Systemic Mastocytosis (SM)

Systemic mastocytosis is a rare hematological neoplasm characterized by the overproliferation of mast cells, a type of white blood cell originating in the bone marrow. These mast cells accumulate in the connective tissues of various organ systems including the skin, digestive tract, liver, spleen, bones, and lungs.1,2 

When activated by an allergen, mast cells release a variety of chemical inflammatory mediators, especially histamine, to aid the immune system in fighting off the perceived threat, causing skin flushing and itching, digestive complaints, and other symptoms of an allergic reaction. If released in large quantities, these mediators may result in serious side effects, particularly low blood pressure and anaphylaxis.2 

Past Clinical Trials

Completed trials have evaluated interventions for systemic mastocytosis, including everolimus, imatinib mesylate, ontak, PA101, AK002, brentuximab vedotin, masitinib, midostaurin, avapritinib, stem cell transplantation, tanespimycin, thalidomide, and nilotinib.3

Current Clinical Trials

Ongoing trials are evaluating or will evaluate interventions for systemic mastocytosis, including masitinib, sarilumab, avapritinib, denosumab, BLU-263, CGT9486, hydroxychloroquine, DCC-2618, SL-401, and flotetuzumab.3

Masitinib is a tyrosine kinase inhibitor affecting the c-Kit pathway. It regulates the binding of the stem cell factor that causes the overproliferation of mast cells. Masitinib is used as an antineoplastic agent to target mast cell tumors.4

Sarilumab is a human anti-interleukin 6 receptor α (anti-IL-6Rα) monoclonal antibody developed to treat adults with moderate to severe rheumatoid arthritis.5,6 Researchers conducting a randomized, double-blinded controlled phase 2 clinical trial are evaluating whether subcutaneous sarilumab might benefit individuals with indolent systemic mastocytosis.7

Avapritinib (Ayvakit™) is a prescription medication developed to treat individuals with advanced systemic mastocytosis.8 It is a tyrosine kinase inhibitor that selectively inhibits KIT D816V, which causes approximately 95% of cases of systemic mastocytosis.9 Although one trial has already been completed and another has gained approval for marketing, 3 clinical trials are active, but not recruiting, to further evaluate the efficacy of avapritinib for advanced systemic mastocytosis.10

Denosumab is an injectable monoclonal antibody classified as a RANK ligand inhibitor that prevents bone loss by blocking a receptor to inhibit osteoclastic activity, and it blocks another receptor to inhibit tumor growth.11 Researchers in one clinical trial intend to investigate the efficacy of denosumab in the treatment of osteoporosis caused by systemic mastocytosis, but they are not currently recruiting for their active trial.12

BLU-263 is a next-generation tyrosine kinase inhibitor that selectively inhibits KIT D816V and is currently undergoing rigorous investigation in a phase 2/3 clinical trial evaluating its safety and efficacy in individuals with indolent systemic mastocytosis or monoclonal mast cell activation syndrome.13

CGT9486, also known as bezuclastinib, is a selective KIT D816V inhibitor that demonstrates minimal brain penetration and is currently under investigation for its efficacy in treating advanced systemic mastocytosis. Other clinical trials have been planned to evaluate its efficacy in treating nonadvanced systemic mastocytosis as well as imatinib-resistant gastrointestinal stromal tumors (GISTs).14

Hydroxychloroquine is an immunosuppressant originally intended to treat and prevent malaria and certain autoimmune conditions such as rheumatoid arthritis and some forms of lupus; it has also recently undergone scrutiny in its potential treatment of coronavirus disease 2019 (COVID-19).15 Researchers in one clinical trial are not yet recruiting for their study, which will investigate the efficacy of hydroxychloroquine in isolated cutaneous mastocytosis patients or patients with indolent systemic mastocytosis with associated skin involvement.16 

DCC-2618, also known as ripretinib, is a broad-spectrum, oral, switch-control kinase inhibitor originally developed to treat GISTs through the inhibition of KIT and PDGFRA gene mutations.17,18 An active, but not yet recruiting, clinical trial has been registered to assess the tolerability, safety, and pharmacokinetics of DCC-2618 in patients with advanced malignancies, including advanced forms of systemic mastocytosis.19

SL-401 is an antineoplastic agent targeting interleukin 3 receptors that was originally developed to treat patients with blastic plasmacytoid dendritic cell neoplasms.20 SL-401 inhibits the growth of cancer stem cells and has also been studied in hematological malignancies.21,22 The Mayo Clinic is currently enrolling participants for a phase 2 open-label, multicenter clinical trial studying the effects of SL-401, also known as tagraxofusp, on individuals with systemic mastocytosis.23

