Aucun titre de diapositive - OVHaihemato.cluster013.ovh.net/AIH/documents/Cours DES/DES...
Transcript of Aucun titre de diapositive - OVHaihemato.cluster013.ovh.net/AIH/documents/Cours DES/DES...
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Mastocytosis
Olivier Hermine MD, PhD
Hematology Department, Necker Hospital
Centre National de référence des mastocytoses, Necker Hospital
CNRS UMR 81 47
Institut Imagine, Necker Hospital
Paris, France
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Mast cells in hypersensitivity type 1
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•Mast cells are tissue cells
•They are prevalent in areas
• which interface directly with
• the external environment
•close to blood vessels and
•nerve endings
•They can respond very
•rapidy to a stimulus
•with the production of a
•whole array of mediators
•Mast cells are sentinentals with strategic location
•from JS. Marshall, Nature Rev Immunol 420: 787- (2004)
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Cancer Allergy
Autoimmunité
Alloreactivity
Acute
chronic
Mastocytosis
Inflammation
fibrosis Neurological
And
Psychiatric
Diseases
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•Mastocytosis
•Mast cells and Diseases
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Definition - Mast cell accumulation in various organs (Skin, GI tract, Liver, Bone and Bone Marrow, etc) -Myeloproliferative disorder; Aggressive vs indolent disease
- Association with hematological disorders - Clinical heterogeneity (Infiltration vs Mediators release)
Photos Pr Bodemer et Dr Barete
MASTOCYTOSIS
Children
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•MCAS
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Updated WHO Classification of Mastocytosis 2016
Cutaneous mastocytosis (CM)
- Maculopapular CM (MPCM) = urticaria pigmentosa (UP)
- Diffuse CM (DCM)
- Mastocytoma of skin
Systemic mastocytosis (SM)
- Indolent SM (ISM)
- Smoldering SM (SSM)
- SM with associated hematologic neoplasm (AHN)*
- Aggressive SM (ASM)
- Mast cell leukemia (MCL)
Mast cell sarcoma
-------------------------------------------------------------------------------------
*The previous term SM-AHNMD (SM with clonal hematologic
non-mast cell-lineage disease) and the new term AHN can be
used synonymously.
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Physiopathology
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MC TC MC T
Stem Cell CD34+ Bone Marrow
Circulation SCF
IL-10
IL-6
SCF
CD34+
c-kit high
FceRI neg
CD13+
MC C
IL-4 SCF
?
Simplified pathways of human MC differentiation
Tissues
IL-4 Survival : SCF
NGF
IL-4
IFN-g
…...
-
0
100
200
Day0 SCF- SCF+
0
500
1000
Day0 SCF- SCF+
0
200
400
Day0 SCF- SCF+
•Day 30
•Day 30
•Day 30
•CD34-Kit+ •CD34+Kit+
•Healthy
•Donor
•(SCF+)
•Mastocytosis
•c-Kit D816V
•Mastocytosis
•c-Kit WT
•Histamine level
•ng/
ml
•ng/
ml
•ng/
ml
•CD34-Kit+
•CD34+Kit+
Sophie Georgin et al, Blood 2010
C-kit+CD34-Mast cell precursors in peripheral blood
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•C-kit activation pathway
•Lyn
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•Ig1 •Ig2 •Ig3 •Ig4 •Ig5 •TM •JM •TK1 •TK2
•1 •2 •3 •4 •5 •6 •7 •8 •9 •10 •11 •12 •13 •14 •15 •16 •17 •18 •19 •20 •21
•Dog mast cell tumor D826-828- InsDT •Q430R
•ins421 aa45
•S479I4
•N508I
•Del/Ins555-559(5)
•ITD571-590(15) •n=88
•Patrice Dubreuil, Katia Hanssen, Sébastien Leutard, Kevun Hahn, Christine Bodemer, Olivier Hermine CEREMAST
•D479N
•V560G D418
D564-576
•E860G D419 (12) •InsFF419
•C443Y •S476I
•ITD501-502(2)
•ITD505-508
•D572A •D816Y(4)
•K509I(6)
•D816I
•ITD502-503(4)
•D816V(353)
•Ig1 •Ig2 •Ig3 •Ig4 •Ig5 •TM •JM •TK1 •TK2
•1 •2 •3 •4 •5 •6 •7 •8 •9 •10 •11 •12 •13 •14 •15 •16 •17 •18 •19 •20 •21
D417-418 D419Y
•n=603 •Human mastocytosis
•MCL leukemia
•And Sarcoma
•No PTD
•Exons 8 to 11 •Exon 17 •WT
•30% of the dogs are mutated
•No PTD
Adult (Indolent and agressive)
•PTD
Pediatric
•No PTD
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Single Gene (C-kit) several diseases
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•Differential colony-forming ability of ECD and D816X mutants expressing Rat2 cells
•Without
•SCF
•With
•SCF
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•Outcome and mutations of c-kit
Patients mastocytosis
Statut of c-Kit
WT Mutation autre que
D816V D816V
Children (N= 59) 15% 46% 39%
Adults (N= 485) 28% 3% 69%
•age
•Mutation %
•persistent
•Mutations
•ex8 & ex9
•puberty
•Mutations
•D816V
•regressive
•50
•75
•25
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Children Mastocytosis
Adult Mastocytosis
Kit Mutations
No senescence Chronic disease
AGRESSIVES Fatal Outcome
Non PTD PTD
Senescence Régression
Conclusions and Perspectives
P-p38 P-p38
p53 ATRX ?
APBs
Telomeres
protection
By TRF2
No protection
of Telomere
By TRF2 Germline mutations
(p53; p16) ?
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•Role of Telomere Maintenance
•Mutation
•D816V
•(Exon 17)
•C-Kit
• Mastocyte Survival
•=> immortalisation
•Indolent Mastocytosis •Télomere maintenance
•Mutation
•Exons 8 à 11
•C-Kit et WT •Proliferation
•Senescence
•Short telomeres
•SCF
•Spontaneous Regression
•Tumor progression - Genetic instability - ALT
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•Role of Telomere Maintenance
•Mutation
•D816V
•(Exon 17)
•C-Kit
• Mastocyte Survival
•=> immortalisation
•Indolent Mastocytosis •Télomere maintenance
•Mutation
•Exons 8 à 11
•C-Kit et WT •Proliferation
•Senescence
•Short telomeres
•SCF
•Spontaneous Regression
•Tumor progression - Genetic instability - ALT
•Agressive Mastocytosis •Télomere maintenance
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•Cytosine
•5-me-Cytosine •5-hme-Cytosine
•Dnmt
•Tet2
•Inhibitors
•(e.g. RG108)
Tet2 is involved in the conversion of 5 meC to 5hmeC at specific genomic loci
•Mutations in SMP and AML
•CMML++
•CMML is associated with MS
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Tet2 mutations are frequent and are correlated to aggressive disease
•Mastocytosis Patient Cohort:
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•Bone marrow derived Tet2-deficient mast cells infected with c-KitD816V have a competitive growth advantage
Confirmed in two independent Tet2-KO models (lacz and flox)
Consistent whether infections are done using « young » or « old » MC cultures (old > 80 days culture with IL3)
•CD
11
7
•Tet2(+/+)
•GFP
•Tet2(+/-) •Tet2(-/-)
•cKitD816V+ •cKitD816V+ •cKitD816V+
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•SRSF2-P95 Hotspot Mutation is Highly Associated with Aggressive Forms of Mastocytosis and Mutations in Epigenetic Regulator Genes •Katia Hanssens, Fabienne Brenet, Julie Agopian, Sophie Georgin-Lavialle, Gandhi Damaj, Laure Cabaret, Maria Olivia Chandesris, Paulo de Sepulveda, Olivier Hermine, Patrice Dubreuil *§ and Erinn Soucie* (Haematologica; in press)
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•ASSOCIATED HEMATOLOGICAL MALIGNANCIES
Travis 1988
Horny 2004
Sotlar 2010
Pardanani 2009
Damaj et al 2013
AHNMD; n (%) 20 (33) 22 (33) 48 134 (40%) 62
Myeloid % 82 90 83 89 82
MDS % 32 9 8 3 28
CMML % 39 27 23 16
MPN % 9 21 45 16
AL % 10 21 3 5
Lymphoid % 11 18
Lymphoma% 6 5 8
MM% N=2 10 4 5 (MGUS)
CLL% 2
•*Damaj et al, CEREMAST, Unpublished data
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Sotlar J Pathol
2010
Horny JCP,
2004
Pardanani Blood 2009
Tefferi Leuk,emia
2009
Traina Plosone
2012
*Damaj 2013
N 48 20 134 23 8 62
D816; n(%) 45 (94) 16 (80) 50 (63) 44 (86)
JAK-2; n(%) na na 6 (8) 2 (7.5)
TET-2; n(%) na na na 8 (35) 5 (62) 12 (32)
ASXL1; n (%) na na na 2(25) 6 (17)
FGFR4; n(%) na na na 7 (18)
CBL; n(%) (12.5)
GENE MUTATIONS IN SM-AHNMD (1)
TET2, ASXL1 are positive, only in the myeloid AHNMD
•*Damaj et al, CEREMAST, Unpublished data
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•Figure 1
•P = 0.003 •ASXL1 negative. median OS: 92.33 (95% CI, not reached)
•AXSL1 positive: median OS: 12.86 (95% CI, 5.56 – 20.17)
•
Gandhi Damaj1,2,3, Magalie Joris1, Olivia Chandesris2,4, Katia Hanssens5, Erinn Soucie5, Danielle Canioni6, Brigitte Kolb7, Isabelle Durieu8, Emanuel Gyan9, Cristina Livideanu10, Stephane Chèze11, Momar Diouf12, Reda Garidi13, Sophie Georgin-Lavialle14, Vahid Asnafi15, Ludovic Lhermitte15, Christian Lavigne16, David Launay17, Michel Arock18,19, Olivier Lortholary20, Patrice Dubreuil5* and Olivier Hermine2,3,4*
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Mastocytosis Heterogeneity and c-kit
•MDS
•CMML
•AML
•Sarcoma
•MCL
•Indolent
Masotcytosis
•Agressive
mastocytosis
•C-kit 816 V
•Tet2
•ASXL1
•JAK2,
• FIP1L1-PDGFR,
•CMML
•Regression
•C-kit 816 V
•negative
•C-kit 816 V
•Other ?
