Histiocytic neoplasms are rare hematologic disorders characterized by pathologic infiltration of activated histiocytes in affected tissues. The treatment of histiocytic neoplasms, including Langerhans cell histiocytosis (LCH) and non-LCH, has advanced in recent years owing to targeted kinase inhibitors (BRAF and MEK) as patients with somatic mutations in the mitogen activated protein kinase (MAPK) pathway derive robust and durable responses with these therapies.1 However, there are patients with non-LCH who do not benefit from targeted therapies, particularly those with histiocytic infiltration of the nervous system, which is associated with mortality in 1 non-LCH disorder. BRAF and MEK inhibitors have limited penetration into the nervous system and worsening neurologic disease despite targeted therapy has been observed.2 These treatments can be limited or contraindicated by disease-related organ dysfunction or comorbidities. The subset of patients without MAPK alterations may not benefit from targeted therapies.