Author Of 4 Presentations
P0223 - “Personalized extended interval dosing of natalizumab in relapsing remitting multiple sclerosis – a prospective multicenter trial in The Netherlands" (ID 1418)
Abstract
Background
Natalizumab is an effective disease-modifying therapy for relapsing remitting multiple sclerosis (RRMS). However, natalizumab trough concentrations remain high in a treatment regimen of 4-weekly infusions in 85% of patients. Previous studies showed that patients on extended interval dosing (EID) of natalizumab had comparable disease activity to standard interval dosing (SID) and a decreased risk of progressive multifocal leukoencephalopathy.
Objectives
To validate the maintenance of efficacy, measured by radiological disease activity, of personalized EID of natalizumab based on natalizumab trough concentrations. Feasibility of further extending intervals up to trough concentration of 5 μg/ml will be studied in a subgroup.
Methods
In this national multicenter prospective study (ClinicalTrials.gov Identifier: NCT04225312), 300 patients diagnosed with RRMS that received ≥ 6 consecutive natalizumab infusions will be included. Patients will be included in the main personalized EID group (aimed trough concentration 10 μg/ml), the low EID group (trough 5 μg/ml) or the SID group. Follow-up is two years with an extension phase of two years with annual MRI brain scans and 6 monthly scans for patients in the low EID group. Questionnaires will be filled in yearly by all participants.
Results
Inclusion of patients started in February 2020. Participants will be included in 22 centers in The Netherlands. So far, 69 patients were included, of whom 19 in the main EID group, showing natalizumab trough concentrations at baseline of 18.5 μg/ml (IQR 9.2 to 30.0). Current treatment intervals are 4 weeks (n=5), 5 weeks (n=5), 6 weeks (n=8) or 7 weeks (n=1). In the low EID group (n=37), natalizumab trough concentrations at baseline were 15.0 μg/ml (IQR 10.3 to 21.8). Current treatment intervals are 4 weeks (n=2), 5 weeks (n=8), 6 weeks (n=17) or 7 weeks (n=10). In the SID group (n=13), natalizumab trough concentrations at baseline were 18.0 μg/ml (IQR 14.5 to 26.0). Wearing-off symptoms were present in 33.9% of participants at baseline. No signs of radiological or clinical disease activity were present during follow-up so far.
Conclusions
Personalized extended interval dosing of natalizumab based on trough concentrations has the potential to become a safe, standardized treatment for RRMS patients using natalizumab. Final results of this study are expected in January 2024.
P0398 - Switching from natalizumab to ocrelizumab in patients with relapsing-remitting multiple sclerosis. (ID 1725)
Abstract
Background
Ocrelizumab (OCR) is an alternative therapy for relapsing-remitting multiple sclerosis (RRMS) patients with an increased risk of natalizumab (NTZ) associated progressive multifocal leukoencephalopathy (PML). We developed a switch protocol for PML surveillance and prevention of rebound disease activity.
Objectives
To evaluate clinical, radiological and biochemical markers in patients switching from NTZ to OCR using the locally developed switch protocol of the MS Center Amsterdam.
Methods
All patients with previous NTZ and current OCR treatment were selected from an ongoing observational cohort study with regular collection of blood samples in the Amsterdam University Medical Center (UMC) MS Biobank. Reasons for therapy switch were discriminated between patients with (indirect switchers) and without (direct switchers) use of other disease modifying treatment (DMT) during interval. Clinical, biochemical and radiological endpoints were prospectively collected from first NTZ to last OCR infusion. Serum neurofilament light (sNfL) was analyzed in direct switchers, using baseline and last follow-up samples during NTZ treatment and samples taken before every OCR infusion.
Results
Forty-one patients with current OCR and previous NTZ treatment were included with a median follow-up of 7.7 years. Twenty-eight patients switched directly, of which 21 due to PML risk. Three direct switchers suffered from a relapse, of which 1 patient showed evidence of disease activity on brain Magnetic Resonance Imaging (MRI). Two other male patients were diagnosed with carry-over PML with favorable outcomes. Before OCR became available, 13 patients switched from NTZ to other DMT due to PML risk but eventually escalated to OCR because of disease activity, progression or adverse events. Among these indirect switchers, 4 patients showed evidence of clinical or radiological disease activity. Excluding carry-over PML, OCR treatment maintained or established complete disease activity suppression in 84% of patients. Clinical measures of disability showed no significant changes. Mean sNfL significantly decreased during NTZ treatment and remained stable during OCR treatment.
Conclusions
A stringent protocol can contribute to an effective switch from NTZ to OCR in RRMS. In this observational cohort study of direct and indirect switchers, disease activity suppression was maintained or established in 84% with concurrent stability of clinical measures and sNfL.
