Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days...

83
Teaching course INDUCTION : When and How Gilles EDAN and Emmanuelle Le Page Paris, 2017

Transcript of Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days...

Page 1: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Teaching course

INDUCTION : When and How

Gilles EDAN and Emmanuelle Le Page

Paris, 2017

Page 2: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Presenter Disclosures

Professor Edan has been a Principal Investigator for Phase 2 and Phase 3 therapeutic MS studies from Bayer, Biogen, Serono, Novartis, Sanofi-Aventis Teva companies

He has also received research support from Bayer, Biogen, Mercks, Novartis, Sanofi , Serono, Teva, and has received honoraria for lectures or consulting from Bayer-Schering , Biogen Idec, LFB , Merck-Serono , Novartis, Sanofi-Aventis

2

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AN INDUCTION STRATEGY :WHY ?

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ASCT/High doses CYC/ Alemtuzumab

MitoxantroneOcrelizumabNatalizumab

Cladribine

DaclizumabFingolimod/

DMF

TeriflunomideINF Beta /GA/

E

F

F

I

C

A

C

Y

S

A

F

E

T

Y1st line

therapies

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Escalation vs Induction therapy (with FDA/EMA approved drugs)

Escalation

Step up

strategy

Baseline

therapy

Induction therapy

Step down

strategy

Maintenance

therapy

ASCT/High doses CYC/ Alemtuzumab

MitoxantroneOcrelizumabNatalizumab

Cladribine

DaclizumabFingolimod/

DMF

TeriflunomideINF Beta /GA/

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Definition : Escalating treatment

• Escalating treatment means to start with the safest MS drugs. Ifthey failed, the escalation to more agressive second line iswarranted

• Advantages: many patients did well receiving relatively safe drugsand never escalated to more agressive drugs

• Disadvantages: Precious years may have been spent receiving atreatment that was not potent enough for some patients,potentially leading to increased disabilities

• Challenge: The key to the success of the escalation therapy is todefine upfront with the patient the exact suboptimal responsethreshold at which the next-level therapeutic option should beintroduced

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Definition : Induction treatment

• Induction means to start with a strong immunointervention

• Advantages: This facilitates an earlier achievement of «no evidenceof disease activity» which is the gold standard for MS treatment insome schools of thoughts

• Disadvantages: some patients may be needlessly exposed to seriousside effects ..

• Challenge: The key to the success of induction treatment is to useimmunosuppressants for the minimum amount of time needed togain adequate control over disease activity, i.e., to start with a strongimmunossuppression followed by a maintenance therapy with saferdrugs .

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INDUCTION STRATEGY:WHEN

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“The initial treatment of early active relapsing remitting MS should be with a potent induction therapy rather than standard immunomodulation then escalation ” for most patients with early RRMS : Moving from the concept «earlier treatment is better for RRMS» to the concept «earlier maximally

efficacious treatment is still better for RRMS» ?

OR

“The initial treatment of early active relapsing remitting MS should be with a potent induction therapy rather than standard

immunomodulation then escalation ” for a selected group of RRMS patients having negative prognostic factors ?

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The window of therapeutic opportunity is highly variable

“The initial treatment of early active relapsing remitting MS should be with a potent induction therapy rather than standard immunomodulation then escalation ” for a selected group of

RRMS patients having negative prognostic factors ?

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We have at clinical onset some pronostic factorson the risk of early disability , the highest being on MRI

>10 lesions

4-9 lesions

1-3 lesions

0 lesion

“The initial treatment of early active relapsing remitting MS should be with a potent induction therapy rather than standard immunomodulation then escalation ” for a selected group of

RRMS patients having negative prognostic factors ?

10 years

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Assessing response to interferon-[beta] in a multicenter

dataset of patients with MS.

