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1
Updates in Mastocytosis
Tracy I. George, M.D.Professor of Pathology
TryptasePD-L1
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Disclosure: Tracy George, M.D.
Research Support / Grants None
Stock/Equity (any amount) None
Consulting Blueprint Medicines
Novartis
Employment ARUP Laboratories
Speakers Bureau / Honoraria None
Other None
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Outline
• Classification
• Advanced mastocytosis
• A case report
• Clinical trials
• Other potential therapies
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Outline
• Classification
• Advanced mastocytosis
• A case report
• Clinical trials
• Other potential therapies
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Mastocytosis symposium and consensus meeting on classification and diagnostic criteria for mastocytosis
Boston, October 25-28, 2012
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2008 WHO Classification Scheme for Myeloid Neoplasms
Polycythemia VeraEssential ThrombocythemiaPrimary Myelofibrosis
Chronic Neutrophilic LeukemiaChronic Eosinophilic Leukemia, NOSHypereosinophilic SyndromeMast Cell DiseaseMPNs, unclassifiable
Chronic Myelomonocytic LeukemiaAtypical Chronic Myeloid LeukemiaJuvenile Myelomonocytic LeukemiaMDS/MPN, unclassifiable
Chronic Myelogenous Leukemia
Myeloid neoplasms associated with PDGFRArearrangementMyeloid neoplasms associated with PDGFRBrearrangementMyeloid neoplasms associated with FGFR1rearrangement (EMS)
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Myeloproliferative Neoplasms
MDS/MPN
Myeloid or lymphoid neoplasmsassociated with eosinophilia and
abnormalities of PDGFRA, PDGFRB, or FGFR1
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2017 WHO Classification Scheme for Myeloid Neoplasms
Polycythemia VeraEssential ThrombocythemiaPrimary Myelofibrosis
Chronic Neutrophilic LeukemiaChronic Eosinophilic Leukemia, NOSMPN, unclassifiable
Chronic Myelomonocytic LeukemiaAtypical Chronic Myeloid LeukemiaJuvenile Myelomonocytic LeukemiaMDS/MPN with ring sideroblasts and thrombocytosis
MDS/MPN, unclassifiable
Chronic Myeloid Leukemia
Myeloid/lymphoid neoplasms with PDGFRArearrangementMyeloid/lymphoid neoplasms with PDGFRBrearrangementMyeloid/lymphoid neoplasms with FGFR1rearrangement Myeloid/lymphoid neoplasms with PCM1-JAK2
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Myeloproliferative Neoplasms
MDS/MPN
Myeloid/ lymphoid neoplasms with eosinophilia and gene
rearrangement
Mastocytosis
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WHO 2008 definition of systemic mastocytosis
Major: Multifocal dense infiltrates of mast cells
Minor:– >25% of mast cells with atypical morphology
– D816V KIT mutation
– CD25 and/or CD2
– Serum total tryptase >20 ng/mL
(unless associated myeloid disorder)
Morgado JM, Sánchez-Muñoz L, Teodósio CG, Jara-Acevedo M, Alvarez-Twose I, Matito A, Fernández-NuñezE, García-Montero A, Orfao A, Escribano L. Immunophenotyping in systemic mastocytosis diagnosis: 'CD25 positive' alone is more informative than the 'CD25 and/or CD2' WHO criterion. Mod Pathol. 2012;25:516-21.
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WHO 2008 definition of systemic mastocytosis
Major: Multifocal dense infiltrates of mast cells
Minor:– >25% of mast cells with atypical morphology
– D816V KIT mutation
– CD25 and/or CD2
– Serum total tryptase >20 ng/mL
(unless associated myeloid disorder)
Morgado JM, Sánchez-Muñoz L, Teodósio CG, Jara-Acevedo M, Alvarez-Twose I, Matito A, Fernández-NuñezE, García-Montero A, Orfao A, Escribano L. Immunophenotyping in systemic mastocytosis diagnosis: 'CD25 positive' alone is more informative than the 'CD25 and/or CD2' WHO criterion. Mod Pathol. 2012;25:516-21.
