Real‐World Usage and Outcomes of Different Siltuximab Dosing Frequency in Idiopathic Multicentric Castleman Disease

Idiopathic multicentric Castleman disease (iMCD) is a rare and heterogeneous cytokine-driven disorder characterized by systemic inflammation, generalized lymphadenopathy, and multiorgan dysfunction [1-5]. Interleukin-6 (IL-6) signaling has been known to play an important role iMCD [6]. Siltuximab, a monoclonal antibody against IL-6, is currently the only therapy approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of iMCD [7-11]. The pivotal randomized phase 2 trial established siltuximab administered at 11 mg/kg intravenously every 3 weeks as the standard of care [7]. However, several challenges remain in the long-term management of iMCD with siltuximab as treatment is often administered indefinitely and the standard every 3 week infusion schedule imposes logistical burdens on patients. These challenges are particularly relevant for patients who achieve sustained remission. Off-trial experience suggests that patients who achieve stable disease (SD) or remission sometimes transition to less frequent dosing intervals. In the long-term extension of the pivotal phase 2 trial, selected patients were able to extend dosing intervals to every 6 weeks without loss of response [9]. However, the safety and effectiveness of de-escalated dosing strategies in routine clinical practice remain uncharacterized. Standard: every 3 weeks (q3w) Escalated: more frequent than q3w De-escalated: less frequent than q3w following prior standard therapy Off treatment: discontinuation of siltuximab without immediate initiation of a subsequent regimen Demographic characteristics, clinical and histopathological subtypes, laboratory findings, and follow-up duration were extracted from medical records. Subtype definitions were based on existing literature [12-15]. The primary outcome was the best clinical response during each regimen. Responses were categorized as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or not evaluable (NE). CR was defined as the resolution of iMCD–related symptoms and normalization of abnormal laboratory findings attributable to iMCD. PR was defined as improvement in at least 50% of disease-related clinical and laboratory abnormalities without meeting criteria for CR. SD was defined as the absence of sufficient improvement in PR and the absence of progression. PD was defined as worsening clinical symptoms or laboratory abnormalities attributable to active disease. Secondary outcomes included the best lymph node response and durable response. Lymph node responses were defined based on radiographic assessment: CR indicated resolution of the index lymph nodes, and PR indicated at least a 50% reduction in lymph node size. Durable response was defined as a sustained clinical response (CR, PR, or SD) without initiation of a new regimen within 1 year following regimen initiation. To address the immortal-time bias, an exploratory 12-months landmark analysis including those who were alive, still on siltuximab without progression or regimen failure, and evaluable at the time was performed to compare the failure-free survival (FFS) between those who only received the standard dosing and who experienced de-escalation. Failure was defined as return to standard dosing, progression, treatment change, or death. Baseline patient characteristics were summarized using medians and interquartile ranges (IQRs) for continuous variables and frequencies with percentages for categorical variables. Comparisons between groups were performed using the Wilcoxon rank-sum test for continuous variables and Fisher's exact test for categorical variables. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to evaluate associations between dosing frequency and treatment responses. FFS was estimated using the Kaplan–Meier method, and survival curves were compared by the log-rank test. Patients without an event were censored at last follow-up. Univariate logistic regression analyses were performed to identify factors associated with durable response. All statistical tests were two-sided, and p values < 0.05 were considered statistically significant. Statistical analyses were performed using JMP version 15.1 (SAS Institute, Cary, NC) and Python. A total of 26 patients with iMCD who received siltuximab were included in the patient-level analysis. Among these, 19 patients received only standard dosing, whereas six patients transitioned to de-escalated dosing following the standard regimen. One patient (a 68-year-old man with iMCD-TAFRO) received an escalated regimen before the standard dosing. Baseline patient characteristics are summarized in Table 1. Histopathological and clinical subtype distributions were similar between the groups, although the standard-dosing group had predominantly iMCD-NOS (58%) vs. predominantly iMCD-IPL (50%) in the de-escalated-dosing group. There were no differences in baseline laboratory findings between the groups. A total of 44 siltuximab regimens were analyzed, including 29 standard regimens, 10 de-escalated regimens, one escalated regimen, and four off-treatment periods. Treatment sequences for individual patients who received non-standard regimens are illustrated in swimmer plots (Figure