Sormani, Maria; Gasperini, Claudio; Romeo, Marzia; Rio, Jordi; Calabrese, Massimiliano; Cocco, Eleonora; Enzingher, Christian; Fazekas, Franz; Filippi,

Massimo; Gallo, Antonio; Kappos, Ludwig; Marrosu, Maria; Martinelli, Vittorio; Prosperini, Luca; Rocca, Maria; Rovira, Alex; Sprenger, Till; Stromillo, Maria;

Tedeschi, Gioacchino; Tintore, Mar; Tortorella, Carla; Trojano, Maria; Montalban, Xavier; Pozzilli, Carlo; Comi, Giancarlo; De Stefano, Nicola

Neurology. 87(2):134-140, July 12, 2016.

17% Treatment failure

27% treatment failure

48% treatment failure

15% EDSS worsening

22% EDSS worsening

29% EDSS worsening

“The initial treatment of early active relapsing remitting MS should be with a potent induction therapy rather than standard immunomodulation then escalation ” for a selected group of

RRMS patients having negative prognostic factors ?

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INDUCTION THERAPY:HOW ?

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JAMA January 26, 2016 Volume 315, Number 4

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Alemtuzumabas an induction treatment

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Study [5] Alemtuzumab

J N 2006

Study Design Observational study

Induction regimen Alemtuzumab 20

mg/day for 5 days

repeated for 3 days

1 year later

Follow-up 2 years

Number of patients 22 RR

MS duration

(mean in years)

2.7

Mean EDSS at

entry

4.8

ARR the 12

previous months

2.9

ARR after start of

treatment

0.19

% of relapses

**reduction

-91%

EDSS change** -1.4

Table 2. Clinical impact of alemtuzumab

in patients with very active or

aggressive RRMS

Young : 32 yEarly disease : 2.7 yVery active : ARR: 2.9Severe relapses: EDSS : 4.8

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Over 7 years, the clinical impact of alemtuzumab observed in this young RRMS patients with early and and active diseasewas:• early and sustained improvement of EDDS in 20%• late and sustained progression of EDSS in 23%• sustained stable EDSS in 57% of the RRMS

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Care IIClear Impact on disability

progression in Suboptimal RRMS responder to

DMDs

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93% des patients alemtuzumab inclus dans l’étude d’extension (années 3 à 6); 88% toujours suivis à 6 ans

50% des patients n’ont reçu ni cycle additionnel d’alemtuzumab, ni autre traitement de fond

Poussée

Lésion IRM

Poussée et lésion IRM

Motifs de cycle additionnel

CARE-MS II Efficacité à long terme

à 6 ans (Poster P681)

Groupe alemtuzumab

% de patients sans activité clinique

Nb. de

Patients 397 387 355365434

Libre depoussée

Libre d’aggravation du handicap

81% 80% 84% 88%

92% 92% 95% 96%

79%

92%

Année 2 Année 3 Année 4 Année 5 Année 6

Année 2 Année 3 Année 4 Année 5 Année 6

% de patients NEDA*

*Absence d’activité clinique (pas de poussée ni de progression

du handicap) et absence d’activité radiologique (pas de lésions

T2 nouvelles ou augmentées, ni de lésions Gd+)

Nb. de

Patients 361 336 304326402

Sans lésions T1 Gd+

Sans lésions T2 nouvelles ou augmentées

87% 89% 90% 91%

69% 70% 68% 69%

91%

76%

SEP ≤ 10 ans

>= 2 poussées en 2 ans (1 sous IFN)

EDSS <= 5

2016

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Autoimmune AE

Cohort of Cambridge

7 years

(N= 87)

CARE-MSI & II

at 6 Y

(N = 918)

Dysthyroïdism

Grave’s disease

ITP

Neutropenia

Haemolytic Anemia

Nephropathy

41%

22 cases (25%)

3 cases (3.4%)

1 case

1 case

1 case

42.3%

5%

21 cases (2.6%)

2 cases

1 spontaneously resolved (5%)

7 > after 1st line treatment (33%)

12 > after 2nde line treatment (57%)

1 splenectomy (5%)

Pic of thyroïd AE during the 3d year (2 Y > 2d cycle) in

CARE-MSI & II

Tuohy et al, 2014 J NeurolNeurosurg Psychiatry

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Mitoxantroneas an induction treatment

Page 23: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Young : 33 yVery active : ARR: 2.5, gado + : 8 active lesionsSevere relapse : EDSS 42/3 naive of previous DMT

