Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service, NUCLEUS, Universidad de Salamanca, Salamanca, Spain.
Spanish Network on Mastocytosis, Toledo and Salamanca, Spain.
Blood. 2019 Aug 1;134(5):456-468. doi: 10.1182/blood.2018886507. Epub 2019 May 31.
Indolent systemic mastocytosis (ISM) patients have a normal life expectancy, except in the 5% to 10% of cases that progress to more advanced SM (advSM), which has a significantly poorer outcome. Mutations in genes other than frequently found in myeloid neoplasms have been associated with a poorer outcome among advSM, whereas limited information exists about their frequency and prognostic impact in ISM. We investigated the frequency and prognostic impact of variants in 18 genes, found to be altered in advSM, in 322 ISM patients (median follow-up, 5.7 years) divided into discovery (n = 200) and validation (n = 122) cohorts. Overall, 71 genetic variants were detected in 55 of 322 (17%) patients. Mutated ISM cases, particularly those carrying , , and/or (//) pathogenic variant allele frequencies (VAFs) ≥ 30%, exhibited significantly shortened ( < .001) progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that serum β2-microglobulin (sβ2M) levels > 2.5 µg/mL (hazard ratio [HR], 9.8; = .001), together with a D816V VAF ≥ 1% in bone marrow (BM) (HR, 10.1; = .02) and pathogenic variants of // VAFs ≥ 30% (HR, 4.2; = .02), were the best combination of independent predictors for PFS. In turn, // gene pathogenic VAF ≥ 30% was the only independent predictor for OS (HR, 51.8; < .001). Based on these variables, 2 scoring systems were constructed for risk stratification of ISM at diagnosis with significantly different 10-year PFS (100%, 91%, 0% for scores of 0, 1, ≥2, respectively) and OS (100% and 50% for scores of 0 and 1) rates.
惰性系统性肥大细胞增多症 (ISM) 患者的预期寿命正常，但在 5%至 10%进展为更高级别的 SM (advSM) 的病例中，预后明显较差。除髓系肿瘤中常发现的突变外，advSM 中还发现其他基因的突变与预后不良相关，而关于这些基因在 ISM 中的频率和预后影响的信息有限。我们研究了在 322 例 ISM 患者（中位随访时间为 5.7 年）中发现的 18 个基因中的 71 个变异的频率和预后影响，这些患者分为发现队列（n = 200）和验证队列（n = 122）。总体而言，在 322 例患者中的 55 例（17%）中检测到 71 个遗传变异。突变的 ISM 病例，特别是那些携带 // 致病性变异等位基因频率（VAF）≥30%的病例，其无进展生存期（PFS）和总生存期（OS）显著缩短（<.001）。多变量分析显示，血清β2-微球蛋白（sβ2M）水平>2.5 µg/mL（危险比 [HR]，9.8； =.001），骨髓（BM）中 D816V VAF≥1%（HR，10.1； =.02）和 // 基因致病性 VAF≥30%（HR，4.2； =.02）是 PFS 的最佳独立预测因子组合。反过来，// 基因致病性 VAF≥30%是 OS 的唯一独立预测因子（HR，51.8；<.001）。基于这些变量，构建了两个评分系统，用于 ISM 诊断时的风险分层，具有显著不同的 10 年 PFS（0、1、≥2 评分的 10 年 PFS 分别为 100%、91%、0%）和 OS（0 和 1 评分的 10 年 OS 分别为 100%和 50%）率。
