[ASCO 2017]原发性CNS淋巴瘤的治疗新选择

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2017年6月2-6日，一年一度的美国临床肿瘤学会（ASCO）年会已在芝加哥举办。当地时间6月3日下午的非霍奇金淋巴瘤专场上，研究人员报道了三种罕见恶性肿瘤的治疗进展（摘要号为7515 和7516），包括难治性和复发性原发中枢神经系统（CNS）淋巴瘤（PCNSL，临床上极具挑战性的弥漫性大B细胞淋巴瘤）、继发性中枢神经系统淋巴瘤（SCNSL）以及原发性玻璃体视网膜淋巴瘤（PVRL）。由于疾病的罕见性，所报道的这两项研究均较小。

来自纽约的Christian Grommes教授报道了伊布替尼单药治疗复发和难治性PCNSL和SCNSL的最新疗效数据（abstract 7515）。该研究共纳入25例成人患者，其中有20例发生了3级毒性事件，包括淋巴细胞减少、血糖升高、ALT升高、血小板减少、肺部感染、AST升高、发热型中性粒细胞减少症、尿路感染、肠炎和贫血等。无患者死亡。

中位随访414天。在接受评估的22例患者中，总反应率为68%（10例完全缓解，7例部分缓解）。

来自弗罗里达的Han W. Tun教授报道了另一项研究（摘要号：7516）的最终结果，该研究探讨了泊马度胺治疗复发/难治性PCNSL和PVRL患者的最大耐受剂量。该研究共纳入29例患者。

最大耐受量确定为5mg/d，治疗21天（28天为一疗程）。结果显示，4例患者获得了完全缓解，2例患者获得了未证实的完全缓解。所有患者的中位无进展生存期为5.3个月，产生缓解的患者中位无进展生存期为9个月。

44%的患者发生了3/4级不良事件，包括白细胞减少、中性粒细胞减少和淋巴细胞减少，52%的患者发生了非血液学不良事件，包括疲劳、脓毒症、呼吸困难、高血糖、呼吸衰竭及肌无力等。

这些研究结果表明，泊马度胺对PCNSL和PVRL患者是“安全有效”的。Tun教授表示，应进一步评估泊马度胺与标准诱导化疗方案、免疫治疗方案以及维持方案联合应用的疗效。

摘要原文

1.  Abstract 7515：Updated results of single-agent ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL).

Background: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in Mantle cell lymphoma, CLL, Marginal Zone, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. 

Methods: Eligible patients had r/r PCNSL or SCNSL, age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. 

Results: Twenty-five patients were enrolled (3 at 560 mg; 22 at 840 mg). Median age was 68 (range 21-85); 15 were women. Median ECOG was 1 (0: 2, 1: 15, 2: 8). 64% had PCNSL and 36% SCNSL; 68% had recurrent disease. Seventeen had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 5 both. Seven grade 4 adverse events were observed in 7 patients neutropenia (in 3 patients), lymphopenia (2), sepsis (1), and ALT elevation (1). Fourteen patients developed 20 grade 3 toxicities, including lymphopenia in 5 patients, hyperglycemia in 3, ALT elevation in 2, thrombocytopenia in 2, lung infection in 2, AST elevation in 1, neutropenia in 1, urinary tract infection in 1, colitis in 1, febrile neutropenia in 1 and fungal encephalitis in 1. The most common toxicities at any grade were hyperglycemia, thrombocytopenia and anemia of which most were grade 1/2. No grade 5 events have been observed. After a median follow-up of 414 days (range 289-674), 22/25 patients were evaluated for response (3 did not complete at least 15 days of drug treatment). Over all response was 68% (17/22; 77% (17/22) in patient that completed at least 15 days of drug treatment) with 10 CR, 7 PR, 2 SD and 3 PD as best response. The median PFS is 4.6 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 15.3 months). The median overall survival has not been reached. 

Conclusions: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 68% of CNS lymphoma patients. Clinical trial information: NCT02315326

2.  Abstract 7516：Phase I clinical trial on pomalidomide and dexamethasone in treating patients with relapsed/refractory primary central nervous system lymphoma (PCNSL) or primary vitreoretinal lymphoma (PVRL).

Background: PCNSL is a diffuse large B cell lymphoma confined to the CNS. Pomalidomide (POM) is a novel immunomodulatory agent with excellent CNS penetration (~40%) based on CNS PK analysis in rats and pre-clinical therapeutic activity against CNS lymphoma. 

Methods: A Phase I clinical trial was undertaken to determine the maximal tolerated dose (MTD) of POM, safety profile and overall response rate (ORR). Treatment consists of POM daily for 21 days every 28 days in combination with dexamethasone 40 mg PO weekly for two cycles followed by POM alone in subsequent cycles until progression or intolerance. 4 dose escalation levels of POM (3mg, 5mg, 7mg, and 10 mg) were planned. Thromboprophylaxis with oral anticoagulant or aspirin was required. MTD determination has been completed and expansion of the MTD cohort is ongoing. Therapeutic responses were evaluated per the international PCNSL collaborative group (IPCG) criteria after 2 cycles of treatment. The trial is registered with ClinicalTrials.gov (#NCT01722305). 

Results: 21 of 25 patients accrued were eligible for assessment. The MTD was determined to be 5 mg qd for 21 days every 28 days. Two DLTs were seen at dose level 3 (Grade 3 dyspnea and grade 4 thrombocytopenia). One DLT was seen in the expanded MTD cohort (Grade 4 neutropenia and lymphocytopenia). ORR for the study (9/21) was 43% (95% CI- 22%, 66%) with 4 CR, 1 CRu and 4 PR. 3 responders completed 2, 4, and 6 cycles before progression. 6 responders have completed 4, 5, 6, 10, 12, and 32 cycles and remain on treatment. ORR for the MTD dose level was (5/12) 42% (95% CI- 15%, 72%) with 3 CR and 2 PR. 2 patients had stable disease (SD). Pseudo-progression was seen in 1 patient. Overall, grade 3/4 toxicity was hematologic (neutropenia, anemia, and thrombocytopenia) in 38.1% and non-hematologic in 33.3% (fatigue, pneumonia, sepsis, syncope, dyspnea, hypoxia, respiratory failure and maculo-papular rash). Percent CSF/blood ratio of POM was determined to be 19% in 1 patient. 

Conclusions: Pomalidomide treatment is feasible with therapeutic activity against relapsed/refractory PCNSL and should be further developed. Clinical trial information: NCT01722305