For U.S. healthcare professionals only

DISCOVER THE CAUSE OF SM: KIT D816V

I am KIT D816V. I am the genomic mutation that is the central driver of systemic mastocytosis (SM). See how I cause uncontrolled proliferation and activation of mast cells, resulting in an array of severe and unpredictable symptoms in your patients.1,7,13

Know the underlying cause of systemic mastocytosis

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0%
The KIT D816V mutation is the central driver of systemic mastocytosis in ~95% of cases.1

Other less common somatic KIT mutations identified in adult systemic mastocytosis include V560G, D815K, D816Y, insVI815-816, D816F, D816H, and D820G.1 Patients with no KIT mutation detected have been described as well in rare cases.14

See how KIT D816V plays a central role in SM

As per the World Health Organization (WHO) guidelines, systemic mastocytosis is a myeloid neoplasm classified into 5 subtypes.10,15,16

Myeloid neoplasms
Mastocytosis
Myeloproliferative neoplasm (MPN)
Myeloid/lymphoid neoplasms with eosinophilia
Myelodysplastic syndrome/ myeloproliferative neoplasm (MDS/MPN)
Myelodysplastic syndrome
Myeloid neoplasm with germline predisposition
flowchart_myloid-m

KIT D816V: The root cause of a broad range of potential clinical consequences1,3,7

The KIT D816V mutation causes the receptor tyrosine kinase to be constitutively active, leading to the uncontrolled proliferation and activation of abnormal mast cells. This occurs across multiple organ systems, including the bone marrow, liver, spleen, skin, and other organs.3,17,18

icn_kitd816v-m@2x
KIT D816V
icn_mastcell-m@2x
MAST CELL20

Activated mast cells release powerful mediators, including:

  •  Cytokine-chemokines
  •  Endothelin
  •  Histamine
  • Nitric oxide
  •  PAF/lipid mediators
  • Tryptase

Cardiovascular3,19

  • Anaphylaxis with hypotension and syncope
  • Dizziness
  • Palpitations

skin3

  • Darier's sign
  • Dermatographism
  • Extreme flushing
  • Pruritus

GASTROINTESTINAL3,19

  • Abdominal pain or cramping
  • Diarrhea
  • Heartburn or reflux
  • Nausea and/or vomiting

Neuropsychiatric5,19

  • Anxiety
  • Brain fog
  • Depression
  • Lack of focus/memory
  • Memory loss
  • Migraines

RESPIRATORY5,19

  • Dyspnea
  • Nasal congestion
  • Throat swelling
  • Wheezing

Musculoskeletal19

  • Bone pain
  • Muscle pain
  • Osteoporosis/ osteopenia

SYSTEMIC5,19

  • Anaphylaxis
  • Fatigue
  • Malaise
  • Weight loss

Organopathy due to mast cell infiltration can also occur, causing lymphadenopathy, splenomegaly/hypersplenism, hepatomegaly/ascites, cytopenias, malabsorption, or protein-losing enteropathy with weight loss.21,22

In addition to acutely debilitating symptoms, systemic mastocytosis can have detrimental long-term outcomes8,10,23

Advanced forms of systemic mastocytosis associated with poor overall survival8,a

ASM (n=41)
41 MONTHS
SM-AHN (n=138)
24 MONTHS
MCL (n=4)
2 MONTHSb
  • 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%.10
Overall survival was examined in a retrospective study that included 342 consecutive adult patients with systemic mastocytosis (includes 183 adults with advanced systemic mastocytosis) seen at the Mayo Clinic between 1976 and 2007.8

Non-advanced forms of systemic mastocytosis can progress to advanced forms11,24,25,c

Data collected from the registry of the European Competence Network on Mastocytosis (ECNM) was used to calculate rates of disease progression for patients with indolent systemic mastocytosis and smoldering systemic mastocytosis.11

~5% of ISM patients progress to more advanced disease (SSM or advanced SM)
pie_ism-653a@2x
ISM (n=653)
~9% of SSM patients progress 
to more advanced disease (advanced SM)
One study cites the rate of progression and/or leukemic transformation in SSM is 18% (4/22)
pie_ism-653b@2x
ISM (n=653)

With progression

Without progression

  • Median follow-up of patients with typical indolent systemic mastocytosis was 4.2 years (range 0 to 31.4 years) and patients with smoldering systemic mastocytosis was 4.3 years (0.3 to 22 years).

