P1140: TIME TO TUMOR, SYMPTOMATIC AND LABORATORY RESPONSES FOLLOWING SILTUXIMAB TREATMENT IN IDIOPATHIC MULTICENTRIC CASTLEMAN DISEASE
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SUBMITTER: van Rhee F
PROVIDER: S-EPMC9429592 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Project description:Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction. Despite the approval of siltuximab, a monoclonal antibody against interleukin-6, for the treatment of iMCD, it is not known how long patients should receive siltuximab before determining whether the treatment is beneficial and should be continued. We performed post hoc analyses of the phase 2 randomized double-blind placebo-controlled trial of siltuximab for the treatment of patients with iMCD to determine the sequence of normalization of laboratory, clinical, and lymph node responses in patients who responded to siltuximab. Seventy-nine patients were enrolled in the trial (siltuximab, n = 53; placebo plus best supportive care, n = 26). Progression-free survival (PFS) was significantly improved in siltuximab-treated patients compared with those receiving placebo (P = .0001). The median PFS was 14.5 months (95% confidence interval, 13.6 months to upper bound not reached) for patients receiving placebo but was not reached for patients receiving siltuximab. In siltuximab-treated patients who achieved durable tumor (radiologic) and symptomatic responses (18 [34%] of 53), the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G. Siltuximab treatment prolongs PFS, rapidly improves symptomatology, and provides meaningful clinical benefit despite some laboratory tests and enlarged lymph nodes taking months to normalize in treatment responders. These data support the continued frontline use of siltuximab for iMCD, as recommended by international guidelines. This trial was registered at www.clinicaltrials.gov as #NCT01024036.
| S-EPMC9631655 | biostudies-literature
Project description: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 summaryThe 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.
| S-EPMC8894931 | biostudies-literature
Project description: Not available
| S-EPMC7820993 | biostudies-literature
Project description: Not available
| S-EPMC9584165 | biostudies-literature
Project description:Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for nonresponders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported 3 anti-IL-6 nonresponders with increased mTOR activation who responded to mTOR inhibition with sirolimus. We investigated mTOR signaling in tissue and serum proteomes from iMCD patients and controls. mTOR activation was increased in the interfollicular space of iMCD lymph nodes (N = 26) compared with control lymph nodes by immunohistochemistry (IHC) for pS6, p4EBP1, and p70S6K, known effectors and readouts of mTORC1 activation. IHC for pS6 also revealed increased mTOR activation in iMCD compared with Hodgkin lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that the mTOR activation in iMCD is not just a product of lymphoproliferation/inflammatory lymphadenopathy. Further, the degree of mTOR activation in iMCD was comparable to autoimmune lymphoproliferative syndrome, a disease driven by mTOR hyperactivation that responds to sirolimus treatment. Gene set enrichment analysis of serum proteomic data from iMCD patients (n = 88) and controls (n = 42) showed significantly enriched mTORC1 signaling. Finally, functional studies revealed increased baseline mTOR pathway activation in peripheral monocytes and T cells from iMCD remission samples compared with healthy controls. IL-6 stimulation augmented mTOR activation in iMCD patients, which was abrogated with JAK1/2 inhibition. These findings support mTOR activation as a novel therapeutic target for iMCD, which is being investigated through a trial of sirolimus (NCT03933904).
| S-EPMC7205815 | biostudies-literature
Project description:Siltuximab is the only US Food and Drug Administration-approved treatment for idiopathic multicentric Castleman disease (iMCD), a rare haematological disorder associated with substantial morbidity and mortality. Although siltuximab induces a response in a significant proportion of iMCD patients via interleukin 6 (IL6) neutralization, it is not universally effective. To develop a predictive model of response, we performed an in-depth analysis of 38 baseline laboratory parameters in iMCD patients from the phase II siltuximab trial who met criteria for treatment response or treatment failure. Univariate analyses identified eight baseline laboratory parameters that were significantly different between responders and treatment failures: albumin, immunoglobulin G (IgG), immunoglobulin A, C reactive protein (CRP), fibrinogen, haemoglobin, sodium and triglycerides. Stepwise logistic regression analysis of these candidate parameters identified a top performing model that included fibrinogen, IgG, haemoglobin and CRP. Based on cross-validation of the final multivariate logistic regression model, the model accurately discriminated responders from those who failed treatment (area under the receiver operator characteristic curve 0·86, 95% confidence interval: 0·73-0·95). All four laboratory parameters associated with response to siltuximab have biological relationships with IL6 and acute inflammation. Our model suggests that iMCD patients with laboratory evidence of an inflammatory syndrome are the best candidates for siltuximab therapy.
