Systemic Mastocytosis (SM)

Mastocytosis is no longer considered a myeloproliferative neoplasm (MPN) subgroup in the 2016 revision of the World Health Organization (WHO) classification of myeloid neoplasms, but rather a separate disease category.¹ Mastocytosis comprises a group of diseases in which excessive amounts of pathologic mast cells proliferate and accumulate in the tissues.² In individuals with systemic mastocytosis, focal and/or diffuse infiltrates of neoplastic mast cells are seen in multiple internal organs, including the bone marrow, liver, spleen, and gastrointestinal tract.³ 

WHO Classification and Diagnostic Criteria for Systemic Mastocytosis 

In 2016, the WHO classified mastocytosis into 3 main types: cutaneous mastocytosis, which involves only the skin; systemic mastocytosis (SM), in which mast cells infiltrate tissues other than the skin; and mast cell sarcoma.⁴ In the updated 2016 WHO classification, SM is further subclassified as indolent SM, smoldering SM, SM with an associated hematologic neoplasm (SM-AHN), aggressive SM, and mast cell leukemia.⁵ Skin involvement is found in indolent systemic mastocytosis, less frequently detected in aggressive systemic mastocytosis, and rarely seen in mast cell leukaemia.³  

The WHO defined diagnostic criteria for SM in 2001, and these were confirmed in WHO updates in 2008 and 2016. The diagnosis of SM can be established by the presence of either 1 major and 1 minor criterion or 3 minor criteria.³

Major SM criterion 

• Multifocal dense aggregates of mast cells (≥15 mast cells per aggregate) are seen in bone marrow biopsy specimens and/or in sections of other extracutaneous organs.³ 

Minor SM criteria 

• More than 25% of all mast cells are atypical cells (type I or type II) on bone marrow smears or are spindle-shaped in mast cell infiltrates detected on sections of visceral organs.
• A KIT point mutation at codon 816 is detected in the bone marrow or another extracutaneous organ
• Mast cells in bone marrow or blood or in another extracutaneous organ exhibit CD2 and/or CD25.
• The baseline serum tryptase level is higher than 20 ng/mL. (If an unrelated myeloid neoplasm is present, this is not a valid SM criterion.³) 

Etiopathogenesis

Regardless of the WHO subtype of SM, gain-of-function somatic mutations in the KIT tyrosine kinase domain, especially the D816V mutation, have been detected in the majority of adult patients with SM. V560G, D815K, D816Y, insVI815-816, D816F, D816H, and D820G are some of the less common (<5%) somatic KIT mutations found in adults with SM.¹

SM Clinical Presentation

​​SM affects multiple organ systems as a consequence of the release of vasoactive mediators.² Mast cells accumulate in the liver, spleen, bone marrow, and small intestine in individuals with SM. The signs and symptoms vary depending on which organs are affected. These include anemia, manifestations of bleeding, abdominal pain, nausea, diarrhea, vomiting, hives, skin flushing, itching, anaphylactoid reactions, hepatomegaly, splenomegaly, and lymphadenopathy.⁶ 

SM Evaluation and Diagnosis 

The initial evaluation should focus on diagnosing the disease and determining its clonal origin. A full medical history is required for a diagnosis. A previous history of anaphylaxis requiring the administration of epinephrine after the ingestion of specific foods or medications or after exposure to other triggers should be noted.²

The most useful test for diagnosing SM is bone marrow biopsy. Complete blood cell counts can identify anemia, leukocytosis (high white blood cell count), and thrombocytopenia. High histamine levels, hypoalbuminemia, and high serum tryptase levels may also be noted. Imaging may aid in determining the extent and stage of disease. Biopsy of affected organs (eg, skin and liver) and genetic testing are also performed.⁶

SM Management 

The treatment of SM is based on the individual patient’s clinical features. Antihistamines, proton pump inhibitors, epinephrine, steroids, mast cell stabilizers, and cromolyn sodium are the medications used according to the presence of multiple symptoms in SM including skin and G.I symptoms, increased stomach acid, anaphylaxis, malabsorption, and bone pains.⁶

There are several approved therapeutics for the treatment of SM. On June 16, 2021, the Food and Drug Administration (FDA) approved Blueprint Medicines’ avapritinib (Ayvakit^®) for the treatment of advanced systemic mastocytosis (AdvSM) in adult patients, as well as patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). According to efficacy data from the drug’s phase 1 EXPLORER (NCT02561988) and phase 2 PATHFINDER (NCT03580655) studies, avapritinib achieved a combined overall response rate (ORR) of 57% in all evaluable patients. Of these patients, 28% experienced complete remissions, and 28% partial remissions, with a 38.3-month median duration of response and a 2.1-month median time to response.⁷

Additionally, the FDA previously approved midostaurin (Rydapt^®) for the treatment of adult patients with advanced SM. 2-Chlorodeoxyadenosine (2-CdA) demonstrates efficacy in all subtypes of SM; response rates are generally comparable to those with midostaurin, although no head-to-head studies have been conducted, and those that have been performed have included small numbers of patients. Interferon alfa has been shown to relieve dermatologic, hematologic, gastrointestinal, and systemic symptoms related to histamine release in all subtypes of SM. Imatinib mesylate (Gleevec™) is also FDA approved with a specific indication for the treatment of adult patients who have aggressive SM without the KIT D816V mutation or with an unknown KIT mutational status.

As of April 20, 2021, ripretinib (DCC-2618) is currently under investigation for the treatment of ASM.¹ 

Read about systemic mastocytosis therapies

References

1. Pardanani A. Systemic mastocytosis in adults: 2021 update on diagnosis, risk stratification and management. Am J Hematol. 2021;96(4):508-525. doi:10.1002/ajh.26118
2. Gangireddy M, Ciofoaia GA. Systemic mastocytosis. StatPearls [Internet]. Published July 21, 2021. Accessed April 11, 2022.
3. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129(11):1420-1427. doi:10.1182/blood-2016-09-731893 
4. Rossignol J, Polivka L, Maouche-Chrétien L, Frenzel L, Dubreuil P, Hermine O. Recent advances in the understanding and therapeutic management of mastocytosis. F1000Res. 2019;8:F1000 Faculty Rev-1961. doi:10.12688/f1000research.19463.1
5. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544
6. Systemic mastocytosis. Genetic and Rare Diseases Information Center (GARD). Updated September 6, 2016. Accessed April 11, 2022.
7. FDA approves avapritinib for advanced systemic mastocytosis. FDA. Accessed July 7, 2022

Reviewed by Debjyoti Talukdar, MD, on 4/17/2022.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.