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Brief Report
May 2017

JAK1 Genomic Alteration Associated With Exceptional Response to Siltuximab in Cutaneous Castleman Disease

Author Affiliations
  • 1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, La Jolla
  • 2Cancer Center, Tokyo Medical and Dental University, Tokyo, Japan
  • 3Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston
  • 4Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California-San Diego, La Jolla
JAMA Dermatol. 2017;153(5):449-452. doi:10.1001/jamadermatol.2016.5554
Key Points

Question  What potential molecular aberration(s) may help explain the exceptional response observed in a patient with cutaneous Castleman disease treated with the anti–interleukin-6 (anti–IL-6) antibody siltuximab?

Findings  In this case report, a missense mutation in the Janus Kinase 1 gene (JAK1V310I) was identified, which is a crucial signaling component of the IL-6/IL-6 receptor/gp130 machinery. JAK1V310I may induce a conformational change that drives Castleman disease by enabling activation of the IL-6R/gp130/JAK1 complex even in the presence of normal levels of IL-6.

Meaning  Genomic profiling of Castleman disease may reveal important molecular drivers of disease, treatment resistance, and therapeutic targets.


Importance  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.

Objective  To investigate and identify molecular aberration(s) that help explain the exceptional response to siltuximab in a patient with cutaneous CD.

Design, Setting, and Participants  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.

Interventions  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.

Main Outcomes and Measures  Identification of pretreatment serum IL-6 levels and somatic variants that may explain the exceptional response to siltuximab in this patient with cutaneous CD.

Results  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.

Conclusions and Relevance  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.