HIV-associated Multicentric Castleman Disease Research Articles

Outcomes in Kaposi's sarcoma-associated herpesvirus -associated primary effusion lymphoma and multicentric Castleman's disease in patients with human immunodeficiency virus (HIV) in a safety-net hospital system.

To describe cases of Kaposi's sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) in patients with HIV from a large, safety-net hospital system in Dallas, Texas, USA. We conducted a retrospective review of patients with HIV-associated PEL and/or MCD. Twelve patients with PEL and 10 patients with MCD were identified. All patients were male and 17 of 20 were men who have sex with men; 66.7% of PEL patients and 50% of MCD patients had concurrent KS at the time of diagnosis; 42% of patients with PEL and 20% of patients with MCD died during the follow-up period. We noted improved survival in our cohort compared to previous studies, particularly in our PEL patients with a median survival of 11.4 months compared to 3-6-month median survival historically. Median follow-up time for MCD patients was 17.5 months. This improved survival is despite suboptimal antiretroviral therapy (ART) adherence at diagnosis, with only 50% of patients on ART at the time of MCD/PEL diagnosis. These data highlight the importance of early recognition of PEL and MCD, and the larger-scale efforts needed to better understand the pathogenetic drivers of clinical outcomes in patients affected by KSHV-related diseases.

Efficacy and Safety of Regimens Used for the Treatment of Multicentric Castleman Disease: A Systematic Review

Introduction:Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder characterized by lymph node enlargement in multiple regions of the body. It includes two heterogeneous subtypes: human herpesvirus 8 (HHV-8) associated MCD and idiopathic MCD (iMCD). This study is focused on the efficacy and safety of treatment regimens for MCD in clinical trials.Methods:A systematic literature search was conducted using PubMed, Embase, Cochrane, Web of Science, Clinicaltrials.gov, ASH, and ASCO meeting websites from inception to May 9, 2021. The initial search revealed 1323 articles. After excluding reviews, duplicates, and non-relevant articles, we included data from 13 articles.Results:Data on 311 patients was included.Siltuximab based regimens:In the two clinical trials where siltuximab was used for iMCD, Cheson criteria (modified to include cutaneous lesions) was used to assess response. In a phase 2 trial by Van Rhee et al. (2014, n=79), the overall response rate (ORR) was 34% vs 0% and grade≥3 adverse events (AEs) were seen in 47% vs 54% of the siltuximab (n=53) and placebo (n=26) groups respectively. In a phase 1 trial by Kurzrock et al. (2013, n=37), 86% of patients improved in at least one clinical benefit response (CBR) component, 33% had confirmed radiological ORR, and 11% had grade≥3 AEs. Van Rhee et al. (2020, n=60) conducted an extension analysis of patients from these two trials. After a median follow-up of 6 years (IQR 5∙11-7∙76), serious AEs were reported in 42% of patients and stable disease (SD) or better of up to 6 years was recorded in 70% of patients.Tocilizumab based regimens:In a phase 2 trial by Ramaswami et al. (2020, n=8), ORR was 63% vs 100%, progression-free survival (PFS) at 4 months was 25% vs 33%, and grade≥3 AEs were reported in 25% vs 67% of HHV-8 associated MCD patients receiving tocilizumab alone vs tocilizumab alongside zidovudine (AZT) and valganciclovir (VGC), respectively. Nishimoto et al. (2005, n=28) reported a 30% reduction (p<0.001) in the mean short axis of swollen lymph nodes, after 1 year of therapy. The 5 year extension study by Nishimoto et al. (2007, n=35) reported 2.3 AEs / patient year.Rituximab based regimens:In a phase 2 trial by Bower et al. (2007, n=21), 67% of HIV-associated MCD patients had a partial response (PR) and 29% had SD on rituximab. The 2-year overall survival (OS) and relapse-free survival were 95% (95% CI, 86% to 100%) and 79% (95% CI, 52% to 100%) respectively. No grade≥3 toxicity was observed. In a phase 2 trial by Gerard et al. (2007, n=24) on rituximab in HIV-associated MCD, the sustained remission rate was 92% (95% CI, 80% to 103%) at day 60. Estimated 1-year OS was 92% (95%CI, 71% to 98%). In a phase 2 trial by Uldrick et al. (2014, n=17), rituximab and doxorubicin (R-dox) were administered to HHV-8 MCD patients. ORR was 82% and OS was 81% (95%CI, 57% to 93%) at 3 years. Ramaswami et al. (2021) reported survival outcomes from the same trial. The 5-year PFS with rituximab (n=8), R-dox followed by no maintenance (n=16), R-dox followed by AZT+VGC (n=10) and R-dox followed by interferon-alpha (n=10) were 71% (95%CI, 26% to 92%), 62% (95%CI, 23% to 85%), 87% (95%CI, 39% to 98%) and 70% (95%CI, 33% to 89%) respectively.Immunomodulatory drug-based regimens:In a phase 2 study by Zhang et al. (2019, n=25), ORR was 48% in iMCD patients on thalidomide, cyclophosphamide, and prednisone. Estimated 1-year OS and PFS were 88% and 60% respectively. Grade≥3 AEs were rash and pneumonitis in 1 (4%) patient each.Proteasome Inhibitor based regimens:Zhang et al. (2020, n=20) reported the efficacy of bortezomib, cyclophosphamide, and dexamethasone in relapsed and refractory (R/R) iMCD patients. Seventy-five percent had PR and 10% had SD. Estimated 1-year PFS and OS were 85% and 90% respectively. No grade≥3 AEs occurred.Antiviral Regimens:In a phase 2 trial by Uldrick et al. (2011, n=14), ORR was 28% in HHV-8 MCD patients on AZT and VGC. Clinical complete response (CR) occurred in 50% of patients. Ramaswami et al. (2021) reported the efficacy of AZT+VGC in 17 patients from the same trial. The 5-year PFS was 26% (95%CI, 8% to 49%).Conclusion:Siltuximab- and thalidomide-based regimens have acceptable efficacy and safety profiles for the treatment of iMCD. Bortezomib appears to be effective for R/R iMCD. Tocilizumab and rituximab showed promising outcomes for the treatment of HHV-8 associated MCD. However, more prospective clinical trials need to be conducted. [Display omitted] DisclosuresAnwer: Allogene Therapeutics: Research Funding; BMS / Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding.

