Castleman Disease

Overview

Castleman disease is a rare group of disorders in which lymph nodes and related immune tissues grow abnormally. It can arise at any age and includes localized unicentric Castleman disease (UCD), usually involving one lymph-node region, and systemic multicentric Castleman disease (MCD), involving multiple lymph-node regions and potentially severe inflammation and organ dysfunction. MCD includes HHV-8-associated disease and HHV-8-negative/idiopathic MCD (iMCD), whose underlying cause remains unknown. UCD treatment guidelines iMCD treatment guidelines

The prognosis differs sharply by subtype. Complete surgical removal of the affected node(s) is often curative for resectable UCD and is the standard of care. By contrast, MCD usually requires long-term systemic treatment rather than a curative local procedure; for iMCD, the preferred first-line treatment is IL-6 pathway blockade with siltuximab, or tocilizumab where siltuximab is unavailable, with corticosteroids and chemotherapy added in selected severe cases. UCD treatment guidelines iMCD treatment guidelines

Scope of Recent Research (2020–present)

Research since 2020 has become substantially more coordinated, particularly for iMCD, through international registries, tissue banking, molecular profiling, and small investigator-led trials. The dominant questions are which immune and stromal-cell pathways drive disease when IL-6 blockade fails, how to identify biologically distinct patient subgroups, and whether already approved drugs can produce deep, durable, treatment-free remissions; a new cure for systemic MCD has not yet been demonstrated. ACCELERATE study design Treatment outcomes in iMCD

Major Breakthroughs and Emerging Therapies

For UCD, the most consequential recent advance has been the 2020 international consensus guideline confirming complete surgical excision as the preferred first-line treatment and often a cure. Research for unresectable UCD is focused on making surgery feasible through approaches such as medical shrinkage of inflammatory masses, embolization to reduce bleeding risk, or selected radiotherapy, rather than on gene or cell therapies. UCD treatment guidelines

For iMCD, a leading drug-repurposing strategy targets the PI3K–AKT–mTOR signaling pathway, which helps regulate immune-cell growth and inflammatory activity. A 2020 study of the severe iMCD-TAFRO subtype found type-I interferon signatures and increased mTOR activation, strengthening the biological rationale for the oral mTOR inhibitor sirolimus. Type-I interferon and mTOR in iMCD-TAFRO A 2024 retrospective study of 26 relapsed or refractory iMCD patients treated with sirolimus-containing regimens reported symptomatic and biochemical responses in 18 patients, but most remained on treatment and the nonrandomized design cannot establish a cure. Sirolimus retrospective study

Researchers are also trying to improve cytokine-directed treatment. VDJ-001, an investigational high-affinity antibody against the IL-6 receptor, was studied in a Chinese phase II program; a 2025 conference report described responses in a small open-label cohort, but the evidence remains preliminary because it has not yet been reported as a full peer-reviewed trial publication. VDJ-001 phase II abstract Meanwhile, an intensive multi-platform study identified increased tumor necrosis factor (TNF) signaling in iMCD-TAFRO and reported a 22-month remission in one highly treatment-refractory patient after adalimumab, a TNF inhibitor, was added to their regimen. This is an important hypothesis-generating result, not proof that TNF inhibition works broadly or cures iMCD. TNF signaling in iMCD

A major conceptual advance is the shift from viewing Castleman disease solely as an abnormal immune-cell disorder to examining the lymph node’s supporting framework, or stroma. Spatial and single-cell profiling published in 2025 identified activated follicular dendritic cells and other stromal-cell populations as likely sources of IL-6 and VEGF signaling, and implicated JAK–STAT, TGF-beta, and MAPK pathways in cell-to-cell disease circuits. These findings create a broader target list, including CXCL13, VEGF-related signaling, and stromal–immune interactions, but none has yet produced a validated curative treatment. Spatial and single-cell mapping

Clinical Trials and Experimental Approaches

The University of Pennsylvania’s phase II sirolimus trial for previously treated iMCD, NCT03933904, was active but not recruiting as of its February 2026 verification. The study enrolled seven participants, with four evaluable for reported analyses; posted results show one participant achieved a durable symptomatic response, while the small sample and incomplete follow-up preclude reliable conclusions about efficacy or remission durability. Sirolimus phase II results

The most notable currently recruiting U.S. interventional study is NCT07085039, a University of Pennsylvania phase II, single-arm trial of the JAK1/2 inhibitor ruxolitinib for adults with iMCD that is refractory to, relapsed after, or cannot tolerate IL-6-directed treatment. The trial began in December 2025, plans to enroll 14 participants, and is designed to assess clinical-benefit response at approximately 12 months; no outcomes are yet available. Ruxolitinib phase II trial Other efforts illustrate the difficulty of small rare-disease trials: a dose-escalation siltuximab study was terminated for an internal company decision without posted results, and a prospective trial of the BTK inhibitor zanubrutinib stopped early after none of its first five participants achieved an overall response at week 12. Siltuximab dose-escalation trial Zanubrutinib trial