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34%

12%

30.8%

3.8%

51.7%

0%

In line with the better control on MRI activity , compared with interferon beta alone, mitoxantrone prior interferon had over 3 years • 65% reduction of EDSS progression• With more impact if baseline EDSS < 4 and if DMT

before trial65% reduction of EDSS progression

Page 25: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Meilleur pronostic si EDSS M0 4 âge < 40 ans

Page 26: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Safety profile with short term use of mitoxantrone• ACF: 1/ 802 and decrease LVEF < 50% in 5% of patients• Age-dependant persitent amenorrhea• Acute leukemia 2 patients (0.25% , 1 died)

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Natalizumab as an induction therapy

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52% reduction of EDSS progression

In RRMS with highly active disease•> 2 relapses•Gado + MRI at baseline

Compared with INF beta, natalizumab had over 2 years •80% reduction ARR•90% reduction new T2 lesions•52% reduction of sustained disability progression

Page 29: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

« Therefore we need different therapeutic stategies to cope with the risk of post_NTZ disease recurrence and a « bridging strategy » with an earlier switch to second line drugs should be taken into accoung » L. Ferrè

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OCRELIZUMABas an induction therapy

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Versus placebo

-89%

-96%

• Mean duration of MS 7 years

• ≥ 2 relapses over the 3 past years (1

within 12 months)

• Mean EDSS 3.5

• 45-50% had Gd+ lesions

Potentiel traitement

inducteur

Page 33: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

‡Continued monitoring occurs if B cells are not repleted.

EDSS, Expanded Disability Status Scale; IFN, interferon; i.v., intravenous; OLE, open-label extension; RMS, relapsing multiple sclerosis

Ran

do

mis

atio

n 1

:1

OLE

scre

en

ing

Safety follow-up

≈48 weeks after the last infusion

Lymphocytes B monitoring ‡

OcrelizumabDose 1 : 300 mg i.v. x 2 (D1 et D15)

Doses 2-4 : 600 mg i.v. x 1

IFN β-1a

Dose : 44 µg s.c. 3 x per week.

Baseline W24 W48 W72 W96

Dose 1 Dose 2 Dose 3 Dose 4Ocrelizumab

• RR MS

• 18-55 Yo

• ≥ 2 relapses in

the 2 past years

or 1 relapse

during the last

year

• EDSS 0-5.5

OPERA I et II

• Mean duration of MS 6.7 years

• 1.3 relapses within the 12 past months

• Mean EDSS 2.8

• 40% had Gd+ lesions

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-46%

-40%

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OPERA I et II -40%

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OPERA I et II et ORATORIO : Tolerance and safety of ocrelizumab

Infusion related

reactions

No increased risk of serious infections

PML :

- none in trials

- 1 case in 2017

Tumoral risk ?

0.4 cancer/100 patient/year in Ocrelizumab

0.2 cancer/100 patient/an in placebo /IFN

Page 37: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Cladribine as an induction therapy

Page 38: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration
Page 39: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Versus placebo

- 33%

-Mean duration of MS 8-9

years

-≥ 1 relapse within the 12

past months

Mean EDSS 2.8 – 3.0

-70% not treated previously

-30% had Gd+ lesions

Page 40: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Efficacy of Cladribine on MS Relapses: CLARITY and CLARITY Extension Studies

Clad 3.5 PBO Clad 3.5 Clad 3.5 Clad 5.25 Clad 3.5 PBO Clad 3.5

60.7% reductionP < 0.0001

• ARR remained low in CLARITY extension study, even for patients who received cladribine followed by placebo

• Switching from placebo to cladribine

• significantly reduced ARR40

Page 41: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Herpetic infections

associated with grade

3 ou 4 lymphopenia

Risk of cancer: not

increased

Page 42: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Key-messages• Both escalating and induction strategies can be successfully applied on

the basis of clinical and radiological tools

• Induction therapy means performing a strong immunossuppressionfollowed by a maintenance therapy with a safe drug

• Among FDA approved immunossuppressants, Mitoxantrone andalemtuzumab are 2 candidates that deserves consideration for aninduction strategy

• Natalizumab in JC neg patients is a better candidate for an escalatingstrategy.

