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Treatment of Idiopathic Castleman Disease

      Keywords

      Key points

      • Accurate diagnosis of the different varieties of multicentric Castleman disease is critical to guiding therapy.
      • Monoclonal antibodies targeting the interleukin-6 signaling pathway are the best-studied agents in idiopathic multicentric Castleman disease and are front-line therapy for more severely ill patients.
      • Rituximab has not been systematically studied, but is commonly used as initial therapy for more indolent idiopathic multicentric Castleman disease.
      • Chemotherapy and immunomodulatory drugs are best reserved for the relapse setting.
      • Autologous stem cell transplantation should be considered for patients with coexistent POEMS syndrome.

      Introduction

      Castleman disease (CD) is a rare, heterogeneous lymphoproliferative disorder first defined in 1954.
      • Castleman B.
      • Towne V.W.
      Case records of the Massachusetts General Hospital; weekly clinicopathological exercises; founded by Richard C. Cabot.
      The variable manifestations of CD and infrequent presentation outside of academic centers of excellence result in difficulty of diagnosis and management of the disease. CD may be divided into 2 major forms. Unicentric CD (UCD) is typically a slow-growing solitary mass occurring at a single anatomic site; although the enlarging mass may compress vital structures, surgical excision is generally curative. In contrast, multicentric CD (MCD) affects multiple lymph node stations and often presents with lymphadenopathy, fever, weight loss, fatigue, edema, anemia, and hypoalbuminemia.
      • Castleman B.
      • Iverson L.
      • Menendez V.P.
      Localized mediastinal lymph node hyperplasia resembling thymoma.
      • Peterson B.A.
      • Frizzera G.
      Multicentric Castleman's disease.
      • van Rhee F.
      • Stone K.
      • Szmania S.
      • et al.
      Castleman disease in the 21st century: an update on diagnosis, assessment, and therapy.
      In severe cases, patients may develop hepatosplenomegaly, massive ascites, pleural effusions, or organ failure, and both UCD and MCD sometimes progress to non-Hodgkin lymphoma (NHL). MCD often concomitantly presents in the context of infection with the human immunodeficiency virus (HIV) and/or human herpesvirus 8 (HHV8). However, approximately 50% of patients with MCD who are negative for HIV and HHV8 comprise a subgroup that has recently been termed as idiopathic MCD (iMCD), as no causative etiology has been established. The rarity of CD has unfortunately limited the ability to perform systematic studies providing solid evidence of superiority of therapeutic strategies. In this article, we report on evidence for various treatments to synthesize a treatment algorithm for the practicing physician.

      Clinical symptomatology of multicentric Castleman disease and role of interleukin-6

      Interleukin-6 (IL6) is a pleiotropic cytokine that plays a pivotal role in the pathogenesis and clinical symptomatology in many patients with iMCD. The notion that IL6 plays a causative role in iMCD is supported by several clinical and experimental observations. Clinically, MCD is characterized by a proinflammatory syndrome giving rise to the so-called B-symptoms comprising fevers, night sweats, malaise, and weight loss.
      • Stone K.
      • Woods E.
      • Szmania S.
      • et al.
      Prevalence of interleukin-6 receptor polymorphism in Castleman disease and association with increased soluble interleukin-6 receptor levels.
      The C-reactive protein (CRP) is commonly elevated and is considered to be a surrogate marker for IL6 bioactivity.
      • Liu Y.C.
      • Stone K.
      • van Rhee F.
      Siltuximab for multicentric Castleman disease.
      Elevated fibrinogen levels in the setting of a systemic inflammatory response can cause deep venous thrombosis and other thrombo-embolic disorders. IL6 is an important growth, differentiation, and survival factor for both plasma cells and lymphocytes contributing to lymph node enlargement, plasmacytic infiltration, hepatosplenomegaly, and reactive bone marrow plasmacytosis with polyclonal hypergammaglobulenemia. IL6 also dysregulates the humoral immune response resulting in positive antinuclear antibody assays in approximately one-third of the patients, immune thrombocytopenia, hemolytic anemia, as well as a host of other autoimmune phenomena likely caused by expansion of CD5+ B-lymphocytes.
      • Hall P.A.
      • Donaghy M.
      • Cotter F.E.
      • et al.
      An immunohistological and genotypic study of the plasma cell form of Castleman's disease.
      • Menke D.M.
      • Tiemann M.
      • Camoriano J.K.
      • et al.
      Diagnosis of Castleman's disease by identification of an immunophenotypically aberrant population of mantle zone B lymphocytes in paraffin-embedded lymph node biopsies.
      Together with other cytokines, IL6 also induces polyclonal T-cell outgrowth reflected by the presence of activated CD8+ T cells and increased soluble IL2 receptor levels. During the inflammatory response, IL6 increases the production of the peptide hormone regulator of iron homeostasis, hepcidin, by the liver. Hepcidin reduces intestinal iron absorption and impairs release of stored iron from macrophages, thus causing anemia.
      • Sharma S.
      • Nemeth E.
      • Chen Y.H.
      • et al.
      Involvement of hepcidin in the anemia of multiple myeloma.
      • Song S.N.
      • Tomosugi N.
      • Kawabata H.
      • et al.
      Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease.
      Furthermore, IL6 inhibits albumin production by the liver, leading to hypoalbuminemia. IL6-induced vascular endothelial growth factor (VEGF) secretion promotes angiogenesis and vascular permeability; the latter combines with hypoalbuminemia to induce edema, ascites, pleural and pericardial effusions, and generalized anasarca due to vascular leak syndrome. In severe cases of iMCD, renal failure occurs, often due to thrombotic microangiopathy and multiorgan failure can ensue, resulting in death.
      The role of IL6 is further underscored by the observation that surgical debulking with removal of lymph nodes can lead to rapid reductions in IL6 levels and clinical improvement.
      • Yoshizaki K.
      • Matsuda T.
      • Nishimoto N.
      • et al.
      Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease.
      Patients who have other malignancies that overproduce IL6 can have pathologic changes in enlarged lymph nodes that resemble CD and that resolve following surgical resection or with monoclonal antibody (mAb)-mediated IL6 blockade.
      • Momoi A.
      • Kojima M.
      • Sakai T.
      • et al.
      IL-6-positive classical Hodgkin's lymphoma co-occurring with plasma cell type of Castleman's disease: report of a case.
      • Gleason B.C.
      • Hornick J.L.
      Inflammatory myofibroblastic tumours: where are we now?.
      IL6 levels can also wax and wane in step with the severity of clinical symptoms.
      • Stone K.
      • Woods E.
      • Szmania S.
      • et al.
      Prevalence of interleukin-6 receptor polymorphism in Castleman disease and association with increased soluble interleukin-6 receptor levels.
      Mice in which IL6 is overexpressed using retroviral transduced bone marrow cells develop a Castleman-like syndrome.
      • Brandt S.J.
      • Bodine D.M.
      • Dunbar C.E.
      • et al.
      Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice.
      • Brandt S.J.
      • Bodine D.M.
      • Dunbar C.E.
      • et al.
      Retroviral-mediated transfer of interleukin-6 into hematopoietic cells of mice results in a syndrome resembling Castleman's disease.
      In IL6 transgenic mice, a similar MCD picture emerges, which is ameliorated by neutralization of IL6 with an antibody directed at the IL6 receptor (IL6R).
      • Aoki Y.
      • Jaffe E.S.
      • Chang Y.
      • et al.
      Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6.
      • Katsume A.
      • Saito H.
      • Yamada Y.
      • et al.
      Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman's disease like symptoms emerged in IL-6 transgenic mice.
      IL6 transcription is regulated by the transcription factor C/EBPβ and CCAAT/enhancer binding protein-β knockout transgenic mice develop lymphadenopathy, splenomegaly, and other Castleman features.
      • Screpanti I.
      • Romani L.
      • Musiani P.
      • et al.
      Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice.
      Interestingly viral IL6 expression in mice also yields an MCD-like phenotype. However, this phenotype is mitigated when the viral IL6 transgene is expressed into IL6 knockout mice suggesting that even in virally induced MCD, endogenous IL6 remains a critical cofactor.
      • Suthaus J.
      • Stuhlmann-Laeisz C.
      • Tompkins V.S.
      • et al.
      HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice.
      Recombinant IL6 given to humans also leads to a syndrome resembling MCD.
      • van Gameren M.M.
      • Willemse P.H.
      • Mulder N.H.
      • et al.
      Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study.
      Polymorphism of a minor IL6R allele is more prevalent in iMCD and may result in increased IL6 trans-signaling.
      • Stone K.
      • Woods E.
      • Szmania S.
      • et al.
      Prevalence of interleukin-6 receptor polymorphism in Castleman disease and association with increased soluble interleukin-6 receptor levels.
      The exact nature of the IL6 secreting cell(s) has not been elucidated and proposed candidates include B-lymphocytes, plasma cells, monocytes, macrophages, follicular dendritic cells, and stromal cells.
      • Yoshizaki K.
      • Matsuda T.
      • Nishimoto N.
      • et al.
      Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease.
      • Ishiyama T.
      • Nakamura S.
      • Akimoto Y.
      • et al.
      Immunodeficiency and IL-6 production by peripheral blood monocytes in multicentric Castleman's disease.
      • Leger-Ravet M.B.
      • Peuchmaur M.
      • Devergne O.
      • et al.
      Interleukin-6 gene expression in Castleman's disease.
      • Lai Y.M.
      • Li M.
      • Liu C.L.
      • et al.
      Expression of interleukin-6 and its clinicopathological significance in Castleman's disease.
      • Chang K.C.
      • Wang Y.C.
      • Hung L.Y.
      • et al.
      Monoclonality and cytogenetic abnormalities in hyaline vascular Castleman disease.
      Although, IL6 may not be of pathogenic significance in all patients, the aforementioned findings have sparked the interest in mAbs therapeutically targeting the IL6 signaling cascade as described later in this article.

