G. Lus

Second University of Naples Department of Medical, Surgical, Neurological, Metabolic and Aging Science

Author Of 3 Presentations

 Program
Disease Modifying Therapies – Risk Management Oral Presentation

FC02.03 - Evaluation of T and B lymphocytopenia in patients treated with Ocrelizumab switching from other treatments compared to naive

Speakers
Authors
Presentation Number
FC02.03
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
13:24 - 13:36

Abstract

Background

Ocrelizumab (Ocre) is an anti-CD20 monoclonal antibody with a known major depleting effect on B cells and marginal on T cells. It is approved for clinical use in highly-active naïve multiple sclerosis (MS) patients and those not responder to previous treatment. In MS patients switching from other drugs prolonged dysfunction of adaptive immune system may occur after discontinuation, posing the need to carefully investigate the safety profile of treatment sequencing.

Objectives

To investigate the B and T cells subsets longitudinal dynamic during treatment with Ocre in patients with MS switching from Fingolimod (FTY) and other treatments (Dimetylfumarate, Interferon Beta, Glatiramer Acetate, Natalizumab, Teriflunomide) compared to naïve patients.

Methods

A multicenter observational 2-year study was conducted in patients starting treatment with Ocre grouped in three arms: naïve (naïve), switching from FTY (pre-FTY), switching from other treatments (other). Data about lymphocyte subtype count (CD3+, CD4+, CD8+ and CD20+) were collected at baseline and every 6 months after starting Ocre. Slope of reduction and proportion of patients with lymphocytes count below the normal lower limit was calculated.

Results

A sample of 135 patients was analysed (37 pre-FTY, 64 other, 34 naïve). At baseline pre-FTY compared to naïve showed significant decrease of CD3+ (1204.54+675.37 cells/mm3 vs 1735.53+653.56, p=0.0003), CD4+ (551.91+254.42 vs 997.03+352.79, p<0.0001), CD8+ (430.38+379.73 vs 537.75+254.34, p=0.027) and CD20+ (88.25+90.94 vs 191.32+149.62, p=0.021) cells. During Ocre the slope of reduction of CD3+ in naïve patients was 5.45 cells/mm3/week (p=0.003). Compared to naïve, the rate of decrease in CD3+ was -1.2 cells/mm3/week in pre-FTY (p=0.087) and +0.19 (p=0.012) in other. The slope of reduction of CD4+ was 2.00 cells/mm3/week in naïve (p=0.072). Compared to naïve the rate of reduction in CD4+ was +0.91 cells/mm3/week in pre-FTY (p=0.061) and +1.70 cells/mm3/week (p=0.012) in other. CD8+ and CD20+ cells decrease was similar among groups (p for interaction between time and treatment = 0.184 and 0.108, respectively). In pre-FTY group compared to baseline the proportion of patients with CD3+ and CD4+ cells lymphopenia was unchanged (16.22% versus 17.14% ; 32.35% versus 34.29%), while the proportion of CD8+ cells was increased (8.82% versus 25.71%).

Conclusions

Our study confirms that Ocre may induce depletion of T cell subsets beyond B cells. Nevertheless, in pre-FTY we also observed a prolonged T- lymphocytopenia , as carry-over effect of the previous therapy. FTY-induced immunosenescence or slow immunoreconstitution may explain this finding.

Collapse
Observational Studies Oral Presentation

PS01.04 - Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies

Speakers
Authors
Presentation Number
PS01.04
Presentation Topic
Observational Studies
Lecture Time
11:00 - 11:12

Abstract

Background

to date, no consensus exists on how aggressively and timely treat relapsing-remitting multiple sclerosis (RRMS) patients.

Objectives

To evaluate disability trajectories in a cohort of RRMS patients stratified according to two different disease modifying therapy (DMT) strategies, early intensive treatment (EIT) or moderate-efficacy treatment followed by escalation to higher-efficacy DMT (ESC).

