Systemic Mastocytosis: Disease State, Diagnosis, and Current Treatment Options

Sponsored by:

• Disease pathogenesis, including mast cell function, KIT structure/function, and KIT D816V mutation • Identifying systemic mastocytosis, including signs, symptoms, and diagnosis • Systemic mastocytosis patient experience • Current systemic mastocytosis treatment options and persisting unmet needs • Summary and unmet needs

2 KIT proto-oncogene, receptor tyrosine kinase. Systemic mastocytosis is a rare, clonal, neoplasm driven by KIT D816V

• SM is a clonal, neoplastic proliferation of mast cells driven by KIT D816V1-3 • KIT D816V is present in ~95% of patients with SM4

• Prognosis for patients with advanced systemic mastocytosis is poor1,5,6 • Historic median overall survival for ASM: ~3.4 years, SM-AHN: ~2.0 years, and MCL: ~2 months5

• Patients with SM may have severe, unpredictable symptoms that negatively affect QOL7-10 • Many patients experience a prolonged time from onset to diagnosis7

• New therapies for systemic mastocytosis that selectively target KIT D816V are needed1,8,11

Click here to visit TargetSM.com for expert perspectives from allergists/immunologists, hematologists/oncologists, and pathologists

ASM, aggressive systemic mastocytosis; KIT, KIT proto-oncogene, receptor tyrosine kinase; MCL, mast cell leukemia; SM, systemic mastocytosis; SM-AHN, systemic mastocytosis with associated hematological neoplasm; QOL, quality of life. 1. Vaes M et al. Front Med. 2017;4:110. 2. Shomali W and Gotlib J. Hematology Am Soc Hematol Educ Program. 2018;2018(1):127-136. 3. Jara-Acevedo M et al. Mod Pathol. 2015;28(8):1138-1149. 4. Garcia- Montero AC et al. Blood. 2006;108(7):2366-2372. 5. Lim KH et al. Blood. 2009;113(23):5727-5736. 6. Sperr WR et al. Lancet Haematol. 2019 Dec;6(12):e638-e649. 7. Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. 8. Gilreath JA et al. Clin Pharm. 2019;11:77-92. 9. Theoharides TC et al. N Engl J Med. 2015;373:163-72. 10. The Mastocytosis Society. Symptoms and Triggers of Mast Cell Activation. 3 https://tmsforacure.org/symptoms/symptoms-and-triggers-of-mast-cell-activation/. Accessed May 1, 2020. 11. Pardanani A. Am J Hematol. 2016;91(11):1146-1159. Disease Pathogenesis Systemic mastocytosis is a rare, clonal mast cell neoplasm driven by the KIT D816V mutation

Systemic mastocytosis is: • Rare, clonal, neoplastic proliferation of mast cells1 • Driven by the KIT D816V mutation in 95% of cases2,3 • Results in heterogenous symptoms due to infiltration of clonal mast cells in different organ systems, including2,4

Bone marrow GI tract Skin Liver Spleen Adult-onset Image courtesy of Tracy George, MD, macropapular cutaneous University of Utah. mastocytosis5 Critical to make a timely diagnosis: • There is an urgent need for diagnosis of advanced and non-advanced SM6 • Non-advanced SM is associated with risk of life-threatening anaphylaxis6 • Advanced SM is associated with reduced OS due to organ damage7,8

GI, gastrointestinal; KIT, KIT proto-oncogene, receptor tyrosine kinase; OS, overall survival; SM, systemic mastocytosis. 1. Vaes M et al. Front Med. 2017;4:110. 2. Jara-Acevedo M et al. Mod Pathol. 2015;28(8):1138-1149. 3. Garcia-Montero AC et al. Blood. 2006;108(7):2366-2372. 4. Rossignol J et al. F1000Res. 2019;8. 5. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 6. Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. 7. Lim KH et al. Blood. 2009;113(23):5727-5736. 5 8. Pardanani A. Am J Hematol. 2019;94(3):363-377. Systemic mastocytosis is classified as a myeloid neoplasm by WHO1

Myeloid Neoplasms1

Myelodysplastic Myeloid/lymphoid syndromes/ Myeloid neoplasms Myeloproliferative Myelodysplastic Mastocytosis neoplasms with myeloproliferative with germline neoplasms (MPN) syndrome eosinophilia neoplasms predisposition (MDS/MPN)

• Prevalence of systemic Cutaneous Systemic Mast Cell Sarcoma1 Mastocytosis (CM)1 Mastocytosis1 mastocytosis is estimated at ~1 in 10,000 adults3

• ISM represents the vast majority Non-Advanced SM2 Advanced SM2 of systemic mastocytosis3

• Indolent SM • Aggressive SM • Up to ~70% of patients with • Smoldering SM • Mast Cell Leukemia (MCL) advanced systemic mastocytosis • Associated Hematologic 4 Neoplasm (AHN) have an associated neoplasm

