小剂量高三尖杉酯碱联合全反式维甲酸及三氧化二砷治疗急性早幼粒细胞白血病的临床研究

doi:10.12092/j.issn.1009-2501.2018.05.014

摘要/Abstract

摘要：

目的:观察在初发急性早幼粒细胞白血病（APL）中应用小剂量高三尖杉醋碱(HHT)联合全反式维甲酸(ATRA)以及三氧化二砷（ATO）作为诱导治疗方案的疗效及诱导治疗期间的不良事件发生情况，并与去甲氧柔红霉素（IDA）联合ATRA及ATO的治疗方案进行对比分析。方法:选取了2004年1月至2013年12月期间收治的的145例APL患者的资料进行回顾性分析，其中HHT治疗组74例，IDA治疗组71例，对比分析两组的完全缓解率（CR），总生存率（OS）以及无事件生存率（EFS）及不良反应发生情况。结果:145例患者的CR率为97.2%（141/145），HHT组与IDA组两组的CR率相似（98.6% vs. 95.7%，P=0.36），到达CR时间分别为32.9 d和33.3 d（P=0.645），获得分子生物学缓解时间分别为1.9月和2.2月（P=0.091），无显著统计学差异。有4例患者早期死亡（2.8%），其中3例死于颅内出血，1例死于呼吸窘迫（ARDS）。平均随访45.6月（0.17～131.5月），两组间的OS和EFS均无统计学差异（P=0.9 ，P=0.093）。一共13例患者复发，其中分子生物学复发5例，中枢神经系统复发2例，两组的复发率差异无统计学意义（6.7% vs. 11.2%，P=0.342）。在亚组分析中，无论是中低危还是高危患者中，两组的OS和EFS也没有显示出统计学差异（均P＞0.05）。在不良反应方面，HHT组的血液学毒性显著低于IDA组（P=0.003），合并1级发热的患者比例低于IDA组（28.3% vs. 45.1%， P=0.037）。其他肝肾及心脏等重要脏器损害，重要脏器出血等发生率在两组间无统计学差异。结论:ATRA及ATO分别联合小剂量HHT和IDA的方案在初治APL患者中的疗效近似，但联合小剂量HHT组的血液学毒性更小，相应的感染发生率更低。

关键词: 白血病, 早幼粒细胞, 急性, 高三尖酯碱, 预后

Abstract:

AIM: To investigate the complete remssion(CR)，overall survival(OS)，event free survival(EFS)and adverse events of newly diagnosised acute promyelocytic leukemia (APL) treated with low dose homoharringtonine(HHT), alltrans retinoic acid(ATRA) and arsenic trioxide(ATO), and to evaluate the efficacy treatment outcome by comparing HHT,ATRA and ATO with idarubicin(IDA), ATRA and ATO. METHODS: A total of 145 cases (74 in HHT group, 71 in IDA group) of newly diagnosed acute promyelocytic leukemia from January 2004 to December 2013 in The First affiliated hospital of Zhejiang University School of Medicine and Yinzhou Hospital Affiliated to Ningbo University were analyzed, and were enrolled in the analyses of clinical feature, molecular biology，OS and EFS after long term follow up．RESULTS:The overall CR of 145 pations was 97.2%(141/145), the CR rate of HTT group and IDA group was similar（98.6% vs. 95.7%，P=0.36）. The interval to achieve hematological CR in two group was 32.89 and 33.3 days，the converting to PML/RARa PCR-negative from the induction therapy was 1.9 and 2.17 months respectively, similarly, there were no significant difference between the two groups (P=0.645 and 0.091, respectively）. Four patients occurred early death (2.8%), 3 cases died of intracranial hemorrhage, 1 case died of respiratory distress (ARDS). With a median follow-up of 45.6 months, the two groups did not differ between the OS and EFS (P=0.9 and 0.093). A total of 13 patients relapse, including 5 cases of recurrence of molecular biology, the central nervous system relapse in 2 cases, there was no statistically significant difference of recurrence rates in the two groups (6.7% vs. 11.2%, P=0.342). And the risk group was not the factor affecting OS and EFS (P>0.05)．While the incidence of hematology toxicity and grade 1 fever in HTT group were significantly lower than IDA group (P=0.003 and 0.037). And no difference was found in terms of liver dysfunction，renal dysfunction，cardiac dysfunction，and visceral bleeding, etc between two groups. CONCLUSION: Our study demonstrated comparable therapeutic effect of low dose HHT or IDA on APL，HHT was also well tolerated and had lower hematology toxicity and infection rate．

Key words: leukemia, promyelocytic, acute, trichothecenes, prognosis

中图分类号:

R733.71

陈冬，陆滢，裴仁治，娄引军，王敬瀚，叶佩佩，张丕胜，金洁. 小剂量高三尖杉酯碱联合全反式维甲酸及三氧化二砷治疗急性早幼粒细胞白血病的临床研究[J]. 中国临床药理学与治疗学, 2018, 23(5): 561-569.

CHEN Dong, LU Ying, PEI Renzhi, LOU Yinjun, WANG Jinghan, YE Peipei, ZHANG Pisheng, JIN Jie. Outcome of acute promyelocytic leukemia treated with low dose homoharringtonine, alltrans retinoic acid and arsenic trioxide[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(5): 561-569.

