非霍奇金淋巴瘤的治疗研究进展
Research Progress in the Treatment of Non Hodgkin’s Lymphoma
DOI: 10.12677/jcpm.2024.32069, PDF, HTML, XML, 下载: 37  浏览: 73 
作者: 周彦云:青海大学研究生院,青海 西宁;罗 伟*:青海大学附属医院血液科,青海 西宁
关键词: 淋巴瘤B细胞非霍奇金淋巴瘤靶向治疗药物治疗Lymphoma B Cell Non Hodgkin’s Lymphoma Targeted Therapy Drug Therapy
摘要: 非霍奇金淋巴瘤(NHL)代表一组异质性淋巴衍生恶性肿瘤,从惰性到高度侵袭性不等。根据肿瘤细胞的来源,本病可分为B细胞淋巴瘤、T/NK细胞淋巴瘤。在B-NHL复发/难治性患者中,挽救性化疗和自体干细胞移植能够治愈50%的患者,而另一半患者的结果令人沮丧,中位总生存期不到12个月。随着非霍奇金淋巴瘤(NHL)治疗的进步,为了提高B-NHL患者的生存率,靶向药物疗法,正在彻底改变B细胞非霍奇金淋巴瘤(B-NHL)的治疗格局。本文就近年来B-NHLs靶向药物的治疗研究作一简要综述。
Abstract: Non Hodgkin’s lymphoma (NHL) represents a group of heterogeneous lymphoid derived malignant tumors, ranging from inert to highly invasive. According to the source of tumor cells, this disease can be divided into B-cell lymphoma and T/NK cell lymphoma. In B-NHL recurrent/refractory patients, salvage chemotherapy and autologous stem cell transplantation can cure 50% of patients, while the results of the other half of patients are disappointing, with a median overall survival of less than 12 months. With the advancement of non Hodgkin’s lymphoma (NHL) treatment, in order to improve the survival rate of B-NHL patients. Targeted drug therapy is completely changing the treatment pattern of B-cell non Hodgkin’s lymphoma (B-NHL). This article provides a brief review of recent research on targeted drug therapy for B-NHLs.
文章引用:周彦云, 罗伟. 非霍奇金淋巴瘤的治疗研究进展[J]. 临床个性化医学, 2024, 3(2): 472-479. https://doi.org/10.12677/jcpm.2024.32069

1. 引言

B细胞非霍奇金淋巴瘤(B-NHL)是一组异质性肿瘤,包括40多种亚型。最常见的类型包括侵袭性弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma, DLBCL)和惰性滤泡性淋巴瘤(indolent follicular lymphoma, FL)。在大多数B-NHL患者中,这些不同的B细胞恶性肿瘤可以通过常规化疗进行治疗[1]。但在一项利妥昔单抗治疗的复发弥漫性大B细胞淋巴瘤(DLBCL)的标准治疗方案中仍有30%患者出现复发/难治性的疾病,导致预后普遍较差[2]。从而降低患者的生存率和整体耐受性。只有50%的复发/难治性患者符合自体干细胞移植(autogenus stem cell transplantation, ASCT)挽救治疗的条件,ASCT后的复发发生率为35%~50% [3]。这些患者的中位总生存期(OS)非常短,为10个月,需要创新疗法来提高总缓解率(ORR)并最终提高OS。靶向药物疗法,正在彻底改变B细胞非霍奇金淋巴瘤(B-NHL)的治疗格局。本文就近年来B-NHLs靶向药物的治疗研究作一简要综述。