Methods

RRMS patients with ≥5-year follow-up and ≥3 visits after start DMT, and a first visit within 3 years from disease onset were selected from the Italian MS Registry. EIT group included patients who received, as first DMT, fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group included those who received the high efficacy DMT after ≥1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score(PS)-matched for characteristics at the first DMT. The follow-up time from the first DMT start has been segmented into 12-month periods. The disability trajectories were evaluated by applying a longitudinal model for repeated measures with an autoregressive variance-covariance structure. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual EDSS changes compared to baseline values (delta-EDSS) in EIT and ESC groups.

Results

The study cohort included 2,652 RRMS patients from 62 Italian MS centers. The PS matching procedure produced 365 pairs. The median (IQR) follow-up after the first DMT start was 8.5 (6.5–11.7) years. All of the ESC patients escalated to a higher-efficacy DMT after a median time of 5.1 (3.1–8.4) years. The estimated baseline EDSS with relative confidence interval (95% CI) value was 2.52 (2.33-2.71) in the ESC group and 2.45 (2.26-2.64) in the EIT group. Mean delta-EDSS at each 12 month period were all significantly (p<0.02) higher in the ESC group compared to the EIT group. In particular, the mean delta-EDSS differences between the two groups tend to increase from 0.1 (0.01-0.19, p=0.03) at 1 year to 0.30 (0.07-0.53, p=0.009) at 5 years and to 0.67 (0.31-1.03, p=0.0003) at 10 years.

Conclusions

Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression and the effect tends to increase over time despite patients in the ESC group escalated to a higher-efficacy DMT.

Collapse
Observational Studies Oral Presentation

PS05.03 - Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort

Speakers
Authors
Presentation Number
PS05.03
Presentation Topic
Observational Studies
Lecture Time
13:27 - 13:39

Abstract

Background

Background: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking, as randomized clinical trials failed to show efficacy in reducing disability progression in this patient population.

Objectives

Objective: To investigate the effectiveness of disease-modifying treatment (DMT) on hard disability outcomes (EDSS 6 and 7) in a real-life population of PPMS patients.

Methods

Methods: Using the Italian MS Registry, we selected PPMS patients with at least three EDSS evaluations and three years of follow-up. Study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients. The impact of DMT on the risk of reaching EDSS 6 and 7 was assessed as a dichotomous variable (yes versus no) and as a time-dependent covariate through multivariable Cox regression models (adjusted for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, annualized relapse rate). We compared outcomes with an as-treated analysis and used propensity-score matching (PSM) to select cohorts with comparable baseline characteristics. DMT-exposure was also evaluated in terms of quartiles of exposure.

Results

Results: Of the 1214 patients we included 671 females, mean ± Standard Deviation baseline age 48.7 ± 11.1 years, mean EDSS score 4.1 ± 1.8, 790 (65%) received a DMT during the follow-up (57% platform and 43% highly active treatments). In the whole sample, after a mean follow-up of 11.6 ± 6.3 years, 994 (82%) patients reached EDSS 6 and 539 (44%) EDSS 7. In the multivariable Cox regression models, the use of DMT analyzed as a dichotomous variable did not influence the risk of reaching EDSS 6 (aHR=1.1, 95% CI 0.95-1.28, p=0.181) and EDSS 7 (aHR = 0.93, 95% CI 0.77-1.12. p = 0.454). However, longer DMT exposure significantly reduced the risk of reaching EDSS 7 (aHR = 0.73, 95% CI 0.56-0.95, p =0.021). Of note, patients in the upper quartile of DMT exposure compared with those with shorter DMT exposure were younger at baseline (mean age 44.1 ± 10.6 years; p < 0.001) and received the first DMT closer to the disease onset (mean time to first DMT 6.8 years ± 6.1 ; p=0.002). All these findings were confirmed in the PSM analysis.

Conclusions

Conclusion: Our results suggest that longer exposure to DMT may delay time to wheelchair in PPMS patients. Moreover, treating younger patients and reducing the delay to treatment initiation may improve the patients’ long-term disability outcomes. To optimize treatment decision-making in PPMS further profiling of the best candidates to treatment is needed.

Collapse