Not All Mast Cell Disease is Systemic Mastocytosis: Mast Cell ...

Not All Mast Cell Disease is Systemic Mastocytosis: Mast Cell ...

Wellapalooza 2016 June 11, 2016 Mast Cell Activation Disease: Current Concepts Lawrence B. Afrin, M.D. Division of Hematology, Oncology & Transplantation University of Minnesota Learning Objectives & Disclaimers Learning Objectives Understand emerging concepts regarding mast cell disease Understand recent, current, and planned research at UMN in mast cell disease Conflicts of Interest None Outline What is mast cell activation disease (MCAD)? What weve long known: General Clinical Theme Allergic diseases..... Allergy Inflammation Mastocytosis..

Allergy + MC Neoplasia Inflammation Whats new: Mast cell activation syndrome (MCAS).. Inflammation Allergy What research are we conducting in MCAD? Allergic Diseases Allergy, asthma, angioedema, urticaria, anaphylaxis 2013: 700 million suffer allergic diseases worldwide 10% of preschoolers worldwide now have food allergies Steadily increasing incidence/prevalence across all ages e.g., China (prevalence): 1999: 3.5%; 2009: 7.7% Greatest increases in children < 5 years old Allergic diseases are conditioned by a number of genes and influenced by environmental factors Incidence of allergic disease in children if neither parent suffers allergic disease: 5-15% only one parent suffers allergic disease: 20-40% both parents suffer allergic disease: 60% Relatively little mortality, but significant QoL effects

1. Prescott SL et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organiz J 2013;6:21, pp. 1-12. 2. Pawlinska-Chmara R et al., Effect of Socio-Economic Status on Quality of Life in People Affected with Respiratory Allergy, pp. 385-392, in M. Pokorski (ed.), Neurobiology of Respiration, Advances in Experimental Medicine and Biology 788, DOI Mastocytosis: A Long History 1869: Urticaria pigmentosa (UP) first described 1877: First description of the mastzelle 1887: UP linked with mastzelles 1933: Suggestion of linkage with internal dz 1939: MC heparin identified 1949: Definitive linkage with systemic dz 1953: MC histamine identified 1987: MC tryptase identified 1988: Travis classification 1995: KIT activating mutation D816V identified 1998: Unique flow cytometric signature found CD117 + (CD25 and/or CD2)

Prevalence of SM: ~1:100,000 Mast Cell Leukemia Prevalence of CM: ~1:10,000 Aggressive Systemic Mastocytosis Systemic mastocytosis with associated hematologic non-mast-cell-lineage disorder Mastocytoma Smoldering Systemic Mastocytosis Diffuse Cutaneous Mastocytosis Urticaria Pigmentosa M Sy as st t o em cy ic to si s

Telangiectasia macularis eruptiva perstans Cutaneous Mastocytosis Prevalence of urticaria: ~1:10 Prevalence of allergy: ~1:5 Urticarias and Angioedema Allergies and Anaphylaxis Prevalence of MCL: ~1:10,000,000 Indolent Systemic Mastocytosis Disorders also featuring inappropriate mast cell

proliferation ~70-90% of all SM Disorders featuring inappropriate mast cell activation Mast Cell Activation The Spectrum of Syndromes Not Yet Otherwise Mast Cell Disease Classified Weve Long Known MCAD: A Brief History

1991: 1st published hypothesis that MCAS ought to exist 2007: 1st case reports of MCAS Some with KIT-D816V, some without 2007: 1st study showing other KIT mutations in most MCAS (Bonn) 2008-: Non-KIT mast cell regulatory gene mutations found in SM 2010: 2nd study showing KIT mutations in most MCAS (Bonn) KIT-D816V rare Few mutations in controls 2010: Proposal of MCAD (Harvard, Vienna, NIH) Includes 1st proposal for MCAS dx criteria 2011: Alternative proposal for MCAS dx criteria (Bonn, MUSC) 2012: Revised (Vienna et al.) proposal for MCAS dx criteria Still many problems 2016: Revised WHO diagnostic criteria for SM

