Cautionary Findings on Acquired Immunodeficiency From Anti-CD20 MS Therapy

Bruce Jancin

May 05, 2020


Thirty-eight percent of a large cohort of multiple sclerosis (MS) patients developed low IgM and 7.4% became hypogammaglobulinemic during a mean 30 months of follow-up on anti-CD20 therapy, Brandi L. Vollmer, MPH, reported online as part of the 2020 American Academy of Neurology Science Highlights.

The hypogammaglobulinemia was preceded by an IgM of 40 mg/dL or less in 35% of cases and was accompanied by concurrent development of low IgM in another 39%, added Ms. Vollmer, a professional research assistant at the Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus, University of Colorado, Denver.

She presented a retrospective study of 527 randomly selected MS patients and another 17 with neuromyelitis optica spectrum disorder who averaged 44 years of age and a 9.2-year disease duration upon commencing rituximab (Rituxan) with close laboratory monitoring. Their mean cumulative rituximab dose during a mean 30.2 months of therapy was 3,312 mg. Ninety-six MS patients eventually switched to ocrelizumab (Ocrevus), accumulating a total dose of 1,175 mg of that anti-CD20 humanized monoclonal antibody.

Absolute lymphocyte count dropped to 500 cells/mm3 or lower in 10.4% of patients at a mean of 11.3 months into anti-CD20 therapy. Low immunoglobulins came later: The mean time to onset of low IgM in affected patients was 19.7 months, and hypogammaglobulinemia, as defined by an IgG of 500 mg/dL or less, occurred at a mean of 36.1 months. Higher cumulative doses of anti-CD20 agents were associated with increased likelihood of hypogammaglobulinemia.

Asked to comment on the research findings, neurologist Nida Laurin, MD, said the Colorado study provides helpful insights into the timing of onset of acquired immunodeficiency in patients on B-cell-targeted therapy.

"This paper informs us that we should monitor our patients much closer for signs of hypogammaglobulinemia and lymphopenia starting with year 2 on therapy, and switch treatment when the threshold is reached. I do expect production of gamma globulins and lymphocytes to recover with discontinuation of anti-CD20 therapy, maybe over a period of 6-10 months. It might also recover with lower-dose therapy because the effect on B cells is dose-dependent," observed Dr. Laurin, an MS specialist at the Banner Health–University Medicine Neuroscience Institute in Phoenix and the University of Arizona in Tucson.

Her colleague Barry Hendin, MD, noted that there is no consensus regarding the best response to all these changes.

"Some clinicians add IVIG, some change therapies, and some observe only," said Dr. Hendin, a neurologist at Banner Health–University Medical Center, Phoenix, and clinical professor of neurology at the University of Arizona in Tucson.

However, Dr. Laurin asserted that it would be a mistake for physicians and patients to shrug off anti-CD20 therapy–induced lymphopenia in light of studies demonstrating that lymphopenia and older age are two main risk factors for progressive multifocal leukoencephalopathy in patients on disease-modifying therapies.

"More cases of PML can be expected with continuous use of anti-CD20 therapies if lymphopenia is ignored," she cautioned.

Depressed levels of IgM and IgG have been associated with increased risk of serious infections. In light of the COVID-19 pandemic and the eventual prospect of a vaccine, it is especially important to avoid putting patients with MS in harm’s way via treatment-induced acquired immunodeficiency, Dr. Laurin said.

Ms. Vollmer reported having no financial conflicts regarding her study. Dr. Laurin reported serving as a speaker or consultant for Alexion, Allergan, Biogen, Bristol-Myers Squibb, EMD Serono, Genentech, Lundbeck, and Sanofi Genzyme. Dr. Hendin serves as a consultant to Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Bristol-Myers Squibb.

SOURCE: Vollmer BL et al. AAN 2020. Abstract S29.002.

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