In a study reported in the Journal of Clinical Oncology, Sven Borchmann, MD, of the German Hodgkin Study Group, University Hospital of Cologne, and colleagues found that pretreatment vitamin D deficiency was associated with significantly poorer progression-free and overall survival in patients receiving first-line treatment for Hodgkin lymphoma in German Hodgkin Study Group trials.¹

We demonstrated for the first time that vitamin D deficiency at baseline is associated with impaired long-term tumor control and survival in patients with [Hodgkin lymphoma]….

— Sven Borchmann, MD. ©University Hospital of Cologne

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Study Details

The analysis involved 351 patients receiving first-line treatment in three randomized German Hodgkin Study Group trials: HD7 in early-stage favorable disease, HD8 in early-stage unfavorable disease, and HD9 in advanced-stage disease. Serum 25-hydroxyvitamin D was used as the marker for vitamin D status, with levels being measured using a commercially validated enzyme-linked immunosorbent assay. Levels of ≥ 50 nmol/L were categorized as sufficient, levels between 30 and 50 nmol/L were considered insufficient, and levels less than 30 nmol/L were categorized as deficient. The investigators noted that these ranges were selected for use based on findings indicating that they are predictive of clinical vitamin D deficiency syndromes. P values for between-group comparisons were obtained from weighted Cox regression analysis stratified by study/treatment arm and adjusted for diagnosis season, age, and sex.

Baseline Vitamin D Levels and Outcomes

Baseline vitamin D deficiency was found in 175 patients (50%), vitamin D insufficiency was noted in 83 patients (24%), and vitamin D sufficiency was reported in 93 patients (26%). Vitamin D sufficiency was more likely in patients diagnosed in summer months (46% vs 25% of those with vitamin D insufficiency and 19% of those with vitamin D deficiency, overall P < .001). No other significant differences among the three groups were found for age, sex, other diagnosis seasons, Karnofsky performance status, International Prognostic Index score, or clinical risk factors consisting of large mediastinal mass (P = .19), extranodal involvement (P = .31), three or more nodal areas (P = .31), elevated erythrocyte sedimentation rate (P = .62), clinical stage IV disease (P = .68), and B symptoms (P = .61).

Vitamin D deficiency was more common in patients with relapsed or refractory disease vs relapse-free controls matched 1:2 by study and treatment (68% vs 41%, P < .001; median baseline levels of vitamin D = 21.4 nmol/L vs 35.5 nmol/L). This difference was present across all studies and treatment groups among the HD7, HD8, and HD9 trial populations, indicating an association between vitamin D deficiency and an increased risk of relapse or disease progression irrespective of initial disease stage or treatment received.

Median follow-up for survival outcomes was 13 years. Progression-free and overall survival were similar among patients with sufficient vs insufficient vitamin D levels, and the two groups were combined for comparisons vs the vitamin D–deficient group. For vitamin D–deficient vs insufficient/sufficient patients, progression-free survival was 74.4% vs 84.6% at 5 years and 64.2% vs 81.8% at 10 years (10-year difference = 17.6%, hazard ratio [HR] = 2.13, P < .001). Overall survival was 87.4% vs 89.4% at 5 years and 76.1% vs 87.2% at 10 years (10-year difference = 11.1%, HR = 1.82, P < .001). Findings were consistent across trials and treatment groups. The investigators noted that the difference in overall survival primarily reflected a higher proportion of Hodgkin lymphoma–related deaths in patients with vitamin D deficiency.

Preclinical Studies

In preclinical studies to assess the potential role of vitamin D in chemosensitivity in Hodgkin lymphoma, the investigators found that treatment of cultured Hodgkin lymphoma cell lines with physiologic doses of vitamin D (calcitriol) resulted in increased antiproliferative effects in combination with chemotherapy. In a Hodgkin lymphoma xenograft model, vitamin D (cholecalciferol dietary supplement) plus chemotherapy reduced the tumor growth rate compared with either alone.

The investigators concluded: “In our study, 50% of patients were vitamin D deficient at first diagnosis of [Hodgkin lymphoma], independent of disease stage or other clinical risk factors. We demonstrated for the first time that vitamin D deficiency at baseline is associated with impaired long-term tumor control and survival in patients with [Hodgkin lymphoma]…. On the basis of our clinical and preclinical findings, we encourage that vitamin D screening and replacement be incorporated into future randomized clinical trials to properly clarify the role of vitamin D replacement therapy in [Hodgkin lymphoma].” ■

DISCLOSURE: For full disclosures of the study authors, visit ascopubs.org.

REFERENCE

1. Borchmann S, Cirillo M, Goergen H, et al: Pretreatment vitamin D deficiency is associated with impaired progression-free and overall survival in Hodgkin lymphoma. J Clin Oncol. October 17, 2019 (early release online).