Correction of Vitamin D Deficiency in Patients with Aggressive B-Cell Lymphomas during Rituximab-Containing Chemotherapy: Impact on Outcome
Authors: Hohaus Stefan , Tisi Maria Chiara , Bellesi Silvia , Maiolo Elena , Tartaglia Germana , Corrente Francesco , Alma Eleonora , D'Alo' Francesco 
Published: October 2019

Abstract
Vitamin D deficiency has been reported to be a risk factor in elderly patients (pts) with diffuse large B cell lymphoma (DLBCL) treated with Rituximab-containing chemotherapy (R-CHOP) (Bittenbring et al, J Clin Oncol 32:3242, 2014). In vitro data suggest that vitamin D supplementation could enhance rituximab-mediated cytotoxicity.
In a single-center study, we prospectively measured 25-OH Vitamin D levels at diagnosis in a cohort of 156 pts with aggressive B cell non-Hodgkin lymphoma (DLBCL NOS, 129 pts; primary mediastinal large B cell lymphoma, 9 pts; B cell lymphoma, unclassifiable with intermediate characteristics between DLBCL and Burkitt lymphoma, 8 pts; T-cell/histiocyte-rich large B cell lymphoma, 4 pts; other forms, 6 pts) who were candidates for Rituximab-containing chemotherapy (R-CHOP or equivalent). Pts with deficient/insufficient vitamin D levels were offered supplementation. We used the formula of Singh (JABFM 27:495, 2014) to calculate the need of Vitamin D supplementation. Vitamin D levels were controlled during supplementation. Event Free Survival (EFS) was defined as time from diagnosis to relapse, disease progression or change of therapy for any reason or death.
Vitamin D levels were considered deficient (<10 ng/ml) in 52 pts (33%), insufficient (10 to 30 ng/ml) in 86 pts (55%), and normal (>30 to 100 ng/ml) in 18 pts (12%). Looking at pts characteristics, there was no difference in vitamin D levels according to sex (p=0.5), age (p=0.8) or stage (p=0.5), while poor performance status (ECOG > 2) and high LDH levels were significantly associated with lower vitamin D levels (p=0.002 and p=0.0007). We observed a weak, but significant negative correlation between Vitamin D levels and Hb and albumin levels (p=0.003 and p=0.0001, respectively). In addition, there was a significant seasonal variation with lowest vitamin D levels in the second trimester (p=0.001).
We implemented an oral substitution regimen with Vitamin D3 (cholecalciferole) to increase vitamin D levels early during treatment. Vitamin D (cholecalciferole 25000 U) was given once a week following a loading phase of daily doses of 25000 U for 1 week in patients with insufficient Vitamin D levels and for 2 weeks with deficient Vitamin D levels. Vitamin D substitution was stopped at end of treatment. This supplementation resulted in substitution of Vitamin D over the treatment period of 4951 U/d in patients with insufficient Vitamin D levels (median of calculated need in 86 pts: 4374 U/d) and of 5612 U/d for patients with deficient Vitamin D levels (median of calculated need 6379 U/d in 52 pts). A total of 116 patients received Vitamin D supplementation. A second determination of Vitamin D levels after a median of 1.7 month in 84 pts showed a significant increase of Vitamin D levels from a median of 17 ng/ml to 33 ng/ml (p=0.001). Supplementation resulted in normalization of Vitamin D levels in 46/84 pts (55%). No episodes of hypervitaminosis or hypercalcemia were observed.
We analyzed the prognostic impact of vitamin D levels at diagnosis and after supplementation. Pts with vitamin D levels in the normal range either at diagnosis or due to supplementation (n=61) had a significant better EFS at 18 months when compared to pts with persistently deficient/insufficient vitamin D levels (n=44) (88% versus 77%, p=0.03). Vitamin D levels at diagnosis before supplementation only showed a trend for impact on EFS (p=0.09).
We conclude that Vitamin D deficiency is frequent in pts with aggressive B-cell lymphomas also in central Italy. Vitamin D supplementation results in improved vitamin D levels. Our data suggest that outcome in pts with DLBCL treated with rituximab-containing chemotherapy may be improved by vitamin D supplementation.

Disclosures
No relevant conflicts of interest to declare.