去甲基化剂在急性髓系白血病中的临床应用及研究进展
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摘要
急性髓系白血病(acute myeloid leukemia,AML)是一种临床和遗传异质性疾病且预后不良。基因组学和分子生物学的最新进展使得对该疾病有了进一步的了解。作为单一药物,去甲基化剂(hypomethy latingagents,HMAs)仅可诱导15%～25%的完全缓解率,但目前的数据表明,在使用HMAs后观察到的中位总生存期(overallsur vival,OS)与强化治疗后观察到的中位OS相当。一些接受HMAs治疗的患者是否可获得长期生存尚不清楚。HMAs与新药的结合现已得到广泛研究,且取得了相当好的疗效。
Acute myeloid leukemia(AML) is a clinical and genetic heterogeneous disease with poor prognosis. Recent advances in genomics and molecular biology have led to a better understanding of the disease. The hypomethylating agents(HMAs) only induced a complete response rate of 15% to 25%. Current data show that the median overall survival observed after HMAs is comparable to that observed after intensive therapy. It is not clear whether patients who receiving HMAs therapy can achieve long-term survival. The combination of HMAs and new drugs has been extensively studied, and a large number of reports have been reported on the combination of HMAs and different drugs for AML, and achieved fairly good results.
Acute myeloid leukemia(AML) is a clinical and genetic heterogeneous disease with poor prognosis. Recent advances in genomics and molecular biology have led to a better understanding of the disease. The hypomethylating agents(HMAs) only induced a complete response rate of 15% to 25%. Current data show that the median overall survival observed after HMAs is comparable to that observed after intensive therapy. It is not clear whether patients who receiving HMAs therapy can achieve long-term survival. The combination of HMAs and new drugs has been extensively studied, and a large number of reports have been reported on the combination of HMAs and different drugs for AML, and achieved fairly good results.
引文
1.Scandura JM,Roboz GJ,Moh M,et al.Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML[J].Blood,2011,118(6):1472-1480.
2.张前鹏,韩永胜.地西他滨治疗血液系统恶性肿瘤的研究进展[J].安徽医药,2017,21(11):1957-1962.ZHANG Qianpeng,HAN Yongsheng.Advances in the study of decitabine in the treatment of hematological malignancies[J].Anhui Medical and Pharmaceutical Journal,2017,21(11):1957-1962.
3.Soshnev AA,Josefowicz SZ,Allis CD.Greater than the sum of parts:complexity of the dynamic epigenome[J].Mol Cell,2016,62(5):681-694.
4.Shah MY,Licht JD.DNMT3A mutations in acute myeloid leukemia[J].Nat Genet,2011,43(4):289-290.
5.Abdel-Wahab O,Levine RL.Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia[J].Blood,2013,121(18):3563-3572.
6.Li S,Garrettbakelman FE,Chung SS,et al.Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia[J].Nat Med,2016,22(7):792.
7.Thomas XG,Arthur C,Delaunay J,et al.A post Hoc sensitivity analysis of survival probabilities in a multinational phase III trial of decitabine in older patients with newly diagnosed acute myeloid leukemia[J].Clin Lymphoma Myeloma Leuk,2014,14(1):68-72.
8.Cancer Genome Atlas Research Network,Ley TJ,Miller C,et al.Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia[J].N Engl J Med,2013,368(22):2059-2074.
9.Emadi A,Faramand R,Car ter-Cooper B,et al.Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia[J].Am J Hematol,2015,90(5):E77-E79.
10.Coombs CC,Sallman DA,Devlin SM,et al.Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia[J].Haematologica,2016,101(11):e457.
11.Tang L,Dolnick A,MacBeth KJ,et al.Impact of gene mutations in older patients with acute myeloid leukemia treated with azacitidine or conventional care regimen[C].Annual ASH Meeting,2016.
12.Mims A,Walker AR,Huang X,et al.Increased anti-leukemic activity of decitabine via AR-42-induced upregulation of miR-29b:a novel epigenetic-targeting approach in acute myeloid leukemia[J].Leukemia,2013,27(4):871-878.
13.Quint?s A,Ravandi F,Liu-Dumlao T,et al.Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia[J].Blood,2012,120(24):4840-4845.
14.Desoutter J,Gay J,Berthon C,et al.Molecular prognostic factors in acute myeloid leukemia receiving first-line therapy with azacitidine[J].Leukemia,2016,30(6):1416-1418.
