HIV-related Lymphomas Research Articles

Complete response to front-line therapies is associated with long-term survival in HIV-related lymphomas in Taiwan

BackgroundThe prognosis for people living with HIV (PLWH) who develop lymphomas has been greatly improved by combination antiretroviral therapy (cART) and anti-CD20 monoclonal antibodies. However, real-world clinical data on this patient group in Asia are limited. MethodsTreatment outcomes were retrospectively examined for 104 PLWH with lymphomas between 2000 and 2019. The cohort comprised five PLWH with Hodgkin lymphoma (HL) and 99 with non-Hodgkin lymphomas, including 61 with diffuse large B-cell lymphoma (DLBCL), 19 with Burkitt lymphoma (BL), nine with primary central nervous system lymphoma (PCNSL) and ten with other subtypes. ResultsThe 5-year overall survival (OS) rates were as follows: HL (100%), PCNSL (76.2%), other subtypes (60.0%), BL (57.4%), and DLBCL (55.6%). Individuals who achieved complete response (CR) to front-line therapies had a significantly better 5-year OS rate than those without (96.2% vs. 17.8%, p < 0.001). PLWH who received cART for ≤6 months had significantly lower CD4+ T-cell counts at lymphoma diagnosis than those who received cART for longer periods (p = 0.048). Additionally, the 5-year OS rate was better for PLWH who received cART for ≤6 months before lymphomas diagnosis than those who received cART for longer periods (64.5% vs. 51.9%, p = 0.114). ConclusionsPLWH with DLBCL or BL had OS rates compatible to patients without HIV infection. Better outcomes for patients achieving CR to front-line therapy and those with shorter cART duration before lymphoma diagnosis suggest an underlying biological distinction in the lymphomas and the involvement of immunity, which warrants further studies.

Patient Characteristics and Outcomes in Plasmablastic Neoplasms: An Institutional Retrospective Study

Introduction: Plasmablastic myeloma (PBM) and plasmablastic lymphoma (PBL) are rare hematologic neoplasms that are pathologically difficult to distinguish. PBM represents less than 5% of all myelomas and is characterized by neoplastic proliferation of atypical plasmablasts in the bone marrow and extramedullary sites. Immunophenotypically, the neoplastic cells lack CD45 expression and exhibit plasma cell markers (CD38, CD138), with MYC overexpression and high proliferative index. PBLs are commonly seen in immunocompromised patients and account for ~2% of all HIV-related lymphomas. Histologically, they resemble diffuse large B cell lymphoma (DLBCL), but have a distinctly immunoblastic or plasmablastic morphology. Similar to PBMs, the neoplastic cells of PBLs are positive for plasma cell markers but negative for conventional B-cell markers (CD20, PAX5). Clinically, plasmablastic neoplasms respond poorly to therapy and have an aggressive clinical course, with median overall survival in some studies ranging from 8 to 15 months. There is no established standard of care for these disorders, and further characterization of this complex patient population is needed. Methods: Patients were identified from the pathology database at Los Angeles General Medical Center and Norris Comprehensive Cancer Center. Patient demographics, treatment, and clinical outcomes were collected for each patient. Overall survival was calculated for the total cohort, as well as patient subgroups including disease type, and HIV status. Results: We retrospectively identified 54 patients diagnosed with plasmablastic neoplasms including PBM (31%, N=17) and PBL (63%, N=34) between January 2017 and May 2022. The median age at diagnosis was 54 years (range 17-91 years) and 78% were male. Hispanic patients represented 70% (N=36) of our total study population. Predisposing immunosuppression was identified in 65% (N=34), including 33% (N=17) on immunosuppressive drugs and 52% (N=27) with non-iatrogenic causes; 38% (N=18) of patients were HIV-positive. Pathologic analysis showed EBER positivity of 44% (N=24), CD138 positivity of 90%, and c-myc positivity of 87%. The most common initial regimens were EPOCH (17%, N=9) and V-EPOCH (33%, N=18). There was no superiority when comparing V-EPOCH versus all other treatment regimens. Seven patients received subsequent consolidation with high-dose chemotherapy followed by autologous hematopoietic transplant. Seven patients were lost to follow-up prior to initiating therapy or evaluating treatment response. Of the patients followed, 11% never started first line therapy, 38% had primary refractory disease, 34% achieved complete response, and 17% relapsed after 6 months of starting therapy. Overall survival (OS) for the total cohort was 73% at 12 months and 60% at 24 months. OS at 12 months varied between different subgroups: PBL (80%), PBM (56%), HIV-positive (86%), and HIV-negative (67%). Although HIV-positive trended towards a better OS than the HIV-negative cohort, it was not statistically significant (p=0.11). Conclusions: Plasmablastic neoplasms remain a heterogeneous group of diseases with a historically poor prognosis. Our PBL patients showed an improved OS at 12 months of 80% compared to the SEER database PBL OS of 56%. This improvement in survival could derive from ethnic variations in tumor biology in this predominantly Hispanic cohort, which is consistent with the improved OS in Hispanic patients seen in the SEER database. Other contributing factors to consider are differences in stage and co-morbidities, increased use of intensive therapies such as V-EPOCH and autologous stem-cell transplant, success of salvage therapies, and improved immune status from treatment of underlying HIV. Further studies are needed to improve therapeutic targets for this patient population.

