This retrospective study enrolled 14 patients diagnosed with MCD treated with at least one dose of Siltuximab as in first line in accordance with clinical practice (11 mg/kg every 3 weeks, until disease progression), between January 2018 and March 2025 at the Hematology Units of Lazio region in Italy (University Hospital Sant’Andrea, University Hospital Umberto I, Catholic University S. Cuore, Tor Vergata University, Campus Biomedico University, Hematology Unit ASL-RM1 and Belcolle Hospital Viterbo). Eligible adults age >18 years with iMCD were diagnosed based on detailed patient history, physical examination, assessment of laboratory abnormalities, pathologic diagnosis, radiologic imaging, and histologically confirmed diagnosis from an excisional lymph node biopsy acquired before enrollment. For each patient, the following data were collected: baseline demographic characteristics (sex and age at diagnosis), clinical characteristics (comorbidities and number of involved lymph node regions), laboratory parameters, treatment exposure, clinical outcomes (treatment response), safety outcomes (adverse events), and follow-up data, including date of last follow-up, vital status at last follow-up, date of death, and cause of death. Patients included in the study were confirmed to be HIV seronegative and human herpesvirus-8 negative, as determined by a polymerase chain reaction test. Written informed consent was obtained from participants. The independent ethics committee approved the protocol (Rif. 7684 Prot. 0565/2024). The study was performed in accordance with the Declaration of Helsinki.

All enrolled patients received at least one dose of Siltuximab every three weeks (11 mg/kg), until treatment failure. Treatment failure was defined as the emergence of new disease-related symptoms with NCI-CTCAE grade ≥3, persistence of disease-related symptoms of grade ≥2 for more than three weeks, an increase in the ECOG performance score by more than one point, persistent symptoms for at least three weeks, or radiological progression. Treatment response was evaluated according to the Castleman Disease Collaborative Network (CDCN) consensus guidelines. Three composite endpoints were used to assess response: (A) four laboratory parameters of inflammatory response and organ function, including hemoglobin, CRP, albumin, and eGFR, with eGFR further subdivided into blood urea nitrogen and serum creatinine levels; (B) four critical clinical symptoms: fatigue, anorexia, fever, and weight change; and (C) lymph node size. Complete remission (CR) required normalization of clinical symptoms, biochemical markers, and lymph node response, assessed using the modified Cheson criteria. Partial remission (PR) was defined by a reduction of more than one NCI-CTCAE grade in clinical symptoms, over 50% improvement in all biochemical markers (though not returning to baseline), and PR in lymph node response. Stable disease (SD) was defined as the absence of CR, PR, or progressive disease (PD). Progressive disease (PD) was defined by a >50% worsening in any biochemical marker, the worsening of symptoms in two consecutive assessments, or a >25% increase in lymph node size. Response assessments were performed according to routine clinical practice, with non-uniform (opportunistic) timing, reflecting the real-world nature of the study. The overall response rate (ORR) was defined as the percentage of patients who achieved CR or PR.

Continuous variables were summarized as median and range (or interquartile range, where appropriate). Categorical variables were reported as frequencies and percentages. Overall survival (OS) was defined as the time from the first dose of Siltuximab to death from any cause. Event-free survival (EFS) was defined as the time from initiation of Siltuximab to discontinuation, disease progression, relapse, or death from any cause, whichever occurred first. Patients without events were censored at the last follow-up. Kaplan–Meier survival analysis was performed to estimate OS and EFS, and log-rank tests were used for comparisons where applicable. Time from diagnosis to treatment initiation (TTT) was calculated as the number of days between the date of diagnosis and the first dose of Siltuximab. Statistical analyses were performed using SPSS version 28.0, with a two-sided p-value <0.05 considered statistically significant.

Fourteen patients with idiopathic Multicentric Castleman Disease (iMCD) treated with first-line Siltuximab were included in this multicenter retrospective study. The median age at diagnosis was 54 years (range, 18–81), with a slight female predominance (8 females, 57%). Histopathological subtypes were plasmacytic in 5 patients (36%), mixed in 6 (43%), and hypervascular in 3 (21%), reflecting the heterogeneous histologic spectrum of iMCD.

At baseline, most patients (92.9%) had an Eastern Cooperative Oncology Group (ECOG) performance status <2, indicating preserved functional capacity. B symptoms (fever, night sweats, or weight loss) were present in 42.9% of patients. Laboratory evaluations revealed evidence of systemic inflammation and immune activation, with a median hemoglobin of 12.0 g/dL (range, 8.5–15.2), median C-reactive protein (CRP) of 8.7 mg/L (range, 0.1–157.3), median erythrocyte sedimentation rate (ESR) of 45 mm/h (range, 2–120), median albumin of 4.2 g/dL (range, 2.4–5.1), and median IgG of 1.6 g/dL (range, 1.01–16.3). Functional imaging with ^18F-FDG PET/CT showed a median SUVmax of 5.3 (range, 2.3–30.5). Baseline demographics and clinical characteristics are summarized in Table 1.

All patients received siltuximab at a standard dose of 11 mg/kg intravenously every three weeks. Concomitant corticosteroids were administered at treatment initiation in six patients (43%), with a median prednisone-equivalent dose of 25 mg die. During treatment with siltuximab, corticosteroids were successfully discontinued with a median time to withdrawal of 1.5 months (range, 1-12), while no patients required steroid re-initiation.

The median duration of siltuximab treatment was 28 months (range, 3–55). The longest-treated patient received siltuximab for 78 cycles. The median follow-up was 13 months (range, 1–49). Patients received a median of 37 cycles of siltuximab, and the median time from diagnosis to treatment initiation (TTT) was 93 days (range, 15–173).

Overall, progression and event free survival were assessed starting from the first siltuximab infusion (T0) and evaluated during routine clinical follow-up visits, reflecting real-world practice. The overall response rate (ORR) was 86%, with complete remission (CR) achieved in 29% of patients, partial remission (PR) in 57%, and stable disease in 14%. Among responders, improvements in constitutional symptoms and laboratory abnormalities were typically observed within the first two months of therapy. The median time to best response was 6 months (range, 1–31).

At data cutoff (31^st March 2025), 12 of 14 patients (85.7%) were alive: one patient died from a lung infection caused by a multidrug-resistant pathogen, and a second patient died due to a lymphoproliferative neoplasm (Diffuse Large B-cell Lymphoma). Three patients discontinued Siltuximab at 18, 20, 41 months respectively, following the diagnosis of another malignancy. A last subject discontinued due to the onset of an adverse event and one due to disease progression. The median duration of response was not reached, reflecting durable benefit with continued therapy. Event-free survival (EFS) was 64.3%, and overall survival (OS) was 85.7% (Figures 1, 2).

Siltuximab was generally well tolerated. No infusion-related reactions were reported during the study period. Grade ≥2 adverse events occurred in 3 patients (21%), including G3 hypertension, G2 transaminitis, and pneumonia in two patients of Grade 3 and 5 respectively. No patient experienced infusion-related reactions and the treatment was otherwise well tolerated. No hematologic toxicities, autoimmune events, or treatment-related deaths were observed. The overall safety profile was consistent with that reported in clinical trials, and no new or unexpected adverse events emerged in this real-world cohort.

This real-world, multicenter experience confirms that first-line Siltuximab is effective and manageable in patients with iMCD, achieving durable disease control in nearly all treated patients. The high ORR, low toxicity burden, and sustained survival observed across multiple centers in the Lazio region emphasize the reproducibility of Siltuximab’s clinical benefits outside of controlled trials.