Treatment of Mastocytosis

Olivier Hermine MD, PhD

Hematology Department, Necker Hospital

Centre National de référence des mastocytoses, Necker Hospital

INSERM U1163 CNRS ERL 8654

Institut Imagine, Necker Hospital

Paris, France

Disclosures

• AB science Co Founder, Consultant, Stock Holder, Research grants

• Novartis Research grants

• Celgene research grants

Definitions and Classifications

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

<2 years

Frequent regression

Reactive disease ?

Adult Young vs Ederly

Adult age onset

Chronic disease

No regression

Clonal disease

Mast cell Leukemia and Sarcoma :

Rare, Rapid Fatal outcome

Mastocytosis : Spectrum of the disease

Mastocytosis : Spectrum of the disease

MCAS

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.

Prognosis

Blood 2009

Prognosis

Blood 2009

Indolent Mastocytosis >80%

Agressive Mastocytosis <20%

Diagnosis

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

Clinical and Biological investigations

• Symptoms: handicap fonctionnel, asthenia, prurit, flush, depression, diarrhea, pollakiuria, vascular instabilities

• Clinical: Weight-nutrition, Skin, tumoral syndrome (Lymph nodes, splenomegaly, hepatomegay)

• Biology: CBC, Liver Enzymes, Albumin, tryptase, IgE, Vitamin D.

• Organ infiltration: skin biopsy, bone marrow, others (digestive tract, liver…). Bone marrow aspiration, Mast cell phenotype

• Screening of c-kit mutation (Skin, infiltrated organ, peripheral blood ?)

• Bone check up: X Ray in case of symptoms, Bone density+++.

• Associated Hematological Neoplasm

Diagnosis Criteria and Classification

Physiopathology

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

…...

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

…...

Oncogenic Mutations of c-kit in Mastocytosis

1

2

Oncogenic Signal

Adult Mutations 85%

Clonal disease +++

No regression

Pediatric Mutations 75%

Clonal disease +++

Regression

Exons 8 to 11 Exon 17 WT

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

Adult

Exons 8 to 11 Exon 17 WT

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

Adult

Exons 8 to 11 Exon 17 WT

Indolent

Vs

Agressive ?

AHN

MCL

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)

Figure 1

Mutations Hierarchy in Mastocytosis

K Hanssens, haematologica in press S Schwaab, Blood 2013

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

Associated Hematological Malignancies

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)

TET2, ASXL1 are positive, only in the myeloid AHNMD

*Damaj et al, CEREMAST, Unpublished data

Genes mtations in Associated Hematological

Malignancies

6%

30%

11%

4%

49%

CM, n=8

ISM, n=39

ASM, n=14

MCS/MCL, n=5

SM AHNMD,n=64

Ederly patients

130 patients (80 Men 50

Women)

Age 75 years [70-90]

AHN

Leucémie, n=7 11%

MDS, n=21 33% MPF, n=29

45%

MGUS/ myélome,

n=3 5%

Lymphome, n=2 3%

non précisé,

n=2 3%

0

2

4

6

8

10

12

14

mutationTET2

mutationJAK 2

mutationSRSF2

mutationASLX1

mutationIDH2

mutationCBL

mutationU2AF1

mutatioNRAS

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)

ASXL1 but not TET2 muations adversely impact overall survival

of patients suffering systemic mastocytosis with associated clonal

hematologic non mast cell diseaes 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*

Schwaab et al., Blood 2013; 122:2460–2466; Jawhar et al., Leukemia 2016; 30:136-143

Overall frequency and prognostic impact of mutated

genes in 70 advanced KIT D816V+ SM patients

0%

20%

40%

60%

80%

100%

60% of patients had ≥2 mutated genes in addition to KIT D816V

Overall survival in advanced SM depending on mutations in the SRSF2/ASXL1/RUNX1 (S/A/R) panel

S/A/Rneg

S/A/Rpos

Clinical and Molecular Based Risk Score

Jawhar et al., Leukemia 2016; 29

Mastocytosis and psychological stress

Alexythymia ++++

Cognitive functions impairement

Depression

Evidence for Cognitive Impairment in Mastocytosis:Prevalence, Features and Correlations to Depression