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WHO 2017 definition of systemic mastocytosis
Major: Multifocal dense infiltrates of mast cells
Minor:– >25% of mast cells with atypical morphology
– D816V KIT mutation
– CD25 with or without CD2
– Serum total tryptase >20 ng/mL
(unless associated myeloid disorder)
Horny H-P et al. Mastocytosis. In: Swerdlow SH et al (eds). WHO Classification of Tumours of Haematopoieticand Lymphoid Tissues. Revised 4th Edition. IARC Press, Lyon, 2017
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WHO 2008 Classification of Mastocytosis
• Cutaneous mastocytosis• Systemic mastocytosis
– Indolent systemic mastocytosis– Systemic mastocytosis with associated clonal,
hematologic non-mast cell lineage disease– Aggressive systemic mastocytosis– Mast cell leukemia
• Mast cell sarcoma• Extracutaneous mastocytoma
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WHO 2017 Classification of Mastocytosis
• Cutaneous mastocytosis• Systemic mastocytosis
– Indolent systemic mastocytosis– Smoldering systemic mastocytosis– Systemic mastocytosis with associated hematologic neoplasm– Aggressive systemic mastocytosis– Mast cell leukemia
• Mast cell sarcoma• Extracutaneous mastocytoma
acute
chronic
P Valent et al. Refined diagnostic criteria and classification of mast cell leukemia and myelomastocytic leukemia: a consensus proposal. Ann Oncol 2014;24(9):1691-1700.
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What is mastocytosis?• Clonal, neoplastic proliferation of mast cells
• Heterogeneous disorder:– Skin lesions that spontaneously regress to highly aggressive
leukemias with short survival and multiorgan failure
• Subtypes determined by distribution and clinical manifestations
?Diagnosis
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Telangiectasia macularis eruptiva perstans(TMEP)
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Adults with cutaneous mastocytosis lesions-Urticaria pigmentosa-TMEP
Systemic mastocytosis-most indolent-fewer advanced
Cutaneous mastocytosis only-sampling error
Work up:1. Skin biopsy2. Serum tryptase (basal and event-related)3. Bone marrow biopsy with appropriate ancillary studies
Berezowska S, Flaig MJ, Rueff F, et al. Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. Mod Pathol 2014;27:19.
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Theoharides TC et al. N Engl J Med 2015;373:163-172.
Clinically Relevant Mediators Released from Mast Cells and Putative Effects.
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Pathogenesis of SM
17
Somatic KIT point mutations in neoplastic mast cells
Constitutive activation of the receptor tyrosine kinase KIT
Induces increased mast cell proliferation and motility, resulting in infiltration of neoplastic mast cells into various organs
Longly Jr BJ, et al. PNAS. 1999;96:1609-1614; Nakagomi N, et al. Lab Invest. 2007;87:365-371;
Horny HP, et al. Pathobiology. 2007;74:121-132; Garcia-Montero AC, et al. Blood. 2006;108:2366-2372.
KIT kit kitkit
kit
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Classification of Mastocytosis
Cutaneous mastocytosis (CM) Systemic mastocytosis (SM)
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Classification of Mastocytosis
CMSystemic mastocytosis (SM)
Indolent SMSmoldering SMSM with an associated hematologic neoplasm (SM-AHN)Aggressive SMMast cell leukemia
Mast cell sarcoma
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Classification of Mastocytosis
CMSystemic mastocytosis (SM)
Indolent SMSmoldering SMSM with an associated hematologic neoplasm (SM-AHN)Aggressive SMMast cell leukemiaMast cell sarcoma
More indolent SM
“Advanced” SM
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Advanced Systemic Mastocytosis
ASM (1+ “C”=cytoreductive requiring findings)
• BM dysfunction cytopenias
• Palpable hepatomegaly with impaired liver function, ascites, +/- portal hypertension
• Skeletal involvement large osteolytic lesions, and/or pathological fractures
• Palpable splenomegaly w/ hypersplenism
• Malabsorption, weight loss due to GI mast cell infiltrates, hypoalbuminemia
Mast cell leukemia
≥20% mast cellson aspirate/PB
SM + AHN-meet WHO criteria for an associated hematological neoplasm-meet SM criteria
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Cytology of mast cells
George and Horny. Systemic mastocytosis. Hematol Oncol N Am 25 (2011): 1067.