ISM, indolent systemic mastocytosis; SM, systemic mastocytosis; WHO, World Health Organization. 1. Horny HP et al. Mastocytosis. In: Swerdlow SH et al, eds. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research and Cancer 6 (IARC);2017:62-69. 2. Sperr WR et al. Lancet Haematol. 2019;6(12):e638-e649. 3. Cohen SS et al. Br J Haematol. 2014;166(4):521-528. 4. Reiter A, et al. Blood. 2020;135(16):1365-1376. KIT plays a critical role in mast cell development and activation

• Mast cells are hematopoietic cells of myeloid origin1 Mast Cells3 • Mast cells express KIT, a tyrosine kinase receptor1,2 • Normal KIT signaling drives mast cell proliferation, survival, and activation as a functioning part of our immune response1,2

Activated mast cells release granules containing proinflammatory mediators2

Mast cells developed in a long-term (80-day) coculture of cord blood nucleated cells. (May-Grunwald/Giemsa staining, x3750.)

KIT, KIT proto-oncogene, receptor tyrosine kinase. 1. Metcalfe DD et al. Overview of mast cells in human biology. In: Akin C, ed. Mastocytosis. Cham, Switzerland: Springer Nature Switzerland AG; 2020:23-24. 2. Theoharides TC et al. N Engl J Med. 7 2015;373(2):163-172. 3. Furitsu T et al. Proc Natl Acad Sci. 1989;86(24):10039-10043. Systemic mastocytosis is driven by the KIT D816V mutation

The KIT D816V mutation is present in ~95% of patients with Position of D816V mutation3 systemic mastocytosis and is an underlying driver of disease1 Domain • The D816V mutation causes structural changes that result in

constitutive activation of KIT2 Ligand binding

like domains like -

Dimerization Ig

Transmembrane

Juxtamembrane

Mast cells harboring the KIT D816V mutation have Kinase I KIT D816V constitutive KIT activation/signaling resulting in Kinase insert uncontrolled mast cell proliferation and activation3,4 Kinase II Cytoplasmic tail

Ig, immunoglobulin; KIT, KIT proto-oncogene, receptor tyrosine kinase. 1. Garcia-Montero AC et al. Blood. 2006;108(7):2366-2372. 2.Laine E et al. PLoS Comput Biol. 2011;6:e1002068. 3. Cruse G et al. Immunol Allergy Clin North Am. 2014;34(2):219-237. 4. Theoharides 8 TC et al. N Engl J Med. 2015;373(2):163-172. Need for better therapeutic options exists in most patients with systemic mastocytosis1

Severe symptoms / Poor QOL2 (Not well controlled with symptom-directed therapies) Non-advanced SM1-6 Advanced SM1-5 ~95% of SM cases are non-advanced SM4 ~5% of SM cases are advanced SM4

ASM, SM-AHN, MCL SSM6 ISM

Minimal organ Organ damage3 damage3

2 Additional therapeutic options needed Mild symptoms / Better QOL (Symptoms well controlled; Minimal impact on ADLs) Symptoms well managed with current therapy

Figures are illustrative. Approximate number of patients based on estimated prevalence for patients with ISM, SSM and advanced SM. ADL, activities of daily living, ASM, aggressive SM; ISM, indolent SM; MCL, mast cell leukemia; QOL, quality of life; SM-AHN, SM with associated hematologic neoplasm; SM, systemic mastocytosis; SSM, smoldering SM; QOL, quality of life. 1. Pardanani A. Am J Hematol. 2016;91(11):1146-1159. 2. Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. 3. Horny HP et al. Mastocytosis. In: Swerdlow SH et al, eds. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research and Cancer (IARC); 2017:62-69. 4. Cohen SS et al. Br J Haematol. 2014;166(4):521-528. 9 5. Sperr WR et al. Lancet Haematol. 2019;6(12):e638-e649. 6. Tefferi A et al. Am J Hematol. 2019;94(1):E1–E2. Advanced systemic mastocytosis is associated with decreased overall survival

Overall survival was examined in a retrospective study that included 342 consecutive adult patients with SM (includes 183 adults with advanced SM) seen at the Mayo Clinic between 1976 and 20071

Median overall survival in advanced SM, by WHO subtype*1

ASM SM-AHN MCL (n=41) (n=138) (n=4) 41 months 24 months 2 months†

In the overall SM cohort‡, 6% (21/342) of patients had leukemic transformation (18/21 to AML and 3/21 to MCL)1

