成人急性骨髓性白血病患者接受異體造血幹細胞移植成效之預測因子探討

Outcome Predictors for Adult Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

廖秀文(Xiu-Wen Liao)

指導教授 ： 方啟泰

國立臺灣大學/公共衛生學院/公共衛生碩士學位學程/碩士(2015年)

https://doi.org/10.6342/NTU.2015.10598

摘要

背景與研究動機
異體造血幹細胞移植 (Allogeneic hematopoietic stem cell transplantation) 是對化學治療無效的白血病唯一的治癒方法，然而移植的風險與預後受到包括病人生理狀況、病程進展以及其他與移植相關的因素影響。EBMT風險分數 (The European Group for Blood and Marrow Transplantation risk score) 及造血幹細胞移植共病分數 (Hematopoietic cell transplantation comorbidity index, HCT-CI) 是兩種常見用來評估移植預後的計分系統，許多研究已經證實EBMT風險分數可以用來評估造血幹細胞移植的預後，而造血幹細胞移植共病分數可以用來評估非復發死亡率。越來越多研究也顯示診斷時的染色體檢查結果與化學治療的預後相關，但是否可以應用於造血幹細胞移植病人，則尚未有相關研究。總而論之，目前並沒有一個整合各種危險因子且經過驗證的風險及預後評估系統可使用，因此一個方便臨床醫師使用的異體移植風險與預後評估系統是相當重要的。

研究目的
本研究的目的是要驗證EBMT風險分數對台灣病人的適用性，以及診斷時的染色體檢查結果應用於造血幹細胞移植病人的顯著性，並且整合EBMT風險分數、造血幹細胞移植共病分數、染色體檢查結果以及其他可能之危險因子，發展出一個方便使用且經過驗證的預測模式，用來評估成人急性骨髓性白血病患者接受異體造血幹細胞移植的存活率、非復發死亡率、累積復發率以及急性移植物抗宿主疾病 (Acute GVHD) 發生率的預測系統。

材料及方法
本研究為一回溯性世代研究，透過中華民國血液及骨髓移植學會的移植登錄計畫平台，以2009-2013年台灣接受造血幹細胞移植的成人急性骨髓性白血病患者資料做為發展世代 (development cohort)，另外以1992-2008年台大醫院成人急性骨髓性白血病患者接受造血幹細胞移植的資料做為驗證世代 (validation cohort)。本研究使用多變項考克斯迴歸模式 (Cox proportional hazard model) 來建構存活率、非復發死亡率、累積復發率以及急性移植物抗宿主疾病發生率預測模式，並以接受者操作曲線下面積 (Area under the receiver operating characteristic curves, AUROC) 驗證模式的預測能力。

