Rituximab-Lenalidomide (REVRI) in Relapse or Refractory Primary Central Nervous System (PCNSL) or Vitreo Retinal Lymphoma (PVRL): Results of a "Proof of Concept" Phase II Study of the French LOC Network-猫眼课题宝

DOI：

10.1182/blood.v128.22.785.785

发表时间：

2016-12

期刊：

Blood

影响因子：

20.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

H. Ghesquières;C. Houillier;O. Chinot;S. Choquet;C. Moluçon-Chabrot;P. Beauchene;R. Gressin;F. Morschhauser;A. Schmitt;E. Gyan;K. Hoang-Xuan;E. Nicolas‐Virelizier;M. Chevrier;A. Savignoni;I. Turbiez;Florence Veillas;V. Soumelis;C. Soussain

原发性中枢神经系统淋巴瘤（PCNSL）是一种弥漫性大b细胞淋巴瘤（DLBCL），以非生发中心（non-GC）亚型为主。尽管在一线治疗中引入大剂量甲氨蝶呤（MTX）后治疗效果有所改善，但在一线治疗和复发时，PCNSL的治疗效果都需要改善。巩固和维持治疗的作用也需要解决。利妥昔单抗和来那度胺的联合作用在非中枢神经系统非gc DLBCL中显示出活性，但其在PCNSL中的活性尚不清楚。方法在这项前瞻性、多中心、开放标签的II期研究中，我们招募了18岁以上的难治性或复发性PCNSL或原发性玻璃体视网膜淋巴瘤（PVRL）的DLBCL型患者。治疗包括诱导期，8个周期，每28天使用R2（利妥昔单抗375/m2 IV D1；来那度胺20 mg/D D1- d21为第一个周期，然后25 mg/D D1- d21为下一个周期，无血液学毒性），然后在有反应的患者中进行维持期，12个周期，每28天使用来那度胺（10 mg/D, D1- d21）。在第一个诱导周期中，如果出现威胁性或症状性水肿，允许使用皮质类固醇。深静脉血栓预防是强制性的。接受完整一个月治疗的患者可评估疗效。根据国际原发性中枢神经系统淋巴瘤协作组（IPCG）标准，主要终点是诱导期结束时的客观缓解率（ORR）。分析基于Fleming9s两步设计（P0 = 10%; P1= 30%）。初步探讨了治疗前后循环NK细胞和T细胞的变化及其与治疗反应的相关性。在2013年9月17日至2015年9月29日期间，从10个中心招募了50名患者（中位年龄：69岁，范围46-86岁）。所有患者此前均接受过高剂量MTX治疗。既往化疗行数中位数为2行（范围1-4）。9名患者先前接受过HD化疗，随后接受了造血干细胞抢救。最初诊断为PCNSL （n = 42）和PVRL （n = 8）。纳入研究时，诊断为PCNSL （n= 41）和PVRL或孤立性PCNSL眼内（IO）复发（n=9）。7例患者伴有脑脊液受累。患者包括在最后一次治疗后复发（80%，中位复发时间= 5.5个月）或难治性疾病（20%）的患者。34例患者在治疗的第一个月接受了皮质类固醇治疗。45例患者在第一个治疗周期后可评估疗效。诱导周期中位数为7（范围1-8）。11例患者报告了3或4级不良事件（感染：n = 10，皮疹：n =1）。第二种癌症（黑色素瘤）发生在一名患者身上。两名患者撤回了他们的同意。在诱导期，观察到的最佳应答是CR （n = 16）、PR （n = 11）、病情稳定（n = 5）和病情进展（n = 11）， ORR为63%（27/43）。在诱导期结束时，43例患者可评估主要目标。ORR为39%(17/43)，其中CR 13例（30%）。在包括PCNSL （n = 13,32%）和IO复发或PVRL （n = 4,44%）的患者中观察到应答。17名患者开始了维持期。中位随访时间为9个月（范围1.1-15.4），整个人群的中位总生存期和无进展生存期分别为15.3个月（95% CI， 9.6 -未达到）和8.1个月（95% CI， 4.2 -未达到）。应答患者的中位应答持续时间为8.9个月（95% CI， 7.6-未达到）。维护阶段的结果尚未公布。结果将进一步更新。结论：这项II期研究表明，利妥昔单抗-来那度胺方案在复发或难治性PCNSL或PVRL中具有显著的活性。等待更长时间随访的最新结果，以更好地评估PFS和中位反应持续时间。该方案值得加入到PCNSL的药物装备中，并进一步探索与其他化疗联合用于一线治疗，作为维持治疗，或作为不适合大剂量甲氨蝶呤的患者的无化疗方案。融资：Celgene， Roche披露：Ghesquieres:Celgene：咨询公司，董事会或咨询委员会成员；罗氏法国：研究经费；Mundipharma:咨询公司。·曲克:Celgene公司:咨询公司;詹森:咨询公司。Morschhauser:Celgene：咨询公司；罗氏：咨询公司；吉利德科学：咨询公司；詹森:谢礼;施维雅：咨询公司。罗氏：研究经费；药理学：研究经费；Celgene：研究经费。

