Tyrosine kinase inhibitors (TKIs) have emerged as an attractive therapeutic option in systemic mastocytosis (SM). When compared with conventional cytoreductive therapy, which has been used in patients with advanced mastocytosis, TKIs show improved tolerability and efficacy and fewer adverse effects.

Though no TKI is currently approved by the US Food and Drug Administration (FDA) for the treatment of indolent SM (ISM), the most common variant of SM, several show great potential. Here we address the role of TKIs in ISM treatment as discussed by Akin et al in the Journal of Allergy and Clinical Immunology.

Most patients with typical ISM have the KIT D816V mutation. In fact, KIT D816V has been proposed as the primary driver of disease evolution and mast cell expansion in both ISM and smoldering SM (SSM). This somatic gain-of-function mutation can be found in neoplastic mast cells and it is responsible for the proliferation, differentiation, and expansion of immature mast cell progenitor cells, as well as the maturation and resistance to apoptosis of mature mast cells.

KIT D816V Inhibitors

Dasatinib (Sprycel®), an SRC/ABL inhibitor approved to treat chronic myeloid leukemia and acute lymphocytic leukemia, has shown activity against imatinib-resistant forms of the BCR-ABL fusion gene. It also inhibited wild-type (WT) and D816V-mutated forms of KIT in vitro. However, there is a lack of meaningful clinical response in D816V KIT+ patients which, together with the high rate of adverse events (including pleural effusions, hematologic toxicities, and headaches), renders dasatinib unsuitable for most people with SM.

Learn more about SM treatment

Midostaurin (Rydapt®) is a multitargeted inhibitor of several kinases, including WT and D816V KIT. Results from 2 studies suggest it is effective in reducing mast cell mediator-related symptoms and skin lesions in ISM. The most common adverse events were nausea and vomiting. Despite its efficacy, the high rate of gastrointestinal toxicity might restrict its use in ISM patients.

Avapritinib (Ayvakit®) is an FDA-approved selective inhibitor of KIT D816V. It shows superior efficacy in inducing disease remission compared to midostaurin (75% vs 17%) based on data from 2 clinical trials. However, it showed some considerable adverse events in patients with advanced SM, such as intracranial bleeding in patients with thrombocytopenia (platelet counts <50,000/mL), neurocognitive alterations, peripheral and periorbital edema, diarrhea, nausea, and cytopenias.

Avapritinib is being evaluated in ISM in a double-blind, placebo-controlled trial. “Over the next several years, one may anticipate finalized, peer-reviewed, and formally published data for this agent in both advanced systemic and indolent mastocytosis,” Below and Michaelis wrote in 2021.

For what is known hitherto, patients in the treatment arm received either 25, 50, or 100 mg of the drug. At 16 weeks of therapy, patients experienced an average of 30% symptom reduction (3% in placebo). The most common adverse events included fluid retention, nausea, diarrhea, and headaches, but no intracranial bleedings were reported (it should be noted that patients enrolled in the study had normal platelet counts). One neurocognitive adverse event (grade 3) was observed in the cohort taking the highest dose. No grade 4 or 5 adverse events occurred.

Two additional KIT D816V inhibitors are being evaluated in ISM and advanced SM clinical settings: the next-generation investigational drug BLU-263 and bezuclastinib (formerly PLX9486). Results are only starting to be divulged, so their efficacy and safety require further investigation, but it is known that they do not penetrate the blood-brain barrier.

Bezuclastinib Clinical Trial for Systemic Mastocytosis Produces Positive Early Results

Other TKIs Relevant in ISM

Imatinib (Gleevec®), the first small-molecule tyrosine kinase inhibitor developed, targets different tyrosine kinases, including WT KIT, but not D816V-mutated KIT. Its use has been approved in adult patients with aggressive SM without the D816V KIT mutation or with unknown KIT mutational status. Therefore, imatinib is not an option for most patients with ISM.

Imatinib has been successfully applied in patients with KIT F522C and K509I mutations and FIP1L1-PDGFRA rearrangement. According to Akin et al, “Imatinib may be particularly effective in rare patients with noncodon 816 gain-of-function KIT mutations rather than those with WT KIT, although other case reports exist describing successful disease remission in patients with ISM and WT KIT.”

Masitinib targets WT KIT and also LYN and FYN. Results from a placebo-controlled phase 3 trial support its efficacy in improving mast cell activation symptoms, regardless of the KIT mutational status. The study reported a slight decrease in serum tryptase levels and improvement of skin lesions. Masitinib is currently undergoing another placebo-controlled phase 3 trial with ISM and SSM patients.

Learn about SM experimental therapies

Ripretinib (Qinlock®, DCC-2618), a switch-control type II kinase inhibitor with broad activity across multiple kinases, including PDGFRα and KIT, induced the apoptosis of neoplastic mast cells in vitro. It showed efficacy against neoplastic mast cells derived from patients with aggressive and multimutated SM. There is a registered trial (NCT02571036) to assess the safety, tolerability, and pharmacokinetics of ripretinib in patients with advanced malignancies, including advanced SM.

Considerations of TKI Therapy in ISM

In general, TKIs seem to be effective in improving mast cell activation symptoms and reducing skin lesions. The improvements observed required continuous exposure to the drug and vanished upon treatment discontinuation.

All patients should be carefully monitored during therapy, in particular for the possible occurrence of neurocognitive alterations, intracranial bleed, and gastrointestinal adverse effects.

The efficacy of TKI therapy in pediatric patients and patients with cutaneous mastocytosis remains unknown. “There is general agreement among experts that systemically administered TKIs are not indicated in pediatric-onset cutaneous mastocytosis, because most pediatric patients have a self-limited disease course as opposed to persistent nature of adult-onset SM,” Akin et al said.

Additionally, their efficacy in combination with other therapies, as well as potential effects on anaphylaxis and osteoporosis should be a focus of future studies.


Akin C, Arock M, Valent P. Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: are we there yet? J Allergy Clin Immunol. 2022;149(6):1912-1918. doi:10.1016/j.jaci.2022.04.020

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

Below S, Michaelis LC. Avapritinib in the treatment of systemic mastocytosis: an update. Curr Hematol Malig Rep. 2021;16(5):464-472. doi:10.1007/s11899-021-00650-4