Systemic Mastocytosis (SM)

Systemic mastocytosis (SM) is a rare disease characterized by a clonal expansion of neoplastic mast cells, which accumulate in the skin and several organs, including the liver and spleen.^1,2 The signs and symptoms of SM depend on which organs are affected and may include anemia, itching, hives, gastrointestinal issues, hepatomegaly, and splenomegaly.³ 

Patients with SM typically have mutations in the active domain of the KIT gene; the most common of these is the D816V mutation on exon 17 of KIT.¹ The KIT oncogene codes for the stem cell factor receptor KIT, which is a transmembrane tyrosine kinase protein involved in the differentiation and proliferation of mast cells.¹ In SM, the activation of KIT results in continuous downstream signaling and the excessive production of mast cells, which in turn accumulate in organs.³ Patients with advanced disease may have SM with an associated hematologic non-mast cell neoplasm, aggressive SM, or mast cell leukemia.⁴

Gleevec^® is a prescription medicine developed by Novartis that is indicated for the treatment of adults with aggressive SM who do not carry the KIT D816V mutation or whose KIT mutational status is unknown.⁵ 

Gleevec Mechanism of Action, Use, and Precautions

The active ingredient in Gleevec is imatinib mesylate, a small ATP-competitive tyrosine kinase inhibitor.^5,6 The main mechanism of action of imatinib mesylate is to inhibit the BCR-ABL tyrosine kinase associated with chronic myeloid leukemia, interfering with cellular proliferation and inducing apoptosis.^1,5 Imatinib mesylate also inhibits the receptor tyrosine kinase for platelet-derived growth factor (PDGF) and the stem cell factor receptor KIT, as well as PDGF- and SCF-mediated cellular events.¹ 

Imatinib mesylate can inhibit the proliferation of mast cells in patients with wild-type KIT or KIT mutations such as V560G, F522C, K509I, and p.419del. Patients with a D816V KIT mutation are naturally resistant to imatinib treatment because of a conformational change in the enzymatic pocket that does not favor drug-receptor binding.¹

The recommended dose of Gleevec for patients with aggressive SM is 400 mg/d, taken orally with a meal and a large glass of water. For patients presenting with aggressive SM and eosinophilia, the recommended dose for the initiation of treatment is 100 mg daily.⁵

The use of Gleevec is associated with edema and fluid retention. Cytopenia, congestive heart failure, hepatotoxicity, kidney dysfunction, and bleeding may also occur. This drug can harm an unborn child, so pregnant women should not be treated with Gleevec. Common side effects of treatment include edema, abdominal pain, vomiting, diarrhea, nausea, fatigue, and rash.⁵

Get full prescribing information for Gleevec on MPR

Imatinib Mesylate in Clinical Studies

The U.S. Food and Drug Administration (FDA) approved imatinib mesylate for the treatment of aggressive SM in 2006.¹ Approval was based on the analysis of single case reports and small series of patients with SM treated with the drug.^1,5 

In an early report, 12 patients with symptomatic mast cell disease were prospectively treated with 100 to 400 mg of imatinib mesylate. Of the 10 patients who could be assessed for a response, 5 had a measurable response to treatment.⁷ Significant mast cell cytoreduction occurred in 4 of the 5 patients, and complete clinical and histological remission in 2. Of the 5 patients presenting with eosinophilia, 3 had a complete clinical and hematological remssion. Two patients in this study had a D816V mutation and did not respond to imatinib.⁷ In addition, a prospective open-label phase 2 clinical study was performed that included 20 patients with SM who received 400 mg of Gleevec once a day.⁶ In this study, 6 patients experienced symptom relief, and 1 patient had a complete remission. Also in this study, patients with a D816V mutation did not derive significant clinical benefit from treatment with imatinib.⁶

A few studies have reported responses to imatinib mesylate in patients with a KIT D816V mutation.^8,9 The differences in the results of published studies require further clarification. In a more recent study, which included 10 patients with SM and no exon 17 KIT mutations, 5 of the patients were sensitive to imatinib. This study also highlighted the potential clinical relevance of imatinib-sensitive mutations involving KIT or PDGFR to successful treatment with imatinib, as opposed to absence of the KIT D816V mutation.¹⁰

References

1. Piris-Villaespesa M, Alvarez-Twose I. Systemic mastocytosis: following the tyrosine kinase inhibition roadmap. Front Pharmacol. 2020;11:443. doi:10.3389/fphar.2020.00443

2. Gilreath JA, Tchertanov L, Deininger MW. Novel approaches to treating advanced systemic mastocytosis. Clin Pharmacol. 2019;11:77-92. doi:10.2147/CPAA.S206615

3. Systemic mastocytosis. Genetic and Rare Diseases Information Center (GARD). Accessed April 18, 2022.

4. 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

5. Gleevec. Highlights of prescribing Information. Novartis. Revised March 2022.

6. Vega-Ruiz A, Cortes JE, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2009;33(11):1481-1484. doi:10.1016/j.leukres.2008.12.020

7. Pardanani A, Elliott M, Reeder T, et al. Imatinib for systemic mast-cell disease. Lancet. 2003;362(9383):535-536. doi:10.1016/s0140-6736(03)14115-3.

8. Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL. Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer. 2006;107(2):345-51. doi:10.1002/cncr.21996

9. Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol. 2009;84(12):790-794. doi:10.1002/ajh.21561

10. Alvarez-Twose I, Matito A, Morgado JM, et al. Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature. Oncotarget. 2016;8(40):68950-68963. doi:10.18632/oncotarget.10711

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

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.