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达沙替尼-倍林妥莫双抗治疗成人费城染色体阳性急性淋巴细胞白血病
Dasatinib–Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults


Robin Foà ... 肿瘤 • 2020.10.22
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全球首次实现Ph+ALL不化疗模式——靶向联合免疫治疗“大显神威”

 

主鸿鹄

浙江大学医学院附属第一医院血液科

 

费城染色体(philadelphiachromosome,Ph)是成人急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)最常见的染色体异常,为22号染色体长臂的BCR基因易位至9号染色体长臂上的ABL基因,形成BCR-ABL融合基因。Ph+ALL复发率高,无病生存时间短且预后较差。异基因造血干细胞移植(allo-HSCT)一直被认为是治愈该疾病的唯一办法。靶向BCR-ABL融合基因的酪氨酸激酶抑制剂(TKI)的出现使Ph+ALL患者疗效及预后得到显著提高。尽管TKI联合化疗在治疗取得显著疗效,但频繁的复发和耐药仍然是临床治疗亟待解决的问题。

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摘要


背景

酪氨酸激酶抑制剂已改善了费城染色体阳性急性淋巴细胞白血病(ALL)患者的结局。分子学缓解是主要治疗目标。

 

方法

我们在新诊断为费城染色体阳性ALL的成人患者(无年龄上限)中对一线治疗开展了一项2期单组试验。本试验给予患者达沙替尼+糖皮质激素治疗,之后给予两个周期的倍林妥莫双抗(blinatumomab)治疗。主要终点是治疗后骨髓内的持续分子学缓解。

 

结果

在本试验纳入的63例患者(中位年龄,54岁;范围,24~82)中,98%达到了完全缓解。达沙替尼诱导治疗结束时(第85日),29%的患者达到了分子学缓解,经过两个周期倍林妥莫双抗治疗后,这一百分比提高至60%;经过更多周期倍林妥莫双抗治疗后,达到分子学缓解的患者百分比进一步提高。中位随访18个月后,总生存率为95%,无病生存率为88%;在有IKZF1缺失+其他遗传畸变(CDKN2ACDKN2BPAX5或这两者[即IKZF1plus])的患者中,无病生存率较低。在诱导治疗期间微小残留病变增多的6例患者中,我们检测到ABL1突变,而且所有这些突变均被倍林妥莫双抗清除。有6例患者复发。本试验共记录到21起3级或更高级别的不良事件。共计24例患者接受了异基因干细胞移植,有1例死亡与移植相关(4%)。

 

结论

在费城染色体阳性ALL成人患者中,基于靶向治疗和免疫治疗策略,采用达沙替尼和倍林妥莫双抗,不包含化疗的诱导和巩固一线治疗达到了较高的分子学缓解率和生存率,且3级或更高级别毒性作用很少(由意大利癌症研究会[Associazione Italiana per la Ricerca sul Cancro]等资助,GIMEMA LAL2116 D-ALBA在EudraCT注册号为2016-001083-11,在ClinicalTrials.gov注册号为NCT02744768)。





作者信息

Robin Foà, M.D., Renato Bassan, M.D., Antonella Vitale, M.D., Loredana Elia, M.D., Alfonso Piciocchi, M.S., Maria-Cristina Puzzolo, Ph.D., Martina Canichella, M.D., Piera Viero, M.D., Felicetto Ferrara, M.D., Monia Lunghi, M.D., Francesco Fabbiano, M.D., Massimiliano Bonifacio, M.D., Nicola Fracchiolla, M.D., Paolo Di Bartolomeo, M.D., Alessandra Mancino, M.S., Maria-Stefania De Propris, Ph.D., Marco Vignetti, M.D., Anna Guarini, Ph.D., Alessandro Rambaldi, M.D., and Sabina Chiaretti, M.D., Ph.D. for the GIMEMA Investigators*
From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell’Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology–Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) — all in Italy. Address reprint requests to Dr. Foà at the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Via Benevento 6, 00161 Rome, Italy, or at rfoa@bce.uniroma1.it. *A complete list of the GIMEMA investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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