VITAMIN D DEFICIENCY IMPAIRS RITUXIMAB-MEDIATED CELLULAR CYTOTOXICITY

To investigate the impact and underlying mechanisms of vitamin D-deficiency (VDD) on the outcome of elderly (61 to 80 years) patients with diffuse large B-cell lymphoma (DLBCL), we measured 413 pretreatment 25-OH-vitamin D serum levels from 2 trials (RICOVER-60 and RICOVER-noRTh) by a commercially available chemoluminescent immunoassay (DiaSorin, LIASON). The 359 RICOVER-60 patients with VDD (defined as serum levels < or =8 ng/ml, determined by an exploratory analysis) and treated with rituximab had a 3-year event-free survival of 59% compared to 79% in patients with vitamin D levels >8 ng/ml; 3-year overall survival was 70% and 82%, respectively. These differences were significant in a multivariable analysis adjusting for IPI risk factors with a hazard ratio (HR) of 2.1 (p=0.008) for event-free and 1.9 (p=0.040) for overall survival. These results were confirmed in an independent validation set of 63 patients from the RICOVER-noRTh study. An explanatory mechanism may be impaired Rituximab-mediated cellular cytotoxicity (RMCC) in VDD individuals. RMCC was determined by LDH release assay of CD20+ Daudi cells attacked by NK-cells. In otherwise healthy volunteers with VDD (8.4+ or -3.0 ng/ml) substituted to normal values (40.6+ or -13.6 ng/ml) the RMCC increased significantly (p