如何克服美罗华耐药

橙色雨丝

This is the first clinical study to demonstrate that the addition of lenalidomide to rituximab overcomes prior rituximab-resistance, and prolongs progression free survival (PFS) in patients with indolent B-cell and mantle cell lymphomas (MCL). 这是第一个验证了在美罗华的基础上加上来那度胺可以帮助惰性淋巴瘤和套细胞淋巴瘤患者克服先前对美罗华耐药并延长无进展生存期的临床试验。

Patients who were previously rituximab resistant, received lenalidomide 10mg daily for 8 weeks, and then four weekly doses of rituximab 375 mg/m2; lenalidomide continued during and after rituximab.
先前对美罗华耐药的患者每日服用10毫克来那度胺并持续八周，然后连续四周每周注射375mg/m2美罗华；在美罗华治疗期间和之后持续服用来那度胺。

Overall response rate (ORR) after 8 weeks of lenalidomide monotherapy was 30.2%; 12 weeks after the addition of rituximab to lenalidomide, ORR increased to 62.8%. The improvement in ORR was most pronounced in follicular lymphoma (FL), with a 3-fold increase in ORR (19% after lenalidomide and 65% after lenalidomide-rituximab).
八周后来那度胺单药治疗的总应答率为30.2%；十二周后通过加入美罗华治疗，总应答率上升到62.8%。总应答率的提升在滤泡性淋巴瘤患者中最明显，达到了三倍的提升（来那度胺后19%，来那度胺+美罗华之后65%）。

The study also demonstrated durable responses, with a median duration of response (DoR) of 24 months. At 5 years, overall survival (OS) was 68.3%, and PFS was 22.2 months.
这项研究显示了持久的应答，中位应答时间为24个月。到第五年，总生存率为68.3%，无进展生存期为22.2%。

Dr Chong and colleagues commented, ‘The unique design of the trial provides new insights into the therapeutic activity of this combination. The results provide convincing clinical evidence of additive activity for the combination of rituximab and lenalidomide’.
钟博士和其同事评价说，“这项试验的独特的设计使我们对这个组合的治疗效果有了新的了解。试验结果为联合美罗华和来那度胺而产生协同效应提供了令人信服的临床依据。”

Overall, the regimen was well-tolerated. The most common adverse events (AEs) were cytopenias, constitutional symptoms, gastrointestinal symptoms, neuropathy, and myalgias, which tended to improve within 1–2 cycles of lenalidomide or resolved with dose interruption, dose reduction, or discontinuation of lenalidomide.
总的来说对此方案的耐受良好。最常见的副作用包括：血细胞减少，系统症状，胃肠道反应，神经病变和肌痛，这些症状一般会在一到两个疗程的来那度胺之后改善或在调整剂量或终止服用来那度胺后消失。

Rationale 药理

Rituximab is an anti-CD20 monoclonal antibody and is used in most treatment regimens for B-cell non Hodgkin lymphomas. Although efficacious, many patients who initially respond eventually become resistant to rituximab. Lenalidomide is an immunomodulatory drug, which enhances antibody dependent cell medicated cytotoxicity (ADCC), reverses tumor-induced immunosuppression, and synergizes with rituximab. This clinical study hypothesized that combining lenalidomide with rituximab would surmount resistance to rituximab in patients who were previously rituximab-resistant.
美罗华是一种抗CD20单克隆抗体，可用于大多数B细胞非霍奇金淋巴瘤。尽管治疗有效，但很多患者在最初应答后最终会对美罗华耐药。来那度胺是一种免疫调节药物，可以提升抗体依赖细胞诱导的细胞毒性，逆转肿瘤引发的免疫抑制，并与美罗华产生协同作用。此项临床研究的理论基础是联合使用来那度胺和美罗华可能会帮助先前对美罗华耐药的患者克服美罗华耐药性。

Study results 试验结果

Fifty patients enrolled on to the study, of which 43 patients completed both response assessments. There were 48% of patients who were rituximab-refractory and 52% of patients who had relapsed within 6 months of prior rituximab or rituximab-containing regimens. The median number of prior therapeutic regimens was 3 (range 1-7).
共有50例患者入组了这项研究，其中有43例完成了一共全部两项应答分析。其中有48%的患者对美罗华耐药，52%的患者在接受美罗华或包含美罗华的方案治疗后6个月内复发。接受过的中位治疗方案数量为3种（1到7）。

Overall, the greatest portion of responses to combination lenalidomide and rituximab occurred after the addition of rituximab. However MCL had a higher response to lenalidomide monotherapy (55%); the addition of rituximab did not change the ORR, although 2 partial responses (PR) improved to complete responses (CR). Median decrease in tumor volume after lenalidomide monotherapy was 17.0%, versus 67.2% after the addition of rituximab to lenalidomide.
总的来说，最大部分对来那度胺和美罗华联合治疗的应答发生在加入美罗华之后。但是，套细胞淋巴瘤对来那度胺单药的应答率更高（55%）；加入美罗华并没有改变总应答率，尽管有两例部分缓解改善成了完全缓解。在来那度胺单药治疗后肿瘤体积降低到中位数值是17%，加入美罗华后则是67.2%。

There was no difference in the number of prior therapies between responders and non responders to the lenalidomide-rituximab combination therapy. No effect was observed of total prior rituximab exposure on response to lenalidomide-rituximab. No difference was observed in the number of patients who responded based on whether they had rituximab-refractory or rituximab relapsed disease (P=0.13).
对来那度胺-美罗华联合治疗的应答者和非应答者，先前接受的治疗方案的数量没有差别。未观察到先前接受的美罗华治疗次数对来那度胺-美罗华联合治疗的应答率有影响。也未观察到美罗华耐药或美罗华治疗后复发在应答患者中的数量的差别。