参考文献

［1］Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias: French-American-British (FAB) co-operative group［J］. Br J Haematol,1976,33(15):451-458.
［2］Bennett JM, Catovsky D, Daniel MT, et al. A variant form of hypergranular promyelocytic leukaemia (M3)［J］. Br J Haematol,1980,44(13):169-170.
［3］Tallman MS, Kwaan HC. Reassessing the hemostatic disorder associated with acute promyelocytic leukemia［J］. Blood,1992,79(11):543-553.
［4］Larson RA, Kondo K, Vardiman JW, etal. Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia［J］. Am J Med,1984,76(10):827-841.
［5］De The H, Lavau C, Marchio A, etal. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR［J］. Cell,1991,66(14):675-684.
［6］Swerdlow SH,Campo E,Harris NL et al. WHO classification of tumours of haematopoietic and lymphoid tissues［J］.Switzerl:WHO Press World Health Oragnization,2008,12(10):152-157.
［7］Huang ME, Ye YC, Chen SR, et al. Use of alltrans retinoic acid in the treatment of acute promyelocytic leukemia［J］. Blood,1988,72(15):567-572.
［8］Tallman MS, Andersen JW, Schiffer CA, et al. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome［J］. Blood,2000,95(11):90-95.
［9］Sanz MA,Martin G ,Gonzalez M, et al.Riskadapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by PETHEMA group［J］.Blood,2004,103(15):1237-1243.
［10］Soignet SL, Maslak P,Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide［J］. NEngl J Med,1998,339(10):1341-1348.
［11］Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients［J］. Blood,1999,94(20):3315-3324.
［12］Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia［J］.J Clin Oncol,2001,19(6):3852-3860.
［13］Vom Baur E, Zechel C, Heery D, et al. Differential liganddependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1［J］. Embo J,1996,15(1):110-124.
［14］Zhang XW, Yan XJ, Zhou ZR, et al. Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML［J］. Science, 2010, 328(5975): 240-243.
［15］Gianni M, Koken MH, ChelbiAlix MK, et al. Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant NB4 cells［J］.Blood, 1998, 91(30):4300-4310.
［16］Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As203 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia.［J］.Proc Natl Acad Sci USA,2004,101(15):5328-5335.
［17］Hu J, Liu YF, Wu CF, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia［J］.Proc Natl Acad Sci USA,2009,106(2):3342-3347.
［18］Iland HJ, Bradstock K, Supple SG, et al. All-transretinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4)［J］. Blood,2012,120(22):1570-1580.
［19］Kantarjian HM, Talpaz M, Santini V, et al.Homoharringtonine:history, current research, and future direction［J］ Cancer, 2001,92(6):1591-1605.
［20］Jin J, Wang JX, Chen FF, et al. Homoharringtoninebased nduction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial［J］.Lancet Oncol,2013,7(12):599-608.
［21］Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet［J］. Blood,2009,113(10):1875-1891.
［22］Chenson BD,Bennett JM,Kopecky KJ,et al.Revised recommendation of the international working group for diagnosis,standardization of response criteria,treatment outcomes,and reporting standards for therapertic trials in acute myeloid leukemia［J］.J Clin Oncol,2003,21(9):4642.
［23］Sanz MA，Talhnan MS，Lo-Coco F．Tricks of the trade for the propriate management of newly diagnosed acute promyelocytic leukemia［J］．Blood，2005，105(23)：3019-3025.
［24］Wang ZY，Chen Z．Acute promyelocytic leukemia：from highly fatal to highly curable［J］．Blood，2008，111(19)：2505-2515.
［25］Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group［J］. Blood,1993,82(8):3241-3249.
［26］De Botton S, Dombret H, Sanz M, et al. Incidence clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL Group［J］. Blood,1998,92(11):2712-2718.
［27］Leung J，Pang A，Yuen WH，et al. Relationship of expression of aqua glyceroporin 9 with arsenic uptake and sensitivity in leukemic cells［J］.Blood,2007,109(2):740-746.
［28］任金海，林凤茹，郭晓楠，等.全反式维甲酸，三氧化二砷联合化疗治疗急性早幼粒细胞白血病临床观察［J］.中华血液学杂志，2004,25(10):437-438.
［29］Berma E, Little C, Kher U, et al. Prognostic analysis of patients with acute promyelocytic leukemia ［J］. Blood,1991,78(Suppl 1):43A.
［30］Burnett AK, Hills RK, Grimwade D, et al.Idarubicin and ATRA is as effective as MRC chemotherapy in patients with acute promyelocytic leukemia with lower toxicity and resource usage: preliminary results of the MRC AML15 Trial［J］. Blood,2007,110(20):589［ASH Annual Meeting Abstracts］.
［31］Renzhi Pei, Junjie Cao, Junxia Ma, et al. Long term curative effects of sequential therapy with all-transretinoic acid, arsenious oxide and chemotherapy on patients with acute promyelocytic leukemia［J］. Hematology, 2012,17(6):311-316.
［32］Wang Y, Lin D, Wei H, et al. Long-term follow-up of homoharringtonine plus all-trans retinoic acid-based induction and consolidation therapy in newly diagnosed acute promyelocytic leukemia［J］.Int J Hematol,2015,101(3):279-285.
［33］Grimwade D, Jovanovic JV, Hills RK, et al. Prospectiveminimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy［J］. J Clin Oncol,2009,27(10):3650-3658.
［34］李萍英,杨永耿,马颖才,等.成人慢性乙型肝炎合并急性淋巴细胞白血病1例报告［J］.临床肝胆病杂志,2015,31(11):1894-1896.
［35］宋斌,陈雁,吴修伟,等.急性髓系白血病幼稚细胞群免疫表型特点和预后分析［J］.疑难病杂志,2016,15(12):1250-1254.

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