• Ocrelizumab ???

• Cladribine might be a good candidate for induction

• Induction therapy is beneficial for a selected group of early agressiveRRMS , having negative predictive factors

Page 43: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

• Monitoring over the first few years significantly refines predictionand facilitates selection of those requiring agressive treatment .

• MRI is a key pronostic marker. The goal of minimal MRI activityover the first few years after clinical onset is important fordefining the therapeutic strategy.

• New MRI techniques (brain and spinal cord imaging) should helpus to identifiy those RRMS patients, especially individuals withoutany real disability, who are more at risk of developing destructiveCNS lesions with or without first line therapy and who aretherefore more eligible for an early and more agressive treatmentstrategy…

Key-messages

Page 44: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Typical active MS

Itn/GATeriflunomide/

DMF/FingolimodDaclizumab

Highly active MS(« aggressive »)

Long term therapyNatalizumab (JCV-)Fingolimod/DMF

Ocrelizumab

InductionAlemtuzumabMitoxantrone

/Cladribine

Starting a DMD in RRMS according to the clinical and MRI data

for the previous 12 months

Page 45: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Score 0: 0 relapse and

0-2 new T2 lesionsNo change

Switch to another « 1st line »Teriflunomide/DMF/fingolimod

daclizumab

Switch to a « 2nd line »Natalizumab (JCV -)

OcrelizumabOr induction strategy

AlemtuzumabMitoxantrone

Cladribine

Score 1: 0 relapse and 3+ new T2 lesions

Or 1 relapse and 0-2 new T2 lesions

Score 2: 2+ relapses

Or 1 relapse and 3+ new T2 lesions

WHEN and HOW to Switch ?

Page 46: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

CASE REPORTS

Page 47: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Case 1 report : Alice, born in 1984

R1: September 2002 (18 years) , she felt parasthesia in 4 limbs for few weeks

R2: End of January 2003, she had walking difficulties : cerebellar ataxia, sensitive deficit in 4 limbs, diplopia, with multiple white matter focal abnormalities on MRI and OB in CSF. She received high dose IV methylprednisolone for 5 days leading to a transitory improvement. On March 2003, rapid worsening of her ambulatory difficulty accompanied by a motor deficit of the right leg and urinary disturbances.

End of March 2003: EDSS 6.5 (6 months after clinical onset)

Page 48: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

MRI N°1 : 04.02.03

T2 T1With Gado

Page 49: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

MRI N°1 : 04.02.03

Flair

TT&

T2

T1With Gado

Page 50: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

R1

Sept

2002

R2

January

2003

MRI N°1

>10 Gd + lesions

EDSS = 6.5

Mar

2003

Induction

treatment

strategy

Page 51: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Highly active MS

(« aggressive »)

Long term therapyNatalizumab (JCV-)Fingolimod/DMF

Ocrelizumab

InductionAlemtuzumabMitoxantrone

/Cladribine

Starting a DMD in RRMS according to the clinical and MRI data for the previous 12 months

Page 52: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Induction treatment followedby maintenance therapy

Mitoxantrone 20 mg IV combined with methylpredninolone 1g IV monthly from April to July 2003

At the end of July 2003 (M 4) ,

•On clinical ground : clear improvement of her ambulatory difficulty (walking distance > 1km without cane), light sensitive deficit and urinary disturbances . EDSS 3

•On MRI : No active lesions

September 2003

Maintenance therapy with INF beta Rebif® (44 microgramme, 3 times /w)

Page 53: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

At Follow-up 2003-2010

Under maintenance therapy with Rebif® 44mcg, 3 times /week

•No new relapse

•No disability progression EDSS (EDSS at 3)

•No new lesion on MRI

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2003

2010

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2003

2010

> 10 Gado+ lesions

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2003

2010

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R1

Sept

2002

R2

Feb

2003

IRM N°1

Gd+ (>10)