Daniela Silva Moura1,2*, Serge Sultan7,8, Sophie Georgin-Lavialle1,3,4, St ephane Barete1,3,5,

Olivier Lortholary1,6, Raphael Gaillard9,10, Olivier Hermine1,3,11,12*

1 Centre de reference des mastocytoses, Hopital Necker Enfants malades, Fondation Imagine Paris, Universite Paris Descartes, Sorbonne, Paris Cite, Paris, France,

2 Universite Paris Descartes, Sorbonne, Paris Cite, Laboratoire de Psychopathologie et Processus de Sante EA 4057, IUPDP Institut de Psychologie, Paris, France, 3 CNRS

UMR8147, Hopital Necker Enfants malades, Paris, France, 4 Service de Medecine Interne, Hopital Europeen Georges Pompidou, Universite Paris Descartes, Sorbonne, Paris

Cite, Paris, France, 5 Departement de dermatologie, Hopital Tenon, Universite Pierre et Marie Curie, Paris, France, 6 Universite Paris Descartes, Sorbonne, Paris Cite, Service

de maladies infectieuses et tropicales, Hopital Necker Enfants malades, Paris, France, 7 Universite de Montreal, Quebec, Canada, 8 Centre de Recherche du CHU Sainte-

Justine, Montreal, Quebec, Canada, 9 INSERM; Universite Paris Descartes, Sorbonne Paris Cite, Laboratoire de Physiopathologie des maladies Psychiatriques, Centre de

Psychiatrie et Neurosciences U894, Paris, France, 10 Universite Paris Descartes, Sorbonne Paris Cite, Faculte de Medecine Paris Descartes, Service Hospitalo Universitaire,

Centre Hospitalier Sainte-Anne, Paris, France, 11 Universite Paris Descartes, Sorbonne, Paris Cite, Service d’hematologie adulte, Hopital Necker-Enfants malades, Paris,

France, 12 Fondation Imagine, IHU Hopital Necker-Enfants malades, Paris, France

Abst ract

Mastocytosis is a heterogeneous disease characterized by mast cells accumulation in one or more organs. We have reportedthat depression is frequent in mastocytosis, but although it was already described, little is known about the prevalence andfeatures of cognitive impairment. Our objective was to describe the prevalence and features of cognitive impairment in alarge cohort of patients with this rare disease (n = 57; mean age= 45) and to explore the relations between memoryimpairment and depression. Objective memory impairment was evaluated using the 3rd edition of the Clinical Memory scaleof Wechsler. Depression symptoms were evaluated using the Hamilton Depression Rating Scale. Age and education levelswere controlled for all patients. Patients with mastocytosis presented high levels of cognitive impairment (memory and/orattention) (n = 22; 38.6%). Cognitive impairment was moderate in 59% of the cases, concerned immediate auditory (41%)and working memory (73%) and was not associated to depression (p$ 0.717). In conclusion, immediate auditory memoryand attention impairment in mastocytosis are frequent, even in young individuals, and are not consecutive to depression. Inmastocytosis, cognitive complaints call for complex neuropsychological assessment. Mild-moderate cognitive impairmentand depression constitute two specific but somewhat independent syndromes in mastocytosis. These results suggestdifferential effects of mast-cell activity in the brain, on systems involved in emotionality and in cognition.

Citat ion: Moura DS, Sultan S, Georgin-Lavial le S, Barete S, Lortholary O, et al. (2012) Evidence for Cognitive Impairment in Mastocytosis: Prevalence, Features andCorrelations to Depression. PLoS ONE 7(6): e39468. doi:10.1371/journal.pone.0039468

Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan

Received February 17, 2012; Accepted May 21, 2012; Published June 20, 2012

Copyright : ß 2012 Moura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: DSM is recipient from a grant from Canceropole Ile-de-France (Appel d’offre SHS2009). SSis a recipient of grants from the French Institut National duCancer (SHS 2010, 2011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compet ing Interests: The authors have declared that no competing interests exist.

