Mast cells were first identified in 1878 by Paul Ehlrich when he observed that certain cells were stained with metachromatic dyes. We now understand mast cells to have their origin in bone marrow precursors; they are myeloid lineage cells that are derived from hematopoietic progenitors such as CD34+ and KIT+. 

Mastocytosis is 1 of 8 categories of myeloproliferative neoplasms identified according to the World Health Organization guidelines. It is a clonal myeloproliferative disorder derived from stem cells, characterized by the dysfunctional growth and accumulation of neoplastic mast cells in various organs in the body. 

The 8 classes of myeloproliferative neoplasms according to the World Health Organization are: 

  • Cutaneous mastocytosis. 
  • Indolent systemic mastocytosis (SM). 
  • Smoldering SM. 
  • SM with an associated clonal hematological nonmast cell lineage disease. 
  • Aggressive SM. 
  • Mast cell leukemia. 
  • Mast cell sarcoma.
  • Extracutaneous mastocytoma. 

In this article, we will be specifically looking at the current therapeutic landscape for indolent and smoldering and advanced SM. 

Indolent and Smoldering Systemic Mastocytosis 

“For many years, the treatment of mastocytosis was largely symptomatic and focused on mediator-release−related symptoms,” wrote Giannetti in the Annals of Allergy, Asthma & Immunology. 

Times have changed. Treatment today focuses on the use of antimediator therapy and cytoreductive therapy. These therapies are important and life-saving, considering that the typical disease course for SM results in increased mast cell infiltration and organ dysfunction and death. 

Although SM is best described as a spectrum of disorders, we can broadly divide the disease into indolent and smoldering on one hand and advanced on the other. With regard to indolent and smoldering SM, symptomatic control remains a primary therapeutic objective. 

“Management of indolent SM and smoldering SM is focused on the prevention and treatment of anaphylactic reactions and symptom control,” Buonomo and colleagues wrote in the Mediterranean Journal of Hematology and Infectious Disease.

Read more about SM treatment 

Let’s explore what this means, system by system. In the skin, symptoms such as flushing, angioedema, and urticaria are commonly reported. To relieve these symptoms, H1-antihistamines are used as first-line drugs. If they do not provide satisfactory symptomatic control, leukotriene antagonists are typically used next.

Gastrointestinal disease in indolent and smoldering SM includes vomiting, nausea, abdominal pain, diarrhea, and gastroesophageal reflux. The first-line choice of medications are H2-antagonists, which work by inhibiting gastric acid secretion. Proton-pump inhibitors are second-line drugs. 

Patients with indolent and smoldering SM may experience cardiovascular symptoms such as presyncope/syncope, tachycardia, and anaphylaxis. The prevalence of anaphylaxis in patients with SM is 100 times that of the general population; physicians should thus prescribe self-injectable epinephrine to patients and ensure that they know how to use the drug accurately. Acute episodes of anaphylaxis should be managed in an emergency setting. 

If all else fails, physicians have the option of using cytoreductive treatment for both indolent and smoldering SM. Cytoreductive treatment is not recommended unless antimediator therapy has failed. 

Advanced Systemic Mastocytosis 

According to Buonomo et al, the umbrella term of “advanced SM” includes aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia. A common feature of all these subtypes is organ damage related to mast cells, which reduces survival and tends to require cytoreductive treatment. 

“Until now, there is no curative option for patients with advanced SM,” Buonomo and colleagues wrote. 

What we do have are a constellation of drugs that are prescribed according to the individual needs of patients. They include imatinib mesylate, interferon alpha, cladribine, midostaurin, avapritinib, and allogeneic stem cell transplantation. 

Let’s take a look at two: imatinib mesylate, a tyrosine kinase inhibitor that is effective for bone marrow burden and constitutional symptoms; and interferon alpha, a cytokine that is effective for skin involvement, osteoporosis, and constitutional symptoms. 

Imatinib mesylate was the first drug approved by the Food and Drug Association (FDA) for patients with SM lacking the cKIT D816V mutation or with unknown cKIT mutational symptoms. Studies demonstrate that imatinib mesylate is more effective in patients with specific cKIT mutational status compared with those with true wild-type cKIT. 

Interferon alpha was historically the first treatment used for SM. An Austrian study demonstrated that a combination of interferon alpha and steroids among 5 patients resulted in 2 having completed resolution of C findings, 1 achieving partial improvement of C findings, 1 having stable disease, and 1 progressing to mast cell leukemia. 

“Despite recent advances and emerging therapeutics, there is still a considerable unmet need for the treatment of patients with systemic mastocytosis,” Giannetti wrote. 

Read more about SM therapies 

The main problem with the types of medications we currently have for SM is that their mechanisms of action provide insufficient symptomatic improvement and have unacceptable toxicity levels. This is true for therapies that block mast cell mediator release, as well as cytoreductive therapy for advanced subtypes of the disease. 

However, research into the therapeutic landscape of SM is constantly evolving our understanding of the disease, and scientists are proposing brilliant ways to manipulate key pathways of mast cell activation and proliferation that may yet prove to be more effective and safer in the long-term that our current arsenal of drugs.

References

Buonomo A, Nucera E, Criscuolo M. Treatment of indolent and advanced systemic mastocytosisMediterr J Hematol Infect Dis. 2022;14(1):e2022040 doi:10.4084/MJHID.2022.040

Giannetti MP. Treatment of systemic mastocytosis: novel and emerging therapiesAnn Allergy Asthma Immunol. 2021;127(4):412-419. doi:10.1016/j.anai.2021.06.021