Castleman Disease Patients Research Articles

Patients with Castleman disease report mild COVID-19 symptoms and mount a humoral response to SARS-CoV-2 vaccination

AbstractThe coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in increased morbidity and mortality in patients with impaired immunity, hematologic malignancies, and on immunosuppressive regimens. COVID-19 can cause a cytokine storm with some patients benefiting from blockade of the proinflammatory cytokine, interleukin 6 (IL-6). Because Castleman disease (CD) is an atypical lymphoproliferative disorder that can involve a cytokine storm and often requires immunosuppressive therapies, including IL-6 inhibition, we sought to evaluate outcomes after COVID-19 and SARS-CoV-2 vaccination in patients with CD. We administered a survey in April 2021 to characterize experiences with COVID-19 and SARS-CoV-2 vaccination among 300 patients enrolled in ACCELERATE, a CD natural history registry. Among 128 respondents, the prevalence of SARS-CoV-2 infection (16/95, 17%), severe disease (1/16, 6%), vaccination rates (112/128, 88%), and vaccine adverse effects after dose 1 (62/112, 55%) were comparable with that of the general US population. Although there were 2 cases of CD flares occurring shortly after SARS-CoV-2 infection (n = 1) and vaccination (n = 1), >100 patients that were infected and/or vaccinated did not experience CD flares. Among patients with CD, the median antispike titer 6 months after the second vaccine dose was comparable to that of individuals with other immune-related diseases and healthy populations. Despite being on immunosuppressive therapies, patients with CD do not appear to be at increased risk of poor COVID-19 outcomes and can mount a humoral response to SARS-CoV-2 vaccination. This study was registered at www.ClinicalTrials.gov as #NCT02817997.

Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement. There are vastly different clinical subtypes, with some patients demonstrating thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly (TAFRO) and others having milder/more moderate symptoms with potential for severe disease (not otherwise specified, NOS). Due to its rarity and heterogeneity, the natural history and long-term burden of iMCD are poorly understood. We investigated real-world medical data from ACCELERATE, a large natural history registry of patients with Castleman disease, to better characterize the long-term disease burden experienced by these patients. We found that iMCD-TAFRO patients face a significant hospitalization burden, requiring more time in the hospital than iMCDNOS patients during the year surrounding diagnosis (median [interquartile range]: 36 [18-61] days vs. 0 [0-4] days; P<0.001). In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO. iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004). Lastly, we observed severe iMCD-related morbidities, such as acute renal failure, sepsis and pneumonia, among others, arising after iMCD diagnosis, impairing the patients' quality of life. These data demonstrate a substantial disease burden experienced by iMCD patients and emphasize the importance of ongoing research into iMCD to aid disease control.

Castleman disease- demographics, associations, and outcomes: an analysis of adult 791 cases.

Castleman disease (CD), also known as angiofollicular lymph node hyperplasia or large lymph node hyperplasia, is a rare medical condition. Despite its rarity, it exhibits diverse clinical presentations and outcomes, which pose challenges for comprehensive understanding and management. This study aims to shed light on the demographics, associations, and outcomes of CD by conducting a retrospective analysis. The National Inpatient Sample (US) was used to identify patients with the diagnosis of Castleman disease using ICD-10 diagnosis code D47.Z2, during the years 2016-2019. Data was collected on demographics, associated diagnoses, treatments and outcomes. Data analysis was performed using STATA Version 17, College Station, TX: Stata Corp LLC. Our study identified 791 hospitalizations involving adult CD patients. The mean age of these patients was 52.4 years, with a male predominance (56.1%). Whites comprised the largest racial group affected (50.1%). Most patients were covered by Medicare (39.6%). The majority received treatment in urban teaching hospitals (84.0%) and large-bed size facilities (62.5%). In-hospital mortality was low at 2.8%, with an average length of stay of 7.5 days and average total charges of $109,308. Common associations included acute kidney injury (27.0%), congestive heart failure (17.1%), sepsis (16.4%), and acute respiratory failure (12.6%). Hematological and lymphatic associations featured anemia (47.5%), thrombocytopenia (12.2%), and other conditions. Red blood cell transfusions were administered to 11.1% of patients. This study contributes valuable insights into CD, a rare and clinically heterogeneous disease. It underscores the importance of recognizing its associations and complications. Additionally, it highlights the need for further research and improved diagnostic and treatment guidelines to address the complexity of this condition.

T-Cells Subsets in Castleman Disease: Analysis of 28 Cases Including Unicentric, Multicentric and HHV8-Related Clinical Forms.

