University of Parma
Department of Medicine and Surgery, Neurosciences Unit

Author Of 3 Presentations

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0314 - Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing-remitting multiple sclerosis (ID 853)

Speakers
Presentation Number
P0314
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Dimethyl fumarate (DMF) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS) patients. Besides a partially known mechanism of action involving both neuroprotective and antioxidant effects, it causes a mean lymphocyte count drop of approximately 30%, typically occurring within the first year of treatment. Several studies investigated the relationship between this reduction and DMF effectiveness, with heterogeneous methods, obtaining contradictory results.

Objectives

To investigate if absolute lymphocyte count (ALC) decrease during DMF treatment is associated with drug effectiveness on clinical and MRI disease activity in a real-life cohort of patients treated with DMF for at least 6 months. Secondary aims were to evaluate ALC variations over time and the impact of baseline demographic and clinical factors on DMF-induced lymphopenia.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational multicentre study, conducted on RRMS patients attending nine MS centers of Emilia-Romagna region (Northern Italy). Multivariate Cox models were performed to evaluate the impact of six month-ALC drop on time to NEDA-3 (“no evidence of disease activity”) status loss and Kaplan-Meier curves were generated to display the results. Multivariate logistic regression was carried out to analyse possible predictors of lymphopenia.

Results

476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed during a mean follow-up time of 29 months (range 6-61 months). A greater lymphocyte decrease was associated with a longer NEDA-3 status (HR 0.87, p = 0.01), relapse-free (HR 0.85, p = 0.03) and MRI activity-free survival (HR 0.80, p < 0.0001). A higher risk of NEDA-3 status loss (p=0.008) was observed in tertile with lower ALC drop (< 11.5%), compared with other tertiles (11.5-40.5% and >40.5% ALC drop, respectively). A shorter activity-free survival was also influenced by younger age at DMF start (HR 0.98, p = 0.03). The nadir of mean ALC drop (-33.6%) and 35% of grade III lymphopenia cases occurred after 12 months of treatment. An older age at DMF start (OR 1.03, 95% CI 1.00-1.06, p = 0.009) and lower ALC at baseline (OR 1.69, 95% CI 1.34-2.14, p < 0.0001) predicted higher risk of lymphopenia.

Conclusions

A higher lymphocyte count drop at six months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0363 - Ocrelizumab as exit strategy from natalizumab: results from a clinical series (ID 854)

Speakers
Presentation Number
P0363
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting (RR) multiple sclerosis (MS), but its prolonged use can be associated with an increased risk of progressive multifocal leukoencefalopathy (PML). Therefore, NTZ is mainly interrupted in the context of PML risk management strategy, but its discontinuation can be followed by a marked increase of disease activity. Currently, there is no consensus on either the duration of the washout period, or the best subsequent treatment approach. Few data are available on the use of anti-CD20 monoclonal antibodies (mostly rituximab) after NTZ withdrawal, whereas only a small case series of patients switching to ocrelizumab (OCR) has been published in literature.

Objectives

To evaluate the effectiveness, tolerability and safety of OCR in a real-world cohort of MS patients switching from NTZ.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational study, performed on MS patients attending Parma MS centre (Northern Italy).

Results

23 patients (14 females, mean age 40.4 ± 8.57 years) were analysed during a mean follow-up of 15 months (range 5-34), since NTZ discontinuation. Patients had the following characteristics at OCR start: RR course in 74% and progressive active disease in 26%, mean EDSS 3.1 (1.5-6.5), mean disease duration 11 ± 5.67 years and median number of NTZ infusions 28 (13-122). The reasons for switch included PML concern in 78% of cases and suboptimal response to NTZ in 22%. The majority (83%) of patients was JCV+ and only 6 were treated with NTZ extended interval dosing for ≥18 months. The median washout period was 50 days (41-251); all patients underwent a brain MRI immediately before OCR start. Only 4/23 (17%) and 1/19 (5%) patients experienced clinical relapses (all within the first 6 months of therapy) and MRI activity, respectively. ARR decreased from 0.41 (during NTZ) to 0.18 with OCR. Mild adverse events (mostly infusion reactions, hypogammaglobulinemia and leukopenia) occurred in 74% of cases. No patients discontinued OCR and no PML cases emerged.