P0481 - Natalizumab discontinuation in a Dutch real-world cohort (ID 1754)
Abstract
Background
Natalizumab is a widely used treatment option for patients with relapsing-remitting multiple sclerosis (RRMS). Identifying characteristics of patients discontinuing natalizumab treatment and reasons for discontinuation could help improve clinical decision making regarding natalizumab treatment in multiple sclerosis (MS).
Objectives
To determine characteristics of RRMS patients that discontinued natalizumab treatment in a Dutch real-world cohort.
Methods
Data were collected from an ongoing observational cohort study of all natalizumab treated patients in the Amsterdam UMC. Standard clinical parameters, total number of natalizumab infusions, reasons for discontinuation and therapies the patients switched to after discontinuation of natalizumab were collected.
Results
254 patients have ever received natalizumab treatment in our cohort, of which 148 patients stopped treatment. Mean age at discontinuation of natalizumab was 40.2 years, and 65.8% was female. Patients received an average of 68 infusions. Median treatment duration with natalizumab was 4.77 years. Mean Expanded Disablity Status Scale (EDSS) was similar at the start and stop of natalizumab treatment. The majority of patients (109 in total (73.6%)) stopped natalizumab treatment solely due to JC virus (JCV) positivity. Eight patients (5.4%) discontinued due to progression of MS, 3 (2.0%) due to pregnancy, 12 (8.1%) due to an allergic reaction or antibodies, 2 (1.4%) due to side effects, 4 (2.7%) due to the patients preference for another therapy, 3 (2.0%) due to clinical stabilisation and the remaining 7 patients (4.7%) due to other reasons. Most patients switched to another type of disease modifying therapy (DMT) after natalizumab discontinuation. Patients most frequently switched to fingolimod (76 patients (51.4%)) or ocrelizumab (26 patients (17.6%)) after discontinuation of natalizumab. Fourteen patients (9.5%) did not start another DMT after natalizumab discontinuation. Thirty-nine patients (26.4%) switched a second time to a different DMT and 19 patients (12.8%) stopped DMT after an initial switch.
Conclusions
Our results suggest JCV positivity to be the most frequent reason for natalizumab discontinuation. The heterogeneity in treatment switches suggests individual treatment plans are frequently present in MS. Recognising reasons for treatment discontinuation and treatment decisions made in our patient cohort can be helpful in future clinical decision making.
P0881 - “Mild disease course of carry-over progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab” (ID 1406)
Abstract
Background
Natalizumab is an effective disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS). However, it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Nine confirmed cases of PML have been reported in patients using ocrelizumab, another effective DMT for MS. In 8 cases, patients previously used natalizumab or fingolimod, likely causing PML. This phenomenon has been described as carry-over PML.
Objectives
To describe the disease course of carry-over PML after switching from natalizumab to ocrelizumab in two patients with RRMS.
Methods
Two case reports with 1 year of follow-up and retrospective longitudinal measurements of serum neurofilament light (sNfL) levels and B-cell count. Both patients provided informed consent.
Results
Regular follow-up showed no disease activity under natalizumab treatment and both patients switched to ocrelizumab following a stringent safety protocol including two additional MRI brain scans and cerebrospinal fluid (CSF) analysis. Both patients received a single infusion of 300 mg ocrelizumab before PML diagnosis. PML was diagnosed ±11 weeks (case 1) and ±13 weeks (case 2) after the last natalizumab infusion. At that time, both patients were asymptomatic. In retrospect, subtle signs suggestive of PML were already present on MRI under natalizumab treatment. One patient developed PML despite extended interval dosing of natalizumab. Both patients developed mild immune reconstitution inflammatory syndrome (IRIS) despite complete B-cell depletion. SNfL levels were 9.9 pg/ml (reference range 1-15 pg/ml) for case 1 and 16.7 pg/ml (reference range 2-18 pg/ml) for case 2 at the time of PML diagnosis and increased to 15.0 pg/ml and 36.5 pg/mL during PML-IRIS. SNfL was not elevated before radiological diagnosis of PML. PML-IRIS lesions stabilized after treatment with mefloquine and mirtazapine followed by methylprednisolone with sNfL levels of 9.0 pg/mL and 12.3 pg/mL, respectively. One patient reported no clinical symptoms and one patient only mild clinical symptoms with full recovery during the disease course of PML-IRIS. Both patients continued with ocrelizumab when B-cells started to repopulate ±10 months after the first ocrelizumab infusion.
Conclusions
The clinical course of carry-over PML was mild in both patients, suggesting that B-cell depletion did not aggravate PML-IRIS in these two patients.