      Multicentric Castleman Disease Classification and Therapy

      It is important to render a correct diagnosis and recognize the distinct variants of MCD, which require different therapy. Until recently, most of the medical literature has focused on patients with HIV who develop MCD and are coinfected with HHV8. HHV8-accociated MCD is a separate entity requiring a different therapeutic approach usually based on rituximab with or without etoposide or doxorubicin. HIV-induced immunosuppression can lead to lytic replication of immunoglobulin (Ig)M/λ restricted plasmablasts, which often express CD20, in the lymph node mantle zones and interfollicular areas that can be efficiently targeted with rituximab.
      • Marcelin A.G.
      • Aaron L.
      • Mateus C.
      • et al.
      Rituximab therapy for HIV-associated Castleman disease.
      • Hoffmann C.
      • Schmid H.
      • Muller M.
      • et al.
      Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease.
      • Gerard L.
      • Michot J.M.
      • Burcheri S.
      • et al.
      Rituximab decreases the risk of lymphoma in patients with HIV-associated multicentric Castleman disease.
      • Uldrick T.S.
      • Polizzotto M.N.
      • Aleman K.
      • et al.
      Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease.
      HHV8 encodes for the viral orthologue of IL6, which can induce the release of human IL6 and precipitate a cytokine storm responsible for the clinical symptomatology. Although HHV8 reactivation is classically associated with HIV infection, cases of HHV8-positive MCD have also been reported without concomitant HIV infection. Furthermore, these HIV-negative cases have similar clinical presentation compared with their HIV-positive counterparts, justifying their classification as a single clinicopathological entity, which require a similar therapeutic approach.
      • Dossier A.
      • Meignin V.
      • Fieschi C.
      • et al.
      Human herpesvirus 8-related Castleman disease in the absence of HIV infection.
      • Nicoli P.
      • Familiari U.
      • Bosa M.
      • et al.
      HHV8-positive, HIV-negative multicentric Castleman's disease: early and sustained complete remission with rituximab therapy without reactivation of Kaposi sarcoma.
      • Marietta M.
      • Pozzi S.
      • Luppi M.
      • et al.
      Acquired haemophilia in HIV negative, HHV-8 positive multicentric Castleman's disease: a case report.
      • Oksenhendler E.
      • Duarte M.
      • Soulier J.
      • et al.
      Multicentric Castleman's disease in HIV infection: a clinical and pathological study of 20 patients.
      HHV8-associated MCD can be recognized by either a positive HHV8 latency associated nuclear antigen test of lymph node tissue or the detection of circulating HHV8 DNA in the peripheral blood indicative of actively replicating HHV8. HHV8 serology should not be used to identify HHV8-positive MCD because it has poor sensitivity and specificity.
      • Dossier A.
      • Meignin V.
      • Fieschi C.
      • et al.
      Human herpesvirus 8-related Castleman disease in the absence of HIV infection.
      It has become increasingly clear that there is a significant population of patients with MCD who are not infected with HIV or HHV8 and are referred to as iMCD. Until recently, there were no uniform diagnostic criteria for iMCD. An international working group from 8 countries has now defined consensus criteria for the diagnosis of iMCD. Patients should have enlargement of 2 or more lymph node stations and lymph node pathology compatible with iMCD. Other diseases that can give rise to similar pathology should be actively excluded. These include autoimmune disorders, such as systemic lupus erythematosus, infections, or lymphoma. Further, patients should have at least 2 of 11 minor criteria, of which one should be a laboratory parameter reflecting an active inflammatory state.
      • Fajgenbaum D.C.
      • Uldrick T.S.
      • Bagg A.
      • et al.
      International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.
      The establishment of these diagnostic criteria will help to evaluate patients, assist physicians to arrive at the correct diagnosis, and lead to the implementation of appropriate therapy as discussed later in this article.
      A subgroup of patients labeled as having TAFRO syndrome (Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, and Organomegaly) appear to be more severely ill and often have renal impairment and have worse outcome than other patients with iMCD.
      • Masaki Y.
      • Nakajima A.
      • Iwao H.
      • et al.
      Japanese variant of multicentric Castleman's disease associated with serositis and thrombocytopenia–a report of two cases: is TAFRO syndrome (Castleman-Kojima disease) a distinct clinicopathological entity?.
      • Inoue M.
      • Ankou M.
      • Hua J.
      • et al.
      Complete resolution of TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) after immunosuppressive therapies using corticosteroids and cyclosporin A: a case report.
      • Iwaki N.
      • Sato Y.
      • Takata K.
      • et al.
      Atypical hyaline vascular-type Castleman's disease with thrombocytopenia, anasarca, fever, and systemic lymphadenopathy.
      • Tedesco S.
      • Postacchini L.
      • Manfredi L.
      • et al.
      Successful treatment of a Caucasian case of multifocal Castleman's disease with TAFRO syndrome with a pathophysiology targeted therapy—a case report.
      • Abdo L.
      • Morin C.
      • Collarino R.
      • et al.
      First European case of TAFRO syndrome associated with Sjogren disease.
      • Iwaki N.
      • Fajgenbaum D.C.
      • Nabel C.S.
      • et al.
      Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease.
      • Yu L.
      • Tu M.
      • Cortes J.
      • et al.
      Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease.
      The clinical course of TAFRO syndrome is more aggressive and characterized by frequent steroid refractoriness requiring additional therapies, including tocilizumab, cytoxic agents, cyclosporin, and rituximab, as reported by Iwaki and colleagues
      • Iwaki N.
      • Fajgenbaum D.C.
      • Nabel C.S.
      • et al.
      Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease.
      in a series of 25 patients. Three of 7 patients did not respond to anti-IL6 mAb therapy. Further, patients often have normal gamma globulin levels, elevated alkaline phosphatase, and relatively modest size lymphadenopathy. Future studies will have to determine whether TAFRO is a distinct clinical entity in the iMCD spectrum with its own pathophysiology and unique cytokine profile, because IL6 seems to be less elevated than in non-TAFRO patients with plasmacytic variant of iMCD. It may be even be that some of these patients will require novel therapeutic approaches.
      It is important to realize that the distinction between UCD and iMCD is not always absolute and that there are patients who have more limited lymph node involvement and are referred to as having “regional” or “oligocentric” CD. Often these patients have no associated B-symptomatology or proinflammatory markers, and these patients should be managed more like UCD. A further group of patients requiring different treatment are patients suffering from both POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) and MCD, or those who have MCD with features of POEMS, but not meeting formal diagnostic criteria of POEMS.
      • Fajgenbaum D.C.
      • Uldrick T.S.
      • Bagg A.
      • et al.
      International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.
      • Dispenzieri A.
      POEMS syndrome: 2017 update on diagnosis, risk stratification, and management.

