Vitamin D and Follicular Lymphoma

摘要 惰性非霍奇金淋巴瘤是不治之症，需要间歇性和经常性的治疗。 在他们漫长的自然史中，病态和昂贵的治疗。强度较低， 这些患者需要更好的耐受性、成本效益的治疗策略。低维生素 诊断惰性淋巴瘤时的D水平与较低的预后密切相关， 治疗低肿瘤负荷、惰性淋巴瘤的标准治疗包括单药治疗 单克隆抗体（利妥昔单抗）。在这个建议中，我们将完成一个双盲，安慰剂- 对照随机试验，评价每日2000 IU口服片剂补充维生素D 持续3年可提高惰性淋巴瘤患者的无进展生存率 单药利妥昔单抗治疗随机化的分层因素将包括组织学 和FL-IPI预后评分。试验的主要终点是无进展生存期， 3年;次要终点包括13周时的反应和总生存期。计划 亚组分析包括滤泡性淋巴瘤组织学和女性。210例随机化 患者，我们将有80%的把握度在双侧α = 0.05水平检测HR = 0.55， 意义本临床试验将在罗切斯特大学威尔莫特癌症中心进行协调 研究所和六个专家淋巴瘤中心从淋巴瘤流行病学的结果 (LEO)财团将参与。我们将利用这个LEO联盟进行肿瘤银行业务， 入组患者的前瞻性患者报告结局。我们还将确定基线是否 和/或血清维生素D水平的再分期可预测维生素D缺乏的患者亚组， 补充特别有效或特别无效。最后，由于有 有证据表明，口服维生素D补充剂的反应可能取决于 维生素D受体（VDR）和维生素D结合蛋白（DPB）的特定基因型，我们将 利用全外显子组测序来确定维生素D相关的生殖系变异是否 在维生素D补充患者的背景下， 惰性淋巴瘤我们的目标是确定维生素D的阈值水平， 是最有效的，生殖系多态性对结果的影响将为未来的试验提供信息。 设计和有助于机械的理解。证明维生素D的益处 这项随机试验中的补充剂将迅速改变大多数人的护理标准。 无痛性淋巴瘤的常见表现，并提供一种低风险，耐受性好， 选择延迟病态治疗的时间。

ABSTRACT Indolent non-Hodgkin lymphomas are incurable diseases, and require intermittent and often morbid and expensive therapy during their prolonged natural history. Lower intensity and better-tolerated, cost-effective treatment strategies are needed for these patients. Low vitamin D levels at diagnosis of indolent lymphomas are strongly associated with inferior outcomes to treatment. Standard therapy for low tumor burden, indolent lymphoma includes a single agent monoclonal antibody (rituximab). In this proposal, we will complete a double-blind, placebo- controlled randomized trial evaluating if vitamin D supplementation with 2000IU oral tablets daily for three years improves the progression-free survival of patients with indolent lymphoma treated with single agent rituximab. Stratification factors for randomization will include histology and FL-IPI prognostic score. The primary endpoint of the trial is progression-free survival over three years; secondary endpoints include response at 13 weeks, and overall survival. Planned subset analyses include follicular lymphoma histology and female sex. With 210 randomized patients, we will have 80% power to detect a HR = 0.55 at a two sided alpha = 0.05 level of significance. This clinical trial will be coordinated at the University of Rochester Wilmot Cancer Institute, and six expert lymphoma centers from the Lymphoma Epidemiology of Outcomes (LEO) Consortium will participate. We will leverage this LEO consortium for tumor banking and prospective patient-reported outcomes of enrolled patients. We will also identify if baseline and/or restaging serum vitamin D levels predict subgroups of patients for whom Vitamin D supplementation is particularly effective or particularly ineffective. Finally, since there is evidence to suggest that response to oral vitamin D supplementation may be dependent upon specific genotypes of the Vitamin D receptor (VDR) and vitamin D binding protein (DPB), we will utilize whole exome sequencing to determine whether vitamin D-related germline variations are critical determinants of outcome in the context of vitamin D supplementation of patients with indolent lymphoma. Our aims the defining threshold levels of vitamin D where supplementation is most effective and the impact of germline polymorphisms on outcome will inform future trial designs and contribute to mechanistic understanding. Demonstrating a benefit to vitamin D supplementation in this randomized trial would rapidly change standard of care in the most common presentation of indolent lymphoma, and provide a low-risk, well-tolerated, inexpensive option delaying the time to morbid treatments.