Vitamin D Deficiency May Impair Rituximab-Mediated Cytotoxicity in Diffuse Large B-Cell Lymphoma

By Will Boggs MD

NEW YORK - Vitamin D deficiency appears to impair rituximab-mediated cellular cytotoxicity (RMCC) and worsens outcomes in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, researchers from Germany report.

"Very low vitamin D levels are associated with worse prognostic factors, but in patients treated with rituximab low vitamin D levels are an independent prognostic factor in a multivariate analysis (stronger than elevated LDH), which is not the case in patients treated without rituximab," Dr. Michael Pfreundschuh from Universitatsklinikum des Saarlandes in Homburg told Reuters Health by email.

Dr. Pfreundschuh and colleagues used data from the RICOVER-60 and RICOVER-noRTh studies to investigate the impact and mechanisms of vitamin D deficiency on outcomes in elderly patients with DLBCL.

Patients with vitamin D levels of 8 ng/mL or below who were treated with rituximab-containing regimens had a three-year event-free survival (EFS) of 59%, compared with 79% in patients whose vitamin D levels were more than 8 ng/mL (adjusted hazard ratio, 2.1; p=0.008).

Three-year overall survival (OS) was also worse in patients with lower vitamin D levels than in patients with higher vitamin D levels (70% vs. 82%; aHR, 1.9, p=0.04); the same was true of progression-free survival.

Among patients treated without rituximab, however, three-year EFS and PFS were similar in the lower- and higher-vitamin D groups. Only OS was significantly better in the patients with higher vitamin D levels (69%) than in those with lower vitamin D levels (53%).

"This can be explained by the fact that all patients for whom CHOP chemotherapy without rituximab failed received rituximab as part of their salvage treatment and benefited from this salvage by being able to exploit the potential of rituximab as a result of their sufficient vitamin D levels," the researchers say.

In a separate evaluation of eight otherwise healthy individuals, achievement of normal vitamin D levels after supplementation resulted in significantly increased RMCC.

"I know no other explanation for this but impairment of NK cell activity and antibody-dependent cellular cytotoxicity (ADCC) by low vitamin D levels," Dr. Pfreundschuh said of the combined findings.

"The optimum vitamin D3 level for antibody-dependent cellular cytotoxicity is unknown and currently being studied by us," Dr. Pfreundschuh said. "For the time being, we recommend a target level of 65 ng/ml, which is the middle of the normal range, and this is also the target level in our ongoing OPTIMAL>60 study in elderly DLBCL patients."

"The ADCC response to vitamin D normalization warrants a prospective study of vitamin D substitution, not only in patients with DLBCL treated with rituximab but also in other treatment regimens with monoclonal antibodies in which ADCC is a relevant effector mechanism, such as trastuzumab in breast cancer and cetuximab in colorectal and head and neck cancer," the researchers conclude.

Dr. Matthew T. Drake from Mayo Clinic College of Medicine in Rochester, Minnesota, who was not involved in the study, recently published a review of vitamin D in cancer patients.

"This works builds on other studies (including 2 from Mayo Clinic) which provided the rationale for the current study, and in general are in agreement with the message described here," he told Reuters Health by email.

"For patients with diffuse large B-cell lymphoma (DLBCL), measuring 25(OH)D levels and ensuring vitamin D sufficiency through supplementation as needed in patients treated with rituximab should be strongly considered," Dr. Drake said.

"Vitamin D may play a role in regulation of the immune system -- there is some data to suggest it may affect the local microenvironment and production of inflammatory mediators," he explained. "Alternatively (or in combination with this), 25(OH)D levels reflect sun exposure, which may reflect that people with higher levels were more active (i.e., more sun exposure) at baseline, thereby portending improved responses and ability to tolerate chemotherapeutic regimens."

In contrast to the results in DLCBL patients, Dr. Rim Ben M'Barek and colleagues from Hopital Bichat in Paris, France, reported in the January Joint Bone Spine that rituximab efficacy in rheumatoid arthritis patients did not appear to correlate with their vitamin D levels.

Non-response rates were somewhat higher among patients with baseline vitamin D deficiency (52.2%) than in those with baseline insufficient (32.7%) or normal (33.3%) vitamin D levels, but these differences were not statistically significant.

About two-thirds of the patients in their report received supplemental vitamin D during the six-month study. The authors of the letter speculated that vitamin D had no apparent immunomodulating effect on B-cell activity, but their report included no measures of ADCC or B-cell activity.

SOURCE: https://bit.ly/1l0ErwN

J Clin Oncol 2014.

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