Diffuse Large B-Cell Lymphoma in the HIV Setting.

Despite the widespread use of combined antiretroviral therapy (cART) and the subsequent decrease in AIDS-defining cancers, HIV-related lymphomas remain a leading cause of morbidity and mortality in people with HIV (PWH). Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype in PWH. This lymphoma is a heterogeneous disease including morphological variants and molecular subtypes according to the cell of origin or the mutation profile. In the pre-cART era, treatment with standard-dose chemotherapy induced high rates of toxicity and outcomes were very poor. The introduction of cART and the incorporation of infection prophylaxis allowed the use of conventional intensive chemotherapy regimens used in the general population, such as R-CHOP or R-EPOCH. The use of cART during chemotherapy treatment was initially controversial due to the potential risk of adverse drug-drug interactions. However, the availability of current cART regimens with less potential to cause drug interactions and evidence that cART improves survival rates in NHL strongly support the use of cART in PWH with DLBCL. Consequently, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PWH with NHL.

Factors associated with survival in patients with lymphoma and HIV: the largest cohort study in Brazil.

To analyze the factors associated with survival in the largest cohort of individuals with HIV and lymphoma so far described in Brazil. A retrospective, observational, multicenter study involving five institutions in São Paulo, Brazil. The medical records of consecutive patients with HIV diagnosed with lymphoma between January 2000 and December 2019 were screened. Inclusion criteria consisted of age over 17 years and a biopsy-confirmed diagnosis of lymphoma. The data collected included age, sex, staging (Ann Arbor system), duration of HIV infection, CD4+ lymphocyte count, HIV viral load, lactate dehydrogenase, erythrocyte sedimentation rate and serum beta-2-microglobulin levels, treatment and outcome. Overall, 276 patients were included. Median age was 42 years. Most patients were male (74.3%) and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (28.6% and 46.4%, respectively). Most had non-Hodgkin lymphomas (89.2%, n = 246), particularly diffuse large B-cell lymphoma (40.9%) and Burkitt lymphoma (26.4%). Hodgkin lymphoma accounted for 9.4%. Advanced stages III/IV were predominant (86.8%). HIV viral load at the moment of lymphoma diagnosis was detectable in 52.9% of patients. A CD4 count of <200 cells/mm3 was recorded for 53% of the patients. Most patients (62.4%) were on combination antiretroviral therapy. The factors that significantly affected survival were: the ECOG performance status, lymphoma subtype, staging, beta-2-microglobulin level, central nervous system (CNS) infiltration, site of CNS infiltration, relapsed/refractory lymphoma and International Prognostic Index score. HIV status, CD4-lymphocyte count and relapsed/refractory disease affected survival. Rituximab did not appear to improve outcome in HIV-related lymphomas.

HIV-related lymphomas.

To summarize the recent evidence on the pathology, current standard of care and recent advances in the treatment of HIV-related lymphomas. Lymphomas remain a major cause of morbidity and mortality in people living with HIV, even in the era of combination antiretroviral therapy (cART). However, treatment outcomes for these malignancies have improved in recent decades, due to full-dose chemotherapy, effective cART and supportive care. Recent advances include the identification of novel driving signaling pathways as promising molecular targets to improve lymphoma outcomes. Patients with HIV-related lymphomas who receive effective cART should be treated like the general population.

HIV-related non-Hodgkin lymphomas affecting the oral cavity: a clinicopathologic study of 11 cases.

Background HIV-related non-Hodgkin lymphomas of the oral cavity are rare lesions with aggressive clinical behaviour. The aim of this study is to describe the clinicopathological features of a series of HIV-related oral non-Hodgkin lymphomas.Material and Methods Eleven cases of oral lymphomas affecting HIV-positive patients were retrieved from 2012 to 2019. Clinicopathological features regarding age, sex, tumour location, clinical presentation, laboratory findings, disease stage and follow-up were obtained. Histologic, immunohistochemical and in situ hybridization for EBV detection were done for diagnosis confirmation. Overall survival was estimated by Kaplan–Meier curve.Results Males predominated, with a mean age of 40.3 years-old. Maxilla and mandible were the mostly affected. Plasmablastic lymphoma and diffuse large B-cell lymphoma not otherwise specified (NOS) were the main histological types. Lesions presented as reddish ulcerated swellings, representing the first sign of AIDS in six cases. Stage IV were common (7 cases) and the mean HIV viral load was 10,557 copies/mL, with a mean of 266 CD4+ cells/mm3, 1,278 CD8+ cells/mm3 and a CD4+/CD8+ ratio of 0.26. Eight patients died of the disease (72.7%). Overall survival revealed that 78.2% of the patients died after 21 months of follow-up.Conclusions HIV-related oral lymphomas present a poor prognosis usually diagnosed in advanced stages and in our series plasmablastic lymphoma was the most common subtype. Key words:Oral cancer, non-Hodgkin lymphoma, HIV, survival, prognosis.

