Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease

Abstract

Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.

Figure 1.

Uniform subclassification for patients with lymph nodes demonstrating features consistent with CD. Patients with lymph nodes demonstrating histology consistent with the CD spectrum (hypervascular/hyaline-vascular, plasmacytic, or mixed features) should be evaluated for number of regions of enlarged lymph nodes. If lymph node involvement is restricted to 1 site, the lesion most likely represents unicentric CD. If multiple sites are involved, patients should be evaluated for HHV-8, POEMS, and other infectious, malignant, and autoimmune disorders that can mimic iMCD. If these conditions are excluded, a diagnosis of iMCD should be considered. iMCD can be further subclassified into patients with iMCD with TAFRO syndrome (iMCD-TAFRO) and others whose subtype is not otherwise specified (iMCD-NOS). Adapted from Fajgenbaum et al.

Figure 2.

Updated model of iMCD pathogenesis. Three hypothesized mechanisms may be responsible for the iMCD cytokine and chemokine storm: first, the autoimmune/autoinflammatory hypothesis involves (1a) auto-antibodies triggering proinflammatory cytokine release by antigen-presenting cells that induce the as-yet-unknown hypercytokine-secreting cell to release IL-6 or other pathologic cytokines; (1b/c) dysregulated signaling in an antigen presenting cell or other as-yet-unknown hypercytokine-secreting cell releasing IL-6 or other pathologic cytokines, or (1d) a defect in the regulation of activated inflammatory cells. The cytokine and chemokine storm is perpetuated by positive feedback of IL-6, other pathologic cytokines, and/or possibly further auto-antibody stimulation. Second, the paraneoplastic syndrome hypothesis involves a somatic mutation in benign or malignant cells inside or outside of the lymph node that causes constitutive cytokine release. Preliminary data suggest these may be lymph node stromal cells. Third, the pathogen hypothesis involves either infection with HHV-8 that is clinically undetectable, a novel virus, or another pathogen signaling proinflammatory cytokines. An active infection by a single virus is less likely based on preliminary data generated from pathogen discovery studies. Regardless of the etiology, the cytokine and chemokine storm is the common pathway that results in the subsequent clinical and histopathological features of iMCD. AAB, autoantibodies; AIHA, autoimmune hemolytic anemia; AIT, autoimmune thrombocytopenia; LAD, lymphadenopathy; PMN, polymorphic neutrophil. Adapted from Fajgenbaum et al.

Figure 3.

The Collaborative Network Approach being used to advance research for iMCD. The Castleman Disease Collaborative Network, patients, physicians, researchers, and industry are taking a systematic approach to advance CD research that may be repeatable by other disease fields. BOD, board of directors; RFP, request for proposals; SAB, scientific advisory board.