*Median follow-up was 20.7 months. †A later study with 23 MCL patients demonstrated a median overall survival for patients with MCL of 1.9 years, with a 10-year survival of 29.9%.2 ‡The overall cohort included 159 patients with ISM, 138 patients with SM-AHN, 41 patients with ASM, and 4 patients with MCL. AML, acute myeloid leukemia; ASM, aggressive systemic mastocytosis; ISM, indolent systemic mastocytosis; MCL, mast cell leukemia; SM, systemic mastocytosis; SM-AHN, systemic mastocytosis with associated hematologic neoplasm; WHO, World Health Organization. 10 1. Lim KH et al. Blood. 2009;113(23):5727-5736. 2. Sperr WR et al. Lancet Haematol. 2019;6(12):e638-e649. Uncontrolled mast cell activation in SM causes severe and unpredictable symptoms1-3

Activated mast cells release • Pruritus powerful mediators, including4: • Dizziness • Extreme flushing • Histamine • Palpitations • Darier’s sign • Tryptase • Anaphylaxis with • Dermatographism • PAF/lipid mediators hypotension and syncope • Cytokines-chemokines Skin Cardiovascular • Nitric oxide • Endothelin • Abdominal pain or • Memory loss cramping • Anxiety • Diarrhea • Depression • Nausea and/or vomiting • Lack of focus/memory • Heartburn or reflux • Brain fog • Migraines Gastrointestinal Neuropsychiatric Mast cell

• Nasal congestion • Bone pain • Throat swelling • Anaphylaxis • Muscle pain • Wheezing • Fatigue • Osteoporosis/osteopenia • Dyspnea • Malaise • Weight loss Respiratory Musculoskeletal Systemic

Organopathy due to mast cell infiltration can also occur, causing lymphadenopathy, splenomegaly/hypersplenism, hepatomegaly/ascites, cytopenias, malabsorption, or protein-losing enteropathy with weight loss5,6

PAF, platelet-activating factor; SM, systemic mastocytosis. 1. Theoharides TC et al. N Engl J Med. 2015;373(2):163-172. 2. Gilreath JA et al. Clin Pharmacol. 2019;11:77-92. 3. Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. 4. Amin K. Respir 11 Med. 2012;106(1):9-14. 5. Gulen T et al. J Intern Med. 2015;279(3):211-228. 6. Mickys U et al. Dig Liver Dis. 2007;39(7):693-697. Spectrum of symptoms for systemic mastocytosis

Patients who reported experiencing moderately to severely bothersome symptoms in the past year (%)

ISM (n=88) Advanced SM (n=13) 100

90 85 85

80 77 72 69 70 62 57 59 60 55 54 54 48 50 46 46 45 45 42 43 38 38 40 33 31 30 23 18

20 Frequency of participant, % participant, of Frequency 10

0 Anaphylaxis Fatigue/tiredness Pain (other than Headache Sweating Abdominal pain Diarrhea Nausea Vomiting Itching Flushing Difficulty abdominal) concentrating Systemic GI Skin Cognitive symptoms symptoms symptoms symptoms

Patients with ISM and advanced SM may experience severe symptoms

GI, gastrointestinal; ISM, indolent systemic mastocytosis; SM, systemic mastocytosis. 12 Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. Debilitating symptoms adversely affect QOL in patients with SM

Impacts of systemic mastocytosis on daily living (n=114)*

Yes† No‡ During the past week, were you limited in doing either your work or other 84% 16% daily activities? Were you limited in pursuing your hobbies or other leisure time activities? 85% 15% Did you worry? 90% 10% Did you feel irritable? 87% 13% Did you feel depressed? 71% 29% During the past week, has your physical condition or medical treatment 88% 12% interfered with your family life? Has your physical condition or medical treatment interfered with your 89% 11% social activities?

>80% of patients are limited in doing work or other daily activities

*Data pooled for ISM, SSM, and advanced SM. †Includes data for ”A Little,” ”Quite a Bit,” and ”Very Much.” ‡Includes data for ”Not at All.” ISM, indolent systemic mastocytosis; QOL, quality of life; SM, systemic mastocytosis; SSM, smoldering systemic mastocytosis. 13 Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. Identifying Systemic Mastocytosis: Signs, Symptoms, and Diagnosis Systemic mastocytosis can be challenging to diagnose

• Due to variable symptoms patients with systemic mastocytosis may interact with many different physicians before receiving a diagnosis, including1-2:

Primary care Dermatology Gastroenterology

Allergy/immunology Endocrinology Hematology/oncology

• Healthcare professionals may have limited knowledge of systemic mastocytosis, so increasing awareness across specialties is critical for facilitating timely diagnosis1,2

Patients with systemic mastocytosis face a diagnostic odyssey with a median time from symptom onset to diagnosis of ~7 years*1

*Based on data from 149 patients with systemic mastocytosis, including patients with indolent systemic mastocytosis (n=80), smoldering systemic mastocytosis (n=13), and advanced systemic mastocytosis (n=13). Data were obtained from Mast Cell Connect, a patient-reported registry that includes 251 patients with systemic mastocytosis or cutaneous mastocytosis who registered on a secure online portal and completed a 25-question survey to provide demographic, disease, and treatment information. The study is institutional review board–approved, and informed consent is required.1 15 1. Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. 2. Russell N et al. J Allergy Clin Immunol Pract. 2019;7(4):1157-1165. Symptoms including skin lesions, anaphylaxis with syncope, and GI involvement, warrant investigation of SM