Normal/reactive/well-differentiated Atypical type I
Atypical type II Metachromatic blast
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Cytology of mast cells
George and Horny. Systemic mastocytosis. Hematol Oncol N Am 25 (2011): 1067.
Normal/reactive/well-differentiated Atypical type I
Atypical type II Metachromatic blast
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Indolent systemic mastocytosistryptase
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ASM-AHN
CD117
ASM-MDS/MPN,U
tryptaseASM-CMML
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Bone marrow aspirate
Mast cell leukemia
Laboratory values:Hb: 8.8 g/dLWBC, PLT: NormalSerum tryptase: 763
Blood smear
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Bone marrow biopsy
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CD117
CD25CD25
CD2
Tryptase IHC positiveKIT D816V positive
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Overall Survival
• Kaplan–Meier survival for SM patients classified by WHO disease type compared with the expected age and sex-matched US population’s survival for the entire cohort 29
Lim, KH. Blood. 2009 Jun 4;113(23):5727.
Years From Diagnosis
ISM (n = 159)100
80
60
40
20
0
0 10 20 30
Surv
ival
ASM (n = 41)AHNMD (n = 138)MCL (n = 4)Matched Controls
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KIT Mutations:Implications for TK Inhibitors
Juxtamembrane domain
Transmembrane domain
Extracellular ligand-binding
domain
Tyrosine kinase domain 1
Tyrosine kinase domain 2
Kinase insert
NH2
COOH
Dimerization domain
GIST Exon 9
GIST: Gastrointestinal stromal tumors; SM: Systemic Mastocytosis; AML: acute myelogenous leukemia;
NK/T-CL: Natural killer/T-cell lymphoma
AML (Asp 419) Exon 8
SM V560G; GIST Exon 11
Sinonasal NK/T-CL V559I,E561K
GIST Exon 13
SM D816V,Y; GIST Exon 17
AML: D816V,Y
Germ cell tumors: D816H
Sinonasal NK/T-CL D816N, D825A
D816V~80%
RareImatinib sensitive
Imatinib resistant
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Treatment
• Challenging due to the diversity and complexity of disease and the lack of a standard and highly effective therapy
• Current therapies include:– Observation– Topical therapies for cutaneous disease– Symptomatic noncytoreductive therapies– Cytoreductive therapy
• Indicated by the presence of organ dysfunction• Used to reduce mast cell burden
31
Akin C, et al. Exp Hematol. 2003;31:686-692; Douglass JA, et al. Allergy. 2010; 65:924-932; Pardanani A, et al. Curr Opin Hematology. 2010;17:125-132; Imatinib package insert.
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Sensitivity of c-KIT D816V-Transformed Ba/F3 Cell Lines to Midostaurin and Imatinib
• Midostaurin inhibited growth of all c-KIT-transformed Ba/F3cell lines
• Cell lines resistant to imatinib due to expression of c-KIT D816V are inhibited by midostaurin
• Results have been confirmed in additional cell lines
32
Growney JD, et al. Blood. 2005;106:721-724; Gotlib J, et al. Blood. 2005;106:2865-2870.
