Patients with systemic mastocytosis (SM) can have a high symptom burden due to the release of mast cell (MC) mediators, including fatigue, musculoskeletal pain, flushing, pruritus, urticaria, abdominal cramping/pain, diarrhea, nausea, vomiting, anaphylaxis, headache, etc. Midostaurin is a multitargeted kinase inhibitor with activity against the KITD816V mutation, that has been approved by the Food & Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL) based on data from two open label phase II studies.^{1, 2} In the D2201 study (NCT00782067) in advanced SM, in addition to an overall response rate of 69% (modified Valent criteria) and 17% (International Working Group [IWG] criteria), significant improvements were observed in health-related quality-of-life measures and investigator-adjudicated MC mediator-related symptoms.³ Based on these data, midostaurin was studied in an open-label, non-randomized, single-center, phase II study (NCT01920204) of 20 indolent SM (ISM) patients with severe MC activation symptoms that were refractory to antihistamine medications.⁴ After 12 weeks of treatment, a median 35% (range 16%–56%, p < .01) reduction in symptom severity was observed, as per the Mastocytosis symptom assessment form (MSAF). There was also a median 29% (range 16%–47%, p < .001) improvement in disease-specific quality-of-life as measured by the Mastocytosis quality-of-life questionnaire (MQLQ). This was associated with a reduction in serum tryptase level (36–15.5 μg/L, p < .001), reduction in bone marrow MC% in 50% of evaluable patients (median 7.5% to 4%), improvement in 80% of patients with urticaria pigmentosa (UP)/skin symptoms, with 40% reduction in median Scoring Mastocytosis (SCORMA) index. In the current study, we reviewed our institutional experience with midostaurin treatment of ISM and smoldering SM (SSM) patients in routine clinical practice.

After approval by the Mayo Clinic institutional review board, consecutive ISM/SSM patients were recruited from the institutional SM database, filtered by documentation of midostaurin treatment by the patient's local or Mayo provider. Conventional criteria were used for SM diagnosis and disease subclassification. Response assessment of MC mediator-related symptoms and skin involvement was adapted from previously described criteria.⁵ Complete response (CR), major response (MR), partial response (PR), and no response (NR) described complete resolution, > 50% resolution, 10–50% resolution, and < 10% resolution of MC symptoms and/or skin lesions, respectively, based on descriptions in treating physician/provider notes, and adjudicated by careful review of the electronic medical record by the first and/or last author. Serial monitoring of serum tryptase level and bone marrow biopsies were performed at the treating physician/provider's discretion. Adverse event grading was as per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Date of the last follow-up was updated through August 2021.

Thirteen patients (median age 50 years, females 77%), of whom 11 had ISM and 2 SSM were recruited (Table S1). Of these, 9 patients (69%) had cutaneous MC involvement, 11 of 12 evaluable patients (92%) had detectable KITD816V mutation, and 10 of 11 evaluable patients (91%) had elevated serum tryptase level at baseline. All patients had MC mediator level symptoms, the most frequent being diarrhea in 77%, pruritus/flushing in 54%, nausea/vomiting in 46%, and abdominal pain/cramping, fatigue, musculoskeletal pain, and weight loss (38% each). The predominant indication for midostaurin treatment was MC symptoms in 10 patients (77%), MC skin lesions in 1 patient (8%), and a combination of both factors in 2 patients (15%). All patients had inadequate symptom control with antihistamine drugs at baseline. In addition, five patients had previously received cromolyn sodium and one patient each had received imatinib and 2-chlorodeoxyadenosine treatment; prior use of cladribine was for 6 months and that of imatinib 19 months.

The median midostaurin starting dose was 200 mg daily (range 50-200 mg) (Table 1). The median treatment duration was 14 months (range 4–36). Complete response, major response, and partial response rates for MC-mediator symptoms and MC-skin lesions were 8%/23%/31% and 22%/11%/11%, respectively. The post-treatment serum tryptase level decreased in nine patients (82%), with normalization of tryptase level in three patients (27%; institutional normal tryptase level was <11.5 mg/dL). The median decrease in tryptase level was 48% (range 30–91) and the median duration to maximum tryptase level decrease was 5 months (range 1–16). A follow-up bone marrow biopsy was obtained in five patients at a median 6 months post-treatment—one patient had complete resolution of MC infiltrates, three patients had decreased MC burden and one patient had no change in MC burden. In a retrospective comparison, response rates appeared broadly similar to Cladribine therapy.⁶ (Table S2).

