Indolent Lymphoma and Vitamin D (ILyAD): A Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Supplemental Effect of Vitamin D on Event-Free Survival in Patients with Low Tumor Burden Indolent Non-Hodgkin Lymphoma Treated with Rituximab

Background: Indolent lymphomas, including follicular lymphoma (FL) and marginal zone lymphoma, are the most prevalent lymphomas in the United States. Though outcomes have improved substantially since the introduction of rituximab, with median overall survival now exceeding 20 yrs for FL, these diseases are characterized by an incurable clinical course (Tan et. al. Blood 2013). A subset of patients has substantially shorter survival and virtually all patients require intermittent or chronic, and often morbid therapy. Moreover, the financial cost of these therapies often exceeds $100,000 annually per patient. Therefore, lower intensity and better-tolerated, cost-effective treatments are needed. An analysis of newly diagnosed FL patients treated with standard chemotherapy plus anti-CD20 therapy in two clinical trials reported a significant association between low vitamin D levels and inferior clinical outcomes; this observation has been subsequently validated by other groups. The magnitude of this association is stronger than the individual clinical prognostic factors within the FL-IPI score and may be the strongest, and only modifiable, association reported to date of a pre-therapy prognostic factor in FL (Kelly et. al. J Clin Oncol 2015). Moreover, rituximab-mediated cytotoxicity is improved in vitro in the setting of sufficient vitamin D (Bittenbring et al. J Clin Oncol 2014). Based upon these observations, we designed a randomized trial to evaluate whether vitamin D supplementation improves outcomes in patients with indolent lymphoma treated with rituximab.

Methods: This NIH-funded, multi-center, double-blind, randomized, placebo-controlled, phase III study is currently enrolling adults with biopsy-proven, indolent, low tumor burden FL, marginal zone, small lymphocytic lymphoma and mucosal associated lymphoid tissue histologies. Subjects are randomized, 2:1, to vitamin D, 2000IU daily or placebo daily for 3 years, or until disease progression. All patients receive standard treatment with rituximab in 4 weekly doses. The primary endpoint is 3-year event free survival (EFS), secondary endpoints include treatment response at week 13 and overall survival. Events are defined as lack of response at week 13, disease progression, initiation of new treatment and death. The study design provides 81% power to detect a HR of 0.55 at a 0.05 significance level, which corresponds to an increase in 3-year EFS from 40% to 60%. The primary analysis will include all treated subjects.

Correlative studies of blood PTH and vitamin D will identify if baseline vitamin D levels can predict patients for whom supplementation is particularly effective or ineffective. Evidence suggests that response to vitamin D supplementation may be dependent upon specific genotypes of the vitamin D receptor and vitamin D binding protein, and we are performing whole exome sequencing of patients to determine whether vitamin D related germline variations are critical determinants of outcome in the context of supplementation.

Implications: A positive finding of our study would have major implications on the treatment of follicular lymphoma and other indolent lymphomas, and given the low cost and low toxicity, the combination of vitamin D with rituximab would likely become standard of care for these patients. The cost of 3 years of vitamin D supplementation for all randomized patients in our trial is less than the commercial cost of two months of lenalidomide treatment for a single patient; lenalidomide has been approved in a similar patient population. Further implications of a positive study include support for subsequent studies of vitamin D supplementation in other lymphoma subtypes, and other malignancies treated with monoclonal antibodies relying on antibody dependent cellular cytotoxicity, such as the subset of breast cancer treated with trastuzumab, and solid tumors treated with cetuximab. Our study is currently open and accruing at 7 centers with an enrollment target of 210 subjects (NCT03078855).