The epidemiology of HHV-8-negative/idiopathic multicentric Castleman disease (iMCD) remains incompletely understood. Prior epidemiologic studies of CD and iMCD have been hampered by difficulties in accurate case ascertainment due to lack of uniform diagnostic criteria and a disease-specific International Classification of Diseases (ICD) code. In this study, we provide reliable estimates of CD and iMCD in the US using a novel claims-based algorithm that includes CD specific ICD-10 diagnosis code (D47.Z2) supported by presence of ≥2 claims codes corresponding to the minor criteria from the international evidence-based diagnostic criteria for iMCD. We additionally analyzed the treatment classes and patterns in the clinical course of iMCD patients. Using an administrative claims database of 30.7 million individuals enrolled between January 1, 2017 and December 31, 2018, we identified 254 iMCD patients with an estimated annual incidence and prevalence of 3.4 (95% CI, 1.4 - 9.2) and 6.9 (95% CI, 3.7 - 13.3) cases per million, respectively. Among iMCD patients, 39% received corticosteroid monotherapy, 33.1% received no iMCD-directed treatment, and 9.8% received IL-6 targeted therapy with tocilizumab or siltuximab. Siltuximab, which is the only FDA-approved treatment and established first-line treatment recommendation, was used in only 8.7% of iMCD patients. This study provides the most up to date understanding of the iMCD disease burden in the US and identifies a major unmet treatment need for IL-6 directed therapy in this vulnerable cohort.

Human herpes virus-8 (HHV8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder sustained by pro-inflammatory cytokines, including interleukin-6 (IL-6). According to the international evidence-based criteria developed by the Castleman Disease Collaborative Network (CDCN), siltuximab, which works by inhibiting IL-6, is the recommended choice for iMCD treatment. We report a case of a 63-year-old white male with iMCD who has been on maintenance therapy with siltuximab for 15 years – representing one of the longest treatment periods of any patient with iMCD treated with siltuximab. The patient initially presented with fatigue and night sweats, with progressive worsening of the symptoms. Whole-body positron emission tomography/computed tomography revealed hypermetabolic lymphadenopathy. The patient had histopathologically confirmed Castleman disease, plasma cell type, and was negative for HHV8 and human immunodeficiency virus. The patient had abnormally high C-reactive protein (CRP) levels, a surrogate measure for IL-6. The patient was treated with high-dose steroids but had recurring lymphadenopathy early on. He was enrolled in the phase I dose-finding clinical trial of siltuximab, during which he achieved marked clinical improvement and sustained inhibition of CRP. The patient was enrolled in the long-term safety study and continues to receive siltuximab at 11 mg/kg every 3 weeks. He is presently receiving commercial siltuximab and has remained asymptomatic, with no evidence of lymphadenopathy. The case study presented is consistent with the evidence that siltuximab is a safe and effective therapy for the long-term management of iMCD. In addition, this case highlights the importance of prompt diagnosis for patients with iMCD, as effective therapy is available for patients as described in the CDCN and National Comprehensive Cancer Network iMCD treatment guidelines. Plain Language Summary The case of a 63-year-old white male with idiopathic multicentric Castleman disease who was successfully treated with siltuximab for 15 years Idiopathic multicentric Castleman disease (iMCD) is a group of rare lymphoproliferative disorders with shared histopathological features that affect lymph nodes in multiple regions of the body. The signs and symptoms of iMCD can be varied, with the disease being mild in some patients while life-threatening in others. A timely diagnosis of iMCD can be challenging but is required for effective management. We report a case of a patient who was diagnosed with iMCD. The patient was given high-dose steroids but continued to show progressive disease. He was then started on siltuximab, a targeted antibody therapy against a specific cytokine (interleukin-6) involved in inflammation. The patient responded well to the treatment, has shown evidence of long-term disease control, and has not reported any serious adverse events related to long-term siltuximab use. He has received 11 mg/kg of siltuximab every 3 weeks for the past 15 years. This case emphasizes the value of using siltuximab therapy for long-term management of this rare disorder. In addition, it highlights the importance of prompt diagnosis for patients with iMCD, as effective therapy is available, as described in iMCD treatment guidelines.

