芦可替尼时代骨髓增殖性肿瘤的治疗策略
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摘要
不同类型的费城染色体阴性的骨髓增殖性肿瘤(MPN)具有相同的JAK2V617F突变;JAK2抑制剂芦可替尼的应用,仅在一部分MPN有效,均提示JAK2靶点非MPN分子通路"惟一"。其中,包括TET2、ASXL1等表观遗传学基因突变参与了MPN进展和转化。此外,真性红细胞增多症(PV)和原发性血小板增多症(ET)患者的治疗目标仍然是避免血栓栓塞,降低急性白血病(AL)和PV或ET后骨髓纤维化(MF)的风险。而原发性骨髓纤维化(PMF)的治疗目标则是提高患者生存质量,延长患者生存期。对PMF患者而言,依据芦可替尼疗效和深度基因检测度进行分层是对现有的临床危险分层治疗的合理补充。
The different types of Ph-negative myeloproliferative neoplasm(MPN) possess the same JAK2V617 F mutation. JAK2 inhibitor, ruxolitinib, is only valid in some of MPN, which indicates JAK2 target is not the only molecular pathway of MPN. Epigenetic genes mutations, including TET2 and ASXL1, are involved in the progression and transformation of MPN. In addition, avoiding thromboembolism and reducing the risk of transformation into acute leukemia(AL) or myelofibrosis(MF) still is the therapeutic goal of polycythemia vera(PV) and essential thrombocytosis(ET). The goal of treatment in primary myelofibrosis(PMF) is to improve the quality of life and prolong the survival of patients. For the patients with PMF, stratification based on the efficacy of ruxolitinib and profound genetic detection is a reasonable supplement to the existing of stratification of clinical risk.
The different types of Ph-negative myeloproliferative neoplasm(MPN) possess the same JAK2V617 F mutation. JAK2 inhibitor, ruxolitinib, is only valid in some of MPN, which indicates JAK2 target is not the only molecular pathway of MPN. Epigenetic genes mutations, including TET2 and ASXL1, are involved in the progression and transformation of MPN. In addition, avoiding thromboembolism and reducing the risk of transformation into acute leukemia(AL) or myelofibrosis(MF) still is the therapeutic goal of polycythemia vera(PV) and essential thrombocytosis(ET). The goal of treatment in primary myelofibrosis(PMF) is to improve the quality of life and prolong the survival of patients. For the patients with PMF, stratification based on the efficacy of ruxolitinib and profound genetic detection is a reasonable supplement to the existing of stratification of clinical risk.
引文
[1]VainchenkerW,Kralov ic sR.Genet icbasi sandmolec ular pathophysiology of classical myeloproliferative neoplasms[J]. Blood,2017, 129(6):667-679.
[2]Breccia M, Andriani A3, Montanaro M, et al. Ruxolitinib in clinical practice for primary and secondary myelofibrosis:an analysis of safety and efficacy of Gruppo Laziale of Ph-negative MPN[J]. Ann Hematol,2017, 96(3):387-391.
[3]Finazzi G. Ruxolitinib in ET:not all MPN are equal[J]. Blood, 2017,130(17):1873-1874.
[4]Ortmann CA, Kent DG, Nangalia J, et al. Effect of mutation order on myeloproliferative neoplasms[J]. N Engl J Med, 2015, 372(7):601-612.
[5]Abdel-WahabO,TefferiA,LevineRL.RoleofTET2andASXL1mutations in the pathogenesis of myeloproliferative neoplasms[J].Hematol Oncol Clin North Am, 2012, 26(5):1053-64.
[6]James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera[J]. Nature,2005, 434(7037):1144-1148.
[7]Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2[J]. N Engl J Med, 2013, 369(25):2391-2405.
[8]Defour JP, Chachoua I, Pecquet C, et al. Oncogenic activation of MPL/thrombopoietin receptor by 17 mutations at W515:implications for myeloproliferative neoplasms[J]. Leukemia, 2016, 30(5):1214-1216.
[9]白洁,薛艳萍,张磊,等.干扰素α-2b治疗真性红细胞增多症及其继发骨髓纤维化患者分子生物学反应的研究[J].中国实验血液学杂志, 2011, 19(2):444-449.
