CLL: a supplementary question?

In this issue of Blood, Shanafelt and colleagues provide the first evidence that vitamin D deficiency is a risk factor for disease progression in chronic lymphocytic leukemia (CLL).¹  Their findings imply that dietary vitamin D supplementation could potentially modify the natural history of this incurable disease.

It has been estimated that approximately 1 billion people worldwide have vitamin D insufficiency due to reduced exposure to sunlight or inadequate dietary intake.²  Vitamin D plays a central role in maintaining serum calcium and skeletal homeostasis but is also involved in the regulation of other vital cellular processes including differentiation, proliferation, apoptosis, and angiogenesis.³  Although its precise mechanisms of action remain incompletely resolved, vitamin D predominantly exerts its effects through the binding of calcitriol, the active form of vitamin D, to its cognate nuclear vitamin D receptor (VDR). A heterodimer, formed with the retinoid X receptor (RXR), then acts as a transcription factor by binding to specific genomic sequences (vitamin D response elements) resulting in altered gene transcription.⁴  The classic target organs of vitamin D are the intestines, kidney, and bone, but several other tissues also express VDRs including normal and neoplastic hematopoietic cells.^5,6 

A large number of studies have investigated a possible role for vitamin D in cancer prevention but, until now, none have shown that this secosteroid hormone is important in CLL. The study of Shanafelt et al¹  clearly demonstrates that vitamin D insufficiency is an independent risk factor in this disease. Remarkably, its prognostic power was evident even in early-stage patients (Rai stage 0) and retained independent prognostic significance in the presence of most of the major known risk factors in multivariate analysis. From a clinical perspective, vitamin D insufficiency represents the first potentially modifiable prognostic marker in CLL by presenting the opportunity for patients to have their serum vitamin D levels checked and, if they are deficient, vitamin D supplements administered to correct the deficit. Given that appropriate vitamin D supplements are likely to have a minimal side-effect profile, it seems plausible that they could be safely incorporated into the “watch-and-wait” strategy currently used for early-stage disease patients. If nothing else, this may well have positive psychological effects for many patients who struggle with feelings of powerlessness after being told they have leukemia that may progress.

Although we still await formal proof that normalizing vitamin D levels can improve clinical outcomes in this disease, there are certainly grounds for optimism. Previous gene expression profiling and protein analysis identified that the VDR is highly expressed in CLL cells compared with normal B and T lymphocytes.^7,8  Furthermore, pharmacologic doses of a vitamin D analog caused preferential in vitro cell killing in primary CLL cells through a p53-independent mechanism.⁸  Taken together, the evidence points toward a potentially important role for vitamin D not only as a prognostic marker but also as a therapeutic target in CLL. On a cautionary note, it would appear that vitamin D levels are subject to heritable genetic variation with 3 pivotal polymorphisms recently being identified.⁹  Furthermore, VDR polymorphisms have been associated with the risk of developing cancer and cancer progression although there are no reported studies in CLL.¹⁰  Therefore, it may not be possible to correct vitamin D insufficiency with dietary supplementation in at least some CLL patients. Only a prospective, well-designed, randomized, control clinical trial of vitamin D supplementation will prove whether we have truly “crossed the Rubicon” in CLL and identified a way of modifying the clinical course of this incurable disease with a simple vitamin tablet.