Background Primary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype. Despite improvement of therapeutic results since the introduction of high-dose methotrexate (MTX) in first-line treatment, improvements of therapeutic results are needed in PCNSL, both in first-line treatment and at relapse. The roles of consolidation and maintenance therapy need to be addressed as well. The association of Rituximab and Lenalidomide has shown activity in non-CNS non-GC DLBCL, but its activity in PCNSL was unknown. Methods In this prospective, multicenter open-label phase II study, we enrolled patients over 18 with a refractory or relapse PCNSL or primary vitreo-retinal lymphoma (PVRL) of DLBCL type. The treatment consisted in an induction phase with 8 cycles of 28 days with R2 (Rituximab 375/m2 IV D1; Lenalidomide 20 mg/D D1-D21 for the first cycle then 25 mg/D D1-D21 for the subsequent cycle in the absence of hematologic toxicity), followed, in responder patients by a maintenance phase with 12 cycles of 28 days with Lenalidomide alone (10 mg/D, D1-D21). Corticosteroids were allowed during the first induction cycle in case of a threatening or symptomatic edema. Deep vein thrombosis prophylaxis was mandatory. Patient who received a complete month of treatment were evaluable for response. The primary end-point was the objective response rate (ORR) at the end of the induction phase, according to the international primary CNS lymphoma collaborative group (IPCG) criteria. The analysis was based of a Fleming9s two-step design (P0 = 10 %; P1= 30%). A pilot exploration of circulating NK and T cells before and after treatment and correlation with therapeutic response was conducted. This study is registered with ClinicalTrials.gov, number NCT01956695 Results Between September 17, 2013 and September 29, 2015, fifty patients (median age: 69, range 46-86) were recruited from 10 centers. All the patients had previously received high-dose (HD) MTX. Median number of previous lines of chemotherapy was 2 (range, 1-4). Nine patients had previous received an HD chemotherapy followed by hematopoetic stem cell rescue. Initial diagnoses were PCNSL (n = 42) and PVRL (n = 8). At time of inclusion in the study, diagnoses were PCNSL (n = 41) and PVRL or isolated intra-ocular (IO) relapse of PCNSL (n=9). Seven patients had concomitant involvement of the cerebrospinal fluid (CSF). Patients were included either for a relapse after last treatment (80 %; median time to relapse = 5.5 months), or for a refractory disease (20 %). Thirty-four patients received concomitant corticosteroids during the first month of treatment. Forty-five patients were evaluable for response after the first cycle of treatment. Median number of induction cycles was 7 (range, 1-8). Grade 3 or 4 adverse events were reported in 11 patients (infection: n = 10, cutaneous rash: n =1). A second cancer (melanoma) occurred in one patient. Two patients withdrew their consent. During the induction phase, best observed responses were CR (n = 16), PR (n = 11), stable disease (n = 5) and progressive disease (n = 11) for an ORR of 63% (27/43). . At the end of the induction phase, 43 patients were evaluable for the primary objective. ORR was 39 % (17/43) including 13 CR (30%). A response has been observed in patients included for a PCNSL (n = 13, 32%) and for an IO relapse or PVRL (n = 4, 44%). Seventeen patients started the maintenance phase. With a median follow-up of 9 months (range, 1.1-15.4), median overall and progression-free survivals of the whole population were 15.3 months (95 % CI, 9.6 - non reached) and 8.1 months (95 % CI, 4.2 - non reached) respectively. Median duration of response in the responder patients was 8.9 months (95 % CI, 7.6- non reached). The results of the maintenance phase are pending. Results will be further updated. Conclusion This phase II study demonstrates a significant activity of the rituximab-lenalidomide regimen in relapse or refractory PCNSL or PVRL. Updated results with a longer follow-up are awaited to better evaluate the PFS and the median duration of response. This regimen warrants to be added in the armamentarium drugs for PCNSL and further explored in combination with other chemotherapies in first-line treatment, as maintenance therapy, or as a chemo-free regimen for patients unfit for high-dose methotrexate. Funding: Celgne, Roche Disclosures Ghesquieres:Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Roche France: Research Funding; Mundipharma: Consultancy. Choquet:Celgene: Consultancy; Janssen: Consultancy. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Soussain:Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding.

Rituximab-Lenalidomide (REVRI) in Relapse or Refractory Primary Central Nervous System (PCNSL) or Vitreo Retinal Lymphoma (PVRL): Results of a "Proof of Concept" Phase II Study of the French LOC Network

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