[10]BaiJ,XueY,YeL,etal.Riskfactorsoflong-termincidencesof thrombosis,myelofibrosisandevolutionintomalignancein polycythemia vera:a single center experience from China[J]. Int J Hematol, 2008, 88(5):530-535.
[11]Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferativeneoplasms:criticalconceptsandmanagement recommendationsfromEuropeanLeukemiaNet[J].JClinOncol,2011, 29(6):761-770.
[12]TefferiA.Primarymyelofibrosis:2017updateondiagnosis,riskstratification, and management[J]. Am J Hematol, 2016, 91(12):1262-1271.
[13]Barbui T, Passamonti F, Accorsi P, et al. Evidence-and consensus-based recommendations for phlebotomy in polycythemia vera[J]. Leukemia,2018, 32(9):2077-2081.
[14]Mesa RA, Jamieson C, Bhatia R, et al. NCCN Guidelines Insights:Myeloproliferative Neoplasms, Version 2.2018[J]. J Natl Compr Canc Netw, 2017, 15(10):1193-1207.
[15]Bai J, Zhang L, Hu X, et al. Investigation of the influence of body weight index to the result of therapeutic erythrocytapheresis in patients with polycythemia vera[J]. Transfus Apher Sci, 2012, 47(3):295-299.
[16]Di Nisio M, Barbui T, Di Gennaro L, et al. The haematocrit and platelet target in polycythemia vera[J]. Br J Haematol, 2007, 136(2):249-259.
[17]Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia:2019 update on diagnosis, risk-stratification and management[J]. Am J Hematol, 2018.[Epub ahead of print]
[18]Kc D, Falchi L, Verstovsek S. The underappreciated risk of thrombosis and bleeding in patients with myelofibrosis:a review[J]. Ann Hematol,2017, 96(10):1595-1604.
[19]Edahiro Y, Gotoh A, Inano T, et al. Transfusion independence achieved with pomalidomide therapy in a patient with primary myelofibrosis[J].Rinsho Ketsueki, 2018, 59(3):323-325.
[20]BaiJ,ShiH,AiL,etal.Survivalandprognosisofpatientswith polycythemiavera:astudyof816patientsinasingleChinese center[J]. Zhonghua Yi Xue Za Zhi, 2015, 95(18):1364-1368.
[21]HansenIO,S?rensenAL,HasselbalchHC.Hasselbalch,Second malignanciesinhydroxyureaandinterferon-treatedPhiladelphianegativemyeloproliferativeneoplasms[J].EurJHaematol,2017,98(1):75-84.
[22]Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2ainpatientswithessentialthrombocythaemiaorpolycythaemia vera:a post-hoc, median 83 month follow-up of an open-label, phase 2trial[J]. Lancet Haematol, 2017, 4(4):e165-e175.
[23]金洁,杜欣,周道斌,等. JAK抑制剂芦可替尼治疗中国骨髓纤维化患者的疗效和安全性:A2202随访一年结果[J].中华血液学杂志, 2016, 37(10):858-863.
[24]GriesshammerM,SaydamG,PalandriF,etal.Ruxolitinibforthe treatmentofinadequatelycontrolledpolycythemiaverawithout splenomegaly:80-week follow-up from the RESPONSE-2 trial[J]. Ann Hematol, 2018, 97(9):1591-1600.
[25]Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide[J]. Blood,2017, 130(17):1889-1897.
[26]Masarova L, Verstovsek S, Hidalgo-Lopez JE, et al. A phase 2 study ofruxolitinibincombinationwithazacitidineinpatientswith myelofibrosis[J]. Blood, 2018. 132(16):1664-1674.
[27]GerdsA,SuD,MartynovaA,etal.RuxolitinibRechallengeCan Improve Constitutional Symptoms and Splenomegaly in Patients With Myelofibrosis:ACaseSeries[J].ClinLymphomaMyelomaLeuk,2018. 18(11):e463-e468.
[28]Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis[J]. Leukemia, 2017, 31(3):775.
[29]Kr?ger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis:a consensus process by an EBMT/ELN international working group[J].Leukemia, 2015, 29(11):2126-2133.
