目的 通过分析以可测量残留病(measurable residual disease,MRD)为导向的风险分层治疗,评估MRD在儿童急性髓系白血病(acute myeloid leukemia,AML)治疗过程中的预后价值。 方法 前瞻性纳入93例AML患儿,按照初诊时遗传学异常、诱导治疗Ⅰ后MRD及骨髓细胞学决定的风险分层完成2015-AML-03方案化疗。以多参数流式细胞术动态监测MRD,分析MRD对3年累积复发(cumulative recurrence,CIR)率、无事件生存(event-free survival,EFS)率、总生存(overall survival,OS)率的影响。 结果 93例AML患儿中,3年CIR率为48%±6%,中位复发时间是11(范围:2~32)个月,3年OS率为65%±6%,3年EFS率为50%±5%。诱导治疗Ⅰ和强化治疗Ⅰ后MRD阳性患儿的3年CIR率均高于MRD阴性患儿,3年EFS率、OS率均低于MRD阴性患儿(P<0.05)。初诊时低危的MRD阳性患儿调整化疗强度后的3年CIR率、EFS率、OS率与MRD阴性患儿相比,差异无统计学意义(P>0.05)。多因素分析表明,强化治疗Ⅰ后MRD阳性是AML患儿3年OS率的危险因素(P<0.05)。 结论 MRD对儿童AML预后有预测价值;利用基于MRD的风险导向治疗,合理应用化疗可能改善儿童AML患儿的整体预后。 引用格式:
Abstract
Objective To study the prognostic value of measurable residual disease (MRD) for childhood acute myeloid leukemia (AML) by analyzing MRD-guided risk stratification therapy. Methods A total of 93 children with AML were prospectively enrolled in this study. Chemotherapy with the 2015-AML-03 regimen was completed according to the risk stratification determined by genetic abnormality at initial diagnosis and MRD and bone marrow cytology after induction therapy I. Multiparameter flow cytometry was used to dynamically monitor MRD and analyze the prognostic effect of MRD on 3-year cumulative incidence of recurrence (CIR) rate, event-free survival (EFS) rate, and overall survival (OS) rate. Results The 93 children with AML had a 3-year CIR rate of 48%±6%, a median time to recurrence of 11 months (range 2-32 months), a 3-year OS rate of 65%±6%, and a 3-year EFS rate of 50%±5%. After induction therapy I and intensive therapy I, the MRD-positive children had a significantly higher 3-year CIR rate and significantly lower 3-year EFS and OS rates than the MRD-negative children (P<0.05). There were no significant differences in 3-year CIR, EFS, and OS rates between the MRD-positive children with a low risk at initial diagnosis and the MRD-negative children after adjustment of chemotherapy intensity (P>0.05). The multivariate analysis showed that positive MRD after intensive treatment I was a risk factor for 3-year OS rate in children with AML (P<0.05). Conclusions MRD has predictive value for the prognosis of children with AML. Based on the MRD-guided risk stratification therapy, reasonable application of chemotherapy may improve the overall prognosis of children with AML. Citation:
关键词
急性髓系白血病 /
可测量残留病 /
2015-AML-03方案 /
多参数流式细胞术 /
儿童
Key words
Acute myeloid leukemia /
Measurable residual disease /
2015-AML-03 regimen /
Multiparameter flow cytometry /
Child
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参考文献
1 Buldini B, Rizzati F, Masetti R, et al. Prognostic significance of flow-cytometry evaluation of minimal residual disease in children with acute myeloid leukaemia treated according to the AIEOP-AML 2002/01 study protocol[J]. Br J Haematol, 2017, 177(1): 116-126. PMID: 28240765. DOI: 10.1111/bjh.14523.
2 Buccisano F, Hourigan CS, Walter RB. The prognostic significance of measurable ("minimal") residual disease in acute myeloid leukemia[J]. Curr Hematol Malig Rep, 2017, 12(6): 547-556. PMID: 29027628. DOI: 10.1007/s11899-017-0420-z.
3 Buccisano F, Maurillo L, Del Principe MI, et al. Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia[J]. Blood, 2012, 119(2): 332-341. PMID: 22039260. DOI: 10.1182/blood-2011-08-363291.
4 van der Velden VHJ, van der Sluijs-Geling A, Gibson BES, et al. Clinical significance of flowcytometric minimal residual disease detection in pediatric acute myeloid leukemia patients treated according to the DCOG ANLL97/MRC AML12 protocol[J]. Leukemia, 2010, 24(9): 1599-1606. PMID: 20668473. DOI: 10.1038/leu.2010.153.
