达沙替尼-博纳吐单抗治疗成人ph+急性淋巴细胞白血病

2020-10-23 网络 网络

自ABL特异性酪氨酸激酶抑制剂问世以来,成人费城染色体(Ph)阳性的急性淋巴细胞白血病(ALL)的预后得到了显著改善。 无论是否进行全身化疗,这些药物的使用都可以使大多数患者获得完全的血液学缓解。

自ABL特异性酪氨酸激酶抑制剂问世以来,成人费城染色体(Ph)阳性的急性淋巴细胞白血病(ALL)的预后得到了显著改善。 无论是否进行全身化疗,这些药物的使用都可以使大多数患者获得完全的血液学缓解。 在ALL的治疗过程中,MRD(最小残留病灶)的减少与治愈机会的增加呈正相关。 基于此,在过去的15年中,GIMEMA(Gruppo Italiano Malattie Ematologiche dell’Adulto)合作试验小组采用了无化疗诱导方案(应用糖皮质激素预处理7天),首先对所有参与试验的患者进行集中评估,以确认是否存在BCR-ABL1基因融合,然后对Ph阳性患者进行诱导,使用酪氨酸激酶抑制剂(加糖皮质激素)。实验中,94-100%的患者获得了完全的血液学缓解,且无论年龄大小,在诱导期几乎没有死亡病例。

该试验小组的单组二期试验在诱导后加双特异性抗CD3和抗CD19单克隆抗体博纳吐进行巩固。 达沙替尼是ABL酪氨酸激酶的第二代抑制剂,相比伊马替尼更为有效。 而博纳吐这一双功能单抗一方面可以激活抗CD3基团的T细胞,一方面可以与抗CD19基团的肿瘤细胞结合,从而促进其细胞毒性的作用。

试验纳入的63例患者(中位年龄为54岁;范围为24至82岁)中,完全缓解者占98%。 达沙替尼诱导治疗结束时(第85天),有29%的患者出现了分子反应,而经过两轮博纳吐单抗的治疗后,这一百分比增加到60%。博纳吐单抗增加一个周期,具有分子反应的患者百分比也进一步增加。 中位随访18个月,总体生存率为95%,无病生存率为88%。 在患有IKZF1缺失加上其他遗传畸变(CDKN2A或CDKN2B,PAX5或两者[即IKZF1plus])的患者中,无病生存率则较低。 在诱导治疗期间,试验小组在6例MRD增加的患者身上检测到了ABL1的突变,并且所有这些突变均已通过博纳吐单抗清除。 复发病例共有6例。 总体上共有21个3级或更高级别的不良反应事件。其中24例患者接受了异体干细胞移植移植,其中1例死亡与移植有关(4%)。

诱导治疗结束时及每次应用博纳吐单抗后的分子应答

 

所有患者的总生存率(图A),无病生存(图B)和复发(图C)的百分比。

 

结论:在该试验中,成年Ph+ALL患者可受益于无化学诱导和巩固方案,先用达沙替尼,再用博纳吐单抗。 这种药物结合应用的方案与完全血液学反应和分子反应的高发生率以及18个月的存活率有关。

 

Dasatinib–Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults

Robin Foà, M.D.,Renato Bassan, M.D.

October 22, 2020
N Engl J Med 2020; 383:1613-1623
DOI: 10.1056/NEJMoa2016272

 

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