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Systemic Mastocytosis: Disease State, Diagnosis, and Current Treatment Options Systemic Mastocytosis: Disease State, Diagnosis, and Current Treatment Options Sponsored by: Blueprint Medicines, TargetSM.com, and associated logos are trademarks of Blueprint Medicines Corporation. © 2020 Blueprint Medicines Corporation. 07/2020 USBP-DASM-20-003.2 Module outline Systemic Mastocytosis: Disease State, Diagnosis, and Current Treatment Options • 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
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