达沙替尼治疗原发性骨髓纤维化21例多中心前瞻性临床研究
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摘要
目的探究达沙替尼治疗原发性骨髓纤维化(PMF)的有效性及安全性。方法共纳入2015-06-01至2017-10-01就诊于河南省7所医院的21例PMF患者,男8例,女13例,中位年龄65岁,口服达沙替尼50 mg,每日2次。用脾脏Ⅰ线长度评估脾脏大小,骨髓增殖性肿瘤(MPN)10症状评分表对患者进行症状评分。结果 21例患者中,17例在达沙替尼治疗1周后观察到显著的脾脏回缩,治疗5～8周达到较稳定的缩脾状态,脾脏较基线缩小2/3左右;3例分别在使用达沙替尼治疗16、18、19周后,骨髓纤维化程度由3级降至1级;达沙替尼治疗前21例患者MPN10症状评分的中位数为32.00 (28.50,38.50),治疗后为23.00 (17.5,28.5),达沙替尼治疗后MPN10症状评分较治疗前明显下降;患者治疗过程中尚未观察到细胞遗传学效应。达沙替尼治疗过程中的不良事件包括贫血、血小板减低、体液潴留、电解质紊乱、疲劳、感染等,发生率>40%,仅有2例因出现心包积液所致呼吸困难而停药。结论达沙替尼治疗对PMF患者有效,其疗效主要表现在缩小脾脏体积、改善生活质量、部分逆转骨髓纤维化,有望恢复骨髓造血,常见的不良反应多为1～2级,多可耐受。
Objective To explore the efficacy and safety of dasatinib in the treatment of patients with primary myelofibrosis(PMF).Methods A total of 21 patients with PMF treated in multicenter were included,8 men and 13 women,with a median age of 65(48-78) years.Patients were administered 50 mg of dasatinib twice a day.The splenomegaly measurement was represented by line"1".The Myeloproliferative Neoplasm Symptom Assessment Form(MPN10) was used to assess the symptoms.Results After an average of 1 week of dasatinib treatment,17 of the 21 patients were observed significant shrinkage of the spleen volume,and the spleen volume reached a stable state in the 5-8 weeks,a reduction of about 2/3 in spleen volume compared to the baseline value.After 16 weeks,18 weeks and 19 weeks of dasatinib treatment,the degree of myelofibrosis in 3 patients was reduced from grade 3 to grade 1.The median MPN10 symptom score of 21 patients was 32.00(28.50,38.50) before treatment and 23.00(17.5,28.5) after treatment.MPN10 symptom score was significantly lower after dasatinib treatment.Cytogenetic responses had not been observed during the treatment.Adverse events with a incidence of more than 40% in the course of dasatinib treatment included anemia,thrombocytopenia,fluid retention,electrolyte disorders,fatigue,infection and so on,only 2 patients stopped taking drugs due to dyspnea caused by pericardial effusion.Conclusion Dasatinib was effective in the treatment of PMF.The therapeutic effects of dasatinib were mainly manifested in reducing the volume of the spleen,improving the quality of life and partly reversing the myelofibrosis,bone marrow hematopoiesis was expected to be restored.Most of the common adverse reactions were grade 1-2 and could be tolerated..
Objective To explore the efficacy and safety of dasatinib in the treatment of patients with primary myelofibrosis(PMF).Methods A total of 21 patients with PMF treated in multicenter were included,8 men and 13 women,with a median age of 65(48-78) years.Patients were administered 50 mg of dasatinib twice a day.The splenomegaly measurement was represented by line"1".The Myeloproliferative Neoplasm Symptom Assessment Form(MPN10) was used to assess the symptoms.Results After an average of 1 week of dasatinib treatment,17 of the 21 patients were observed significant shrinkage of the spleen volume,and the spleen volume reached a stable state in the 5-8 weeks,a reduction of about 2/3 in spleen volume compared to the baseline value.After 16 weeks,18 weeks and 19 weeks of dasatinib treatment,the degree of myelofibrosis in 3 patients was reduced from grade 3 to grade 1.The median MPN10 symptom score of 21 patients was 32.00(28.50,38.50) before treatment and 23.00(17.5,28.5) after treatment.MPN10 symptom score was significantly lower after dasatinib treatment.Cytogenetic responses had not been observed during the treatment.Adverse events with a incidence of more than 40% in the course of dasatinib treatment included anemia,thrombocytopenia,fluid retention,electrolyte disorders,fatigue,infection and so on,only 2 patients stopped taking drugs due to dyspnea caused by pericardial effusion.Conclusion Dasatinib was effective in the treatment of PMF.The therapeutic effects of dasatinib were mainly manifested in reducing the volume of the spleen,improving the quality of life and partly reversing the myelofibrosis,bone marrow hematopoiesis was expected to be restored.Most of the common adverse reactions were grade 1-2 and could be tolerated..
引文
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[13]Cruz FF,Horta LF,Maia Lde A,et al.Dasatinib reduces lung inflammation and fibrosis in acute experimental silicosis[J].PLoSOne,2016,11(1):e0147005.
[2]Mohamed M,Beamish M,Grabek I.Chronic myeloid leukaemia masquerading as primary myelofibrosis[J].Pathology,2014,46(1):75-77.
[3]Verstovsek S,Tefferi A,Cortes J,et al.Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases,including systemic mastocytosis[J].Clin Cancer Res,2008,14(12):3906-3915.
[4]Tefferi A,Vardiman J W.Classification and diagnosis of myeloproliferative neoplasms:the 2008 World Health Organization criteria and point-of-care diagnostic algorithms[J].Leukemia,2008,22(1):14-22.
[5]Giovanni B,Dominique B,Jean B,et al.Response criteria for myelofibrosis with myeloid metaplasia:results of an initiative of the European Myelofibrosis Network(EUMNET)[J].Blood,2005,106(8):2849-2853.
[6]Trotti A.The evolution and application of toxicity criteria[J].Semin Radiat Oncol,2002,12(suppl):1-3.
[7]Verstovsek S,Mesa RA,Gotlib J,et al.A double-blind,placebocontrolled trial of ruxolitinib for myelofibrosis[J].N Engl J Med,2012,366(9):799-807.
[8]Harrison C,Kiladjian JJ,AI-Ali HK,et al.JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis[J].N Engl JMed,2012,366(9):787-798.
[9]Ye JY,Chan GC,Yang M,et al.Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway[J].Haematologica,2010,95(10):1745-1753.
[10]Shu LL,Yang M.Imatinib in treatment of thrombocythemia and other myeloproliferative diseases[J].J Exp Hematol,2012,20(20):1507-1512.
[11]O'Hare T,Walters DK,Stoffregen EP,et al.In vitro activity of BcrAbl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants[J].Cancer Res,2005,65(11):4500-4505.
[12]Yilmaz O,Oztay F,Kayalar O.Dasatinib attenuated bleomycin-induced pulmonary fibrosis in mice[J].Growth Factors,2015,33:366-375.
[13]Cruz FF,Horta LF,Maia Lde A,et al.Dasatinib reduces lung inflammation and fibrosis in acute experimental silicosis[J].PLoSOne,2016,11(1):e0147005.