刘加军：原发中枢神经系统淋巴瘤治疗进展（中）_京智康,家庭健康智能终端,大健康,我淘健康

原发中枢神经系统淋巴瘤（PCNSL）是指起源于中枢神经系统且具有侵袭性的结外非霍奇金淋巴瘤，病灶原发且仅限于中枢神经系统（大脑、脑膜、眼及其附属器和脊髓）^[1]。该病发病率低，仅占颅内肿瘤的4%，占所有结外淋巴瘤的4%-6%，预后差，复发率高，近一半的患者2年内复发^[2,3]。PCNSL发病的主要危险因素之一是免疫缺陷，自2000年以来，PCNSL的发病率一直在以每年增加1.6％的速度增长，特别是在免疫功能正常的患者和老年人（＞60岁）中^[4]。因为血脑屏障的存在，标准淋巴瘤化疗对PCNSL的作用有限，大剂量甲氨蝶呤（HD-MTX）加或不加全脑放射治疗（WBRT）是最有效的治疗方法。尽管PCNSL对初始治疗的缓解率很高，但总体预后仍然很差。随着对PCNSL病理生理的不断深入研究，已经发现B细胞受体通路（BCR）、Toll样受体通路（TLR）、免疫逃避机制、肿瘤免疫微环境受抑制是PCNSL发病中的关键机制。PCNSL的治疗逐渐有了新的方向，靶向治疗和免疫治疗及与之相关的联合用药成为研究热点。本文从外科手术治疗、放疗、化疗、造血干细胞移植、靶向治疗及免疫治疗六个方面系统地回顾了PCNSL的治疗，并总结新型药物现有的临床证据，供广大读者参考。

在上一期文章中，我们对PCNSL的外科手术治疗、放疗和化疗进行了总结（详情请戳《刘加军教授谈原发中枢神经系统淋巴瘤治疗进展（上）》，今天，我们一起来看看PCNSL的造血干细胞移植和靶向治疗进展吧！

造血干细胞移植

大剂量化疗联合自体干细胞移植（HDC-ASCT）在PCNSL中的运用越来越得到关注，常常作为复发难治患者的主要挽救性治疗手段。已有研究证明了其在提高PCNSL缓解率、延长OS方面的有效性^[24,29,30]，且这一治疗方式在青年患者中效果更好^[31]。Soussain等人^[32]对PCNSL复发患者的队列研究表明，以噻替哌为基础的强化化疗加造血干细胞移植挽救治疗患者的5年无事件生存（EFS）率和OS率分别为37.8%和51.4%。Schorb E等人的一项回顾性多中心研究表明^[33]，在接受HDC-ASCT的老年PCNSL患者（≥65岁）中，69.2%的患者达到CR，17.3%达到部分缓解（PR），中位PFS和中位OS分别为51.1个月和122.3个月，但其疗效仍需前瞻性研究进一步支持。另有报道接受HDC-ASCT的患者3年OS率为60%，3年EFS率为53%^[34,35]。还有研究评估了HD-ASCT和WBRT强化治疗PCNSL患者的疗效和毒性^[36]，研究中共纳入140例18-60岁新诊断的PCNSL患者，HDC-ASCT组患者的2年PFS率为87%，且进行HDC-ASCT后观察到患者的神经认知评分总体改善，而WBRT与认知结果恶化相关。然而，许多患者在复发时不符合HCT-ASCT的条件，这些患者的预后仍然很差。

靶向治疗

利妥昔单抗

PCNSL病理表型大多为弥漫性大B细胞淋巴瘤（DLBCL），在WHO的分类中，弥漫性大B细胞来源的PCNSL被认为是DLBCL的独特亚型，这一类肿瘤组织广泛表达B细胞抗原，如CD19、CD20、CD79a，同时，Mum-1、IRF4几乎均为阳性表达，50%表达BCL-6，约10%表达CD10。因此，利妥昔单抗可能会改善疾病的预后，但因其BBB穿透性差，其疗效仍不确定。一项回顾性队列研究对接受HD-MTX+替莫唑胺或HD-MTX+替莫唑胺+利妥昔单抗的患者进行了疗效和生存率分析，两组的中位PFS分别为7.3个月和56.7个月，HD-MTX+替莫唑胺+利妥昔单抗联合治疗PCNSL患者短期疗效确切，且可提高患者生存率，副作用轻微，患者一般可耐受^[38]。另一项对108例PCNSL患者的随机对照研究发现^[39]，与HD-MTX联合WBRT相比，HD-MTX联合利妥昔单抗组的ORR明显较高（81.5% vs 57.4%），1年OS率分别为83.3%（45/54）和63.0%（34/54），1年PFS率分别为70.4%（38/54）和46.3%（25/68），3年OS率分别为57.4%（31/54）和31.5%（17/54），3年PFS率为27.8%（15/54）和14.8%（8/54）。NCCN指南已将利妥昔单抗推荐为PCNSL的一线联合用药。但Miyakita等研究人对19例复发PCNSL患者进行的回顾性研究^[40]结果表明，HD-MTX+利妥昔单抗组66.6%的复发患者达到CR/未经确认的完全缓解（CRu），13.3%的患者达到PR，这与HD-MTX单药治疗组相当，两组之间肿瘤进展的中位时间没有显著差异。另外，在一项关于利妥昔单抗联合替莫唑胺治疗复发性PCNSL的前瞻性多中心研究中^[41]，只有14%的可评估患者达到CR，中位PFS为7周。