MCAD: Emerging Understanding Mast Cell Leukemia Aggressive Systemic Mastocytosis Systemic mastocytosis with associated hematologic non-mast-cell-lineage disorder Mastocytoma Smoldering Systemic Mastocytosis Diffuse Cutaneous Mastocytosis Urticaria Pigmentosa M Sy as st t o em cy ic to si s Telangiectasia macularis

eruptiva perstans Cutaneous Mastocytosis Urticarias and Angioedema Indolent Systemic Mastocytosis Disorders also featuring inappropriate mast cell proliferation Allergies and Anaphylaxis Mast Cell Activation Syndromes Not Yet Otherwise Classified Disorders

featuring inappropriate mast cell activation Normal mast cell biology From allthingsstemcell.com Normal mast cell biology Hematopoietic origin, brief circulation Normally 0.05% of marrow nucleated cells Typically < 2% even in systemic mastocytosis Unique flow cytometric signature (incl. CD117+, CD25/2-) Maturation completed in all vascularized tissues Especially abundant beneath environmentally exposed mucosal/epithelial surfaces and adjacent to blood and lymphatic vessels and nerves, permitting sentinel function Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nature Immunology 2008;9:1215-23. Ribatti D. The development of human mast cells: an historical reappraisal. Exp Cell Res 2016;342(2):210-5.

Relatively immobile once localized in Normal mast cell biology Functions (when appropriately stimulated): Synthesize active substances Some stored in granules of highly heterogeneous content Release various mediators upon various triggerings Phagocytose particulate material including bacteria, erythrocytes, schistosomes, metals, etc. KIT stem cell factor receptor and tyrosine kinase (on 4q11-12) is expressed at high levels on the mastocyte surface Critical for many mast cell functions including Akin C, Metcalfe DD. The biology of Kit in disease and the application of pharmacogenetics. J Allergy Clin Immunol 2004; 114:1319. Gordon JR et al. Mast cells as a source of multifunctional cytokines. Immunol Today 1990;11:458.

survival, differentiation, chemotaxis, and Okayama Y, Kawakami T. Development, migration, and survival of mast cells. Immunologic Research 2006;34(2):97- Normal mast cell biology Many triggers Classic: Adjacent high-affinity IgE receptors (FcRI) RI) with bound IgE get crosslinked by polyvalent antigen Physical stimuli: Pressure/trauma, heat, cold, UV, etc. Many other receptors for: histamine (H1/H2/H3/H4), SCF, IgG, C3a, C5a, PAF, CRF, neuropeptides (VIP, substance P, somatostatin, etc.), opioids, paralytics, benzodiazepines, cannabinoids, etc. etc. etc. Also many of the Toll-like receptors (affinities for various microbial proteins) Bischoff SC et al. J Exp Med 1992;175:237. Theoharides TC et al. Trends Pharmacol Sci 2008;29:375382. Conrad DH et al. J Immunol 1975;114:1688.

Woolhiser MR et al. Eur J Immunol 2001;31:3298. Nilsson G et al. J Immunol 1996;157:1693. Marshall JS et al. Int Arch Allergy Immunol 2003;132:87. Church MK et al. Int Arch Allergy Appl Immunol 1991;94:310. Stellato C et al. Anesthesiology 1991;74:1078. Moss J et al. Anesthesiology 1983;59:330. Miller LG et al. Pharmacology 1988;36:5260. Samson M-T et al. J Immunol 2003;170:4953-4962. Kajiwara N et al. J Allergy Clin Immunol 2010;125:1137. Theoharides TC, et al. New Engl J Med 2015;373:163-72. Normal mast cell biology Capable of synthesizing and releasing many mediators Many expressible at very high levels Some stored in fully active form in electron-dense secretory granules, tightly packaged with serglycin proteoglycans Heparin proteoglycan Pro-inflammatory cytokines Chondroitin sulfate proteoglycan Superoxide dismutase

