Infantile Aggressive Systemic Mastocytosis Complicated by Liver Fibrosis Treated With Oral Midostaurin

Introduction. Mastocytosis is a rare clonal disorder characterized by extreme proliferation of mast cells in cutaneous and other organs. It has an estimated prevalence of 1/10,000 people. In children, the most common form is cutaneous mastocytosis. Systemic mastocytosis accounts for less than 10% of pediatric mastocytosis cases. In most cases, mutations in the receptor tyrosine kinase KIT lead to uncontrolled proliferation of mast cells. Management of pediatric mastocytosis is based on trigger avoidance and histamine receptor blockade to control symptoms associated with mast cell mediator release. Because involvement of bone marrow and extracutaneous organs is rarely seen, there are few pediatric treatments, with no FDA-approved cytoreductive therapies for aggressive systemic mastocytosis in infants. Midostaurin, a multi-kinase inhibitor, is approved for treatment in adults.

Case Presentation. We describe the case of a 3-month-old male who presented with diffuse brown pruritic patches, hepatosplenomegaly, and tryptase markedly elevated at 187 ng/mL. Bone marrow biopsy confirmed the diagnosis of systemic mastocytosis with multifocal infiltrates. Skin biopsy revealed mast cell infiltration of the superficial dermis and diffuse aberrant CD30 expression. Serum KITD816V mutation was positive. The patient was started on a regimen of H1 and H2 blockade and cromolyn. Three months later, he presented with fever, progressive hepatosplenomegaly and increased tryptase, indicating he had aggressive form of mastocytosis. FDA emergency expanded use of midostaurin was applied for and approved with an initial starting dose of 30 mg/m² every 12 hours.

Results. The patient’s tryptase levels declined from 234 ng/mL to 192 ng/mL within 5 days of initiating therapy. Two weeks later, he had improvements in appearance of cutaneous disease and a reduction in hepatosplenomegaly. The patient continued to improve over the next several months. Midostaurin was adjusted based on symptom control to his current dose of 60 mg/m2 every 12 hours. Monitoring of tryptase and liver function continued in 3-month intervals. Remarkably, his tryptase continued to decline to a nadir of 68 ng/mL. Liver function and hepatic fibrosis have remained stable and the patient continues to thrive at 3 years following initiation of midostaurin.

Conclusion. Our case highlights the lack of available cytoreductive treatments for aggressive pediatric systemic mastocytosis. With initiation of oral midostaurin, the patient’s disease trajectory and daily quality of life have dramatically transformed. He continues to perform well without any apparent systemic effects, and with regular interval monitoring for adverse effects of bone marrow suppression, pulmonary toxicity, and QTc prolongation. Follow-up will involve maintaining the current dosage of midostaurin with close outpatient monitoring until tryptase levels for age normalize and/or if presentation of a new adverse response occurs.