結果
發展世代共有372人列入分析。EBMT風險分數為0-1, 2-4, 5-7分者，其5年存活率分別為70.2%, 43.5%及29.2% (P=0.001)；2年非復發死亡率分別為18.3%, 26.1%及31.4%；5年累積復發率分別為30.6%, 51.8%及53%；EBMT風險分數為0-1分者，100天急性移植物抗宿主疾病發生率則明顯低於2-7分者 (P=0.037)。
病人若有高風險染色體分類，其5年存活率為21.8%，明顯低於低風險染色體分類的病人 (43.5%，p<0.001)。2年非復發死亡率也得到類似的結果，低風險染色體分類的病人2年非復發死亡率為23.4%，高風險染色體分類的病人則為49.3% (P<0.001)。5年累積復發率及100天急性移植物抗宿主疾病發生率在不同染色體分類的病人則沒有統計上顯著的差異。
造血幹細胞移植共病分數為0-2分者，其5年存活率為38.3%，高於共病分數大於2分者的36.4% ( P=0.069)。造血幹細胞移植共病分數為0-2分及大於2分者者，其2年非復發死亡率分別為23.3%及35.6%，達到統計上顯著的差異(P=0.037)。5年累積復發率及100天急性移植物抗宿主疾病發生率在不同造血幹細胞移植共病分數的病人則沒有統計上顯著的差異。
存活率的預測系統為0-10分，預測因子包括EBMT風險分數、高風險染色體分類以及人類白血球組織抗原 (HLA) 相合度；發展世代計算出的AUROC為0.6546 (95% CI: 0.60-0.71)，而驗證世代則為0.7439 (95% CI: 0.68-0.81)。非復發死亡率的預測系統為0-16分，預測因子包括EBMT風險分數、高風險染色體分類以及非原發白血病 (2nd AML)；發展世代計算出的AUROC為0.6256 (95% CI: 0.56-0.69)，而驗證世代則為0.6375 (95% CI: 0.56-0.72)。累積復發率的預測系統為1-5分，預測因子包括高風險染色體分類、診斷時白血球數量以及移植前減劑量調適治療 (Reduced-intensity conditioning regimen)；發展世代計算出的AUROC為0.5822 (95% CI: 0.53-0.64)，而驗證世代則為0.5864 (95% CI: 0.51-0.66)。急性移植物抗宿主疾病發生率的預測系統為0-9分，預測因子包括調整過的EBMT風險分數及人類白血球組織抗原相合度；發展世代計算出的AUROC為0.5988 (95% CI: 0.54-0.66)，而驗證世代則為0.6509 (95% CI: 0.58-0.72)。
預估評分為0-1, 2-5, 6-10分者，其5年存活率分別為69.5%, 47.2%及22%；預估評分為0-2, 3-6, 7-16分者，其2年非復發死亡率分別為13.2%, 25.1%及42%；預估評分為1-2, 3-4, 5分者，其5年累積復發率分別為43.7%, 48.5%及61.8%；預估評分為0-2, 3-4, 5-9分者，其100天急性移植物抗宿主疾病發生率分別為26.5%,
39.3%及60.6%。

討論
本研究證實EBMT風險分數也適用於台灣民眾，並且可以預測存活率、非復發死亡率、累積復發率及急性移植物抗宿主疾病發生率，若加上診斷時染色體檢查的結果，將可增加整體預測力。本研究也發現人類白血球組織抗原相合度是存活率及急性移植物抗宿主疾病發生率的重要預測因子；非原發白血病對非復發死亡率有重要的影響；而移植前調適治療的種類則為累積復發率的重要預測因子。本研究經過外部資料的驗證，這個方便、簡單的預後評估系統對臨床幫助很大，
且其結果具一般性應用。未來若加入更精確的造血幹細胞移植共病分數及分子生物標記資料是否可以更進一步增加預測力，值得進一步探討。

關鍵字

異體造血幹細胞移植 ； 急性骨髓性白血病 ； EBMT風險分數 ； 染色體 ； 預測模式

並列摘要

Background
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a potentially curative treatment for acute leukemia, however, there are many patient-related, disease-related, and transplant-related factors influencing prognosis. The European Group for Blood and Marrow Transplantation (EBMT) risk score and Hematopoietic cell transplantation comorbidity index (HCT-CI) were two commonly used scoring systems to predict the outcome and NRM for patients undergoing Allo-HSCT, however, the integrated predictor model was not validated in an external cohort. Therefore, a useful pre-transplant assessment tool of potential risks and benefits can enhance decision making process for both health care professionals and patients whether or not to proceed with Allo-HSCT.

Aims
This study aimed to validate the prognostic utility of EBMT risk score in Taiwan and the prognostic significant of cytogenetics for Allo-HSCT, and to incorporate EBMT risk score, the United Kingdom Medical Research Council (MRC) classification of cytogenetics, HCT-CI, and other known predictors of outcome into a simple and
easy-to-use predictive score with improved prediction of OS, NRM, cumulative incidence of relapse, and cumulative incidence of acute GVHD for adult AML patients who underwent Allo-HSCT.

