Clinical and research application of MRI in diagnosis and monitoring of multiple sclerosis

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1 24-25 February Siena, Italy Clinical and research application of MRI in diagnosis and monitoring of multiple sclerosis IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION

2 What is to be considered Treatment Failure in MS? Claudio Gasperini Centro di Riferimento Regionale per la Sclerosi Multipla Ospedale S Camillo-Forlanini di Roma 2

3 Background Several therapeutic opportunities for MS patients Current MS treatments reduce frequency of relapses, disability progression and disease activity (as measured by MRI). Response varies among patients. Difficult to assess How to switch after suboptimal response? 3

4 Assessment of treatment response Disease progression Disability Relapses MRI activity Focal inflammation (relapses / MRI lesions) Diffuse damage accumulation (neurodegeneration / failure of repair; disability / atrophy) 4

5 Treatment goals in MS: paradigm shifts driven by emerging therapies Symptom management Slowing disability progression No evidence of disease activity (NEDA) Recovery of function The growing availability of drugs active against MS over years leads to greater expectations modified from Ransohoff RM et al. Nat Rev Neurol

6 NEDA Clinical trial data NEDA at 1 year 34% for PegInterferon (ADVANCE) 47% for Natalizumab (AFFIRM) 39% for Daclizumab (SELECT) NEDA at 2 years 37% for Natalizumab (AFFIRM) 39% for Alemtuzumab (CARE-MS I) 32% for Alemtuzumab (CARE-MS II) 46% for Cladribine (CLARITY) 28% for Dimethyl Fumarate (DEFINE) 33% for Fingolimod (FREEDOMS) 18% and 23% for Teriflunomide 7mg and 14mg (TEMSO) NEDA at 3 years 19% for Glatiramer Acetate (CombiRx) 21% for IFN-B 1a (CombiRx) 33% for Glatiramer Acetate+IFNB1a (CombiRx) NEDA-4: 20% for Fingolimod (FREEDOMS+FREEDOMS II) 6

7 NEDA NEDA is an important therapeutic goal in MS care. Data from clinical trials show that NEDA is a very interesting outcome measure, showing clear difference between placebo and treated arms. However, only a minor portion of patients (range 18-46%) are NEDA in the short term after treatment with current DMT s In clinical settings, NEDA is difficult to sustain in the long term. Should we aim for minimal evidence of disease activity (MEDA)? The definition of NEDA should evolve as new metrics are adopted into clinical practice (e.g,t25fw, SDMT, brain atrophy, etc.) 7

8 Defining treatment response is challenging: the proportion nonresponders varies depending on definition Patients (N = 393) treated with IFN β for 2 years. Rίo J, et al. Nat Rev Neurol 2009; 5: Non-responder definitions % non-responders Hazard ratio A 1 EDSS point confirmed at 6 months B Presence of any relapse C 2 relapses D A decrease in relapse rate of < 30% compared with the 2 years before therapy 16 E A decrease in relapse rate of < 50% compared with the 2 years before therapy F No decrease in or identical relapse rate compared with the 2 years before therapy G Definition A or B H Definition A or E I Definition A and B J Definition A and E Patients (N = 393) treated with IFN β for 2 years. Rίo J, et al. Nat Rev Neurol 2009; 5:

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11 MRI and identification of responders 242 RRMS patients with IFN beta-1a treatment (follow-up anni) Definition of not responder: ( pazienti 2 or more clinical relapses during follow-up (35% dei OR 3.6, IC 95% OR 2.8, IC 95% Pozzilli et al., Neurol Sci 2005

12 Responders Poor responders Poor Response defined as an increase of at least 1 point of EDSS confirmed at 6 months

13 MRI+relapses -> disability (INDIVIDUAL LEVEL) PRISMS study (scifn -1a) 0-1 year 0-2 years PTE, % (95%CI) IFN MRI lesions Progression 63 (20-215) Placebo Relapses Progression 61 (15-234) MRI lesions and relapses P=0.038 Progression 100 (32-311) p=

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16 Training set (PRISMS) Validation set (Barcelona) 2-3 (high risk) 1 0 (low risk)

17 Training set (PRISMS) ? 1 relapse or >=2 new T2 lesions in month No relapse and <2 new T2 lesions in month

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19 Assessing response to Interferon in a large multicentre clinical dataset of patients with multiple sclerosis MP Sormani, C Gasperini, Rocca M, Rio J, Calabrese M, Cocco E, Enzingher C, Fazekas F, Filippi M, Gallo A, Kappos L, Marrosu M, Martinelli V, Montalban X, Prosperini L, Rovira A, Sprenger T, Stromillo ML, Tedeschi G, Tintorè M, Tortorella C, Trojano M, Pozzilli C, Comi G, N De Stefano, MD on behalf of the MAGNIMS study group. Conclusion: Results of the study suggest that substantial MRI activity, better if in combination with clinical relapses, is needed during the first year of treatment with Interferon to significantly increase the risk of disability worsening in the short-term. Accepted Neurology 19

20 MAGNIMS Project - Participating Centers

21 MAGNIMS Project - Participating Centers Center Patient # % Rome Milan Barcelona Bari Cagliari Siena Verona Graz Napoli Basel 14.7 Total Center Patient # % Rome Milan Barcelona Other MAGNIMS Total In the statistical analysis, centers with small sample size (<10% of the whole group) were grouped to allow heterogeneity tests among centers 21

22 Disability progression across centers 0 new T2 lesions 1 or more new T2 lesions Rome Milan Barcelona Other MAGNIMS p<0.001 p<

23 Optimized score Multivariate Cox model on the merged MAGNIMS dataset for risk of 3-year disability progression (n=1280) Variables HR (95%CI) p NewT2 lesions=0 Ref NewT2 lesions= ( ) 0.73 NewT2 lesions= ( ) 0.68 NewT2 lesions= ( ) 0.04 NewT2 lesions= ( ) <0.001 NewT2 lesions= ( ) 0.18 NewT2 lesions= ( ) <0.001 Relapse=0 Ref Relapse= ( ) <0.001 Relapse= ( ) <

24 MAGNIMS Score Score 0: 0 Relapses and 0-2 New T2 Lesions Score 1: 0 Relapses and 3+ New T2 Lesions, or 1 Relapses and 0-2 New T2 Lesions Score 2: 2+ Relapses or 1 Relapse and 3+ New T2 Lesions 24

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26 Summary With a suboptimal response on first-line drugs, a change in management strategy needs to be considered Combination of both clinical and MRI measures is the best way to assess treatment response Integrated scoring systems incorporating clinical and MRI measures of disease activity could be useful for a personalized approach to treatment 26

27 Thank you for your kind attention!!! 27

28 Relevance of lesion location Sombekke et al Neurology 2013 Tintore et al Neurology 2010