P26 A case of B-cell lymphoma affecting the eye in a patient with rheumatoid arthritis following a reduction in the frequency of rituximab therapy

P26 A case of B-cell lymphoma affecting the eye in a patient with rheumatoid arthritis following a reduction in the frequency of rituximab therapy

'Peeling back the onion layers': the challenge of HIV-associated multicentric Castleman's disease.

'Peeling back the onion layers': the challenge of HIV-associated multicentric Castleman's disease.

HIV-associated multicentric Castleman disease: a report of 19 cases at an oncology institution.

The aim of this study is to describe the clinical characteristics and outcome of multicentric Castleman disease (MCD) in HIV-infected patients at an oncological referral center in Mexico. Clinical records at the HIV-AIDS clinic of all patients diagnosed with MCD from 1994 to 2018 were reviewed. There were 19 patients, mean age was 31.3 ± 8.4 years, and 17 (89.5%) were males. Fifteen patients (79%) had also Kaposi sarcoma (KS). Main clinical characteristics were multiple lymphadenopathy (95%), systemic symptoms (63%), and hepatosplenomegaly (50%). Computed tomography scan and 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography showed multiple lymphadenopathy, inversion of the liver:spleen uptake ratio, with an increase in SUVmax (5.7). The histopathology report described plasma cells in 58%, mixed type in 26%, and hyaline vascular in 16%. Eleven patients (57.9%) received different chemotherapy regimens. Seven patients died (36.8%): four related to MCD progression or chemotherapy complications, median survival was eight months. For those patients who survived, median, follow-up was 28 months (p &lt; 0.001). The incidence of MCD in people living with HIV is probably underestimated. In patients with lymphadenopathy, B symptoms, deranged inflammatory markers, and/or disseminated KS, a biopsy of an enlarged lymph node is warranted, and the histology should be reviewed by an experienced pathologist.