15.Smith ZD,Meissner A.DNA methylation:roles in mammalian development[J].Nat Rev Genet,2013,14(3):204-220.
16.Colacino JA,Arthur AE,Dolinoy DC,et al.Pretreatment dietary intake is associated with tumor suppressor DNA methylation in head and neck squamous cell carcinomas[J].Epigenetics,2012,7(8):883-891.
17.Lugthart S,Figueroa M E,Bindels E,et al.A berrant D N Ahypermethylation signature in acute myeloid leukemia directed by EVI1[J].Blood,2011,117(1):234-241.
18.Figueroa ME,Lugthart S,Li Y,et al.DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia[J].Cancer Cell,2010,17(1):13-27.
19.Jasielec J,Saloura V,Godley LA.The mechanistic role of DNA methylation in myeloid leukemogenesis[J].Leukemia,2014,28(9):1765-1773.
20.Fenaux P,Mufti GJ,Hellstrom-Lindberg E,et al.Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes:a randomised,open-label,phase III study[J].Lancet Oncol,2009,10(3):223-232.
21.Silverman LR,Mckenzie DR,Peterson BL,et al.Further analysis of trials with azacitidine in patients with myelodysplastic syndrome:studies 8421,8921,and 9221 by the Cancer and Leukemia Group B[J].J Clin Oncol,2006,24(24):3895-3903.
22.Dombret H,Seymour JF,Butr ym A,et al.Results of a phase3,multicenter,randomized,open-label study of azacitidine vs conventional care regimens in older patients with newly diagnosed acute myeloid leukemia[C].Milan,Italy:Proceedings of the 19th Congres of the European Hematology Association,2014.
23.Lübbert M,Rüter 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].Haematologica,2012,97(3):393-401.
24.Becker H,Suciu S,Rüter BH,et al.Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation(RAEBt)-results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group(GMDSSG)[J].Ann Hematol,2015,94:2003-2013.
25.Kantarjian H,Oki Y,Garcia-Manero G,et al.Results of a randomized study of 3 schedules of low-dose dec itabine in higher-r i sk myelodysplastic syndrome and chronic myelomonocytic leukemia[J].Blood,2007,109(1):52-57.
26.Steensma DP,Baer MR,Slack JL,et al.Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes:the alternative dosing for outpatient treatment(ADOPT)trial[J].J Clin Oncol,2009,27(23):3842-3848.
27.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.
28.Garcia-Manero G,Gore SD,Kambhampati S,et al.Efficacy and safety of extended dosing schedules of CC-486(oral azacitidine)in patients with lower-risk myelodysplastic syndromes[J].Leukemia,2016,30(4):889-896.
29.Ebrahem Q,Mahfouz RZ,Durkin L,et al.Mechanisms of resistance to 5-azacitidine/decitabine in MDS-AML and pre-clinical in vivo proof of principle of rational solutions to extend response[J].Blood,2015,126:678.
30.Müller-Tidow C,Tschanter P,R?llig C,et al.A zacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia:the AML-AZA trial of the Study Alliance Leukemia[J].Leukemia,2016,30(3):555-561.
31.Tan P,Wei A,Mithraprabhu S,et al.Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome[J].Blood Cancer J,2014,4(1):e170.
32.Prebet T,Sun Z,Figueroa ME,et al.Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes:results of the US Leukemia Intergroup trial E1905[J].J Clin Oncol,2014,32(12):1242-1248.
33.Garcia-Manero G,Atallah E,Khaled SK,et al.Final results from a phase 2 study of pracinostat in combination with azacitidine in elderly patients with acute myeloid leukemia(AML)[J].Blood,2015,126:453.
34.Narayan R,Garcia JS,Percival ME,et al.Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome[J].Leuk Lymphoma,2016,57(3):609-615.
35.Wei A,Tan P,Perruzza S,et al.Maintenance lenalidomide in combination with 5-azacitidine as post-remission therapy for acute myeloid leukaemia[J].Br J Haematol,2015,169(2):199-210.
36.Chang E,Ganguly S,Rajkhowa T,et al.The combination of FLT3 and DNA methyltransferase inhibition is synergistically cytotoxic to FLT3/ITD acute myeloid leukemia cells[J].Leukemia,2016,30(5):1025-1032.