•C-kit 816 V
•Pediatric forms
•Other ckit mutations
•WT c-kit
•Adult Forms
•Sarcoma
•MCL
•Other ckit mutations
•WT c-kit
•Others SMP
•other ?
•NHL
•Agressive
•Masotcytosis
(rare)
•Cytokines (CD40L)
•Tet2
•ASXL1
•C-kit 816 V
•Tet2
•ASXL1
•others
•Tet2
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Diagnosis
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Urticaria pigmentosa
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Bone involvement
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Osteosclerosis
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Mastocytosis Diagnosis
1. DARIER ’S SIGN FOR CUTANEOUS MASTOCYTOSIS (Skin involvement is not required)
2. HISTOLOGY FOR CUTANEOUS AND/OR SYSTEMIC
MASTOCYTOSIS (required)
- TOLUIDINE BLUE
- ANTI -TRYPTASE STAINING
- CD117+, CD2+ and/or CD25+, CD15-
3. MAST CELL MEDIATORS
- Total tryptase >20ng/ml
- Soluble C-kit level
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Major and Minor WHO Criteria of Systemic Mastocytosis (SM criteria)*
Major criterion:
Multifocal dense infiltrates of mast cells
(>15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s)
Minor criteria:
a. >25% of all mast cells are atypical cells
(type I or type II) on bone marrow smears or are spindle-shaped in mast cell infiltrates detected on sections of visceral organs
b. KIT point mutation at codon 816 in the bone marrow or another extracutaneous organ
c. mast cells in bone marrow or blood or another extracutaneous organ expresses CD2 or/and CD25
d. Baseline serum tryptase concentration >20 ng/ml (in case of an unrelated myeloid neoplasm is not valid as an SM criterion)
If at least one major and one minor or three minor criteria
are fulfilled
the diagnosis is systemic mastocytosis = SM
*SM criteria have been defined by the WHO in 2001 and confirmed in 2008 and 2016.
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Treatment
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Prognosis
•Blood 2009
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Prognosis
•Blood 2009
•Indolent Mastocytosis >80%
•Agressive Mastocytosis
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Therapeutic decision
• Agressive disease : Reduction of life expectancy
and organ failure
• Indolent disease : No life expectancy reduction,
no organ failure , Handicap associated with
symptoms (patient vs physician)
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Protocols for treatment of Indolent
Mastocytosis
Should we treat these patients ?
On what basis ?
What should be the end points of treatment ?
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Identification of all systemic manifestations in patients suffering from
mastocytosis
• From 2004, 363 mastocytosis patients and 90 controls in France were asked to rate their overall disability (OPA score) and the severity of 38 individual symptoms.
• A specific questionnaire (AFIRMM V1), encompassing these 38 symptoms, has been created and validated.
PLoS ONE. 2008 May 28;3(5):e2266
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Identification of all systemic manifestations in patients suffering from
mastocytosis
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Course of Tumoral mass (3 months)
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•Patient ISM
•53 years old
•Cognitive impairment
•IRM/ASL: artérial spin labelling, Flow blood in the brain
•Perfusion MRI
•Control
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•Hyperperfusion of central grey nuclei : 11 patients with cognitive imapirement vs 33 controls
•p
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•Hypoperfusion of the anterior Cingulum antérieur in 10 patients with depression and mastocytosis Vs. 18 patients with Mastocytosis but not depressed
•p
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•IDO
•Hypothesis
•TNFa
•
•Tryptophane
•Kynurenine
•Acid
•xanthurenic
•Acid
•quinolenic
•Neurotoxicity
•Oxidative stress
•apoptosis
•-
•+
•Cognition (?)
•serotonin
•Low serotonin
•Depression ?
•Proteases
•Histamine
Others
•ASL
•abnormalities
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Fig 2
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Eviction of mast cells stimulants: depend on the patient history
Aim at inhibiting mediator release by mast cell or mediators effects.
- Anti-H1 : pruritus, flush and sometimes GI pains.
- Anti-H2 : essentially GI pains.
- Aspirin : for flushing, tachycardia, but may cause vascular collapse!!!
- Corticoids : for local treatment of cutaneous lesions, ascite, malabsorption, GI cramps
(budesonide: corticoïde à délitement entéral)
- Cromoglycate disodium : non specific mediator release symptoms
- Anti-leucotriènes (montelukast-singulair): for respiratory manifestations
- Epinephrin : Hypotension
- Biphosphonates : bone pain and bone loss
SYMPTOMATIC THERAPIES OF MASTOCYTOSIS
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Cytoreductive treatment
• Interferon alpha
• Cladribine
• Kinase inhibitors
• Thalidomide
• Rapamycine
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Cytoreductive Treatments
• High dose steroids
• Alpha Interferon (?)
• Cladribine
• Kinases Inhibitors
• Thalidomide
• mTOR inhibitors (Rapamycine, Temsirolimus)
• Bone marrow transplantation
• Treatment of AHNMD
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Cladribine Treatment • 0.14 mg/kg 5 days a week in 2 hour infusion or
subcutaneously
• 1 to 6 cycles repeated every 4 to 12 weeks
• Usually no premedication with corticosteroids or
antihistaminic
• Antibiotic prophylaxis with Co-trimoxazole and Valaciclovir
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•Clinical response
•Clinical improvement for
• 10/11 mediator release
symptoms including
anaphylaxis
• 5/6 mast cell infiltration-related
symptoms including urticaria
pigmentosa, and organomegaly
(P
-
•38 patients (80%) comprising 11 CR, 17 MR and 10 PR.
