Do you know TAFRO?

In this issue of Blood, van Rhee et al report an evidence and opinion–based framework for treatment of idiopathic multicentric Castleman disease (CD), including consideration of how to assess therapeutic response and the pitfalls found in complex situations.¹ 

CD is an uncommon lymphoproliferative disorder with remarkably heterogeneous clinicopathologic findings united by the hallmark pathologic feature of angiofollicular lymph node hyperplasia.²  Consequently, CD does not have a uniform presentation or uniform symptoms.³  At diagnosis, it is important to determine whether a patient has localized (ie, unicentric) or disseminated (ie, multicentric; MCD) disease, also termed idiopathic MCD (iMCD) after a negative human herpes virus 8 test. Multisystem manifestations are present when associated with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, skin changes) syndrome.⁴ 

Patient presentations vary from asymptomatic to critically ill. The velocity of the disease likewise can vary from indolent to aggressive and immediately life threatening. This heterogeneity makes diagnosis and management a nightmare for most practitioners who rarely encounter CD during their careers.

Elevated inflammatory serum levels of interleukin-6 levels (IL-6) and vascular endothelial growth factor (VEGF) are frequently seen in CD. It is likely that all patients with CD do not have the same pathogenesis, and van Rhee and colleagues have previously proposed potential etiologies, including an autoimmune process, an autoinflammatory process, and a neoplastic process.⁵  Given the wide spectrum of presentations and etiologies, it is not surprising that the treatment approach varies significantly depending on the patient. Likewise, it is not surprising that not all cases suspected of being CD are confirmed.

In asymptomatic cases, active surveillance without therapy may be appropriate. In patients with symptoms, treatment has included surgery, radiotherapy, variable intensity corticosteroid treatment, lymphoma-based chemotherapy, anti-CD20 antibodies, interferon, anti–IL-6 antibodies, autologous hematopoietic stem cell transplantation, and allogeneic hematopoietic stem cell transplantation. The frequent elevation of IL-6 in patients with iMCD led to the use of anti–IL-6 antibodies in these patients. Anti–IL-6 antibodies including siltuximab and tocilizumab (if siltuximab is not available) frequently benefit these patients.^6,7  Relapse is frequent in patients in whom the antibody is discontinued. The authors recommend pursuing alternative therapies in patients who do not respond to an anti–IL-6 antibody or who subsequently progress. As the use of anti–IL-6 therapies has likely increased with its use in patients with cytokine release syndrome after infusion of chimeric antigen receptor T cells,⁸  more practitioners have become familiar with use of these agents.

With the current scrutiny of the influence of the pharmaceutical industry and the expensive of medications (such as the anti–IL-6 therapies), it is important to review the conflicts of interest listed by authors of clinical papers. In this case, several of the authors listed a relationship with a manufacturer of an anti–IL-6 antibody. Importantly, the authors of this paper based their recommendations on published data and their extensive clinical experience. Moreover, they had editorial control over the content of the manuscript.

The authors identify a specific population within iMCD that has a worse prognosis. The TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis of bone marrow, and organomegaly) syndrome is often associated with an elevated VEGF level and a lower IL-6 level.⁹  A normal γ-globulin (immunoglobulin G [IgG], IgM, and IgA) and a highly vascular lymph node architecture, possibly related to VEGF secretion, have also been noted. Patients with TAFRO-like presentations may benefit from alternative iMCD treatments as suggested by the authors.

CD is not a uniform entity. Some patients require less intensive therapy or local therapy alone. However, it is clear that a significant number of patients with symptomatic iMCD can benefit from an anti–IL-6 antibody, and that this may be the most effective therapy for many of these patients. It is important to remember that improved understanding of the biology of iMCD subtypes and subsequent rational reporting of disease response might lead to new and better therapeutic approaches. There are also patients in whom older treatment paradigms still offer the best chance for benefit. However, the authors have provided a useful outline for therapy that will prove valuable to hematologists and oncologists caring for patients with iMCD.