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Vitamin D levels may affect follicular lymphoma outcomes
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Low levels of serum vitamin D were associated with greater rates for mortality and disease progression in patients with follicular lymphoma, according to study results.
The association between poorer OS and low vitamin D levels did not reach statistical significance in one of the study cohorts; however, results from the overall population may be consistent enough to suggest that serum vitamin D may be a modifiable factor associated with outcomes in this setting, according to the researchers.
“There is a long history of evidence that vitamin D and sunlight might impact lymphoma risk, and recently there have been studies in other subtypes of lymphoma that vitamin D status can help predict lymphoma prognosis,” Jonathan W. Friedberg, MD, of the Wilmot Cancer Center at the University of Rochester School of Medicine and Dentistry, told HemOnc Today. “The study of follicular lymphoma is a particular area of interest because it is an indolent disease where you have time to study the effects of supplementation.”
Friedberg and colleagues evaluated data from previously untreated patients with newly diagnosed follicular lymphoma from SWOG (n = 183) clinical trials or the Lymphoma Study Association (LYSA) PRIMA trial (n = 240). A majority of both study cohorts were male (SWOG, 55%; LYSA, 53%) and aged 60 years or younger (SWOG, 71%; LYSA, 64%).
Patients in the SWOG cohort received CHOP chemotherapy plus rituximab (Rituxan, Genentech/Biogen Idec) or iodine-131 tositumomab (Bexxar, GlaxoSmithKline) between 1998 and 2008. Patients in the LYSA cohort received rituximab plus chemotherapy and were randomly assigned to rituximab maintenance or undergo observation.
Researchers measured 25-hydroxyvitamin D in baseline serum samples using a liquid chromatography-tandem mass spectrometry method. Vitamin D deficiency was defined as levels less than 20 ng/mL in the SWOG cohort and less than 10 ng/mL in the LYSA cohort.
PFS served as the study’s primary endpoint. Using these definitions, 15% of the SWOG cohort was vitamin D deficient (median serum 25-hydroxyvitamin D, 31 ng/mL) and 25% of the LYSA cohort was considered deficient (median serum 25-hydroxyvitamin D, 17 ng/mL).
After a median follow-up of 5.4 years in the SWOG cohort, 18% (n = 33) of the cohort had died and 44% (n = 81) had experienced progression. There was no association between vitamin D deficiency and cause of death or clinical response (OR for complete response = 1.14; 95% CI, 0.46-2.81). However, patients who were vitamin D deficient had significantly inferior PFS (HR = 2; P = .011) and OS (HR = 3.57; P = .003) compared with patients with higher vitamin D levels.
After a median follow-up of 6.6 years in the LYSA cohort, 10% (n = 25) had died and 47% (n = 112) experienced progression. There was no association between vitamin D deficiency and cause of death, and an equal proportion of patients who were and were not deficient demonstrated a clinical response to treatment.
Although patients with a vitamin D deficiency in the LYSA cohort demonstrated inferior PFS compared with patients with higher levels (HR = 1.66; P = .013) rates, the association between lower vitamin D and OS did not reach statistical significance (HR = 1.84).
Limitations to these data exist, Friedberg said.
“We were not able to define and appropriate threshold based on the differential characteristics of the European and American patient populations,” Friedberg said.
It is not clear at this point whether vitamin D supplementation is warranted, he added.
“In an era when we’re using different types of therapies, including novel oral agents and targeted therapies, there may be some data sets that allow us to do see if vitamin D is prognostic,” Friedberg said. “Ultimately, we will have to see how the community receives this to determine whether there will be energy to consider a trial of supplementation. It might be interesting to see if we can delay the time to treatment by giving vitamin D.” – by Cameron Kelsall
For more information:
Jonathan W. Friedberg, MD, can be reached at the James P. Wilmot Cancer Center at the University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 704, Rochester, NY 14642; e-mail: jonathan_friedberg@urmc.rochester.edu.
Disclosure: Friedberg reports a consulting role with Bayer, Kite Pharmaceuticals and Trubion and research funding from Genentech, Janssen Pharmaceuticals, Millennium Pharmaceuticals and Seattle Genetics. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Stephen M. Ansell, MD, PhD
Patients with follicular lymphoma have a variable clinical course, with some patients requiring no therapy for an extended period and others requiring combination chemoimmunotherapy very soon after diagnosis. Identification of a prognostic factor that is easily determined or measured would allow for the identification of patients with good outcomes vs. those with poorer outcomes. Such a prognostic factor may allow for optimization of therapy and selection of appropriate treatment.Kelly and colleagues reported that serum vitamin D levels are prognostic in patients with follicular lymphoma. Using two independent cohorts of patients, one from the United States and one from France, they showed that pre-treatment serum levels of vitamin D were associated with PFS and OS. Vitamin D deficiency was shown to be associated with obesity, diagnosis in winter months and poor prognostic features, such as a poor performance status and a low hemoglobin level. In both cohorts, vitamin D-deficient patients had a significantly poorer PFS compared with their counterparts with normal vitamin D levels. In the U.S. cohort, vitamin D deficiency also was associated with poor OS. The prognostic significance of vitamin D deficiency retained its significance when assessed in a multivariate analysis, making it an independent prognostic variable.
The finding that serum vitamin D levels are associated with outcome in follicular lymphoma is not surprising. Other studies that included patients with diffuse large B-cell lymphoma and chronic lymphocytic leukemia have also shown pretreatment vitamin D levels to be prognostic. This study now confirms that vitamin D levels are also important in follicular lymphoma. The findings of the study should be interpreted with some caution, however. As acknowledged by the authors, there are some potential biases that were inadvertently introduced into the study. For example, not all patients who were included in the trials that served as the basis for this study had a serum specimen available for vitamin D analysis. In fact, only approximately a quarter of the patients treated on the various trials were included in the vitamin D analysis. This potentially could introduce a selection bias into the study. Further, the definitions of vitamin D deficiency differed in the two cohorts based on regional recommendations for vitamin D deficiency. This again might have introduced some potential biases.
The biological relevance of a low vitamin D level is an area that needs investigation. As discussed by the authors, low vitamin D levels may interfere with macrophage function and this may account in some part for the poor prognosis of patients with low vitamin D levels. Macrophages play a significant role in the body’s response to monoclonal antibody therapy, and compromised macrophage function due to low vitamin D levels could make the response to therapy less effective. This, however, is conjecture and requires further study. It is also possible that a low vitamin D level is in some way a surrogate for patients with a less healthy lifestyle. The fact that serum vitamin D levels were associated with performance status and also with adverse prognostic factors such as anemia suggests patients who are sick may have lower vitamin D levels, and the poor prognosis is related to being ill and not just the vitamin D level.
The key question, however, is whether the low vitamin D levels are in some way a surrogate for an underlying component of tumor biology or whether this constitutes a therapeutic opportunity. Randomized control trials will be needed to test whether replacement of low vitamin D levels in patients who are vitamin D deficient will result in an improvement in the clinical outcome of these patients. Alternatively, it could be that the tumor cells themselves account for the low vitamin D levels and therapy will need to be directed at the tumor cell itself.
Regardless of the mechanisms associated with vitamin D deficiency, the data presented confirm that serum vitamin D levels are a useful prognostic factor in follicular lymphoma. Restoring vitamin D levels may represent a simple and nontoxic therapeutic opportunity for these patients.
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