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•Progression free survival
•Median PFS = 3.7 (0.1-8.6)
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•Overall survival
•Whole group
•Median OS = 8.2 (0.1-9.1) years
•According to WHO sub-types
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Discussion on Cladribine
2-CdA is active in mastocytosis
Its activity seems to be more pronounced on fatigue, flush, GI
symptoms and pruritus, skin infiltration
Median duration of response remains to be precisely determined but
some patients have long term responses
Haematological toxicities and infections were manageable and were
more frequent in the aggressive forms of the disease
Further work is needed to determine optimal therapy schedule and
usefulness of maintenance therapy to prevent relapse
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15e Colloque de la Recherche de la Ligue contre le cancer, Nice, 24-25 janvier 2013
Oncogenic Mutations of c-kit in Mastocytosis
1
2
Oncogenic Signal
Adult Mutations 85%
Clonal disease +++
No regression
Pediatric Mutations 75%
Clonal disease +++
Regression Sarcoma
Human
Dogs
Exons 8 to 11 Exon 17 WT
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Effect of STI 571on proliferation of cell lines
with juxtamembrane or V814 c-kit mutations
0
20
40
60
80
100
120
0 0.1 1 10
µM
% C
PM
Ba/F3 Kit+IL3
Ba/F3 Kit+SCF
∂27
FMA 3
KIT G559
IC2 V814
P815 (V814)
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c-kit Mutations in Mastocytosis
NH2
COOH
c c
c c
c c
c c
F522C
Akin et al. Blood. 103:3222, 2004
•Location: Exon 10 (Transmembrane)
•Type: Germline
•Clinical features:
Childhood onset CM
SSM in early 20s
Well-differentiated phenotype
•Functional studies: Gain-of-function
•Inhibition by imatinib: Yes (in vitro and clinically)
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Therapy with imatinib in a patient with transmembrane c-kit
mutation: Proof of concept
0 25 50 75 100 1250
50
100
150
200
Days
Try
pta
se (
ng
/ml) 100 mg/d
200 mg/d
300 mg/d
400 mg/d
Akin, Fumo, Yavuz, Lipsky, Neckers, Metcalfe. Blood, 103:3222, 2004
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Signaling of PI-3k/Akt/mTOR •C-KIT
•- •PI •3 kinase
•AKT
•- •m •TOR
•1 •Cyclin D •CDK’s
•G •1 •S
•Cell division
•G •0 •(resting cell)
•+ •P-p70S6k
•Translation/apoptosis
•4EBP/eIF4E
•RAPAMYCINE
-
•BMMC
•c-kit wt •BMMC
•c-kit 816
•La mutation D816V du c-kit confère à la cellule BMMC la sensibilité à la Rapamycine
•Lignée BMMC •cellules mastocytaires dérivées de moelle osseuse de souris
•transgéniques pour le c-kit humain
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Rapamycin and MS
•Stop IFN
•CDA 1
•CDA 2
•Start IFN
•Start Rapamycin
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PKC412 (N-benzyl staurosporine)
• Inhibits PKC, VEGFR,
Kit, PDGFR, flt3
• Phase I/II trials in
hematologic and solid
tumors
– Nausea, vomiting,
diarrhea, fatigue
• Inhibits D816V c-kit
•Gotlib et al. Blood, in press, 2005
•BAF3 D816V cells
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Baseline Patient and Disease Characteristics.
Gotlib J et al. N Engl J Med 2016;374:2530-2541
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Best Overall Response to Midostaurin in the Primary Efficacy Population.
Gotlib J et al. N Engl J Med 2016;374:2530-2541
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Overall Survival
•Median duration of follow-upa: 27 months (range: 11-38)
Kaplan-Meier Estimate for Overall Survival Median
ASM Not reached
MCL 22.6 months
•a Time from treatment start to data cut-off.
Deaths, n
12
9
3
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•Prospective survey of PKC412 compassionate use for adult patients suffering from AdSM in France. Survival
curves in PKC412 treated and control groups at the last follow-up in April 2015.
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Baseline TMSAS
Best TMSAS value
on treatment
Lack of energy Feeling drowsy
Diarrhea
Feeling bloated
Difficulty concentrating
Difficulty sleeping
Cough
Dry mouth
Pain
Weight loss
Worrying
Shortness of breath
Feeling nervous
Sweats Dizziness
Feeling irritable
Feeling sad
Itching Lack of
appetite Nausea
Change in way food tastes
Swelling of
arms/legs
Skin changes
Problems with sex
Vomiting
Numbness in hands/feet
Urinary problems
Don’t look like myself
Difficulty swallowing
Mouth sores
Constipation
Hair loss
Decreased Frequency of MSAS Symptoms
(n = 79)
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TITLE: HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR
ADVANCED SYSTEMIC MASTOCYTOSIS
Authors: Celalettin Ustun1, Andreas Reiter2, Bart L Scott3, Ryotaro Nakamura4,
Gandhi Damaj5, Sebestian Kreil2, Ryan Shanley6, William J. Hogan7, Miguel-
Angel Perales8, Tsiporah Shore9, Herrad Baurmann10, Robert Stuart11, Bernd
Gruhn12, Michael Doubek13, Jack W. Hsu14, Eleni Tholouli15, Tanja Gromke16,
Lucy A. Godley17, Livio Pagano18, Andrew Gilman19, Eva Maria Wagner20, Tor
Shwayder21, Martin Bornhäuser22, Esperanza B. Papadopoulos8, Alexandra
Böhm23, Gregory Vercelotti1, Maria Teresa Van Lint24, Christoph Schmid25,
Werner Rabitsch26, Vinod Pullarkat27, Faezeh Legrand28, Ibrahim Yakoub-
agha29, Wael Saber30, John Barrett31, Olivier Hermine32, Hans Hagglund33,
Wolfgang R. Sperr34, Uday Popat35, Edwin P.Alyea36, Steven Devine37, H.
Joachim Deeg3, Daniel Weisdorf1, Cem Akin38, Peter Valent34
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ITK for indolent diseases
• New ITK
• Inhibiton of Mast cell activation
• Cytoreductive on Mast cells
• Not cytoreductive on other cells
• Not toxic (short term and long term)
– Genotoxic, carcinogenic
– Cardiotoxic (Abl++, Src, VEGF, Herg chanel, etc)
-
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1010,10,050,01
DO
49
0 n
m
AB 1010 (µM)
Inhibition of c-Kit phosphorylation
•Masitinib formula: C28H30N6OS
•Molecular weight:
•AB1010 (mesylate salt): 594.76
•AB1003 (free base): 498.66
•Masitinib® belongs to the ATP binding pocket molecules kinase inhibitor 2-amino-4-aryl-thiazole family
•c-Kit •c-Kit
•Proliferation
•AB1010
•Proliferation
•AB1010
•Anti-c-Kit
•Anti-Phospho Kit Tyr 729
•Anti-Phospho Tyr 4G10
M
e
N
S
N
H
N
H
O
N
N
N
M
e
-
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1010,10,050,01
DO
49
0 n
m
AB 1010 (µM)
Inhibition of c-Kit phosphorylation
•Masitinib formula: C28H30N6OS
•Molecular weight:
•AB1010 (mesylate salt): 594.76
•AB1003 (free base): 498.66
•Masivet® belongs to the ATP binding pocket molecules kinase inhibitor 2-amino-4-aryl-thiazole family
•c-Kit •c-Kit
•Proliferation
•AB1010
•Proliferation
•AB1010
•Anti-c-Kit
•Anti-Phospho Kit Tyr 729
•Anti-Phospho Tyr 4G10
M
e
N
S
N
H
N
H
O
N
N
N
M
e
-
•Masitinib
•Masitinib selectivity
•Data from Ambit analysis
•(http://www.kinomescan.com/TREEspot/TREEspot.aspx)
•Data from AB Science)
•122
-
Masitinib demonstrated efficacy in improving handicaps associated with
mastocytosis
•Trend for a better response in patients started with the
•highest dose of 6 mg/kg/day
0
5
10
Wee
k 0
Wee
k 12
Wee
k 24
Week 0
Week 12
Week 24
0
1,5
3
Wee
k 0
Wee
k 12
Wee
k 24
0
4
8
12
16
Wee
k 0
Wee
k 12
Wee
k 24
0
7
14
Wee
k 0
Wee
k 12
Wee
k 24
patients with pruritus score ≥6 (n=14)
patients with at least 1 flush/day (n=16)
patients with Hamilton score ≥10 (n=13)
patients with pollakiuria: miction ≥8/Jour (n=7)
•-49,9%
•-63,7%
•-50%
•-36,9%
•Mictions/day
•Depressive
•status
•Pruritus Score
•Flushes/day
•PP population
-
Effects of Masitinib on psychiatric
symptoms
-
ASL MRI outcome
•Before Masitinib therapy •Six months after Masitinib therapy
-
•Le masitinib a démontré une activité dans deux études de phase 2 dans les deux variantes génétiques de la maladie, avec ou sans mutation D816.
