强化免疫抑制治疗联合不同方案重组粒细胞集落刺激因子治疗儿童重型再生障碍性贫血的临床研究

Immunosuppressive therapy using antithymocyte globulin and cyclosporin A with or without human granulocyte colony-stimulating factor in children with acquired severe aplastic anemia

目的 评价在儿童重型再生障碍性贫血（SAA）免疫抑制治疗（IST）不同时期应用重组粒细胞集落刺激因子（G-CSF）的疗效差异及安全性.方法 回顾性分析2000年2月至2010年9月中国医学科学院血液病医院儿童血液病诊疗中心收治的105例SAA患儿资料.将105例患儿按G-CSF的使用时期分为4组：A组（27例）：全程未使用G-CSF;B组（24例）：IST治疗前即开始应用G-CSF;C组（24例）：IST治疗同时应用G-CSF;D组（30例）：IST治疗结束后开始使用G-CSF.观察IST治疗的总体疗效.比较4组患儿开始治疗后4、6、12和24个月的治疗反应率、复发率、死亡率、生存期、IST前感染的持续时间、IST后感染的发生率、感染相关死亡率、克隆性演变发生率、生存率以及影响患儿长期生存的可能因素.结果 ①105例SAA患儿IST治疗后4、6、12和24个月的总体治疗反应率（完全缓解率＋部分缓解率）分别为：50.5％（7.6％＋42.9％）;60.0％（21.9％＋38.1％）;67.6％（38.1％＋29.5％）;69.5％（40.0％＋29.5％）,2年总体生存率为90.5％,随访39 （28～169）个月,总体生存率为87.6％.②4组患儿IST后4、6、12、24个月的治疗反应率差异无统计学意义（P均＞0.05）.③4组患儿IST后4、6、12、24个月的死亡率差异无统计学意义（P均＞0.05）.④105例患儿中共有4例在治疗后的6～ 24个月内复发,均在G-CSF使用组.⑤G-CSF的早期应用不能减少IST前感染的持续时间,对降低败血症、感染性休克等严重感染的发生及相关死亡也无明显作用（P均＞0.05）.⑥随访39（28 ～169）个月,105例患儿中共有2例发生了急性髓系白血病/骨髓增生异常综合征转化,均为G-CSF使用组患儿.⑦Kaplan-meier生存分析显示：4组患儿长期生存率差异无统计学意义（P=0.703）.⑧Cox回归多因素分析同样显示：G-CSF的应用情况对患儿的长期生存无明显影响（P =0.277）,而患儿确诊时的年龄以及首诊时是否同时存在感染对患儿的长期生存具有独立的预后意义（P＜0.05）.结论 应用G-CSF联合IST未能提高本病的近期治疗反应率,也不能降低感染发生率及相关死亡率;对患儿的长期生存无明显影响;对于其可能增加急性髓系白血病/骨髓增生异常综合征转化风险应引起注意.

Objective To compare the efficacy and safety of four different regimens for pediatric severe aplastic anemia （SAA） with immuno-suppressive therapy （IST） with or without combined human granulocyte colony-stimulating factor （G-CSF）.Method The authors retrospectively analyzed 105 children with SAA treated with IST with or without G-CSF in the hospital from February 2000 to September 2010.Regimen A,without G-CSF in the whole treatment,was used to treat Group A patients,n =27 ; Regimen B,G-CSF,was initiated in Group B,n =24,before the IST until hematologic recovery; Regimen C,G-CSF,was used together with the IST for Group C patients,n =24,until hematologic recovery ; Regimen D,G-CSF was used for Group D,n =30,after the end of IST until hematologic recovery.The response rate,relapse rate,mortality,infection rate,infection-related death rate,risk of evolving into MDS/AML,survival rate,factors affecting the time of event-free survival and so on.Result ① The response （CR ＋ PR） rates 4,6,12 and 24 months after IST of the whole series of 105 SAA children were 50.5% （7.6% ＋ 42.9%）,60.0%（21.9% ＋38.1%）,67.6% （38.1% ＋29.5%） and 69.5% （40.0% ＋29.5%） respectively.The 2-year survival rate was 90.5% ; the follow-up of the patients for 13 years showed that the whole survival rate was 87.6%.② The differences of the response rates 4,6,12 and 24 months after IST of the 4 groups were not significant （P 〉 0.05）.③ No significant differences were found in the mortalities 4,6,12 and 24 months among the 4 groups （P 〉0.05）.④ Of the 105 patients,4 children had relapsed disease in the period of time from 6 to 24 months after IST.All the four patients belonged to the groups with G-CSF.⑤ The use of G-CSF could not decrease the infection period before IST （day） （P =0.273）,and it had no impact on the infection rate after IST （P =0.066）.It did not reduce the rates of septicemia and infectious shock.And to the infection-related death rate no significant conclusion can be made.⑥ Follow up of the patients for 13 years,showed that 2 had the evolution to MDS/AML in the 105 patients and the two children belonged to the groups with G-CSF.⑦ Kaplan-meier curve analysis did not show any differences in the survival rates of the four groups.⑧ Cox regression analysis showed that the use of G-CSF had no benefit to the patients＇ long term survival.While the age of diagnosis and the infection history before IST were significantly related to the patients＇ long term survival.Conclusion The use of G-CSF did not contribute to the early response and could not reduce the infection rate,infection-related death rate and the patients＇ long term survival.There were no significant differences in the survival rates of the four groups.Attention should be paid to the risk of the evolution to MDS/AML.