Vitamin D deficiency and supplementation in patients with aggressive B-cell lymphomas treated with immunochemotherapy

Abstract

Vitamin D deficiency has been reported to be a negative prognostic factor in elderly patients with aggressive B-cell lymphomas. In vitro data suggest that vitamin D supplementation may enhance rituximab-mediated cytotoxicity. We prospectively assessed 25-hydroxyvitamin D [25(OH)D] levels at diagnosis in a cohort of 155 patients with aggressive B-cell lymphomas of whom 128 had diffuse large B-cell lymphoma (DLBCL) not otherwise specified. 25(OH)D levels were deficient (<20 ng/mL) in 105 (67%), insufficient (20-29 ng/mL) in 32 (21%), and normal (≥30 ng/mL) in 18 (12%) patients with a seasonal variation. Patient characteristics associated with lower 25(OH)D levels were poor performance status, overweight, B-symptoms, elevated LDH, lower albumin and hemoglobin levels. As a result of a change in practice pattern, 116 patients received vitamin D3 (cholecalciferol) supplementation that included a loading phase with daily replacement and subsequent maintenance phase with a weekly dose of 25,000 IU until end of treatment. This resulted in a significant increase in 25(OH)D levels, with normalization in 56% of patients. We analyzed the impact of 25(OH)D levels on event-free survival in patients treated with Rituximab-CHOP. 25(OH)D levels below 20 ng/mL at diagnosis and IPI were independently associated with inferior EFS. Moreover, patients with normalized 25(OH)D levels following supplementation showed better EFS than patients with persistently deficient/insufficient 25(OH)D levels. Our study provides the first evidence that achievement of normal 25(OH)D levels after vitamin D3 supplementation is associated with improved outcome in patients with DLBCL and deficient/insufficient 25(OH)D levels when receiving rituximab-based treatment.

Keywords: Aggressive B-cell lymphoma; Vitamin D; prognosis; supplementation.

Figure 1

Supplementation with vitamin D3 during rituximab‐containing chemotherapy. Three different vitamin D3 (cholecalciferol) regimens were applied. Regimen 1 consisted in weekly administration of 25,000 IU vitamin D3. In regimen 2 and 3, patients started with a loading phase of vitamin D3 25,000 IU daily for 7 or 14 days, respectively, and then continued with 25,000 IU weekly till the end of therapy.

Figure 2

25(OH)D levels in 155 patients with aggressive B‐cell lymphomas. (A) Box‐plot of 25(OH)D levels. The upper border of the box indicates the upper quartile (75th percentile) while the lower border indicates the lower quartile (25th percentile), and the horizontal line in the box the median. The vertical lines are the whiskers indicating the upper and lower adjacent values. (B) Distribution of patients according to 25(OH)D levels considered to be normal (≥30 ng/mL), insufficient (20–29 ng/mL), or deficient (<20 ng/mL). C) Seasonal variation in 25(OH)D levels were significantly lower in the period from April to June (P < 0.001).

Figure 3

Variation in 25(OH)D levels during supplementation. (A) in patients supplemented with vitamin D3 according to regimen 1, (B) patients supplemented with regimen 2. (C) Proportion of patients with 25(OH)D levels during supplementation in the normal (≥30 ng/mL), insufficient (20–29 ng/mL), and deficient (<20 ng/mL) range. 25(OH)D levels were measured in 81 patients.

Figure 4

Event‐free survival in patients with aggressive B‐cell lymphoma according to 25(OH)D levels at diagnosis. (A) Group A (n = 50 patients) had 25(OH)D levels ≥ 20 ng/mL at diagnosis, group B (n = 104 patients) had 25(OH)D levels <20 ng/mL at diagnosis. The survival difference is statistically significant (P = 0.01). (B) The survival analysis was restricted to 116 patients treated with R‐CHOP containing full dose of doxorubicin, according to 25(OH)D levels. Group A (n = 43 patients) had 25(OH)D levels ≥20 ng/mL at diagnosis, group B (n = 73 patients) had 25(OH)D levels <20 ng/mL at diagnosis. The difference is statistically significant (P = 0.03).

Figure 5

Event‐free survival in patients with aggressive B‐cell lymphoma according to 25(OH)D levels following supplementation. The survival analysis was restricted to 68 patients treated with R‐CHOP containing full dose of doxorubicin, according to 25(OH)D levels. Group A (n = 36 patients) had normal (≥30 ng/mL), and group B lower than normal (<30 ng/mL) 25(OH)D levels after loading phase. The survival difference is statistically significant (P = 0.02).