Treatment was discontinued in six patients (46%) due to complete response (n = 1), adverse effects (n = 1), no-response (n = 2) and adverse effects-suboptimal response (n = 2). Of 12 patients where data was available, midostaurin was dose reduced in 9 patients (75%); dose reductions were due to side effects, mostly worsening GI symptoms (nausea, vomiting, diarrhea, belching, dysgeusia), fatigue, and insomnia. Dose reduction did not lead to loss of response in any previously responding patient, including the patient with CR where midostaurin was discontinued with the intention to resume in case of increase in tryptase level above 20 mg/dL; the tryptase level in this patient remained stable and symptoms did not recur after drug discontinuation. Most GI side effects were most were grade 1/2 in severity—two patients developed grade 3 vomiting and one patient grade 3 diarrhea. The three patients without dose reduction started treatment at 50, 100, and 200 mg daily. The median dose at last follow-up was 100 mg daily (range 50–200 mg). There were no documented instances of significant QTc prolongation, pancreatitis or persistent cytopenias. All patients were alive at last follow-up.

The current study, which had a longer treatment duration than the previously published prospective study,⁴ confirms that midostaurin treatment has clinical benefit in ISM/SSM patients; 62% and 44% had improvement in MC-related mediator symptoms and MC skin lesions, respectively. Clinical responses to midostaurin were associated with significant reductions in serum tryptase levels and possibly, a decrease in bone marrow MC burden, although small patient numbers and a lack of central histopathology review precludes any definite conclusions with regards to the latter. The tolerability of midostaurin was limited by a high incidence of gastrointestinal adverse effects, which led to frequent dose reduction (nine patients) and/or treatment discontinuation (five patients); these observations raise questions regarding the drug's utility in a patient population needing long-term treatment for a relatively indolent disease. Limitations of the current study include its retrospective design, use of nonuniform midostaurin doses, and lack of use of validated patient-reported outcome forms to assess treatment-associated changes in patient symptoms and quality-of-life.

由于肥大细胞 (MC) 介质的释放，全身性肥大细胞增多症 (SM) 患者可能会出现高症状负担，包括疲劳、肌肉骨骼疼痛、潮红、瘙痒、荨麻疹、腹部绞痛/疼痛、腹泻、恶心、呕吐、过敏反应、 Midostaurin 是一种多靶点激酶抑制剂，具有针对KIT D816V 突变的活性，已被美国食品药品监督管理局 (FDA) 和欧洲药品管理局 (EMA) 批准用于治疗侵袭性 SM (ASM)、SM 与相关血液肿瘤 (SM-AHN) 和肥大细胞白血病 (MCL) 基于来自两项开放标签 II 期研究的数据。^{1, 2}在晚期 SM 的 D2201 研究 (NCT00782067) 中，除了 69%（修改的 Valent 标准）和 17%（国际工作组 [IWG] 标准）的总体响应率外，还观察到与健康相关的质量改善显着。 -生活测量和研究者裁定的 MC 介质相关症状。³基于这些数据，midostaurin 在一项开放标签、非随机、单中心、II 期研究 (NCT01920204) 中进行了研究，研究对象为 20 名具有严重 MC 活化症状且抗组胺药物难以治疗的惰性 SM (ISM) 患者。⁴治疗 12 周后，中位数为 35%（范围 16%–56%，p < .01) 根据肥大细胞增多症症状评估表 (MSAF)，观察到症状严重程度降低。 通过肥大细胞增多症生活质量问卷 (MQLQ) 测量，疾病特异性生活质量也有中位数 29%（范围 16%–47%，p < .001）改善。这与血清类胰蛋白酶水平降低（36–15.5 μg/L，p  < .001）、50% 可评估患者的骨髓 MC% 降低（中位数 7.5% 至 4%）、80%患有色素性荨麻疹 (UP)/皮肤症状的患者，中位评分肥大细胞增多症 (SCORMA) 指数降低 40%。在目前的研究中，我们回顾了我们在常规临床实践中对 ISM 和阴燃 SM (SSM) 患者进行米多司林治疗的机构经验。