Conclusions

OCR is effective and well tolerated in highly active MS patients switching from NTZ. A median 6-week transition period appears reasonably safe to balance the risk of disease reactivation with that of opportunistic infections. Larger datasets are needed to confirm the risk of carryover PML in relationship with the length of washout period.

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Imaging Poster Presentation

P0600 - Longitudinal evolution of cortical lesions in an Italian cohort of multiple sclerosis patients (ID 731)

Speakers
Presentation Number
P0600
Presentation Topic
Imaging

Abstract

Background

Cortical lesions (CLs) have recently acquired a great relevance in multiple sclerosis (MS), both at diagnosis and during the monitoring of the disease, because of their impact on long-term prognosis. However, there is still limited knowledge about the evolution of CLs in time.

Objectives

The aim of the present observational study was to investigate, retrospectively, the longitudinal evolution of CLs number in comparison to FLAIR-T2 hyperintense white matter lesions (WMLs) in a cohort of MS patients in a single MS centre.

Methods

We included all consecutive patients with a relapse-onset MS referred to MS centre of Parma (Italy) who performed at least two MRI scans including double inversion recovery sequences from 2014 to 2019, collecting demographic, clinical and MRI data.

Results

We included 140 MS patients, 67.9% female, with the following characteristics at first MRI: relapsing-remitting (RR) course in 84.3% and secondary progressive (SP) in 15.7% of cases, mean age 40.1±10.49 years, mean disease duration 169.7±100.75 months, mean EDSS 2.5±1.30, mean number of WMLs 24.8±16.50 and of CLs 2.5±2.87. After a mean follow-up of 51.8±8.32 months we observed a conversion to SP phase in 2.1% and a 3-mo-confirmed EDSS progression in 13.6% of patients, with a mean EDSS of 2.6±1.48 and mean number of relapses of 1.1±1.95. During the follow-up only 3.6% of patients did not take any therapy, while 47.1% and 49.3% were on a first-line and a second-line disease-modifying treatment (DMT), respectively. Occurrence of ≥1 new WML or CL appeared in 37.9% and 12.9% of cases, respectively, with a mean number of new WMLs of 1.8±5.58 and new CLs of 0.2±0.6. New CLs never appeared without concomitant WMLs, but 44.4% of cases with new CLs occurred in patients with 1-2 new WMLs and 26.7% of patients with 1-2 new WMLs had ≥1 new CL. At multivariate analysis the risk of occurrence of new CLs was higher in patients with a higher number of new WMLs at last MRI (OR 1.44, CI95% 1.17-1.78, p=0.001) and lower in those who remained RR (OR 0.04, CI95% 0.002-0.76, p=0.03).

Conclusions

In our cohort we observed an overall low MRI activity, probably related to the high percentage of patients on DMT. New CLs appeared in a small percentage of patients and were strictly related to new WMLs. Nevertheless, they added clinical relevance to a consistent proportion of cases characterised by otherwise minimal MRI activity, with important implications for therapeutic switch.

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Presenter Of 2 Presentations

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0314 - Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing-remitting multiple sclerosis (ID 853)

Speakers
Presentation Number
P0314
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Dimethyl fumarate (DMF) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS) patients. Besides a partially known mechanism of action involving both neuroprotective and antioxidant effects, it causes a mean lymphocyte count drop of approximately 30%, typically occurring within the first year of treatment. Several studies investigated the relationship between this reduction and DMF effectiveness, with heterogeneous methods, obtaining contradictory results.

