title: JAK1 Genomic Alteration Associated With Exceptional Response to Siltuximab in Cutaneous Castleman Disease.
abstract: Castleman disease (CD) is an ultrarare, interleukin-6 (IL-6)-driven lymphoproliferative disorder whose underlying molecular alterations are unknown. Siltuximab (anti-IL-6 antibody) is approved for treatment of this disease. To our knowledge, genomic sequencing of CD has not been reported.
  
  
  
  To investigate and identify molecular aberration(s) that help explain the exceptional response to siltuximab in a patient with cutaneous CD.
  
  
  
  This case study examines data from comprehensive genomic profiling (using targeted next-generation sequencing) of tissue from a patient with cutaneous CD who demonstrated an exceptional response to siltuximab treated at a National Cancer Institute-designated Comprehensive Cancer Center.
  
  
  
  Intravenous siltuximab 12 mg/kg every 3 weeks. Tissue from the patient was interrogated by next-generation sequencing (405 genes). Serum was evaluated for IL-6 levels by enzyme-linked immunoassay.
  
  
  
  Identification of pretreatment serum IL-6 levels and somatic variants that may explain the exceptional response to siltuximab in this patient with cutaneous CD.
  
  
  
  Patient pretreatment serum IL-6 levels were normal. Treatment with siltuximab resulted in a complete response lasting 7 years. Next-generation sequencing demonstrated a JAK1V310I missense mutation. Janus Kinase 1 (JAK1) is a crucial signaling component of the IL-6/IL-6 receptor/gp130 machinery. JAK1V310I may induce a conformation change with functional activation effect leading to enhanced sensitivity to the IL-6 ligand.
  
  
  
  Our observations suggest that a JAK1 alteration may explain the underlying biology of a patient's cutaneous CD, as well as the patient's exceptional response to siltuximab.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, La Jolla.
authors.forename: Maulik
authors.initials: M
authors.lastname: Patel
authors.affiliation: Cancer Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Sadakatsu
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Pilat
authors.affiliation: Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California-San Diego, La Jolla.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D005871:Castleman Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D023281:Genomics; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology*; D053613:Janus Kinase 1 / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C504234:siltuximab