IC50 for midostaurin: 44 nMIC50 for imatinib: > 1 uM
3H
-Th
ymid
ine
Inco
rpo
rati
on
( %
)
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Midostaurin
33
Potent inhibitor of all common mutant forms of c-KIT, including D816V,D816Y
May preferentially inhibit cells expressing mutant c-KIT compared to wild-type c-KIT
Counteracts anti-IgE-induced release of histamine in blood basophils and cultured cord blood cell-derived mast cells
• Effects were dose-dependent; occurred at pharmacologic concentrations
Growney JD, et al. Blood. 2005;106:721-724.
Krauth M-T, et al. Clin Exp Allergy. 2009; 39:1711-1720].
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TRYP CD25
CD34CD25
CD34
TRYP
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June 30, 2016;374:2530-2541.
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Gotlib J et al. N Engl J Med 2016;374:2530-2541.
Baseline Patient and Disease
Characteristics
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Overall Survival
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Response over Time
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Overall Response Rate by Subgroups
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C
Overall Survival by Response in Mast Cell Leukemia
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Gotlib J et al. N Engl J Med 2016;374:2530-2541.
ClinicopathologicalMeasures of Response
Bone marrow mast cell burden
Serum tryptase
Spleen volume
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Histologic Regression in ASM patient
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Improvements in Alkaline Phosphatase, Eosinophil, and Monocyte Levels
Alk Phos
Eos
Monos
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Improvements in Quality of Life
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Study Conclusions
• Midostaurin can:
– Reverse organ damage
– Decrease splenomegaly
– Decrease BM mast cells
– Improve patient-reported symptoms and quality of life
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Midostaurinin advanced SM, 10 year
follow-up
DeAngelo DJ, George TI, Linder A, Langford C, Perkins C, Ma J, Westervelt P, Merker JD, Berube C, Coutre S, Liedtke M, Medeiros B, Sternberg D, Dutriex C, Ruffie PA, Corless C, Graubert TJ, Gotlib J (2018). Leukemia, 32(2), 470-478.
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Midostaurin treatment is associated with a significant decrease inCD25 expression on neoplastic mast cells
CD25 expression on neoplastic mast cells by flow cytometry in patients #1, #2, and #3 before (A-C) and on day 28 (patient #1, D), day 89 (patient #2, E), and day 336 (patient #3, F) of midostaurintherapy.
A B
D E
C
F
Patient #1 Patient #2 Patient #3
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Midostaurin therapy is associated with sustained decreases in CD25 expression
CD25 expression on neoplastic mast cells by mean fluorescence intensity (MFI; A, C, E) andpercent of mast cells positive for CD25 (B, D, F) over time in patient #1 (A-B), patient #2 (C-D), andpatient #3 (E-F). The shaded area indicates time on midostaurin therapy.
0
20
40
60
80
100
-10 40 90 140 190 240 290 340 390
%C
D2
5
po
sit
ive
mast
ce
lls
Days of treatment
1.E+03
1.E+04
1.E+05
-10 10 30 50 70 90
CD
25
M
FI
Days of treatment0
50
100
-10 10 30 50 70 90
% C
D2
5
po
sit
ive
m
ast
ce
lls
Days of treatment
1.E+02
1.E+03
1.E+04
1.E+05
-10 40 90 140 190 240 290 340 390
CD
25
M
FI
Days of treatment
1.E+03
1.E+04
1.E+05
-50 0 50 100 150 200 250 300 350 400 450 500 550
CD
25
M
FI
Days of treatment0
20
40
60
-50 0 50 100 150 200 250 300 350 400 450 500 550
% C
D2
5
po
sit
ive
m
ast
ce
lls
Days of treatment
A
C
B
E F
D
#1
#2
#3
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Proposed mechanism for midostaurin-induced CD25 downregulation
Mutant Kit
Constitutive signaling
STAT5 pSTAT5
Transcription
CD25
Mutant Kit
Other RTKs?
STAT5
PKC412
pSTAT5
Other RTKs?
