Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus, is a DNA oncovirus known for its role in the development of Kaposi’s sarcoma (KS) and several lymphoproliferative disorders (LPDs). HHV-8 promotes lymphoproliferation via the activation of the interleukin-6 receptor signaling pathway, as well as a host of other regulatory mechanisms. The spectrum of HHV-8-associated LPDs is increasing. The World Health Organization has recently updated the classification of HHV-8-associated LPDs by introducing HHV-8-positive germinotropic LPD (GLPD) in addition to the previously recognized entities of HHV-8-positive diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), primary effusion lymphoma (PEL), and HHV-8-positive multicentric Castleman’s disease (MCD). We present here a case of an HIV-positive woman with a history of KS, who later developed three HHV-8-associated LPDs, including HHV-8-positive MCD, PEL, and GLPD. To the best of our knowledge, this is the first reported case of a patient with this combination of individually rare HHV-8-associated LPDs. This case illustrates the spectrum and the sequential development of the different clinical manifestations of HHV-8-associated diseases. Detection of HHV-8 can have clinical significance in the diagnosis and management of certain HHV-8-associated conditions. Recently discovered variants of HHV-8-associated LPDs indicate that this group represents a diverse spectrum of disorders, whose classification may require further refinement beyond the currently recognized entities.
Purpose: A Phase 2 trial of stereotactic radiation therapy and in situ cytotoxic virus therapy in metastatic triple-negative breast cancer (mTNBC) patients followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mTNBC patients. Methods: In this single-arm, open-label Phase 2 trial, mTNBC patients were treated with ADV/HSV-tk (5 x 1011 vp) intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200mg, Q3w). The primary endpoint was clinical benefit rate (CBR, CR, PR or SD≥ 24 weeks per RECIST version1.1 at non-irradiated site). Secondary endpoints included duration on treatment (DoT), OS and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. Results: 28 patients were enrolled and treated. CBR was seen in 6 patients (21.4%) including two CR (7.1%), one PR (3.6%) and three SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with CyTOF and IMC revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. Conclusions: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated mTNBC patients. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.
Background Daratumumab-based treatment regimens for MM have improved outcomes for both transplant-eligible and ineligible patients. As a result, patients are receiving longer exposure to this CD38 targeting monoclonal antibody. Adverse events (AE) including hypogammaglobulinemia, neutropenia, and lymphopenia have been reported in both clinical trials and retrospective studies, but with limited and contrasting data on the associated risk of developing infections. Furthermore, there remains a paucity of data on the risk of developing opportunistic infections in this growing patient population. The aim of this study is to assess the association between daratumumab-containing regimens and the development of opportunistic infections as reported to the Food and Drug Administration's Adverse Events Reporting System (FAERS), a pharmacovigilance monitoring database. Methods/Materials FAERS was queried for AE reports to evaluate the association of Cytomegalovirus reactivation (CMVr), Hepatitis B reactivation (HBVr), progressive multifocal leukoencephalopathy (PML), Herpes Zoster (HZ), Tuberculosis (TB), Pneumocystis Jirovecii (PJP), and Bronchopulmonary Aspergillosis (BA) with daratumumab-containing regimens from 2015-2021. The strength of an association between an infection reported with daratumumab in MM was compared with all events reported in MM treated patients, and the composite of all reported AE cases in FAERS. Signal disproportionality was calculated by using the reporting odds ratio (ROR), with the precision of the ROR determined by 95% confidence intervals (95% CI). Associated p-values were calculated by using chi-squared or Fisher's Exact test, with a p-value <0.05 considered statistically significant. Other reported variables concomitantly reported with daratumumab-treated patients were collected, including reported chemotherapy, >1 MM regimen, proteasome inhibitor (PI) use, or lenalidomide use. Results Out of the 12,393,747 AE cases reported to FAERS, there were 288,294 (2.3%) AE reported with MM patients, of which 7,152 (2.5%) were reported with daratumumab. There were 195 (2.7%) opportunistic infections reported with daratumumab, with a median age of 64 (42-89) years, and 64 (32.8%) were females. HZ (N=49, 25.1%) was the most common, followed by CMVr (N=43, 22.0%), PML (N=35, 17.9%), PJP (N=34, 17.4%), BA (N=16, 8.2%), HBVr (N=13, 6.7%), and TB (N=5, 2.5%). Neutropenia was reported in 29 (14.9%) of these patients, lymphopenia in 6 (3.1%), and hypogammaglobulinemia in 1 (0.51%) case. With comparison to all reported events in the FAERS database, a significant signal disproportionality was found with HZ (ROR 3.48 [95% CI 2.63, 4.61], p<0.0001), CMVr (ROR 33.31 [95% CI 24.61, 45.08], p<0.0001), PML (ROR 16.69 [95% CI 11.96, 23.31], p<0.0001), PJP (ROR 12.87 [95% CI 9.18, 18.05], p<0.0001), BA (ROR 9.82 [95% CI 6.01, 16.06], p<0.0001), and HBVr (ROR 9.35 [95% CI 5.42, 16.14], p<0.0001). When comparing reported infections with AE associated with MM patients in FAERS, HZ (ROR 1.59 [95% CI 1.19, 2.11], p=0.0015), CMVr (ROR 28.82 [95% CI 19.44, 42.72], p<0.0001), PML (ROR 13.04 [95% CI 8.89, 19.12], p=<0.0001), PJP (ROR 9.58 [95% CI 6.59, 13.96],p<0.0001), BA (ROR 11.46 [95% CI 6.56, 20.01], p<0.0001), HBVr (ROR 4.41 [95% CI 2.49, 7.83],p<0.0001), and TB (ROR 6.15 [95% CI 2.39, 15.78], p<0.0001) met statistical significance (Table 1). The proportion of concomitant medications reported with daratumumab is reported in Figure 1. Conclusion This study suggests a significant association between daratumumab-based regimens and multiple opportunistic infections. Patients with known chronic viral infections or who are heavily pretreated should be monitored for these potential complications. FAERS data is beneficial in reporting associations between medications and AE but does not necessarily indicate causality. Further studies are needed to corroborate these findings. Figure 1 Figure 1. Disclosures Ganguly: Kadmon: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.
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