Prurit Flush Dépression Asthénie
AB04010 sans
D816V
AB06013
avec D816V
AB04010
sans D816V
AB06013
avec D816V
AB04010
sans D816V
AB06013
avec D816V
AB06013
avec D816V
% de variation entre le niveau de référence et la semaine 12 (LOCF)
N 19 21 17 6 3 9 13
Moyenne ± SD
-33.5 ± 43 -45.0 ± 52 -70.1 ± 50 -60.3 ±50 -40.6 ± 48 -44.2 ± 33 -38.1 ±28
P-value 0.016 0.002 0.002 0.047 NS 0.002
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Caractéristiques des patients
-
Masitinib Placebo p-value
Odd ratio (CI95%)
Critère principal
4H75% Le taux de réponse cumulée à 75% sur les handicaps de prurit, ou de bouffée de chaleur, ou de dépression ou d’asthénie
mITT/MDF
mITT/OC
18.7%
24.1%
7.4%
7.9%
0.0076*
0.0014*
3.63
4.90
•* Avec 10,000 re-randomisation en population mITT ; Résultats calculés selon la méthode MDF (Missing Data Equal Failure). Ainsi, si une donnée est manquante en raison de l’absence du patient lors d’une visite protocolaire, la réponse est considérée négative. ; OC: Cas observés
Critères secondaires
3H75% Le taux de réponse cumulée à 75% sur les handicaps de prurit, ou de bouffée de chaleur, ou de dépression
mITT/MDF 24.7% 9.8% 0.0071 3.06
2H75% Le taux de réponse cumulée à 75% sur les handicaps de prurit, ou de bouffée de chaleur
mITT/MDF 27.2% 10.7% 0.038 2.63
Prurit 75% Le taux de réponse cumulée à 75% sur les handicaps de prurit
mITT/MDF 22.0% 7.3% 0.0322 3.13
Analyses supportives
Flush75% Le taux de réponse cumulée à 75% sur les handicaps de bouffée de chaleur
mITT/MDF 39.9% 19.0% NS 3.03
Dépression (Hamilton 75%) Le taux de réponse cumulée à 75% sur les handicaps de dépression
mITT/MDF 18.6% 7.6% NS 2.71
Asthénie (FIS 75%) Le taux de réponse cumulée à 75% sur les handicaps d’asthénie
mITT/MDF 7.7% 3.2%
-
•Les analyses sur la réponse par patient ont confirmé le bénéfice pour les patients.
•AB06006 –Analyses supportives – Période W8-W24
Analyses supportives
Patient ayant 2 handicaps lors de leur entrée dans l’étude Nombre de patients ayant une réponse (75 %) pour au moins 2 handicap(s) au cours de la période globale
mITT/MDF 21.0% 0% NA
Patient ayant 3 handicaps lors de leur entrée dans l’étude Nombre de patients ayant une réponse (75 %) pour au moins 3 handicap(s) au cours de la période globale
mITT/MDF 12.5% 0% NA
Patient ayant 4 handicaps lors de leur entrée dans l’étude Nombre de patients ayant une réponse (75 %) pour au moins 4 handicap(s) au cours de la période globale
mITT/MDF 16.7% 0% NA
Masitinib Placebo p-value Odd ratio
(CI95%)
Analyses supportives
RÉPONSE PAR PATIENT à 75% Nombre de patients ayant une réponse (75%) pour au moins 1 handicap au cours de la période globale
mITT/MDF 26.7% 12.8% 0.0193 2.48
mITT / OC 34.1% 13% 0.005 4.90
•mITT population : population en intention de traiter modifiée •Ces résultats sont calculés selon la méthode Missing Data Equal Failure (MDF). Ainsi, si une donnée est manquante en raison de l’absence du patient lors d’une visite protocolaire, la réponse est considérée négative.
•OC: Cas observés – NA : Non applicable
-
•Le pourcentage de patients répondeurs à 50% est supérieur à 60% sur prurit, flush, et dépression.
•AB06006 - Analyse supportive – Taux de réponse par patient et par handicap
Alnalyse Handicape Niveau de réponse
Taux de réponse sous Masitinib
Au moins une réponse sur le
handicap
Prurit 75% 46%
50% 60%
Flush 75% 69%
50% 75%
Dépression (Hamilton) 75% 30%
50% 65%
Asthénie (FIS)
75% 14%
50% 27%
•Non GEE model. Analysis per patient
-
Masitinib Placebo p-value Odds
ratio(CI95%)
Analyses à long terme
4H75% Le taux de réponse cumulée à 75% sur les handicaps de prurit, ou de bouffée de chaleur, ou de dépression ou d’asthénie
mITT/MDF 17.2% 7.1% 0.0102 3.37
mITT/OC 27.1% 10.2% 0.0031 3.66
3H75% Le taux de réponse cumulée à 75% sur les handicaps de prurit, ou de bouffée de chaleur, ou de dépression
mITT/MDF 22.1% 8.6% 0.0030 3.10
mITT/OC 35.1% 12.1% 0.0003 3.87
•Le bénéfice observé au cours des six premiers mois de traitement était maintenu à 2 ans.
•AB06006 – Analyses à long terme sur le critère principal et les critères secondaires
•Période W8-W96
•mITT population : population en intention de traiter modifiée •Ces résultats sont calculés selon la méthode Missing Data Equal Failure (MDF). Ainsi, si une donnée est manquante en raison de l’absence du patient lors d’une visite protocolaire, la réponse est considérée négative.
•OC: Cas observés
-
Masitinib Placebo p-value
Tryptase - Patients ayant un niveau de tryptase ≥20 µg/L au moment de
leur entrée dans l’étude 46 44
0.0001 Variation relative moyenne par rapport à la valeur de référence
Moyenne±SD -18.0 ± 21.4 2.2 ± 26.9
Urticaire Pigmentaire (UP) - Patients ayant de l’urticaire pigmentaire
au moment de leur entrée dans l’étude 33 36
0.0210 Variation relative de surface corporelle couverte d’urticaire pigmentaire
(Correction de Wallace par rapport à la valeur de référence) -12.34 ± 26.41 15.91 ± 59.79
Signe de Darier – Nombre de patients (au moment de leur entrée dans
l’étude) 37 37
0.0187 Taux de disparition du Signe de Darier (oui/non) chez les patients ayant
le Signe de Darier lors de leur entrée dans l’étude 18.92% 2.70%
•Le masitinib a démontré une activité sur les marqueurs objectifs de l'activation et de l’excès des mastocytes
•AB06006 – Analyses d'efficacité basées sur des critères d’évaluation objectifs
•Période W8-W96
-
•Chez les patients ayant la mutation D816V, le masitinib a été capable de réduire la surface couverte d’urticaire pigmentaire après un traitement à long terme.
•AB06013 – Effets sur la peau chez un patient de sexe masculin avant (2007) et après (2008, 2014) traitement avec le masitinib
•.
•09-2007 VELA •03-2008 VELA
•(+ 6 mois)
•04-2014 VELA
•(+ 6.5 ans)
•Dr Stéphane BARETE – Service de dermatologie Hôpital Tenon
-
Masitinib
(pm=1321)
Placebo
(pm=1031) Delta
Au moins un événement indésirable
(indépendamment de la causalité) 5.3 6.1 -0.8
Décès 0.0 0.1 -0.1
Effet indésirable sérieux non mortel (SAEs) 2.1 1.8 0.3
Effet indésirable sévère (CTCAE grade 3/4) 3.2 2.9 0.3
Effet indésirable entraînant le retrait du patient (non mortel) 1.5 0.4 1.1
Effet indésirable conduisant à une réduction de dose 1.4 0.1 1.3
•. Pm = patient-mois. Incidence: Le numérateur est le nombre de patients avec au moins un événement indésirable, le dénominateur est la somme de la durée d'exposition (en mois). Le taux est calculé pour 100 patients-mois. Delta = masitinib moins placebo
•L'incidence des événements indésirables sur la période globale de l’étude était comparable entre les bras de traitement masitinib et placebo, sans effets toxiques mortels
•AB06006 – Incidence (pour 100 patients-mois) des événements indésirables
•Période globale de l’étude
L'incidence des effets indésirables était une mesure plus pertinente que la fréquence des effets indésirables, dans la mesure où certains patients ont reçu du masitinib pendant plus de 2 ans
La durée moyenne du traitement était de 18,9 mois pour le masitinib et de 16,4 mois pour le placebo
-
•La mastocytose systémique indolente est une maladie sévère et invalidante qui représente un fort besoin médical non satisfait.
•Mastocytose
•Mastocytose indolente
•(cutanée ou systémique)
•Mastocytose Agressive
•Pas de symptôme ou
•symptômes sans handicap •Symptômes avec handicap
•Médicaments cytoréducteurs
•Interferon
•Cladribine
•Temsirolimus+ Arac
•Anticorps
•PKC412
•Allogreffe
•Traitement symptomatique ou non
•Traitement symptomatique
•Anti H1, 2, Cromolyn, etc
•Pas de handicap •Handicap
•Pas d’autre traitement
•IFN, 2CDA,
•Masitinib ?
-
Masitinib does not inhibit c-kit D816 V ??
-
•Bien qu'il ne bloque pas la mutation D816V, le masitinib semble capable d'inhiber la dégranulation lors d’une hyperactivation des mastocytes. •
•Le masitinib inhibe l'hyperactivation des mastocytes FcƐR-dépendent
•The RBL-2H3 rat mast cell leukemia cell line is heterozygous for KIT, carrying both wild-type (WT) and exon 17 mutation alleles D817V . These cells have constitutive activation of KIT and are capable of degranulation upon FcɛRI-stimulation by ovalbumin (OVA). OVA administration induces β-hexosaminidase release (an established biomarker of mast cell degranulation) from these constitutive activated mast cells, whereas no degranulation is induced by stem cell factor (SCF, the ligand for c-Kit) activation.
