Mastocytosis was classified by the World Health Organization in 2019 as a disease distinct from myeloproliferative neoplasms. Patients with mastocytosis have multifocal clusters of abnormal mast cells that vary in size and shape. 

Mastocytosis is a heterogeneous disease; it may be skin-limited (cutaneous mastocytosis) or it may involve extracutaneous systems (systemic mastocytosis). Systemic mastocytosis is the more aggressive of the two, often resulting in multiorgan dysfunction and reduced survival. Systemic mastocytosis itself can be divided into 5 variants: indolent, smoldering, hematological neoplasm-associated, aggressive, and mast cell leukemia.

The classification system of systemic mastocytosis presents an opportunity for physicians to tailor treatment according to the severity of the subtypes described. Pragmatically, these 5 variants of systemic mastocytosis can be further simplified into two: indolent and advanced.

Studies have demonstrated that a majority of adult systemic mastocytosis cases involve gain-of-function somatic mutations in KIT. However, it is important to note that they do not occur in every case of mastocytosis, and there is scientific debate about whether these mutations alone can account for the diversity of symptoms observed in patients. 

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Scientists have studied mouse models to determine the extent to which genetic mutations translate into mastocytosis phenotype. One study used transgenic mice expressing human KIT D816V in mature mast cells. Researchers reported that only 30% of these mice developed a limited form of mastocytosis at 12-18 months of age. Because of this study and others, we remain unsure of the exact role that KIT mutations play in driving the disease.

The primary purpose of understanding the genetics underlying mastocytosis is to know what can be targeted in therapeutic research. 

Personalizing Treatment Approaches

“European Competence Network on Mastocytosis guidelines recommend that every [systemic mastocytosis] patient, regardless of the presence of mediator symptoms, history of anaphylaxis, or bone disease, should be preferentially managed and followed up by a multidisciplinary team with at least a hematologist, an allergologist and an endocrinologist,” Sciumè and colleagues wrote in Pharmaceuticals.

Treatment for systemic mastocytosis is highly personalized due to the heterogeneous nature of its presentation. Let’s first discuss symptom-specific treatment. 

Pruritus should be treated with H1 antagonists. Gastrointestinal symptoms, such as abdominal pain, cramping, nausea, and vomiting, should be treated with H2 antagonists. Osteoporosis should be managed with bisphosphonates. 

Symptom-specific management of patients with systemic mastocytosis is important because symptomatic relief can positively impact patients’ quality of life. If symptoms are mild, physicians can choose to adopt a “wait and see” approach; on the other hand, aggressive symptoms can be managed more aggressively, with such approaches as utilizing cytoreductive therapy for mast cell debulking.

Finding Therapeutic Solutions

Since KIT D816V has been frequently found in systemic mastocytosis, it has become an attractive therapeutic target for medical researchers. Scientists have examined the use of various tyrosine kinase inhibitors, such as midostaurin (Rydapt®) and avapritinib (Ayvakit™).

Midostaurin was approved in 2017 by the US Food and Drug Administration (FDA) for adults with aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia.  Avapritinib, on the other hand, received FDA approval for use in advanced systemic mastocytosis (encompassing aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia) in 2021.

These two tyrosine kinase inhibitors have been evaluated in patients with various subtypes of systemic mastocytosis and have shown promise. For midostaurin, the response rate in patients with advanced systemic mastocytosis was around 50% to 75%, with 57% of patients experiencing a 50% decrease or more in bone marrow mast cells. For avapritinib, the response rate in patients with advanced systemic mastocytosis was 75% to 100%, with 93% of patients experiencing a decrease of 50% or more in bone marrow mast cells. 

“Both midostaurin and avapritinib treatment have resulted in reproducible histopathologic changes in the [bone marrow], reflecting the effects of KIT inhibition,” Reiter and colleagues summarized in Blood.

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An emerging therapeutic area of interest is passive immunotherapy targeting IgE-dependent mast cell degranulation. This form of treatment is particularly relevant in patients with recurrent anaphylaxis. Omalizumab, a humanized IgG monoclonal anti-IgE antibody, is one such treatment. 

Studies demonstrate that omalizumab can successfully ameliorate a number of pathological symptoms in patients with indolent systemic mastocytosis, including gastrointestinal, cutaneous, and cardiovascular symptoms. Around 84% of patients who took omalizumab experienced complete cessation of severe idiopathic anaphylactic episodes. 

Future Directions 

The midostaurin and avapritinib trials successfully demonstrated that they can have different response rates among different subtypes of systemic mastocytosis. “The midostaurin and avapritinib studies provide a foundation for future trial designs and priorities,” Reiter and colleagues wrote. 

It is crucial that medical researchers recognize that systemic mastocytosis is a highly heterogeneous disease; it has 5 subtypes for a reason. Future research should continue to investigate treatment response according to disease subtypes, as scientists may discover that a drug is more efficacious in one subtype compared to others. 

In addition, we need to broaden our understanding of the role that gain-of-function mutations in KIT play in the pathophysiology, disease course, and prognosis of systemic mastocytosis. This will allow us to continue targeting this mutation through innovative drug design. 

“Collaboration between biopharma and [the European Competence Network on Mastocytosis], the American Initiative on Mast Cell Diseases, and patient advocacy groups will be required to address the unmet research needs of this rare disease population,” Reiter and colleagues concluded. 


Sciumè M, De Magistris C, Galli N, et al. Target therapies for systemic mastocytosis: an updatePharmaceuticals (Basel). 2022;15(6):738. Published online June 11, 2022. doi:10.3390/ph15060738

Reiter A, George TI, Gotlib J. New developments in diagnosis, prognostication, and treatment of advanced systemic mastocytosisBlood. 2020;135(16):1365-1376. doi:10.1182/blood.2019000932

Pardanani A. Systemic mastocytosis in adults: 2021 update on diagnosis, risk stratification and managementAm J Hematol. 2021;96(4):508-525. doi:10.1002/ajh.26118