Vitamin D in patients with low tumour-burden indolent non-Hodgkin lymphoma treated with rituximab therapy

Dr Jonathan Friedberg - University of Rochester, Rochester, USA

The ILyAD study was a study that examined a vitamin D intervention in patients with low tumour burden follicular lymphoma. We’ve known now for eight or nine years that patients who are diagnosed with follicular lymphoma and who have a low vitamin D level have an inferior outcome. That’s been shown reproducibly across several datasets after our initial publication. So the concept of this trial was to ask the question if whether supplementing patients with vitamin D could improve outcome in patients with follicular lymphoma.

What was the study design?

So this was a placebo-controlled randomised trial where patients who had low tumour burden follicular lymphoma, as defined by the GELF criteria, or patients who had other indolent lymphoma subtypes, including small lymphocytic lymphoma and marginal zone lymphoma, were randomised to the following. So, all patients got rituximab weekly times four, and then two thirds of the patients got vitamin D which was 2000 units per day for up to three years, and one third of the patients got a placebo. It was a placebo-controlled trial.

All patients started the vitamin D or the placebo at the same time that the rituximab was started. At week 13, the patients were reassessed for response. If patients had a response, either a PR or a CR, they continued on either the vitamin D or placebo, as I said, for up to three years. If they did not have a response, that was considered an event, and they were then off of the trial.

What were the key results?

So, first of all, from the standpoint of safety, there was no signal of concern. We did measure vitamin D levels, which were blinded to the investigators, and we demonstrated that we were able to increase the vitamin D levels in the patients who got vitamin D supplementation. And that was also a surrogate measure of adherence to the trial. The other interesting finding as far as the vitamin D level, somewhat surprising to us, the median vitamin D level of patients coming on study was higher than we expected, and we had very few patients with vitamin D levels that were less than 20. That was different from what we had seen in the preliminary data from prior studies, and I think that speaks to the fact that many patients are receiving supplementation of vitamin D from their primary care physicians, presumably for bone health.

From an efficacy standpoint the study was a negative trial. There was no benefit to the addition of vitamin D as compared to rituximab alone. In fact whatever subgroup we looked at – histology-specific subgroup, risk subgroups within follicular lymphoma, or baseline vitamin D levels – we were unable to show that any group seemed to benefit from the vitamin D. So at this point I would say that we cannot recommend vitamin D supplementation and this suggests that at least for this population of patients the low vitamin D level being prognostic of poorer outcome is really a surrogate marker for illness or other things rather than a biomarker that we can act upon.

Any further questions to be answered with this research?

The one outstanding question is whether patients who have a low vitamin D level would benefit from supplementation. We didn’t have enough patients in that group, and in the United States it may be hard to find those patients now. However, in Europe supplementation is not routine; milk is not fortified. Given the fact that there are often latitudes that preclude a lot of sunshine during winter months in Europe, many patients there are quite low in vitamin D levels, at least compared to the US population. So whether colleagues in Europe may want to ask this question in a slightly different way, still suggests the possibility of an interesting and unanswered question. But in the US, I think that it's settled that at least right now there would be no role to supplement these patients with vitamin D.

I’d like to thank the other participating sites who participated in this trial. Doing a placebo-controlled trial is a heavy lift, and obviously the patients who agreed to participate as well.