* E-mail: d.moura.nck@gmail.com (DSM); ohermine@gmail.com (OH)

Int roduct ion

Mastocytosis is a rare and heterogeneous disease characterised

by accumulation of mast cells in one or several organs [1–3].

Based on organ dysfunction, systemic mastocytosis is divided

into indolent (. 90% of cases) and aggressive forms [3,4].

Although in its indolent form mastocytosis is not a life

threatening disease, deregulated mast cells activation and

degranulation lead to the liberation of a panel of mediators

(such as serotonin, histamine, tryptase, heparin, substance P,

interleukins (IL8, IL4, IL10), TNF alpha…). Patients suffer from

various clinical symptoms related to mast-cell degranulation

and/ or infiltration. These symptoms can be chronic (pruritus,

urticaria pigmentosa, headache, articular and muscular pain,

memory loss, attention impairment, depression) or paroxysmal

(Flush, anaphylactic like episodes, syncope) [5]. Chronic

symptoms of mastocytosis can be especially disabling and can

significantly affect patients in their personal, social and

professional life domains [6]. In this study, we report an

assessment of chronic memory and attention impairment in

mastocytosis and we explore the interrelationships with depres-

sion, age, education level, treatment and forms of the disease.

Cognitive complaints (memory and attention disturbances) are

common in mastocytosis and in our recent work 38% of patients

reported to feel concerned by these symptoms [6]. To date, only

the study of Rogers and collaborators has evaluated cognitive

impairments in 10 patients diagnosed with systemic mastocytosis

by using a valid psychometric measure of memory function [7].

These authors brought for the first time evidence for memory and

attention impairment in 70% of their sample of patients with

systemic mastocytosis. They suggested that mast cellsderegulation

impact memory function through mediators released including

histamine. Other neuropsychiatric symptoms such as depression

are also present with high frequency in mastocytosis. The

prevalence of depression was estimated 40%, 70% and 64%

according to methods and cut offs used for investigation [6–8].

While prevalence and features of depression in mastocytosis has

PLoS ONE | www.plosone.org 1 June 2012 | Volume 7 | Issue 6 | e39468

Hyperperfusion of central grey nuclei : 11 patients with cognitive imapirement vs 33 controls

Corelation with cognitive dysfunctions

p<0.001

Hypoperfusion of the anterior Cingulum antérieur 10 patients with depression and mastocytosis Vs. 18 patients with

Mastocytosis but not depressed

p<0.001

IDO

Trypytophan metabolism and Mastocytosis Georgin Lavialle et al, Molecular Psychiatry, 2016

TNFa

Tryptophane

Kynurenine

Acid

xanthurenic

Acid

quinolenic

Neurotoxicity

Oxidative stress

apoptosis

-

+

Cognition (?)

serotonin

Low serotonin

Depression ?

Proteases

Histamine

Others

ASL

abnormalities

Treatment

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)

Treatment of Indolent Diseases

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

Identification of all systemic manifestations in

patients suffering from mastocytosis

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

ITK for indolent diseases

• New ITK

• Inhibiton of Mast cell activation (c-kit, Lyn, Fyn, etc)

• Cytoreductive on Mast cells (optional ++)

• Not cytoreductive on other cells

• Not toxic (short term and long term)

– Genotoxic, carcinogenic

– Cardiotoxic (Abl++, Src, VEGF, Herg chanel, etc)

Masitinib – Kinase inhibitory activity profile Masitinib is a tyrosine kinase inhibitor that target mast cells and macrophages.

[1] Dubreuil 2009, PLoSONE.4(9):e7258 ; AB Science. [2] Davis 2011, Nat Biotechnol;29(11):1046

Target IC50 [nM] Kd [µM]

KIT wild-type (WT) 200 0.008

FYN 240 0.14

LYN 225 0.061

D816V KIT (exon 11) 5,000

KIT mutation (exon 17) 0.3

MCSFR-1 90 0.0076

PDGFRb 300 0.0084

PDGFRα 50 0.0025

Kinase Inhibition Profile of Masitinib

Masitinib (AB1010) Midostaurin (PKC412)

DAY 0

Case Report in Dog Mast Cell Tumor

DAY 3 DAY 18