www.excemed.org

IMPROVING THE PATIENT’S LIFE THROUGH

MEDICAL EDUCATION

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

24-25 February 2016 - Siena, Italy

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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

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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?

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Assessment of treatment response

Disease progression

Disability

Relapses

MRI activity

Focal inflammation

(relapses / MRI lesions)

Diffuse damage accumulation

(neurodegeneration / failure of repair; disability / atrophy)

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No evidence of

disease activity (NEDA) Slowing disability

progression Symptom management

Treatment goals in MS: paradigm shifts driven by emerging therapies

The growing availability of drugs active against MS over years leads to greater expectations

modified from Ransohoff RM et al. Nat Rev Neurol 2015

Recovery of function

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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)

NEDA – Clinical trial data

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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.)

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Defining treatment response is challenging: the proportion non-

responders varies depending on definition

• Patients (N = 393) treated with IFN β for ≥ 2 years.

Rίo J, et al. Nat Rev Neurol 2009; 5:553–560. Non-responder definitions % non-responders Hazard ratio

A ≥ 1 EDSS point confirmed at 6 months 18 39.623

B Presence of any relapse 45 6.366

C ≥ 2 relapses 20 4.562

D A decrease in relapse rate of < 30% compared with the 2 years before therapy 16 4.830

E A decrease in relapse rate of < 50% compared with the 2 years before therapy 20 4.009

F No decrease in or identical relapse rate compared with the 2 years before therapy

15 4.620

G Definition A or B 49 10.028

H Definition A or E 30 19.869

I Definition A and B 13 41.143

J Definition A and E 7 24.544

Patients (N = 393) treated with IFN β for ≥ 2 years. Rίo J, et al. Nat Rev Neurol 2009; 5:553–560.

242 RRMS patients with IFN beta-1a treatment (follow-up 4.3 2.3 anni)

Pozzilli et al., Neurol Sci 2005

MRI and identification of responders

Definition of not responder:

2 or more clinical relapses during follow-up (35% dei pazienti)

OR 3.6, IC 95% 1.3-10.2 OR 2.8, IC 95% 1.1-7.3

Responders

Poor responders

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

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0-1 year 0-2 years PTE, % (95%CI)

MRI lesions Progression 63 (20-215)

Relapses Progression 61 (15-234)

MRI lesions and relapses

Progression 100 (32-311)

PRISMS study (scIFN-1a)

MRI+relapses -> disability (INDIVIDUAL LEVEL)

P=0.038

p=0.038

IFN

Placebo

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16

0 (low risk)

1

2-3 (high risk)

Training set (PRISMS)

0

1

2-3

Validation set (Barcelona)

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0

1

2-3

Training set (PRISMS)

?

0

2-3

No relapse and =2 new T2 lesions in month 12-

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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

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610

568

233 120

106

91

88

32

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MAGNIMS Project - Participating Centers

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Center Patient # %

Rome 610 32.3

Milan 568 30.1

Barcelona 233 12.3

Bari 120 6.3

Cagliari 106 5.6

Siena 91 4.8

Verona 88 4.7

Graz 32 1.7

Napoli 27 1.4

Basel 14 .7

Total 1890 100

Center Patient # %

Rome 610 32.3

Milan 568 30.1

Barcelona 233 12.3

Other MAGNIMS 479 25.3

Total 1890 100

In the statistical analysis, centers

with small sample size (

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Disability progression across centers

p

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Optimized score

Variables HR (95%CI) p

NewT2 lesions=0 Ref

NewT2 lesions=1 0.93 (0.62-1.4) 0.73

NewT2 lesions=2 1.09 (0.71-1.68) 0.68

NewT2 lesions=3 1.65 (1.01-2.70) 0.04

NewT2 lesions=4 2.26 (1.29-3.97)

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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

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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

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Thank you for your kind attention !!!

Tintore et al Neurology 2010 Sombekke et al Neurology 2013

Relevance of lesion location