Introduction: Lymphocytes, including lymphoma cells require many micronutrients to grow and differentiate properly. Vitamin D is one of the most studied micronutrients in this context. Its deficiency is often related to a worse prognosis, but clinical trials with vitamin D substitution produced controversial results. We hypothesized that vitamin D, but also other micronutrients may play a role in lymphoma prognosis. We analyzed a set of selected micronutrients (vitamin D, vitamin B12, folate, zinc, and selenium) in a robust cohort of lymphoma patients.

Methods: We present single-center retrospective analysis of prospectively collected data on consecutively included patients with newly diagnosed NHL. Blood samples for micronutrient analysis were taken once before the start of any therapy; basic clinical and demographic data were obtained from the Czech Lymphoma Study Group registry. First, we tested the relationship between each micronutrient and clinical parameters. Next, we analyzed if the deficit of one micronutrient is associated with others, and calculated their impact on survival parameters (progression-free survival, PFS; overall survival, OS). The project was approved by ethical board of University Hospital Brno, Czech Republic.

Results: In total, we recruited 1196 lymphoma patients newly diagnosed between 05/2011 and 06/2020. Median age at diagnosis was 65 years; 49.5% were males. The median follow-up of the cohort is 3.9 years (0.003-13.01), 334/1196 (27.9%) patients died (median follow-up of living patients is 4.6 years; range 0.05-11.88). There were 474 (39.6%) patients with diffuse large B-cell lymphoma (DLBCL), 220 (18.4%) with follicular lymphoma (FL), 93 (7.7%) with mantle cell lymphoma (MCL), 135 (11.3 %) with marginal zone lymphoma (MZL), 201 (16,8%) with other subtype of B-NHL, 73 (6.2%) with T-non-Hodgkin lymphoma (T-NHL). Clinical stage ≥3 was present in 724 (60,5%) pts, ECOG ≥2 was in 251 (21%) pts, and elevated LDH in 795 (66,5%) of cases. Vitamin D deficiency (≤50 nmol/L) was found in 59.9% of patients at diagnosis, including severe deficiency (<30 nmol/L) in 32% of cases. Selenium deficiency (<0.66 µmol/L) was present in 31.7%, zinc deficiency (<10 µmol/L) in 18.7%, and vitamin B12 deficiency (<145 pmol/L) in 6.6% of patients, whereas folate was normal in 99,6% of patients. According multivariate analysis, deficit of vitamin D was strongly associated with deficit of selenium, zinc, folate, hypoalbuminemia (p<0.001) and elevated CRP (p<0.001). Vitamin D, zinc and selenium levels were significantly lower in older patients, those with aggressive lymphoma subtype, higher LDH, and ECOG ≥2 (all p<0.0001).

Vitamin D deficiency was strongly associated with shorter OS (median 8,9 yrs vs. not reached (NR); p<0.0001) and PFS (median 5,06 yrs vs. NR; p<0,0001). Moreover, patients with blood zinc levels <10 µmol/L and selenium <0.66 µmol/L also had shorter median OS (4.4 vs. 8.9 yrs and 2.6 vs. 8.9 respectively) and PFS (2.4 vs. 13.1 yrs and 1.7 vs. 13.0 yrs; all p< 0.001). Vitamin B12 and folate levels showed no significant prognostic association.

Based on results above, we constructed a cumulative “micronutrient score”, which included vitamin D (cut-off 40 nmol/L), selenium (cut-off 0.66 μmol/L) and zinc (cut-off 10 μmol/L) in 659 pts with all three parameters known. Patients without any deficiency (n=227) had significantly better OS and PFS (medians NR) versus patients with lack of one (n=211), two (n=146) or all three nutrients (n=75), with respective median OS 8.9 yrs, 4.78 yrs and 1.23 yrs (p<0.0001), and PFS 13,01 yrs, 2,4 yrs, and 0,93 yrs (p<0.0001). We calculated the same score for patients with DLBCL (n=269) and FL (n=114) separately. For DLBCL pts with 0, 1, 2 or 3 micronutrient deficiencies, median OS were NR vs. 8.9 vs. 4.42 vs. 1.31 yrs (p<0.0001), and median PFS were NR vs. NR vs. 2.4 vs. 0.99 yrs (p<0.0001). For FL, the differences were not significant.

Conclusion: Deficiencies of vitamin D and immune micronutrients (especially selenium and zinc) are common in lymphoma patients at diagnosis and are associated with higher disease aggressivity and reduced survival. Routine assessment of these deficiencies may help to identify patients at high risk, and substitution could help improve treatment results by optimizing immune and regenerative functions. Prospective trials are needed to confirm our results.

Supported by grant: NU23-03-00127

On behalf of Czech Lymphoma Study Group

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2025
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