Systemic mastocytosis (SM) has greatly benefited from the broad application of precision medicine techniques to hematolymphoid neoplasms. Sensitive detection of the recurrent KIT D816V mutation and use of next generation sequencing (NGS) panels to profile the genetic landscape of SM variants have been critical adjuncts to the diagnosis of SM, subclassification of SM, and development of clinical-molecular prognostic scoring systems. Multilineage KIT involvement and multi-mutated clones are characteristic of advanced SM, especially SM with an associated hematologic neoplasm (SM-AHN). A major challenge is how to integrate conventional markers of mast cell disease burden (percent bone marrow mast cell infiltration, serum tryptase levels) with molecular data (e.g. serial monitoring of both KIT D816V variant allele frequency and NGS panels) to lend more diagnostic and prognostic clarity to the heterogeneous clinical presentations and natural histories of advanced SM. The approval of the multikinase / KIT inhibitor midostaurin has validated the paradigm of KIT inhibition in advanced SM, while the efficacy and safety of 2nd generation agents, such as the switch-control inhibitor ripretinib (DCC-2618) and the D816V-selective inhibitor avapritinib (BLU-285) are being further defined in ongoing clinical trials. Looking forward, perhaps the most fruitful marriage of the advances in molecular genetics and treatment will be the design of adaptive basket trials that combine histopathology and genetic profiling to individualize treatment approaches for patients with diverse AHNs and relapsed/refractory SM.

中文翻译：

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晚期全身性肥大细胞增多症的诊​​断、预后和治疗的新进展

系统性肥大细胞增多症 (SM) 极大地受益于精准医学技术在血淋巴肿瘤中的广泛应用。对复发性 KIT D816V 突变的敏感检测和使用下一代测序 (NGS) 面板来描绘 SM 变异的遗传景观，已成为 SM 诊断、SM 子分类和临床分子预后评分系统开发的关键辅助手段。多系 KIT 受累和多突变克隆是晚期 SM 的特征，尤其是伴有血液系统肿瘤 (SM-AHN) 的 SM。一个主要的挑战是如何将肥大细胞疾病负担的传统标志物（骨髓肥大细胞浸润百分比、血清类胰蛋白酶水平）与分子数据（例如 KIT D816V 变异等位基因频率和 NGS 面板的连续监测），为晚期 SM 的异质临床表现和自然病史提供更多的诊断和预后清晰度。多激酶/KIT 抑制剂midostaurin 的批准验证了晚期SM 中KIT 抑制的范例，同时第二代药物如开关控制抑制剂ripretinib (DCC-2618) 和D816V 选择性抑制剂avapritinib 的有效性和安全性(BLU-285) 在正在进行的临床试验中得到进一步定义。展望未来，分子遗传学和治疗进展最富有成效的结合可能是适应性篮式试验的设计，结合组织病理学和遗传分析，为不同 AHN 和复发/难治性 SM 患者提供个性化的治疗方法。