Wheal-and-flare reaction is Small monomorphic elicited by stroking lesion lesions appear on the with a tongue spatula1 thighs or trunk of the body1 Maculopapular lesions with Darier’s sign is a highly specific diagnostic feature1,2 Initiate testing for serum tryptase and KIT D816V at the first sign of the disease

50% of adult patients experience recurrent or unexplained anaphylaxis1,3 Anaphylaxis with Many patients report hypotension and nausea, vomiting Symptoms can be syncope is not and/or diarrhea4,5 unpredictable and severe4,5 uncommon4

GI, gastrointestinal; KIT, KIT proto-oncogene, receptor tyrosine kinase; SM, systemic mastocytosis. 1. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 2. Broesby-Olsen S et al. Acta Derm Venereol. 2016;96(5):602-612. 3. Pardanani A. Am J Hematol. 2019;94(3):363-377. 4. Gilreath JA 16 et al. Clin Pharmacol. 2019;11:77-92. 5. Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. Diagnostic work-up includes physical exam and imaging

Physical exam1-3 • Complete medical history • Full-body skin exam (including Darier’s sign) • Palpation for hepatomegaly, splenomegaly, or lymphadenopathy

Imaging (when appropriate)1,3 • CT or ultrasound to look for enlarged liver, spleen, or lymph nodes • Bone densitometry (DEXA scan) • Skeletal x-ray or nuclear medicine bone scan • Endoscopy/colonoscopy

CT, computed tomography; DEXA, dual-energy x-ray absorptiometry. 17 1. Arock M et al. Leukemia. 2015;29(6):1223-1232. 2. Theoharides TC et al. N Engl J Med. 2015;373(2):163-172. 3. The Mastocytosis Society. Tests. https://tmsforacure.org/tests/. Accessed May 1, 2020. KIT D816V testing is a critical part of diagnostic work-up

Mutation testing1-4 • If diagnosis of SM is suspected, NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) recommend first using a highly sensitive assay such as ASO-qPCR on the peripheral blood to detect KIT D816V1 – When applied to the bone marrow, these assays can detect the mutation in >80% of patients with SM1 – Myeloid mutation panels are not recommended for the detection of KIT D816V as these NGS assays exhibit low sensitivity (~5%)1 – Full KIT sequencing recommended if D816V negative, other alterations in KIT are rare2 • Testing for additional genomic mutations via NGS, especially in advanced SM2 • Excluding hereditary alpha tryptasemia via testing for alpha tryptase gene duplications/triplications3,4

Pathology/biochemical testing2 • CBC and chemistry profile • Serum tryptase, LDH, albumin, calcium, and ALP • Tissue biopsy (eg, bone marrow) with phenotyping of mast cells by IHC and/or flow cytometry

ALP, alkaline phosphatase; CBC, complete blood count; IHC, immunohistochemistry; KIT, KIT proto-oncogene, receptor tyrosine kinase; LDH, lactic acid dehydrogenase; NGS, next-generation sequencing; PCR, polymerase chain reaction; SM, systemic mastocytosis. 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Systemic Mastocytosis V.1.2020. © 2020 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed June 9, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 2. Arock M et al. Leukemia. 2015;29(6):1223-1232. 3. Lyons JJ et al. Nat Genet. 2016;48(12):1564-1569. 4. Akin C et al. 18 Anaphylaxis in mastocytosis. In: Akin C, ed. Mastocytosis. Cham, Switzerland: Springer Nature Switzerland AG; 2020:23-34. Serum tryptase testing is another key component of diagnosis

Patients with symptoms of mast cell activation1

Physical exam and imaging1

Serum total tryptase1

<11.5 ng/mL2,* 11.5–20 ng/mL1 >20 ng/mL1

• Possible systemic mastocytosis1 • WHO minor diagnostic criterion for • Mastocytosis unlikely; but cannot be • Screen for hereditary alpha-tryptasemia3,† systemic mastocytosis (total serum 2 tryptase persistently >20 ng/mL‡)4 ruled out • Screen for KIT D816V in peripheral blood with high-sensitivity assay1 • Screen for hereditary alpha-tryptasemia3,†

Bone marrow biopsy and screen for KIT D816V mutation

*Normal median tryptase level in the healthy population is 5 ng/mL. †Elevated tryptase levels can also be observed in patients with hereditary alpha-tryptasemia without mastocytosis. ‡Unless there is an associated myeloid neoplasm, in which case this parameter is not valid. KIT, KIT proto-oncogene, receptor tyrosine kinase; WHO, world health organization. 1. Theoharides TC et al. N Engl J Med. 2015;373(2):163-172. 2. Akin C, Valent P. Immunol Allergy Clin North Am. 2014;34(2):207-218. 3. Lyons JJ et al. Nat Genet. 2016;48(12):1564-1569. 4. Horny HP et al. 19 Mastocytosis. In: Swerdlow SH et al, eds. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research and Cancer (IARC);2017:62-69. High-sensitivity KIT D816V assays screen for SM in peripheral blood