Changes in the intracellular localization of STAT5 with midostaurin
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Outline
• Updates on classification
• Advanced mastocytosis
• A case report
• Clinical trials
• Other potential therapies
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CD30 expression in systemic mastocytosis
JM Morgado, O Perbellini,RC Johnson, C Teodosio, A Matito, I Alvarez-Twose, P Bonadonna, A Zamo M Jara-Acevedo, A Mayado, A Garcia-Montero, M Mollejo, TI George, R Zanotti, A Orfao, L Escribano, L Sanchez-Munoz. CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis. Histopathology 2013;63(6):780-7.
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CD30 expression in systemic mastocytosis
JM Morgado, O Perbellini,RC Johnson, C Teodosio, A Matito, I Alvarez-Twose, P Bonadonna, A Zamo M Jara-Acevedo, A Mayado, A Garcia-Montero, M Mollejo, TI George, R Zanotti, A Orfao, L Escribano, L Sanchez-Munoz. CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis. Histopathology 2013;63(6):780-7.
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Clinical trial with anti-CD30 drug does not demonstrative clinical activity in advanced systemic mastocytosis
10 patients:-8 stable disease-1 progressive disease-1 not evaluable due to early death unrelated to study
Baird JH, Verstovsek S, George TI, Reyes I, Abuel J, Perkins C, Langford C, Schroeder K, Gotlib J. Phase 2 study of Brentuximab Vedotin in patients with advanced systemic mastocytosis. ASH 2017.
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Hatch EW, Geeze MB, Martin C, Salama ME, Hartmann K, Eisenwort G, Blatt K, Valent P, Gotlib J, Lee JH, Chen L, Ward HH, Lidke DS, George TI (2018). Variability of PD-L1 expression in mastocytosis. Blood Adv 2(3), 189-199.
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Immunohistochemistry
M Geeze, E Hatch, C Martin, S Perkins, K Hartmann, P Valent, J Gotlib, D Lidke. USCAP 2016
PD-1PD-L1
Smoldering systemic mastocytosis
PD-L1 PD-1
Mast cell leukemia
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Flow cytometry
Indolent SM
Indolent SM
Indolent SM
Mast cell leukemia
Mast cell leukemia
Aggressive SM
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Multiplex immunohistofluorescence
Mast cell leukemia, spleen Tryptase (red), PDL1 (green)
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Cutaneous mastocytosis
Mast cell leukemia, spleen
Tryptase (red) PDL1 (green)
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PD-1/PD-L1 are novel therapeutic targets for mastocytosis
Diagnosis PD-L1 expression PD-1 expression
SM 17/22 (77%) 0/25
CM 23/25 (92%) 4/27 (15%)
MML 1/2 0/2
MMAS 0/3 0/3
MPN 0/16 0/17
MDS 0/18 0/18
MDS/MPN 0/5 0/5
Healthy/ reactive BM
0/15 0/21
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PD-1/PD-L1 are novel therapeutic targets for mastocytosis
Diagnosis PD-L1 expression PD-1 expression
SM 17/22 (77%) 0/25
CM 23/25 (92%) 4/27 (15%)
MML 1/2 0/2
MMAS 0/3 0/3
MPN 0/16 0/17
MDS 0/18 0/18
MDS/MPN 0/5 0/5
Healthy/ reactive BM
0/15 0/21
MCL 3/3 (100%)
ASM 2/2 (100%)
SM-AHN 9/12 (75%)
SSM 1/2 (50%)
ISM 3/4 (75%)
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Conclusions
• Updates on classification
• Advanced mastocytosis
• A case report
• Clinical trials
• Other potential therapies
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Thank you collaborators!
Jason GotlibDan ArberSusan AtwaterBruno MedeirosAthena Cherry
Chris CorlessIlana KeptenJeffrey Tyner
Peter Valent
Hans-Peter HornyKarl Sotlar
Eric Hsi
Timothy GraubertDan Deangelo
Natasha SavageFarrukh Awan
REMA (Spanish Network on Mastocytosis)