本帖最后由 橙色雨丝 于 2016-3-23 19:45 编辑
Novel Agents on Horizon for Follicular Lymphoma 滤泡性淋巴瘤的新药－来自2016年国际血液肿瘤大会的消息 Friday, March 18, 2016 （文章选自OncLive）
John P. Leonard, MD
A diverse collection of novel agents are on the horizon that could further improve the long-term outcomes experienced by patients with follicular lymphoma, particularly those with relapsed or refractory disease, according to a presentation by John P. Leonard, MD, at the 2016 International Congress on Hematologic Malignancies. 在2016年国际血液肿瘤大会上，根据John P. Leonard医生的演讲，各种即将出现的新药将进一步改善滤泡性淋巴瘤患者的转归，尤其是那些复发和耐药的患者。
“Most patients will not die from follicular lymphoma, and that's very reassuring. About 80% of patients will die with their follicular lymphoma and not of their follicular lymphoma,” said Leonard,Richard T. Silver Distinguished Professor of Hematology and Medical Oncology,New York-Presbyterian Weill Cornell Medical Center. “That really tells you something. If 80% of patients are not going to die from their disease, we can make a patient feel a lot better and can guide how we treat the patient.” “大部分患者将不会死于滤泡性淋巴瘤，这是非常肯定的。大约80%的患者将可以带瘤生存，直至死于其它原因，”纽约Presbyterian Weill Cornell医疗中心的杰出教授莱昂纳德说，“这真的很有意义。如果80%的病人不会因为这种疾病而死亡，我们可以让病人感觉好多了，而且可以指导我们给病人提供治疗。”
Next-generation anti-CD20 antibodies havebeen explored for relapsed follicular lymphoma, noted Leonard; however,superiority over traditional rituximab (Rituxan) has not yet been established.In late February 2016, the FDA approved the anti-CD20 agent obinutuzumab(Gazyva) in combination with bendamustine for patients with follicular lymphoma following rituximab-based therapy. 莱昂纳德指出，下一代的抗CD20抗体已经在复发的滤泡性淋巴瘤上做了探索，但是，是否优于传统的利妥昔单抗还不确定。2016年2月底，FDA批准了对接受过利妥昔单抗治疗的滤泡性淋巴瘤患者使用抗CD20单抗obinutuzumab和苯达莫司汀联合的方案。
In the pivotal phase III GADOLIN study,obinutuzumab plus bendamustine followed by obinutuzumab maintenance reduced the risk of disease progression by 52% compared with bendamustine alone in patients with follicular lymphoma (HR, 0.55; P <.0001). At a median follow-up of 24.1months, the risk of death was reduced by 38% with the obinutuzumab regimen compared with bendamustine alone (HR, 0.62; 95% CI, 0.39-0.98).
在关键性的GADOLIN三期临床试验中，obinutuzumab联合苯达莫司汀加上obinutuzumab维持相对于苯达莫司汀单药将疾病进展的风险降低了52%。中位随访24.1个月后，用obinutuzumab的方案比苯达莫司汀单药的方案使死亡的风险降低了38%。
“I am not sure how much it is going to change practice, perhaps for some people it will,” said Leonard. “I would have honestly liked to know how rituximab would have stacked up, which in this setting is a more clinically relevant question.”
