CLL: a supplementary question?

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BlankCLL: a supplementary question?

Pepper, and Fegan

CARDIFF UNIVERSITY

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.

Footnotes

Conflict-of-interest disclosure: The authors declare no competing financial

interests.

REFERENCES

1.. Shanafelt TD, Drake MT, Maurer MJ, et al. Vitamin D insufficiency and

prognosis in chronic lymphocytic leukemia. Blood. 2011;117(5):1492–1498

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D3 receptors in human leukocytes. Science. 1983;221(4616):1181–1183

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