A Placebo-Controlled Exploratory Trial of Sirolimus for Tocilizumab-Resistant Idiopathic Multicentric Castleman Disease: Early Termination and Long-Term Extension Results Based on Descriptive Results From Two Patients.

Background Idiopathic multicentric Castleman disease (iMCD) remains challenging to treat, with a considerable number of patients showing insufficient response to tocilizumab, the current standard therapy for iMCD. Sirolimus, an mTOR inhibitor, is a potential therapeutic option for tocilizumab-resistant cases based on its mechanism of action and preliminary case reports. Methods This investigator-initiated, multicenter, exploratory, placebo-controlled study was designed to evaluate sirolimus (2 mg daily) versus placebo in patients with tocilizumab-resistant iMCD. The primary endpoint was the change in the CHAP (CRP, Hemoglobin, Albumin, Performance Status) score from baseline at week 16. The study was prematurely terminated due to recruitment challenges and the impact of the COVID-19 pandemic, enrolling only two of the planned 20 participants. Both patients completed a 40-week open-label extension phase of sirolimus treatment. Results Two patients were randomized (one sirolimus and one placebo). The primary endpoint of the CHAP score reduction was not achieved during the 16-week double-blind phase. However, the sirolimus-treated patient maintained disease stability (CHAP score remained at 1), whereas the placebo patient experienced disease progression (CHAP score increased from 3 to 5). The secondary outcomes showed contrasting patterns: the sirolimus patient demonstrated improvements in the physician's global assessment and quality of life measures, while the placebo patient showed deterioration. During the extension phase, the patient initially assigned to placebo experienced significant improvement after switching to sirolimus (CHAP score decreased from 5 to 3, meeting the criteria for a clinically meaningful response). No serious adverse events were reported during the 40-week study period. Conclusions While the study's early termination with only two patients prevents definitive efficacy conclusions, the contrasting disease trajectories between treatment groups and the improvement observed when the placebo patient switched to sirolimus suggest a potential therapeutic benefit. The favorable safety profile of extended sirolimus treatment supports further investigation in larger, adequately powered studies of tocilizumab-resistant iMCD.