KIT D816V analysis on peripheral blood should be performed using a high-sensitivity PCR assay (<0.1%)1-3 • Low-sensitivity methods may fail to detect KIT D816V, particularly in patients with1,3: – Low mast cell burden – Limited systemic disease (eg, ISM) • Few commercial laboratories are currently offering high-sensitivity assays—it is important to confirm with the lab availability of high-sensitivity assays before sending the sample1,4-8

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)9: • If diagnosis of SM is suspected, NCCN Guidelines recommend first using a highly sensitive assay such as ASO-qPCR on the peripheral blood to detect KIT D816V • Myeloid mutation panels are not recommended for the detection of KIT D816V as these NGS assays exhibit low sensitivity (~5%)

ASO-qPCR, allele-specific oligonucleotide-quantitative PCR; ISM, indolent systemic mastocytosis; KIT, KIT proto-oncogene, receptor tyrosine kinase; NGS, next-generation sequencing; PCR, polymerase chain reaction; SM, systemic mastocytosis. 1. Arock M et al. Leukemia. 2015;29(6):1223-1232. 2. Kristensen T et al. Eur J Haematol. 2016;96(4):381-388. 3. Akin C et al. Anaphylaxis in mastocytosis. In: Akin C, ed. Mastocytosis. Cham, Switzerland: Springer Nature Switzerland AG; 2020:23-34. 4. Mayo Clinic Laboratories. https://www.mayocliniclabs.com/test-catalog/Overview/88802. Accessed May 1, 2020. 5. BloodCenter of Wisconsin. https://www.versiti.org/Custom/Files/Versiti/bd/bddd7755-540c-4f8f-8c9d-98c8ed2a7377.pdf. Published February 2016. Accessed May 1, 2020. 6. Versiti. https://www.versiti.org/medical-professionals/products- services/diagnostic-labs/4750. Accessed May 1, 2020. 7. ARUP Laboratories. KIT (D816V) Mutation by PCR. https://ltd.aruplab.com/Tests/Pub/3000440. Accessed May 1, 2020. 8. ARUP Laboratories. KIT Molecular Testing. https://ltd.aruplab.com/api/ltd/pdf/294. Accessed May 1, 2020. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Systemic Mastocytosis V.1.2020. © 2020 National 20 Comprehensive Cancer Network, Inc. All rights reserved. Accessed May 21, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. Analysis of D816V mutation in peripheral blood is useful in screening for SM

Peripheral blood can be used for initial screening, but thorough analysis of KIT mutational status should include bone marrow evaluation1

Test result in peripheral blood1-3

KIT D816V detected Perform detailed KIT mutational analysis on bone marrow KIT D816V not detected in a patient with high suspicion of SM

High-sensitivity assays (<0.1%) are recommended for detection of KIT D816V in bone marrow1,2,4

KIT, KIT proto-oncogene, receptor tyrosine kinase; SM, systemic mastocytosis. 1. Arock M et al. Leukemia. 2015;29(6):1223-1232. 2. Akin C et al. Anaphylaxis in mastocytosis. In: Akin C, ed. Mastocytosis. Cham, Switzerland: Springer Nature Switzerland AG; 2020:23-34. 3. Referenced with permission from the NCCN Guidelines® for Systemic Mastocytosis V.1.2020. © 2020 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed May 21, 2020. To view the most recent and complete version of the Eur J 21 guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way 4. Kristensen T et al. Haematol. 2016;96(4):381-388. WHO criteria are used to diagnose systemic mastocytosis

Diagnosis of systemic mastocytosis per WHO criteria requires major and ≥1 minor criterion OR ≥3 minor criteria Major criterion Multifocal dense mast cells infiltrates (≥15 mast cells in aggregates) are detected in sections of bone marrow and/or sections of other extracutaneous organ(s)

Minor criteria In bone marrow biopsy sections or biopsy sections from other extracutaneous organs, >25% of the mast cells in the infiltrate appear spindle-shaped or have atypical morphologic features; or >25% of all mast cells in bone marrow aspirate smears are immature or have atypical features

Presence of an activating point mutation in KIT at codon 816 in bone marrow, blood, or another extracutaneous organ

Mast cells in bone marrow, blood, or other extracutaneous organs express CD25 ± expression of CD2 in addition to normal mast cell markers*

Serum total tryptase persistently >20 ng/mL (if the patient has an associated myeloid neoplasm, this parameter is not valid)

