Systemic Mastocytosis (SM)


Several experimental therapies are currently being investigated in patients with systemic mastocytosis (SM). 


Midostaurin (Rydapt®), also known as PKC412, is an orally active multikinase inhibitor that was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). The drug blocks the kinase activity of the receptor tyrosine kinase protein KIT and inhibits the immunoglobulin E (IgE)-dependent secretion of mediators in vitro.1

The FDA approval was based on the results of an open-label, single-arm phase 2 study (NCT00782067)2 of 116 patients with advanced SM treated with midostaurin. The patients demonstrated an overall 60% response rate, and 45% of them had a major response, defined as complete resolution of at least one type of mastocytosis-related organ damage. In addition, midostaurin reduced mast cell (MC) infiltration of bone marrow and lowered serum tryptase levels.3 In a follow-up study of these patients, midostaurin treatment substantially improved health-related quality of life and MC mediator-related symptoms.

The positive response to midostaurin treatment in patients with advanced SM prompted further studies to assess the efficacy of midostaurin in patients with indolent systemic mastocytosis (ISM). A small, open-label, nonrandomized phase 2 study (NCT01920204) of 20 patients with ISM or smoldering SM (SSM) treated with midostaurin demonstrated a significant decrease in symptoms and a reduction in serum tryptase levels. Nausea was the most common adverse event, reported in 80% of patients.5


Avapritinib (Ayvakit™) is a small-molecule drug that selectively targets the tyrosine kinases KIT and platelet-derived growth factor receptor-alpha (PDGFRA), with high potency for the KIT D816V mutation. It has been approved for the treatment of patients with unresectable gastrointestinal stromal tumors  (GISTs) and PDGFRA exon 18 mutations and is currently being studied for mastocytosis.6 The phase 1 Explorer trial in patients with advanced SM reported an overall response rate of 77%.7 In an interim analysis of an ongoing phase 2 study (NCT03580655)8 of patients with advanced SM (ASM, SM-AHN, or MCL), avapritinib treatment was well tolerated and resulted in an overall response rate of 75%, with reductions in serum tryptase levels and bone marrow MC burden.9

A 3-part phase 2 study (NCT03731260)10 is evaluating the safety and efficacy of avapritinib in patients with ISM or SSM. In initial data from the study, patients exhibited a substantial reduction in serum tryptase levels.11 Skin biopsy revealed a reduction in  cutaneous lesions in SM.12


Mastinib is a highly efficient and selective oral tyrosine kinase inhibitor that controls MC activity via inhibition of the c-Kit and Lyn and Fyn kinase signaling pathways; thus, it is of potential benefit in SM therapy. This drug has a higher affinity for wild-type KIT than for D816V-mutated KIT. Therefore, mastinib treatment is recommended primarily to improve quality of life rather than to preferentially eliminate D816V mutation-bearing MCs.

In 2010, a phase 2 study assessed the safety and efficacy of masitinib for the treatment of ISM with related handicap (ie, disabilities associated with flushes, depression, pruritus, and poor quality of life) in 25 patients in whom the D816V mutation was absent in at least one affected organ. The study revealed an overall response rate in 56% of patients, with continuous improvement through an extension phase (>60 weeks).13

A multicenter, randomized, double-blind, placebo-controlled phase 3 study (NCT00814073)14 enrolled 135 patients with severely symptomatic ISM or SSM across 15 countries. In this study, 18.7% of the patients had a major response (defined as a >75% decrease from baseline in pruritus, flushing, depression, or fatigue). The medication was well tolerated; diarrhea (4%) and urticaria (2%) were the most frequent serious adverse effects.15

CGT9486 (PLX9486)

CGT9486 (also known as PLX9486) is a selective tyrosine kinase inhibitor (TKI) with activity against activating KIT mutations. In vitro, CGT9486 demonstrated potent inhibition of the growth of BaF3 cells bearing the D816V mutation. Further, CGT9486 demonstrated the ability to reduce tumor burden significantly in a patient-derived GIST xenograft model involving activating KIT mutations.16