Castleman disease (CD) is a rare lymphoproliferative disorder that includes various clinico-pathological subtypes. According to clinical course, CD is divided into unicentric CD (UCD) and multicentric CD (MCD). MCD is further distinguished based on the etiological driver in herpes virus-8-related MCD (that can occur in the setting of HIV); in MCD associated with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes); and idiopathic MCD (iMCD). The latter can also be divided in iMCD-TAFRO (thrombocytopenia, anasarca, fever, myelofibrosis, organomegaly) and iMCD not otherwise specified. To date, CD pathogenesis is still uncertain, but CD may represent the histological and clinical result of heterogeneous pathomechanisms. Transcriptome investigations in CD lymph nodes have documented the expression and up-regulation of different cytokines; furthermore, few recent studies have shown alterations of different T-cell subsets in CD patients, suggesting a possible role of the nodal microenvironment in CD development. On this basis, our study aimed to investigate the distribution of T-cell subsets in the clinico-pathological spectrum of CD. We evaluated the CD4/CD8 ratio and the number of T-regulatory (T-reg) FOXP3+ cells in 28 CD cases. In total, 32% of cases showed a decreased CD4/CD8 ratio due to increased CD8+ T-cells, including both UCD, iMCD, and HHV8+ MCD cases. The T-reg subset analysis revealed a statistically significant (p < 0.0001) lower mean number of FOXP3+ T-reg cells in CD cases when compared with non-specific reactive lymph nodes. We did not find statistically significant differences in T-reg numbers between the different CD subtypes. These findings may suggest that alterations in T-cell subpopulations that can lead to disruption of immune system control may contribute to the numerous changes in different cellular compartments that characterize CD.

A national, multicenter, retrospective study of Castleman disease in China implementing CDCN criteria

Castleman disease (CD) is a group of rare and heterogenous lymphoproliferative disorders including unicentric CD (UCD), human herpesvirus-8(HHV-8)-associated multicentric CD (HHV8-MCD), and HHV-8-negative/idiopathic multicentric CD (iMCD). Knowledge of CD mainly comes from case series or retrospective studies, but the inclusion criteria of these studies vary because the Castleman Disease Collaborative Network (CDCN) diagnostic criteria for iMCD and UCD were not available until 2017 and 2020, respectively. Further, these criteria and guidelines have not been systematically evaluated. In this national, multicenter, retrospective study implementing CDCN criteria, we enrolled 1634 CD patients (UCD, n=903; MCD, n=731) from 2000 to 2021at 40 Chinese institutions to depict clinical features, treatment options, and prognostic factors of CD. Among UCD, there were 162 (17.9%) patients with an MCD-like inflammatory state. Among MCD, there were 12 HHV8-MCD patients and 719 HHV-8-negative MCD patients, which included 139 asymptomatic MCD (aMCD) and 580 iMCD meeting clinical criteria. Of 580 iMCD patients, 41 (7.1%) met iMCD-TAFRO criteria, the others were iMCD-NOS. iMCD-NOS were further divided into iMCD-IPL (n=97) and iMCD-NOS without IPL (n=442). Among iMCD patients with first-line treatment data, a trend from pulse combination chemotherapy toward continuous treatment was observed. Survival analysis revealed significant differences between subtypes and severe iMCD (HR=3.747; 95% CI: 2.112-6.649, p<0.001) had worse outcome. This study depicts a broad picture of CD, treatment options and survival information in China and validates the association between the CDCN's definition of severe iMCD and worse outcomes, requiring more intensive treatment. Beijing Municipal Commission of Science and Technology, CAMS Innovation Fund and National High Level Hospital Clinical Research Funding.

Clinical and histopathology characteristics of Castleman disease: a multicenter study of 51 Brazilian patients.

Castleman's disease (CD) is a rare and heterogeneous lymphoproliferative disorder, with limited available clinical information in Brazil. A retrospective study was carried out through information contained in the medical records of 51 patients, between July 1999 and June 2020. Seven patients were excluded, and 44 were analyzed in total. The average age of unicentric CD (UCD) patients was 35years old and of multicentric CD (MCD) patients was 49years old (p = 0.013). Regarding gender, there was a predominance of females among patients with UCD (68.4%) and males in patients with MCD (57.9%) (p = 0.103). The most common site of involvement in UCD was the cervical region (36.8%). A total of 73.7% of patients with UCD and 68.4% of patients with MCD presented the histological form hialyne-vascular (HV) (p = 0.499). Most patients with laboratory abnormalities had MCD. A total of 78% of the patients were asymptomatic, with the majority of symptomatic patients with MCD (p = 0.042). Only two of the 27 patients evaluated for the presence of human immunodeficiency virus (HIV) had positive serology. HHV-8 was evaluated in 14 cases, being positive in two. Of the patients with UCD, 94.7% underwent excisional biopsy, against only 41.2% of patients with MCD (p = 0.01). The mean follow-up was 61months. We observed similarities in the clinical profile between patients in our study and patients described in the literature, such as gender, mean age, B symptoms, visceromegaly, fluid accumulation, and treatment. Unlike the literature, the cervical region was the most affected site, besides the greater association of the HV histological subtype among patients with MCD.

