Vitamin D deficiency linked to poor outcome in patients with Hodgkin lymphoma

Vitamin D, a precursor of the corticosteroid hormone calcitriol, is not only important for appropriate calcium homeostasis and bone heath, but some studies suggest that its higher levels are associated with lower risk of developing certain types of cancer.^1,2 Recently, the incidence of Hodgkin lymphoma (HL) has been demonstrated to peak during early spring, which coincides with lower levels of vitamin D after winter months due to insufficient exposure to the UVB irradiation required for vitamin D synthesis.^3–5 Sven Borchmann and colleagues carried out a randomized, case-controlled study to further evaluate the association between vitamin D deficiency and the incidence of HL, as well as its impact on patients’ mortality.⁶

Study design and patient characteristics

• Patients enrolled on trials with the German Hodgkin Study Group were randomised to risk-adapted first-line treatment with chemotherapy with or without radiotherapy
  • patients with early-stage favourable HL (HD7)⁷
  • patients with early-stage favourable unfavourable HL (HL8)⁸
  • patients with advanced-stage HL (HD9)⁹
• Two matched non-relapsed case control patients were used for each patient with relapsed or progressive disease

Main results

• In total, 351 patients were analyzed with a median follow-up of 13 years
• Patient characteristics were similar, with the exception of seasonal diagnosis effect (Table 1)
• Median pre-treatment vitamin D level was 30nm/L and was similar between treatment arms and stages
• At baseline, 50% of patients were categorized as vitamin D deficient
• As expected, patients diagnosed during winter were most likely to have insufficient/deficient levels of vitamin D, while those diagnosed during the summer were most likely to have sufficient levels

Table 1. Selected patient characteristics by vitamin D status

	Deficient (<30nmol/L; %) n= 175	Insufficient (between ≥30nmol/L and <50nmol/L; %) n= 83	Sufficient (≥50nmol/L; %) n= 93	P
* summer versus other seasons; IPS, International Scoring System
Median age	32 (16–75)	33 (17–71)	31 (16–66)	0.73
Sex Female Male	73 (42) 102 (58)	27 (33) 56 (67)	41 (44) 52 (56)	0.21
Diagnosis season Summer Autumn Winter Spring	33 (19) 36 (21) 52 (30) 54 (31)	21 (25) 17 (20) 16 (19) 29 (35)	43 (46) 22 (24) 13 (14) 15 (16)	<0.0001*
IPS <2 ≥2	88/129 (68) 41/129 (32)	53/71 (75) 18/71 (25)	64/84 (76) 20/84 (24)	0.52

• There was no correlation between the performance status or hematological toxicity and the level of vitamin D at diagnosis
• Across all studies and treatment arms pre-treatment vitamin D deficiency was associated with relapsed/refractory (R/R) disease
  • 63% of R/R cases versus 41% of relapse-free cases were recorded as vitamin D deficient (p< 0.001)
• No adverse effect on clinical outcomes was observed in patients with insufficient levels of vitamin D when compared to those with sufficient levels
• Patients with baseline vitamin D deficiency had significantly lower progression-free survival (PFS) (HR= 2.13; 95% CI, 1.84–2.48; p< 0.001) and overall survival (OS) (HR= 1.82; 95% CI, 1.53–2.15; p< 0.001) compared to patients with higher vitamin D levels
  • 5-year PFS difference 10.2% (95% CI, 0.8–19.6)
  • 10-year PFS difference 17.6% (95% CI, 6.9–28.4)
  • 5-year OS difference 2% (95% CI, -5.3–9.3)
  • 10-year OS difference 11.1% (95% CI, 2.1–20.2)
• In vitro studies revealed increased cytotoxic effect of doxorubicin and etoposide on HL cells pre-treated with physiological doses of calcitriol. Moreover, supplementation with vitamin D in combination with chemotherapy in animal models resulted in significantly reduced tumour growth (p=0.008), compared to placebo or monotherapies

Conclusion

Based on preclinical and clinical data, the authors advocate for further clinical trials in patients with HL to include monitoring of vitamin D levels and supplementation to further elucidate its role in control of HL.