An open-label, multicenter phase 2 study (NCT04996875) is currently recruiting approximately 140 patients with advanced SM (ASM, SM-AHN, or MCL) to assess the safety and efficacy of treatment with orally administered CGT9486. The study is in 2 parts: a dose confirmation part and a dose expansion part. It is expected to be completed in September 2025.17

A randomized, double-blind, placebo-controlled phase 2 study (NCT05186753) is currently recruiting patients with non-advanced SM (ISM or SSM) to assess the safety and efficacy of CGT9486 in addition to best supportive care. The study will comprise 3 parts. The recommended dose will be selected in part 1. In part 2, patients will be randomly assigned to the selected dose of CGT9486 or to placebo. The patients who complete part 1 or part 2 may participate in part 3, in which all patients will receive CGT9486. The study is expected to be completed in November 2026.18

Ripretinib (DCC-2618)

Ripretinib (Qinlock®, DCC-2618) is a potent switch-control type II kinase inhibitor that broadly inhibits several receptor tyrosine kinases, including PDGFRA and KIT. It strongly inhibits exon 17 KIT mutations that are refractory to conventional, currently marketed KIT inhibitors. It works by “locking” the KIT protein into an inactive, nonsignaling conformation that interferes with the KIT signaling pathway and prevents MC activation. Ripretinib has been shown to inhibit activation loop mutations in KIT and PDGFRA.19 DCC-2618 has also been shown to be a potent inhibitor of multiple KIT mutations that cause SM and of several different activating exon 17 mutations.20

In vitro, DCC-2618 inhibits the activation, survival, and growth of multiple cell types involved in advanced SM. It prevents the proliferation and survival of neoplastic MCs from patients with advanced SM (ASM or MCL). In addition, DCC-2618 was found to suppress the growth and survival of primary neoplastic eosinophils obtained from patients with SM. DCC-2618 also decreased mediator release after IgE activation.21

An ongoing open-label, multicenter phase 1 (NCT02571036) dose escalation study is evaluating the safety, pharmacokinetics, and efficacy of orally administered DCC-2618 in patients with advanced SM (ASM, SM-AHN, or MCL).22

Tagraxofusp (SL-401)

Tagraxofusp (Elzonris®) is an engineered molecule in which diphtheria toxin is covalently attached to a portion of the cytokine interleukin 3. The drug binds to the beta chain of the interleukin 3 receptor (CD123), which is expressed on neoplastic MCs and mediates endocytosis.16 Once the drug is taken up via binding to CD123, the toxic part is released and induces cytotoxicity through protein inhibition.23

A study of a small cohort of 58 patients with SM aimed to define CD123 expression patterns and their clinical significance. The study found that CD123 was expressed in 61% of patients with ISM, 100% of patients with ASM, and 57% of patients with SM-AHN.24

Lirentelimab (AK002)

Lirentelimab is a novel humanized immunoglobulin G1 (IgG1) monoclonal antibody targeted against Siglec-8, which is an inhibitory receptor selectively expressed on MCs and eosinophils. Lirentelimab binding to Siglec-8 may trigger the inhibition of MCs and apoptosis of eosinophils.25

In 2019, a phase 1 study of 12 patients with ISM demonstrated that AK002 therapy resulted in a substantial decrease in skin, gastrointestinal, neurologic, and musculoskeletal symptoms. Further, the study reported a significant improvement in patients’ quality of life.26