经 Mayo Clinic 机构审查委员会批准后，从机构 SM 数据库中招募了连续的 ISM/SSM 患者，并通过患者当地或 Mayo 提供者的米多司林治疗文件进行过滤。常规标准用于 SM 诊断和疾病亚分类。MC 介质相关症状和皮肤受累的反应评估改编自先前描述的标准。⁵完全缓解 (CR)、主要缓解 (MR)、部分缓解 (PR) 和无缓解 (NR) 描述了 MC 症状的完全消退、> 50% 消退、10-50% 消退和 < 10% 消退和/或皮肤损伤，分别基于治疗医师/提供者笔记中的描述，并通过第一作者和/或最后作者仔细审查电子病历来判断。由治疗医师/提供者自行决定对血清类胰蛋白酶水平和骨髓活检进行连续监测。不良事件分级是根据美国国家癌症研究所的不良事件通用术语标准 (CTCAE) v5.0。最后一次随访的日期更新至 2021 年 8 月。

招募了 13 名患者（中位年龄 50 岁，女性 77%），其中 11 名患有 ISM，2 名 SSM 被招募（表 S1）。其中，9 名患者 (69%) 有皮肤 MC 受累，12 名可评估患者中有 11 名 (92%) 可检测到KITD816V 突变，11 名可评估患者中有 10 名 (91%) 在基线时血清类胰蛋白酶水平升高。所有患者都有 MC 介质水平的症状，最常见的是 77% 的腹泻，54% 的瘙痒/潮红，46% 的恶心/呕吐，以及腹痛/痉挛、疲劳、肌肉骨骼疼痛和体重减轻（各 38%） . midostaurin 治疗的主要适应症是 10 名患者 (77%) 的 MC 症状，1 名患者 (8%) 的 MC 皮肤病变，以及 2 名患者 (15%) 的两种因素的组合。所有患者在基线时抗组胺药的症状控制不足。此外，5名患者曾接受色甘酸钠治疗，1名患者曾接受伊马替尼和2-氯脱氧腺苷治疗；先前使用克拉屈滨为 6 个月，而伊马替尼为 19 个月。

midostaurin 起始剂量中位数为每天 200 mg（范围 50-200 mg）（表 1）。中位治疗时间为 14 个月（范围 4-36）。MC 介导症状和 MC 皮肤病变的完全缓解率、主要缓解率和部分缓解率分别为 8%/23%/31% 和 22%/11%/11%。9 名患者 (82%) 治疗后血清类胰蛋白酶水平下降，3 名患者类胰蛋白酶水平正常化 (27%；机构正常类胰蛋白酶水平 <11.5 mg/dL)。类胰蛋白酶水平下降的中位数为 48%（范围 30-91），达到最大类胰蛋白酶水平下降的中位持续时间为 5 个月（范围 1-16）。5 名患者在治疗后中位 6 个月时进行了随访骨髓活检——一名患者的 MC 浸润完全消退，3 名患者 MC 负担降低，1 名患者 MC 负担没有变化。在一项回顾性比较中，反应率似乎与克拉屈滨治疗大体相似。⁶（表 S2）。

6 名患者 (46%) 因完全缓解 ( n  = 1)、不良反应 ( n  = 1)、无反应 ( n  = 2) 和不良反应 - 反应不佳 ( n = 2)。在有数据的 12 名患者中，9 名患者（75%）减少了米托司林的剂量；剂量减少是由于副作用，主要是恶化胃肠道症状（恶心、呕吐、腹泻、嗳气、味觉障碍）、疲劳和失眠。减少剂量不会导致任何先前有反应的患者失去反应，包括 CR 患者，其中停用米多司他林打算在类胰蛋白酶水平升高超过 20 mg/dL 的情况下恢复；该患者类胰蛋白酶水平保持稳定，停药后症状未复发。大多数胃肠道副作用的严重程度为 1/2 级——两名患者出现 3 级呕吐，一名患者出现 3 级腹泻。三名未减少剂量的患者开始以每天 50、100 和 200 毫克的剂量进行治疗。最后一次随访的中位剂量为每天 100 mg（范围 50-200 mg）。没有记录到显着 QTc 延长、胰腺炎或持续性血细胞减少的实例。末次随访时所有患者均存活。

本研究的治疗持续时间比之前发表的前瞻性研究要长，⁴证实midostaurin 治疗对ISM/SSM 患者有临床益处；分别有 62% 和 44% 的 MC 相关介质症状和 MC 皮肤病变有所改善。对 midostaurin 的临床反应与血清类胰蛋白酶水平的显着降低以及可能与骨髓 MC 负荷的降低有关，尽管患者数量少且缺乏中央组织病理学检查排除了关于后者的任何明确结论。midostaurin 的耐受性受到胃肠道不良反应高发生率的限制，导致频繁减少剂量（9 名患者）和/或停止治疗（5 名患者）；这些观察结果提出了关于该药物在需要长期治疗相对惰性疾病的患者群体中的效用的问题。