      Therapeutic Options for Idiopathic Multicentric Castleman Disease

      Overview

      A large variety of different treatments have been used to manage iMCD. These therapeutic modalities include surgery, corticosteroids, rituximab, combination chemotherapy, autologous stem cell transplantation (ASCT), mAbs interrupting the IL6 signaling cascade, novel agents such as bortezomib, thalidomide, the IL1-antagonist, anakinra, and other immunomodulatory molecules, such as interferon-α and all-trans retinoic acid. Most of these reports are based on small series, case reports, literature reviews, and retrospective analyses of institutional experiences. Only one prospective randomized placebo-controlled trial has been conducted in iMCD studying the efficacy of the IL6-neutralizing mAb siltuximab.
      • van Rhee F.
      • Casper C.
      • Voorhees P.M.
      • et al.
      A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease.
      Interpretation of the data is further hampered by the previous lack of uniform diagnostic criteria, clinical heterogeneity of the various patient populations, likely bias toward reporting positive findings, important missing clinical parameters (eg, HHV8 status), and inconsistency in measuring outcome parameters. There are also presently no biomarkers that predict response to a specific therapy. Treatment recommendations are therefore not based on hard clinical evidence, but rather on the expert opinion of those actively involved in the care of patients with iMCD and with knowledge of the literature.

      Overall outcome of idiopathic multicentric Castleman disease

      Several studies have reported on the outcome of MCD. Dispenzieri and colleagues
      • Dispenzieri A.
      • Armitage J.O.
      • Loe M.J.
      • et al.
      The clinical spectrum of Castleman's disease.
      reported on a retrospective series of 113 patients treated at the Mayo Clinic and the University of Nebraska. The 5-year overall survival (OS) was only 65% for patients with MCD versus 91% for patients with UCD. With a median follow-up of 5.8 years, 37 patients had died. This patient cohort was not formally tested for HIV or HHV8, but none had clinical AIDS at diagnosis nor subsequently during follow-up. Because of existing referral patterns, this patient population was enriched for POEMS syndrome, which likely impacted outcome. The 5-year OS for patients without coexistent POEMS syndrome was respectively 65% for patients without peripheral neuropathy and only 51% for patients who did suffer from peripheral neuropathy. The most indolent course was observed in patients who had POEMS syndrome with coexistent osteosclerotic lesions who enjoyed a 5-year OS of 90%, contrasting to those without osteosclerosis who fared worse with a dismal 5-year OS of 27%. Most of these patients were treated with steroids or chemotherapy. One can only speculate that patients with MCD without POEMS may have benefited from modern treatment approaches with rituximab or anti-IL6 agents, whereas those with POEMS would presently be considered for ASCT. Talat and Schulte
      • Talat N.
      • Schulte K.M.
      Castleman's disease: systematic analysis of 416 patients from the literature.
      reported on 384 HIV-negative patients with MCD, of whom 148 had 3-year disease-free survival (DFS) data. Patients with plasmacytic variant of MCD had a 3-year DFS of only 45%. Three-year DFS was significantly better in younger patients (<37), female patients, or those with hyaline-vascular versus plasmacytic pathology. It was not possible to evaluate how outcome was influenced by different therapeutic interventions because treatment details were not supplied. Liu and colleagues
      • Liu A.Y.
      • Nabel C.S.
      • Finkelman B.S.
      • et al.
      Idiopathic multicentric Castleman's disease: a systematic literature review.
      performed a systematic literature review of 114 patients with iMCD who were treated with a variety of modalities, including steroids, chemotherapy, rituximab, and anti-IL6 mAbs. The 2-year OS was 88% with a follow-up of 29 months; 27 (22%) patients died during the follow-up period. Interestingly, 24 patients had a separate malignant disease (solid tumor, n = 13; hematologic malignancy, n = 11) either at diagnosis of iMCD or during follow-up. Two-year survival was significantly better in patients without a malignancy (92% vs 70%). Other adverse prognostic features included age older than 37 years, plasmacytic histology, thrombocytopenia, hypergammaglobulinemia, and features of TAFRO syndrome, although statistical significance was achieved only for a concomitant malignancy. Taken together, these studies did not identify any consistent prognostic factors across all studies, but findings do poignantly highlight that iMCD is a life-threatening disorder for many patients, with DFS and OS rates that are typically seen with malignant disorders.

