Department of Hematology/HCT, City of Hope National Medical Center, Duarte.
Department of Pathology, City of Hope, Duarte.
Haematologica. 2023 Jan 1;108(1):150-160. doi: 10.3324/haematol.2021.280203.
Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell's C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS.
体细胞突变被认为是慢性髓单核细胞白血病 (CMML) 的一个重要预后因素。然而，关于异体造血细胞移植 (HCT) 后其对结局的影响，相关数据有限。在本协作中心国际血液和骨髓移植登记处/样本库进行的登记分析中，我们确定了 313 名 CMML 成年患者（中位年龄：64 岁，范围：28-77 岁），他们在 2001-2017 年间接受了异体 HCT，并且在预处理开始前获得了外周血样本的可用生物样本。多变量分析中，中间 2 分（HR=1.46，P=0.049）或高分（HR=3.22，P=0.0004）CMML 特异预后评分系统（CPSS）与总生存相关。当应用分子信息 CPSS-Mol 预后模型时，高 CPSS-Mol 评分（HR=2，P=0.0079）与总生存显著相关。最常见的体细胞突变是 ASXL1（62%）、TET2（35%）、KRAS/NRAS（合并 33%）和 SRSF2（31%）。DNMT3A 和 TP53 突变与总生存降低相关（HR=1.70[95%CI：1.11-2.60]，P=0.0147 和 HR=2.72[95%CI：1.37-5.39]，P=0.0042），而 DNMT3A、JAK2 和 TP53 突变与无病生存降低相关（HR=1.66[95%CI：1.11-2.49]，P=0.0138，HR=1.79[95%CI：1.06-3.03]，P=0.0293，HR=2.94[95%CI：1.50-5.79]，P=0.0018）。唯一与复发增加相关的突变是 TP53（HR=2.94，P=0.0201）。然而，鉴于 CMML 中 TP53 突变的罕见性，应谨慎解读 TP53 突变的影响。我们计算了 CPSS 和 CPSS-Mol 的 Harrell's C 指数拟合优度，两者非常相似。总之，通过登记处数据，我们确定了接受异体 HCT 的 CMML 患者的突变情况，并证明了 CPSS-Mol 与移植结局之间存在关联，尽管在 CPSS 提供的风险预测之外，并没有显著提高风险预测能力。
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