地西他滨联合亚砷酸诱导治疗中高危骨髓增生异常综合征及慢性粒单核细胞白血病47例临床研究
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摘要
目的探讨地西他滨联合亚砷酸方案诱导治疗中高危骨髓增生异常综合征(MDS)及慢性粒单核细胞白血病(CMML)的临床疗效。方法收集2016年4月至2018年12月中国贫血东部协作组接受地西他滨联合亚砷酸治疗的中高危MDS患者39例及CMML患者8例。地西他滨20 mg/(m~2·d)联合亚砷酸0.15 mg/(m~2·d),治疗5 d,4～6周1个疗程,完全缓解(CR)或部分缓解(PR)者进入巩固周期,分析疗效及影响因素。结果中位疗程为2个疗程(1～12个疗程),31例(66.0%)获得了临床反应,中位疗效持续时间16周(2～52周)。CR 8例(17.0%),PR 10例(21.3%),血液学改善12例(25.5%),骨髓CR 1例(2.1%),疾病稳定8例(17.0%),疾病进展1例(2.1%)。二代测序基因检测中,33例发现25个基因突变70次。表观遗传学基因突变率(57.6%)高于剪接子复合物(33.5%)、转录因子和激酶系统(54.5%)和TP53组(21.2%),差异有统计学意义(P<0.01),但疗效差异无统计学意义(分别为47.4%、54.5%、50.0%和85.7%,P=0.977)。治疗有效患者等位基因突变频率(VAF)显著下降(16.67%对10.26%,P=0.014)。结论地西他滨联合亚砷酸方案诱导治疗中高危MDS及CMML的疗效佳,且不良反应少。二代基因突变检测结果可能与疗效反应有关。
Objective To evaluate the clinical efficacy of decitabine combined with arsenious acid in the treatment of patients with higher-risk myelodysplastic syndromes(MDS) and chronic myelomonocytic leukemia(CMML). Methods Totally 39 patients with MDS and 8 patients with CMML received the treatment of decitabine and arsenious acid from April 2016 to December 2018. Decitabine [20 mg/(m~2·d)] and arsenious acid [0.15 mg/(m~2·d)] were administered intravenously for 5 consecutive days every 4-6 weeks. Patients who achieved complete or partial remission entered into the consolidation cycle. Efficacy and influencing factor were analyzed. Results Clinical response were observed in 31 patients after a median of 2 courses(ranging 1-12) of treatment. The overall response rate(ORR) was 66.0%. The median duration of response was 16 weeks(ranging 2-52 weeks). There were 8 cases(17.0%) of complete remission(CR), 10 cases(21.3%) of partial remission(PR),12 cases(25.5%) of hematological improvement(HI), 1 case(2.1%) of marrow complete remission(mCR), 8 cases(17.0%) of stable disease(SD), and 1 case(2.1%) of progressive disease(PD). By next generation sequencing, 25 genes mutated with 70 times in 33 cases. The mutation frequency of epigenetic regulators(57.6%) was higher than splicing factors(33.5%), transcription factors and kinase signaling(54.5%),and TP53(21.2%)(P<0.01). There was no significant difference in response rates among these patients(47.4%, 54.5%, 50.0% and85.7%, P=0.977). Gene mutation frequency(VAF) of patients who responded to the regimen declined significantly(16.67% vs. 10.26%,P=0.014). Conclusion Decitabine combined with arsenious acid has significant effect in the treatment of patients with higher-risk MDS and CMML and is well-tolerated. Gene mutation test results by next generation sequencing might be related to clinical response.