A small sample: Chemokines Acid hydrolases IL-1, IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL-16, IL-18, IL-21, IL-23, IL-25, IFN-, TNF- MCP-1, IL-8, RANTES, eotaxin, leukotrienes B4, C4, D4, E4 (SRS-A), CCL2, CCL3, CCL4, CCL5, CCL11, CCL19, CCL20, CCL21, CXCL8, CXCL10, XCL-1 Proteases Tryptase, chymase, ACE, carboxypeptidase, cathepsin G, cysteinyl cathepsins, metalloproteinases Growth factors

IL-3, GM-CSF, bFGF, VEGF, TGF-, PDGF, EGF, NGF, SCF, angiopoietin Vascular permeability, vasodilatation Histamine, 5-hydroxytryptamine, tryptase, NO, VLA4 Platelet aggregation and thrombosis: PAF, thromboxane Theoharides TC et al. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunological Reviews Glucuronidase, galactosidase, hexosaminidase, peroxidase Arylsulphatase A Prostaglandin D2, thromboxane Serotonin

Antimicrobial agents IFN-, IFN-, IFN-, cathelicidin, LL-37 CRH TSLP Want more? See http:// www.cells-talk.com/index.php/page/c opelibrary?key=mast%20cells Criteria for Systemic Mastocytosis WHO 16: Indol. SM, smold. SM, SM-AHN, aggressive SM, MC leukemia 1 major + 1 minor, or 3+ minor criteria Only major criterion: Multifocal, dense infiltrates of mast cells consisting of 15 or more mast cells in aggregates detected in sections of bone marrow and/or other extracutaneous organs, confirmed by tryptase immunohistochemistry or other special stains 4 minor criteria: More than 25% of MCs in biopsy sections or bone marrow aspirate smears showing spindle shape or atypical morphology Expression of CD2 and/or CD25 by marrow, blood, or extracutaneous organs MCs KIT codon 816 mutation in bone marrow, blood, or other extracutaneous organs

Different KIT mutations different phenotypes D816V: MC clusters, spindle forms, expression of CD25, histamine, CPA, etc. Extracellular domain: AKT activation Arber DA et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-2405. al. Unique effects of KIT D816V in BaF3 cells: induction of cluster formation, histamine synthesis, and early mast cell differentiation antigens. J Immunol Mayerhofer M et 2008;180:5466-5476. Teodosio C et al. Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes. J Allergy Clin Immunol 2010;125:719-726.e4. Yang Y et al. Pediatric mastocytosis-associated KIT extracellular domain mutations exhibit different functional and signaling properties Blood 2010 Aug 19, 116(7):11141123. Serum total tryptase (25% of MC protein!) persistently > 20 ng/ml The Problem Chronic Fatigue Syndrome! Fibromyalgia! Refractory GERD! POTS!

Just Old Age! Granuloma Annulare, or Chronic Inflammatory Demyelinating Polyneuropathy, ororor! What to do when it behaves like mast cell disease but isnt allergic disease or mastocytosis: Consider mast cell activation syndrome Proposed Criteria for MCAS Self-described consensus proposal Problem: Methods by which consensus was obtained History consistent with chronic and/or recurrent aberrant mast cell mediator release Problem: Few symptoms listed in proposal (e.g., flushing) Not SM and no better-fitting disease

Rise in tryptase (within 4h of flare) of 20% + 2 ng/ml over asymptomatic baseline Problem: Problem: Problem: Problem: establishing asymptomatic baseline getting blood for tryptase level drawn within 4h of flare allows levels well within normal range to signify disease no published data whether this distinguishes nl./abnl. fluctuation Response to mast cell-targeted therapy Problem: requires therapy prior to diagnosis Problem: should diagnosis of this very heterogeneous disease be ruled out if 1 or 2 lines of empiric therapy fail? Valent P et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012 Jan;157:215-225. Akin C et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126:1099-1104.e4. Proposed Criteria for MCAS Alternative proposal (structure similar to WHO criteria for SM): Major criteria: Multifocal or disseminated dense infiltrates of mast cells in bone marrow biopsies and/or

