Successful Management of D816V Mutated c-KIT Systemic Mastocytosis with Chronic Imatinib: A Case Report

First characterized in France in 1936, systemic mastocytosis (SM) is a rare disorder by an excessive proliferation and accumulation of abnormal mast cells in extracutaneous tissues (Nettleship et al., 1869). The release of large quantities of vasoactive mediators by these cells results in allergic- and anaphylactic-type reactions in one or more organ systems. Given the similarity of symptoms between allergic reactions and SM and the rarity of the condition, SM is often missed and misdiagnosed (Schwaab et al., 2020). Once considered a subtype of myeloproliferative neoplasms, mastocytosis was reclassified in the 2016 revision to the World Health Organization (WHO) due to advances in understanding of the disorder (Arber, et al., 2016). Presented below is a case of a severe systemic mastocytosis with an initially positive D816V mutated c-kit successfully managed with long-term imatinib use alongside intermittent bone marrow biopsies (BMB) to monitor what is now an indolent systemic mastocytosis.

69 year-old female with a past medical history of paroxysmal atrial fibrilation, hashimoto's thyroiditis, metabolic syndrome, and gastro-esophageal reflux (GERD) presents to clinic for routine management of what was previously severe systemic mastocytosis (SSM) and now is indolent systemic mastocytosis with the help of imatinib. To help control her ISM her medications include a daily histamine-1 blocker (ranitidine), a daily histamine-2 blocker (diphenhydramine), and a twice-daily histamine-1 antagonist (cetirizine). Originally evaluated in 2005 with a bone marrow biopsy (BMB) and found to have a Asp816Val (D816V) c-kit mutation, she was placed on imatinib with significant clinical improvement. This seemed to support that the D816V mutation may cause constitutional activation of the c-kit transmembrane protein and thus sensitivity to imatinib therapy. This despite the FDA labeling for imatinib as only to be used in SM patients without the common D816V mutation or for whom the mutational status is unknown (Reference ID: 4957210, 2001). Interestingly, after being placed on imatinib her repeat bone marrow biopsies in 2011 and 2015 indicated that the D816V mutation was no longer present in her CD117 positive mast cells but continued to benefit from imatinib therapy. This finding is suggestive of two unique mast cell populations as imatinib continued to help maintain a low tryptase level and decrease the severity of reactions. When reactions did occur, she treated them at one point with a cocktail of an histamine-2 blocker (ranitidine), histamine-1 blocker (diphenhydramine), and a mast cell stabilizer (cromolyn) and without requiring the use of epinephrine. As a part of her longitudinal observation, she received an additional BMB in 2022 that revealed a minimal residual monocytosis that persisted with less than 10% nucleated cells, an age-appropriate trilinear hematopoiesis, decreased iron stores without ringed sideroblast formation. Flow cytometry was indicative of a typical female karyotype with the population of aberrant mast cells that is consistent with the diagnosis of ISM. Importantly, no abnormalities were detected in the FLT3, IDH1, IDH2, NPM1 genes which, if abnormal, could obfuscate the apparent efficacy of imatinib treatment in the management of SM. Given the dearth of mastocytosis in the BMB and the absence of ongoing end-organ damage, the patient meets the definition of ISM. After the most recent BMB the patient altered her daily regimen due to gastric upset and found she could take of her histamine-1 blocker (diphenhydramine) once daily along with a twice daily regimen of her imatinib (split into two smaller daily doses), histamine-1 antagonist (cetirizine), her histamine-2 antagonist (famotidine), and citalopram (selective serotonin reuptake inhibitor or SSRI) with improved symptomatic control to this day.

This case serves to illustrate the diagnostic and therapeutic challenges associated with SM, as well as the potential therapeutic use of imatinib in patients with D816V outside of its original FDA indication. Further characterization of the effect of imatinib on D816V mutated SM may warrant the consideration of expanding the FDA indications for imatinib as its role and efficacy outside of solely D816V negative c-kit MS.