Idiopathic Multicentric Castleman's Disease with Concurrent Renal Involvement

Introduction Castleman Disease (CD) is a rare non-clonal benign lymphoproliferative disease.CD can be classified into various subtypes based on etiology, clinical and histological findings. Management of CD varies based on the diagnosis and patient's condition and it can range from surgical excision to more aggressive systemic therapies such as anti-IL-6, steroids, and chemotherapy. It can rarely present with renal involvement, which is poorly understood. Case Presentation A 31-year-old male patient with a history of hospital admission one month prior to the present illness for persistent abdominal pain, with an incidental finding of splenomegaly and generalized lymphadenopathy on imaging, was admitted to the hospital for a 2-week history of generalized swelling with associated 20-pound weight gain, poor oral intake, nausea, vomiting, and loose stools. Laboratory work-up (TABLE 1) revealed hyponatremia with sodium of 117 mmol/L and renal failure with a creatinine of 1.6 mg/dL. Urinalysis showed proteinuria of 2+ and 24-hour collection revealed 300 mg of total protein. Heart failure was not noted on echocardiogram and biochemical or imaging findings were not suggestive of liver cirrhosis. Fluid restriction and diuretics were initiated. The patient improved initially but his hospital course was complicated by worsening renal failure and normochromic, normocytic anemia. Nephrology, Gastroenterology, Pulmonology, and Surgery were consulted. Excisional lymph node biopsy was performed revealing multicentric Castleman's Disease, negative for HHV-8. A kidney biopsy was performed later, consistent with thrombotic microangiopathy (Figure 1). VEGF and IL-6 were elevated. Hemodialysis was entertained,steroids were started, and Siltuximab was ordered but could not be obtained at the institution. Tocilizumab was started instead. The patient had a dramatic improvement after the treatment initiation and a week later the patient was discharged home. The patient's renal function was back to baseline and he was asymptomatic during the one-month follow-up visit. Discussion CD is a rare lymphoproliferative disease and renal involvement in CD is even rarer. There is still no consensus on how to manage CD patients with renal involvement. Here, we present an iMCD-NOS patient with renal involvement. Given the different therapeutic approaches, a final diagnosis of CD subgroups is important. The diagnosis of TAFRO, a rare clinicopathologic variant of idiopathic multicentric Castleman disease characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly was under consideration but discarded due to the patient lacking thrombocytopenia and it was decided to classify the patient under the not otherwise specified category. Renal complications from CD are uncommon and can include a variety of histopathological findings on biopsy, including thrombotic microangiopathy and membranoproliferative glomerulonephritis, among others.Our patient had thrombotic microangiopathy based on the renal biopsy findings. The pathophysiology of CD is not well understood. It is well known that IL-6 plays a role as increased levels of this proinflammatory marker have been associated with disease activity. Interestingly, increased serum levels of IL-6 and other cytokines have been observed in patients with several diseases characterized by renal thrombotic microangiopathy. Therefore, we hypothesize that increased IL-6 levels in patients with CD create an unhealthy environment for the renal microarchitecture that may result in thrombotic microangiopathy. As demonstrated by our case, improvement of renal function can be achieved after treating this pro-inflammatory state with systemic therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HUMAN HERPESVIRUS 8 (HHV8)-NEGATIVE MULTICENTRIC CASTLEMAN DISEASE LEADING TO GROUP 1 PULMONARY ARTERY HYPERTENSION AND CLINICALLY SIGNIFICANT RIGHT VENTRICULAR SYSTOLIC DYSFUNCTION

HUMAN HERPESVIRUS 8 (HHV8)-NEGATIVE MULTICENTRIC CASTLEMAN DISEASE LEADING TO GROUP 1 PULMONARY ARTERY HYPERTENSION AND CLINICALLY SIGNIFICANT RIGHT VENTRICULAR SYSTOLIC DYSFUNCTION

Analysis of albumin as a prognostic factor in HHV-8/HIV-negative Castleman disease from a multicenter study

As a rare lymphoproliferative disorder, many patients with HHV-8/HIV-negative Castleman disease (CD) have hypoalbuminemia. However, data is limited on whether hypoalbuminemia is an independent predictor of CD. We retrospectively collected data from 230 patients diagnosed at 12 medical centers in China and the U.S. Different classifications included 147 patients with unicentric CD (UCD) and 83 with idiopathic multicentric CD (iMCD). Adjusted smooth curve fitting showed that the relationship between albumin and all-cause death of patients with CD and iMCD was linear. Cox proportional hazards regression modeling showed a negative association between the risk of death and albumin level (hazard ratio [HR]: 0.84; 95% CI, 0.76, 0.93). Using the Kaplan–Meier method, we determined that hypoproteinemia was a risk factor for poorer prognosis in patients with CD, UCD, and iMCD. Albumin was independently and negatively associated with the risk of death in CD patients, especially those with iMCD.

18F-FDG PET/CT and contrast-enhanced CT in the diagnosis of Castleman disease.

Castleman disease (CD) is a rare group of lymphoproliferative disorders, which is easily confused with lymphoma or other solid tumors. Hence, this study aimed to investigate the diagnostic role of 18F-FDG PET/CT and contrast-enhanced CT (CECT) in patients with CD. Clinicopathological characteristics, and 18F-FDG PET/CT and CECT findings and parameters were retrospectively reviewed in 32 patients with CD. These 32 patients (12 males, 20 females; median age, 41years) consisted of 17 unicentric CD (UCD) patients and 15 multicentric CD (MCD) patients. Compared with MCD, UCD had a higher prevalence in female (82.4% vs. 40.0%) and hyaline vascular subtype (94.1% vs. 40.0%) (P < 0.05). FDG uptake was avid in all cases, including moderate uptake in 7 cases and intense uptake in 25 cases. The median SUVmax, SUVmean, MLV, and TLG of all cases were 4.4 (range, 1.4-23.6), 2.7 (range, 1.1-15.2), 26.6 (range, 4.8-393.0), and 78.8 (range, 9.4-1545.6), respectively. The lesions of 29 cases showed homogeneous enhancement, and marked enhancement was observed in 27 cases. 18F-FDG PET/CT corrected 6.3% CECT diagnoses, while CECT corrected 37.5% PET/CT diagnosis. The accuracy of combined PET/CT and CECT was superior to PET/CT or CECT alone (78.1%, 31.3%, and 62.5%). Besides, higher SUVmax and SUVmean were found in male subjects, MCD, and plasma cell subtype (P < 0.05), while higher MLV and TLG were observed in larger lesion size and volume (P < 0.05). Castleman disease most commonly appears as marked and homogeneous enhancement meanwhile with moderate or intense FDG uptake. 18F-FDG PET/CT combined with CECT was the effectively diagnostic modality for CD. The glucose metabolism of CD was associated with gender, clinical classification, histopathological classification, and lesion size and volume.