“我不知道这将在何种程度上改变医疗实践，可能对某些人来说是会发生的，”莱昂纳德说，“我真心的希望知道，如果与利妥昔单抗相比较的话会是一种什么情况，对复发难治的病人来说这是一个与临床关系更密切的问题。”
In another study, 90 patients with relapsed follicular lymphoma were randomized to receive lenalidomide (Revlimid) plus rituximab (n = 45) or lenalidomide alone (n = 45). The overall response rate(ORR) was 44% with lenalidomide alone and 75% with lenalidomide plus rituximab.The median event-free survival (EFS) was 1.2 and 2.0 years, with the single-agent and combination, respectively. 在另一项临床试验中，90例复发的滤泡性淋巴瘤患者被随机分配接受来那度胺加利妥昔单抗（45例）或来那度胺单药（45例）治疗。来那度胺单药治疗的总有效率是44%，来那度胺加利妥昔单抗的总有效率是75%。中位无进展生存期分别为1.2年和2.0年。
The phase III AUGMENT study is currently enrolling patients with follicular lymphoma and marginal zone lymphoma in orde rto compare rituximab plus placebo with rituximab plus lenalidomide. The primary endpoint of the study is progression-free survival (PFS), with secondary outcome measures focused on response, EFS, and time to next therapy. AUGMENT三期临床试验目前正在入组滤泡性淋巴瘤和边缘带淋巴瘤病人，以便比较利妥昔单抗加安慰剂与加来那度胺的效果。这项试验的主要终点是无进展生存，次要考量指标包括应答率，无事件生存，以及开始下次治疗的时间。
“This seems like it has significant efficacy in relapsed, not refractory, patients. I think this is an interesting approach,” said Leonard. “看起来这个方案对复发，但不是耐药的患者有显著的疗效。我认为这是一个很不错的方案。”莱昂纳德说。
The B-cell receptor also represents an important target for patients with B-cell malignancies. The PI3K deltainhibitor idelalisib (Zydelig) and the BTK inhibitor ibrutinib (Imbruvica) have shown promise for patients with relapsed follicular lymphoma. 对于B细胞淋巴瘤患者，B细胞受体也代表着一个很重要的药物标靶。PI3K抑制剂idelalisib和BTK抑制剂ibrutinib对复发的滤泡性淋巴瘤显示出很好的潜力。
In July 2014, the FDA approved idelalisibas a single agent for patients with indolent non-Hodgkin lymphoma, including follicular lymphoma. In the study that led to the FDA approval, most patients were refectory to bendamustine and rituximab. The ORR with idelalisib was 56%.The median PFS was 11 months and the median overall survival (OS) was 20.3months. 2014年7月，FDA批准将idelalisib作为单药用于惰性的非霍奇金淋巴瘤，包括滤泡性淋巴瘤。在向FDA申报批准的临床研究中，大部分病人都对苯达莫司汀和利妥昔单抗耐药。Idelalisib的总有效率是56%。中位无进展生存期是11个月，中位总生存率是20.3个月。
The main adverse events (AEs) associated with idelalisib include diarrhea/colitis, which occurs in 50% of patients(grade ≥3, 19%). Outside of this, the most common grade ≥3 AEs were neutrophil decrease (28%), platelet decrease (8%), and dyspnea (5%). 与idelalisib相关的主要不良事件包括腹泻／结肠炎，大约50%的病人发生（大于三级的有19%）。除此之外，最常见的三级不良事件有中性粒下降（28%），血小板下降（8%）和呼吸困难（5%）。
“This looks like a pretty meaningful response and duration of response in refractory patients,” said Leonard. “There has been some data reported recently that seem to show some toxicity when it isused in combination. For those using this drug now: be careful. There may be aninfectious issue or other issues, but for me, at this point, I only use this drug as a single agent.” “对于耐药的病人，这种应答率和应答持续时间看起来是很不错的，”莱昂纳德说，“最近有些报道说idelalisib与其它药物联合使用产生了一些毒性。对于那些正在使用这个药物的患者：要小心。也许有感染或者其它问题，但是就我来说，在目前，我只会将这个药物作为单药使用。”
