):511-519. doi: 10.1093/bjd/ljad191.
Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell (MC) accumulation and MC-driven signs and symptoms. Currently used therapies are not approved and have limited efficacy. Lirentelimab (AK002) is a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8 that inhibits MC activation.
To determine the safety, tolerability and efficacy of lirentelimab in reducing the symptoms of ISM.
At a specialty centre for mastocytosis in Germany, we conducted a phase I first-in-human single-ascending and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had World Health Organization-confirmed ISM and an unsatisfactory response to available treatment. In part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01 or 0.03 mg kg-1; in part B, patients received one lirentelimab dose of 0.3 mg kg-1 or 1.0 mg kg-1; and in part C, patients received either 1.0 mg kg-1 lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one dose of 1 mg kg-1 followed by five doses of 3-10 mg kg-1 every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS) and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose.
In 25 patients with ISM (13 in parts A + B and 12 in part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events (AEs) were feeling hot (76%) and experiencing a headache (48%). No serious AEs occurred. Median MSQ and MAS symptom severity scores in part C improved (vs. baseline) across all symptoms [MSQ: skin (38-56%), gastrointestinal (49-60%), neurological (47-59%), musculoskeletal (26-27%); MAS: skin (53-59%), gastrointestinal (72-85%), neurological (20-57%), musculoskeletal (25%)]. Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%) and skin (44%).
Lirentelimab was generally well tolerated and improved symptoms and quality of life in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM.
惰性系统性肥大细胞增多症（ISM）的特征是肥大细胞（MC）过度积聚以及由MC引发的体征和症状。目前使用的疗法未获批准且疗效有限。利仑替单抗（AK002）是一种抗唾液酸结合免疫球蛋白样凝集素（Siglec）-8的单克隆抗体，可抑制MC激活。
确定利仑替单抗减轻ISM症状的安全性、耐受性和疗效。
在德国一家肥大细胞增多症专科中心，我们对利仑替单抗开展了一项针对ISM患者的I期首次人体单剂量递增和多剂量临床试验。符合条件的成年人患有世界卫生组织确认的ISM，且对现有治疗反应不佳。在A部分，患者接受0.0003、0.001、0.003、0.01或0.03 mg kg-1的单剂量利仑替单抗；在B部分，患者接受0.3 mg kg-1或1.0 mg kg-1的一剂利仑替单抗；在C部分，患者每4周接受1.0 mg kg-1利仑替单抗，共6个月，或接受递增剂量的利仑替单抗（一剂1 mg kg-1，随后每4周接受五剂3 - 10 mg kg-1）。主要终点是安全性/耐受性。次要终点包括末次给药后2周时肥大细胞增多症症状问卷（MSQ）、肥大细胞增多症活动评分（MAS）和肥大细胞增多症生活质量问卷（MC-QoL）评分相对于基线的变化。
25例ISM患者（A + B部分13例，C部分12例；中位年龄51岁，76%为女性，诊断后中位时间4.6年）中，最常见的治疗相关不良事件（AE）是感觉发热（76%）和头痛（48%）。未发生严重AE。C部分所有症状的MSQ和MAS症状严重程度评分中位数均有改善（相对于基线）[MSQ：皮肤（38 - 56%）、胃肠道（49 - 60%）、神经（47 - 59%）、肌肉骨骼（26 - 27%）；MAS：皮肤（53 - 59%）、胃肠道（72 - 85%）、神经（20 - 57%）、肌肉骨骼（25%）]。所有领域的MC-QoL评分中位数均有改善：症状（39%）、社会生活/功能（42%）、情绪（57%）和皮肤（44%）。
利仑替单抗总体耐受性良好，可改善ISM患者的症状和生活质量。对于ISM应考虑利仑替单抗的治疗潜力。