Methodologies and Scientific Approaches

The field increasingly combines longitudinal clinical data with laboratory samples. The ACCELERATE registry collects patient-reported and medical-record data, pathology, imaging, and biospecimens internationally, enabling expert diagnostic review and real-world comparisons of treatment response in a disease too rare for frequent large randomized trials. ACCELERATE study design In a 2023 analysis of 102 expert-confirmed iMCD cases, anti-IL-6 therapy with or without corticosteroids was associated with a 52% response rate, whereas corticosteroid treatment alone was associated with a 3% response rate. Treatment outcomes in iMCD

At the laboratory level, researchers use serum proteomics, single-cell RNA sequencing, spatial transcriptomics, immune-cell stimulation experiments, and computational drug-repurposing models to connect disease activity with potential treatment targets. A recent TNF study combined these methods with a machine-learning framework that ranked already approved drugs for possible use in iMCD, while tissue-mapping studies aim to identify the specific cells producing inflammatory signals. TNF signaling in iMCD Spatial and single-cell mapping

Leading Institutions and Funding

The University of Pennsylvania, University of Arkansas for Medical Sciences, Peking Union Medical College Hospital, Johns Hopkins University, Children’s Hospital of Philadelphia, and international CDCN collaborators are prominent contributors to current Castleman disease research. The University of Pennsylvania leads ACCELERATE, the sirolimus study, and the recruiting ruxolitinib study; the latter lists Incyte Corporation and the National Heart, Lung, and Blood Institute as collaborators. ACCELERATE registry Ruxolitinib phase II trial

The Castleman Disease Collaborative Network (CDCN) has supplied essential rare-disease infrastructure and targeted seed funding. Its reported Million Dollar Bike Ride grants included $64,590 in 2020 for JAK1/2-target research, $64,205 in 2021 for CXCL13 biomarker and target research, $60,570 in 2022 for a spatiotemporal gene atlas, $63,270 in 2023 for patient-derived cell transplantation in immunodeficient mice, and $58,775 in 2024 for pathogenic T-cell clonality research. CDCN Million Dollar Bike Ride grants The CDCN reports approximately $1 million directly invested in research that helped generate more than $7 million in additional research support. CDCN impact history

Strengths, Limitations, and Challenges

The strongest feature of the current effort is its practical, data-driven focus on treatment-resistant disease. Researchers are testing mechanisms suggested by patient samples and then prioritizing medicines that can be repurposed quickly, such as sirolimus, ruxolitinib, and adalimumab. The field has also developed more consistent composite response criteria that consider symptoms, laboratory inflammation and organ function, and lymph-node size rather than relying on one measure alone. iMCD treatment guidelines TNF signaling in iMCD

The central limitation is that iMCD is both rare and biologically heterogeneous. Most trials enroll very few people, often lack a control group, and measure response while patients continue therapy, making it difficult to distinguish durable disease control from cure. IL-6 blockade remains highly valuable but does not help every patient, and the negative zanubrutinib study shows that a plausible immune target can still fail clinically. Access to expert pathology review, specialty care, expensive biologics, and clinical trials also remains uneven. Treatment outcomes in iMCD Zanubrutinib trial

Outlook and Future Directions

As of September 11, 2026, UCD is frequently curable with complete surgery, but a curative therapy for systemic MCD—especially iMCD—remains out of reach. The most important milestones to watch are full publication and longer follow-up from the sirolimus and VDJ-001 studies, recruitment and results from the ruxolitinib phase II trial, replication of TNF-inhibition findings in more patients, and validation of stromal-cell, CXCL13, and molecular-subtype biomarkers that could match each patient to the pathway actually driving their disease. Sirolimus phase II results Ruxolitinib phase II trial Spatial and single-cell mapping

References

• Castleman disease — NIH Genetic and Rare Diseases Information Center, 2026.
• International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease — van Rhee et al., 2020.
• International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease — van Rhee et al., 2018.
• ACCELERATE: A Patient-Powered Natural History Study Design Enabling Clinical and Therapeutic Discoveries in a Rare Disorder — Pierson et al., 2020.
• Treatment consistent with idiopathic multicentric Castleman disease guidelines is associated with improved outcomes — Pierson et al., 2023.
• Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease — Pai et al., 2020.
• Sirolimus is effective for refractory/relapsed idiopathic multicentric Castleman disease: A single-center, retrospective study — Zhang et al., 2024.
• Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease: Study Results — ClinicalTrials.gov, 2026.
• An open-label Phase II trial of VDJ-001, a high-affinity IL-6R antagonist antibody, for the treatment of patients with idiopathic multicentric Castleman disease — Zhang et al., 2025.
• Identifying and Targeting TNF Signaling in Idiopathic Multicentric Castleman Disease — Mumau et al., 2025.
• Spatial and single cell mapping of Castleman disease reveals key stromal cell types and cytokine pathways — Smith et al., 2025.
• Ruxolitinib in Previously Treated Idiopathic Multicentric Castleman Disease — ClinicalTrials.gov, 2026.
• Siltuximab In Siltuximab-RElapsed/REfractory Multicentric CAstleman Disease — ClinicalTrials.gov, 2021.
• A prospective study of zanubrutinib, a Bruton tyrosine kinase inhibitor, in relapsed/refractory idiopathic multicentric Castleman disease — Zhang et al., 2024.
• International Registry for Patients With Castleman Disease — ClinicalTrials.gov, 2026.
• Million Dollar Bike Ride — Castleman Disease Collaborative Network, 2026.
• Our Story — Castleman Disease Collaborative Network, 2026.