Introduction
Multicentric Castleman disease is an uncommon disease. 1 Diagnosis can be challenging and treatment options are limited. 2 , 3 Combined with prompt and accurate diagnosis, siltuximab has offered hope for disease control and improvement of quality of life. 4 – 6 In the case presented here, the patient experienced symptoms for over two decades before receiving an accurate diagnosis and has now received siltuximab therapy for more than 15 years – representing one of the longest treatment periods with the drug. All patient details relating to this case have been de-identified in accordance with the Health Insurance Portability and Accountability Act (HIPAA) safe harbor method. This report adheres to the CARE case report guidelines and an ethics approval waiver was granted by the US Oncology, Inc., Institutional Review Board (IRB).
Case presentation
The patient is a 63-year-old white male who initially presented with fatigue and night sweats in his late 20s. He reported that he had been experiencing these symptoms for nearly two decades and, over time, he got used to feeling unwell. In the 5 years prior to seeking medical care, he reported that his symptoms were getting progressively worse. The patient had a history of neuropathy and hypercholesterolemia. He went to see his primary care physician regarding his symptoms in 1999 and a chest X-ray showed lung nodules. A computed tomography (CT) scan of the chest showed several non-calcified pulmonary nodules with small lymph nodes in the hilum and the axilla. A 1.5 cm retroperitoneal lymph node adjacent to the celiac axis was observed. A transbronchial biopsy of the nodule was suggestive of sarcoidosis, and the patient’s serum protein level was elevated. The erythrocyte sedimentation rate (ESR) in 2000 was high (39 mm/h, normal range <30 mm/h).
Shortly after, a bone marrow aspiration was performed, which showed no significant abnormalities. During this time, the patient’s symptoms became worse. He was referred to see a local surgeon for an excisional biopsy of the palpable left inguinal lymph node. Pathology was consistent with Castleman disease, plasma cell type, as described by the angiofollicular hyperplasia on the pathology report from the local hospital in Ohio in 2005. Polymerase chain reaction testing revealed no human herpes virus-8 (HHV8) in the peripheral blood and the patient had negative human immunodeficiency virus (HIV) serology. As the patient did not display symptoms matching the diagnostic criteria for TAFRO [Thrombocytopenia, Ascites (anasarca) myeloFibrosis, Renal dysfunction, Organomegaly] syndrome, a diagnosis of iMCD-not otherwise specified (iMCD-NOS) was reached. 7 Bone marrow aspiration and biopsy showed normocellular marrow with normal maturation. There was no histological or flow cytometric evidence of malignant lymphoma or multiple myeloma. The patient tested negative for antinuclear antibodies and no reticulin fibrosis was present. Evaluation of the patient found no evidence of monoclonal gammopathy.
In 2005, the patient’s levels of pro-inflammatory cytokine interleukin-6 (IL-6) were highly elevated (90.9 pg/ml, normal range ⩽1.8 pg/ml), as were his levels of its surrogate measure, C-reactive protein (CRP; 47.2 mg/dl, normal range ⩽0.8 mg/dl), confirming the presence of systemic inflammation ( Figure 1 ). The levels of immunoglobulin (Ig)G (3500 mg/dl, normal range 767–1590 mg/dl) and IgA (502 mg/dl, normal range 61–356 mg/dl) were elevated. Serum protein electrophoresis did not reveal the presence of monoclonal protein. The leukocyte count was normal (7700/mm 3 , normal range 5000–10,000). Patient had normal levels of hemoglobin (13.6 g/dl, normal range 13.0–18.0 g/dl), platelets (407,000/µl, normal range 150,000–450,000/µl), and creatinine (0.8 mg/dl, normal range 0.7–1.3 mg/dl).
The patient was initially treated with methylprednisolone in 2005, after which his symptoms improved and CRP levels were markedly reduced. However, he developed progressive lymphadenopathy shortly after completion of the steroid treatment. He was thus treated with pulsed dexamethasone, at a dosage of 40 mg daily, after which his lymph nodes reduced in size. However, again after completion of the treatment, his lymphadenopathy recurred. After this treatment course, the patient had more difficulty tolerating further steroid therapy, developing increased fatigue and loss of appetite. He was administered dexamethasone for an additional 4 days; however, his IL-6 levels were abnormally high (79.4 pg/ml).