2. BTK抑制剂

B细胞非霍奇金淋巴瘤是由一组异质性恶性肿瘤组成。从历史上看,治疗的支柱是细胞毒性化疗,但近几十年来,靶向治疗已被纳入早期的一线治疗中。B细胞受体(BCR)信号通路与多种B细胞恶性肿瘤的发病机制有关。最近,已经开发出许多药物来靶向BCR通路的各种成分。其中一个关键靶点是布鲁顿酪氨酸激酶(BTK),它是早期BCR信号通路的组成部分。在正常B细胞中,BTK的激活(通过其磷酸化反映)触发下游事件,并最终激活核因子κB (NF-κB)通路,从而增加B细胞的存活、增殖、分化为浆细胞和随后的抗体产生[4] [5]。这一途径的药物改变了一线和复发/难治性(R/R)环境中的管理格局。目前已有五种BTKi被批准用于人类,包括伊布替尼、阿卡替尼、泽布替尼、替布替尼和奥布替尼。第一代BTKi伊布替尼。自2013年以来,它已被间歇性批准用于治疗MCL、CLL/SLL、慢性移植物抗宿主病(GVHD)、WM和MZL的单药治疗或联合治疗[6]。伊布替尼首次被批准用于治疗MCL,基于II期数据显示,在复发/难治性情况下的总缓解率(ORR)为68%。该缓解率接近高度骨髓抑制挽救性化疗[7]。一项III期PHOENIX试验评估了伊布替尼与安慰剂联合一线R-CHOP治疗非GCB亚型疾病患者,但未能显示伊布替尼联合R-CHOP的总生存获益。然而,该研究确实在<60岁人群中显示出无事件生存期(event free survival, EFS)、PFS和OS获益[8]。在老年患者群体中缺乏益处的部分原因归因于联合治疗的毒性增加,从而限制了最佳CIT剂量。后来,对年轻患者进行更深入的亚组分析显示,MCD和N1亚型的ABC淋巴瘤在伊布替尼联合R-CHOP组的3年内EFS和OS为100%,而单独使用R-CHOP组为42.9%和50% [9]。第二代BTKi旨在最大限度地提高效果和选择性BTK占有率,同时降低对脱靶激酶的活性。这些抑制剂的代表包括阿卡替尼(ACP-196)、泽布替尼(BGB-3111)、替布替尼(ONO/GS-4059)和奥布替尼(ICP-022)。体外研究表明,阿卡替尼的靶点特异性高于伊布替尼,对其他激酶成员ITK、TXK、BMX和TEC的选择性分别为323倍、94倍、19倍和9倍[10]。同样,一项III期研究的数据显示,与伊布替尼相比,泽布替尼治疗WM患者的反应更好,毒性更低[11]。奥布替尼(ICP-022)在人体内长期给药后显示出奥布替尼优异的安全性和耐受性。2020年,奥布替尼在中国获得有条件批准,用于治疗既往接受过至少一种治疗的MCL和CLL/SLL患者[12]。然而,替布替尼对TEC激酶的选择性比伊布替尼低约2.4倍[13]。替布替尼同时占据BTK和TEC可显著抑制巨噬细胞集落刺激因子(M-CSF)和RANKL驱动的破骨细胞分化和骨质流失[14]。从以上数据来看,BTK抑制剂在治疗中取得了不错的效果,目前对BTK抑制剂的相关研究仍在进行中。

3. CD20单抗

CD20是B细胞恶性肿瘤中公认的治疗靶点[15]。表达从前B细胞阶段开始,一直持续到最终分化为浆细胞。这种模式,以及恶性B细胞上CD20的一致和高水平表达,使CD20成为治疗靶点[16]。CD20单抗主要有利妥昔单抗、奥妥珠单抗(GA101)、奥法妥尤单抗和乌利妥昔单抗。1990年代,随着重组嵌合鼠/人I型抗CD20单克隆抗体(mAb)利妥昔单抗(Rituximab/® MABTHERA®)靶向治疗的引入,CD20阳性B细胞恶性肿瘤患者的前景有所改善[17]。自1997年首次获批以来,利妥昔单抗彻底改变了B细胞恶性肿瘤的治疗。它既可作为单药治疗和联合治疗,也可用于诱导和复发,也可作为维持治疗[18]。利妥昔单抗的早期试验侧重于复发或难治性CD20阳性低级别FL患者的单药治疗,缓解率为48% [17]。利妥昔单抗与伊布替尼联合研究,结果显示在R/R MCL患者中安全且可耐受。在一项针对复发/难治MCL的开放标签2期试验中,利妥昔单抗联合伊布替尼的ORR和CR分别为88%和44%,反应较高[19]。Obinutuzumab (GA101)是一种靶向CD20的人源化抗体,已在MCL临床前模型中证明有效[20]。该抗体在Fc部分具有非岩藻糖基化糖,旨在克服对利妥昔单抗的耐药机制。在GAUGUIN 2期试验中,Obinutuzumab作为复发/难治性MCL的单药治疗(n = 15)显示ORR为27% [21]。随后,在复发和未经治疗的MCL患者(n = 48)中研究了obinutuzumab与伊布替尼和维奈托克的联合治疗(OAsIs;一项1/2期试验)。该联合疗法耐受性良好,复发患者的CR为67%,未经治疗的MCL患者的CR为86.6% [22]。对于伊布替尼耐药的MCL患者,这种联合治疗可被视为一种可能的挽救疗法。