-
HYPOTHESIS
•MCAS
•MSI
•Families of MCAS and Mastocytosis
C-Kit D816V mutation is not the only mutation that explains different phenotypes of the disease
One or many mutations, probably germ line mutations, are responsible of mast cell activation symptoms and MCAS
Could this mutation play a role in other inflammatory diseases?
- Absence of correlation between : pathologic mast cell burden and intensity of mast cell activation symtoms in the same patient
- Use of Masitinib (tyrosine kinase inhibitor): relieves mast cell activation symptoms (non efficient when D816V is mutated)
•Crit Rev Oncol Hematol. 2015 Feb;93(2):75-89. doi: 10.1016/j.critrevonc.2014.09.001. Epub 2014 Sep 28.
•The genetic basis of mast cell activation disease - looking through a glass darkly. Molderings GJ.
http://www.ncbi.nlm.nih.gov/pubmed/?term=Molderings GJ[Author]&cauthor=true&cauthor_uid=25305106http://www.ncbi.nlm.nih.gov/pubmed/?term=Molderings GJ[Author]&cauthor=true&cauthor_uid=25305106
-
• Mastocytose et maladies inflammatoire mastocytoses familiales
-
• Mastocytose et maladies inflammatoires mastocytoses familiales
-
•159
Comparaison
des 2 populations
nb % forme familiale nb % forme familiale prévalence
Polyarthrite rhumatoïde 600 000 1,00% 6% 100 1,38% 19% 3,00E-04
Spondylarthrites Ankylosantes 200 000 0,32% 10% 34 0,47% 17% 2,00E-02
Sclérose en plaques 60 000 0,10% 6% 44 0,61% 20% 2,00E-44
Maladie de Crohn 70 000 0,11% 25% 35 0,48% 17% 6,00E-21
Atteints de Mastoçytose (7247 inds)population Française
-
Spectrum of MCAS
•Mastocytosis
•Other diseases
•RA, psoriasis,
•MS,IBD,PS,ICys
•Depression
•Idiopathic
•Mast cell activation
-
Spectrum of MCAS
•Mastocytosis
•Other diseases
•RA, psoriasis,
•MS,IBD,PS,ICys
•Depression
•Idiopathic
•Mast cell activation
•C-kit+ X • X
•X =kinase inhibited by Masitinib
-
Spectrum of MCAS
•Mastocytosis
•C-kit*
•PLCgamma2*?
•Other?
•PLCgamma2*?
•other
•Other diseases
•RA, psoriasis,
•MS,IBD,PS,ICys
•Depression
•Idiopathic
•Mast cell activation
•PLCgamma2*?
•other
Other =Inhibited by Masitinib
-
Cancer Allergy
Autoimmunité
Alloreactivity
Acute
chronic
Mastocytosis
Inflammation
fibrosis Neurological
And
Psychiatric
Diseases
-
Preliminary evidence suggests that masitinib may be able to reverse hypoperfusion in mastocytosis patients, with a concomitant improvement in cognitive functions.
•Functional disorders
associated with mastocytosis do
not appear in conventional MRI
but appear on MRI measuring cerebral blood
flow.
•Could this also be the case in Alzheimer's
disease?
•Representative images from mastocytosis patient comparing ASL-MRI •before masitinib treatment (A) and after 6 month treatment (B)
•A •B
•PRECLINICAL DATA – ASL-MRI OBSERVATIONS
-
•BRAIN BLOOD PERFUSION: SIMILARITY MASTOCYTOSIS AND ALZHEIMER’S DISEASE
•Representative images from a control patient (Fig. A&B), an AD patient (Fig. C), and a mastocytosis patient (Fig. D), illustrating
the impaired cognitive functions.
•[Figs. A&C] Alzheimers Dement. 2012 Jan; 8(1): 51–59. [Figs. B&D] Pr Bodaert Pr O. Hermine. Hôpital Necker-Paris.
•C
•Patients
•Alz
heim
er
•D
•Mas
tocy
tosi
s
•B
•Heal
thy
volu
nteer
•A
•Control
•Heal
thy
volu
nteer
• Measurement of cerebral blood flow using arterial spin
labeling MRI reveals similar
hypoperfusion patterns between
mastocytosis patients with
impaired cognitive functions (memory and/or attention) and AD patients
-
167
PUTATIVE MECHANISM OF ACTION OF MASITINIB IN ALZHEIMER’S DISEASE
has been hypothesized that phosphorylated tau could trigger a
neurodegenerative cascade that may require the expression of
cell cycle markers in neurons prior to the apoptotic process [72].
Moreover, Fyn overexpression was found to accelerate synapse
loss and the onset of cognitive impairment in the J9 (APPswe/
Ind) transgenic AD mouse model, while blocking the Fyn
expression rescued synapse loss in the J20 (APPswe/Ind)
mice [73]. While tau is generally considered an axonal protein,
it does have a role in dendrites as well. It has been demon-
strated that tau participates in postsynaptic targeting of Fyn to
dendrites [74,75]. In dendrites, Fyn is capable of interacting with
NMDARs, thus regulating receptor activity [75,76]. Fyn kinase
could potentiate the neurotoxic process through the phosphory-
lation of the subunit 2 (NR2B) of the NMDAR in dendritic
spines, which results in stabilization of the receptor’s interaction
with the postsynaptic density protein PSD-95. The exact mech-
anism of b-amyloid–Fyn–NMDAR interaction likely involves
the formation of the complex between b-amyloid, the prion
protein (PrP) and the metabotropic glutamate receptor
5 (mGluR5) which can promote Fyn activation, ultimately
leading to the phosphorylation of the NR2B [74,77–79]. As men-
tioned above, tau plays a key role by delivering Fyn
postsynaptically.
Interestingly, saracatinib (AZD0530) is another Src inhibitor
which targets Fyn. Although at the beginning this drug was
developed for cancer treatment, it was abandoned for this
application. Currently, two clinical trials are testing the efficacy
of saracatinib in early-stage AD ([80] and [81]).
In conclusion, treatment with masitinib may provide dual
benefits in AD pathology. On the one hand, inhibition of the
MCs may reduce neuroinflammation via MCs–glia axis
modulation. On the other hand, cognitive
improvementsasaresult of Fyn inhibition
are likely independent of b-amyloid pro-
duction and amyloid plaqueload (FIGURE 2).
Safety & tolerability
Based on a number of clinical trials
which considered masitinib for a range of
conditions including AD, the drug
appears to be well tolerated in humans.
The majority of the reported AEs are
consistent with other TKIs already on the
market. Edema, rash, nausea, vomiting
and diarrhea are commonly reported.
However, these AEs are generally tran-
sient and are well within the acceptable
thresholds for this type of symptomatic
treatment. For an in-depth overview of
the safety data reported in clinical trials,
refer to Table 4 of [9] and Table 3 of [47].
Conclusion
The failure of AD treatments developed
over the last few decades demonstrates the
complexity of the underlying pathology. Masitinib may not be
an all-encompassing cure-all for the disease, but depending on
the results of ongoing and future clinical trials, it may have a
chance to becomean additional disease-modifying compound in
the arsenal of physicians aiming to treat this debilitating
condition.
Expert commentary
Over the years, a number of hypotheses have been proposed to
explain the etiology of AD. These include: the amyloid cascade
hypothesis, mitochondrial hypothesis, dendritic hypothesis, cell
cycle hypothesis and the inflammatory hypothesis [4–8,10–12,18].
If one assumes that each of these hypotheses describes an aspect
of the disease, then the complexity of AD pathology becomes
apparent. With the involvement of multiple signaling cascades,
it is quite possible that a single drug could target more than
one pathway. Such is the case of masitinib, a TKI which is
capable of both c-kit and Fyn inhibition.
