Siltuximab-mediated suppression of CRP is associated with clinical response in idiopathic multicentric castleman disease

Abstract

Abstract Introduction Idiopathic multicentric Castleman disease (iMCD) is a rare and serious disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction. The cytokine interleukin-6 (IL-6) is a known key driver of iMCD pathophysiology. Elevated IL-6 activity induces an increase in C-reactive protein (CRP) production in the liver, positioning CRP levels as a surrogate measure of IL-6 activity. In clinical trials and real-world studies, siltuximab, the only FDA-approved and front-line therapy for iMCD, showed a sustained and durable clinical response including sustained suppression of CRP and an acceptable safety profile. Siltixumab-IL6 complex interferes with the accurate measurement of IL-6 by available immunoassays, therefore other markers such as CRP can be used for monitoring disease activity. Reduction in CRP levels has been shown to correlate with positive treatment outcomes. However, CRP dynamics have not been systematically studied across different response groups. This study explores temporal changes in CRP levels in individuals treated with siltuximab and evaluates the relationship between biological control of CRP and clinical response. Methods We interrogated the ACCELERATE natural history registry, the largest international Castleman disease registry, and the pivotal Phase II trial cohort (ClinicalTrials.gov: NCT01024036) for siltuximab-treated patients who had baseline and post-siltuximab CRP measurements. Temporal changes in CRP levels were investigated for 18 weeks (corresponding to 6 cycles). In patients from the siltuximab clinical trial, complete or partial response (CR or PR) was defined using the modified Cheson criteria. Separately, the response criteria for patients in ACCELERATE required a 50% reduction in the proportion of abnormal minor criteria from the iMCD diagnostic criteria between treatment initiation and time of best response. Repeat CRP measurements were analysed across different cycles stratified by clinical response groups (CR, PR, stable disease [SD] ≥18 weeks, SD <18 weeks, and progressive disease [PD]). Effect of time and clinical response on the maximal changes in CRP levels with siltuximab was evaluated using repeated measures analyses with a mixed modelling approach. Results A total of 69 patients treated with siltuximab (11 mg/kg) every 3 weeks were analyzed in the study, which included 53 patients from the Phase II trial and 16 eligible patients from the ACCELERATE registry. 13 patients had a CR, 21 patients had a PR, 19 patients had an SD ≥18 weeks, 12 patients had an SD <18 weeks, and 4 patients had PD. Upon qualitative review of CRP levels over time, a partial siltuximab-mediated reduction in CRP levels was observed from baseline to Cycle 1 in all groups. However, repeated measures (mixed model) analyses showed that CRP levels were only significantly reduced from baseline to Cycle 1 in patients who experienced CR (adjusted p < 0.0001) or PR (adjusted p = 0.0012). No significant reduction was observed for patients with SD ≥18 weeks (adjusted p = 0.7042), SD <18 weeks (adjusted p = 0.9341) and PD (adjusted p = 0.2605). The reduction in CRP was only complete and sustained in the individuals who had a CR from Cycle 2 and onwards. Changes in CRP levels (from baseline to Cycle 1) were dependent on both time and clinical response (F [4–64] = 2.736, p = 0.0363). Discussion The observed CRP reduction across all patients regardless of response suggests that early changes in CRP do not predict subsequent clinical outcomes. Monitoring CRP dynamics over time is likely a better marker for disease control than immediately after beginning therapy. While CRP reduction is observed quickly across all groups, significant reduction only occurred in patients who would go on to respond to siltuximab, and maintaining low CRP levels across treatment cycles, as observed from Cycle 2 and onwards, is associated with sustained CR. This suggests that CRP levels do not come down as substantially and rebound in non-responders over time and underscores the importance of continued IL-6 pathway suppression to maintain disease control in iMCD. This study reveals a highly dynamic relationship between maximal CRP reduction and both time and clinical response, suggesting that initial rapid suppression combined with sustained reduction are associated with the best outcomes.