NPM1突變急性骨髓性白血病診斷時共同基因突變或染色體核型變化對臨床預後之影響

Abstract

Nucleophosmin 1（NPM1）突變是急性骨髓性白血病（acute myeloid leukemia, AML）中常見的基因異常之一。此類突變通常代表屬於預後良好的亞型，尤其是在未合併 FLT3-ITD 的情況下。然而，若同時存在其他基因共同突變或染色體異常，其對此亞型病患預後的影響，尚未完全清楚，近年來仍在研究中。 本研究為一項回溯性世代研究，納入國立台灣大學醫學院附設醫院共 1,520 位被診斷為 AML 的成人病患。所有病患皆接受染色體核型分析與次世代定序（next generation sequencing）檢測，涵蓋 54 個與骨髓腫瘤相關的基因。由於 NGS 檢測上的限制，FLT3-ITD 與 CEBPA 突變以聚合酶鏈反應（PCR）搭配螢光毛細管電泳進行分析。 在 1,520 位 AML 病患中，共有 330 位（21.7%）帶有 NPM1 突變，另有 1,190 位（78.3%）為 NPM1 野生型（wild-type）。在 313 位具NPM1分型資料的 NPM1 突變病患中，A 型最為常見（231 人，占 73.8%），其次為 B 型（24 人，占 7.7%）與 D 型（23 人，占 7.3%），其他亞型則占 11.2%。與 NPM1 野生型相比，NPM1突變病患年齡較長、診斷時白血球數較高，且較少見不良風險染色體異常（如單體核型及與骨髓化生不良相關之核型異常）。在共同突變方面，NPM1突變病患最常合併的基因突變包括 FLT3-ITD、DNMT3A、FLT3-TKD、IDH2、TET2 及 IDH1；而 TP53 突變與骨髓化生不良相關基因突變則較為罕見。雖然尚未達統計顯著，但 NPM1 D 型病患合併骨髓化生不良相關基因突變的比例（17.4%）高於 A 型（14.7%）與 B 型（4.2%）。 接受標準化療的 NPM1突變病患，其一年存活率（overall survival）優於NPM1 野生型病患（74% vs. 68%，P＝0.002）。然而，若同時存在 FLT3-ITD 或 DNMT3A 突變，則存活率顯著下降。帶有與骨髓化生不良相關基因突變的 NPM1突變病患，其疾病完全緩解率（complete remission, CR）低於未帶此類與骨髓化生不良相關基因突變NPM1突變病患（53.3% vs. 81.6%）；若合併與骨髓化生不良相關之染色體異常者，其 CR 率亦較低。不過，由於樣本數有限，整體存活率與無事件存活率（event-free survival）之差異未達統計顯著。 共同突變的存在可能削弱原本NPM1突變AML 所具備的良好預後優勢。儘管帶有骨髓化生不良相關基因突變或染色體異常的 NPM1突變病患比例較低，但此類病患往往預後較差。此結果突顯出對 NPM1突變AML 病患進行全面性基因檢測及染色體分析與風險評估的重要性。

Nucleophosmin 1 (NPM1) mutation, a common genetic alteration in acute myeloid leukemia (AML), indicates a favorable-risk subset, notably without FLT3-ITD co-mutation. The impact of co-mutations and cytogenetic abnormalities on the prognosis of this AML subtype is actively being studied. A retrospective cohort study conducted at National Taiwan University Hospital (NTUH) comprised 1,520 adults diagnosed with AML. Cytogenetic analyses and next generation sequencing (NGS) for 54 myeloid-neoplasm-related genes were performed. Due to NGS limitations, FLT3-ITD and CEBPA were analyzed with polymerase chain reaction (PCR) and fluorescence capillary electrophoresis. Among 1,520 AML patients, NPM1 mutations were identified in 330 patients (21.7%), while the remaining 1,190 (78.3%) had wild-type NPM1. Among 313 NPM1-mutated (NPM1mut) patients with typing data, type A was the most prevalent (231, 73.8%), followed by type B (24, 7.7%) and type D (23, 7.3%). Other subtypes accounted for 11.2%. NPM1mut patients were older, had higher what blood cell counts at diagnosis, and showed fewer adverse-risk cytogenetics (e.g., monosomal karyotype and myelodysplasia-related [MR] cytogenetic abnormalities) compared to NPM1 wild-type (NPM1wt) patients. In terms of co-mutations, FLT3-ITD, DNMT3A, FLT3-TKD, IDH2, TET2, and IDH1 were the most commonly seen in NPM1mut AML, while TP53 and MR gene mutations were less frequent. Although not statistically significant, subtype D patients showed numerically higher rates of MR gene mutations (17.4%) compared to subtype A (14.7%) and B (4.2%). Within the NPM1mut cohort treated with standard chemotherapy, the 1-year overall survival (OS) rate was higher compared to NPM1wt cases (74% vs. 68%, P=0.002). However, survival was significantly reduced in patients harboring co-mutations such as FLT3-ITD and DNMT3A mutation. NPM1mut patients with MR gene mutations had a lower complete remission (CR) rate compared to those without (53.3% vs. 81.6%). Similarly, those with MR cytogenetic abnormalities also had reduced CR. However, due to limited case numbers, statistical significance was not reached for OS and event-free survival (EFS) differences. Co-mutations can interfere with the favorable prognosis associated with NPM1mut AML. Though rare, NPM1mut cases with MR gene mutations or cytogenetic abnormalities tend to have a worse prognosis. This highlights the importance of comprehensive genetic profiling in NPM1mut AML.