Increased production of b-amyloid may be a cause of early-
onset familial AD. As a result of genetic mutations affecting
APP processing, excessive accumulation of b-amyloid in the
brain leads to senile plaque formation. Since amyloid plaques
are clearly not a component of a healthy brain, immune system
response is eventually activated. Indeed, previous studies have
shown the existence of an inflammatory process around the
plaques, which presumably favors the loss of neighboring neu-
rons [82–87]. Activated microglia would then be responsible for
the generalized cerebral inflammation. If that was the principal
driving force behind AD-related neurodegeneration, then the
NSAID treatment would be expected to be of great benefit to
AD sufferers. This is not entirely the case, however, as only
Inhibition of neuroinflammator y
process Glial cells
Modulation of NMDA
receptor
Inhibition of
tau phosphorilation
Inhibition of FYN kinase
Memory process improvement
Prevention of cell cycle re-entry
Mast cellsMasitinib
Neuron
Figure 2. A proposed mechanism w hereby masit inib could exert neuroprotect ive
effects in Alzheimer’s disease. Fyn signaling in the hippocampus is, at least partially,
regulating cell cycle re-entry, neuronal memory process, tau phosphorylation and also
NMDA receptor. In addition, masitinib inhibits c-kit receptor in mast cells and, thus, the
neuroinflammatory process.
NMDA: N-methyl-D-aspartate.
Drug Prof ile Folch, Petrov, Ettecho et a l.
doi: 10.1586/14737175.2015.1045419 Expert Rev. Neurother.
Exp
ert
Rev
iew
of
Neu
roth
erap
euti
cs D
ownl
oade
d fr
om i
nfor
mah
ealt
hcar
e.co
m b
y 16
1.11
6.33
.27
on 0
5/11
/15
For
per
sona
l us
e on
ly.
B-Amyloid Substance
CD47
Masit inib for the treatment
of mild to moderate
Alzheimer’s diseaseExpert Rev. Neurother. Early online, 1–10 (2015)
Jaume Folch1,
Dmitry Petrov2,
Miren Ettecho2,
Ignacio Pedros1,
Sonia Abad2,
Carlos Beas-Zarate3,4,
Alberto Lazarowski5,
Miguel Marin6,
Jordi Olloquequi7,
Carme Auladell8 and
Antoni Camins* 2,6
1Unitat de Bioquimica i Biotecnologı́a,
Facultat de Medicina i Ciències de la
Salut, Universitat Rovira i Virgili, Reus,
Tarragona, Spain2Unitat de Farmacologia I Farmacognòsia,
Facultat de Farmàcia, Institut de
Biomedicina (IBUB), Centrosde
Investigacion Biomedica en Red de
EnfermedadesNeurodegenerativas
(CIBERNED), Universitat de Barcelona,
Barcelona, Spain3Departamento de Biologı́a Celular
y Molecular, C.U.C.B.A., Universidad
de Guadalajara and Division de
Neurociencias, Sierra Mojada 800, Col.
Independencia, Guadalajara, Jalisco
44340, Mexico4Centro de Investigacion Biomedica de
Occidente (CIBO), Instituto Mexicano del
Seguro Social (IMSS), Jalisco 44340,
Mexico5Instituto de Investigacionesen
Fisiopatologı́a y Bioquı́micaClı́nica
(INFIBIOC), Facultad de Farmacia y
Bioquı́mica, Universidad de Buenos
Aires (UBA), BuenosAires, Argentina6Centro de Biotecnologı́a, Universidad
Nacional de Loja, Av. Pı́o Jaramillo
Alvarado y Reinaldo Espinosa, La
Argelia, Loja, Ecuador7Facultad de Cienciasde la Salud,
Universidad Autonoma de Chile, Talca,
Chile8Departament de Biologia Cellular,
Facultat de Biologia, Universitat de
Barcelona, Barcelona, Spain
* Author for correspondence:
Alzheimer’s disease (AD) is a degenerative neurological disorder that is the most common
cause of dementia and disability in older patients. Available treatments are symptomatic in
nature and are only sufficient to improve the quality of life of AD patients temporarily.
A potential strategy, currently under investigation, is to target cell-signaling pathways
associated with neurodegeneration, in order to decrease neuroinflammation, excitotoxicity,
and to improve cognitive functions. Current review centers on the role of neuroinflammation
and the specific contribution of mast cells to AD pathophysiology. The authors look at
masitinib therapy and the evidence presented through preclinical and clinical trials. Dual
actions of masitinib as an inhibitor of mast cell–glia axis and a Fyn kinase blocker are
discussed in the context of AD pathology. Masitinib is in Phase III clinical trials for the
treatment of malignant melanoma, mastocytosis, multiple myeloma, gastrointestinal cancer
and pancreatic cancer. It is also in Phase II/III clinical trials for the treatment of multiple
sclerosis, rheumatoid arthritis and AD. Additional research is warranted to better investigate
the potential effects of masitinib in combination with other drugs employed in AD treatment.
KEYWORDS: Alzheimer . inflammation . masitinib . neurodegeneration . tau
Alzheimer’s disease (AD) was first described
over a century ago by the physician Alois
Alzheimer, but still, more than 100 years later,
the root cause of the disorder is not
completely understood [1]. Currently available
pharmaceutical interventions are inadequate
and provide only slight improvement in dis-
ease symptoms [2,3]. Recently, researchers have
made a number of breakthroughs in uncover-
ing the molecular mechanisms involved in dis-
ease pathogenesis [4,5]. This work has led to
the identification of novel molecular targets
and drug candidates, some of which are
already on the market, with others in various
stages of preclinical and clinical development.
As the loss of cholinergic neurons in the
frontal cortex and the hippocampus is a prom-
inent histopathological feature of AD and
other dementias, initial drug development
efforts have focused on restoring central cho-
linergic transmission [3]. Acetylcholinesterase
inhibitors (AchEIs), which include donepezil,
rivastigmine and galantamine, are indicated for
the treatment of patients with mild to moder-
ately severe Alzheimer’s dementia [2,3]. These
compounds increase cholinergic transmission
by inhibiting acetylcholinesterase at the synap-
tic cleft. Unfortunately, the therapeutic efficacy
of AchEIs is limited and the available drugs in
this class do not halt disease progression [2,3,6].
Cognitive decline in AD patients has also
been linked to neuronal damage as a result of
excitotoxicity caused by the persistent overacti-
vation of N-methyl-D-aspartate receptor
(NMDAR) by the amino acid glutamate [7,8].
Memantine is an NMDAR antagonist admin-
istered for the treatment of moderate to severe
AD, which reduces glutamatergic excitotoxic-
ity [3,9]. However, just as with AchEIs, the
beneficial effects of memantine are modest,
and the treatment is largely palliative.
Another key aspect of AD pathology which
hasbeen thesubject of intensiveresearch interest
(with vast financial resources invested) concerns
elucidating the exact role b-amyloid peptide
plays in disease progression. It is well known
that AD is neuropathologically characterized by
senile(amyloid) plaques, consistingof extracellu-
lar deposits of b-amyloid protein, and by the
intraneuronal neurofibrillary tangles, comprising
informahealthcare.com 10.1586/14737175.2015.1045419 Ó 2015 Informa UK Ltd ISSN 1473-7175 1
Drug Prof ile
Exp
ert
Rev
iew
of
Neu
roth
erap
euti
cs D
ownl
oade
d fr
om i
nfor
mah
ealt
hcar
e.co
m b
y 16
1.11
6.33
.27
on 0
5/11
/15
For
per
sona
l us
e on
ly.
Masit inib for the treatment
of mild to moderate
Alzheimer’s diseaseExpert Rev. Neurother. Early online, 1–10 (2015)
Jaume Folch1,
Dmitry Petrov2,
Miren Ettecho2,
Ignacio Pedros1,
Sonia Abad2,
Carlos Beas-Zarate3,4,
Alberto Lazarowski5,
Miguel Marin6,
Jordi Olloquequi7,
Carme Auladell8 and
Antoni Camins* 2,6
1Unitat de Bioquimica i Biotecnologı́a,
Facultat de Medicina i Ciències de la
Salut, Universitat Rovira i Virgili, Reus,
Tarragona, Spain2Unitat de Farmacologia I Farmacognòsia,
Facultat de Farmàcia, Institut de
Biomedicina (IBUB), Centrosde
Investigacion Biomedica en Red de
EnfermedadesNeurodegenerativas
(CIBERNED), Universitat de Barcelona,
Barcelona, Spain3Departamento de Biologı́a Celular
y Molecular, C.U.C.B.A., Universidad
de Guadalajara and Division de
Neurociencias, Sierra Mojada 800, Col.
Independencia, Guadalajara, Jalisco
44340, Mexico4Centro de Investigacion Biomedica de
Occidente (CIBO), Instituto Mexicano del
Seguro Social (IMSS), Jalisco 44340,
Mexico5Instituto de Investigaciones en
Fisiopatologı́a y Bioquı́micaClı́nica
(INFIBIOC), Facultad de Farmacia y
Bioquı́mica, Universidad de Buenos
Aires (UBA), BuenosAires, Argentina6Centro de Biotecnologı́a, Universidad
Nacional de Loja, Av. Pı́o Jaramillo
Alvarado y Reinaldo Espinosa, La
Argelia, Loja, Ecuador7Facultad de Cienciasde la Salud,
Universidad Autonoma de Chile, Talca,
Chile8Departament de Biologia Cellular,
Facultat de Biologia, Universitat de
Barcelona, Barcelona, Spain
* Author for correspondence:
Alzheimer’s disease (AD) is a degenerative neurological disorder that is the most common
cause of dementia and disability in older patients. Available treatments are symptomatic in
nature and are only sufficient to improve the quality of life of AD patients temporarily.