      Surgery and irradiation

      Complete surgical resection is rarely feasible in iMCD, although it is often curative for UCD. In a series of 127 patients with MCD, debulking surgery did not improve 10-year OS whether surgery was performed alone or as adjunct therapy.
      • Talat N.
      • Belgaumkar A.P.
      • Schulte K.M.
      Surgery in Castleman's disease: a systematic review of 404 published cases.
      Other investigators have also not reported meaningful contributions of surgery in the MCD setting.
      • Herrada J.
      • Cabanillas F.
      • Rice L.
      • et al.
      The clinical behavior of localized and multicentric Castleman disease.
      • Bowne W.B.
      • Lewis J.J.
      • Filippa D.A.
      • et al.
      The management of unicentric and multicentric Castleman's disease: a report of 16 cases and a review of the literature.
      There is no role for splenectomy as a diagnostic procedure, but it can occasionally be useful in the management of therapy-resistant hemolytic anemia.
      • Lerza R.
      • Castello G.
      • Truini M.
      • et al.
      Splenectomy induced complete remission in a patient with multicentric Castleman's disease and autoimmune hemolytic anemia.
      Similarly, there is no established role for radiotherapy in MCD.
      • Chronowski G.M.
      • Ha C.S.
      • Wilder R.B.
      • et al.
      Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy.
      Patients with coexistent POEMS syndrome and a localized plasmacytoma may benefit from local radiotherapy, although it is not clear to what extent any associated iMCD would be improved.

      Corticosteroids

      Corticosteroids can suppress the hypercytokinemia in iMCD, but this typically requires high-dose therapy, which cannot be sustained for a prolonged period. Long-term disease control and lasting remissions with steroid therapy are uncommon, and relapses occur frequently on cessation of therapy or during steroid tapering.
      • Herrada J.
      • Cabanillas F.
      • Rice L.
      • et al.
      The clinical behavior of localized and multicentric Castleman disease.
      • Bowne W.B.
      • Lewis J.J.
      • Filippa D.A.
      • et al.
      The management of unicentric and multicentric Castleman's disease: a report of 16 cases and a review of the literature.
      • Chronowski G.M.
      • Ha C.S.
      • Wilder R.B.
      • et al.
      Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy.
      • Kessler E.
      Multicentric giant lymph node hyperplasia. A report of seven cases.
      • Weisenburger D.D.
      • Nathwani B.N.
      • Winberg C.D.
      • et al.
      Multicentric angiofollicular lymph node hyperplasia: a clinicopathologic study of 16 cases.
      • Frizzera G.
      • Peterson B.A.
      • Bayrd E.D.
      • et al.
      A systemic lymphoproliferative disorder with morphologic features of Castleman's disease: clinical findings and clinicopathologic correlations in 15 patients.
      Prolonged steroid therapy also increases the risk of bacterial infection and sepsis. Steroids can be useful in achieving initial disease control in combination with chemotherapy, rituximab, or anti-IL6 mAb therapy and should be seen as an adjunct therapy. Selected patients may benefit from low-dose steroid therapy in the maintenance setting, usually in combination with other agents.
      • Nishimoto N.
      • Kanakura Y.
      • Aozasa K.
      • et al.
      Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease.
      • van Rhee F.
      • Wong R.S.
      • Munshi N.
      • et al.
      Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.

      Chemotherapy

      There has been no systematic evaluation of chemotherapy in controlled studies. Typically, chemotherapy regimens have been adopted from NHL therapy and include CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisolone) or CVAD (cyclophosphamide, vincristine, adriamycin, etoposide)-like regimens with or without rituximab. The authors of this article have used combination chemotherapy used for myeloma, for example, VDTPACE (velcade [bortezomib], dexamethasone, thalidomide, cisplatinum, adriamycin, cyclophosphamide, etoposide).
      • van Rhee F.
      • Szymonifka J.
      • Anaissie E.
      • et al.
      Total therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy.
      Lasting remissions have been reported by some investigators. In one early report, 27% of patients had a sustained remission,
      • Herrada J.
      • Cabanillas F.
      • Rice L.
      • et al.
      The clinical behavior of localized and multicentric Castleman disease.
      whereas Chronowski and colleagues
      • Chronowski G.M.
      • Ha C.S.
      • Wilder R.B.
      • et al.
      Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy.
      observed a progression-free survival (PFS) varying from 23 to 119 months in 4 of 9 responding patients. Zhu and colleagues
      • Zhu S.H.
      • Yu Y.H.
      • Zhang Y.
      • et al.
      Clinical features and outcome of patients with HIV-negative multicentric Castleman's disease treated with combination chemotherapy: a report on 10 patients.
      reported on 10 patients with iMCD treated with CHOP or COP (cyclophosphamide, vincristine [Oncovin], prednisolone). One achieved complete response (CR), and 6 had a partial response (PR), with all 7 patients remaining alive with a median follow-up of 34 months. However, others failed to document meaningful responses.
      • Weisenburger D.D.
      • Nathwani B.N.
      • Winberg C.D.
      • et al.
      Multicentric angiofollicular lymph node hyperplasia: a clinicopathologic study of 16 cases.
      • Frizzera G.
      • Peterson B.A.
      • Bayrd E.D.
      • et al.
      A systemic lymphoproliferative disorder with morphologic features of Castleman's disease: clinical findings and clinicopathologic correlations in 15 patients.
      In a recent retrospective literature review, cytotoxic therapy induced CR in 19 of 43 patients with a median time to treatment failure of 6 months.
      • Liu A.Y.
      • Nabel C.S.
      • Finkelman B.S.
      • et al.
      Idiopathic multicentric Castleman's disease: a systematic literature review.
      It seems appropriate to reserve chemotherapy for the salvage setting in view of its toxicity and the availability of other active agents, such as rituximab and the anti-IL6 mAbs, tocilizumab and siltuximab. A notable exception to this recommendation may be critically ill patients who fail to respond to mAb therapy and steroids. In this setting, prompt institution of combination chemotherapy can be literally lifesaving.