Idiopathic multicentric Castleman disease: bringing order to chaos

Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder characterised by lymphadenopathy and systemic symptoms, in some cases leading to organ failure. The condition must be distinguished from unicentric Castleman disease, which is generally curable with local therapy, and HHV-8-associated Castleman disease, for which an effective treatment approach has been defined. 1 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 Crossref PubMed Scopus (171) Google Scholar , 2 Bower M How I treat HIV-associated multicentric Castleman disease. Blood. 2010; 116: 4415-4421 Crossref PubMed Scopus (87) Google Scholar , 3 Fajgenbaum DC Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018; 132: 2323-2330 Crossref PubMed Scopus (26) Google Scholar A hallmark of idiopathic multicentric Castleman disease is hypersecretion of cytokines, particularly IL6, the triggering factors for which might be multiple, leading to a common pathway of cytokine derangement. 3 Fajgenbaum DC Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018; 132: 2323-2330 Crossref PubMed Scopus (26) Google Scholar Although lymphocytes are non-clonal, the clinical spectrum ranges from non-severe to life-threatening. Long-term safety of siltuximab in patients with idiopathic multicentric Castleman disease: a prespecified, open-label, extension analysis of two trialsThese results show that siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease. Full-Text PDF

Relapse of HHV8-positive multicentric Castleman disease following rituximab-based therapy in HIV-positive patients

AbstractSuccessful treatment of HIV-associated multicentric Castleman disease (HIV+MCD) with rituximab-based approaches has dramatically improved survival and reduced the risk of human herpesvirus 8 (HHV8)-associated lymphoma. Longer term outcomes including relapse rates have not been described and are important to establish the potential role of maintenance therapy. A prospective cohort of 84 patients with biopsy-proven HIV+MCD were treated with risk-stratified rituximab-based therapy. Four patients (5%) died of refractory HIV+MCD and 80 achieved clinical remission. The median follow-up for the 80 patients was 6.9 years and their 5-year overall survival was 92% (95% confidence interval [CI], 85 to 99). Eighteen have relapsed (all histologically confirmed), including 5 with concomitant HHV8-associated lymphoma and MCD at relapse. The 5-year relapse-free survival is 82% (95% CI, 72 to 92). No clinical or laboratory findings that were present at MCD diagnosis predicted subsequent relapse, and the median time to first relapse was 30 months (maximum, 10 years). There were no significant differences in clinicopathological features at initial diagnosis and at relapse. All patients were successfully retreated at relapse with rituximab-based therapy. Only 1 patient died of relapsed MCD (at fifth relapse 9.4 years after initial diagnosis). Despite the use of rituximab, the risk of developing HHV8-associated lymphoma was significantly elevated in this cohort, with an incidence of 11.4/1000 person-years. The relatively low relapse rate and high salvage rates at relapse reduce the potential benefit of maintenance therapy; this should only be advocated in the context of a clinical trial.

Extracavitary primary effusion lymphoma associated with hemophagocytic lymphohistiocytosis.

Extracavitary primary effusion lymphoma associated with hemophagocytic lymphohistiocytosis.

Characteristics and survival for HIV-associated multicentric Castleman disease in Malawi.

IntroductionClinical reports of multicentric Castleman disease (MCD) from sub-Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma-associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region.MethodsWe describe HIV-positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi's 16 million people. We included adult patients≥18 years of age with HIV-associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015.Results and discussionMCD patients had a median age of 42.4 years (range 37.2–51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status ≥3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6–9.3) than KS (11.0 g/dL, range 9.1–12.0, p=0.011) or NHL (11.2 g/dL, range 4.5–15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7–3.2) than KS (3.7 g/dL, range 3.2–3.9, p=0.013) or NHL (3.4 g/dL, range 1.8–4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/µL (range 108–1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2–105.3) than KS (14.2 months, range 6.8–21.9, p=0.039) or NHL (13.8 months, range 0.2–98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL.ConclusionsHIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high mortality. Improvements in awareness, diagnostic facilities, treatment and supportive care are needed to address this likely under-recognized public health problem in SSA.