Same as WHO in sections of other extracutaneous organ(s) (e.g., gastrointestinal tract biopsies; CD117-, tryptase- and CD25-stained) Unique constellation of clinical complaints as a result of a pathologically increased mast New cell activity (mast cell mediator release syndrome) Minor criteria: Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal Same as WHO morphology (>25%) in bone marrow smears or in histologies Mast cells in bone marrow express CD2 and/or CD25 Same as WHO Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proven. Evidence of a pathologically increased release of mast cell mediators (serum tryptase, urinary N-methylhistamine, plasma heparin, serum chromogranin A, or other mast cellspecific mediators (e.g., leukotrienes, prostaglandin D 2)) Expanded Expanded

Diagnosis made when either both major criteria, or second major criterion + at least one minor criterion, or any three minor criteria are met and no other diagnosis that better accounts for the full range and duration of all the symptoms and findings in the history, exam, and labs Molderings G, et al. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol MCAS: Emerging Understanding Increasing estimates of prevalence 1-17% of the general first-world population? Increasing evidence of critical mast cell If MCAS dominantly manifests as involvement insyndrome Asthma (4-20%) Irritable bowel chronic inflammatory disease (CID), Obesity (37%) (11%)

syndrome might itsfatigue prevalence even higher Depression Chronic syndromebe (5%) (3%) syndrome Atherosclerosis within populations enriched for CID (?) Fibromyalgia (1-10%) Etc. etc. etc. etc. (e.g., (2-20%) inpatients)? Diabetes mellitus What Portions of These Populations Bear Clonal Mast Cell Disease? Est. Global Prev. Theoharides TC. Clin Ther 2013;35:544-7.

Afrin LB. Oral Surg Oral Med Oral Path Oral Radiol Endodontol 2011;111:465-472. Haenisch B, et al. Immunol 2012;137:197-205. Pejler G, et al. Blood 2010;115(24):4981-4990. Theoharides TC, et al. Biochim Biophys Acta 2012 Jan;1822(1):21- Est. Global Prev. Brightling CE, et al. Curr Allergy Asthma Reports 2005;5:130-135. Blanco I, et al. Clin Rheumatol 2010;29:1403-1412. Theoharides TC, et al. J Clin Psychopharmacol 2005;25:515-520. Theoharides TC, et al. J Clin Psychopharmacol 2004;24:577-581. Molderings GJ, et al. PLoS One 2013;8(9):e76241 Frieling T, et al., Z Gastroenterol 2011;49:191-194. MCAS: Emerging Biology May be clonal in most cases More than 50 mutations (mostly heterozygous, but still functionally dominant) found scattered across all domains of KIT Most patients have multiple KIT (and other) mutations No commercial assays yet for most of these mutations but not yet independently confirmed thus issue of non-clonal vs. undetermined

clonality Molderings GJ et al. Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder. Scand J Gastroenterol 2007; 42(9):1045-1053. Molderings GJ et al. Comparative analysis of mutation of tyrosine kinase Kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. Immunogenetics 2010;62:721-727. Readily available genome/exome sequencing may MCAS: Do the Biology Math MCs produce and release scores of mediators 1 mutation aberrant release of N mediators Multiple KIT mutations in most MCAS patients? Multiple genes mutated in most MCAS patients? Each mediator has its Potential for Multisystem Polymorbidity and Clinical Heterogeneity

MCAS: Presentation Typical presentation Age of onset: typically < 20 but unrecognized for decades Usually multisystem; can affect every system Symptoms often (but not always) inflammatory Perplexingly inconstant course: Abnormalities often externally inapparent (she looks fine!) Chronic or waxing/waning or episodic (flares, spells) Different symptoms at different times Often no apparent triggers Mediators: Tryptase (total & mature) usually normal (reflects MC load >> activation) Heparin, CGA, PGD and histamine (& metabolites), LTE4 often elevated 2 Many MDs, many dxs (often non-specific, idiopathic, somatic) Patients commonly cease reporting symptoms ROS important! 1. Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201. 2. Zenker N, Afrin LB. Blood 2015;126:5174.