  1. Valent P, Akin C, Hartmann K, et al. Midostaurin: a magic bullet that blocks mast cell expansion and activation. Ann Oncol. 2017;28(10):2367-2376. doi:10.1093/annonc/mdx290
  2. Efficacy and Safety of Midostaurin in Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia. October 13, 2008. Completed August 14, 2017.
  3. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374(26):2530-2541. doi:10.1056/NEJMoa1513098
  4. Hartmann K, Gotlib J, Akin C, et al. Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis. J Allergy Clin Immunol. 2020;146(2):356-366.e4. doi:10.1016/j.jaci.2020.03.044
  5. van Anrooij B, Oude Elberink JNG, Span LFR, et al. Midostaurin in patients with indolent systemic mastocytosis: an open-label phase 2 trial. J Allergy Clin Immunol. 2018;142(3):1006-1008.e7. doi:10.1016/j.jaci.2018.06.003
  6. Heinrich MC, Jones RL, von Mehren M, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020;21(7):935-946. doi:10.1016/S1470-2045(20)30269-2
  7. Deininger MW, Gotlib JR, Robinson WA. Clinical activity in a phase 1 study of BLU285, a potent, highly-selective inhibitor, of KIT D816V in advanced systemic mastocytosis (AdVSM). Blood. 2017;130(Suppl 1):2. Accessed May 3, 2022.
  8. (PATHFINDER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis. July 9, 2018. Updated March 28, 2022. Accessed May 3, 2022.
  9. Gotlib J, Reiter A, Radia DH, et al. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med. 2021;27(12):2192-2199. doi:10.1038/s41591-021-01539-8
  10. (PIONEER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Indolent Systemic Mastocytosis. November 6, 2018. Updated February 2, 2022. Accessed May 3, 2022.
  11. Akin C, Oude Elberink H, Gotlib JR, et al. Results from Pioneer: a randomized, double-blind, placebo-controlled, phase 2 study of avapritinib in patients with indolent systemic mastocytosis. Paper presented at: 62nd ASH Annual Meeting and Exposition, December 2020; New Orleans, LA. Abstract 1248.
  12. George TI, Broesby-Olsen S, Wada D, et al. Changes in mast cell numbers and phenotype in patients with indolent systemic mastocytosis treated with avapritinib. Poster presented at: AACR 2021, April 9-14, 2021, Virtual Format.
  13. Paul C, Sans B, Suarez F, et al. Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. Am J Hematol. 2010;85(12):921-925. doi:10.1002/ajh.21894
  14. Masitinib in Severe Indolent or Smoldering Systemic Mastocytosis. December 23, 2008. Updated December 3, 2019.
  15. Lortholary O, Chandesris MO, Bulai Livideanu C, et al. Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. Lancet. 2017;389(10069):612-620. doi:10.1016/S0140-6736(16)31403-9
  16. Gebreyohannes YK, Burton EA, Wozniak A, et al. PLX9486 shows anti-tumor efficacy in patient-derived, tyrosine kinase inhibitor-resistant KIT-mutant xenograft models of gastrointestinal stromal tumors. Clin Exp Med. 2019;19(2):201-210. doi:10.1007/s10238-018-0541-2
  17. (Apex) CGT9486 in Patients With Advanced Systemic Mastocytosis. August 9, 2021. Updated February 2, 2022.
  18. (Summit) A Study to Evaluate the Efficacy and Safety of CGT9486 Versus Placebo in Patients With Indolent or Smoldering Systemic Mastocytosis. January 11, 2022. Updated April 18, 2022.
  19. 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
  20. Smith BD, Hood MM, Wise SC, et al. DCC-2618 is a potent inhibitor of wild-type and mutant KIT, including refractory exon 17 D816 KIT mutations, and exhibits efficacy in refractory GIST and AML xenograft models. Cancer Res. 2015;75(15_Supplement):2690. doi:10.1158/1538-7445.AM2015-2690
  21. Schneeweiss M, Peter B, Bibi S, et al. The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis. Haematologica. 2018;103(5):799-809. doi:10.3324/haematol.2017.179895
  22. A Safety, Tolerability and PK Study of DCC-2618 in Patients With Advanced Malignancies. October 8, 2015. Updated April 20, 2021.
  23. 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
  24. Collier RJ. Diphtheria toxin: mode of action and structure. Bacteriol Rev. 1975;39(1):54-85. doi:10.1128/br.39.1.54-85.1975
  25. Pardanani A, Reichard KK, Zblewski D, et al. CD123 immunostaining patterns in systemic mastocytosis: differential expression in disease subgroups and potential prognostic value. Leukemia. 2016;30(4):914-918. doi:10.1038/leu.2015.348
  26. Siebenhaar F, Bonnekoh H, Hawro T, et al. Safety and efficacy data of AK002, an anti-Siglec-8 monoclonal antibody, in patients with indolent systemic mastocytosis (ISM): results from a first-in-human, open-label phase 1 study. Available at: Accessed May 3, 2022.

Reviewed by Hasan Avcu, MD, on 5/2/2022.