Chifotides Helen T, Bose Prithviraj
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
Clin Lymphoma Myeloma Leuk. 2025 Jan;25(1):1-12. doi: 10.1016/j.clml.2024.06.005. Epub 2024 Jun 25.
Systemic mastocytosis (SM) is a heterogeneous myeloid neoplasm, characterized by clonal proliferation of mast cells (MCs) in ≥ 1 extracutaneous organs, including the bone marrow (BM) and gastrointestinal tract. Aberrant MC proliferation is driven by mutation KIT D816V in ≈90-95% of SM patients. Indolent SM (ISM) is the most common SM subtype with various symptoms that can be severe. Advanced SM (AdvSM) has markedly poor prognosis. The advent of KIT inhibitors, targeting mutant KIT and neoplastic MCs, led to a paradigm shift in SM management and markedly improved outcomes. Midostaurin inaugurated the era of KIT inhibitors and was approved for AdvSM in 2017. Avapritinib is the first highly potent and selective inhibitor of KIT D816V that was approved to treat AdvSM and symptomatic ISM (platelets ≥ 50 × 10/L), in the US, in 2021 and 2023, respectively. Pooled analysis of the EXPLORER and PATHFINDER studies, assessing avapritinib in AdvSM, demonstrated rapid and profound reductions (≥ 50%) in markers of MC burden, high response rates (71-75%), and prolonged survival. In the PIONEER study, avapritinib significantly and rapidly improved symptoms/quality of life, and reduced markers of MC burden in ISM patients. The investigational agents bezuclastinib and elenestinib are highly potent and selective inhibitors of KIT D816V with minimal blood-brain barrier penetration. Bezuclastinib reduced markers of MC burden by ≥ 50% in ≈50% of AdvSM patients and ≈90-100% of nonAdvSM patients and reduced symptoms (≥ 50%) in the APEX and SUMMIT studies, respectively. Elenestinib demonstrated dose-dependent efficacy in reducing MC burden markers and improved symptoms in ISM patients in the HARBOR study.
系统性肥大细胞增多症（SM）是一种异质性髓系肿瘤，其特征是肥大细胞（MC）在包括骨髓（BM）和胃肠道在内的≥1个皮肤外器官中克隆性增殖。约90 - 95%的SM患者中，MC异常增殖由KIT D816V突变驱动。惰性SM（ISM）是最常见的SM亚型，有多种可能严重的症状。晚期SM（AdvSM）的预后明显较差。靶向突变型KIT和肿瘤性MC的KIT抑制剂的出现，导致了SM治疗模式的转变，并显著改善了治疗结果。米哚妥林开创了KIT抑制剂时代，并于2017年被批准用于AdvSM。阿伐替尼是首个高效、选择性的KIT D816V抑制剂，分别于2021年和2023年在美国被批准用于治疗AdvSM和有症状的ISM（血小板≥50×10⁹/L）。对评估阿伐替尼治疗AdvSM的EXPLORER和PATHFINDER研究的汇总分析表明，MC负荷标志物迅速且显著降低（≥50%），缓解率高（71 - 75%），生存期延长。在PIONEER研究中，阿伐替尼显著且迅速地改善了ISM患者的症状/生活质量，并降低了MC负荷标志物。研究药物贝祖司他尼和艾乐替尼是高效、选择性的KIT D816V抑制剂，血脑屏障穿透性极小。在APEX和SUMMIT研究中，贝祖司他尼分别使约50%的AdvSM患者和约90 - 100%的非AdvSM患者的MC负荷标志物降低≥50%，并减轻了症状（≥50%）。在HARBOR研究中，艾乐替尼在降低MC负荷标志物方面显示出剂量依赖性疗效，并改善了ISM患者的症状。
