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Vitamin D Deficiency Worsens Response to Rituximab in Older Patients With Diffuse Large B-Cell Lymphoma

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Key Points

  • Vitamin D deficiency was associated with significantly poorer event-free survival, progression-free survival, and overall survival in patients receiving R-CHOP.
  • In patients receiving CHOP alone, vitamin D deficiency was associated with no significant difference in event-free survival or progression-free survival but poorer overall survival.
  • Vitamin D substitution to normal levels in patients with deficiency significantly improved rituximab-mediated cellular cytotoxicity.

In a study reported in the Journal of Clinical Oncology, Bittenbring et al found that vitamin D deficiency was associated with poorer outcome in older patients receiving R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma but less so among patients receiving CHOP alone. Vitamin D substitution in deficient patients was found to increase rituximab-mediated cellular cytotoxicity, raising questions regarding the effect of vitamin D deficiency on other antibodies that act via antibody-mediated cellular cytotoxicity.

The study involved analysis of pretreatment serum 25-hydroxyvitamin D3 levels (measured by chemoluminescent immunoassay) in 359 patients aged 61 to 80 years in the RICOVER-60 study comparing R-CHOP-14 with CHOP alone and in 63 patients from the RICOVER-noRTh study in which patients received R-CHOP-14 without radiotherapy.

Effect on Outcome

For RICOVER-60 patients receiving rituximab with vitamin D levels ≤ 8 ng/mL vs >8 ng/mL, 3-year event-free survival was 59% vs 79%, 3-year progression-free survival was 64% vs 81%, and 3-year over survival was 70% vs 82%. On multivariate analysis adjusting for International Prognostic Index (IPI) risk factors, those with vitamin D deficiency had significantly poorer event-free survival (hazard ratio [HR] = 2.1, P = .008), progression-free survival (HR = 1.8, P = .047), and overall survival (HR = 1.9, P = .040). 

For patients not receiving rituximab with vitamin D levels ≤ 8 ng/mL vs > 8 ng/mL, 3-year event-free survival was 43% vs 48%, progression-free survival was 46% vs 53%, and overall survival was 53% vs 69%. Multivariate analysis showed no significant difference in event-free survival (HR = 1.2, P = .388) or progression-free survival (HR = 1.4, P = .172) but significantly poorer overall survival in those with vitamin D deficiency (HR = 1.8, P = .025). 

In the RICOVER-noRTh validation cohort, according to the vitamin D thresholds, 3-year event-free survival was 11% (at 32 months) vs 65%, progression-free survival was 33% vs 76%, and overall survival was 33% vs 85%. Multivariate analysis showed significantly poorer event-free survival (HR = 4.0, P = .003) and overall survival (HR = 4.1, P = .014) and borderline significantly poorer progression-free survival (HR = 2.6, P = .063) among those with vitamin D deficiency.

Rituximab-Mediated Cellular Cytotoxicity

Assessment of rituximab-mediated cellular cytotoxicity using a lactate dehydrogenase release assay of CD20-positive Daudi cells showed significantly increased activity at rituximab concentrations > 0.001 µg/mL in seven patients with vitamin D deficiency after an increase in levels to an average of 41 ng/mL with vitamin D substitution.

The investigators concluded: “[Vitamin D deficiency] is a risk factor for elderly patients with [diffuse large B-cell lymphoma] treated with R-CHOP. That [vitamin D deficiency] impairs [rituximab-mediated cellular cytotoxicity] and substitution improves [rituximab-mediated cellular cytotoxicity] strongly suggests that vitamin D substitution enhances rituximab efficacy, which must be confirmed in appropriately designed prospective trials addressing [vitamin D deficiency] and substitution not only in [diffuse large B-cell lymphoma], but also in malignancies treated with other antibodies, of which the major mechanism of action is antibody-dependent cellular cytotoxicity (eg, trastuzumab [Herceptin] in breast cancer and cetuximab in colorectal cancer).”

Michael Pfreundschuh, MD, of Universitätsklinikum des Saarlandes, Homburg, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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