3. Schwartz LB. J Immunol 2003;170(11):5667-73 and Immunol Allergy Clin N Am 2006;26:451-63. 4. Hamilton MJ et al. J Allergy Clin Immunol 2011;128;147-52. 4. Vysniauskaite M et al. PLoS One 2015 Apr 24;10(4):e0124912. 5. Ferrer M et al. Clin Exp Allergy 2010 Dec;40(12):1760-6. 6. Sala-Cunill A et al. Int Arch Allergy Immunol 2013;160(2):192-9. MCAS: Presentation Constitutional Fever, chills, fatigue, sweats, weight or or , pruritus Odd and prolific sensitivities (drugs, foods, environs) Eyes Irritation, episodic inability to focus vision, blepharospasm Ears Irritation, hearing deficit and/or tinnitus Nose Irritation, sores, epistaxis, coryza Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201.

MCAS: Presentation Nodes Borderline pathologic, waxing/waning, migratory adenopathy Left upper quadrant (splenic?) discomfort common Path: usually reactive lymphocytosis, occ. sinus histiocytosis Pulmonary Waxing/waning migratory edema/inflammation (e.g., cough) Dyspnea (normal PFTs; I just cant catch a deep breath) Cardiovascular Unprovoked presyncope/syncope, labile BP/pulse, Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201. MCAS: Presentation GI Inflammation (any/all luminal segments, solid organs) Refractory GERD, IBS, mild LFTs common Diarrhea constipation

Queasiness, nausea, vomiting (sometimes cyclical) Malabsorption common (gen., or selected micronutrients) Hepatic involvement common, usually inflamm./fibrosis GU Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201. MCAS: Presentation Musculoskeletal and Joints Myositis, osteopenia and/or osteosclerosis Diffusely migratory soft tissue pain; fibromyalgia, CRPS NSAIDs/narcs often unhelpful (may trigger flares!) Skin/Integument Lesions (many types), rashes (many types, often migratory), pruritus, flushing, angioedema, dermatographism Hair/nail/dental dystrophy CNS

Headache, vertigo, syncope, tic/tremor, weakness, dysautonomia Migratory paresthesias, insomnia very common Wide range of psychiatric disorders also found in MCAD Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201. MCAS: Presentation Heme Counts often normal, or or H/H (subtle RDW, MCH common) or WBC (subtle/intermit. monos, eos, &/or basos common) or plts or clotting Marrow Usually normal (histology, IHC, cytogenetics, flow, PCR) Most common abnormality: mild dysplasia (unclass. MDS/MPN) Immunity Hypersensitivities, risk for malig., autoimm., infection Poor healing Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201. MCAS: Presentation

Endocrinologic/metabolic Delayed puberty/menarche, dysmenorrhea, endometriosis Osteopenia/osteoporosis, osteosclerosis Hypo/hyperthyroidism, hyperferritinemia (inflammatory) or electrolytes, lipids (often hypertriglyceridemia) Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201. MCAS: Diagnosis Traditional diagnostic paradigm (symptom A + exam finding B + test result C suspect diagnosis D) doesnt work for MCAS Instead, need to recognize either of two metapatterns: Multiple chr. inflamm. ills often unsatisfactorily responsive to Rx

Definitively diagnosed ailment which doesnt Molderings G et al. Die systemische Mastzellerkrankung mit gastrointestinal betonter Symptomatik - eine Checkliste als Diagnoseinstrument. Deutsche medizinische Wochenschrift 2006 Sep 22; 131(38):2095100. Alfter K et al. New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. Liver MCAS: Diagnosis Best diagnostic aids: Most physicians best friend: a complete history and exam Faith in Occams Razor: which scenario is more likely? Multiple diagnoses/problems all independent of each other vs. One diagnosis thats biologically capable of causing

most or all of the findings (i.e., the simplest solution, MCAS Diagnostic Work-Up: 2016 Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014 Mar;3(1):1-17. MCAS: Prognosis No epidemiologic studies of prognosis yet Present gestalt impression: After the first three years, survival curves parallel the general population (similar to indolent systemic mastocytosis) So, like allergic diseases and ISM, reduced survival is a relatively small problem in MCAS, and instead most suffer reduced QoL (anywhere from mild to severe, variable over time) until the disease is accurately diagnosed and effectively controlled Many therapies (targeting many receptors and pathways) found helpful in various MCAD/MCAS patients Cytotoxic chemotherapy unlikely to help MCAS

