Is 'severe’ imcd-IPL really severe?

Abstract

Abstract Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder with heterogeneous clinical manifestations. It can be classified into three clinical subtypes: iMCD-not otherwise specified (iMCD-NOS), iMCD-idiopathic plasmacytic lymphadenopathy (iMCD-IPL), and iMCD-thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly (iMCD-TAFRO). Among the three subtypes, iMCD-IPL is typically associated with an indolent disease course and a more favorable prognosis. However, in current clinical practice, treatment decisions for iMCD still follow the severity-based model proposed by the Castleman Disease Collaborative Network (CDCN) in 2018, regardless of clinical subtype-specific disease behavior. Severe iMCD patients typically received intensive regimens, involving anti-interleukin-6 (IL-6) agents combined with high-dose steroids and/or cytotoxic chemotherapy, whereas non-severe iMCD patients were managed with less aggressive therapies, such as anti-IL-6 monotherapy. Given the indolent nature of iMCD-IPL, the application of a uniform severity-based treatment framework to all iMCD-IPL patients warrants reevaluation. This single-center retrospective study included patients diagnosed with iMCD-IPL and iMCD-NOS at Peking Union Medical College Hospital between January 2000 and March 2025. Based on CDCN-defined severity criteria, patients were stratified into four groups: severe iMCD-IPL, non-severe iMCD-IPL, severe iMCD-NOS, and non-severe iMCD-NOS. Kaplan-Meier curves were generated to assess overall survival (OS) for the four patient groups, and intergroup differences were compared by log-rank test. For severe iMCD-IPL patients, two subgroups were defined based on whether the actual treatment received consistent with the recommended regimen for severe iMCD (“severe-type” vs. “non-severe-type”), and their baseline characteristics, treatment responses, and safety profiles were compared. A total of 152 iMCD-IPL patients (37 severe, 115 non-severe) and 186 iMCD-NOS patients (52 severe, 134 non-severe) were enrolled. The median follow-up duration was 45.1 months (range, 0.4-295.2). Kaplan-Meier analysis showed none of the four subgroups reached median OS. There was no significant difference in OS between severe iMCD-IPL and non-severe iMCD-NOS (log-rank p = 0.402). Severe iMCD-NOS exhibited relatively poorer outcomes, with significantly inferior survival compared to severe iMCD-IPL (log-rank p = 0.008), non-severe iMCD-IPL (log-rank p = 0.001), and non-severe iMCD-NOS (log-rank p = 0.002). Among the 37 severe iMCD-IPL patients, 13 patients (35.1%) were treated as “severe-type” therapy and 24 patients (64.9%) received “non-severe-type” therapy. Baseline clinical manifestations (e.g., fatigue, anorexia, fever, weight loss, hepatosplenomegaly, splenomegaly, and pulmonary involvement) and laboratory data (e.g., hemoglobin, platelet, albumin, alkaline phosphatase, serum creatinine,immunoglobulin G, C-reactive protein, and IL-6) were comparable between the two groups. Among the severe iMCD-IPL, the median time to next treatment (TTNT) was 128.3 months, with no significant difference between the two treatment groups (Log-rank p = 0.52). Response rates at 3 months (77.8% vs. 60.0%, p = 0.40), 6 months (64.7% vs. 55.6%, p = 0.69), and best response (78.3% vs. 70.0%, p = 0.67) favored the “severe-type” treatment group numerically but did not reach statistical significance. Regarding safety, 3 patients (23.1%) in the “severe-type” treatment group experienced adverse events, including one case of grade 4 leukopenia, whereas the “non-severe-type” treatment group showed a more favorable safety profile. In conclusion, the current CDCN severity-based stratification does not adequately reflect the prognostic characteristics of the iMCD-IPL subtype. 'Severe’ iMCD-IPL might not be really severe and could benefit from “non-severe-type” treatment.