本帖最后由 橙色雨丝 于 2015-1-26 15:20 编辑
Sustained Remission with the Combination Biologic Doublet of Lenalidomide Plus Rituximab As Initial Treatment for Mantle Cell Lymphoma: A Multi-Center Phase II Study Report 生物治疗的双药组合来那度胺和美罗华作为套细胞淋巴瘤的一线方案获得持续缓解:一项多中心二期研究的报告 BACKGROUND: Initial treatment for mantle cell lymphoma (MCL) is not standardized. Current conventional upfront chemoimmunotherapies are generally not curative. Lenalidomide, an immunomodulatory compound which targets both the tumor cells directly and the tumor microenvironment, has shown clinical efficacy either alone or in combination with rituximab in relapsed MCL. We report the mature findings of the first study of a chemotherapy-free approach as initial treatment for MCL, using lenalidomide and rituximab as a combination biologic doublet. 背景:套细胞淋巴瘤(MCL)没有标准的初治方案。目前常规的一线化学免疫疗法通常不能治愈。来那度胺作为一种免疫调节化合物可以直接作用于肿瘤细胞也可作用于肿瘤微环境, 作为单药或者与美罗华联合在复发的MCL上显示出临床效果。我们在此报告有关将来那度 胺和美罗华作为生物治疗的双药组合用于MCL初治的首项非化疗治疗方案的研究。 METHODS: The study protocol includes both an induction phase and a maintenance phase. During the induction phase, lenalidomide is administered at 20 mg daily on days 1-21 of a 28-day cycle for a total of 12 cycles, with dose escalation to 25 mg daily if tolerated. Standard dose rituximab is administered weekly x 4 during cycle 1, then once every other cycle, for a total of 9 doses. During the maintenance phase which starts with cycle 13, lenalidomide is administered at 15 mg daily on days 1-21 of a 28-day cycle, with rituximab maintenance once every other cycle until progression of disease. The primary objective was to evaluate overall response rate (ORR). Secondary objectives included safety analysis, progression- free survival, overall survival, and QOL assessment. 方法:研究过程包括一个诱导阶段和一个维持阶段。在诱导阶段,在每次28天的一个疗程 中,从第1天到第21天,来那度胺每天给药20毫克,共进行12个疗程,如果可以耐受的话剂 量可增加到每天25毫克。在第一个疗程中,每周注射标准剂量的美罗华,共四次,然后每 隔一个疗程再注射一次美罗华,总共注射九次。从第13个疗程开始进入维持阶段,在每个28 天的疗程中从第1天到第21天来那度胺每天给药15毫克,并且每隔一个疗程注射一次美罗华, 直到出现疾病进展为止。研究的首要目的是评估总应答率(ORR)。次要目的包括安全性 分析,无进展生存期,总生存期和生活质量分析。 RESULTS: From 7/2011 to 4/2014, 38 subjects with previously untreated MCL were enrolled at 4 centers, and the study met its accrual. At study entry, median age was 65 years (range 42-86), and the M:F ratio was 2.5:1. All patients had stage III/IV disease, 14 (37%) had elevated LDH, and 34 (89%) had bone marrow involvement. MIPI scores were evenly distributed between low-, intermediate-, and high-risk (34%, 34%, and 32% respectively). Ki67 index was <30% in 26 (68%) subjects. Treatment was generally well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (47% in total, 42% with induction, 24% with maintenance), thrombocytopenia (13%) and anemia (8%). Grade 3-4 non- hematologic toxicities including rash (26%), tumor flare (11%), serum sickness associated with rituximab (8%) and fatigue (8%), were reported during induction phase only. Grade 1-2 infections including URI (34%), UTI (16%), sinusitis (11%) and bronchitis (8%) were reported during both induction and maintenance. One patient developed grade 3 cholangitis from cholecystitis requiring cholecystectomy. Secondary malignancy was reported in an 86 yo patient who developed melanoma in-situ and