[30]VerstovsekS,MesaRA,GotlibJ,etal.Adouble-blind,placebocontrolled trial of ruxolitinib for myelofibrosis[J]. N Engl J Med, 2012,366(9):799-807.
[31]HarrisonC,KiladjianJJ,Al-AliHK,etal.JAKinhibitionwith ruxolitinib versus best available therapy for myelofibrosis[J]. N Engl J Med, 2012, 366(9):787-798.
[32]Vannucchi AM. Ruxolitinib versus standard therapy for the treatment of polycythemia vera[J]. N Engl J Med, 2015, 372(5):426-435.
[33]Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatmentofinadequatelycontrolledpolycythaemiaverawithout splenomegaly(RESPONSE-2):a randomised, open-label, phase 3b study[J]. Lancet Oncol, 2017, 18(1):88-99.
[34]Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroidrefractor ygraft-versus-hostdiseaseafterallogeneicstemcell transplantation:a multicenter survey[J]. Leukemia, 2015, 29(10):2062-2068.
[35]CaocciG,MurgiaF,PoddaL,etal.ReactivationofhepatitisB virusinfectionfollowingruxolitinibtreatmentinapatientwith myelofibrosis[J]. Leukemia, 2014, 28(1):225-227.
[36]TefferiA.Primarymyelofibrosis:2019updateondiagnosis,riskstratification and management[J]. Am J Hematol, 2018.[Epub ahead of print]
[2]Breccia M, Andriani A3, Montanaro M, et al. Ruxolitinib in clinical practice for primary and secondary myelofibrosis:an analysis of safety and efficacy of Gruppo Laziale of Ph-negative MPN[J]. Ann Hematol,2017, 96(3):387-391.
[3]Finazzi G. Ruxolitinib in ET:not all MPN are equal[J]. Blood, 2017,130(17):1873-1874.
[4]Ortmann CA, Kent DG, Nangalia J, et al. Effect of mutation order on myeloproliferative neoplasms[J]. N Engl J Med, 2015, 372(7):601-612.
[5]Abdel-WahabO,TefferiA,LevineRL.RoleofTET2andASXL1mutations in the pathogenesis of myeloproliferative neoplasms[J].Hematol Oncol Clin North Am, 2012, 26(5):1053-64.
[6]James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera[J]. Nature,2005, 434(7037):1144-1148.
[7]Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2[J]. N Engl J Med, 2013, 369(25):2391-2405.
[8]Defour JP, Chachoua I, Pecquet C, et al. Oncogenic activation of MPL/thrombopoietin receptor by 17 mutations at W515:implications for myeloproliferative neoplasms[J]. Leukemia, 2016, 30(5):1214-1216.
[9]白洁,薛艳萍,张磊,等.干扰素α-2b治疗真性红细胞增多症及其继发骨髓纤维化患者分子生物学反应的研究[J].中国实验血液学杂志, 2011, 19(2):444-449.
[10]BaiJ,XueY,YeL,etal.Riskfactorsoflong-termincidencesof thrombosis,myelofibrosisandevolutionintomalignancein polycythemia vera:a single center experience from China[J]. Int J Hematol, 2008, 88(5):530-535.
[11]Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferativeneoplasms:criticalconceptsandmanagement recommendationsfromEuropeanLeukemiaNet[J].JClinOncol,2011, 29(6):761-770.
[12]TefferiA.Primarymyelofibrosis:2017updateondiagnosis,riskstratification, and management[J]. Am J Hematol, 2016, 91(12):1262-1271.
[13]Barbui T, Passamonti F, Accorsi P, et al. Evidence-and consensus-based recommendations for phlebotomy in polycythemia vera[J]. Leukemia,2018, 32(9):2077-2081.
[14]Mesa RA, Jamieson C, Bhatia R, et al. NCCN Guidelines Insights:Myeloproliferative Neoplasms, Version 2.2018[J]. J Natl Compr Canc Netw, 2017, 15(10):1193-1207.
[15]Bai J, Zhang L, Hu X, et al. Investigation of the influence of body weight index to the result of therapeutic erythrocytapheresis in patients with polycythemia vera[J]. Transfus Apher Sci, 2012, 47(3):295-299.