BTK抑制剂

在PCNSL中，原癌基因的体细胞突变程度高，在几乎所有PCNSL中都观察到导致核因子κB（NF-κB）信号通路激活的突变，例如MYD88和CD79b突变已被确定为PCNSL中最常见的突变，以上强调了PCNSL发病对BCR信号通路的依赖^[37]。鲁顿酪氨酸激酶（BTK）在调节BCR和TLR下游的致癌信号转导中起重要作用^[42,43]。这为BTK抑制剂治疗PCNSL提供了理论基础。一项Ⅰb期临床试验^[44]探讨了伊布替尼/HD-MTX/利妥昔单抗联合治疗对复发难治性PCNSL的疗效，80%的患者有临床反应，没有3-5级毒性事件或剂量限制性毒性。另有关于伊布替尼的荟萃分析^[45]显示，在PCNSL患者中，包括新诊断的PCNSL和复发难治性PCNSL，治疗中包含伊布替尼的患者的合并ORR为72%（95% CI：63%-80%，I²=49.20%，p=0.06），合并CR率和PR率分别为53%（95% CI：33%-73%，I²=75.04%,p=0.00）和22%（95% CI：14%-30%，I²=46.30%，p=0.07）。tirabrutinib是一种二代高选择性口服BTK抑制剂，它在治疗复发难治性PCNSL的研究中^[46]，患者的ORR为64%，中位PFS为2.9个月，常见的≥3级不良事件为中性粒细胞减少症（9.1%）、淋巴细胞减少症（6.8%）、白细胞减少症（6.8%）和多形性红斑（6.8%），研究中仅一例每天服用480mg剂量的患者出现5级不良事件（耶氏肺孢子菌肺炎和间质性肺病）。另外，阿卡替尼在复发难治性PCNSL中的Ⅱ期试验（CT04548648）目前正在进行中。

mTOR和PI3K抑制剂

哺乳动物雷帕霉素靶蛋白（mTOR）是一种丝氨酸-苏氨酸蛋白激酶，属于磷酸肌醇3-激酶（PI3K）相关激酶家族。PI3K/AKT/mTOR通路通过整合来自生长因子、激素、营养素和能量代谢的信号来调节蛋白质合成以调节细胞生长和增殖^[47]。针对PI3K/AKT/mTOR信号通路的抑制剂主要包括PI3K抑制剂、mTOR抑制剂和PI3K-mTOR双重抑制剂。mTOR和PI3K抑制剂逐渐出现在复发难治性PCNSL的临床试验中，但疗效差强人意。报道的第一个靶向药物是德国多中心II期试验中的mTOR抑制剂替西罗莫司^[48]，其治疗PCNSL的ORR为54%，但中位PFS仅为2.1个月，中位OS为3.7个月,并且治疗相关毒性很大，最常见是高血糖、骨髓抑制、感染（主要是肺炎）和疲劳。5例患者死于治疗相关并发症，占治疗相关死亡率的13%。另一项针对PI3K/mTOR轴的研究使用了泛PI3K抑制剂Buparlisib，其单药治疗复发难治性PCNSL的ORR仅为25%^[64]。尽管mTOR或PI3K抑制剂的现有证据并不令人信服，但临床前研究表明，BTK抑制剂与PI3K抑制剂或mTOR抑制剂组合具有协同抗淋巴瘤作用，尤其是在CD79B突变细胞中^[48],因此mTOR抑制剂和PI3K抑制剂在PCNSL中的运用仍然具有研究前景。

BCL-2抑制剂

18q21（包括BCL-2基因座）的增加是PCNSL中最常见的遗传失衡之一^[49-51]。通过免疫组化发现41.8%-93%的PCNSL表达BCL-2^[52]。有研究表明，PCNSL中BCL-2的高表达与不良预后相关^[53]。BCL-2可以被小分子维奈克拉靶向，维奈克拉是一种高度选择性的BCL-2抑制剂，已被FDA批准用于治疗慢性淋巴细胞白血病。在动物模型中也发现维奈克拉似乎具有有限的CNS渗透^[54]。BCL-2抑制剂可能成为BCL-2过表达PCNSL的潜在治疗药物，但其真正的应用价值仍需前瞻性临床药物试验证据进一步支持。

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刘加军教授

教授、主任医师、博士生导师
中山大学附属第三医院血液内科主任
欧洲肿瘤协会抗癌分会会员
中国免疫协会会员
广东省医疗行业协会常委
广东省血液学会会员等
主研方向：白血病细胞凋亡信号转导机制、造血干细胞移植、血液肿瘤的分子靶向治疗、基因治疗及新型抗肿瘤药物的机制研究等。
医疗专长：从事内科血液学临床医疗工作20多年。多年来从事白血病细胞凋亡信号转导机制及血液肿瘤的分子靶向治疗研究。对各种贫血、出血性疾病及血液肿瘤有熟练的诊治能力。诊疗疾病包括血液病造血干细胞移植、白血病化疗、恶性淋巴瘤和多发性骨髓瘤等恶性血液疾病的个体化治疗方案选择、各种原因不明的贫血、不明原因的长期发热以及淋巴结肿大的鉴别诊断和治疗等。

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刘加军：原发中枢神经系统淋巴瘤治疗进展（中）

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刘加军：原发中枢神经系统淋巴瘤治疗进展（中）

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