Profile of vascular markers and CT enhancement of hyaline vascular type Castleman's disease.

Blood vessels in lymph nodes (LNs) are unique in comprising both capillaries and high endothelial venules (HEVs). Hyaline vascular type Castleman's disease accompanies robust angiogenesis, but it is unclear how the capillaries and HEVs respond. We retrospectively examined surgical specimens of hyaline vascular type unicentric Castleman's disease patients (n=24) and control LNs (n=9). We performed immunohistochemistry of CD 31 for capillaries and MECA-79 for HEVs and calculated their microvascular density. We measured CT enhancement as the ratio of Hounsfield Units (HUs) of the target lesion against muscle compared with microvascular density. The microvascular density of Castleman's disease specimen were (CD 31+) 169.7±77.6, (MECA-79+) 203.5±96.7, and the microvascular density of control LNs were (CD 31+) 80.7±20.1, (MECA-79+) 67.4±23.7, respectively. The microvascular density of both CD 31+ (P<0.001) and MECA-79+ (P<0.001) was higher in Castleman's disease. A positive correlation existed between CT HU ratio and microvascular density for both markers (CD 31: r=0.517, P=0.002; MECA-79: r=0.521, P=0.002). Intra-nodal angiogenesis of Castleman's disease involves robust proliferation of not only CD 31+ capillaries, but also MECA-79+ HVEs, which each correlated with degree of CT enhancement.

Emerging morbidities and health care resource utilization in idiopathic multicentric Castleman disease patients: A population-level analysis using health claims-based dataset.

e18792 Background: Idiopathic multicentric Castleman disease (iMCD) is a hematologic disorder characterized by systemic inflammation, polyclonal lymphoproliferation, and multi-organ dysfunction due to hypercytokinemia often including interleukin-6 (IL-6). iMCD patients have had historically poor outcomes, particularly prior to the advent of anti-IL-6 therapy. We recently found that ̃90% of iMCD patients did not have any claims for anti-IL-6 therapy. One potential reason for inadequate treatment is limited understanding of associated morbidities that can be controlled with therapy. We aimed to assess emergent morbidities in iMCD patients using a large administrative claims database. Methods: An iMCD cohort was identified using an administrative health claims dataset that enrolled 30.7 million US patients between January 1, 2017 and December 2, 2020. This is an updated analysis from a previously published health claims study ( Mukherjee et al, 2022). iMCD patients were identified based on CD-specific ICD-10 diagnosis code (D47·Z2), negative HHV-8 and HIV status, and diagnostic or laboratory claims for ≥2 minor criteria. Post-diagnosis hospitalizations, emergency room (ER) visits, and emergent morbidities in iMCD patients were identified in claims data and compared to non-iMCD cohort matched (1:50) by age group (0-17, 18-44, 45-54, 55-64, &gt; 65 years), sex, insurance type, database history, and region. The iMCD cohort was further stratified by age (0-44 years, 45-60 years, &gt; 60 years) or treatment (iMCD-directed therapy, steroid only, and no treatment) for subgroup analyses of morbidity rates. Results: We identified 271 individuals likely to have iMCD (iMCD patients) (mean age: 50·8 years; 59·4% female), including 191 patients previously reported (ASH, 2021). We found significantly higher odds of organ dysfunction (n = 116, OR = 6·5, 95% CI = 4·9, 8·5) and thrombotic events (n = 79, OR = 4·8, 95% CI = 3·4, 6·7) in iMCD patients compared to a matched non-iMCD cohort. We observed increasing proportions of morbidities with advancing age in iMCD and matched non-iMCD cohorts. Similar morbidity trends were observed in all three iMCD treatment cohorts. A high proportion of iMCD patients required an ER visit (47.8% and 42.6% in the year before and after initial diagnosis), dropping to 13.5% in the second year after diagnosis. A similar pattern was observed in inpatient stays, with a marked increase in patients hospitalized for &gt; 5 days increasing from 6·2% two years prior to diagnosis to 34·3% and 15·6% in the two subsequent years. Conclusions: We report high odds of organ dysfunction and thrombotic events in iMCD patients from this population analysis of patient-claims data. In this iMCD cohort with previously reported low use of iMCD-directed therapies, a high proportion of patients required ER visits and inpatient hospitalizations.

