Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days...
Transcript of Teaching course INDUCTION : When and How...Induction regimen Alemtuzumab 20 mg/day for 5 days...
Teaching course
INDUCTION : When and How
Gilles EDAN and Emmanuelle Le Page
Paris, 2017
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
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AN INDUCTION STRATEGY :WHY ?
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
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/
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
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 .
INDUCTION STRATEGY:WHEN
“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 ?
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 ?
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
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 ?
INDUCTION THERAPY:HOW ?
JAMA January 26, 2016 Volume 315, Number 4
Alemtuzumabas an induction treatment
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
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
Care IIClear Impact on disability
progression in Suboptimal RRMS responder to
DMDs
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
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
Mitoxantroneas an induction treatment
Young : 33 yVery active : ARR: 2.5, gado + : 8 active lesionsSevere relapse : EDSS 42/3 naive of previous DMT
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
Meilleur pronostic si EDSS M0 4 âge < 40 ans
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)
Natalizumab as an induction therapy
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
« 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
OCRELIZUMABas an induction therapy
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
‡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
-46%
-40%
OPERA I et II -40%
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
Cladribine as an induction therapy
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
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
Herpetic infections
associated with grade
3 ou 4 lymphopenia
Risk of cancer: not
increased
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
• 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
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
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 ?
CASE REPORTS
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)
MRI N°1 : 04.02.03
T2 T1With Gado
MRI N°1 : 04.02.03
Flair
TT&
T2
T1With Gado
R1
Sept
2002
R2
January
2003
MRI N°1
>10 Gd + lesions
EDSS = 6.5
Mar
2003
Induction
treatment
strategy
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
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)
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
2003
2010
2003
2010
> 10 Gado+ lesions
2003
2010
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
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
April 2014
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
Typical active MS
IFN /GATeriflunomide/
DMF/FingolimodDaclizumab
Starting a DMD in RRMS according to the clinical and MRI data for the previous 12 months
• 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
Score 0: 0 relapse and 0-2 new T2 lesions No change
WHEN and HOW to Switch ?
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
Typical active MS
IFN /GATeriflunomide/
DMF/FingolimodDaclizumab
Starting a DMD in RRMS according to the clinical and MRI data for the previous 12 months
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
juillet
juillet
décembre
décembre
2 lésions actives
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 ?
• => 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
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 ?
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
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 ?
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
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+
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
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
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
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
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
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