Merkel cell carcinoma following 18 month of therapy. As of July 2014 at a median follow-up of 24 months (range 3-35 months), 37 patients are alive, and 36 patients are evaluable for efficacy with at least one response assessment. Two patients were inevaluable – one withdrew consent, and one was intolerant of tumor flare. The ORR for all patients is 84.2% (95% CI = 68.7% to 94%) with 52.6% CR (95% CI = 35.8% to 69%). Median time to objective response was 2.8 months, with median time to CR achieved at 11 months. Thirty (79%) patients remain on study without evidence of disease progression, including 24 who have completed induction and are now in maintenance. During induction, 29% of patients tolerated dose escalation of lenalidomide to 25 mg from 20 mg, while 39% required dose reduction to 15 mg or less. Six evaluable patients had disease progression – 3 with primary refractory disease, 3 progressed following initial responses (1 CR with PFS of 18 months, 2 PRs with PFS at 14 and 25 months, respectively). Median progression-free survival and duration of response have not been reached. The 2- yr PFS rate is estimated at 83.9% (95% CI = 65.2% to 93.1%). Neither MIPI score nor Ki67 index correlated with response. Quality of life parameters were maintained or improved during treatment by FACT-Lym analysis. 结果:从2011年7月到2014年4月,分别在四个中心共有38位先前未经过治疗的MCL患者, 满足了研究的人数要求。研究开始时,中位年龄为65岁(42到86之间),男女比例为2.5:1。 所有患者均为三期或四期,14人(37%)有LDH升高,34人(87%)有骨髓侵犯。MIPI评 分在低、中、高风险组平均分布(分别为34%,34%和32%)。Ki67指数有26人(68%) 低于30%。总体上对治疗耐受良好,有一些意料中的副作用。三到四级的血液毒性包括中 性粒细胞减少症(共47%,42%发生在诱导阶段,24%发生在维持阶段),血小板减少症 (13%)和贫血(8%)。三到四级非血液毒性包括皮疹(26%),肿瘤闪烁现象(11%), 与美罗华相关的血清病(8%)和乏力(8%),不过都发生在诱导阶段。一二级的感染包 括消化系统感染(34%),泌尿系统感染(16%),鼻窦炎(11%)和支气管炎(8%), 在诱导阶段和维持阶段均有出现。有一位患者出现了由胆囊炎引发的三级的胆道炎,做了胆 囊切除术。发生二次肿瘤是一位86岁的患者,在治疗18个月后出现了原位黑色素瘤和梅克尔细胞癌。到2014年7月为止,中位随访期为24个月(3到35个月),37位患者依然生存, 36位患者接受了至少一次应答率评估。有两位患者未接受评估,其中一位退出试验,另一 位不能忍受肿瘤闪烁现象。所有患者的总应答率为84.2%(95% CI=68.7%-94%), 52.6%的患者获得CR(95% CI=35.8%-69%)。中位可客观评估的时间为2.8个月,中 位获得CR的时间为11个月。30位(70%)还在研究中的患者没有出现疾病进展,包括24 位完成诱导治疗目前还在维持中的患者。在诱导阶段,29%的患者可以耐受将来那度胺剂量从20毫克上升为25毫克,而39%的患者需要将剂量降低到15毫克甚至更低。6位可评估 患者出现疾病进展,3位原发耐药,3位在诱导后出现进展(1位CR后无进展生存期18个月, 2位PR的无进展生存期分别为14和25个月)。中位无进展生存期和应答持续期尚未达到。2 年无进展生存率估计为83.9%(95% CI=65.2%-93.1%)。MIPI和Ki67指数均与应答无 关。在治疗期间生活质量的各种参数得到维持或提高。 CONCLUSIONS: This study provides the first demonstration that a chemotherapy- free, combination biologic approach is feasible and active as initial therapy for mantle cell lymphoma. A high proportion of MCL patients can achieve durable remissions while maintaining quality of life with the frontline therapy of lenalidomide up to 25 mg daily given 21 out of 28 days combined with rituximab. These data justify further evaluation of the lenalidomide + rituximab regimen both alone and as a platform for the integration of novel agents in combination approaches in MCL, particularly in the upfront setting. 结论:这项研究首次证明非化疗的联合生物治疗方案对套细胞淋巴瘤初治可行并有效。大部分MCL患者经每天最多25毫克来那度胺21天给药28天一个疗程并联合美罗华进行一线治疗 后能获得可持续的缓解并维持适当的生活质量。这些数据为对来那度胺加美罗华作为一个独 立的方案或者作为一个方案平台联合其它新药作为治疗MCL的一线方案做进一步研究提供了依据。 | 
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发表于 2015-1-26 15:13:44
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