地西他滨联合预激方案治疗53例复发难治正常核型急性髓系白血病的疗效分析

Outcomes of refractory or relapsed DNMT3A ＋ cytogenetically normal acute myeloid leukemia patients followed the therapy including decitabine combined with CAG or CAG-like regimen

目的观察地西他滨联合预激方案再诱导治疗伴DNA甲基转移酶（DNMT3A）基因突变的复发难治正常核型急性髓系白血病（CN—AML）的疗效。方法回顾性分析2011年4月至2014年10月接受地西他滨联合预激方案再诱导治疗的53例复发或难治CN．AML患者的临床特征及对地西他滨联合预激方案的治疗反应，其中伴DNMT3A基因突变（DNMT3A＋）24例，不伴DNMT3A基因突变（DNMT3A-）29例。结果DNMT3A＋组患者中位年龄为46（26～68）岁，与DNMT3A组差异无统计学意义，WBC中位数19．5（0．5-218．5）×10^9／L，骨髓原始细胞中位数0．635（0．020～0．920），较DNMT3A-组高，但差异亦无统计学意义（P值均〉0．05）。DNMT3A＋患者对地西他滨联合预激方案治疗的总体反应率（ORR）达62．50％，完全缓解（CR）率为54．17％，DNMT3A＋组分别为48．28％和37．93％，两组相比差异无统计学意义（P值分别为0．407、0．277）。两组患者应用地西他滨联合预激方案再诱导治疗的不良反应类似。53例患者中，共有29例患者伴有FLT3-ITD突变，FLT3-ITD＋／DNMT3A＋组（14例）与FLT3-ITD＋／DNMT3A-组（15例）的ORR及CR率差异有统计学意义（P值分别为0．040、0．042）。DNMT3A＋组与DNMT3A-组1年总生存（OS）率分别为59．58％和54．09％，差异无统计学意义（P=0．438）。后期25例患者行异基因造血干细胞移植，DNMT3A＋CN．AML患者1年OS率为87．50％，1年无病生存（DFS）率为72．73％；DNMT3A-组1年OS率为61．54％，1年DFS率为58．02％；两组差异无统计学意义（P值分别为0．456、0．217）。结论地西他滨联合预激方案是复发难治CN．AML有效且安全的再诱导治疗手段，FLT3-ITD＋／DNMT3A＋组CN—AML患者对地西他滨联合预激方案的反应率优于FLT3-ITD＋／DNMT3A组。地西他滨桥接allo—HSCT可以提高CN—AML患者的OS率。

Objective To study clinical characteristics of refractory or relapsed DNMT3A ＋ cytogenetically normal acute myeloid leukemia （CN-AML） patients, and to explore the overall response rate （ORR） and side effects of these patients followed the therapy including decitabine with CAG or CAG- like regimen. Methods In this study we retrospectively analyzed 53 refractory or relapsed CN-AML patients receiving the therapy including decitabine combined with CAG and CAG-like regimen in our center from April 2011 to October 2014. The clinical characteristics and ORR were further analyzed. Based on gene mutations, these patients could be divided into 2 groups： DNMT3A＋ AML patients （n=24） and DNMT3A- AML patients （n=29）. Results The median age of DNMT3A＋ AML patients was 46 years old, higher white blood cells and bone marrow blasts were observed in DNMT3A＋ AML group. The ORR and complete response （CR） rate of DNMT3A＋ group were 62.50% and 54.17%, respectively. No differences were observed in ORR and CR rates （P〉0.05）between these two groups. DNMT3A＋/FLT3-ITD＋ CN-AML patients （n=14） had higher ORR and CR rates than DNMT3A/FLT3-ITD＋CN- AML patients （n=15） （P= 0.040 and 0.042, respectively）. The one-year overall survival （OS） of DNMT3A ＋ AML group and DNMT3A-AML group were 59.58%, 54.09%, no differences were observed （P=-0.438）. 25 patients received further therapy of allo-HSCT, the one-year OS of DNMT3A＋ CN-AML was 87.50% and one-year disease free survival （DFS） was 72.73%, while the one-year OS was 61.54% and one-year DFS was 58.02% in DNMT3A-group. No differences were observed between 2 groups （P=0.456, 0.217）. Conclusions Decitabine combined with CAG or CAG-like regimen was an effective and safe treatment for refractory or relapsed CN-AML patients. Compared to DNMT3A-/FLT3-ITD ＋ CN-AML patients, DNMT3A＋/FLT3-ITD＋ CN-AML patients had higher ORR and CR rates. Decitabine bridged hematopoietic stem cells transplant could likely improve the survival of refractory or relapsed CN-AML patients. [Key words] Decitabine; Leukemia, myeloid, acute; Recurrence; Refractory diseases; DNA modification methylases