Characteristics and survival for HIV-associated multicentric Castleman disease in Malawi

Characteristics and survival for HIV-associated multicentric Castleman disease in Malawi

Short-term efficacy of the IL6 receptor antibody tocilizumab in patients with HIV-associated multicentric Castleman disease: report of two cases

Multicentric Castleman disease (MCD) is a lymphoproliferative disorder caused by human herpesvirus 8 (HHV8) infection HIV associated MCD (HIV-MCD) presents with various clinical symptoms. Many HIV-negative MCD patients are often treated with anti-human interleukin-6 (IL6) receptor monoclonal antibodies (tocilizumab), and successful results have been reported. IL-6 plays an important role in the development of both HIV-positive and HIV-negative MCD; however, the efficacy of tocilizumab in HIV-MCD patients is unknown. We herein report the clinical and biologic courses of two HIV-MCD patients treated with tocilizumab. In both cases, a significant and rapid clinical improvement was observed after the first infusion. However, the treatment efficacy was not maintained for a long period, and relapse occurred at 15 and 22 weeks, respectively. Both patients received rituximab and subsequently achieved complete clinical remission. Our report, in addition to data presented in the literature, suggests that tocilizumab could be an initial treatment option in patients with HIV-MCD.

Multicentric Castleman's Disease and Hiv

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder found with a higher frequency in HIV-seropositive patients. Human herpes virus 8 is found in virtually all cases of HIV-associated MCD. The majority of cases of MCD in patients with HIV are also associated with Kaposi's sarcoma. The dysregulated production of human IL-6 is thought to be an important factor in the pathogenesis of MCD. HIV-seropositive individuals with MCD have a significantly greater risk of developing non-Hodgkin lymphomas than their HIV-seronegative counterparts. MCD occurring in HIV patients has been associated with a poor prognosis. With newer therapy regimens, it is hoped that the prospects of HIV-infected patients with MCD will improve.

Beneficial course of two cases of HIV-associated multicentricCastleman disease treated with HIV antiretroviral therapy

Beneficial course of two cases of HIV-associated multicentricCastleman disease treated with HIV antiretroviral therapy

HIV-Associated Multicentric Castleman's Disease

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder. It is found with higher frequency in patients with HIV infection, with systemic symptoms and poor prognosis. We present the case of a 32-year old man with HIV disease, Kaposi's sarcoma, lymphadenopathy, fever and hemolytic anemia. A diagnosis of Castleman's disease is confirmed through biopsy and treatment is often based only on published case reports. Systemic treatments for MCD have included chemotherapy, anti-herpes virus, highly active antiretroviral therapy and, more recently, monoclonal antibodies against both IL6 and CD20.

Beneficial course of two cases of HIV-associated multicentric Castleman disease treated with HIV antiretroviral therapy

Beneficial course of two cases of HIV-associated multicentric Castleman disease treated with HIV antiretroviral therapy

Rituximab decreases the risk of lymphoma in patients with HIV-associated multicentric Castleman disease

AbstractHIV-associated multicentric Castleman disease (MCD) is associated with a high risk of developing nonHodgkin lymphoma (NHL). Rituximab is effective in HIV-MCD, but its impact on NHL incidence remains unknown. From a single-center prospective cohort, 113 patients were identified with a diagnosis of HIV-MCD for the present study. To compare the incidence of NHL between patients who had received a rituximab-based treatment (R+ group) and those who had not (R− group), data were analyzed before and after matching on propensity scores and after multiple imputation. The mean follow-up was 4.2 years. In the R− group (n = 65), 17 patients developed NHL (incidence, 69.6 of 1000 person years). In the R+ group (n = 48), only 1 patient developed NHL (incidence, 4.2 of 1000 person years). Based on the propensity score-matching method, a significant decrease in the incidence of NHL was observed in patients who had been treated with rituximab (hazard ratio, 0.09; 95% confidence interval, 0.01-0.70). Ten Kaposi sarcoma (KS) exacerbations and 1 newly diagnosed KS were observed in 9 patients after rituximab therapy. Rituximab was associated with an 11-fold lower risk of developing lymphoma. KS exacerbation was the most challenging adverse event after rituximab therapy.

Can plasma HHV8 viral load be used to differentiate multicentric Castleman disease from Kaposi sarcoma?

