Real-World Data of Siltuximab for Chinese Patients with Imcd: Combination with BCD Regimen Benefits Severe Cases

Introductions: Idiopathic multicentric Castleman disease (iMCD) accounts for a significant portion of Castleman disease (CD) cases, presenting with systemic lymphadenopathy, constitutional inflammatory symptoms, polyclonal lymphoproliferation, and multiple organ system dysfunction. It is predominantly driven by a cytokine storm, with interleukin-6 (IL-6) being the key mediator. Consequently, siltuximab, which targets IL-6 directly, is recommended by the Castleman Disease Collaborative Network (CDCN) as a first-line treatment for iMCD, showing high response rates in non-severe iMCD patients. Severe iMCD patients encounter more aggressive cytokine storms, thus requiring more intensive interventions, such as the combination of siltuximab with high-dose steroids. However, substantial real-world data on the use of siltuximab in China were lacking, and treatment for patients with severe iMCD remains challenging. Following the approval of siltuximab by the National Medical Products Administration in December 2021 and its subsequent commercial availability in China in July 2022, we initiated the first real-world retrospective study to focus on the effectiveness and safety of siltuximab in Chinese patients with iMCD, offering crucial real-world insights.

Methods: This single-center, retrospective study was conducted at the Peking Union Medical College Hospital, involving iMCD patients treated with siltuximab from July 2022 to March 2024. The diagnostic criteria for iMCD were as follows (CDCN criteria): 1) histopathologic lymph node features consistent with the iMCD spectrum, 2) enlarged lymph nodes in two or more lymph node stations, and 3) satisfying at least two of 11 criteria including one laboratory criterion as proposed by the CDCN and failing to satisfy any of the CDCN's suggested exclusion criterion. Patients were classified into iMCD-TAFRO and iMCD-NOS based on specific diagnostic criteria. Disease severity was categorized according to the CDCN consensus. Treatment response was evaluated as per the CDCN consensus guidelines and the overall response was defined as the symptomatic and biochemical response, except for the lymph node response in imaging. Demographic, clinical, and laboratory data, and treatment options were extracted from medical records. Follow-up data were collected from medical record systems and phone contacts. Study endpoints include overall response rates at Weeks 3, 6, 9, and 12 and adverse events during the treatment and follow-up periods. Fisher's exact test and Student's t-test were used to compare dichotomous variables and continuous variables, respectively. Univariate logistic regression was performed to analyze the potential factors for treatment response.

Results: This single-center retrospective study included 43 iMCD patients in China, with a median follow-up time of 4.6 months (range: 1.5-9.5 months). The median age at the initiation of siltuximab was 42 years (range: 15-70 years), and 51.2% of the patients were men (n = 22). Severe iMCD was observed in 20 patients (46.5%). The overall response rate (including symptomatic and biochemical response) was 59% at week 3 and increased to 91% at week 12, with complete and partial response rates of 54% and 37%, respectively. Patients who received siltuximab as a first-line treatment exhibited better treatment response (OR = 0.040, 95% CI, 0.004-0.390, p=0.006). Inflammatory markers (such as IL-6 and high-sensitivity C-reactive protein [hsCRP]) and pathologic types showed no predictive role in the treatment responses. Eighteen patients, who were all classified as severe iMCD, received combined therapy with bortezomib, cyclophosphamide, and dexamethasone (BCD); of them, the overall response rate was 50% at week 3, which increased to 100% at week 12. During the follow-up, adverse reactions included mild skin-related reactions (grade 1 or 2) in three patients, and severe pneumonia (grade 3) in one patient.

Conclusions: The study reinforced the existing evidence regarding the efficacy and safety of siltuximab in treating iMCD and underscored the remarkable effectiveness of the combination therapy of siltuximab with the BCD regimen, especially for patients with severe iMCD.

No relevant conflicts of interest to declare.