Systemic mastocytosis severely impacts patients' lives, and can lead to psychosocial consequences and poor quality of life13,19

icn_steroids@2x

High unmet clinical need:

  • There are no approved treatment options for indolent systemic mastocytosis and no approved selective inhibitors for KIT D816V in advanced systemic mastocytosis21
  • 75% of patients with indolent systemic mastocytosis take ≥4 classes of medication to manage their disease26
icn_neuro@2x

Psychological consequences:

  • Patients live in fear of anaphylaxis or other symptom flare-ups, such as frequent diarrhea19
  • In a survey of 363 patients with systemic mastocytosis, 72% reported psychological impact13,19
icn_qol@2x

Quality of life impact:

  • The sudden onset of gastrointestinal, cognitive, and anaphylactic symptoms severely impacts patients’ ability to perform regular work or daily activities19
  • In a survey of 101 patients with indolent or smoldering systemic mastocytosis19:
    • Over 80% of patients with indolent systemic mastocytosis reported being limited in doing work or daily activities
    • Over 50% of patients reported that daily activities were either “very much” or “quite a bit” limited
    • 63% of patients with indolent systemic mastocytosis reported that hobbies and leisure activities were either “very much” or “quite a bit” limited
Learn how to identify systemic mastocytosis through hallmark symptoms.
SUSPECT SM
  1. Garcia-Montero AC, et al. Blood. 2006;108(7):2366-2372.
  2. Verstovsek S. Eur J Haematol. 2013;90(2):89-98.
  3. Gilreath JA, et al. Clin Pharmacol. 2019;11:77-92.
  4. Metcalfe DD. Blood. 2008;112(4):946-956.
  5. Theoharides TC, et al. N Engl J Med. 2015;373(2):163-172.
  6. Hartmann K, et al. J Allergy Clin Immunol. 2016;137(1):35-45.
  7. Shomali W, Gotlib J. Hematology Am Soc Hematol Educ Program. 2018(1):127-136.
  8. Lim KH, et al. Blood. 2009;113(23):5727-5736.
  9. Kibsgaard L, et al. Derm. 2020;6:294-300.
  10. Sperr WR, et al. Lancet Haematol. 2019;6(12):e638-e649.
  11. Trizuljak J, et al. Allergy. 2020;75(8):1927-1938.
  12. Arock M, et al. Leukemia. 2015;29(6):1223-1232.
  13. Hermine O, et al. PLoS One. 2008;3(5):e2266.
  14. Chatterjee A, et al. Oncotarget. 2015;6(21):18250-18264.
  15. Arber DA, et al. Blood. 2016;127(20):2391-2405.
  16. Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Rev 4th ed. International Agency for Research on Cancer (IARC); 2017.
  17. da Silva EZ, et al. J Histochem Cytochem. 2014;62:698-738.
  18. Valent P, et al. Blood. 2017;129(11):1420-1427.
  19. Jennings SV, et al. Immunol Allergy Clin North Am. 2018;38(3):505-525.
  20. Amin K. Respir Med. 2012;106(1):9-14.
  21. Gulen T, et al. J Intern Med. 2016;279(3):211-228.
  22. Mickys U, et al. Dig Liver Dis. 2007;39(7):693-697.
  23. Akin C, Castells M; World Allergy Organization. July 2011. Updated March 2017. Accessed October 9, 2020.  https://www.worldallergy.org/education-and-programs/education/allergic-disease-resource-center/professionals/mastocytosis-where-are-we-now.
  24. Pardanani A, et al. Blood. 2010;115(1):150-151.
  25. Pardanani A. Am J Hematol. 2013;88(7):612-624.
  26. Data on file. Blueprint Medicines Corporation. Cambridge, MA. 2020.
  27. Kristensen T, et al. Am J Hematol. 2014;89(5):493-498.
  28. van Anrooij B, et al. Allergy. 2016;71(11):1585-1593.
  29. Vos B, et al. J Allergy Clin Immunol Pract. 2017;5(5):1264-1271.
  30. Berezowska S, et al. Mod Pathol. 2014;27(1):19-29.
  31. Gulen T, et al. J Allergy Clin Immunol Pract. 2017;5:1248-1255.
  32. Hahn HP, Hornick JL. Am J Surg Pathol. 2007;31(11):1669-1676.
  33. Craig JW, et al. Mod Pathol. 2020;133(6):1135-1145.
  34. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Systemic Mastocytosis V.1.2020. ©National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed September 11, 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.
  35. Pardanani A. Am J Hematol. 2019;94(3):363-377.
  36. Akin C, Valent P. Immunol Allergy Clin North Am. 2014;34(2):207-218.
  37. Valent P, et al. Int J Mol Sci. 2019;20(12):2976.
  38. Akin C. J Mol Diagn. 2006;8(4):412-419.

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