[16]Di Nisio M, Barbui T, Di Gennaro L, et al. The haematocrit and platelet target in polycythemia vera[J]. Br J Haematol, 2007, 136(2):249-259.
[17]Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia:2019 update on diagnosis, risk-stratification and management[J]. Am J Hematol, 2018.[Epub ahead of print]
[18]Kc D, Falchi L, Verstovsek S. The underappreciated risk of thrombosis and bleeding in patients with myelofibrosis:a review[J]. Ann Hematol,2017, 96(10):1595-1604.
[19]Edahiro Y, Gotoh A, Inano T, et al. Transfusion independence achieved with pomalidomide therapy in a patient with primary myelofibrosis[J].Rinsho Ketsueki, 2018, 59(3):323-325.
[20]BaiJ,ShiH,AiL,etal.Survivalandprognosisofpatientswith polycythemiavera:astudyof816patientsinasingleChinese center[J]. Zhonghua Yi Xue Za Zhi, 2015, 95(18):1364-1368.
[21]HansenIO,S?rensenAL,HasselbalchHC.Hasselbalch,Second malignanciesinhydroxyureaandinterferon-treatedPhiladelphianegativemyeloproliferativeneoplasms[J].EurJHaematol,2017,98(1):75-84.
[22]Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2ainpatientswithessentialthrombocythaemiaorpolycythaemia vera:a post-hoc, median 83 month follow-up of an open-label, phase 2trial[J]. Lancet Haematol, 2017, 4(4):e165-e175.
[23]金洁,杜欣,周道斌,等. JAK抑制剂芦可替尼治疗中国骨髓纤维化患者的疗效和安全性:A2202随访一年结果[J].中华血液学杂志, 2016, 37(10):858-863.
[24]GriesshammerM,SaydamG,PalandriF,etal.Ruxolitinibforthe treatmentofinadequatelycontrolledpolycythemiaverawithout splenomegaly:80-week follow-up from the RESPONSE-2 trial[J]. Ann Hematol, 2018, 97(9):1591-1600.
[25]Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide[J]. Blood,2017, 130(17):1889-1897.
[26]Masarova L, Verstovsek S, Hidalgo-Lopez JE, et al. A phase 2 study ofruxolitinibincombinationwithazacitidineinpatientswith myelofibrosis[J]. Blood, 2018. 132(16):1664-1674.
[27]GerdsA,SuD,MartynovaA,etal.RuxolitinibRechallengeCan Improve Constitutional Symptoms and Splenomegaly in Patients With Myelofibrosis:ACaseSeries[J].ClinLymphomaMyelomaLeuk,2018. 18(11):e463-e468.
[28]Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis[J]. Leukemia, 2017, 31(3):775.
[29]Kr?ger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis:a consensus process by an EBMT/ELN international working group[J].Leukemia, 2015, 29(11):2126-2133.
[30]VerstovsekS,MesaRA,GotlibJ,etal.Adouble-blind,placebocontrolled trial of ruxolitinib for myelofibrosis[J]. N Engl J Med, 2012,366(9):799-807.
[31]HarrisonC,KiladjianJJ,Al-AliHK,etal.JAKinhibitionwith ruxolitinib versus best available therapy for myelofibrosis[J]. N Engl J Med, 2012, 366(9):787-798.
[32]Vannucchi AM. Ruxolitinib versus standard therapy for the treatment of polycythemia vera[J]. N Engl J Med, 2015, 372(5):426-435.
[33]Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatmentofinadequatelycontrolledpolycythaemiaverawithout splenomegaly(RESPONSE-2):a randomised, open-label, phase 3b study[J]. Lancet Oncol, 2017, 18(1):88-99.
[34]Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroidrefractor ygraft-versus-hostdiseaseafterallogeneicstemcell transplantation:a multicenter survey[J]. Leukemia, 2015, 29(10):2062-2068.
[35]CaocciG,MurgiaF,PoddaL,etal.ReactivationofhepatitisB virusinfectionfollowingruxolitinibtreatmentinapatientwith myelofibrosis[J]. Leukemia, 2014, 28(1):225-227.
[36]TefferiA.Primarymyelofibrosis:2019updateondiagnosis,riskstratification and management[J]. Am J Hematol, 2018.[Epub ahead of print]