Objectives

To investigate if absolute lymphocyte count (ALC) decrease during DMF treatment is associated with drug effectiveness on clinical and MRI disease activity in a real-life cohort of patients treated with DMF for at least 6 months. Secondary aims were to evaluate ALC variations over time and the impact of baseline demographic and clinical factors on DMF-induced lymphopenia.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational multicentre study, conducted on RRMS patients attending nine MS centers of Emilia-Romagna region (Northern Italy). Multivariate Cox models were performed to evaluate the impact of six month-ALC drop on time to NEDA-3 (“no evidence of disease activity”) status loss and Kaplan-Meier curves were generated to display the results. Multivariate logistic regression was carried out to analyse possible predictors of lymphopenia.

Results

476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed during a mean follow-up time of 29 months (range 6-61 months). A greater lymphocyte decrease was associated with a longer NEDA-3 status (HR 0.87, p = 0.01), relapse-free (HR 0.85, p = 0.03) and MRI activity-free survival (HR 0.80, p < 0.0001). A higher risk of NEDA-3 status loss (p=0.008) was observed in tertile with lower ALC drop (< 11.5%), compared with other tertiles (11.5-40.5% and >40.5% ALC drop, respectively). A shorter activity-free survival was also influenced by younger age at DMF start (HR 0.98, p = 0.03). The nadir of mean ALC drop (-33.6%) and 35% of grade III lymphopenia cases occurred after 12 months of treatment. An older age at DMF start (OR 1.03, 95% CI 1.00-1.06, p = 0.009) and lower ALC at baseline (OR 1.69, 95% CI 1.34-2.14, p < 0.0001) predicted higher risk of lymphopenia.

Conclusions

A higher lymphocyte count drop at six months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0363 - Ocrelizumab as exit strategy from natalizumab: results from a clinical series (ID 854)

Speakers
Presentation Number
P0363
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting (RR) multiple sclerosis (MS), but its prolonged use can be associated with an increased risk of progressive multifocal leukoencefalopathy (PML). Therefore, NTZ is mainly interrupted in the context of PML risk management strategy, but its discontinuation can be followed by a marked increase of disease activity. Currently, there is no consensus on either the duration of the washout period, or the best subsequent treatment approach. Few data are available on the use of anti-CD20 monoclonal antibodies (mostly rituximab) after NTZ withdrawal, whereas only a small case series of patients switching to ocrelizumab (OCR) has been published in literature.

Objectives

To evaluate the effectiveness, tolerability and safety of OCR in a real-world cohort of MS patients switching from NTZ.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational study, performed on MS patients attending Parma MS centre (Northern Italy).

Results

23 patients (14 females, mean age 40.4 ± 8.57 years) were analysed during a mean follow-up of 15 months (range 5-34), since NTZ discontinuation. Patients had the following characteristics at OCR start: RR course in 74% and progressive active disease in 26%, mean EDSS 3.1 (1.5-6.5), mean disease duration 11 ± 5.67 years and median number of NTZ infusions 28 (13-122). The reasons for switch included PML concern in 78% of cases and suboptimal response to NTZ in 22%. The majority (83%) of patients was JCV+ and only 6 were treated with NTZ extended interval dosing for ≥18 months. The median washout period was 50 days (41-251); all patients underwent a brain MRI immediately before OCR start. Only 4/23 (17%) and 1/19 (5%) patients experienced clinical relapses (all within the first 6 months of therapy) and MRI activity, respectively. ARR decreased from 0.41 (during NTZ) to 0.18 with OCR. Mild adverse events (mostly infusion reactions, hypogammaglobulinemia and leukopenia) occurred in 74% of cases. No patients discontinued OCR and no PML cases emerged.

Conclusions

OCR is effective and well tolerated in highly active MS patients switching from NTZ. A median 6-week transition period appears reasonably safe to balance the risk of disease reactivation with that of opportunistic infections. Larger datasets are needed to confirm the risk of carryover PML in relationship with the length of washout period.

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