The Mayo vitamin D paper

I have now had a chance to study the paper from the Mayo Clinic that found an association between low levels of vitamin D and poor prognosis in CLL. Obvious to all is the possibility that vitamin D supplements might improve the lot of CLL patients. Do we have enough information to recommend this?

390 patients with CLL (diagnosed by the 1996 guidelines of >5000/cu mm of lymphocytes in the blood) were observed. The following prognostic factors were measured at diagnosis: Rai stage, CD38, ZAP-70, IGHV mutations, CD49d, and FISH for del 13q, +12, del 11q and del 17p. All had their 25(OH) vitamin D levels measured in their serum. This was the discovery cohort. A confirmation cohort comprised 159 other untreated patients.

Vitamin D insufficiency was defined as <25 ng/mL. 119/390 (30.5%) patients in the discovery cohort were found to be vitamin D insufficient. Insufficiency had no relationship with any of the prognostic factors measured, or to the time of the year that it was measured. Time to treatment (TTT) and overall survival (OS) were shorter in the vitamin D insufficient cases.

In the confirmation cohort 39.9% were vitamin D insufficient. Again this did not correlate with other prognostic factors, except in the case of CD38 with which there was a statistically significant correlation. Again both TTT and OS were shorter in the vitamin D insufficient group. On multivariate analysis vitamin D insufficiency was an independent prognostic factor for TTT but not for OS.

Interestingly, for patients with mutated VH genes or with negative ZAP-70, having a low vitamin D level had no effect on overall survival, but it was associated with a poorer outcome for ZAP-70 positive patients and those with unmutated VH genes. It had a deleterious effect on patients with standard risk FISH (del 13q, normal karyotype and 12+) but did not influence those with poor risk FISH (del 1q and del 17p).

It is important to remember that association is not the same as causation. Even if causation were proved one would not know which caused which. Does having a poor prognosis CLL make your vitamin D level go down or vice versa? It helps if you want to suggest causation to have a plausible mechanism to account for it. The vitamin D receptor is highly expressed on B lymphocytes and it is known that vitamin D derivatives can induce caspase 3 and caspase 9-dependent apoptosis in the test tube. A number of biochemical pathways within B cells are influenced by vitamin D analogs including the MAPK pathway and the ERK pathway.

Low serum vitamin D levels have been found in association with an increased incidence of colorectal, breast and other cancers and there is one randomized clinical trial which found that supplementing the diet with vitamin D plus calcium reduced the incidence of cancer over that of women given a placebo. Unfortunately there was also a statistically significant reduction in incidence among women who were given calcium without vitamin D.

Thus it should not be assumed that vitamin D supplements will improve the lot of patients with CLL. It may do so but it should not be assumed. As a warning we should remember that two observational studies suggested that low levels of vitamin A (in the form of beta-carotene) were associated with a higher incidence of lung cancer. Unfortunately dietary supplementation made no difference to the incidence.

A clinical trial of vitamin D supplementation in CLL is clearly warranted, but at the moment there is no need for everybody with ‘insufficient’ levels to visit the health food shop.