Multirefractory pediatric advanced systemic mastocytosis and mast cell leukemia with a subsequently detected KIT N822K mutation: a case report

Mastocytosis is a rare clonal disorder characterized by the abnormal accumulation of mast cells (MCs) in one or more tissues and organs. It is categorized into cutaneous mastocytosis (CM), mast cell sarcoma (MCS), and systemic mastocytosis (SM), a rare clonal disorder affecting multiple organs, including the bone marrow (BM), skin, gastrointestinal (GI) tract, liver, spleen, bones, and lymph nodes (LNs). Serum tryptase is a key diagnostic marker reflecting the mast cell (MC) burden. Advanced SM (AdvSM), including aggressive SM (ASM), SM associated with a hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL), carries an exceptionally poor prognosis and presents significant therapeutic challenges because of resistance to conventional cytoreductive therapies. We report the case of an 8-year-old boy with AdvSM who presented with painful bilateral cervical lymphadenopathy, initially suspected to have reactive lymphadenitis, or Kikuchi’s disease. Persistent symptoms prompted lymph node (LN) excisional biopsy, BM evaluation, and serum tryptase measurement, confirming SM associated with a hematologic neoplasm (SM-AHN). No KIT mutations were detected in the initial LN or BM specimens; however, repeat BM analysis during progression identified KIT N822K. Initial treatment with steroids and H1 antihistamines failed. The patient underwent imatinib, cladribine (2-CdA), and allogeneic hematopoietic stem cell transplantation (HSCT), but the organ burden of MCs persisted and serum tryptase levels remained markedly elevated. Subsequent treatments with midostaurin and a combination of venetoclax plus azacitidine were also ineffective, and the disease progressed, resulting in death. Serial molecular profiling suggested molecular heterogeneity between the MC disease and the associated myeloid component, with KIT N822K detected during progression. This rare pediatric case highlights the urgent need for further research into the molecular pathogenesis of AdvSM and the development of novel targeted therapies and immunotherapies.