      Rituximab

      The introduction of rituximab in patients with HIV-positive, HHV8-positive MCD has greatly improved outcome in several studies and significantly decreased the risk of transformation to lymphoma.
      • Gerard L.
      • Michot J.M.
      • Burcheri S.
      • et al.
      Rituximab decreases the risk of lymphoma in patients with HIV-associated multicentric Castleman disease.
      • Uldrick T.S.
      • Polizzotto M.N.
      • Aleman K.
      • et al.
      Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease.
      • Bower M.
      • Powles T.
      • Williams S.
      • et al.
      Brief communication: rituximab in HIV-associated multicentric Castleman disease.
      • Gerard L.
      • Berezne A.
      • Galicier L.
      • et al.
      Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's disease: ANRS 117 CastlemaB trial.
      • Bower M.
      • Newsom-Davis T.
      • Naresh K.
      • et al.
      Clinical features and outcome in HIV-associated multicentric Castleman's disease.
      Rituximab eliminates a reservoir of CD20+ B-cells and plasmablasts in which HHV8 lytically replicates explaining its activity in HHV8-positive MCD. Rituximab has also been widely used for the treatment of iMCD and is recommended by the National Comprehensive Cancer Network guidelines as one of the primary therapies for iMCD (www.nccn.org). However, there have been no clinical trials assessing the efficacy of rituximab and there have been remarkably few case reports or series in the literature pertaining to iMCD.
      • Ocio E.M.
      • Sanchez-Guijo F.M.
      • Diez-Campelo M.
      • et al.
      Efficacy of rituximab in an aggressive form of multicentric Castleman disease associated with immune phenomena.
      • Ide M.
      • Ogawa E.
      • Kasagi K.
      • et al.
      Successful treatment of multicentric Castleman's disease with bilateral orbital tumour using rituximab.
      • Gholam D.
      • Vantelon J.M.
      • Al-Jijakli A.
      • et al.
      A case of multicentric Castleman's disease associated with advanced systemic amyloidosis treated with chemotherapy and anti-CD20 monoclonal antibody.
      In one report describing 25 cases of iMCD, the CR and PR rates with rituximab as first-line therapy were 20% and 48%, respectively, with the anti-IL6 mAb siltuximab outperforming rituximab in terms of PFS.
      • Yu L.
      • Tu M.
      • Cortes J.
      • et al.
      Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease.
      More encouragingly, in another series, 5 of 8 patients achieved CR with rituximab as sole therapy and only one failed therapy.
      • Liu A.Y.
      • Nabel C.S.
      • Finkelman B.S.
      • et al.
      Idiopathic multicentric Castleman's disease: a systematic literature review.
      Despite the lack of robust data, the use of rituximab is firmly entrenched in the treatment of iMCD and perceived as a therapy of limited duration, which can induce durable remissions. Furthermore, many oncologists feel very comfortable with rituximab, which was first approved in 1997 and is widely used for the treatment of a variety of B-lymphoid malignancies, including follicular and diffuse large-cell lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia. Although no formal clinical studies are anticipated in the future, the ACCELERATE registry of the Castleman Disease Collaborative Network (CDCN) will play an important future role in collecting “real-life” data regarding the efficacy of rituximab and help to further clarify the role of rituximab in iMCD (www.cdcn.org).