We measured plasma human herpesvirus 8 (HHV8) DNA load in consecutive patients presenting with HIV-associated multicentric Castleman disease (MCD) and in contemporaneous patients who had Kaposi sarcoma (KS), lymphoma or other diagnoses. All 11 patients with MCD had detectable plasma HHV8 DNA compared with 18 (72%) of 25 patients with KS, none with lymphoma and one of 38 patients with other diagnoses. Detectable plasma HHV8 DNA levels were higher among MCD patients, median (interquartile range [IQR]) = 43,500 (5200-150,000) copies/mL, when compared with those with KS, median (IQR) = 320 (167-822) copies/mL and those with lymphoma and other diagnoses (one-way analysis of variance; P = 0.0303). Using receiver operating characteristic analysis, a cut-off of >1000 copies HHV8 DNA/mL of plasma helped to discriminate between MCD and other diagnoses, with a specificity of 94.7% and a negative predictive value of 97.3%. The level of HHV8 viraemia, while not diagnostic, may aid discrimination between patients with MCD and those with KS and other systemic illnesses.

Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease

AbstractAlthough HIV-associated multicentric Castleman disease (HIV-MCD) is not classified as an AIDS-defining illness, mortality is high and progression to lymphoma occurs frequently. At present, there is no widely accepted recommendation for the treatment of HIV-MCD. In this retrospective (1998-2010), multicentric analysis of 52 histologically proven cases, outcome was analyzed with respect to the use of different MCD therapies and potential prognostic factors. After a mean follow-up of 2.26 years, 19 of 52 patients died. Median estimated overall survival (OS) was 6.2 years. Potential risk factors, such as older age, previous AIDS, or lower CD4 T cells had no impact on OS. Treatment was heterogeneous, consisting of cytostatic and/or antiviral agents, rituximab, or combinations of these modalities. There were marked differences in the outcome when patients were grouped according to MCD treatment. Patients receiving rituximab-based regimens had higher complete remission rates than patients receiving chemotherapy only. The mean estimated OS in patients receiving rituximab alone or in combination with cytostatic agents was not reached, compared with 5.1 years (P = .03). Clinical outcome and overall survival of HIV-MCD have markedly improved with rituximab-based therapies, considering rituximab-based therapies (with or without cytostatic agents) to be among the preferred first-line options in patients with HIV-MCD.

HIV-associated multicentric Castleman disease.

HIV-associated multicentric Castleman disease (HIV MCD) is a rare lymphoproliferative disorder, the incidence of which appears to be increasing in the highly active antiretroviral therapy era. Current knowledge of the disease is limited and this review will discuss what is known about the pathophysiology, diagnosis, management, and prognosis of HIV MCD. HIV MCD has been shown to be associated with infection with human herpesvirus-8. Vascular endothelial growth factor and the cytokine interleukin-6 (IL-6) are also thought to play a role in the pathogenesis of MCD. Currently, rituximab is often used alone or in combination with chemotherapy for treatment of MCD. Novel monoclonal antibodies targeting IL-6 and the IL-6 receptor are also being studied for the management of this disease. Because HIV MCD is an uncommon diagnosis, comprehensive clinical studies have not been done, and understanding of the disease is incomplete. Further studies are needed to make definitive conclusions regarding optimal treatment of HIV MCD.

Plasma HHV8 DNA predicts relapse in individuals with HIV-associated multicentric Castleman disease

AbstractHIV-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder caused by infection with human herpesvirus-8. The disease follows a relapsing and remitting clinical course, with marked systemic symptoms during an active attack, which can prove fatal. Its incidence is rising, and new data indicate the utility of the anti-CD20 monoclonal antibody rituximab at inducing remissions in both first- and second-line settings, although biomarkers associated with relapse have not been previously identified. In 52 individuals with a histologic diagnosis of HIV-MCD, we performed univariate and multivariate analyses to predict factors associated with an HIV-MCD attack. Although a younger age (< 50 years) was associated with an attack, the strongest association was observed with plasma levels of human herpesvirus-8 DNA. Rising levels predicted an attack (hazard ratio = 2.9; 95% confidence interval, 1.3-6.7), and maintenance therapy with rituximab should be considered in these individuals.