AXG, adult XG; CN V, trigeminal nerve; Co, cobimetinib; Cr, crizotinib; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; D, dabrafenib; FU, follow-up; F, female; JXG, juvenile XG; M, male; MFB, multifocal bone; MS, multisystem; PCD, plasma cell dyscrasia; RO, risk organ; SS, single system; Tx, therapies; T, trametinib; UC, unclassifiable; UFB, unifocal bone; V, vemurafenib.

Given that different molecular assays were used for detection of genetic alterations, it cannot be excluded that (rare) genetic variants have been missed.

In addition to neurodegenerative lesions, this patient potentially had an orbital lesion. The orbital lesion was surgically excised; histopathologic analysis could not confirm LCH involvement.

MRI revealed mild progressive cerebellar atrophy. The orbital lesion was surgically excised; therefore, response to targeted therapy is not applicable.

In this patient with brain lesions characteristic of ND-LCH, droplet digital polymerase chain reaction analysis of DNA extracted from blood leukocytes detected a BRAF^V600E mutation.

This patient had diabetes insipidus since 2013, and later panhypopituitarism. However, the diagnosis of LCH was made in 2018, when organs other than the pituitary (bone, skin, and lungs) became involved.

This patient potentially had residual skin lesions. All other lesions present at diagnosis had resolved at the time of onset of ND-LCH and start of targeted therapy.

This is patient 4 from a study by Renier et al.⁶⁰ 

This patient is reported in a study by Pegoraro et al.⁶¹ 

One year before ECD diagnosis (at the age of 5 years), this patient was diagnosed with multifocal skin JXG.

Eight years before the diagnosis of ECD (at 38 years of age), this patient already had a thickened pituitary stalk.

All or some of these treatments were given before the diagnosis of a histiocytic neoplasm was made.

These 2 patients also received dasatinib for their second hematologic malignancy, including BCR::ABL1–positive CML (patient 25) or B-ALL with high PDGFRB expression by RNA sequencing (patient 37).

In this patient, response of neurodegenerative lesions was not evaluated radiologically. However, neurologic symptoms (including dysarthria) appeared to slightly improve during targeted therapy, although this was not substantiated with repeated neurologic assessments using validated rating scales for neurologic symptoms.

In tissue samples taken after disease progression despite chemotherapy, subclonal BRAF^G469R (calcaneus), BRAF^D594N (iliac bone), and MTOR^S2215Y (iliac bone) mutations were also detected.

This does not include the prior treatments for the patient's B-ALL, before the diagnosis of secondary HS. For the initial B-ALL, this patient received chemotherapy (ALLTogether NCI HR protocol), followed by immunotherapy (2× CD19-directed CAR-T cell infusions; later 2 courses of 4 weeks of blinatumomab). The patient never achieved minimal residual disease negativity by polymerase chain reaction analysis of immunoglobulin gene rearrangements; the lowest minimal residual disease value was 0.02% at 6 weeks after first CAR-T cell infusion.