Early switching to ofatumumab avoids a rebound effect after natalizumab cessation in multiple sclerosis patients

Abstract

Background

A risk of disease reactivation has been clearly identified after natalizumab cessation in patients with multiple sclerosis (MS). Several studies have demonstrated a low risk of reactivation or rebound in patients switching to anti-CD20, but limited data are available concerning ofatumumab.

Objective

In the present study, we evaluated a cohort of 61 MS patients who switched from natalizumab to ofatumumab.

Results

After a mean follow-up of 2.4 years (range: 6 months to 4 years), none of the patients had experienced any clinical relapse or magnetic resonance imaging reactivation.

Conclusion

We confirm that ofatumumab is likely an effective option, using a short washout period following natalizumab discontinuation.

Introduction

Natalizumab is a well-known and highly effective drug and in France has been available for multiple sclerosis (MS) treatment since 2007. Since then, a large number of MS patients have switched from natalizumab to another drug, mainly due to JC virus (JCV) positivity. However, after natalizumab cessation, more than 30% of patients are reported to have clinical or radiological reactivation, sometimes with a rebound effect.^1–3 Fingolimod was the first option in this case before anti-CD20 drugs, with fewer relapses than with interferon beta or glatiramer acetate, ² but nevertheless with a relatively high risk of reactivation.^2,3 This risk is reduced in the case of a short washout period (1 month or less) between the two drugs. ³ We recently demonstrated that switching from natalizumab to ocrelizumab appears safe and reduces the risk of relapse compared with fingolimod. ⁴ Only a few studies in the literature have reported a possible activity rebound after switching from natalizumab to ofatumumab, and relevant data remain scarce. ⁵ In the present study, we report real-world data from patients followed up in two large university hospital MS centers in France who switched from natalizumab to ofatumumab.

Methods

This retrospective observational study was conducted in two regions of France (Alsace and Aquitaine). We included all relapsing-remitting MS and relapsing secondary progressive MS (SPMS) patients starting ofatumumab after natalizumab cessation between January 2021 and June 2024. The database was closed on December 31, 2024, thereby ensuring a minimum follow-up period of 6 months for all patients. All patients were diagnosed according to the revised 2017 McDonald criteria. ⁶ Treatment with natalizumab was performed every 4 weeks (intravenously or subcutaneously) without extended-interval dosing. European Database for Multiple Sclerosis (EDMUS) software was used for the collection of data. ⁷ Clinical visits were scheduled every 6 months. The following data were collected: the number of relapses in the 12 months before natalizumab cessation, the number of relapses at 1 and 2 years after the introduction of ofatumumab, the Expanded Disability Status Scale score every 6 months, the last brain magnetic resonance imaging (MRI) performed before natalizumab cessation, the re-baseline brain MRI (performed 3–6 months after introduction of ofatumumab), and then the MRI every year thereafter. All patients gave written informed consent to be included in the EDMUS database.

Statistical analysis

We only performed descriptive analyses, with mean values, standard deviations and ranges.

Data availability

Data extracted from the EDMUS database are available as an anonymized table.

Results

The main results are summarized in Table 1. Sixty-one patients (56 women and 5 men) with a mean age (mean ± standard deviation (SD)) of 42 ± 11.3 years (range: 22–62) switched from natalizumab to ofatumumab. Patients’ mean disease duration was 16.7 ± 9.3 years (range: 2–43) and mean time on natalizumab was 6.5 ± 4.1 years (range: 6 months to 13 years). Fifty-four patients were in an relapsing remitting form, and seven were transitioning to SPMS. The choice for this switch to ofatumumab was due to a positive JCV index (n = 50), evolution to SPMS (n = 7), natalizumab intolerance or personal convenience, including the availability of ofatumumab at home (n = 4). None of the patients experienced relapses on natalizumab in the 12 months before the switch. The mean washout delay between the two drugs was 35 ± 8 days (range: 24–45). The mean time on ofatumumab was 2.4 ± 1.3 years (range: 6 months to 4 years). All patients were followed up for at least 6 months, 59 for at least 12 months and 32 for at least 24 months. No relapses or new MRI T1 gadolinium-enhancing and/or T2 lesions occurred during the entire follow-up period. We observed no serious infections and especially no progressive multifocal leukoencephalopathy.

Table 1.

Profile of patients in the ofatumubab cohort.

Characteristics	Patients
Sex (% of women)	92%
Age (years) (mean ± SD)	42 ± 11.3
Disease duration (years) (mean ± SD)	16.7 ± 9.3
EDSS at the switch (mean ± SD) (n = 61)	2.3 ± 1.9
EDSS score after 1 year (mean ± SD) (n = 59)	2.02 ± 1.8
EDSS score after 2 years (mean ± SD) (n = 32)	1.94 ± 1.8
Number of patients with a relapse after one year (n = 59)	0/59 (0%)
Number of patients with a relapse after two years (n = 32)	0/32 (0%)
First brain MRI after cessation (3-6 months) New gad + lesion or new T2 lesion	0/61 (0%)
Brain MRI after 12-18 months New T2 lesion	0/59 (0%)
Brain MRI after 24 months New T2 lesion	0/32 (0%)

EDSS: Expanded Disability Status Scale; MRI: magnetic resonance imaging; SD: standard deviation.

Discussion

The data in this article and our previous publication ⁴ support the use of anti-CD20 therapies (ocrelizumab or ofatumumab) as safe and effective options after natalizumab cessation. This option, using anti-CD20 after Natalizumab cessation, was also proposed first with Rituximab in 2016 with good results. ⁸ In a previous study, we observed relapses in 10.4% of patients in the ocrelizumab cohort and 31.5% of patients in the fingolimod cohort, but the MRIs of patients treated with ocrelizumab remained stable, suggesting a possible overdiagnosis of relapses due to pseudo-relapse ⁴ or relapse with stable MRI. ⁹ A recent study on patients from the MSBase registry also suggests that the use of anti-CD20 drugs in the case of natalizumab failure could be a good option. ¹⁰ In the present cohort treated with ofatumumab, we did not observe any clinical or radiological activity. Switching from natalizumab to ofatumumab seems to be safe and may be a good option, regardless of the reason for switching (JCV seroconversion, SPMS transition, patient convenience or drug intolerance). A recent study showed a possibly higher risk of reactivation after natalizumab cessation in patients on ofatumumab (30.3%) compared with those on ocrelizumab (14.2%), but the number of patients on ofatumumab was low in this propensity score-unadjusted subgroup, and there was no difference at 6 months after the switch in T2 MRI lesions between the two drugs. Furthermore, this relapse rate seems to be very high compared with our data and real-life experience, likely due to a washout delay between the two drugs that was higher than in our study (60 ± 14 days vs. 35 ± 8 days in our cohort). ⁵ The washout period is a key point and has to be short after lymphocytic blocker drug cessation, and especially anti-very late antigen-4, as recommended by the French MS society. ¹¹ Unless natalizumab cessation is urgently required, careful consideration should be given to the timing and preparation of the switch. Thus, vaccinations with inactivated vaccines (pneumococcal or hepatitis B) or COVID-19 vaccines may be performed under natalizumab in order not to extend the washout period and to ensure optimal immunogenicity rather than under anti-CD20 drugs.

We acknowledge that our study has several limitations, including the retrospective design, the small sample size and the relatively short follow-up.

In conclusion, in our real-world cohort, switching from natalizumab to ofatumumab was safe and effective, with no observed relapses or MRI activity over a mean 2.4-year follow-up. These results highlight the importance of a short transition period (≤6 weeks) and warrant confirmation in larger, prospective studies.