Scholl Sebastian, Theuer Claudia, Scheble Veit, Kunert Christa, Heller Anita, Mügge Lars-Olof, Fricke Hans-Joerg, Höffken Klaus, Wedding Ulrich
Department of Internal Medicine II (Oncology and Hematology), Universitätsklinikum, Jena, Germany.
Eur J Haematol. 2008 Mar;80(3):208-15. doi: 10.1111/j.1600-0609.2007.01019.x.
Nucleophosmin (NPM1) and Flt3 internal tandem duplications (Flt3-ITD mutations) represent the most frequent molecular aberrations in patients with acute myeloid leukemia (AML). While NPM1 mutations are associated with favourable prognosis in younger AML patients, Flt3-ITD mutations reflect an unfavourable prognostic factor in these patients. So far, especially NPM1 mutations have not yet been evaluated exclusively in older patients.
We retrospectively analysed the prevalence of NPM1 and Flt3-ITD mutations and its association with complete remission (CR), and survival in 99 elderly patients (median age 71 yr, range 60-85 yr) newly diagnosed for AML. Primary treatment approach was curative in 54, and palliative in 38 patients, while seven patients received best supportive care only. The mean follow-up of surviving patients was 600 d.
Sixty-seven patients were tested negative for NPM1 and Flt3-ITD mutations (group 1), 16 patients carried only a NPM1 mutation (group 2) and nine patients had only a Flt3-ITD mutation (group 3) while additional seven patients were positive for both aberrations (group 4). We can demonstrate a significant higher rate of CR comparing wildtype vs. NPM1 positive patients (40.5% for group 1 vs. 80.0% for group 2, P = 0.03) for patients receiving curative therapy. Interestingly, there is no significant difference in overall survival between group 1 and group 2 (Log-rank test P = 0.22, median 440 d vs. 1125 d). In contrast, patients carrying a Flt3-ITD mutation had a significant worse overall survival compared to wildtype patients (P = 0.03, median 210 d for group 3 + 4 vs. 634 d for group 1 + 2) while no difference of CR rate could be observed (42.8% vs. 48.9%, P = 0.91).
As elderly but medically fit patients with AML carrying a NPM1 mutation have a high CR rate, age itself should not be a barrier for induction treatment. However, new therapeutic concepts of postremission therapy (e.g. allogeneic stem cell transplantation after dose-reduced conditioning) should be considered for these patients in first CR.
核磷蛋白（NPM1）和Flt3内部串联重复突变（Flt3-ITD突变）是急性髓系白血病（AML）患者中最常见的分子异常。虽然NPM1突变与年轻AML患者的良好预后相关，但Flt3-ITD突变反映了这些患者的不良预后因素。到目前为止，尤其是NPM1突变尚未在老年患者中进行专门评估。
我们回顾性分析了99例新诊断为AML的老年患者（中位年龄71岁，范围60-85岁）中NPM1和Flt3-ITD突变的发生率及其与完全缓解（CR）和生存的关系。54例患者采用根治性治疗，38例采用姑息性治疗，7例仅接受最佳支持治疗。存活患者的平均随访时间为600天。
67例患者NPM1和Flt3-ITD突变检测为阴性（第1组），16例患者仅携带NPM1突变（第2组），9例患者仅携带Flt3-ITD突变（第3组），另外7例患者两种异常均为阳性（第4组）。我们可以证明，接受根治性治疗的患者中，野生型与NPM1阳性患者相比，CR率显著更高（第1组为40.5%，第2组为80.0%，P = 0.03）。有趣的是，第1组和第2组的总生存期无显著差异（对数秩检验P = 0.22，中位生存期分别为440天和1125天）。相比之下，携带Flt3-ITD突变的患者与野生型患者相比，总生存期显著更差（P = 0.03，第3组+第4组中位生存期为210天，第1组+第2组为634天），而CR率无差异（42.8%对48.9%，P = 0.91）。
由于携带NPM1突变的老年但身体状况良好的AML患者CR率较高，年龄本身不应成为诱导治疗的障碍。然而，对于这些首次CR的患者，应考虑缓解后治疗的新治疗概念（如减剂量预处理后的异基因干细胞移植）。
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