*CD25 is the more sensitive marker by flow cytometry or immunohistochemistry. CD, cluster of differentiation; KIT, KIT proto-oncogene, receptor tyrosine kinase; WHO, World Health Organization. 22 Pardanani A. Am J Hematol. 2019;94(3):363-377. B findings indicate organ involvement without dysfunction

B findings

• High mast cell burden (demonstrated on bone marrow biopsy): >30% infiltration by mast cells (focal, dense aggregates) and serum total tryptase >200 ng/mL • Signs of dysplasia or myeloproliferation in non-mast cell lineage(s), but criteria are insufficient for definitive diagnosis of an associated hematologic neoplasm, with blood counts that are normal or only slightly abnormal • Hepatomegaly without impairment of liver function, palpable splenomegaly without hypersplenism, and/or lymphadenopathy on palpation or imaging

23 Pardanani A. Am J Hematol. 2019;94(3):363-377. C findings indicate organ dysfunction

C findings

• Bone marrow dysfunction due to neoplastic mast cell infiltration, characterized by ≥1 cytopenia(s): absolute neutrophil count <1.0 × 109/L, hemoglobin level <10 g/dL, or platelet count <100 × 109/L2 • Palpable hepatomegaly with impaired liver function, ascites and/or portal hypertension1,2 • Skeletal involvement, with large osteolytic lesions ± pathologic fractures (pathologic fractures due to osteoporosis are not a C finding) 2 • Palpable splenomegaly with hypersplenism (hypersplenism is defined as splenomegaly in association with a cytopenia [eg, platelets <100 × 109/L])2-4 • Malabsorption with weight loss due to infiltration of mast cells into gastrointestinal organs/tissues2

1. Vaes M et al. Front Med. 2017;4:110; 2. Pardanani A. Am J Hematol. 2019;94(3):363-377. 3. Caro J et al. Hypersplenism and hyposplenism. In: Lichtman MA, et al, eds. Williams Hematology, 8th ed. McGraw- 24 Hill Medical; 2010. 4. George TI et al. Hematol Oncol Clin North Am. 2011;25(5):1067-1083. B and C findings are used to determine subtype

Subtype Diagnostic criteria for subtyping

• Meets criteria for SM and no C findings Indolent systemic mastocytosis • No evidence of associated hematologic neoplasm

Smoldering systemic • Same as ISM, but with ≥2 B findings mastocytosis • No C findings

Aggressive systemic • ≥1 C finding(s) mastocytosis • No evidence of MCL Systemic mastocytosis • Meets criteria for SM and criteria for AHN as a distinct entity with associated per WHO classification hematological neoplasm • Bone marrow aspirate smears show ≥20% mast cells Mast cell leukemia • In classic cases, mast cells comprise ≥10% of white blood cells

AHN, associated hematologic neoplasm; ISM, indolent systemic mastocytosis; MCL, mast cell leukemia; SM, systemic mastocytosis; WHO, World Health Organization. 25 1 Pardanani A. Am J Hematol. 2019;94(3):363-377. Patient Experience Prolonged time to diagnosis in systemic mastocytosis

Given that systemic mastocytosis is associated with nonspecific symptoms, patients may present to a diverse group of specialists leading to challenges in diagnosis1,2

Median time to diagnosis from symptom onset*1 Diagnostic odyssey for patients with systemic mastocytosis Advanced SM ~3 years • Before receiving diagnosis, patients with mastocytosis visited a median of 3 specialists*1 Indolent/ smoldering SM ~9 years • ~50% consulted 3 to 6 physicians while seeking diagnosis*1

• Heterogenous presentation and unfamiliarity with the disease may delay time from symptom onset to diagnosis1 • 82% of patients with indolent disease reported being troubled by physicians’ lack of knowledge of mastocytosis 1

*Based on data from 149 patients with systemic mastocytosis, including patients with indolent systemic mastocytosis (n=80), smoldering systemic mastocytosis (n=13), and advanced systemic mastocytosis (n=13). Data were obtained from Mast Cell Connect, a patient-reported registry that includes 251 patients with systemic mastocytosis or cutaneous mastocytosis who registered on a secure online portal and completed a 25-question survey to provide demographic, disease, and treatment information. The study is institutional review board–approved, and informed consent is required. SM, systemic mastocytosis. 27 1. Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. 2. Pardanani A et al. Am J Hematol. 2016;91(11):1146-1159. Patients with systemic mastocytosis are often misdiagnosed

• Given its low prevalence and nonspecific symptoms, systemic mastocytosis may be mistaken for other disorders1-9 – Some patients may remain undiagnosed until they are exposed to triggers (eg, insect sting) and experience anaphylactic reactions or even death2-5 • A high index of clinical suspicion is needed to avoid misdiagnosis and delayed treatment9

