- 學位論文
重新審驗並驗證根據2017歐洲白血病研究網做風險分級的台灣急性骨髓性白血病病患
Re-Examination and Validation of ELN-2017 Risk Classification in Acute Myeloid Leukemia Patients in Taiwan
摘要
急性骨髓性白血病是一個異質性高且源自於骨髓的血液惡性疾病。急性骨髓性白血病是成人最常見的急性白血病，不僅導致高致死率，而且對醫療經濟也產生巨大的負擔。近年拜生物科技快速進步所賜，得以揭開急性骨髓性白血病特殊的染色體和基因突變的演化，並且發現這些變化和病人的預後息息相關。認知到這點，歐洲白血病研究網（European LeukemiaNet, ELN）首先在2010年提出了風險預後分級，並在2017年發表修正後的風險分級，將分級從四類（良好、次等-I、次等-II、差）減少為三類（良好、次等、差）。2017歐洲白血病研究網的風險分級建議指引已經被全世界廣為接受和使用，但卻只有少數幾篇研究驗證此風險分級整體在真實世界的可行性，尤其是缺乏在亞洲族群相關的大型驗證研究。在本研究中，我們分析了總共1158位新診斷非M3（FAB分類）的急性骨髓性白血病患者，其中的807位有接受標準誘導性化學治療的病患進一步納入做預後與存活分析，其結果在整體上驗證了這些病患可以根據2017歐洲白血病研究網的建議指引做出良好的風險分級。但我們發現其中存在幾個有爭議的分類細項，包括即便有預後較佳NPM1突變的保護，較低的FLT3-ITD突變率不一定意味著有較好的預後；另外，有第六對和第九對染色體轉位變化的病人，若能在達到第一次完全緩解就盡快接受異體造血幹細胞移植，將有很高的機會能夠長期存活；而主要發生在亞洲族群的第七對和第十一對染色體轉位變化，預後極差，應該要在亞洲的患者做初始治療評估時加入此染色體變化，讓風險評估更為完整。因此，根據以上的分析結果，我們提出了一個根據2017歐洲白血病研究網的風險分級的修正版本，透過比較兩者在整體存活率（overall survival, OS）以及無復發存活期（relapse-free survival, RFS）的時間相關ROC曲線下的面積（AUC），證明了我們所提出的修正後版本比原本的2017歐洲白血病研究網的風險分級預測表現更佳。但隨著檢驗技術的進步和各種標靶藥物的發展，治療的成績和預後將不再只侷限在初始診斷的染色體變化和基因突變，也因此，風險分級在未來勢必會需要不斷做修正，以跟上時代的進步並符合每個病人不同的情況。
並列摘要
Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy originated from bone marrow. AML is the most common type of acute leukemia in adults, [1, 2] which not only greatly contributes to the mortality but also causes a substantial economic burden. [3] Recent advances reveal distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. The European LeukemiaNet (ELN) first proposed recommendations for risk stratification in adult AML by incorporation of these genetic alternations in 2010, and later published a revised version in 2017. The ELN-2017 risk stratification has been widely adopted, but was only validated in few studies on the whole [4, 5]. In other words, there is still lack of validation study in large cohorts, especially in Asian population. In this study, a total of 1158 patients with newly diagnosed non-M3 AML in Taiwan was included, in which 807 patients who received standard induction chemotherapy were selected for prognosis and survival analysis. In general, we demonstrated that the ELN-2017 risk stratification can well stratify our patients. Nevertheless, there were several controversial issues; the low allelic ratio of FLT3-ITD was not necessary associated with a better prognosis, even with mutated NPM1, patients with t(6;9) can achieve long-term survival once they receive allogeneic hematopoietic stem cell transplantation (HCT) after their first complete remission (CR), and t(7;11), which occurs preferentially in Asian patients, is considered to be an additional genetic subset due to its dismal outcome. Based on the above findings, we proposed a modified version of ELN-2017 risk stratification and demonstrated its better performance in prognostic assessment by higher time-dependent area under the curve (AUC) for overall survival (OS) and relapse free survival (RFS). The ELN-2017 risk stratification, as well as our proposed modified version, both provide the prognostic assessment in pretreatment stage based on conventional standard induction chemotherapy. As many novel targeted agents already in our clinical practice or in the development, the risk stratification must continue to be modified in order to catch up the advance of novel therapeutic agents.