37.Muppidi MR,Portwood S,Griffiths EA,et al.Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid leukemia[J].Clin Lymphoma Myeloma Leuk,2015,15:S73-S79.
38.Borthakur G,Kantarjian HM,O’Brien S,et al.The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients(Pts)with FLT3-ITD mutated myeloid leukemias:interim report of a phase I/II trial[J].Blood,2014,124:388.
39.Daver N,Kantarjian H,Ravandi F,et al.A phase II study of decitabine and gemtuzumab ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome[J].Leukemia,2016,30(2):268-273.
40.Fathi AT,Erba HP,Lancet JE,et al.SGN-CD33A plus hypomethylating agents:a novel,well-tolerated regimen with high remission rate in frontline unfit AML[J].Blood,2015,126:454.
41.Navada SC,Silverman LR,Hearn KP,et al.A phase II study of the combination of oral rigosertib and azacitidine in patients with myelodysplastic syndromes(MDS)[J].Blood,2015,126:910.
2.张前鹏,韩永胜.地西他滨治疗血液系统恶性肿瘤的研究进展[J].安徽医药,2017,21(11):1957-1962.ZHANG Qianpeng,HAN Yongsheng.Advances in the study of decitabine in the treatment of hematological malignancies[J].Anhui Medical and Pharmaceutical Journal,2017,21(11):1957-1962.
3.Soshnev AA,Josefowicz SZ,Allis CD.Greater than the sum of parts:complexity of the dynamic epigenome[J].Mol Cell,2016,62(5):681-694.
4.Shah MY,Licht JD.DNMT3A mutations in acute myeloid leukemia[J].Nat Genet,2011,43(4):289-290.
5.Abdel-Wahab O,Levine RL.Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia[J].Blood,2013,121(18):3563-3572.
6.Li S,Garrettbakelman FE,Chung SS,et al.Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia[J].Nat Med,2016,22(7):792.
7.Thomas XG,Arthur C,Delaunay J,et al.A post Hoc sensitivity analysis of survival probabilities in a multinational phase III trial of decitabine in older patients with newly diagnosed acute myeloid leukemia[J].Clin Lymphoma Myeloma Leuk,2014,14(1):68-72.
8.Cancer Genome Atlas Research Network,Ley TJ,Miller C,et al.Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia[J].N Engl J Med,2013,368(22):2059-2074.
9.Emadi A,Faramand R,Car ter-Cooper B,et al.Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia[J].Am J Hematol,2015,90(5):E77-E79.
10.Coombs CC,Sallman DA,Devlin SM,et al.Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia[J].Haematologica,2016,101(11):e457.
11.Tang L,Dolnick A,MacBeth KJ,et al.Impact of gene mutations in older patients with acute myeloid leukemia treated with azacitidine or conventional care regimen[C].Annual ASH Meeting,2016.
12.Mims A,Walker AR,Huang X,et al.Increased anti-leukemic activity of decitabine via AR-42-induced upregulation of miR-29b:a novel epigenetic-targeting approach in acute myeloid leukemia[J].Leukemia,2013,27(4):871-878.
13.Quint?s A,Ravandi F,Liu-Dumlao T,et al.Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia[J].Blood,2012,120(24):4840-4845.
14.Desoutter J,Gay J,Berthon C,et al.Molecular prognostic factors in acute myeloid leukemia receiving first-line therapy with azacitidine[J].Leukemia,2016,30(6):1416-1418.
15.Smith ZD,Meissner A.DNA methylation:roles in mammalian development[J].Nat Rev Genet,2013,14(3):204-220.
16.Colacino JA,Arthur AE,Dolinoy DC,et al.Pretreatment dietary intake is associated with tumor suppressor DNA methylation in head and neck squamous cell carcinomas[J].Epigenetics,2012,7(8):883-891.
17.Lugthart S,Figueroa M E,Bindels E,et al.A berrant D N Ahypermethylation signature in acute myeloid leukemia directed by EVI1[J].Blood,2011,117(1):234-241.
18.Figueroa ME,Lugthart S,Li Y,et al.DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia[J].Cancer Cell,2010,17(1):13-27.
19.Jasielec J,Saloura V,Godley LA.The mechanistic role of DNA methylation in myeloid leukemogenesis[J].Leukemia,2014,28(9):1765-1773.
