Disease Overview

Mastocytosis encompasses a spectrum of conditions characterized by the abnormal proliferation and accumulation of mast cells in various tissues. In systemic mastocytosis, neoplastic mast cells form localized or widespread infiltrates in multiple organs such as the bone marrow, liver, spleen, and gastrointestinal tract. There are three types of mastocytosis: cutaneous, systemic, and mast cell sarcoma. Cutaneous mastocytosis affects only the skin, while systemic mastocytosis (SM) involves the infiltration of mast cells into tissues beyond the skin. Systemic mastocytosis is further categorized as indolent SM, smoldering SM, SM with an associated hematologic neoplasm (SM-AHN), aggressive SM, and mast cell leukemia. Skin involvement is commonly observed in indolent systemic mastocytosis, less frequently in aggressive systemic mastocytosis, and rarely in mast cell leukemia. 

Diagnosis

The World Health Organization (WHO) established diagnostic criteria for systemic mastocytosis in which the diagnosis requires meeting either one major and one minor criterion or three minor criteria. Major SM criteria includes multifocal dense aggregates of mast cells (≥15 mast cells per aggregate) seen in bone marrow biopsy specimens. The minor SM criteria is when more than 25% of all mast cells are atypical cells (type I or II) on bone marrow smears, a KIT point mutation at codon 816 is detected in the bone marrow, Mast cells exhibit CD2 and/or CD25, or the baseline serum tryptase level is >20 ng/mL. 

The initial assessment should prioritize diagnosing the condition and establishing its clonal origin. A thorough medical history is essential in this process. It’s important to note any previous episodes of anaphylaxis that required the administration of epinephrine due to specific foods, medications, or other triggers.

Bone marrow biopsy is the most important diagnostic test for systemic mastocytosis (SM). Blood tests, including complete blood cell counts, can reveal abnormalities such as anemia, leukocytosis (elevated white blood cell count), and thrombocytopenia. Additionally, elevated levels of histamine, hypoalbuminemia, and increased serum tryptase levels may be observed. Imaging studies may assist in assessing the disease’s extent and stage. Biopsies of affected organs like the skin and liver, as well as genetic testing, are also commonly conducted.

 Signs and Symptoms

Systemic mastocytosis (SM) impacts several organ systems due to the release of vasoactive mediators. Symptoms vary based on the affected organs since mast cells have the ability to accumulate in the liver, spleen, bone marrow, and small intestine of individuals with SM. Due to this, signs and symptoms of SM may include anemia, bleeding manifestations, abdominal pain, nausea, diarrhea, vomiting, hives, skin flushing, itching, anaphylactoid reactions, enlarged liver (hepatomegaly), enlarged spleen (splenomegaly), and swollen lymph nodes (lymphadenopathy).

 Disease Management and Treatment

Treatment for systemic mastocytosis (SM) is tailored to each patient’s clinical presentation. Medications such as antihistamines, proton pump inhibitors, epinephrine, steroids, mast cell stabilizers, and bisphosphonates are prescribed based on the specific symptoms the patient is displaying. This can include skin and gastrointestinal issues, increased stomach acid, anaphylactic reactions, malabsorption problems, and bone pain.

Several therapies have been approved for treating SM. Avapritinib (Ayvakit®) is FDA approved for advanced systemic mastocytosis (AdvSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Midostaurin (Rydapt®) has also been FDA-approved for adult patients with advanced SM. 2-Chlorodeoxyadenosine (2-CdA) shows efficacy across all SM subtypes, with response rates generally comparable to midostaurin. Interferon alfa is effective in alleviating symptoms related to histamine release in various SM subtypes, addressing dermatologic, hematologic, gastrointestinal, and systemic symptoms. Imatinib mesylate (Gleevec™) is FDA-approved specifically for adult patients with aggressive SM lacking the KIT D816V mutation or with an unknown KIT mutational status. Ripretinib (DCC-2618) is currently under investigation as a potential treatment for aggressive systemic mastocytosis.