S1). The distribution of dosing intervals among non-standard regimens is summarized in Table S1, with regimens ranging from every 4 to 16 weeks. Regimen-level treatment responses are summarized in Table 2. Among the de-escalated dosing group, there was a high proportion of CR (60%) and PR (30%). The single-escalated regimen with weekly dosing achieved a PR. Among off-treatment periods, one patient maintained CR while three experienced PD. There was no difference between the groups in terms of lymph node responses (p = 0.072). All 10 de-escalated regimens had a durable response vs. 55% among standard regimens (p = 0.014). Thirteen patients who only received the standard dosing and six patients who had de-escalation after the standard dosing were included for a FFS analysis (Table 3). Compared to the standard dosing group, there was no difference in FFS in the de-escalated group (hazard ratio 0.35, 95% CI 0.040–3.0; p = 0.34) (Figure S2). 1-year FFS from the landmark were 81.8% and 83.8% in the standard and de-escalated groups, respectively. Univariate analyses were performed to evaluate factors associated with durable response (Table S2). Female sex and higher serum albumin were significantly associated with durable response (OR 4.5, 95% CI 1.1–20.5; p = 0.04; unit OR 3.5, 95% CI 1.3–9.6; p = 0.006). Baseline inflammatory markers, including CRP and IL-6 levels, and histopathological or clinical subtypes, were not significantly associated with durable response. In this retrospective single-institution analysis of patients with iMCD treated with siltuximab, patients who transitioned to de-escalated siltuximab dosing maintained high rates of clinical and durable responses, suggesting that treatment intensity might be reduced in selected patients once sustained disease control has been achieved. The standard practice for siltuximab for iMCD is to maintain patients on indefinite treatment with every 3 or 6 weeks. Although it has been shown to improve outcomes in iMCD [11, 16], the cumulative burden of indefinite therapy can be substantial. In our cohort, de-escalated regimens were associated with high disease control, with objective response rates of 90%. Importantly, although extension beyond every 6 weeks with siltuximab was not allowed during the pivotal trial [9], the results showed that some patients received infusions as infrequently as every 12–16 weeks. In practice, physicians rarely consider reducing dosing frequency in patients with ongoing disease activity. De-escalation may occur after sustained symptom resolution and biochemical improvement on laboratory findings. The results of FFS analysis from the 12-month landmark, which only included those who attained durable responses, support a response-adapted de-escalation approach and highlight the importance of longitudinal response assessment to adjust treatment intensity. Also, the findings raise a question of whether some patients may eventually discontinue siltuximab altogether. Although most patients in our cohort continued receiving maintenance treatment, four patients had periods off therapy without immediate disease progression (Figure S2). Because relapse remains a concern and the natural history of untreated iMCD is not fully understood, treatment discontinuation should be approached cautiously and ideally within the context of careful clinical monitoring. Future research is warranted to prospectively establish the criteria for de-escalation and to confirm whether the therapeutic siltuximab level was maintained on de-escalated dosing. Several limitations should be acknowledged. First, due to the retrospective nature of the study, there is potential selection bias, particularly in decisions regarding dose escalation or de-escalation, as patients who transitioned to de-escalated regimens may have represented a subgroup with favorable treatment responses. Second, the cohort size was relatively small given the rarity of iMCD. Third, regimen-level analyses may not fully capture time-dependent factors influencing treatment decisions, such as evolving disease severity or physician preference. In conclusion, de-escalated siltuximab dosing schedules were associated with maintained clinical responses in selected patients with iMCD without increased treatment failure once the durable response was achieved. While the findings suggest that treatment intensity may be reduced in some patients once remission is achieved, larger multi-institutional studies will be necessary to validate predictors of successful de-escalation and to determine whether treatment discontinuation may be feasible in selected patients. Y.N. wrote the manuscript. M.S.E., A.H., T.H., and A.D. revised the manuscript and provided critical feedback. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. Y.N. receives research funding from Recordati Rare Disease, the manufacturer of siltuximab. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1: Details of Dosing Frequency in Non-standard Regimens. Table S2: Univariate Analyses for Factors Associatied with Durable Response. Figure S1: Treatment Sequences in Individual Patients who received non-standard siltuximab dosing. Figure S2: Failure-free Survival from the 12-month Landmark. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.