Disorders that can mimic systemic mastocytosis8

Inflammatory Irritable bowel Malabsorption bowel disease syndrome

Myeloproliferative Urticaria Endocrine disorders disease

Idiopathic MCAS Monoclonal MCAS Cryptogenic cirrhosis10

MCAS, mast cell activation syndrome. 1. Theoharides TC et al. N Engl J Med. 2015;373(2):163-172. 2. Reiter N et al. Lancet. 2013;382(9901):1380. 3. Geerlings SE et al. Neth J Med. 2001;58(2):45-51. 4. Kors JW et al. J Intern Med. 1993;233(3):255- 258. 5. Vaughan ST et al. Anaesthesia. 1998;53(8):804-807. 6. Kirsch R et al. Mod Pathol. 2008;21(12):1508-1516. 7. Mallya KP et al. J Clin Diagn Res. 2013;7(10):2276-2277. 8. NORD. Rare Disease Database: 28 Mastocytosis. https://rarediseases.org/rare-diseases/mastocytosis/. Accessed March 6, 2020. 9. Pardanani A. Am J Hematol. 2016;91(11):1146-1159. 10. Jiang ZG, et al. Gastroenterology. 2018;155(1):23-24. Non-advanced forms of systemic mastocytosis can progress

• Data collected from the registry of the European Competence Network on Mastocytosis (ECNM) was used to calculate rates of disease progression for patients with ISM and SSM1

Percent of patients with disease progression, by subtype*:

~5% of patients progress ~9% of patients progress to more advanced disease (SSM to more advanced disease or advanced SM) (advanced SM) One study cites the rate of progression and/or leukemic transformation in SSM is 18% (4/22)2,3

ISM (n=653) SSM (n=53) With progression Without progression

*Median follow-up of patients with typical ISM was 4.2 years (range 0 to 31.4 years) and patients with SSM was 4.3 years (0.3 to 22 years). ISM, indolent systemic mastocytosis; SM, systemic mastocytosis; SSM, smoldering systemic mastocytosis. 29 1. Trizuljak J et al. Allergy. 2020 Feb 28. doi: 10.1111/all.14248. 2. Pardanani A et al. Blood. 2010;115(1):150-151. 3. Pardanani A et al. Blood. 2013;121(16):3085-3094. Systemic mastocytosis may be missed in patients with suspected myeloid neoplasms

Concomitant, undiagnosed systemic mastocytosis has been identified upon detection of KIT mutations in patients with confirmed or suspected myeloid neoplasms

Myeloid neoplasm and KIT D816V (n=22)*

10 Systemic mastocytosis • Nearly all patients with KIT mutation 9 diagnosed with a chronic myeloid No systemic mastocytosis 8 neoplasm (20/22, 91%) were confirmed 7 to have SM-AHN* 6 5 • In 35% of those confirmed (7/20), there 4 was no clinical or pathologic suspicion 3 of a systemic mast cell disorder, and a 2

Number Number of patients diagnosis of SM-AHN was not rendered 1 upon initial pathologic review 0 CMML MDS/MPN-UMDS/MPN-U MDSMDS (SLD, (SLD, MLD or MPNMPN (PV, (PV, MPF PMF, or MLD,EB-1) or EB-1) orMPN-U) MPN-U)

*8-year retrospective review of 64 patients with suspected or confirmed myeloid malignancies with pathogenic KIT mutations. CMML, chronic myelomonocytic leukemia; EB-1, excess blasts-1; MDS, myelodysplastic syndrome; MDS/MPN, myelodysplastic/myeloproliferative neoplasm; MLD, multilineage dysplasia; MPN, myeloproliferative neoplasm; PMF, primary myelofibrosis; PV, polycythemia vera; SM-AHN, systemic mastocytosis with associated hematologic neoplasm; SLD, single lineage dysplasia; U, unclassifiable. 30 Craig JW et al. Modern Pathol. 2020;10.1038/s41379-019-0447-x. Mast cell activation in SM has a wide array of triggers

Individual patients may react to variable triggers1

Potential triggers1-4

• Heat, cold, or sudden temperature changes • Contrast dyes • Stress (emotional, physical, including pain) • Odors (natural/chemical odors, perfumes, scents) • Environment (weather changes, pollution) • Stings and venoms (insects, spiders, jellyfish, snakes) • Exercise • Infections (viral, bacterial, fungal) • Fatigue • Mechanical irritation (friction or vibration) • Spicy food • Surgery • Alcohol • Vaccinations • Drugs, particularly opioids, antibiotics, NSAIDs, • Medical procedures (eg, endoscopy, colonoscopy) alcohol-containing medicines, and IV vancomycin