Post hoc analysis of a long-term safety extension study: Responses to siltuximab in idiopathic multicentric Castleman disease patients receiving on-label dosing.

e19586 Background: Siltuximab is the only FDA- and EMA-approved therapy for idiopathic multicentric Castleman disease. Its long-term efficacy and safety were established in a 6-year extension study featuring patients who responded to treatment or had stable disease in a phase 1 or phase 2 trial. However, dosage could be adjusted at physician discretion; of 60 patients, 33 remained on the on-label dosing of 11 mg/kg administered every 3 weeks. To assess the safety and efficacy of on-label dosing, we performed a post hoc analysis in patients who maintained this dosing. Methods: A mixed-effects model was used to analyze longitudinal measurements for tumor response, C-reactive protein (CRP), hemoglobin (Hb), erythrocyte sedimentation rate (ESR), fibrinogen, albumin, and platelet counts at multiple time points. Adverse events (AEs) were also assessed. Greenhouse–Geisser correction was used to ensure that the assumption of sphericity was met for the mixed-effects model. Tukey post hoc correction was applied to determine significant differences between specific time points. Results: Of the 33 patients on 3-week dosing, one transitioned to receiving siltuximab every 6 weeks for 25 cycles but restarted 3-weekly dosing due to suspected progressive disease (PD). Disease control was observed in 31 of the 33 patients (93.9%) at their last on-study assessment (complete response [CR] in 9 [27.3%]). Quantitative analyses were performed on the 32 patients who maintained 3-weekly dosing until their last on-study assessment. Siltuximab led to sustained mean levels of CRP, Hb, ESR, fibrinogen, albumin, and platelet counts for the duration of the study. In the 19 patients with residual IL-6 activity at screening (CRP levels &gt; 4 mg/L) there was an overall reduction in CRP from baseline at multiple time points. This group showed a trend towards improved total Hb levels, which increased by 9.43% (adjusted p = 0.048) at cycle 31, and some demonstrated an improvement in ESR, fibrinogen, and albumin levels. All patients reported AEs, mostly grade 1 or 2, with no deaths. At point of enrolment into the extension study, the three most common AEs were hypertension (36.4%), fatigue (42.4%), and pain (51.5%). Conclusions: Our findings show that long-term on-label dosage of siltuximab sustains an improved inflammatory profile and disease control.[Table: see text]

Comprehensive analysis of 65 patients with Castleman disease in a single center in China

This study aimed to investigate the epidemiologic, clinical, pathological characteristics, and treatment of patients with Castleman disease (CD) in a single center in China. We retrospectively analyzed the data of 65 Chinese CD patients, divided into unicentric CD (UCD) and multicentric CD (MCD) groups, and also microscopic subtypes as hypervascular (HV), plasmacytic (PC) and Mixed. Based on whether HHV-8 infection existed, MCD was subdivided into HHV-8-associated MCD and idiopathic Castleman disease (iMCD). Detailed epidemiologic, clinicopathological, and treatment data were analyzed and discussed. Of total 65 patients (UCD 33, MCD 32), HV (81.8%) accounted for the most of UCD and total. More females in UCD (60.6%) and more males in MCD (65.6%) were observed. CD occurred in all age groups, most commonly in 40–49 years. The mean age of onset of total was 38.5 years with PC higher than HV (45.5 vs. 35.1 years, P = 0.0413). The median diagnosis delay of MCD was longer than that of UCD (3.00 vs. 1.25 months, P = 0.0436). Abdomen (39.4%) and neck (30.3%) were the most-seen locations of lymphadenopathy in UCD, with neck (65.6%) being predominant in MCD. Mean major diameter of specimens of UCD was greater than MCD (6.4 vs. 3.1 cm, P < 0.0001). These results provided the featured and detailed profile of Castleman disease in Henan province in China with a considerable number of cases, which presented distinct evidence with other studies.

Clinical and Molecular Characteristics of 60 Patients With Human Immunodeficiency Virus-Negative Castleman Disease.

Castleman disease (CD) is a rare lymphoproliferative disorder. The mechanistic target of rapamycin (mTOR) pathway is a key regulator of various cellular functions, which may be related with the potential mechanisms of CD occurrence. We retrospectively collected the clinical information of 60 CD patients diagnosed in the First Affiliated Hospital of Zhengzhou University. And FFPE biopsy specimens were collected from 31 patients (12 unicentric CD patients and 19 multicentric CD patients) to detect the mTOR pathway protein expression. We are the first to demonstrate that thrombocytopenia and hypoalbuminemia are independent poor prognostic factors for CD. Moreover, mTOR activation was higher in CD compared to reactive lymphoid hyperplasia (used as a control group). This study offers some elucidation for the management and treatment of CD patients.

The disease course of Castleman disease patients with fatal outcomes in the ACCELERATE registry.