Methods
This was a retrospective cohort study, including a nationwide cohort from TBMT registry (Taiwan Society of Blood and Marrow Transplantation registry) during 2009-2013 (development cohort), and a cohort of hematopoietic stem cell transplantation recipients at National Taiwan University Hospital during 1992-2008 (validation cohort).
Both EBMT risk score and HCT-CI and all other clinical variables were evaluated the Cox proportional hazard assumption. To create an easily applicable scoring system, the regression coefficient in the final model for each risk predictor was divided by the regression coefficient for the EBMT risk score and rounded to the nearest integer value.
The sensitivity and specificity of the predictive scores in discrimination between the good risk and poor risk of clinical outcome was evaluated using the receiver operating characteristic (ROC) curves. The area under ROC curves (AUROC) were calculated, and the AUROC of the development cohort and the validation cohort were
compared.

Results
There were 372 patients in the development cohort. The 5-year OS were 70.2%, 43.5%, and 29.2% for patients with a score of 0-1, 2-4, and 5-7 (P=0.001). The 2-year NRM were 18.3% for score 0-1, 26.1% for score 2-4, and 31.4% for score 5-7. The 5-year cumulative incidence of relapse were 30.6%, 51.8%, and 53% for patients with score 0-1, 2-4, and 5-7, respectively. The 100-day cumulative incidence of acute GVHD grade 2 to 4 was significantly better in patients with score 0-1 than in patients with score 2-7 (P=0.037).
The 5-year OS for patients with unfavorable-risk cytogenetics was significantly lower than that for those in favorable/intermediate-risk group (21.8% vs. 43.5%, P<0.001). Similar results were obtained for NRM, the 2-year NRM were 49.3% and 23.4% for patients with unfavorable-risk cytogenetics and low risk, respectively. No statistically significant difference was found for 5-year cumulative incidence of relapse and cumulative incidence of acute GVHD grade 2 to 4.
The 5-year OS for patients with HCT-CI score 0-2 and score greater than 2 were 38.3% and 36.4%, respectively. The 2-year NRM was significantly better in patients
with HCT-CI score 0-2 (23.3%) then in patients with score greater than 2 (35.6%) (P=0.037). Neither 5-year cumulative incidence of relapse nor cumulative incidence of acute GVHD grade 2 to 4 were found statistically significant differences.
The independent risk predictors for OS (AUROC=0.6546, 95% CI: 0.60-0.71) were EBMT risk score, unfavorable-risk cytogenetics at diagnosis, and HLA (Human leukocyte antigen) disparity. The independent risk predictors for NRM (AUROC=0.6256, 95% CI: 0.56-0.69) included EBMT risk score, unfavorable-risk cytogenetics at diagnosis, and 2nd AML. The unfavorable-risk cytogenetics at diagnosis, WBC count at diagnosis, as well as reduced-intensity conditioning regimen were predictors for cumulative incidence of relapse (AUROC=0.5822, 95% CI: 0.53-0.64), the modified EBMT risk score and HLA disparity were independent risk predictors for cumulative incidence of acute GVHD grade 2 to 4 (AUROC=0.5988, 95% CI: 0.54-0.66).

Conclusions
The EBMT risk score has strong impact on OS, NRM, cumulative incidence of relapse, and grade 2 to 4 acute GVHD, and MRC classification of cytogenetics at diagnosis improved the AUROC of OS, NRM, and cumulative incidence of relapse compared with EBMT risk score as a single predictor. In addition, HLA disparity was independent risk factor for both OS and cumulative incidence of acute GVHD. Secondary AML and reduced-intensity conditioning regimen were important predictors for NRM and cumulative incidence of relapse. This nationwide cohort validated the prognostic utility of EBMT risk score in Taiwanese.

並列關鍵字

Allogeneic hematopoietic stem cell transplantation ； Acute myeloid leukemia ； EBMT risk score ； Cytogenetics ； Predicted model

參考文獻

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