PFS was 16.5 months for FL and 24.4 months for MCL (P=0.52). The most common toxicities included gastrointestinal complaints (74%), fatigue (62%), Grade 3–4 neutropenia (34%), rash (26%), exacerbation of pre-existing peripheral neuropathy (20%), and myalgias (18%).
滤泡性淋巴瘤和套细胞淋巴瘤的无进展生存期分别为16.5个月和24.4个月。主要毒性反应包括胃肠道症状（74%），乏力（62%），3-4度中性粒细胞减少（34%），皮疹（26%），先前存在的周边神经炎的加重（20%），和肌痛（18%）。


Study design 试验设计

A single-center, prospective, open-label, Phase 2 clinical study investigating a combination of lenalidomide plus rituximab in patients with previously treated, rituximab-refractory or resistant indolent B-cell or MCL lymphoma. Patients were required to have CD20 antigen-expressing FL, MCL, small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma or marginal zone lymphoma (MZL).
一项单中心，前瞻性，开放式，二期临床研究调查先前接受过治疗，美罗华耐药的惰性B细胞淋巴瘤或套细胞淋巴瘤患者对来那度胺-美罗华联合治疗的应答。患者要求具有表达CD20的滤泡性淋巴瘤，套细胞淋巴瘤，小淋巴细胞淋巴瘤，淋巴浆细胞淋巴瘤或边缘区淋巴瘤。

Patients also needed to have rituximab-resistant, progressive, and measurable lymphoma. Exclusion criteria included previous lenalidomide treatment, active infection and CNS involvement.
患者还要求对美罗华耐药，处于进展期并有可测量病灶。排除条件包括以前接受过来那度胺治疗，活动性感染和中枢神经系统侵犯。

Patients received lenalidomide 10mg daily for 8 weeks, and then received four weekly doses of rituximab 375 mg/m2; lenalidomide continued during and after rituximab. Response to therapy was assessed after 8 weeks of lenalidomide monotherapy and 12 weeks after first dose of rituximab. The primary endpoint was ORR after lenalidomide and rituximab. Secondary endpoints included PFS, DoR/time to progression, and OS.
患者每日服用10毫克来那度胺并持续八周，然后连续四周每周注射375mg/m2美罗华；在美罗华治疗期间和之后持续服用来那度胺。在服用来那度胺单药八周后和十二周后完成首次美罗华注射后进行应答评估。首要评估项目是来那度胺和美罗华之后的总应答率，次要评估项目包括无进展生存期，应答持续时间/再次进展时间，以及总生存率。
REFERENCES

橙色雨丝

阴平阳秘 发表于 2015-2-8 16:45
Dear 雨丝，谢谢你的倾情翻译整理，有个问题想问一下你: 研究中是否提及美罗华耐药的标准？比如半年内复发 ...

全文都在这里了，没有提及耐药的标准。里面似乎将美罗华耐药分为两类，一类是原发耐药，称为refractory，另一类是六个月内复发的，称为resistant。其实我也不清楚这两个词有什么区别，在其它的文献中我也见过笼统的称为refractory的，其定义就包括对美罗华治疗无应答的和经美罗华或含美罗华方案治疗后6个月内复发的。

洪飞

谢谢雨丝辛苦整理翻译，32个赞

阴平阳秘

Dear 雨丝，谢谢你的倾情翻译整理，有个问题想问一下你: 研究中是否提及美罗华耐药的标准？比如半年内复发？抑或是半年内进展？跪求解答！

演绎『宽燕』

希望看到t细胞的有进展

梅朵儿

赞一个，谢谢雨丝的辛勤劳动。

P...

赞一个！吃水不忘挖井人！

quickrun

怎么判断美罗华耐药还是方案不对？弥漫大B，RCHOP一疗增强CT提示变化不大，二疗刚结束，过几周再评估。谢谢雨丝大哥。

橙色雨丝

quickrun 发表于 2019-8-1 11:36
怎么判断美罗华耐药还是方案不对？弥漫大B，RCHOP一疗增强CT提示变化不大，二疗刚结束，过几周再评估。谢谢 ...

高侵袭性在两三个疗程后做PET评估，低侵袭性在三四个疗程后做PET评估。

滤泡战斗者—林

橙色雨丝 发表于 2019-8-1 12:00
高侵袭性在两三个疗程后做PET评估，低侵袭性在三四个疗程后做PET评估。

雨丝大神你好，我是滤泡淋巴瘤一级四期的，前两个疗程用R-CHOP后，增强CT评估没有达到PR，问了两个不同医院的医生，一个给的建议是继续R-CHOP，第三疗程后再评估，另一个给的建议是换成BR方案，您觉得哪个方案会好一点呢？

橙色雨丝

滤泡战斗者—林 发表于 2020-11-7 23:24
雨丝大神你好，我是滤泡淋巴瘤一级四期的，前两个疗程用R-CHOP后，增强CT评估没有达到PR，问了两个不同医 ...

没有换方案的明确指征吧，只要治疗有效就继续，没有哪里规定二疗后必须至少PR。

滤泡战斗者—林

谢谢雨丝大神，现在打算换BR方案，大部分的专家是说要BR，能BR两个疗程后再看看效果，谢谢！