SummaryCastleman disease (CD) describes a group of rare, potentially fatal lymphoproliferative disorders. To determine factors associated with mortality in CD, we analysed data from deceased patients in the ACCELERATE registry and compared them with matched controls. We analysed demographic, treatment and laboratory data from all deceased CD patients, matched controls and a subgroup of idiopathic multicentric Castleman disease (iMCD) patients. Of the 140 patients in ACCELERATE with a confirmed CD diagnosis, 10 had died. There were 72 patients with confirmed iMCD; six were deceased. The deceased CD cohort had more hospitalisations per year, higher overall hospitalisations and more days hospitalised per month, and received more treatment regimens per year than the matched‐control group. Analysis of laboratory values showed a significantly decreased absolute lymphocyte count at months 3 and 6 in the deceased cohort compared with controls. Among iMCD patients, there was a higher proportion of iMCD‐TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction and organomegaly) cases in the deceased group. The deceased iMCD group had significantly lower immunoglobulin M, international normalised ratio and platelet count. These data demonstrate that there may be differences between patients who have fatal and non‐fatal outcomes, and provide preliminary suggestions for parameters to evaluate further.

Clinicopathological and therapeutic analysis of Castleman's disease in children

Objective: To investigate the clinical features, pathological phenotype, treatment and prognosis of Castleman's disease in children. Methods: Clinical data of 15 children diagnosed with Castleman's disease in Henan Provincial People's Hospital and the First Affiliated Hospital of Zhengzhou University from May 2010 to October 2019 were analyzed retrospectively. The clinical characteristics, laboratory examination and histopathological data were analyzed. Results: Among the 15 Castleman's disease patients, 12 were males and 3 females. The age of first visit was 12 (10, 15) years. The time from mass discovery to pathologic diagnosis was 9.0 (2.0, 13.0) months. The majority of patients were unicentric (13 cases), and the histopathological type was hyaline vascular (11 cases). Unicentric lesions were most common in the neck (11 cases), all 13 patients received complete surgical resection of the lesions, the follow-up time was 20.0 (13.5, 50.5) months, and the prognosis was good. Two cases were multicentric type, the pathological types were mixed variant, meeting the criteria of idiopathic Castleman's disease, the two children underwent partial surgical resection, one was treated with rituximab and prednisone and the other was treated with thalidomide and prednisone. The follow-up time was 32 months and 10 month, both of them had good prognosis. Conclusions: Most cases of Castleman's disease in children are diagnosed late, and the unicentric type is dominant. The most common pathological type is hyaline vascular, which is characterized by painless lymphadenopathy, while multicentric type has systemic symptoms and both of them have a good overall prognosis.

Safety and Tolerability of Sars-Cov-2 Vaccination and Natural History of Infection Among Patients with Castleman Disease

Castleman Disease (CD) represents a group of rare and heterogeneous hematologic disorders that have common lymph node histopathology. Patients with CD are often immunosuppressed as a consequence of immunemodulating therapy or possibly due to an underlying immunologic dysfunction attributable to B-cell dysfunction. The most severe CD cases experience a cytokine storm disorder, a life-threatening exacerbation of circulating cytokines and immune-cell hyperactivation. Infection with SARS-CoV-2 progresses to a severe cytokine storm in the most severe cases of COVID-19. Interleukin-6 (IL-6) is central to the pathogenesis of CD, and increased IL-6 often accompanies severe COVID-19 cases; inhibition of IL-6 with monoclonal antibodies has been shown to be effective therapy for both CD and severe COVID-19. We therefore sought to understand the impact of COVID-19 infection on the natural history of CD and also examined the safety and tolerability of COVID-19 vaccines in this vulnerable patient population.Patients enrolled in a longitudinal natural history study of CD (N=298) were invited to participate in a survey designed to characterize their experience with COVID-19 disease and vaccination. Surveys were emailed to all eligible patients, and reminders were sent up to 3 times. All data is self-reported; descriptive analyses are reported herein.Of the 298 patients who received a survey, 101 (33.9%) completed it. Sixty-nine (68%) had been tested for SARS-CoV-2 at least once, and 10 (14.5%) reported testing positive - including 6 UCD, 3 iMCD, and 1 HHV8+ MCD patients. The reported prevalence of SARS-CoV-2 infection in the US compares at 10.5%. Two of the 10 patients reported asymptomatic disease (both UCD), 7 reported mild disease (4 UCD, 1 iMCD, 1 HHV8+MCD), and 1 reported moderate disease requiring hospitalization but not a ventilator or intensive care (iMCD). This severity distribution suggests that these potentially immunocompromised patients experience a range of disease severity consistent with SARS-CoV-2 infection in the broader US population. The most commonly-reported symptoms included fevers/chills, headaches, and loss of taste or smell (N=7 each), as well as shortness of breath/difficulty breathing, muscle and body aches, and cough (N=5 each). Rarer symptoms were also noted among the iMCD patients, including discoloration of skin, lips, or nailbeds (N=1) and newfound confusion (N=2). Two of the 10 patients reported stopping siltuximab treatment during their COVID-19 diagnosis; both subsequently resumed treatment. No other treatment changes were reported.Of the 101 respondents, 87 (86%) had received at least 1 vaccine dose. Treatments, such as immunosuppressants and immunomodulators, were paused for 7 of these patients including, during the vaccination period; this was presumably done to increase the likelihood of a robust response to the vaccine. Fifty-one patients (59%) reported side effects to either dose 1 or 2. Side effects were generally mild, and none required hospitalization. Side effects were more commonly reported after dose 2, with the most common being arm pain (N=34), fatigue (N=30), and headache (N=26). Of those who reported not receiving the vaccine, 2 intend to receive it in the future, 5 reported being unsure about receiving it, and 7 do not intend to receive the vaccine. Common concerns include potential interaction with CD (N=9) and limited safety data (N=8).This study represents the first investigation into the experience of CD patients with SARS-CoV-2 testing, diagnosis, and vaccination. We did not observe a markedly increased inflammatory response to SARS-CoV-2 infection, and vaccination was well-tolerated. A limitation is self-selection survey bias; it is possible that those who chose to participate represent those who had a milder reaction in general. However, it is noteworthy that there were no reports of severe disease in this sample. The prevalence of confirmed SARS-CoV-2 infection in this cohort (14.5%) is marginally higher than reported in the US population (10.5%) but statistical comparisons were not performed given that this study does not provide a general epidemiological estimate. However, the distribution of symptoms and vaccine adverse effects in this sample were comparable to the general population. Though additional follow-up is planned for the future, these data are an important basis for understanding the interaction of SARS-CoV-2 and CD. DisclosuresCasper: EUSA Pharma: Consultancy. Fajgenbaum: Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’; EUSA Pharma: Research Funding. OffLabel Disclosure:Our abstract makes reference to the following: “Interleukin-6 (IL-6) is central to the pathogenesis of CD, and increased IL-6 often accompanies severe COVID-19 cases; inhibition of IL-6 with monoclonal antibodies has been shown to be effective therapy for both CD and severe COVID-19.” Inhibition of IL-6 with monoclonal antibodies for use in COVID-19 is off-label.

