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Chronic lymphocytic leukemia slowed by vitamin D - Mayo Nov 2010

2 minute 46 second Video by Mayo Clinic

Researchers at Mayo Clinic have found a significant difference in cancer progression and death in chronic lymphocytic leukemia (CLL) patients who had sufficient vitamin D levels in their blood compared to those who didn’t.

In the Mayo Clinic study, published online in the journal Blood, the researchers found that patients with insufficient levels of vitamin D when their leukemia was diagnosed progressed much faster and were about twice as likely to die as were patients with adequate levels of vitamin D.

They also found solid trends:increasing vitamin D levels across patients matched longer survival times and
decreasing levels matched shortening intervals between diagnosis and cancer progression.
The association also remained after controlling for other prognostic factors associated with leukemia progression.

The finding is significant in a number of ways. For the first time, it potentially offers patients with this typically slower growing form of leukemia a way to slow progression, says the study’s lead author, Tait Shanafelt, M.D., a hematologist at Mayo Clinic in Rochester, Minn.

Dr. Shanafelt explains the significance of the study findings
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Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia

Tait D. Shanafelt1, Matthew T. Drake2, Matthew J. Maurer3, Cristine Allmer3, Kari G. Rabe3, Susan L. Slager3, George J. Weiner4, Timothy G. Call1, Brian K. Link4, Clive S. Zent1, Neil E. Kay1, Curtis A. Hanson5, Thomas E. Witzig1, and James R. Cerhan6
1 Division of Hematology,
2 Division of Endocrinology, Department of Internal Medicine, and
3 Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN;
4 Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City, IA; and
5 Department of Pathology and
6 Division of Epidemiology, Mayo Clinic, Rochester, MN

Vitamin D insufficiency is common globally and low levels are linked to higher cancer incidence. Although vitamin D insufficiency is related to inferior prognosis in some cancers, no data exist for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We evaluated the relationship of 25(OH)D serum levels with time-to-treatment (TTT) and overall survival (OS) in newly diagnosed CLL patients participating in a prospective cohort study (discovery cohort) and a separate cohort of previously untreated patients participating in an observational study (confirmation cohort). Of 390 CLL patients in the discovery cohort, 119 (30.5%) were 25(OH)D insufficient. After a median follow-up of 3 years, TTT (hazard ratio[HR] = 1.66; P = .005) and OS (HR = 2.39; P = .01) were shorter for 25(OH)D-insufficient patients. In the validation cohort, 61 of 153 patients (39.9%) were 25(OH)D insufficient. After a median follow-up of 9.9 years, TTT (HR = 1.59; P = .05) and OS (HR 1.63; P = .06) were again shorter for 25(OH)D-insufficient patients. On pooled multivariable analysis of patients in both cohorts adjusting for age, sex, Rai stage, CD38 status, ZAP-70 status, immunoglobulin heavy chain variable (IGHV) gene mutation status, CD49d status, and cytogenetic abnormalities assessed by interphase fluorescent in situ hybridization testing, 25(OH)D insufficiency remained an independent predictor of TTT (HR = 1.47; P = .008), although the association with OS was not significant (HR = 1.47; P = .07). Vitamin D insufficiency is associated with inferior TTT and OS in CLL patients. Whether normalizing vitamin D levels in deficient CLL patients would improve outcome merits clinical testing.

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CLL: a supplementary question?

Blood. 2011 Feb 3;117(5):1439-40.
Pepper C, Fegan C. 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). 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.

Conflict-of-interest disclosure: The authors declare no competing financial interests. ? © 2011 by The American Society of Hematology

REFERENCES

? Shanafelt TD, Drake MT, Maurer MJ, et al. Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood 2011;117(5):1492-1498. Abstract/FREE Full Text

  • Holick MF. Vitamin D deficiency. N Engl J Med 2007;357(3):266-281. CrossRefMedline
  • Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab 2009;94(1):26-34. Abstract/FREE Full Text
  • Ramagopalan SV, Heger A, Berlanga AJ, et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease. Genome Res 2010;20(10):1352-1360. Abstract/FREE Full Text
  • Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 1983;221(4616):1181-1183. Abstract/FREE Full Text
  • Minghetti PP, Norman AW. 1,25(OH)2-vitamin D3 receptors: gene regulation and genetic circuitry. FASEB J 1988;2(15):3043-3053. Abstract
  • Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001;194(11):1639-1647. Abstract/FREE Full Text
  • Pepper C, Thomas A, Hoy T, et al. The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. Blood 2003;101(7):2454-2460. Abstract/FREE Full Text
  • Ahn J, Yu K, Stolzenberg-Solomon R, et al. Genomic-wide association of circulating vitamin D levels. Hum Mol Genet 2010;19(13):2739-2745. Abstract/FREE Full Text
  • Raimondi S, Johansson H, Maisonneuve P, Gandini S. Review and meta-analysis on vitamin receptor polymorphisms and risk of cancer. Carcinogenesis 2009;30(7):1170-1180. Abstract/FREE Full Text

See also VitaminDWiki

Attached files

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1244 CLL vitamin D.jpg admin 13 Apr, 2012 03:42 10.84 Kb 4635
1243 Blood-2011-Shanafelt-1492-8.pdf PDF admin 13 Apr, 2012 03:37 555.80 Kb 985
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