Personalized Medicine in Histiocytic Disorders: Novel Targets in Patients Without MAPK Alterations

Authors

Katherine E.R. Smith

¹Department of Hematology, Mayo Clinic, Rochester, MN

Katherine E.R. Smith, Aldo A. Acosta-Medina, Surendra Dasari, Wasantha Ranatunga, Karen L. Rech, Aishwarya Ravindran, Jason R. Young, Patrick W. McGarrah, Gordon J. Ruan, Saurabh S. Zanwar, Jenny J. Li, Julio C. Sartori-Valinotti, Jessica N. Snider, Thomas E. Witzig, Gaurav Goyal, Ronald S. Go, Jithma P. Abeykoon

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PURPOSE

BRAF and MEK inhibitors are standard treatments in histiocytic disorders, such as Erdheim-Chester disease (ECD). Some patients lack MAPK-pathway alterations, making these treatments less effective.

We describe three patients with histiocytic disorders who have novel non-MAPK pathway alterations. These alterations were studied through genomic and in silico analyses when applicable, then treated with off-label medications rationally selected on the basis of genomic alterations.

Patient 1 had rapidly progressive ECD involving the CNS. A CSF1R in-frame deletion (p.S560_P566del) was identified, and in silico modeling predicted a gain-of-function mutation. This alteration was targeted with pexidartinib, which led to a clinical complete response (CR) within 2 months, and a partial response (PR) on imaging after 3 months. After 15 months, the disease became resistant to pexidartinib and transformed to histiocytic sarcoma. Patient 2 has skin-only involvement of a xanthogranuloma disorder. A KIF5B-FGFR1 fusion was identified on RNA sequencing and targeted with pemigatinib. At 24 months of follow-up, she remains in a clinical PR. Patient 3 has ECD involving the bone marrow, gastrointestinal tract, and subcutaneous tissues. A MEF2C-FLT3 fusion was identified and targeted with sorafenib. He achieved a clinical CR and radiographic PR within 3 months, which has continued for 30 months.

We report three patients with histiocytic disorders harboring novel alterations who had sustained responses to off-label kinase inhibitors specific to their histiocytic disorder. Pathogenic variants outside of the MAPK pathway, including variants of unknown significant, may be targeted with readily available small molecules.