4. 蛋白酶体抑制剂

26S蛋白酶体是一种大型的ATP依赖性蛋白水解机器,作为泛素蛋白酶体系统(UPS)的一部分,代表了真核细胞通过选择性破坏错误折叠或受损的多肽来确保细胞内蛋白质质量的最终机制[23]。这种用泛素标记的有害蛋白质的有序降解过程对正常的细胞周期和功能至关重要,保护细胞免受热休克或氧化应激,而蛋白酶体途径的抑制会导致细胞周期停滞和细胞凋亡。由于UPS的失调可能在肿瘤进展、耐药性和免疫监视改变中发挥作用,蛋白酶体已成为癌症的重要和新型治疗靶点[24]。蛋白酶体抑制剂(PIs)在过去十年中已成为治疗多发性骨髓瘤(MM)和套细胞淋巴瘤(MCL)的广泛使用药物。p27蛋白酶体降解增加与MCL中OS降低有关[25]。MCL的特征是NF-κB通路的组成型激活[26]。IκB激酶抑制剂在体外诱导MCL细胞凋亡的能力证实了NF-κB作为该病的治疗靶点[27]。SWOG试验进一步表明,在既往未经治疗的MCL患者中,与单独化疗方案相比,硼替佐米联合化疗后硼替佐米维持治疗的2年PFS率提高了一倍(62% vs 30%) [28]。分子异质性是弥漫性大B细胞淋巴瘤(DLBCL)的一个公认特征,在核型、基因组和转录组亚型之间结局各不相同[29] [30]。临床试验已经测试了额外的靶向治疗是否可以通过调节恶性B细胞中的异常细胞内通路来改善结果[31] [32]。REMoDL-B III期适应性试验比较了利妥昔单抗、环磷酰胺、多柔比星、长春新碱和泼尼松龙(R-CHOP)与R-CHOP + 硼替佐米(RB-CHOP)在非霍奇金淋巴瘤(DLBCL)患者中的疗效。在登记的1077名患者中,有801名被确定为活化B细胞(ABC)、生发中心B细胞或MHG淋巴瘤。中位随访64个月时,硼替佐米对PFS或OS没有总体获益(5年PFS风险比[HR],0.81;P = 0.85;OS HR,0.86;P = 0.32)。然而,RB-CHOP后ABC淋巴瘤的PFS和OS有所改善:R-CHOP组的5年OS为67%,RB-CHOP组为80% (HR, 0.58; 95% CI, 0.35~0.95; P = 0.32)。MHG淋巴瘤的5年PFS更高:29% vs 55% (HR, 0.46; 95% CI, 0.26~0.84)。ABC和MHG DLBCL患者可能受益于在初始治疗中将硼替佐米添加到R-CHOP中[33]。这项实验从OS/PFS证明了蛋白酶抑制剂对B-NHLs有着较好的效果。

5. PI3K/AKT/mTOR通路抑制剂

磷脂酰肌醇3-激酶(PI3K)是细胞内信号转导酶家族,可以将磷酸基团连接到膜包埋磷脂酰肌醇(PI)肌醇部分的3’-羟基。PI3K已被证明在细胞增殖、生长、存活、运动和代谢中发挥重要作用。近年来,PI3K信号通路已成为大量药物发现和开发工作的主要焦点。选择性(PI3K)抑制剂已被批准用于治疗慢性淋巴细胞白血病 (CLL)/小淋巴细胞淋巴瘤(SLL)和惰性非霍奇金淋巴瘤(iNHL),例如滤泡性淋巴瘤和边缘区淋巴瘤。四种选择性PI3K抑制剂已获得FDA加速批准,用于治疗复发/难治性(R/R)CLL和/或iNHL患者[34]。PI3K的催化亚基(p110)以四种亚型存在:αβδγ。虽然αβ亚型几乎无处不在,但δγ亚型优先在白细胞中表达,并在B细胞、T细胞和髓系细胞功能的适应性和先天免疫反应中发挥重要作用[35] [36] [37]。PI3K‐δ抑制包括对恶性B细胞的多种关键作用,包括阻断肿瘤微环境介导的恶性B细胞增殖和迁移,以及抑制肿瘤细胞来源的趋化因子分泌[38]。此外,PI3K-γ抑制被认为通过抑制T细胞和巨噬细胞向微环境衍生趋化因子迁移来阻断肿瘤微环境的形成,并阻断巨噬细胞极化为支持肿瘤的M2表型[39] [40] [41]。在转化后的FL异种移植模型中,与单独抑制任一亚型相比,联合抑制PI3K-δ和PI3K-γ增强了肿瘤生长抑制,表明互补的双重亚型对肿瘤生长和存活的贡献。因此,与单独抑制PI3K-δ相比,双重PI3K-δγ抑制可能会增强淋巴恶性肿瘤患者的治疗效果[42]。PI3K抑制作为iNHL的治疗策略得到了idelalisib (一种口服PI3K-δ抑制剂)和copanlisib (一种静脉内给药的PI3K-α和PI3K-δ抑制剂)的研究数据的支持。根据单臂2期试验的数据,这两种疗法都获得了FDA的加速批准,用于治疗既往接受过两种全身治疗的复发性FL患者。在各自的关键研究中,接受idelalisib或copanlisib治疗的iNHL患者的ORR分别为57%和59% [43] [44]。在RR iNHL患者中,duvelisib的临床益处在各个剂量水平上都得到了证明,58%的患者有反应,其中19%的患者有完全反应。反应时间很快,大多数反应是通过第一次反应评估(2个月)实现的。中位DOR和PFS分别为17个月和15个月,进一步支持了具有临床意义的活动。在FL患者亚组中,疗效同样稳健,总体缓解率为58%,包括25%的CR患者,中位DOR为18.4个月。在分析时,未达到整体iNHL患者群体的中位OS,估计18个月时的生存概率为75%。在经过大量预处理的复发/难治性iNHL患者中,口服duvelisib单药治疗显示出快速、具有临床意义的活性和可接受的安全[42]

