Swimmer plot of outcomes in patients with ALK-positive histiocytosis (n = 11) or atypical ALK-rearranged histiocyte-rich tumors (n = 2) treated with ALK inhibition. ALK inhibition was initiated at timepoint zero. Median time on ALK inhibition was 16 months in ALK-positive histiocytosis patients (range 3-43 months). Responses were measured by CT, MRI, and/or PET-CT in all patients. Dose reductions were 67% (90 mg brigatinib/d → 30 mg/d) and 50% (1200 mg alectinib/d → 900 mg/d → 600 mg/d) in Case 15 and Case 26, respectively. Case 39 developed a severe (grade 3) anaphylactic shock on the first day of crizotinib administration, requiring the patient to be resuscitated. The patient subsequently received vinblastine/prednisone-based chemotherapy with progressive disease and then switched to alectinib with objective response after 2 months. Case A1 developed a subcutaneous gluteal metastasis during treatment with alectinib (supplemental Figure 3C), which was found to harbor an ALK p.I1171N mutation, a mutation known to confer secondary resistance to alectinib.^78,79 Therefore, the patient switched to lorlatinib and later to ceritinib after repeated progressive disease. Due to continuing progressive disease during treatment with ceritinib, the patient recently stopped ceritinib, received 3 weeks of bridging therapy with lorlatinib during antalgic radiotherapy of 2 metastases, and subsequently started vinblastine/prednisone-based chemotherapy. VBL/PRED, vinblastine and prednisone-based chemotherapy.