A potential strategy, currently under investigation, is to target cell-signaling pathways
associated with neurodegeneration, in order to decrease neuroinflammation, excitotoxicity,
and to improve cognitive functions. Current review centers on the role of neuroinflammation
and the specific contribution of mast cells to AD pathophysiology. The authors look at
masitinib therapy and the evidence presented through preclinical and clinical trials. Dual
actions of masitinib as an inhibitor of mast cell–glia axis and a Fyn kinase blocker are
discussed in the context of AD pathology. Masitinib is in Phase III clinical trials for the
treatment of malignant melanoma, mastocytosis, multiple myeloma, gastrointestinal cancer
and pancreatic cancer. It is also in Phase II/III clinical trials for the treatment of multiple
sclerosis, rheumatoid arthritis and AD. Additional research is warranted to better investigate
the potential effects of masitinib in combination with other drugs employed in AD treatment.
KEYWORDS: Alzheimer . inflammation . masitinib . neurodegeneration . tau
Alzheimer’s disease (AD) was first described
over a century ago by the physician Alois
Alzheimer, but still, more than 100 years later,
the root cause of the disorder is not
completely understood [1]. Currently available
pharmaceutical interventions are inadequate
and provide only slight improvement in dis-
ease symptoms [2,3]. Recently, researchers have
made a number of breakthroughs in uncover-
ing the molecular mechanisms involved in dis-
ease pathogenesis [4,5]. This work has led to
the identification of novel molecular targets
and drug candidates, some of which are
already on the market, with others in various
stages of preclinical and clinical development.
As the loss of cholinergic neurons in the
frontal cortex and the hippocampus is a prom-
inent histopathological feature of AD and
other dementias, initial drug development
efforts have focused on restoring central cho-
linergic transmission [3]. Acetylcholinesterase
inhibitors (AchEIs), which include donepezil,
rivastigmine and galantamine, are indicated for
the treatment of patients with mild to moder-
ately severe Alzheimer’s dementia [2,3]. These
compounds increase cholinergic transmission
by inhibiting acetylcholinesterase at the synap-
tic cleft. Unfortunately, the therapeutic efficacy
of AchEIs is limited and the available drugs in
this class do not halt disease progression [2,3,6].
Cognitive decline in AD patients has also
been linked to neuronal damage as a result of
excitotoxicity caused by the persistent overacti-
vation of N-methyl-D-aspartate receptor
(NMDAR) by the amino acid glutamate [7,8].
Memantine is an NMDAR antagonist admin-
istered for the treatment of moderate to severe
AD, which reduces glutamatergic excitotoxic-
ity [3,9]. However, just as with AchEIs, the
beneficial effects of memantine are modest,
and the treatment is largely palliative.
Another key aspect of AD pathology which
hasbeen thesubject of intensiveresearch interest
(with vast financial resources invested) concerns
elucidating the exact role b-amyloid peptide
plays in disease progression. It is well known
that AD is neuropathologically characterized by
senile(amyloid) plaques, consistingof extracellu-
lar deposits of b-amyloid protein, and by the
intraneuronal neurofibrillary tangles, comprising
informahealthcare.com 10.1586/14737175.2015.1045419 Ó 2015 Informa UK Ltd ISSN 1473-7175 1
Drug Prof ile
Exp
ert
Rev
iew
of
Neu
roth
erap
euti
cs D
ownl
oade
d fr
om i
nfor
mah
ealt
hcar
e.co
m b
y 16
1.11
6.33
.27
on 0
5/11
/15
For
per
sona
l us
e on
ly.
-
168
ANIMAL MODEL (APPXPS1DE9): COGNITIVE EVALUATION IN A CURATIVE SETTING
Masitinib was evaluated for its effect on memory deficit in AD mice (Tg) versus using the Morris Water Maze (MWM) in a curative setting (mice aged 12-14 months)
The MWM test evaluates hippocampal-dependent learning, including acquisition of spatial memory and long-term spatial memory, which is often affected in AD.
Blinded study
During learning End of learning period
Hidden platform (target)
B Delatour et al ICM Paris
-
Genotype effect observed between wild-type (WT) and APPxPS1dE9 (Tg) mice treated with vehicle (Veh)
1 2 3 4 5
0
5
1 0
1 5
T o ta l d is ta n c e tra v e lle d V e h (T g v s W T 1 -5 D ) (R O M A N E 1 -2 )
d a y s
m
T g V e h (n = 8 )
W T V e h (n = 1 0 )
•Tot
al d
ista
nce (
m)
trav
elled
•by
cont
rol (V
eh)
mic
e
1 2 3 4 5
0
5
1 0
1 5
T o ta l d is ta n c e tra v e lle d M a s it in ib (T g v s W T 1 -5 D ) (R O M A N E 1 -2 )
d a y s
m
T g M a s it in ib (n = 9 )
W T M a s itin ib (n = 9 )
Disappearance of genotype effect on mice treated with masitinib
Masitinib treatment improves cognitive function, with spatial memory returning to normal levels
•Tot
al d
ista
nce (
m)
trav
elled
•by
mas
itin
ib t
reat
ed m
ice
•MWM Acquisition phase
•Preclinical Data – Animal Model • (Cognitive Evaluation in a Curative Setting)
-
•Percentage use of spatial strategy. ** p
-
•PRECLINICAL DATA – ANIMAL MODEL (HISTOPATHOLOGY - AMYLOID LOADS)
Masitinib treatment decrease the amyloid charges (Congo red +) in the hippocampus of young APP/PS1dE9 mice
Tg
Veh
(n
=6)
Tg
Masit
inib
(n
=9)
0 .0 0
0 .0 2
0 .0 4
0 .0 6
0 .0 8
A m y lo id lo a d (H ip p o c a m p u s )
***
-
Alzheimer’s Disease – Previous clinical data •Phase 2 Effect of Masitinib
•Alzheimers Res Ther. 2011 Apr 19;3(2):16. doi: 10.1186/alzrt75.
•Efficacy results in mild-to-moderate Alzheimer's disease
•(Phase 2 ; n=34 patients)
-8
-6
-4
-2
0
2
4
6
8
10
12
Week 0 Week 12
p=0.035
Week 24
p=0.128
Me
an
ch
an
ge
fro
m b
as
eli
ne
±s
tan
da
rd e
rro
r ADAS-ADL Masitinib Placebo
wo
rse
nin
g -
imp
rove
me
nt
•The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory) is a subscale of daily living assessing items such as toileting, feeding, dressing, and physical ambulation
-
Mastocytoses
Syndrome d’activation mastocytaire
Mastocytoses : Prolifération clonale de mastocytes Accumulation (médullaire,
cutanée++) Mutation somatique gène CKIT
Syndrome d’activation mastocytaire : Activation exagérée mastocytes Pas critères de mastocytose Plus fréquent Clinique :
• Asthénie • Flush, prurit • Douleurs ostéo-articulaires • Troubles digestifs • Troubles neuropsychiatriques • Symptômes d’allergie
Traitement : Antihistaminiques Inhibiteurs de Tyrosine Kinase
MALADIES LIEES AU MASTOCYTE
-
•Laboratoire d’hématologie - NEM
•Vahid Asnafi Ludovic Lhermitte
•Patrick Villarese
•Julie Bruneau
•Sophie Georgin-Lavialle
•Zakia Belaid-Choucair
•Geneviève Courtois
•Marie Bouillié
•Francine Côté
•Pascal Amireault
•Flavia Guillem
•David Sibon
•Yves Lepelletier
•Inserm U891 - Marseille
•Patrice Dubreuil
•Sébastien Letard
•Service de pathologie - NEM
•Nicole Brousse Danielle Canioni
•Sylvie Fraitag Stéphanie Leclerc-Mercier
•Gisèle, Martine, Annie, Stéphanie, Marie-Aimée…
•Service de pathologie - HMN
•Philippe Gaulard Nicolas Ortonne
•Nadine Martin
•Laboratoire de cytogénétique - NEM
•Serge Romana Isabelle Radford-Weiss
•Gwendoline Soler
•Centre de référence des mastocytoses - NEM
•Olivier Hermine Christine Bodemer
•Olivier Lortholary
•Laboratoire Télomères - Institut Curie
•Arturo Londono-Vallejo
•Irena Draskovic
Bonne année 2013!