Most pts eventually identify a significantly helpful regimen Roberts LJ, Anthony LB, Oates JA. Disorders of Vasodilator Hormones: Carcinoid Syndrome and Mastocytosis in Wilson JD, Foster DW, Kronenberg HM, et al., eds., Williams Textbook of Endocrinology, 9th ed., 1998, W. B. Saunders Company, Philadelphia, pp. 1718-1732. Lim K-H, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009;113:5727-5736. MCAS: Treatment 2016: Largely as for indolent mastocytosis Identify and avoid triggers Inhibit mediator production Inhibit mediator release Block actions of released mediators Cytotoxic and cellular therapy only for aggressive SM, MCL Secondary issues and comorbidities MCAS: Treatment 2016: Largely as for indolent mastocytosis Identify and avoid triggers (antigenic and physical) Or try desensitization therapy if feasible Be aware: medication excipients often are prominent triggers Trying alternative (commercial or compounded) formulations often necessary

Inhibit mediator production Inhibit mediator release Block actions of released mediators Cytotoxic and cellular therapy only for aggressive SM, MCL Secondary issues and comorbidities MCAS: Treatment 2016: As for mastocytosis Identify and avoid triggers Inhibition of mediator production Steroids, NSAIDs Vitamin C Possibly also hydroxyurea (or even IMiDs?) Inhibition of mediator release (stabilization) Blockade of released mediators Rarely (if ever): Cytotoxic therapy Hypothetical: Cellular therapy Secondary issues and comorbidities MCAS: Treatment 2016: As for mastocytosis Identify and avoid triggers

Inhibition of mediator production Inhibition of mediator release (stabilization) Cromolyn (oral and/or inhaled non-absorbed) Can trigger flares 1st few days; tachyphylaxis can abrogate efficacy Imatinib (FDA approved for CML, Pentosan (especially for interstitial cystitis) mastocytosis) Tyrosine kinase inhibitors Dasatinib (FDA approved for CML) Interferon (& pegylated form?)Nilotinib (FDA approved for CML)

Omalizumab (anti-IgE) Sunitinib (FDA approved for renal cell Ca & GIST) Azathioprine or other ISTs Midostaurin (investigational) mTOR inhibitors? Masitinib (investigational) Benzodiazepines and imidazopyridines e.g., lorazepam, clonazepam, flunitrazepam, zolpidem Blockade of released mediators Rarely (if ever): Cytotoxic therapy Hypothetical: Cellular therapy Secondary issues and comorbidities MCAS: Treatment 2016: As for mastocytosis Identify and avoid triggers Inhibition of mediator production Inhibition of mediator release (stabilization) Blockade of released mediators

Antihistamines (even cont. IV diphenhydramine in severely afflicted pts) Often impressive benefits even absent rhinosinusitis and dyspepsia Can also stabilize mast cells via their autoexcitatory H /H 1 2 receptors Leukotriene antagonists Calcium/vit. D, bisphosphonates, denosumab for osteoporosis/ osteopenia TNF antagonists (etanercept, adalimumab, infliximab)? IL-1 antagonists (e.g., anakinra), IL-1 antagonists (e.g., canakinumab)? MCAS: Treatment 2016: As for mastocytosis Identify and avoid triggers Inhibition of mediator production Inhibition of mediator release (stabilization) Blockade of released mediators Rarely (if ever): Cytotoxic therapy