| S-EPMC9547643 | biostudies-literature
Project description:Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.
| S-EPMC9499480 | biostudies-literature
Project description:Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood cytokine storm-driven inflammatory disorder. Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking. Here we show, by comparison of levels of 1,178 proteins in sera of healthy participants (N = 42), patients with iMCD (N = 88), and with related diseases (N = 60), a comprehensive landscape of candidate disease mediators and predictors of siltuximab response. C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD. Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points. Our study thus suggests that CXCL13 is a predictive biomarker of response to siltuximab in iMCD.
| S-EPMC9700691 | biostudies-literature
Project description:BackgroundIdiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder mediated by excessive proinflammatory cytokine signaling, most notably by interleukin 6 (IL-6). IL-6-induced extramedullary hematopoiesis (EMH) has been reported in murine models of iMCD. Herein we present four cases of iMCD with EMH in humans.Case seriesThe index case is a 24-year-old white woman who presented with pancytopenia, hepatosplenomegaly, and diffuse lymphadenopathy (LAD) with EMH in core lymph node biopsies. We then searched ACCELERATE, a Castleman disease (CD) natural history registry, and identified three additional CD cases with EMH reported in biopsies: A 23-year-old Asian man with fatigue, edema, LAD, and splenomegaly; a 20-year-old white man with fever, dyspnea, LAD, and hepatosplenomegaly; and a 50-year-old white man with constitutional symptoms, LAD, and myelodysplastic syndrome in bone marrow with a KRAS mutation.ResultsAll four patients presented with thrombocytopenia and fever and/or markedly elevated C-reactive protein. Patient 1 had iMCD-NOS (not otherwise specified) with severe thrombocytopenia, reticulin fibrosis in bone marrow, small volume LAD and organomegaly but no anasarca. The other three patients had iMCD-TAFRO (thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly). Two had mixed CD and two had hypervascular CD in lymph nodes. All four had bone marrow hypercellularity and megakaryocyte hyperplasia and two had reticulin fibrosis.ConclusionsThis case series demonstrates that EMH can be seen in CD, particularly in iMCD-TAFRO. Given the similarity of this finding to previous murine models of IL-6-induced marrow and lymph node changes we hypothesize that this is an IL-6-mediated phenomenon.
| S-EPMC11537811 | biostudies-literature
Project description:ObjectivesCastleman disease (CD) is a heterogeneous group of disorders involving systemic inflammation and lymphoproliferation. Recently, clonal mutations have been identified in unicentric CD (UCD) and idiopathic multicentric CD (iMCD), suggesting a potential underlying neoplastic process.MethodsPatients with UCD or iMCD with next generation sequencing (NGS) data on tissue DNA and/or circulating tumor DNA (ctDNA) were included.ResultsFive patients were included, 4 with iMCD and 1 with UCD. Four patients (80%) were women; median age was 40 years. Three of five patients (60%) had ≥1 clonal mutation detected on biopsy among the genes included in the panel. One patient with iMCD had a 14q32-1p35 rearrangement and a der(1)dup(1)(q42q21)del(1)(q42) (1q21 being IL-6R locus) on karyotype. This patient also had a NF1 K2459fs alteration on ctDNA (0.3%). Another patient with iMCD had a KDM5C Q836* mutation, and one patient with UCD had a TNS3-ALK fusion but no ALK expression by immunohistochemistry.ConclusionsWe report 4 novel somatic alterations found in patients with UCD or iMCD. The 1q21 locus contains IL-6R, and duplication of this locus may increase IL-6 expression. These findings suggest that a clonal process may be responsible for the inflammatory phenotype in some patients with UCD and iMCD.
| S-EPMC9624446 | biostudies-literature