Sophie, Patrice, Alexandre et Thibault
•Inserm U768 - NEM
•Patrick Revy
•Tangui Le Guen
•Merci
•U8147
•Plateforme d’imagerie cellulaire - Imagine
•Raphaëlle Devaux Nicolas Goudin
•Meriem Garfa-Traore
-
Mechanism of action of Masitinib ?
-
Kinase inhibitor in Mastocytosis with C-kit D816V
Melanocytes
Normal Mastocytes
Mutated Mastocytes
SCF
SCF
SCF
Urticaria pigmentosa
Symptoms
+
Tumoral Syndrome
C Findings
D816V C-Kit* WT C-Kit
WT C-Kit
ITK
-
•Famillial MCAS and Mastocytosis
-
Rapamycin and MS
•Stop IFN
•CDA 1
•CDA 2
•Start IFN
•Start Rapamycin
-
•Histamine, cytokines, protéases (tryptase), prostaglandines, ROS
•Variations pression
température
•Peptides, hormones
•IgE
•SCF
•c-Kit
•HOMEOSTASIE
•Mastocyte
•FcεRI
•REPONSE
•IMMUNITAIRE
•PROLIFERATION
•Système cardiovasculaire
•Vasodilatation hypotension
•Perméabilité Œdème
•Voies aériennes
•Bronchoconstriction
•Toux
•Dyspnée
•Peau
•Prurit
•Flush
•Urticaire
•DEGRANULATION
•LT régulateur
•TLRs
•Pathogènes (Bactéries, virus,
parasites)
•LB
•Cellule dendritique
•Cytokines pro-inflammatoires (TNF-α, IL-6,
IL-8 …)
•OX40L
•OX40
•4-1BBL •HLA/Ag
•FcεRI
•LT effecteur
•OX40 •4-1BB
•TCR
•TCR
•CCL2, 4, 5, 10 CXCL10
•TGFß TNF-α IL-6
•CD40L
•CD40
•Histamine, PGD, PGE TNF-α, IL-
1, IL16, IL-18
•IL-4, IL-6, IL-13
•FcεRI
•IgE/Ag
•HLA/Ag
•HLA/Ag
•BCR
•Migration
•Prolifération
•Activation
•Phénotype TH17
•Migration
•Maturation
•Activation
•Prolifération
•Activation
•Recombinaison isotypique (IgE)
•Frenzel et al, JBS 2013
-
Anti IgE therapy
-
Psychiatric symptoms and anti IgE
Treatment
• 18 years old pts, Famillial history of MCAS and Mastocytosis.
MCAS (dermographism, GI tract symptoms, Pain). No skin
lesions, no bone marrow involvement, No C-kit D816V mutation.
Nl tryptase level. History of chronic and acute hallucination
episodes. Refractory to Anti- psychotic drugs. Xolair Treatment :
total disappearance of Hallucinations.
• 45years old pts, ISM, tryptase 45ng/ml. Episodes of flushes
followed by acute aggressivness (Twice in trial because of acute
violence). No efficacy of anti-psychotic drugs. MRI shows
hypersignal in the limbic region of the white matter. Resolution of
episodes on Xollair therapy.
-
Role of Ustekinumab (Stelara°) anti IL12/IL23
• Young women 21 years. Past history of ISM. Flushes, GI Tract
Pain, Fatigue, depression, memory loss. Joint pain, Lumbar pain.
No clinical and Xray signs of psoriasis or spondylarthritis
• Failure to Mast cell symptomatic treatment
• Disappearance of all symptoms on Stelara treatment
(90mg/3months)
• 35 years old women. Past history of Pain+++, depression, fatigue,
GI tract pain, diarrhea, flushes, dermographism, No UP, no mast
cell infiltration. Ankylositing spondylarthritis (B27 negaive).
Failure of Mast cell mediatior inhibitor, opoid treatmemt,anti-TNF
therapy. Success of Stelara° on joint pain but also on most of the symptoms of MCAS including Psyschiatric
-
Cytoreductive treatment Aggressive
diseases
• Interferon alpha
• Cladribine
• Kinase inhibitors
• Thalidomide
• Rapamycine
-
PKC412: Discussion and perspectives
• Longer follow up and comparison with matched patients who did not receive Midostaurin is required to assess its value to improve overall survival
• Is complete response a goal to achieve ?
• Use of Midostaurin in combination (2-CDA, 5-AZA, decitabine, chemotherapy) to improve the response rate and survival particularly in AHNMD, MCL and MCS
• Use of Midostaurin before allogenous bone marrow transplantation
• Midostaurin monitoring to improve safety and response : • Compliance
• Absorption
• Drug interactions
• Organ dysfunction
Dr P Bourget, Head Chief of the Clinical Pharmacy Department of Necker Hospital
• Facing a multi-target drug and the need to treat for life / until progression, what do we know about the potential long term side effects ?
– Induction of secondary neoplasia
– Role in progression of the AHNMD
-
Perspective mTOR
• Temsirolimus in combination
• High efficiency of temsirolimus + high dose
ARAC in agressive and mast cell leukemia
-
•Idolent
•Aggressive
-
Mastocytosis
Indolent Mastocytosis (cutaneous or systemic)
Agressive Mastocytosis
No symptoms or symptoms without handicap
Symptoms with handicap
Symptomatic treatment
No handicap
No further treatment Further treatment: IFN, 2CDA, TKI (Masitinib)
mTOR, other
Handicap
No or symptomatic treatment
Cytoreductive drugs Demethylating
PKC412 Cladribine
Temsirolimus+ Arac Others
BMT
-
Treatment Strategy
• Define prognosis factors
• Define symptoms
• C-findings : ASM or AHNMD (MDS/MPN) ?
• Which treat first ? Or treat in combination
• PKC412 vs Cladribine vs mTOR inhibtion
• Chemotherapy
• Demethylating agent
-
MANIFESTATIONS CLINIQUES
SAM
a
40,8
%
n=
53
AEG:
42,3
%
n=55
HSM
G
32,3%
n=42 ostéoporo
se 23,8%
n=31 fracture
38.7%, n=12
HTP/asci
te 13,1%
n=17
Trouble
s
Digestif
s : 30%
n=39
Délai médian diagnostic : 12 mois à partir des premiers
symptômes
Cutan
é
TMEP
ou UP
:
25,4%
n=33
-
Le gène KIT avait été séquencé chez 53 patients avec 44 mutations retrouvées (83%)
GENETIQU
E
D816V, n=40 75%
OTHER, n=4 8%
Wild Type, n=4 8%
NOT FOUND,
n=5 9%
-
Parmi les 47 patients de la cohorte française, 32 ont eu une recherche de mutations additionnelles :
MUTATIONS ADDITIONNELLES
0
2
4
6
8
10
12
14
mutationTET2
mutationJAK 2
mutationSRSF2
mutationASLX1
mutationIDH2
mutationCBL
mutationU2AF1
mutatioNRAS
-
TABLEAU TYPIQUE
Clinique OMS Biologie Génétique
AEG KIT D816V
SAMA AHNMD Anémie +/- TET2
HSMG Thrombopéni
e +/- SRSF2
Troubles
digestifs +/- JAK2
-
ENFANTS
ADULTE
JEUNE
> 70 ANS
Signes cliniques Cutané Cutané et neuropsy AEG et
troubles dig Stade OMS CM ISM
AHNMD
Biologie N N
Anomalies NFS
Tryptase N 1,5 – 2 N 10
N
Génétique KIT 50% 89%
75%
D816V Evolution Bénigne Bénigne Morbi-
mortalité élevée
-
•Les sponsors…
•MERCI
Laboratoire d’hématologie
Vahid Asnafi
Ludovic Lhermitte
Patrick Villarese
Unité CNRS 8147
Olivier Hermine
Julie Bruneau
Service de pathologie NEM
Nicole Brousse
Danielle Canioni
Sylvie Fraitag
Laboratoire de cytogénétique
Serge Romana
Isabelle Radford-Weiss
Centre de référence des mastocytoses
Olivier Hermine
Chritine Bodemer
Olivier Lortholary
Stéphane Barète
Olivia Chandesris
Daniella Moura
Inserm UMR 891
Patrice Dubreuil
Sébastien Letard
Pr Jean-Marie Launay
Pr Raphaël Gaillard
Dr Harry Sokkol
Laboratoire Télomères Curie
Arturo Londono-Vallejo
•Aux patients
•Aux médecins qui incluent des patients