An evaluation of guidelines for idiopathic multicentric Castleman disease supports use of IL-6 agents as first-line treatment.

In 2018, van Rhee and colleagues published international consensus guidelines for idiopathic multicentric Castleman disease (iMCD), a rare hematologic disorder that affects 1,000 to 1,200 patients in the United States annually. The authors of these guidelines based the recommendations on a review of data then available from a limited number of clinical trials and small case series.

To assess the performance of the guidelines, Sheila K. Pierson, MS, and colleagues performed a large-scale evaluation of the effectiveness of iMCD treatments in patients, and published results in Blood Advances. The findings support using anti-IL-6 agents as first-line treatment and cytotoxic chemotherapy for patients with severe, refractory disease, while limiting use of corticosteroid monotherapy.

“Our objective was to systematically evaluate treatments included in the guidelines in a large, real-world population of patients with iMCD that was representative of the spectrum of disease severity,” says Pierson. “The data reveal a higher response to siltuximab ± corticosteroids than in the Phase 2 clinical trial and support defining response using clinical metrics, which are aligned with patient-reported challenges.”

Gathering Data on Patients With iMCD

The study examined using data from the ACCELERATE Natural History Registry, a longitudinal, observational study of patients with Castleman disease. Patients of all ages self-enrolled in ACCELERATE between October 2016 and August 2022.The research team abstracted all medical record data from time of diagnosis until time of analysis were into database, which a panel of iMCD expert clinicians and hematopathologists used to review and adjudicate each case to confirm a diagnosis, resulting in a cohort of 102 patients.

The mean age was 35.9. Nearly 60% of patients had the TAFRO subtype of Castleman disease, which involves the presence of thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis/renal dysfunction (R), and organomegaly (O) and has an onset that often requires urgent intervention. The authors established an inventory of iMCD treatments and regimens, evaluated regimen effectiveness and timing of treatment, and characterized response by disease severity at the time of regimen initiation.

The team used three markers of disease activity to quantitatively assess regimen performance: hemoglobin, albumin, and C-reactive protein (CRP). They also performed a time-to-event analysis to assess the durability of treatment regimens (Figure).

First-Line Use of Siltuximab Common

“We identified 41 unique drugs that have been used in treatment of iMCD. Fifty percent of patients received siltuximab ± corticosteroids at least once,” says Pierson. “Our finding that 85% of patients with iMCD were treated with siltuximab or tocilizumab conflicts with a recent epidemiologic study, which reported treatment with IL-6-directed therapy in fewer than 10% of these patients, based on insurance data.”

The real-world data in this study also showed that siltuximab is effective. “Siltuximab with or without corticosteroids as recommended first-line in the consensus treatment guidelines was associated with a 52% response,” says Pierson. “It also demonstrated strong durability over rituximab with or without corticosteroids. Moreover, we found comparable responses in patients with both mild/moderate and severe disease.

The authors’ analysis of laboratory parameters showed that siltuximab ± corticosteroids resulted in a substantial and statistically significant increase in hemoglobin when compared with both rituximab ± corticosteroids (P=0.034) and corticosteroid monotherapy (P<0.001). The siltuximab combination was the only regimen that produced a clinically substantial improvement in CRP.

“Our objective laboratory metrics and time-to-event data support recommendations in the current treatment guidelines to administer anti-IL-6 therapy with or without corticosteroids and to limit corticosteroid monotherapy,” says Pierson.

Implications for Clinical Practice

The findings are applicable to patient care and should increase confidence in current treatment guidelines for patients with iMCD, Pierson continues. “The key takeaway is that physicians caring for patients with Castleman disease should apply the treatment guidelines in their clinical practices.”

Determining the best second-line treatment for iMCD, however, requires more research.

“Studies are needed to identify a consensus therapy for patients who do not respond to siltuximab (those who are refractory to anti-IL-6 treatment),” she says. “The biggest research priority for Castleman disease is finding additional, new treatments that are effective.”