BACKGROUND: Human herpesvirus-8-negative/idiopathic multicentric Castleman disease (iMCD) is a heterogenous group of diseases characterized by proinflammatory hypercytokinemic state with a wide range of systemic manifestations ranging from generalized lymphadenopathy to death in severe cases. Limited data has shown an increased prevalence of organ dysfunction and cancers in iMCD patients either as a result of underlying disease pathophysiology or treatment received. The objective of this study was to assess the healthcare resource utilization, patterns of iMCD-related comorbidities, and survival of iMCD patients in a real-world setting. METHODS: We performed a retrospective analysis of administrative claims data for >30 million United States patients continuously enrolled over a three-year study period from January 1, 2017 and December 31, 2019. Patients were identified as iMCD if they had an ICD-10 diagnosis code for Castleman disease (D47.Z2) and ≥2 diagnostic codes corresponding to the minor criteria from the international evidence-based consensus diagnostic criteria for iMCD. Exclusion criteria included history of HIV, HHV-8, lymphoma, myeloma, lupus, or rheumatoid arthritis within one year of diagnosis of Castleman disease. Index diagnosis date (IDD) was defined as the first time a patient received a diagnosis for Castleman disease using the new ICD-10 code (D47.Z2) or the general code for lymphadenopathy (785.6) in ICD-9 that included Castleman disease, whichever was diagnosed first between 2006 and 2019. Included patients were followed for up to 5 years from IDD and evaluated for post-diagnosis hospitalizations, emergency room visits, hematologic malignancies, non-hematologic malignancies, thromboses, and organ dysfunction. Estimated average survival was calculated based on estimated incidence and prevalence rates for the iMCD patient population, assuming a stable incidence. RESULTS: We identified 191 iMCD patients including 109 women (57%) and 82 men (43%) with a mean age of 51 years (range: 6 - 90). The average post-diagnosis follow up was 3.2 years after IDD (range: 0.3 - 14.1). Within the first year of iMCD diagnosis, 58.9% of patients required inpatient hospitalization and 53.4% had at least one emergency room visit. Among the patients who remained enrolled after the first year, an average of 25.1% were hospitalized and 36.1% visited the emergency room during each subsequent year (Table 1). The annual rate of hospitalizations and emergency room visits for the entire database of >30 million patients was 9.0% and 20.6%, respectively. As shown in Table 2, the annual prevalence of iMCD-related comorbidities in this cohort was 18.2% for non-hematologic malignancies, 6.3% for hematologic malignancies (including lymphomas and myelomas from second year follow up onwards), 5.8% for thromboses, 5.7% for renal failure, and 5.2% for respiratory failure. Based on an average annual incidence of 2.45 (95% CI, 0.85 - 8.60) per million and average prevalence of 6.31 (95% CI, 3.25 - 13.05) per million, we estimated an average survival of 2.57 (95% CI, 1.59 - 4.25) years after diagnosis in this study time period. DISCUSSION: Using a large nationally representative health claims database, we identified a cohort of iMCD patients and found a high rate of hospitalizations and emergency room visits in the first five years following diagnosis. The annual prevalence of iMCD-related organ failure was approximately 5-6% primarily involving renal and respiratory systems. This study provides further evidence to support the previously reported increase in frequency of subsequent hematologic and non-hematologic malignancies in iMCD patients. In the five-year follow up period, the average estimated survival of iMCD patients was 2.57 (95% CI, 1.59 - 4.25) years after diagnosis, which is shorter than previously published average survival durations based on academic medical centers. The worse survival in this cohort may represent iMCD survival outside of academic medical centers or may reflect inaccuracies in estimated incidence and prevalence which were used to estimate average survival. Further studies are needed to compare outcomes to age-matched controls and to determine whether these adverse outcomes are broadly seen across iMCD patients or instead attributable to a smaller subset of more severe cases. Disclosures Mukherjee: Bristol Myers Squib: Honoraria; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees. Martin:EUSA Pharma: Current Employment. Sande:EUSA Pharma: Current Employment. Glen:HVH Precision Analytics: Current Employment. Paige:HVH Precision Analytics: Consultancy. Yarlagadda:HVH Precision Analytics: Current Employment. Fajgenbaum:EUSA Pharma: Research Funding; Janssen Pharmaceuticals: Research Funding.

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