There are several issues to consider when determining which therapy to administer following relapse for follicular lymphoma, including the indication for therapy, the bulk of disease,comorbidities, toxicity concerns, and the potential for transformation.However, in most cases, a majority of patients (80%) will live a normal lifespan, Leonard added. 在滤泡性淋巴瘤复发后，确定采用何种治疗方法时有几个问题要考虑，包括治疗指征，肿块大小，并发疾病，毒性的问题，和潜在的转化风险。然而，在大多数情况下，大部分病人（80％）都可以有正常人一样的生存期，莱昂纳德补充道。
“The biggest unmet need is the 20% of patients who are going to die of their disease or who are more likely to die oftheir disease,” he said. “This is the group of patients who progress. What dowe do with these patients?” “最大的未能得到满足的医疗需求是那20%将会死于这种疾病，或者最有可能死于这个疾病的病人，”他说，“这组病人的疾病会不断进展。对这些病人我们怎么办？”
There are a number of studies ongoing toaddress these concerns, including studies assessing the immune checkpoint inhibitors. The phase II CheckMate-140 trial is exploring nivolumab (Opdivo)for patients with follicular lymphoma following progression on a CD20 antibody and an alkylating agent (NCT02038946). Additionally, a phase II study is looking at the combination of rituximab and pembrolizumab (Keytruda) forpatients with relapsed follicular lymphoma (NCT02446457). 目前，有一系列的临床试验在试图解答这个问题，包括那些评估免疫检查点抑制剂的试验。二期的CheckMate－140试验正在探索用nivolumab治疗经CD20抗体和烷化剂治疗后进展的滤泡性淋巴瘤。此外，一项二期研究将利妥昔单抗和pembrolizumab联合来治疗复发的滤泡性淋巴瘤。
In a small 30-patient study, pidilizumabplus rituximab demonstrated an ORR of 66% in relapsed follicular lymphoma,which primarily consisted of complete responses. The median PFS was 18.8months. In a second small phase I study assessing nivolumab as a single agent,patients with pretreated follicular lymphoma (n = 10) experienced an ORR of 40% after 40 weeks of follow-up. 在一个30例患者的小规模研究中，pidilizumab加利妥昔单抗在复发的滤泡性淋巴瘤中取得了66%的总有效率，其中大部分是完全缓解。中位无进展生存期是18.8个月。在第二个小规模一期试验中，novolumab单药使用在先前接受过治疗的10例滤泡性淋巴瘤中显示了40%的总有效率，随访时间40周。
“These responses are meaningful, not as dramatic as we have seen in Hodgkin's, but it is meaningful,” said Leonard.“The question is, 'can you develop this drug in follicular lymphoma?' You would think that we would be able to develop a biomarker for response to aninhibitor, because the immune microenvironment makes a big difference infollicular lymphoma. Hopefully, we can identify a subset of patients where those response rates will be much better.” “这种应答率是有意义的，尽管不像霍奇金病那么高，但是依然很不错，”莱昂纳德说，“问题是，你是否专门针对滤泡性淋巴瘤来开发这种药？你会认为我们应该能够开发出一个生物标记物来判断病人是否会对某一种抑制剂产生应答，因为免疫微环境对滤泡性淋巴瘤来说非常关键。最好的是，我们有办法来确定可以获得更高的应答率的病人亚群。”
As trials are conducted, questions still remain regarding whether PFS is a meaningful endpoint for patients with follicular lymphoma, Leonard said. Future studies should focus on more than efficacy, he noted, with an emphasis on the delivery of care and the costs. 随着临床试验的进行，关于无进展生存对于滤泡性淋巴瘤是否还是一个有意义的终点的问题将会持续被提起，莱昂纳德说。未来的研究将不仅限于效果，还将注重病人的关照和成本。
“We need to focus on the goals of therapy. Are we curing the patients? What's the quality of life? I don't think PFS necessarily correlates with quality of life, we need to have quality of life endpoints that are real and robust and reflect what the value is to patients,”said Leonard. “We need to look at chronic toxicities and look at compliance issues.” “我们要注重治疗的目的。我们治愈病人了吗？生活质量如何？我不认为无进展生存与生存质量一定相关，我们需要以生存质量为终点，这个指标真实可靠，并可以充分反映带给病人的价值，”莱昂纳德说，“我们需要关注慢性的毒性并检查遵守医嘱方面的问题。” | 
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