. However, there are no corresponding worsening of symptoms or signs of a “wearing off” effect, new research shows.
“Most people expect that since this is a B-cell depleting drug, that if you are not depleting B cells, then that should be reflected clinically and there should be some breakthrough activity,” said study investigator Joshua D. Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care in Wellesley, Massachusetts.
Dr. Joshua D. Katz
“So [these results] were a surprise, but I would not conclude from our data that B-cell repletion does not put someone at risk. We can only say that we didn’t observe anybody having a breakthrough,” he added.
The research was presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
Real-world study
Preapproval clinical trials of ocrelizumab suggest about 5% of patients experience a repletion of B cells. However, the timing and association with breakthrough symptoms were unclear.
To investigate, Dr. Katz and colleagues conducted two studies. The first is a substudy of the prospective ACAPELLA trial to assess ocrelizumab-associated adverse events in a real-world population. The study included 294 patients with relapsing and progressive forms of MS treated with at least two cycles of ocrelizumab, given as infusion once every 6 months.
The results showed that overall, 91 (31%) of the 294 patients had some degree of repletion at one or more timepoints.
In categorizing patients according to their highest CD19 measure after two cycles, 108 patients (64.7%) had no significant repletion of B-cells after infusion, defined as an increase of less than 10 cells/μL, while 45 (26.9%) were considered mild repleters, defined as having increases of 10-49 cells/μL.
Seven patients (4.2%) were moderate repleters, with an increase of 50-79 cells/μL, and 7 (4.2%) were categorized as marked repleters, with increases of 80 or more cells/μL.
Eight patients in the study fully repleted, with values from 114-319 cells/μL, occurring between 23 and 34 weeks of the last infusion.
However, there was no relationship between repletion of the B-cells and clinical or MRI evidence of relapse.
Of note, the proportion of patients who did not have B-cell repletion increased with greater numbers of infusions. Whereas 64.7% were non-repleters at cycle 2, that number increased to 88.8% by cycle 6, with a slight drop to 85.6% being non-repleters by cycle 7 (36 months).
“Mild B-cell repletion was fairly common after two cycles of ocrelizumab, but with repeated dosing, a greater proportion of patients were non-repleters, suggesting that cumulative exposure to ocrelizumab results in greater depletion,” the researchers noted.
However, “while the number of moderate or marked repleters in our study was small, they had a tendency to remain repleters over time with subsequent infusions,” they added.
In looking at patient characteristics, moderate and marketed repleters had higher mean BMI (34.1 and 32.6, respectively) compared with the non- and mild repleters (27.0 and 29.4, respectively; P < .0001).
Dr. Katz noted that the increased risk of B-cell repletion with higher BMI was not a surprise. This association, he said, “makes sense” because patients’ relative exposure to ocrelizumab decreases with higher BMI. Similar patterns with BMI were observed in the clinical trial for ocrelizumab approval, in which patients with lower BMI tended to have greater improvement.