6. BCL抑制剂

BCL-2是在调节细胞凋亡中起重要作用的蛋白质,细胞凋亡是多细胞生物发育和正常生理学的关键过程。该蛋白质家族的基本机制是由促生存蛋白的作用给出的,促生存蛋白通过与它们的对应物(细胞凋亡的效应蛋白)直接结合来抑制细胞凋亡。BCL-2家族由几种蛋白质组成,这些蛋白质根据它们在抗凋亡蛋白中的结构进行分类,例如BCL-2、BCL-xL、BCL-W、A1、MCL1、BCL-RAMBO、BCL-B和BCL-G蛋白,以BAX、BAK、BBID和BOK为代表的促凋亡蛋白,而成员被认为是促凋亡效应子,仅BH3蛋白为BIM,BAD、BIK、NOXA、HRK和PUMA [45]。由于BCL-2参与细胞凋亡的调节,这一过程的逃避与恶性过程的产生直接相关[46],BCL-2家族成员表达的改变被报道为癌症产生和促进的基础[47]。因此,BCL-2蛋白家族的研究对于理解和潜在治疗癌症至关重要。Venetoclax是一种有效的选择性口服BCL-2抑制剂,已被批准用于CLL和其他血液恶性肿瘤,并在MCL中具有稳健的临床前活性。在R/R MCL中唯一发表的Venetoclax单药治疗研究是一项I期试验,其中28例BTKi初治患者接受可变Venetoclax剂量治疗,ORR (CR)为75% [48]。PFS为14个月,12个月OS为82% [49]。Eyre等人发表了一项回顾性多中心真实的世界分析,分析了20例BTKi进展后接受单药Venetoclax治疗的患者,结果显示ORR为53% (CR 18%),OS较短,为9.4个月[50]。另一个由24例接受Venetoclax +/− 其他药物治疗的R/R MCL患者组成的单一机构队列显示出相似的结果(ORR 55%和OS 13.5个月),在接受联合治疗的患者中观察到差异[51]。Sawalha等人在重度预治疗的R/R MCL患者中,使用Venetoclax单药治疗(62%)或联合治疗(39%)的经验最多(N = 81),其中82%的患者对BTKi难治。ORR为42% (CR 18%),Venetoclax单药治疗与维奈克拉组合。在多变量分析中,接受Venetoclax联合治疗的患者的中位OS为12.5个月,Venetoclax剂量越高,生存期越长[52]。迄今为止,许多Venetoclax联合其他靶向药治疗NHL的临床研究正在进行中。

7. 结语

在B-NHL患者中,大多数患者可以通过常规化疗进行治疗,但仍有部分患者出现复发/难治性的疾病,导致预后普遍较差,从而降低患者的生存率和整体耐受性。本综述总结了BTK抑制剂、CD20单抗、蛋白酶体抑制剂、PI3K/AKT/mTOR通路抑制剂、BCL抑制剂等靶向药物在非霍奇金淋巴治疗中的有效性和前景,同时期待靶向药物可以为非霍奇金患者带来新的希望。

NOTES

*通讯作者。

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