Flotetuzumab is a monoclonal antibody that inhibits cancer growth and metastasis. Researchers are currently recruiting for a phase 1 clinical trial analyzing the potential of flotetuzumab to treat patients with advanced CD123-positive hematological malignancies, including systemic mastocytosis.24 


  1. Systemic mastocytosis. MedlinePlus. Updated August 18, 2020. Accessed April 21, 2022. 
  2. Systemic mastocytosis – symptoms and causes. Mayo Clinic. November 20, 2020. Accessed April 21, 2022.
  3. Search of: systemic mastocytosis. Accessed April 21, 2022.
  4. Masitinib – an overview. ScienceDirect. Accessed April 21, 2022. 
  5. Sarilumab (Kevzara®) drug information sheet. Johns Hopkins Arthritis Center. Accessed April 21, 2022.
  6. Huizinga TWJ, Fleischmann RM, Jasson M, et al. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY part A trial. Ann Rheum Dis. 2014;73(9):1626-1634. doi:10.1136/annrheumdis-2013-204405
  7. Safety and efficacy of subcutaneous sarilumab in improving the quality of life in people with indolent systemic mastocytosis. December 10, 2018. Updated April 21, 2022. Accessed April 21, 2022.
  8. Ayvakit™ (avapritinib tablets). Blueprint Medicines. Accessed April 21, 2022. 
  9. Ayvakit™ (avapritinib tablets) – for U.S. healthcare professionals only. Blueprint Medicines. Accessed April 21, 2022.
  10. Search of: avapritinib | systemic mastocytoses. Accessed April 21, 2022.
  11. Denosumab injection. MedlinePlus. Updated March 25, 2022. Accessed April 21, 2022. 
  12. Interest of denosumab treatment in osteoporosis associated to systemic mastocytosis (DenosuMast). January 17, 2018. Updated April 14, 2021. Accessed April 21, 2022.
  13. Castells M, Si TD, Bhavsar V, He K, Akin C. A phase 2/3 study of BLU-263 in patients with indolent systemic mastocytosis or monoclonal mast cell activation syndrome. J Allergy Clin Immunol. 2022;149(2):AB221. doi:10.1016/j.jaci.2021.12.721
  14. Guarnieri A, Chicarelli M, Cable L, et al. Preclinical data with KIT D816V inhibitor bezuclastinib (CGT9486) demonstrates high selectivity and minimal brain penetrance. Blood. 2021;138(Supplement 1):4595. doi:10.1182/blood-2021-152770
  15. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. US Food and Drug Administration (FDA). Updated July 1, 2020. Accessed April 21, 2022.
  16. Hydroxychloroquine in isolated cutaneous mastocytosis patients or indolent systemic mastocytosis with associated skin involvement patients (HCQMa). October 20, 2021. Accessed April 21, 2022.
  17. Ripretinib. Deciphera Pharmaceuticals, Inc. Accessed April 21, 2022. 
  18. Smith BD, Kaufman MD, Lu WP, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019;35(5):738-751.e9. doi:10.1016/j.ccell.2019.04.006
  19. A safety, tolerability, and PK study of DCC-2618 in patients with advanced malignancies. October 8, 2015. Updated April 20, 2021. Accessed April 21, 2022. 
  20. Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood. 2014;124(3):385-392. doi:10.1182/blood-2014-04-566737
  21. SL-401 in combination with azacitidine or azacitidine/venetoclax in acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS) or blastic plasmacytoid dendritic cell neoplasm (BPDCN). April 13, 2017. Updated November 2, 2021. Accessed April 21, 2022.
  22. Alkharabsheh O, Frankel AE. Clinical activity and tolerability of SL-401 (tagraxofusp): recombinant diphtheria toxin and interleukin-3 in hematologic malignancies. Biomedicines. 2019;7(1):6. doi:10.3390/biomedicines7010006
  23. SL-401 in advanced, high risk myeloproliferative neoplasms (systemic mastocytosis, advanced symptomatic hypereosinoophic disorder, chronic myelomonocytic leukemia). Mayo Clinic. Accessed April 21, 2022. 
  24. Flotetuzumab for the treatment of relapsed or refractory advanced CD123-positive hematological malignancies. December 23, 2020. Updated November 3, 2021. Accessed April 21, 2022.

Reviewed by Kyle Habet, MD, on 4/21/2022.