      Anti-IL6 agents

      IL6 binds to the IL6R, which is present as soluble or membrane-bound, producing a complex that binds to the glycoprotein 130 (gp130), resulting in dimerization and activating of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade promoting cell survival and proliferation. The introduction of mAbs directed at the IL6 pathway is an important contribution to the therapeutic armamentarium for iMCD. Two mAbs that target the IL6 signaling cascade have been extensively studied in iMCD (Fig. 1). Tocilizumab is a humanized Igκ mAb that binds to both the soluble and membrane-bound forms of the IL6R. Siltuximab is a chimeric human-murine Igκ mAb, which directly binds to IL6. The first clinical application of an IL6 mAb in a patient with CD was reported by Beck and colleagues
      • Beck J.T.
      • Hsu S.M.
      • Wijdenes J.
      • et al.
      Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody.
      using the murine antibody BE-8. Although the antibody induced a clinical response, symptoms rapidly recurred after cessation of therapy. The antibody had a short half-life and was unable to block large quantities of IL6, leading to the search for more potent antibodies.
      Figure thumbnail gr1
      Fig. 1Blockade of IL6 signaling by monoclonal antibodies. IL6 signaling occurs when IL6 interacts with either the soluble or membrane-bound form of IL6R. In association with the signal transducer gp130, this complex results in dimerization and activation of the JAK/STAT signaling cascade. The mAbs siltuximab and tocilizumab disrupt IL6 signaling by blocking IL6 or the IL6R (in soluble or membrane-bound form), respectively.
      Sato and colleagues
      • Sato K.
      • Tsuchiya M.
      • Saldanha J.
      • et al.
      Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth.
      subsequently created a humanized anti-IL6R antibody by grafting the complementarity region of the murine anti-IL6R antibody, PM-1, onto human IgG creating rhPM-1, later referred to as MRA or tocilizumab. Nishimoto and colleagues
      • Nishimoto N.
      • Sasai M.
      • Shima Y.
      • et al.
      Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy.
      first reported on the treatment of 7 patients with MCD in Japan with tocilizumab. All 7 patients tested negative for HIV and HHV8. Tocilizumab improved clinical symptoms and reduced levels of CRP, fibrinogen, serum amyloid A, and gamma globulins in all patients. There was also virtual complete resolution of lymph adenopathy demonstrated by computed tomography (CT) scanning, and repeat lymph node biopsy during therapy showed improvement in histologic changes with reduction in number and size of follicles as well as decrease in vascularity in terms of hyaline capillaries in the interfollicular areas. In a subsequent open-label multicenter, prospective study 28 patients with iMCD, all with plasmacytic variant, were treated with tocilizumab (8 mg/kg) every 2 weeks for 16 weeks followed by continued dosing at the discretion of the investigator, mostly at 2-weekly intervals (53% of patients) or 4-weekly intervals (18%). Two patients were seropositive for HHV8 and all were HIV-negative. All patients were significantly symptomatic, had elevated CRP and IL6 levels, and most had severe anemia and hypoalbuminemia.
      Patients showed significant reduction in lymphadenopathy by 16 weeks, with 52% of patients achieving lymph node sizes of less than 1 cm by 1 year. Apart from resolution of symptoms such as fatigue, nutritional status, cholesterol, and body mass improved in all patients. There was rapid normalization in several key indicators of systemic inflammation, such as CRP, albumin, and IgG. Eight of 12 patients with iMCD-related skin disorders experienced improvement. Fifteen patients were on steroid therapy at the onset of tocilizumab therapy and 11 of these were able to discontinue steroids or decrease the dose. At the time of reporting, all but 1 patient continued to receive MRA therapy for more than 3 years and treatment was well tolerated with only 2 patients experiencing a serious adverse event, cellulitis, possibly related to tocilizumab. Fourteen patients had mild and transient infusion reactions. Overall, both studies showed that tocilizumab had significant activity in the treatment of iMCD with acceptable toxicity. As a result of these initial 2 studies, tocilizumab was registered as an orphan drug for MCD in 2005 in Japan, becoming the first approved drug for the therapy of MCD anywhere in the world.
      In a follow-up report in 2007, by which time 35 patients had been treated, 30 (86%) remained on study over a period of 5 years with continued response. Furthermore, pulmonary diffuse hyperplasia, which is much more common in the Asian population, was present in 31 patients and showed significant improvement.
      • Nishimoto N.
      • Honda O.
      • Sumikawa H.
      • et al.
      A long-term (5-year) sustained efficacy of Tocilizuman for multicentric Castleman's disease and the effect on pulmonary complications.
      The safety and efficacy of tocilizumab has been confirmed over the years in numerous case reports and small series.
      • Kawabata H.
      • Kadowaki N.
      • Nishikori M.
      • et al.
      Clinical features and treatment of multicentric Castleman's disease : a retrospective study of 21 Japanese patients at a single institute.
      • Matsuyama M.
      • Suzuki T.
      • Tsuboi H.
      • et al.
      Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease.
      • Nagao A.
      • Nakazawa S.
      • Hanabusa H.
      Short-term efficacy of the IL6 receptor antibody tocilizumab in patients with HIV-associated multicentric Castleman disease: report of two cases.
      Tocilizumab has also been used successfully in the pediatric population.
      • Galeotti C.
      • Boucheron A.
      • Guillaume S.
      • et al.
      Sustained remission of multicentric Castleman disease in children treated with tocilizumab, an anti-interleukin-6 receptor antibody.
      The most common side effects are increases in bilirubin, hypercholesterolemia, and mild thrombocytopenia.
      • Ding C.
      • Jones G.
      Anti-interleukin-6 receptor antibody treatment in inflammatory autoimmune diseases.
      Siltuximab is an IL6 neutralizing mAb, which prevents IL6 from binding to both the soluble and membrane-bound IL6R. It has a high affinity for human IL6, but does not bind to viral IL6. A prospective open-label study with 7 cohorts enrolled 67 patients, including 37 with iMCD, 17 with NHL, and 13 with multiple myeloma.
      • van Rhee F.
      • Fayad L.
      • Voorhees P.
      • et al.
      Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease.
      • Kurzrock R.
      • Voorhees P.M.
      • Casper C.
      • et al.
      A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease.
      The first 5 cohorts studied escalating siltuximab doses: 3 mg/kg every 2 weeks, 6 mg/kg every 2 weeks, 12 mg/kg every 3 weeks, 6 mg/kg weekly, and 12 mg/kg every 2 weeks. Cohort 6 evaluated 12 mg/kg given at a shorter infusion time (1 hour rather than 2 hours). Cohort 7 was an expansion cohort confined to patients with iMCD who received siltuximab at 9 or 12 mg/kg via a 1-hour infusion. The overall response rate in iMCD in terms of reduction of lymphadenopathy was 52% (CR, n = 1; PR, n = 11). Three patients had an unconfirmed PR, 20 stable disease, and only 1 had disease progression.
      There was a relation between siltuximab dose and response, with 73% of patients receiving 12 mg/kg responding versus 33% given lower doses. The CR and 8 of the 11 PRs were seen at the dose level of 12 mg/kg. Responses were seen in all histopathologic subtypes: hyaline-vascular (5 of 18), mixed-cellularity (1 of 2), and plasmacytic (6 of 12). The median time to progression was not reached with a follow-up of 29 months. A so-called Clinical Benefit Response (improvement in hemoglobin, weight, decrease in anorexia, fever/night sweats, and lymphadenopathy) was observed in 87% of patients, with 43% improving in ≥4 parameters. The most frequent side effects were thrombocytopenia, hypertriglyceridemia, and neutropenia. The incidence of serious infection across the Phase I and extensions study was 0.02 per patient year. No opportunistic infections were seen, although approximately a quarter to a third of patients did receive herpes zoster prophylaxis. Nineteen patients with iMCD went on to receive treatment in an extension study for a median of 5.1 years (range 3.4–7.2) and no disease relapse or cumulative toxicity was observed.
      • van Rhee F.
      • Casper C.
      • Voorhees P.M.
      • et al.
      A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease.
      Eight of the 19 patients were able to reduce the dose interval to 6-weekly infusions.
      In a subsequent randomized, double-blind, placebo-controlled Phase II study conducted in 19 countries, 79 patients were assigned to either siltuximab 11 mg/kg every 3 weeks (n = 53) or best supportive care (n = 26), allowing for prednisone 1 mg/kg (or equivalent).
      • van Rhee F.
      • Wong R.S.
      • Munshi N.
      • et al.
      Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.
      The primary endpoint was durable tumor and symptomatic response defined as PR or CR by modified Cheson criteria and ≥18 weeks’ improvement or stabilization of 34 MCD-related symptoms. A significantly higher tumor and symptomatic response was seen in patients treated with siltuximab (34% vs 0%), with 17 patients reaching a PR and 1 a CR. The median time to a symptomatic response was 33 days. However, involution of lymphadenopathy with siltuximab was more gradual, with a median time to response of 155 days. Median time to treatment failure was not reached in the siltuximab arm versus 134 days in the placebo arm. Median time to next treatment was not reached with siltuximab and 280 days with placebo. Fifty-nine percent of patients on the siltuximab arm remained on therapy, compared with 19% in the placebo arm. The tumor response rate (38% vs 4%), durable symptomatic response (57% vs 19%), and complete resolution of symptoms (25% vs 0%) were all superior in the siltuximab arm. There were rapid reductions in CRP, hepcidin, ferritin, fibrinogen, and increases in hemoglobin and albumin.
      • van Rhee F.
      • Wong R.S.
      • Munshi N.
      • et al.
      Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.
      • Casper C.
      • Chaturvedi S.
      • Munshi N.
      • et al.
      Analysis of inflammatory and anemia-related biomarkers in a randomized, double-blind, placebo-controlled study of Siltuximab (anti-IL6 monoclonal antibody) in patients with multicentric Castleman disease.
      Patients reported improvements in iMCD symptoms, such as fatigue and weakness, and objectively reversal of muscle wasting was noted by CT-scanning.
      • van Rhee F.
      • Rothman M.
      • Ho K.F.
      • et al.
      Patient-reported outcomes for multicentric Castleman's disease in a randomized, placebo-controlled study of siltuximab.

      Kirk M, Kurzrock R, van Rhee F, et al. Siltuximab reverses muscle wasting in patients with multicentric Castleman's disease. Blood 2013;122(21).

      The adverse event profile was similar to that observed in the Phase I study. Subgroup analyses showed that all durable tumor and symptomatic responses occurred in patients with plasmacytic or mixed-cellularity pathology. In patients with hyaline-vascular pathology, benefit in tumor and symptomatic response were observed as assessed by the investigators rather than central review. Also, the median time to treatment failure in this subgroup was longer with siltuximab compared with placebo (206 vs 70 days). As previously discussed in the Phase I study, clinical responses were observed in patients with hyaline-vascular pathology suggesting that this group of patients with iMCD may still derive benefit from siltuximab therapy. Based on these data, siltuximab was approved for iMCD in the United States, Europe, and Canada in 2014 and in Brazil in 2015.
      In clinical practice, both tocilizumab and siltuximab appear equally effective in the management of iMCD and have a similar toxicity profile. Mild thrombocytopenia is common, as are increases in cholesterol. Occasional mild elevation of bilirubin levels occurs. Disadvantages of both drugs are that treatment is not curative and is essentially life-long because relapses have been reported on discontinuation of therapy. However, in many patients, the dosing intervals can be extended. Future studies will have to answer the question, whether some patients remain in remission off therapy and can be managed with a more limited treatment course.

