Lortholary Olivier, Chandesris Marie Olivia, Bulai Livideanu Cristina, Paul Carle, Guillet Gérard, Jassem Ewa, Niedoszytko Marek, Barete Stéphane, Verstovsek Srdan, Grattan Clive, Damaj Gandhi, Canioni Danielle, Fraitag Sylvie, Lhermitte Ludovic, Georgin Lavialle Sophie, Frenzel Laurent, Afrin Lawrence B, Hanssens Katia, Agopian Julie, Gaillard Raphael, Kinet Jean-Pierre, Auclair Christian, Mansfield Colin, Moussy Alain, Dubreuil Patrice, Hermine Olivier
Department of Infectious Diseases and Tropical Medicine and Centre d'Infectiologie Necker-Pasteur, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Centre de Référence des Mastocytoses, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Université Paris Descartes, Paris, France.
Department of Hematology, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France.
Lancet. 2017 Feb 11;389(10069):612-620. doi: 10.1016/S0140-6736(16)31403-9. Epub 2017 Jan 7.
Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments.
In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073.
Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment).
These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis.
AB Science (Paris, France).
惰性系统性肥大细胞增多症，包括冒烟型系统性肥大细胞增多症这一亚型，是一种与生活质量下降相关的终身性疾病。马西替尼可抑制参与惰性系统性肥大细胞增多症发病机制的KIT和LYN激酶。我们旨在评估在对最佳对症治疗无反应的重度症状患者中，马西替尼对比安慰剂的安全性和疗效。
在这项随机、双盲、安慰剂对照的3期研究中，我们在15个国家的50个中心纳入了根据世界卫生组织分类或基于组织学标准记录的肥大细胞增多症确诊的惰性或冒烟型系统性肥大细胞增多症的成人患者（年龄18 - 75岁）。方案修订后，我们排除了皮肤型或非重度系统性肥大细胞增多症患者。患者通过中心随机分组（1:1），接受口服马西替尼（24周内每日6 mg/kg，可能延长疗程）或匹配的安慰剂，并根据严重症状进行最小化处理。主要终点是在以下至少一种严重基线症状方面的累积反应（第8 - 24周内较基线改善≥75%）：瘙痒评分9分或更高、每周潮红8次或更多、汉密尔顿抑郁量表评分19分或更高、或疲劳影响量表评分75分或更高。我们在经过修正的意向性治疗人群中，通过广义估计方程模型，使用针对罕见疾病的重复测量方法评估治疗效果，该人群包括所有分配接受治疗的参与者减去那些因非治疗相关原因退出的人。我们在所有接受至少一剂研究药物的患者中评估安全性。本试验已在ClinicalTrials.gov注册，编号为NCT00814073。
在2009年2月19日至2015年7月15日期间，135名患者被随机分配至马西替尼组（n = 71）或安慰剂组（n = 64）。至24周时，马西替尼组主要终点的累积反应率为18.7%（656.5个可能反应中有122.6个反应 [加权广义估计方程]），而安慰剂组为7.4%（656.5个中有48.9个反应；差异11.3%；优势比3.6；95% CI 1.2 - 10.8；p = 0.0076）。常见的严重不良事件（与安慰剂组差异>4%）为腹泻（马西替尼组70例中有8例 [11%]，安慰剂组63例中有1例 [2%]）、皮疹（4例 [6%] 对0例）和乏力（4例 [6%] 对1例 [2%]）。最常见的严重不良事件为腹泻（3例患者 [4%] 对1例 [2%]）和荨麻疹（2例 [3%] 对0例），未发生危及生命的毒性反应。安慰剂组有1例患者死亡（与研究治疗无关）。
这些研究结果表明，马西替尼是治疗有重度症状的惰性或冒烟型系统性肥大细胞增多症的一种有效且耐受性良好的药物。
AB Science（法国巴黎）
