“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.
“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” Walo, an immunologist at Ramon y Cajal University Hospital, Madrid, Spain, told Medscape Medical News.
She presented the findings at the recent 8th Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Walo explained.
The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.
Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.
Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.
Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.
No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B cell percentages.
Analysis of blood lymphocyte profiles showed no difference in T cell subsets between those who had an autoimmune event and those who did not.
Still, there were important differences in the B cell profile, Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”
Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.
When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).
The researchers calculated a CD19+ B cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment vs those with lower levels (odds ratio 14.67, P ≤ .0001).
Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002).
Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Walo noted.
She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.
“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.
Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented.
She says that if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B cell counts.
“For those with high levels of B cells — and particularly plasmablasts — alemtuzumab may not be the best treatment to choose,” Walo said.
During the post-presentation discussion, the suggestion was raised of giving an anti-B cell drug before alemtuzumab to try and prevent autoimmunity.
Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti-B cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”
Commenting on the study, session comoderator Darin Okuda, MD, professor in the Department of Neurology and Neurotherapeutics at UT Southwestern Medical Center, Dallas, Texas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”
Commenting for Medscape Medical News, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”
Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”
The study had no specific funding listed. Walo has disclosed no relevant financial relationships.
8th Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020: Session PS09.03. Presented September 12, 2020.