20.Fenaux P,Mufti GJ,Hellstrom-Lindberg E,et al.Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes:a randomised,open-label,phase III study[J].Lancet Oncol,2009,10(3):223-232.
21.Silverman LR,Mckenzie DR,Peterson BL,et al.Further analysis of trials with azacitidine in patients with myelodysplastic syndrome:studies 8421,8921,and 9221 by the Cancer and Leukemia Group B[J].J Clin Oncol,2006,24(24):3895-3903.
22.Dombret H,Seymour JF,Butr ym A,et al.Results of a phase3,multicenter,randomized,open-label study of azacitidine vs conventional care regimens in older patients with newly diagnosed acute myeloid leukemia[C].Milan,Italy:Proceedings of the 19th Congres of the European Hematology Association,2014.
23.Lübbert M,Rüter 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].Haematologica,2012,97(3):393-401.
24.Becker H,Suciu S,Rüter BH,et al.Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation(RAEBt)-results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group(GMDSSG)[J].Ann Hematol,2015,94:2003-2013.
25.Kantarjian H,Oki Y,Garcia-Manero G,et al.Results of a randomized study of 3 schedules of low-dose dec itabine in higher-r i sk myelodysplastic syndrome and chronic myelomonocytic leukemia[J].Blood,2007,109(1):52-57.
26.Steensma DP,Baer MR,Slack JL,et al.Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes:the alternative dosing for outpatient treatment(ADOPT)trial[J].J Clin Oncol,2009,27(23):3842-3848.
27.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.
28.Garcia-Manero G,Gore SD,Kambhampati S,et al.Efficacy and safety of extended dosing schedules of CC-486(oral azacitidine)in patients with lower-risk myelodysplastic syndromes[J].Leukemia,2016,30(4):889-896.
29.Ebrahem Q,Mahfouz RZ,Durkin L,et al.Mechanisms of resistance to 5-azacitidine/decitabine in MDS-AML and pre-clinical in vivo proof of principle of rational solutions to extend response[J].Blood,2015,126:678.
30.Müller-Tidow C,Tschanter P,R?llig C,et al.A zacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia:the AML-AZA trial of the Study Alliance Leukemia[J].Leukemia,2016,30(3):555-561.
31.Tan P,Wei A,Mithraprabhu S,et al.Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome[J].Blood Cancer J,2014,4(1):e170.
32.Prebet T,Sun Z,Figueroa ME,et al.Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes:results of the US Leukemia Intergroup trial E1905[J].J Clin Oncol,2014,32(12):1242-1248.
33.Garcia-Manero G,Atallah E,Khaled SK,et al.Final results from a phase 2 study of pracinostat in combination with azacitidine in elderly patients with acute myeloid leukemia(AML)[J].Blood,2015,126:453.
34.Narayan R,Garcia JS,Percival ME,et al.Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome[J].Leuk Lymphoma,2016,57(3):609-615.
35.Wei A,Tan P,Perruzza S,et al.Maintenance lenalidomide in combination with 5-azacitidine as post-remission therapy for acute myeloid leukaemia[J].Br J Haematol,2015,169(2):199-210.
36.Chang E,Ganguly S,Rajkhowa T,et al.The combination of FLT3 and DNA methyltransferase inhibition is synergistically cytotoxic to FLT3/ITD acute myeloid leukemia cells[J].Leukemia,2016,30(5):1025-1032.
37.Muppidi MR,Portwood S,Griffiths EA,et al.Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid leukemia[J].Clin Lymphoma Myeloma Leuk,2015,15:S73-S79.
38.Borthakur G,Kantarjian HM,O’Brien S,et al.The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients(Pts)with FLT3-ITD mutated myeloid leukemias:interim report of a phase I/II trial[J].Blood,2014,124:388.
39.Daver N,Kantarjian H,Ravandi F,et al.A phase II study of decitabine and gemtuzumab ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome[J].Leukemia,2016,30(2):268-273.
40.Fathi AT,Erba HP,Lancet JE,et al.SGN-CD33A plus hypomethylating agents:a novel,well-tolerated regimen with high remission rate in frontline unfit AML[J].Blood,2015,126:454.
41.Navada SC,Silverman LR,Hearn KP,et al.A phase II study of the combination of oral rigosertib and azacitidine in patients with myelodysplastic syndromes(MDS)[J].Blood,2015,126:910.