      Immunomodulatory agents

      A variety of other agents have been reported to have activity in iMCD, mostly in case reports. IL1 is upstream of IL6 in the inflammatory pathway and activates nuclear factor kappa B (NF-κB), leading to transcription of proinflammatory cytokines, including IL6. There have been reports of patients responding to the IL1β receptor antagonist, anakinra. One patient had failed tocilizumab, whereas the response in the second patient was partial and this patient later received tocilizumab.
      • Galeotti C.
      • Tran T.A.
      • Franchi-Abella S.
      • et al.
      IL-1RA agonist (anakinra) in the treatment of multifocal Castleman disease: case report.
      • El-Osta H.
      • Janku F.
      • Kurzrock R.
      Successful treatment of Castleman's disease with interleukin-1 receptor antagonist (Anakinra).
      Bortezomib similarly inhibits the NF-κB pathway and has been used alone or in combination with other drugs to treat several patients.
      • Lin Q.
      • Fang B.
      • Huang H.
      • et al.
      Efficacy of bortezomib and thalidomide in the recrudescent form of multicentric mixed-type Castleman's disease.
      • Hess G.
      • Wagner V.
      • Kreft A.
      • et al.
      Effects of bortezomib on pro-inflammatory cytokine levels and transfusion dependency in a patient with multicentric Castleman disease.
      • Yuan Z.G.
      • Dun X.Y.
      • Li Y.H.
      • et al.
      Treatment of multicentric Castleman's disease accompanying multiple myeloma with bortezomib: a case report.
      Thalidomide is a potent immunomodulatory agent, which inhibits the production of several cytokines, including IL1, IL6, IL12, tumor necrosis factor-α, and VEGF. There have been reports of activity in iMCD, including a patient with TAFRO syndrome, who had tocilizumab-refractory and prednisone-refractory ascites.
      • Starkey C.R.
      • Joste N.E.
      • Lee F.C.
      Near-total resolution of multicentric Castleman disease by prolonged treatment with thalidomide.
      • Lee F.C.
      • Merchant S.H.
      Alleviation of systemic manifestations of multicentric Castleman's disease by thalidomide.
      • Tatekawa S.
      • Umemura K.
      • Fukuyama R.
      • et al.
      Thalidomide for tocilizumab-resistant ascites with TAFRO syndrome.
      • Ramasamy K.
      • Gandhi S.
      • Tenant-Flowers M.
      • et al.
      Rituximab and thalidomide combination therapy for Castleman disease.
      Other immunomodulatory agents, such as interferon-α and all-trans-retinoic acid, induced complete remissions in incidental cases.
      • Tamayo M.
      • Gonzalez C.
      • Majado M.J.
      • et al.
      Long-term complete remission after interferon treatment in a case of multicentric Castelman's disease.
      • Simko R.
      • Nagy K.
      • Lombay B.
      • et al.
      Multicentric Castleman disease and systemic lupus erythematosus phenotype in a boy with Klinefelter syndrome: long-term disease stabilization with interferon therapy.
      • Andres E.
      • Maloisel F.
      Interferon-alpha as first-line therapy for treatment of multicentric Castleman's disease.
      • Rieu P.
      • Droz D.
      • Gessain A.
      • et al.
      Retinoic acid for treatment of multicentric Castleman's disease.
      Although there is rationale for these agents, none has been studied in a systematic fashion and these agents are best reserved for refractory cases or used as adjunctive therapy.
      Perhaps more exciting agents are the calcineurin inhibitor cyclosporine and the mammalian target of rapamycin (m-TOR) inhibitor sirolimus. There is emerging evidence that patients with iMCD have activated T-cells and elevated soluble IL2 receptor levels.
      • Kawabata H.
      • Takai K.
      • Kojima M.
      • et al.
      Castleman-Kojima disease (TAFRO syndrome): a novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly : a status report and summary of Fukushima (6 June, 2012) and Nagoya meetings (22 September, 2012).
      Cyclosporin binds to cyclophilin and inhibits the phosphatase activity of calcineurin, thereby reducing the release of inflammatory cytokines by T-lymphocytes. Cyclosporin-induced remission in 2 patients with TAFRO syndrome who had failed corticosteroids and tocilizumab and prednisone, respectively.
      • Inoue M.
      • Ankou M.
      • Hua J.
      • et al.
      Complete resolution of TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) after immunosuppressive therapies using corticosteroids and cyclosporin A: a case report.
      • Yamaga Y.
      • Tokuyama K.
      • Kato T.
      • et al.
      Successful treatment with cyclosporin A in tocilizumab-resistant TAFRO syndrome.
      Sirolimus inhibits the m-TOR pathway critical to T-cell activation and VEGF secretion. Elevated VEGF levels are common in iMCD and resolve with successful anti-IL6 mAb therapy. Furthermore, high VEGF levels are also frequently seen in POEMS. However, some patients with iMCD fail tocilizumab or siltuximab, and in 1 patient, an extended remission for more than 39 months was maintained with sirolimus and intravenous immunoglobulin after reinduction of combination chemotherapy. Sirolimus is an interesting agent that deserves further investigation in the therapy of iMCD either during remission induction or as maintenance strategy.

      Treatment Guidelines and Algorithm

      The treatment algorithm depicted in Fig. 2 outlines a practical approach to the therapy of iMCD. It is critical to select the appropriate therapy for individual patients. More severely ill patients will typically have more marked B-symptoms, thrombocytopenia rather than thrombocytosis, renal dysfunction or other organ dysfunction, and clinical evidence of vascular leak syndrome with ascites and or/pleural effusions. On the other end of the spectrum, some patients have few clinical symptoms and minor findings in terms of abnormal physical examination or laboratory values.
      Figure thumbnail gr2
      Fig. 2Therapeutic algorithm for the management of iMCD. Front-line therapy of iMCD is determined by disease severity at presentation. Further modifications to treatment strategy are dependent on response to front-line approach and clinical features.
      In one study, 60% of patients did not receive siltuximab as front-line therapy and, as previously stated, there may be a bias toward using rituximab.
      • Yu L.
      • Tu M.
      • Cortes J.
      • et al.
      Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease.
      How does one decide to start with rituximab or anti-IL6 mAb (tocilizumab or siltuximab)? In the randomized Phase II siltuximab study, CR and PR were seen in only 34% of patients, although more than 50% remained on study. This study may have enrolled patients who were less sick due to presence of a placebo arm in which patients at best could receive prednisone at a maximum dose of 1 mg/kg. Furthermore, there were stringently defined failure criteria, which may have not allowed some patients time to respond. In contrast, Nishimoto and colleagues

      Nishimoto N, Honda O, Sumikawa H, et al. A long-term (5 year) sustained efficacy of tocilizumab for multicentric Castleman's disease and the effect on pulmonary complications. ASH Annual Meeting Abstracts. Atlanta (GA), December 8–11, 2007.