Avoidance lists should be individualized for each patient5

IV, intravenous, NSAID, nonsteroidal anti-inflammatory drug; SM, systemic mastocytosis. 1. The Mastocytosis Society. Symptoms and Triggers of Mast Cell Activation. https://tmsforacure.org/symptoms/symptoms-and-triggers-of-mast-cell-activation/. Accessed January 8, 2019. 2. Silva I et al. Allergol Immunopathol (Madr). 2008;36(3):154-163. 3. Gulen T et al. Anaphylaxis in mastocytosis. In: Akin C, ed. Mastocytosis. Cham, Switzerland: Springer Nature Switzerland AG; 2020:141-155. 4. Castells M et al. Drug allergy and perioperative management of mastocytosis. In: Akin C, ed. Mastocytosis. Cham, Switzerland: Springer Nature Switzerland AG; 2020:175-186. 5. Gulen T et al. J 31 Intern Med. 2015;279(3):211-228. Current Treatment Options and Persisting Needs Treatment options for systemic mastocytosis are limited

Overview of treatment options for patients with systemic mastocytosis1,2

Non-advanced systemic mastocytosis Advanced systemic mastocytosis

Trigger avoidance Symptomatic therapy* Symptomatic therapy* Cytoreductive therapy

Experimental therapy† TKI therapy Stem cell transplant

Experimental therapy†

• For patients with non-advanced SM, current treatment options may offer control of symptoms3,4 • For patients with advanced SM, therapeutic reduction of mast cell burden is necessary to prevent further organ damage and to extend survival; current treatments may offer temporary mast cell reduction via cytoreduction3,4

There remains an unmet need for therapies that selectively target KIT D816V without substantial off-target activity1,4

*Therapies can include antihistamine, anti-inflammatory, cromolyn sodium, corticosteroids, epinephrine, proton pump inhibitors, anti-IgE. †Including agents under investigation in clinical trials. IgE, immunoglobulin E; KIT, KIT proto-oncogene, receptor tyrosine kinase; TKI, tyrosine kinase inhibitor. 1. Pardanani A. Am J Hematol. 2019;94(3):363-377. 2. Scherber RM et al. Br J Haematol. 2018;180(1):11-23. 3. Cardet JC et al. Expert Opin Pharmacother. 2013;14(15):2033-2045. 4. Gilreath JA et al. Clin 33 Pharmacol. 2019;11:77-92. Polypharmacy is common in patients with non-advanced SM

% of patients who have ~75% of patients with ISM have taken ≥4 classes Drug Class received this type of treatment of drugs to manage their disease

H1 antihistamines 98% 2% Number of H2 antihistamines 93% drug classes 14% 5% Cromolyn sodium 66% 1

Leukotriene inhibitors 62% 18% 2 3 Corticosteroids 55% 13% 4 Epinephrine 48% 5 Proton pump inhibitors 46% 6 Anti-IgE 18% 20% 20% 7 Cytoreductive agents 15% 8% 8+ N=103

IgE, immunoglobulin E; ISM, indolent systemic mastocytosis; SM, systemic mastocytosis. 34 Data on file. Adelphi Observational Study. July 2018. Data cutoff March 2018. Summary and Unmet Needs Clinical unmet need for patients with systemic mastocytosis

SM is a rare clonal mast cell neoplasm driven by the KIT D816V mutation1-4

Many patients experience a prolonged time from onset to diagnosis, with an average time from symptom onset to diagnosis of ~7 years5

Patients with SM may have severe, unpredictable symptoms that negatively affect QOL5-8

Prognosis for patients with advanced SM is poor; historic median overall survival for ASM: ~3.4 years, SM-AHN: ~2.0 years, and MCL: ~2 months1,9,10

New therapeutic options that selectively target KIT D816V are needed1,6,11

ASM, aggressive systemic mastocytosis; KIT, KIT proto-oncogene, receptor tyrosine kinase; MCL, mast cell leukemia; SM, systemic mastocytosis; SM-AHN, systemic mastocytosis with associated hematological neoplasm; QOL, quality of life. 1. Vaes M et al. Front Med. 2017;4:110. 2. Shomali W and Gotlib J. Hematology Am Soc Hematol Educ Program. 2018;2018(1):127-136. 3. Jara-Acevedo M et al. Mod Pathol. 2015;28(8):1138-1149. 4. Garcia- Montero AC et al. Blood. 2006;108(7):2366-2372. 5. Jennings SV et al. Immunol Allergy Clin North Am. 2018;38(3):505-525. 6. Gilreath JA et al. Clin Pharm. 2019;11:77-92. 7. Theoharides TC et al. N Engl J Med. 2015;373:163-72. 8. The Mastocytosis Society. Symptoms and Triggers of Mast Cell Activation. https://tmsforacure.org/symptoms/symptoms-and-triggers-of-mast-cell-activation/. Accessed May 1, 2020. 9. Lim KH 36 et al. Blood. 2009;113(23):5727-5736. 10. Sperr WR et al. Lancet Haematol. 2019 Dec;6(12):e638-e649. 11. Pardanani A. Am J Hematol. 2016;91(11):1146-1159. Visit TargetSM.com to view and download additional slide modules from the perspectives of experts in • Allergy/immunology • Hematology/oncology • Pathology