Characterization of Castleman Disease Reveals Patients with Oligocentric Adenopathy and Clinicopathologic Characteristics Similar to Unicentric Castleman Disease

Castleman disease (CD) describes a group of heterogeneous lymphoproliferative disorders with characteristic histopathology that are classified based on the number of enlarged lymph node (LN) stations, etiological drivers, and clinical phenotype. CD histopathology includes a broad spectrum from plasmacytic to hyaline/hyper vascular with a mixed pattern in between. Unicentric CD (UCD) involves a single enlarged LN station and mild symptoms, whereas multicentric CD (MCD) involves multiple stations of enlarged LNs and more severe symptoms. MCD is subclassifed into Human Herpesvirus-8 associated MCD, POEMS-associated MCD, and idiopathic MCD (iMCD). iMCD cases are further subdivided into thrombocytopenia, anasarca, fever/elevated C-reactive protein (CRP), renal dysfunction, organomegaly (TAFRO) or iMCD-not otherwise specified (NOS), who often have thrombocytosis and hypergammaglobulinemia. Recently, it has been reported that some iMCD patients can have more oligocentric lymphadenopathy (above or below the diaphragm) whereas others have generalized lymphadenopathy (above and below the diaphragm). Given the heterogeneity across CD, we leveraged data from a longitudinal natural history study of CD to characterize the spectrum of CD. Specifically, we set out to determine if patients with multicentric lymphadenopathy localized to above or below the diaphragm (oligocentric CD, OCD) appeared to be more similar to UCD or iMCD with more generalized lymphadenopathy.In total, 130 patients enrolled in an international CD registry were confirmed to have CD by a panel of experts. Patients were assigned UCD, OCD, or iMCD per the following: UCD, 1 station of enlarged LNs (N=32); OCD, ≥2 stations of enlarged LNs, either above or below the diaphragm (N=29); iMCD, ≥2 stations of enlarged LNs, both above and below the diaphragm (N=69). Clinical data is provided closest to date of diagnosis +/-90 days. Sustained response is defined as ≥50% symptom improvement sustained without the addition of subsequent drug treatments. When appropriate, statistical testing was performed by Chi-square, Fisher's exact, or two-tailed T test.Among the 69 iMCD patients, 42 (61%) were classified as TAFRO and 27 (39%) were NOS. In contrast, only 1 of 29 OCD patients (3%) was TAFRO and 28 (97%) were NOS. No UCD patients were TAFRO. Breakdown of histopathological subtype can be found in Table 1. There was a mean (SD) of 8.4 (3.7) enlarged LNs in iMCD at diagnosis, compared with 2.8 (1.4) in OCD and 1 (0) in UCD. While enlarged LNs in the abdomen/pelvis region occurred in 56% of UCD, only 19% of OCD patients demonstrated lymphadenopathy in this region. Clinically, OCD patients demonstrated symptoms and laboratory abnormalities more comparable to UCD than iMCD (Table 2). In fact, there was no difference in symptoms between UCD and OCD groups, while there were significantly more symptoms in iMCD than OCD. iMCD had significantly worse anemia, albumin, creatinine, CRP, and other markers of inflammation than OCD, whereas OCD patients had significantly increased CRP (p=0.03) and alkaline phosphatase (p=0.03) compared to UCD. IgM was greater in OCD than both UCD (p=0.02) and iMCD (p=0.01) (Table 2). The number of patients receiving drug treatments differed by subtype: 7 UCD (22%), 18 OCD (62%), and 67 iMCD (97%). Fifty-five patients (UCD: 1, OCD: 7, iMCD: 47) received anti-IL-6 therapy (+/- steroids), including the only FDA-approved drug, siltuximab. Sustained response to anti-IL-6 (+/- steroids) was observed in 23/47 (49%) iMCD, 3/7 (43%) OCD, and 0/1 UCD. Within iMCD clinical subgroups, response was observed in 12/27 (44%) iMCD-TAFRO and 11/20 (55%) iMCD-NOS as well as across the histopathogical subtypes, suggesting that anti-IL-6 therapy can be effective across the spectrum.Overall, this study highlights the heterogeneity of CD. Importantly, it uncovers a group of CD patients that meet diagnostic criteria for iMCD but their lymphadenopathy is confined to above or below the diaphragm and they appear to behave more similarly to UCD. Given that 1/3 of OCD patients were managed without drug treatment, further work is needed to determine the relative benefits of UCD-like surgical treatment versus iMCD-like drug-based therapy for OCD. The clinical subtype of TAFRO, which was present in more than half of the iMCD patients, was observed in only one OCD case and no UCD cases. Further work is needed to determine optimal treatments across these subgroups. [Display omitted] DisclosuresBagg: Scopio Labs: Research Funding. Lim: EUSA Pharma: Honoraria. Srkalovic: Takeda: Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau; EUSA Pharma: Speakers Bureau; Foundation Medicine: Speakers Bureau. Uldrick: Merck: Other: Receives study drug; Roche: Research Funding; Regeneron: Current Employment; Celgene: Research Funding. Fajgenbaum: Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’; EUSA Pharma: Research Funding.

