Serum IL-6 levels following siltuximab administration in castleman disease

e19545 Background: Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder. Though etiology is unknown, interleukin-6 (IL-6) is a driver in a portion of cases. Siltuximab is a monoclonal antibody that targets IL-6 and has been approved by the Food and Drug Administration to treat iMCD. Treatment guidelines for iMCD note that IL-6 directed therapy can result in spurious elevation of serum IL-6, based on anecdotal reports. This could lead physicians to erroneously infer treatment failure. Herein we investigate an international natural history registry of CD to evaluate whether IL-6 levels are increased following siltuximab. Methods: Data on peak IL-6 levels measured in patients before and after receiving siltuximab was available for 40 patients. C-reactive protein (CRP) levels measured near peak IL-6 values before and after siltuximab were also collected where available (n=32). Peak IL-6 values were standardized by the upper end of the reference range. Median values and interquartile ranges were calculated for pre- and post-siltuximab CRP and peak IL-6 values. Wilcoxon signed-rank tests were used for statistical comparison. Results: Our cohort consisted of 40 patients who had lymph node histopathology consistent with Castleman disease. An expert panel confirmed 16 iMCD, 5 POEMS-MCD, 1 regional CD, 3 unicentric CD, 11 other diagnoses, and 4 remain to be determined. Breakdown by gender was 50% male (n=20) and 50% female (n=20) with a mean age of 40.76 years. We analyzed peak standardized IL-6 levels before and after treatment with siltuximab. Prior to treatment with siltuximab, the median IL-6 level was 3.18, whereas after treatment with siltuximab, the median IL-6 level was elevated to 557 (p = 1.8 x 10 -12 ). Given that CRP is a well-established biomarker of IL-6 activity, we investigated whether the increased IL-6 was a reflection of increased disease activity in these patients. Here, we found that median CRP before treatment was 59.7 mg/L, whereas after treatment, median CRP decreased to 4.95 mg/L (p = 0.0005) suggesting that IL-6 levels were rising despite reduced disease activity. IL-6 levels rose almost 200-fold while CRP reduced over 10-fold. Conclusions: Our results indicate that IL-6 levels significantly increase after patients receive siltuximab. Given that CRP is a biomarker of IL-6 activity, we infer that IL-6 is artificially elevated but not having a functional impact in the patient. Therefore, IL-6 levels should not be measured after siltuximab is given and they should not be used to guide treatment decisions. [Table: see text]