      reported a continued response rate of 86% to tocilizumab with more than 90% of patients having elevated IL6 levels and all had a clear systemic inflammatory syndrome underscored by abnormal acute phase reactants, anemia, and hypoalbuminemia. A systematic literature review compared baseline of features of patients mostly treated on the siltuximab trials and found less severe clinical and biochemical features in the clinical trial patients.
      • Liu A.Y.
      • Nabel C.S.
      • Finkelman B.S.
      • et al.
      Idiopathic multicentric Castleman's disease: a systematic literature review.
      Although numbers were small, the 2-year survival was best in patients treated with anti-IL6 mAbs. Yu and colleagues
      • Yu L.
      • Tu M.
      • Cortes J.
      • et al.
      Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease.
      reported a superior CR rate with siltuximab compared with rituximab-based chemotherapy (43% vs 20%), with a strong trend to superior DFS. The main message from these considerations is that the principal beneficiaries of siltuximab or tocilizumab therapy are patients who are more severely afflicted and have a clear proinflammatory syndrome. It is important to realize that it takes time to respond to anti-IL6 mAb therapy, and induction therapy with siltuximab or tocilizumab is best paired with concomitant steroid therapy, which can later be tapered. Patients who attain a sustained response should be maintained on anti-IL6 mAb therapy and in many, dosing intervals can be expanded.
      More severely ill patients who do not respond to IL6 blockade probably comprise 2 patient populations. One group of patients consists of those for whom anti-IL6 agents as sole intervention do not suffice and combination chemotherapy with addition of rituximab may be required to gain control of the disease. There still may be a role for tocilizumab or siltuximab during maintenance. In a second group, IL6 may not be the key driver of the disease and other cytokines and chemokines may play a critical role, which is an active topic of investigation. Preliminary data in 2 patients suggest that the m-TOR pathway is activated in the lymph nodes with TAFRO syndrome and one has used sirolimus to maintain remission (Fajgenbaum personal communication, 2017). Future studies will have to determine whether biomarkers, such as VEGF, can be used to stratify a maintenance approach.
      Patients with milder disease are candidates for a more limited treatment approach with 4 to 8 weekly doses of rituximab 375 mg/m2, which are often combined with steroids. In one study, combination chemotherapy was not superior to rituximab.
      • Yu L.
      • Tu M.
      • Cortes J.
      • et al.
      Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease.
      Rituximab is considerably less toxic and seems therefore a reasonable option for this patient group.
      • Yu L.
      • Tu M.
      • Cortes J.
      • et al.
      Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease.
      Responding patients may not require a maintenance approach. Treatment failures could go on to receive anti-IL6 mAb therapy. Chemotherapy or immunomodulatory agents are best reserved for more refractory patients.
      Patients with coexistent POEMS syndrome may require both therapy for POEMS and their iMCD. The progressive sensorimotor polyneuropathy of POEMS does not respond to anti-IL6 mAb therapy. However, anti-IL6 therapy or rituximab may be useful to treat iMCD in patients with both POEMS and iMCD. ASCT is not routinely recommended for iMCD and has been limited to case reports.
      • Tal Y.
      • Haber G.
      • Cohen M.J.
      • et al.
      Autologous stem cell transplantation in a rare multicentric Castleman disease of the plasma cell variant.
      • Repetto L.
      • Jaiprakash M.P.
      • Selby P.J.
      • et al.
      Aggressive angiofollicular lymph node hyperplasia (Castleman's disease) treated with high dose melphalan and autologous bone marrow transplantation.
      • Ogita M.
      • Hoshino J.
      • Sogawa Y.
      • et al.
      Multicentric Castleman disease with secondary AA renal amyloidosis, nephrotic syndrome and chronic renal failure, remission after high-dose melphalan and autologous stem cell transplantation.
      • Advani R.
      • Warnke R.
      • Rosenberg S.
      Treatment of multicentric Castleman's disease complicated by the development of non-Hodgkin's lymphoma with high-dose chemotherapy and autologous peripheral stem-cell support.
      However, patients with coexistent for POEMS syndrome should be considered for ASCT. Some patients with iMCD have features of POEMS (eg, osteosclerotic bone lesions), but do not meet the criteria for the diagnosis of POEMS. Usually these patients do not have a marked proinflammatory syndrome and are preferably managed with rituximab-based therapy as initial intervention.
      There are presently no established criteria for measuring response. Ideally, measurement of response should take into account (1) the different manifestations of the disease, which can be broken down into lymphadenopathy/organomegaly, clinical symptomatology, and laboratory parameters; and (2) the kinetics of the response. It is important to recognize that clinical and laboratory parameters often improve more rapidly with anti-IL6 agents, although it takes 6 doses to achieve steady state with siltuximab. In contrast, the involution of lymph nodes with anti-IL6 mAbs occurs at much slower pace than other therapeutic interventions. In this context, it is useful to point out that anti-IL6 mAbs are not lympholytic, but merely neutralize important growth and survival stimuli. These considerations highlight the need for establishing consensus criteria to measure response at well-defined time points, which will facilitate comparisons of future studies.
      In clinical practice laboratory markers, such as CRP, erythrocyte sedimentation rate, hemoglobin, and albumin are useful in monitoring response. IL6 levels become uninformative after treatment with tocilizumab and siltuximab due to complexing of IL6 with these drugs leading to falsely elevated IL6 levels. Resolution of lymphadenopathy will be more rapid with chemotherapy and rituximab rather than anti-IL6 mAb therapy. Symptoms and physical findings often also improve rapidly with the exception of symptomatology due to vascular leak syndrome; ascites can be especially persistent, and may take 2 to 3 months to resolve fully.

      Summary

      Much progress has been made in our understanding of the heterogeneous iMCD disease spectrum, leading to a new classification and diagnostic criteria.
      • Fajgenbaum D.C.
      • Uldrick T.S.
      • Bagg A.
      • et al.
      International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.
      • Fajgenbaum D.C.
      • van Rhee F.
      • Nabel C.S.
      HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy.
      Anti-IL6 mAbs are an important new tool for the therapy of iMCD and should be considered as front-line therapy for many patients, especially those who are more symptomatic. However, enthusiasm should be tempered by the notion that not all respond and that therapy is not curative. Ultimately, further progress must come from future research elucidating the cause(s) of iMCD, leading to the development of rational and definitive therapies for all patients. Reporting of patients to the CDCN global ACCELERATE registry, which plans to enroll 500 patients over the next 5 years, will permit more comprehensive characterization of the clinical features and natural history of iMCD.
      • Fajgenbaum D.C.
      • Ruth J.R.
      • Kelleher D.
      • et al.
      The collaborative network approach: a new framework to accelerate Castleman's disease and other rare disease research.
      A comprehensive real-world analysis of the efficacy of existing therapies will allow for better tailoring of treatments to individual patients in the future.

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