Ongoing Symptoms and Reduced Health Measures in Unicentric Castleman Disease Patients Despite Perceived-to-be Curative Surgical Excision

Unicentric Castleman disease (UCD) is one of several subtypes of Castleman disease that share characteristic histopathology. While UCD involves one region of enlarged lymph nodes (LN) and milder symptoms, idiopathic multicentric CD (iMCD) involves multiple regions of enlarged lymph nodes and cytokine-driven organ dysfunction. UCD symptoms can occur due to compression of neighboring structures or inflammatory cytokine production. Complete excision of the enlarged LN is reported in the literature to be curative in 84-96% of UCD patients. However, many UCD patients describe persistence or worsening of symptoms post excision despite normal laboratory values and absence of measurable disease. To better characterize and describe the experience of individuals diagnosed with UCD, we administered surveys to UCD patients to capture information about general quality of life (QOL), specific health measures, and ongoing UCD symptoms.All patients enrolled in the ACCELERATE Natural History registry who either self-reported a UCD diagnosis or were suspected to have a UCD diagnosis were invited to participate in the Rand36-item Short Form survey, the EQ-5D-5L, the MCD Symptom Score survey, all of which are validated instruments, as well as an additional form regarding ongoing symptoms. Among the 107 UCD patients invited to participate, 51 (48%) responded. Descriptive analyses were conducted on all 51 respondents with a self-reported UCD diagnosis. Subsequently, a subset consisting of 25 respondents, who had been reviewed by a panel of physicians that confirmed a UCD diagnosis (confirmed subcohort, CS), was analyzed.Mean (SD) EQ-5D-5L health index score (100 being perfect health, 0 being worst health imaginable) of the 51 patients was 67.6 (19.9), compared to a representative sample of the US population whose score was 80.4. Patients reported having poor health over the prior 4 weeks, with low scores indicating high levels of fatigue (38.8) and poor general health (47.7). These are notable and comparable to scores for fatigue (52.2) and general health (57.0) among a separate cohort of patients with diabetes, hypertension, coronary heart disease, and/or depression.Strikingly, 57% of patients reported continuation of symptoms post-LN excision, with an additional 16% being unsure. Only 29% reported complete symptom resolution, with the remainder reporting partial resolution (29%), stable disease (20%), worsening disease (12%), or unsure (10%). Nearly all 51 respondents underwent their LN-excision >1 year prior (93%). Fatigue (61%) and night sweats (39%) were most commonly reported in patients with continued symptoms. In fact, 27 patients (53%) reported ongoing symptoms on the day of survey completion with 93% of those patients reporting fatigue that day. Of note, sub-group analyses of the CS revealed similar findings, with a potential trend towards slightly better overall health with mean (SD) health index score 72.6 (14.5), fatigue (44%) and night sweats (36%), and ongoing symptoms reported in 40%. Of the patients in the CS, all had a complete resection, with 3 demonstrating subsequent lymphadenopathy in new regions ranging from 6 months to 5 years after their initial excision.Overall, these data suggest that UCD patients who have had resection of disease continue to experience symptoms that affect QOL. Patients reported lower QOL than a representative national average, as well as health measures comparable to a separate cohort of individuals with chronic health conditions. Of note, the full cohort of self-reported individuals consistently reported lower scores compared to the subset of patients with confirmed UCD (not statistically tested). Of the 26 non-confirmed cases, 8 did not achieve criteria to meet UCD and 18 have not yet been reviewed by our physician panel. A different undiagnosed disorder may be the root cause of symptoms in a portion of these patients and others may be experiencing symptoms due to a co-occurring disorder. These results may be confounded by reporting bias and may not be representative of the full UCD population. Nevertheless, these data suggest that perceived-to-be curative excision does not result in symptom-free outcomes in a substantial proportion of patients and that symptom management may be required beyond excision. Future work is needed to correlate these findings with clinical, laboratory, and experimental data to further elucidate mechanisms and treatment options. DisclosuresFajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’.