The patient provided informed consent to participate and be treated in the dose-finding phase I siltuximab study ( NCT00412321 ) in 2005. His fluorodeoxyglucose positron emission tomography (FDG-PET) scan in 2005 showed multiple areas of increased metabolism, suggestive of widespread lymphadenopathy ( Figure 2 ). He received 95 doses of siltuximab. He tolerated the treatment well and achieved complete remission. His CRP levels were well controlled, indicative of sustained inhibition of IL-6 by siltuximab. IgG, ESR, and fibrinogen levels also normalized during siltuximab therapy ( Figure 1 ).
The patient had short-term and long-term follow-up FDG-PET scans in 2005 and 2010. His hypermetabolic lymphadenopathy was resolved ( Figure 2 ). The patient was subsequently enrolled on the long-term siltuximab safety study ( NCT01400503 ) and was administered a further 100 doses of siltuximab at 11 mg/kg. The patient maintained his complete response throughout the study. He completed the safety study in 2017 and transitioned after US Food and Drug Administration (FDA) approval to commercial siltuximab, which he presently is still receiving at a dose of 11 mg/kg every 3 weeks. At the time of writing, the patient has received a total of 272 siltuximab doses. He is doing well on treatment and is essentially asymptomatic. At the last office visit, his examination was normal and there was no palpable lymphadenopathy.
Discussion
iMCD is a rare lymph node disorder that can be underdiagnosed. A major barrier to patients obtaining access to effective therapy is the time taken to receive the correct diagnosis. iMCD can be confused with other diseases that can cause similar histopathology and symptoms, for example autoimmune disorders (e.g. lupus), lymphoma, IgG4-related lymphadenopathy reactive due to viral etiology, sarcoidosis, etc. The Castleman Disease Collaborative Network (CDCN) diagnostic criteria stipulate that other disorders which can give rise to Castleman-like histopathology require specific exclusion. 3
Patients can have symptoms, including fever, sweats, splenomegaly, malaise, and abnormal laboratory results. IL-6 can be elevated in many cases and this patient was found to have very high IL-6 levels. He was quite symptomatic for many years and was initially treated with steroids, but responded poorly. Once enrolled in the siltuximab dose-finding phase I trial, he responded very well and achieved a complete symptomatic and tumor response that has been maintained throughout his therapy. He has been on maintenance therapy for 15 years, during which he has received nearly 300 infusions of the drug, with complete symptomatic control, resolution of lymphadenopathy, and excellent tolerance; this represents one of the longest treatment periods with siltuximab of any iMCD patient.
The phase I study was a dose-finding study in which patients who received the highest dose of siltuximab achieved the main efficacy endpoint of clinical benefit response. 4 No dose-related or cumulative toxicity was observed with the use of siltuximab during a long-term extension study. 5 A pivotal phase II trial confirmed the safety and efficacy of siltuximab across multiple sites. 5 , 6 In the treatment arm of the phase II study, 34% of patients achieved the primary endpoint of durable tumor and symptomatic response, compared with 0% in the placebo arm. 5 In addition, 57% achieved a symptomatic response and 38% had a tumor response, compared with 19% and 4% in the placebo arm, respectively. 5 In the long-term extension study, which included patients who had at least stable disease after receiving siltuximab in the randomized phase of the phase I and II studies, a disease control rate of 70% was observed in patients with follow-up of up to 6 years. 8 Of the 30% of patients in the study who discontinued, only four were due to progressive disease ( n = 2) or adverse events ( n = 2). 8 These data show that in those patients who do respond to siltuximab, long-term, sustainable responses are possible and treatment is well tolerated over long treatment periods without cumulative toxicity.
Currently, siltuximab is the only FDA-approved treatment for iMCD and is approved for all patients with multicentric Castleman disease that is HHV8 and HIV negative. As detailed in the CDCN treatment guidelines, where it is available, siltuximab is the recommended treatment choice. 2 This case highlights the importance of prompt diagnosis for iMCD patients, as effective therapy is available, as described in iMCD treatment guidelines. 2 Those who respond to siltuximab therapy may experience long-term disease control.