M0 M1

Apr

2003

3 monthly

courses

Mitox 20 mg

+ MP 1g

IRM N°2

inactive

IRM N°3

inactive

EDSS = 6,5

EDSS = 3

M2

Jul

2003

M6 M12 M90

IFN beta-1a

44 mcg 3 / w

IRM

inactive

Page 58: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

At Follow-up 2010-2015

• Reduced and stopped in 2013 INF injections

• New T2 lesions and active MRI in April 2014

• She started Tecfidera in June 2014 and at last follow-up•No clinical disease activity

•No EDSS progression

•No additionnal lesion on MRI

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April 2014

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Case report 2: Beatrix C. born in 1983

• July 2013 : blurred vision in right eye and retro-orbituitary pain for 3 weeks

MRI : one Hypersignal on T2 , Gado enhancement on T1 at the right optic nerve and one affecting the white matter in the right frontal lobe (gado -)

CSF : OCB +

blood and CSF: AQP4 –

• Octobre 2013 : left ON treated with high dose MP 1g for 3 days

Brain MRI unchangedSpinal cord MRI : normal

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Page 62: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Typical active MS

IFN /GATeriflunomide/

DMF/FingolimodDaclizumab

Starting a DMD in RRMS according to the clinical and MRI data for the previous 12 months

Page 63: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

• Glatiramer Acetate (COPAXONE) started in US in february 2014

• Ac anti MOG négatif

• At last follow-up February 2017

• Clinical remission ;

• Brain and spinal cord MRI unchanged with 1 frontal lesion

• The patient asks for an oral medication .

Case report 2: Beatrix C. born in 1983

Page 64: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Score 0: 0 relapse and 0-2 new T2 lesions No change

WHEN and HOW to Switch ?

Page 65: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Case report 3: Delphine born in 1997

• January 2013 : numbness on left hemiface

• April 2013 : paresthesia left hemi-tongue with light

dypshagia for few days

• CSF : OCB +

• On MRI

Page 66: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration
Page 67: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Typical active MS

IFN /GATeriflunomide/

DMF/FingolimodDaclizumab

Starting a DMD in RRMS according to the clinical and MRI data for the previous 12 months

Page 68: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Case report 3: Delphine born in 1997

• => First line treatment => IFN b 1a IM september 2013

• At Follow-up

• March 2014 : paresthesia right hemi-face

• May 2014 Right optic neuritis with visual acuity 7/10

• On MRI in May 2014 : 2 active lesions

Page 69: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

juillet

juillet

décembre

décembre

Page 70: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

2 lésions actives

Page 71: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Switch to another « 1st line »Teriflunomide/DMF/fingolimod

daclizumab

Switch to a « 2nd line »Natalizumab (JCV -)

Fingolimod (JC+)Ocrelizumab

Or induction strategyAlemtuzumabMitoxantrone

Cladribine

Score 1: 0 relapse and 3+ new

T2 lesionsOr 1 relapse and 0-2

new T2 lesions

Score 2: 2+ relapses

Or 1 relapse and 3+ new T2 lesions

WHEN and HOW to Switch ?

Page 72: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

• => DMF (TECFIDERA) June 2014

• At follow-up:

• July 2014 right ON 7/10 (MP 3g) total recovery

• September 2014: Diplopia (MP 3g): total recovery

• December 2014 , on annual MRI : 4 additionnal T2 lesions (1 gado+)

Case report 3: Delphine born in 1997

Page 73: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Switch to a « 2nd line »Natalizumab (JCV -)

Fingolimod (JC+)Ocrelizumab

Or induction strategyAlemtuzumabMitoxantrone

Cladribine

Score 2: 2+ relapses

Or 1 relapse and 3+ new T2 lesions

WHEN and HOW to Switch ?

Page 74: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

She is JC Positive

=> Feb 2015 : Fingolimod (GILENYA)

At follow-up

• July 2015, on IRM : 2 new T2 lesions ( no gado )

• August 2015 diplopia for 7 days (MP 3g ) total recovery

• December 2015 on MRI : 3 additionnal T2 lesions

Case report 3: Delphine born in 1997

Page 75: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Switch to a « 2nd line »Natalizumab (JCV -)

Fingolimod (JC+)Ocrelizumab

Or induction strategyAlemtuzumabMitoxantrone

Cladribine

Score 2: 2+ relapses

Or 1 relapse and 3+ new T2 lesions

WHEN and HOW to Switch ?

