化疗联合异基因自然杀伤细胞巩固治疗低中危急性髓系白血病的疗效观察

Observation on the efficacy of consolidation chemotherapy combined with allogeneic natural killer cell infusion in the treatment of low and moderate risk acute myeloid leukemia

目的评价巩固化疗联合异基因NK细胞输注治疗低中危急性髓系白血病(AML)的疗效。方法回顾性分析2014年1月至2019年6月北京大学人民医院诊治的23例经化疗达血液学完全缓解(CR),且巩固治疗3个疗程后,应用巩固化疗联合异基因NK细胞回输治疗的低中危AML患者,对照组为1∶2配对的46例AML患者,配对因素为患者的性别、年龄、诊断、预后危险分层、诱导CR及NK细胞输注前巩固化疗的疗程数。比较两组微小残留病(MRD)转阴率、复发率、无白血病生存(LFS)及总生存(OS)。结果治疗组23例低中危AML患者于巩固化疗第4~7个疗程共输注NK细胞45次,中位NK细胞输注数量7.5(6.6~8.6)×10^9/L,NK细胞中位存活率95.4%(93.9%~96.9%),中位扩增倍数141.1(86.1~171.1),其中中位CD3-CD56+细胞数5.0(1.4~6.4)×10^9/L,占回输细胞总数的76.8%(30.8%~82.9%);CD3+CD56+细胞数0.55(0.24~1.74)×10^9/L,占回输细胞总数的8.8%(4.9%~20.9%)。NK细胞输注前,治疗组MRD阳性患者为9例(39.1%),对照组MRD阳性患者为19例(41.3%),两组间差异无统计学意义(χ^2=0.030,P=0.862)。治疗组输注NK细胞前后疗效评估与同期对照组对比,MRD阴性转阳性比例两组差异无统计学意义[14.3%(2/14)对22.2%(6/27),χ^2=0.037,P=0.847]。治疗组MRD由阳性转为阴性的患者占66.7%(6/9),明显高于对照组的10.5%(2/19)(χ^2=6.811,P=0.009)。其中治疗组有1例MRD阴性患者发生了形态学复发,对照组有2例MRD阳性患者形态学复发。截至末次随访,中位随访35(10~59)个月,治疗组与对照组MRD阴性患者比例差异无统计学意义[43.5%(10/23)对43.5%(20/46),χ^2=1.045,P=0.307]。在形态学复发方面,虽然两组差异无统计学意义,但是治疗组形态学复发患者比例明显低于对照组[30.4%(7/23)对50.2%(24/46),χ^2=2.929,P=0.087]。治疗组预计3年LFS率为(65.1±11.1)%,明显高于对照组的(50.0±7.4)%(P=0.047)。治疗组、对照组的预计3年OS率分别为(78.1±10.2)%、(65.8±8.0)%(P=0.212)。结论巩固化疗联合异基因NK细胞输注可能有助于低中危AML患者达到更深层次的缓解,减少远期复发。

Objective To evaluate the efficacy of consolidation chemotherapy combined with allogeneic natural killer(NK)cell infusion in the treatment of low or intermediate-risk(LIR)acute myeloid leukemia(AML).Methods A cohort of 23 LIR AML patients at hematologic complete remission(CR)received NK cell transfusion combined with consolidation chemotherapy after 3 consolidation courses from January 2014 to June 2019 were reviewed.Control group cases were concurrent patients from Department of Hematology,and their gender,age,diagnosis,risk stratification of prognosis,CR and the number of courses of consolidate chemotherapy before NK cell transfusion were matched with LIR AML patients.Results A total of 45 times of NK cells were injected into 23 LIR AML patients during 4 to 7 courses of chemotherapy.The median NK cell infusion quantity was 7.5(6.6-8.6)×10^9/L,and the median survival rate of NK cells was 95.4%(93.9%-96.9%).Among them,the median CD3-CD56+cell number was 5.0(1.4-6.4)×10^9/L,accounting for 76.8%(30.8%-82.9%);The number of CD3+CD56+cells was 0.55(0.24-1.74)×10^9/L,accounting for 8.8%(4.9%-20.9%).Before NK cell infusion,the number of patients with positive MRD in the treatment and control groups were 9/23(39.1%)and 19/46(41.3%)(χ^2=0.030,P=0.862)respectively.After NK infusion,There was no significant difference in terms of MRD that went from negative to positive between the treatment and the control groups(14.3%vs 22.2%,χ^2=0.037,P=0.847).In the treatment group,66.7%(6/9)of the MRD were converted from positive to negative,which was significantly higher than that in the control group(10.5%,2/19)(χ^2=6.811,P=0.009).Morphological recurrence occurred in 1 case of MRD negative in the treatment group and 2 cases of MRD positive in the control group.By the end of follow-up,the median follow-up was 35(10-59)months,the number of patients with morphological recurrence in the treatment group was 30.4%(7/23),which was significantly lower than that in the control group(50.2%,24/46)(χ^2=2.929,P=0.087),although there was no statistically significant difference between the two groups.There was no significant difference on MRD-negative between the treatment and the control groups(43.5%vs 43.5%,χ^2=1.045,P=0.307).The 3-year leukemia-free survival was better in the treatment group[(65.1±11.1)%]than that in the control group[(50.0±7.4)%](P=0.047).The 3-year overall survival in the treatment and control groups were(78.1±10.2)%and(65.8±8.0)%(P=0.212),respectively.Conclusion The consolidation of chemotherapy combined with allogeneic NK cell infusion contributed to the further remission of patients with LMR AML and the reduction of long-term recurrence.