Objective To evaluate the clinical efficacy of decitabine combined with arsenious acid in the treatment of patients with higher-risk myelodysplastic syndromes(MDS) and chronic myelomonocytic leukemia(CMML). Methods Totally 39 patients with MDS and 8 patients with CMML received the treatment of decitabine and arsenious acid from April 2016 to December 2018. Decitabine [20 mg/(m~2·d)] and arsenious acid [0.15 mg/(m~2·d)] were administered intravenously for 5 consecutive days every 4-6 weeks. Patients who achieved complete or partial remission entered into the consolidation cycle. Efficacy and influencing factor were analyzed. Results Clinical response were observed in 31 patients after a median of 2 courses(ranging 1-12) of treatment. The overall response rate(ORR) was 66.0%. The median duration of response was 16 weeks(ranging 2-52 weeks). There were 8 cases(17.0%) of complete remission(CR), 10 cases(21.3%) of partial remission(PR),12 cases(25.5%) of hematological improvement(HI), 1 case(2.1%) of marrow complete remission(mCR), 8 cases(17.0%) of stable disease(SD), and 1 case(2.1%) of progressive disease(PD). By next generation sequencing, 25 genes mutated with 70 times in 33 cases. The mutation frequency of epigenetic regulators(57.6%) was higher than splicing factors(33.5%), transcription factors and kinase signaling(54.5%),and TP53(21.2%)(P<0.01). There was no significant difference in response rates among these patients(47.4%, 54.5%, 50.0% and85.7%, P=0.977). Gene mutation frequency(VAF) of patients who responded to the regimen declined significantly(16.67% vs. 10.26%,P=0.014). Conclusion Decitabine combined with arsenious acid has significant effect in the treatment of patients with higher-risk MDS and CMML and is well-tolerated. Gene mutation test results by next generation sequencing might be related to clinical response.
引文
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[11]Lee JH,Jang JH,Park J,et al.A prospective multicenter observational study of decitabine treatment in Korean patients with myelodysplastic syndrome[J].Haematologica,2011,96(10):1441-1447.
[12]Welch JS,Petti AA,Miller CA,et al.TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes[J].N Engl J Med2016,375(21):2023-2036.
[13]庞艳彬,赵松颖,薛华,等.骨髓增生异常综合征患者淋巴细胞绝对值计数与地西他滨治疗反应的关系[J].解放军医学杂志,2018,43(3):239-243.
[2]Kantarjian HM,Thomas XG,Dmoszynska A,et al.Multicenter randomized,open-label,phase III trial of decitabine versus patient choice,with physician advice,of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia[J].J Clin Oncol,2012,30(21):2670-2677.
[3]Issa JP,Garcia-Manero G,Huang X,et al.Results of phase 2randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia[J].Cancer,2015,121(4):556-561.
[4]Lübbert M,Ruter BH,Claus R,et al.A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy[J].Haematologica2012,97(3):393-401.
[5]何广胜.机制导向治疗——地西他滨治疗骨髓增生异常综合征[J].中国实用内科学杂志,2015,35(2):126-128.
[6]Schiller GJ,Slack J,Hainsworth JD,et al.Phase II multicenter study of arsenic trioxide in patients with myelodysplastic syndromes[J].J Clin Oncol,2006,24:2456-2464.
[7]Vey N,Bosly A,Guerci A,et al.Arsenic trioxide in patients with myelodysplastic syndromes:a phase II multicenter study[J].J Clin Oncol,2006,24:2465-2471.
[8]Emadi AA,Gore SDS.Arsenic trioxide-An old drug rediscovered[J]Blood Rev,2010,24(4):191-199.
[9]Cui X,Wakai T,Shirai Y,et al.Arsenic trioxide inhibits DNAmethyltransferaseand restores methylation-silenced genes in human livercancer cells[J].Hum Pathol,2006,37:298-311.
[10]Chen G,Wang Y,Huang H,et al.Combinationof DNA methylation inhibitor 5-azacytidine and arsenic trioxide has synergistic activity in myeloma[J].Eur J Haematol,2010,82(3):176-183.
[11]Lee JH,Jang JH,Park J,et al.A prospective multicenter observational study of decitabine treatment in Korean patients with myelodysplastic syndrome[J].Haematologica,2011,96(10):1441-1447.
[12]Welch JS,Petti AA,Miller CA,et al.TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes[J].N Engl J Med2016,375(21):2023-2036.
[13]庞艳彬,赵松颖,薛华,等.骨髓增生异常综合征患者淋巴细胞绝对值计数与地西他滨治疗反应的关系[J].解放军医学杂志,2018,43(3):239-243.