Page 76: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

She is JC positive

=> Feb 2016 : Anti CD20 (RITUXIMAB )

At follow-up (up to February 2017)

•May 2016 L’hermite sign positive only (EDSS=0)

•October 2016 : unchanged brain MRI and normal Spinal MRI

Case report 3: Delphine born in 1997

Page 77: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Case 4 Virginie born in 1981MS started at 21 Yo Highly active MS, but controlled by

mitoxantrone and natalizumab

6 courses 3 courses

1 Y 4 Y

Elsep

Betaferon

17courses

Irreversible EDSS = 3.0

1st pregnancy

Within 9 months after

delivery, under Gilenya

and mitox

3 relapses

EDSS 3.0 to 7.0

MRI: Gd +++

Elsep

2d pregnancy

JC+

Page 78: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Highly active MS

(« aggressive »)

Long term therapyNatalizumab (JCV-)Fingolimod/DMF

Ocrelizumab

InductionAlemtuzumabMitoxantrone

/Cladribine

Starting a DMD in RRMS according to the clinical and MRI data for the previous 12 months

Page 79: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Highly active MS, but controlled by

mitoxantrone and natalizumab

6 courses 3 courses

1 Y 4 Y

Elsep

Betaferon

17courses

Irreversible EDSS = 3.0

1st pregnancy 2d pregnancy

JC+Within 9 months after

delivery, under Gilenya

and mitox

3 relapses

EDSS 3.0 to 7.0

MRI: Gd +++

Elsep

EDSS 7.0 to 3.0, stable

NEDA until june 2017 = 5 Y

Reversible Graeve’s

disease

Alemtuzumab

Case 4 Virginie born in 1981MS started at 21 Yo

Page 80: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

1ère grossesse

6 Y

Imurel

6 Y

Avonex

Tysabri

30 courses

Gilenya

CopaxoneElsep 3 courses

Stop Tysabri® because

“doesn’t feel sick”

Spinal cord relapse

Tysabri® again

JC+ Stop Tysabri®

6 courses

Rebond >

Tysabri® stop,

not controlled by

Gilenya®

Severe

ON

Case 5 Françoise born in 1968MS started at 25 Yo

Page 81: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

Highly active MS

(« aggressive »)

Long term therapyNatalizumab (JCV-)Fingolimod/DMF

Ocrelizumab

InductionAlemtuzumabMitoxantrone

/Cladribine

Starting a DMD in RRMS according to the clinical and MRI data for the previous 12 months

Page 82: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

1ère grossesse

6 Y

Imurel

6 Y

Avonex

Tysabri

30 courses

Gilenya

CopaxoneElsep 3 courses

Stop Tysabri® because

“doesn’t feel sick”

Spinal cord relapse

Tysabri® again

JC+ Stop Tysabri®

6 courses Alamtuzumab

Aug 2014 (AI)

NORB

sévère

Diplopia

recovered

Rebond >

Tysabri® stop,

not controlled by

Gilenya®

Case 5 Françoise born in 1968MS started at 25 Yo

Page 83: Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days repeated for 3 days 1 year later Follow-up 2 years Number of patients 22 RR MS duration

1990 : ONMRI

normal

Between 2001→2003 2 relapses /year with sequelea and ↗ T2

Lesions Refused any DMD

Within 6 months

EDSS 3,5 →6 SP active MS (+ 10 gado )

Suboptimal response to mitoxantrone between 2004 →2006 (EDSS 6.5)

Reached EDSS 7 in 2009/2010 +

disease activity on MRI

Alemtuzumab 20 mg/j for 5 days in

2010 12 mg/j for 3 d in 2012 ;EDSS 8 and still MRI activity

Resistant to any DMD EDSS reached 7,5 / 8 in 12 years , having both a progressive and active disease

Case 6 Annabelle born in 1984MS started at 16 Yo