CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease

Abstract

Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood cytokine storm-driven inflammatory disorder. Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking. Here we show, by comparison of levels of 1,178 proteins in sera of healthy participants (N = 42), patients with iMCD (N = 88), and with related diseases (N = 60), a comprehensive landscape of candidate disease mediators and predictors of siltuximab response. C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD. Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points. Our study thus suggests that CXCL13 is a predictive biomarker of response to siltuximab in iMCD.

Unmet Clinical Needs in the Management of Idiopathic Multicentric Castleman Disease: A Consensus-based Position Paper From an ad hoc Expert Panel

“… 83 Lymph nodes from patients with iMCD-TAFRO showed an increased expression of CXCL13 compared with lymph nodes of patients with iMCD-NOS. 83 A longitudinal analysis of sera samples of the phase 2 trial 68 was not able to identify pretreatment-specific biomarkers of siltuximab response, but identified CXCL13 as the only protein that was significantly different between responders and nonresponders at early and late time points, with a significant difference observed as early as after 8 days of treatment, in both the primary and validation cohorts. 83 The results indicate that a decrease in CXCL13 of 17% or more after starting siltuximab treatment is predictive of a good response to siltuximab.…”

“…Identifying and validating the subgroup with a superior response to siltuximab was considered the first validated predictive algorithm for response to siltuximab in iMCD. The same authors found that serum CXCL13 was higher in iMCD patients compared with healthy controls but did not differ between iMCD‐TAFRO and iMCD‐NOS 83 . CXCL13 showed potential to discriminate from a portion of pathologies with overlapping features as its serum levels were elevated compared with rheumatoid arthritis and HHV‐8‐MCD patients but not for patients with Hodgkin lymphoma 83 .…”

“…The same authors found that serum CXCL13 was higher in iMCD patients compared with healthy controls but did not differ between iMCD-TAFRO and iMCD-NOS. 83 CXCL13 showed potential to discriminate from a portion of pathologies with overlapping features as its serum levels were elevated compared with rheumatoid arthritis and HHV-8-MCD patients but not for patients with Hodgkin lymphoma. 83 Lymph nodes from patients with iMCD-TAFRO showed an increased expression of CXCL13 compared with lymph nodes of patients with iMCD-NOS.…”

“…CXCL13 showed potential to discriminate from a portion of pathologies with overlapping features as its serum levels were elevated compared with rheumatoid arthritis and HHV‐8‐MCD patients but not for patients with Hodgkin lymphoma 83 . Lymph nodes from patients with iMCD‐TAFRO showed an increased expression of CXCL13 compared with lymph nodes of patients with iMCD‐NOS 83 . A longitudinal analysis of sera samples of the phase 2 trial 68 was not able to identify pretreatment‐specific biomarkers of siltuximab response, but identified CXCL13 as the only protein that was significantly different between responders and nonresponders at early and late time points, with a significant difference observed as early as after 8 days of treatment, in both the primary and validation cohorts 83 .…”

Siltuximab administration results in spurious IL‐6 elevation in peripheral blood

“…1,3 Additionally, a recent serum proteomics study identified and validated C-X-C Motif Chemokine Ligand-13 (CXCL13) as a predictive biomarker of response to siltuximab as early as day 8 after siltuximab initiation; however, CXCL13 is not yet widely available for clinical use. 2 Ultimately, these results indicate that IL-6 values should not be measured after siltuximab administration and should not be used to guide treatment decisions.…”