Supplemental Material
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Supplemental material, sj-docx-2-tah-10.1177_20406207221082552 for Idiopathic multicentric Castleman disease treated with siltuximab for 15 years: a case report by Evan Lang, Brenda Sande, Samantha Brodkin and Frits van Rhee in Therapeutic Advances in Hematology
Acknowledgments
The authors thank the patient who kindly volunteered to participate in this study. They also thank Rory Elsome and Azhaar Ashraf from TVF Communications (London, UK) for providing medical writing assistance and EUSA Pharma for their support.
Footnotes
Author contributions: Evan Lang: Conceptualization; Data curation; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Visualization; Writing – original draft; Writing – review & editing.
Brenda Sande: Project administration; Writing – review & editing.
Samantha Brodkin: Project administration; Writing – review & editing.
Frits van Rhee: Data curation; Investigation; Methodology; Resources; Validation; Visualization; Writing – review & editing.
Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.L. received consultant fees from EUSA Pharma. F.v.R. received consultant fees from EUSA Pharma, GlaxoSmithKline, Karyopharm, Takeda, Sanofi, and the Castleman Disease Collaborative Network, and research funding from Janssen Pharmaceuticals and Bristol Myers Squibb. B.S. and S.B. are employees of EUSA Pharma.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Medical writing assistance was funded by EUSA Pharma.
Ethics statement: Written informed consent was obtained from the patient for publication of this case report. Ethics approval was not required for this case report and a waiver was granted by the US Oncology, Inc., Institutional Review Board (IRB).
ORCID iD: Evan Lang https://orcid.org/0000-0003-3926-0013
Contributor Information
Evan Lang, Oncology Hematology Care, Inc., 5053 Wooster Road, Cincinnati, OH 45226, USA.
Brenda Sande, Medical Affairs, EUSA Pharma, Burlington, MA, USA.
Samantha Brodkin, Medical Affairs, EUSA Pharma, Burlington, MA, USA.
Frits van Rhee, Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
References
1. van Rhee F, Greenway A, Stone K. Treatment of idiopathic Castleman disease. Hematol Oncol Clin North Am 2018; 32: 89–106.
2. van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood 2018; 132: 2115–2124.
3. Fajgenbaum DC, Uldrick TS, Bagg A. et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood 2017; 129: 1646–1657.
4. van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol 2010; 28: 3701–3708.
5. Kurzrock R, Voorhees PM, 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. Clin Cancer Res 2013; 19: 3659–3670.
6. van Rhee F, Casper C, Voorhees PM, 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. Oncotarget 2015; 6: 30408–30419.
7. Masaki Y, Kawabata H, Takai K, et al. 2019 updated diagnostic criteria and disease severity classification for TAFRO syndrome. Int J Hematol 2020; 111: 155–158.
8. van Rhee F, Casper C, Voorhees PM, et al. Long-term safety of siltuximab in patients with idiopathic multicentric Castleman disease: a prespecified, open-label, extension analysis of two trials. Lancet Haematol 2020; 7: e209–e217.
Associated Data
Supplementary Materials
sj-docx-1-tah-10.1177_20406207221082552 – Supplemental material for Idiopathic multicentric Castleman disease treated with siltuximab for 15 years: a case report
Click here for additional data file.
Supplemental material, sj-docx-1-tah-10.1177_20406207221082552 for Idiopathic multicentric Castleman disease treated with siltuximab for 15 years: a case report by Evan Lang, Brenda Sande, Samantha Brodkin and Frits van Rhee in Therapeutic Advances in Hematology
sj-docx-2-tah-10.1177_20406207221082552 – Supplemental material for Idiopathic multicentric Castleman disease treated with siltuximab for 15 years: a case report
Click here for additional data file.
Supplemental material, sj-docx-2-tah-10.1177_20406207221082552 for Idiopathic multicentric Castleman disease treated with siltuximab for 15 years: a case report by Evan Lang, Brenda Sande, Samantha Brodkin and Frits van Rhee in Therapeutic Advances in Hematology