Smoldering Systemic Mastocytosis Without Detectable KIT Mutation: A Debilitating Course and Therapeutic Challenge

ABSTRACT Systemic mastocytosis (SM) is a clonal hematologic neoplasm driven by activating KIT mutations, particularly D816V. Indolent SM typically follows a stable course, progression to higher‐burden subtypes is uncommon. However, management of KIT‐negative disease remains poorly defined. We describe rare and clinically challenging case of KIT‐negative indolent systemic mastocytosis progressing to smoldering systemic mastocytosis (SSM) with progressive symptoms and limited treatment options. A female in her 30s with almost 10 years history of indolent SM developed progressive constitutional symptoms, gastrointestinal distress, diffuse pain, and worsening cutaneous lesions. Serum tryptase nearly doubled from 46.2 ng/mL to 88.5 ng/mL. Repeat bone marrow biopsy demonstrated marked disease progression with 40% mast cell infiltration (CD117+, CD25+), compared to 5%–10% at initial diagnosis. Imaging revealed mediastinal lymphadenopathy. Molecular testing was negative for KIT D816V and other KIT mutations. She was diagnosed with smoldering systemic mastocytosis, was managed symptomatically with antihistamines, antiemetics, cromolyn sodium and an epinephrine auto‐injector for anaphylaxis control. Despite maximal anti‐mediator therapy, symptoms remained severe: persistent nausea, vomiting, bone pain, dizziness, skin lumps, skin rash and generalized discomfort. Omalizumab was initiated for refractory mediator‐related symptoms but was discontinued because of treatment‐associated anaphylaxis. Given the absence of detectable D816V mutation, imatinib was initiated and was associated with reduced epinephrine use and stabilization of cutaneous disease. This case highlights several clinically relevant considerations: nonadvanced SM subtypes may carry substantial morbidity, progression can occur even without detectable KIT mutations, and therapeutic decisions in mutation‐negative disease require individualized molecular and clinical reassessment. As targeted therapies increasingly shape mastocytosis treatment algorithms, improved understanding of therapeutic responsiveness in KIT‐mutation–negative SSM is essential to optimize management and avoid treatment delays in symptomatic patients.