5 Brodersen LE, Gerbing RB, Pardo ML, et al. Morphologic remission status is limited compared to ΔN flow cytometry: a Children's Oncology Group AAML0531 report[J]. Blood Adv, 2020, 4(20): 5050-5061. PMID: 33080007. PMCID: PMC7594384. DOI: 10.1182/bloodadvances.2020002070.
6 Keino D, Kinoshita A, Tomizawa D, et al. Residual disease detected by multidimensional flow cytometry shows prognostic significance in childhood acute myeloid leukemia with intermediate cytogenetics and negative FLT3-ITD: a report from the Tokyo children's cancer study group[J]. Int J Hematol, 2016, 103(4): 416-422. PMID: 26781613. DOI: 10.1007/s12185-016-1937-y.
7 Zhu HH, Zhang XH, Qin YZ, et al. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial[J]. Blood, 2013, 121(20): 4056-4062. PMID: 23535063. DOI: 10.1182/blood-2012-11-468348.
8 Rubnitz JE, Inaba H, Dahl G, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial[J]. Lancet Oncol, 2010, 11(6): 543-552. PMID: 20451454. PMCID: PMC3171799. DOI: 10.1016/S1470-2045(10)70090-5.
9 Rubnitz JE. How I treat pediatric acute myeloid leukemia[J]. Blood, 2012, 119(25): 5980-5988. PMID: 22566607. PMCID: PMC3383013. DOI: 10.1182/blood-2012-02-392506.
10 沈悌, 赵永强. 血液病诊断及疗效标准[M]. 4版. 北京: 科学出版社, 2018: 91-94.
11 Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party[J]. Blood, 2018, 131(12): 1275-1291. PMID: 29330221. PMCID: PMC5865231. DOI: 10.1182/blood-2017-09-801498.
12 杨脉. 2015-AML03方案治疗儿童急性髓细胞白血病91例结果分析[D]. 重庆: 重庆医科大学, 2019.
13 Campagne O, Delmas A, Fouliard S, et al. Integrated pharmacokinetic/pharmacodynamic model of a bispecific CD3xCD123 DART molecule in nonhuman primates: evaluation of activity and impact of immunogenicity[J]. Clin Cancer Res, 2018, 24(11): 2631-2641. PMID: 29463552. DOI: 10.1158/1078-0432.CCR-17-2265.
14 Raedler J, Heyde S, Kolokythas M, et al. Venetoclax and decitabine for relapsed paediatric myelodysplastic syndrome-related acute myeloid leukaemia with complex aberrant karyotype after second stem cell transplantation[J]. Br J Haematol, 2020, 189(6): e251-e254. PMID: 32342493. DOI: 10.1111/bjh.16682.
15 Tarlock K, Alonzo TA, Gerbing RB, et al. Gemtuzumab ozogamicin reduces relapse risk in FLT3/ITD acute myeloid leukemia: a report from the children's oncology group[J]. Clin Cancer Res, 2016, 22(8): 1951-1957. PMID: 26644412. PMCID: PMC4834220. DOI: 10.1158/1078-0432.CCR-15-1349.
16 Buccisano F, Palmieri R, Piciocchi A, et al. Use of measurable residual disease to evolve transplant policy in acute myeloid leukemia: a 20-year monocentric observation[J]. Cancers (Basel), 2021, 13(5): 1083. PMID: 33802502. PMCID: PMC7959451. DOI: 10.3390/cancers13051083.
17 Zhang N, Shao JB, Li H, et al. Re-induction with modified CLAG regimen in relapsed or refractory acute myeloid leukemia in children bridging to allogeneic hematopoietic stem cell transplantation[J]. World J Pediatr, 2020, 16(2): 152-158. PMID: 31748985. DOI: 10.1007/s12519-019-00321-8.
18 Tierens A, Bj?rklund E, Siitonen S, et al. Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study[J]. Br J Haematol, 2016, 174(4): 600-609. PMID: 27072379. DOI: 10.1111/bjh.14093.
19 Buldini B, Maurer-Granofszky M, Varotto E, et al. Flow-cytometric monitoring of minimal residual disease in pediatric patients with acute myeloid leukemia: recent advances and future strategies[J]. Front Pediatr, 2019, 7: 412. PMID: 31681710. PMCID: PMC6798174. DOI: 10.3389/fped.2019.00412.