Hydroxyurea, alkylators, taxanes, etc. Fludarabine, cladribine, cytarabine, etc. Alemtuzumab, daclizumab Hypothetical: Cellular therapy Secondary issues and comorbidities MCAS: Treatment 2016: As for mastocytosis Identify and avoid triggers Inhibition of mediator production Inhibition of mediator release (stabilization) Blockade of released mediators Rarely (if ever): Cytotoxic therapy Hypothetical: Cellular therapy Allogeneic stem cell transplantation Secondary issues and comorbidities MCAS: Treatment 2016: As for mastocytosis Inhibition of mediator production Inhibition of mediator release (stabilization)

Blockade of released mediators Rarely (if ever): Cytotoxic therapy Hypothetical: Cellular therapy Treatment of secondary issues Frequent mistake by patients and providers: Assuming a symptom (new or old, chronic or acute) is directly due to MCAS MCAS does not render one immune to developing other disease Regardless of the likelihood that a symptom may ultimately stem from MCAS, rule out other reasonable diagnostic considerations before assuming MCAS is the (direct) cause! Illnesses secondary to mast cell disease require full treatment until the mast cell disease is controlled, and even then the horse is sometimes already out of the barn: malignancy and autoimmunity rarely, if ever, spontaneously remit simply with MCAD: Research at UMN Completed or in progress: Characterization of a Large MCAS Population Utility of Various Mediators in Diagnosing MCAS Confirmation/Extension of Clonality in MCAS Genomic Profiling of Urticaria Pigmentosa Mast Cell Disease in Chronic GI Tract Graft Vs. Host Disease Proposals Actively in Development: GWAS in MCAD

Masitinib in MCAS MCAD in Dercums Disease (collaboration with U. Arizona) MCAD: Whats next? RESEARCH Improved diagnostic techniques Early genomic sequencing of isolated mast cells to distinguish primary from secondary disease and identify mutational patterns correlating with various clinical presentations? Etiology Environmental? Genetic? Epigenetic? Viral? Therapy Predictive biomarkers Targeted therapies EDUCATION (providers, payers, patients, grantors)

UMN Mast Cell Disease Program: A Multidisciplinary Team Hem/Onc: Anesthesiology: Larry Afrin, MD Cela Ustun, MD Elif Cingi, MD Radiology: Greg Vercellotti, MD Kalpna Gupta, PhD Zuzan Cayci, MD Pathology: Peds Hem/Onc: Lucie Turcotte, MD Peds Derm: Sheilagh Maguiness, MD Allergy: Doug McMahon, MD

Michael Wexler, MD Dermatology: Dan Miller, MD GI: Alex Khoruts, MD ED: Greg Loppnow, MD Endocrinology: Tasma Harindhanavudhi, MD Pulmonary: Erhan Dincer, MD Community Medicine http://mastcell.umn.edu Greg Plotnikoff, MD Sophia Yohe, MD Michael Linden, MD Mahmoud Khalifa, MD Lab Medicine: Tony Killeen, MD, PhD Amy Saenger, PhD

Clinical Laboratory: Karri Cargill, MLS Genetics Informatics: Kevin Silverstein, PhD Lauren Mills, PhD Christy Henzler, PhD Pharmacology & Precision Medicine: Pam Jacobson, PharmD Epidemiology: Heather Nelson, PhD Veterinary Clinical Sciences Michael Henson, DVM, PhD Clinical Support: Maureen Collins-Fuchs, RN Lucy Reinhardt, P.A. Countless others Summary MCAD Diagnostic Class General Prevalen

ce Allergic Diseases Prevalent Mastocytosis Rare Phenotype Allergy Inflammation Tryptase usually Normal Allergy & MC Neoplasia Elevated Tryptase dominantly reflects total Inflamm. body MC load, not activation state MCAD symptoms usually from MC

activation, not load MCAS Prevalent Inflammation Allergy Most MCAD patients Normal have normal survival, making disease control even more important (QoL) can eventually find significantly helpful therapy once diagnosed Challenges: Heterogeneity (mutational origin?) No biomarkers yet to predict helpful therapy Education of providers, payers, regulators, grantors Questions?

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