Clinical and Therapeutic Implications of Epstein-Barr Virus in HIV-Related Lymphomas.

Simple SummaryEpstein–Barr virus (EBV) is involved in lymphomagenesis, especially lymphomas affecting populations with immunodeficiencies, such as people living with HIV (PLWH). The pathogenic roles of EBV in lymphomas arising in PLWH are mediated by several viral proteins, as well as cooperation between EBV and HIV. The presence of EBV in these lymphomas conditionate some of their epidemiological, pathological, and clinical characteristics, as well as their prognosis. In this article, the authors review the different EBV-associated lymphomas affecting PLWH, analyzing the influence of EBV on the epidemiology, etiopathogenesis, clinical features, treatment, diagnosis and prognosis of each lymphoma subtype. Furthermore, new EBV-targeted therapies currently under development for some lymphomas are discussed.The incidence of lymphomas is increased in people living with HIV (PLWH). Aggressive B-cell non-Hodgkin lymphomas (NHLs) are the most common and are considered an AIDS-defining cancer (ADC). Although Hodgkin lymphoma (HL) is not considered an ADC, its incidence is also increased in PLWH. Among all HIV-related lymphomas (HRL), the prevalence of Epstein–Barr virus (EBV) is high. It has been shown that EBV is involved in different lymphomagenic mechanisms mediated by some of its proteins, contributing to the development of different lymphoma subtypes. Additionally, cooperation between both HIV and EBV can lead to the proliferation of aberrant B-cells, thereby being an additional lymphomagenic mechanism in EBV-associated HRL. Despite the close relationship between EBV and HRL, the impact of EBV on clinical aspects has not been extensively studied. These lymphomas are treated with the same therapeutic regimens as the general population in combination with cART. Nevertheless, new therapeutic strategies targeting EBV are promising for these lymphomas. In this article, the different types of HRL are extensively reviewed, focusing on the influence of EBV on the epidemiology, pathogenesis, clinical presentation, and pathological characteristics of each lymphoma subtype. Moreover, novel therapies targeting EBV and future strategies to treat HRL harboring EBV are discussed.

Hodgkin Lymphoma in People Living with HIV.

Simple SummaryHodgkin lymphoma (HL) is a non-AIDS defining neoplasm, but people living with HIV (PLWH) have between a 5- and 26-fold higher risk of developing it than the general population. Epstein-Barr virus is present in almost all HIV-related HL cases, and plays an important role in its etiopathogenesis. Despite the aggressive characteristics, the prognosis of HL affecting PLWH is similar to that of the general population if patients are treated following the same recommendations. Administration of cART concomitantly with chemotherapy is highly recommended. However, this combination may be challenging due to drug–drug interactions and overlapping toxicity. Thus, interdisciplinary collaboration between hemato-oncologists and HIV specialists is crucial for the optimal treatment of both lymphoma and HIV infection.Despite widespread use of combined antiretroviral therapy (cART) and increased life expectancy in people living with HIV (PLWH), HIV-related lymphomas (HRL) remain a leading cause of cancer morbidity and mortality for PLWH, even in patients optimally treated with cART. While the incidence of aggressive forms of non-Hodgkin lymphoma decreased after the advent of cART, incidence of Hodgkin lymphoma (HL) has increased among PLWH in recent decades. The coinfection of Epstein–Barr virus plays a crucial role in the pathogenesis of HL in the HIV setting. Currently, PLWH with HRL, including HL, are treated similarly to HIV-negative patients and, importantly, the prognosis of HL in PLWH is approaching that of the general population. In this regard, effective cART during chemotherapy is strongly recommended since it has been shown to improve survival rates in all lymphoma subtypes, including HL. As a consequence, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential drug–drug interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PLWH with HL. In this article the authors review and update the epidemiological, clinical and biological aspects of HL presenting in PLWH with special emphasis on advances in prognosis and the factors that have contributed to it.

Coinfection with HCV or HBV Increases the Risk of Lymphoma in HIV-Positive Patients: A Combined Analysis of the Lymphovir-ANRS-CO16 and Fhdh-ANRS-CO4 Cohorts

BACKGROUNDHuman immunodeficiency virus (HIV) infection has been linked to an increased risk of non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). In the HIV-uninfected population, hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are both associated with an increased risk of NHL. Scarce data suggest an increased risk of HL in patients chronically infected with HBV. HCV and HBV coinfections are frequent among persons living with HIV (PLWHIV). The impact of HCV and HBV infections on HIV-associated lymphoma in the era of combined antiretroviral therapy (cART) deserves evaluation. METHODSWe compared the prevalence of HBV and HCV coinfections between PLWHIV with lymphoma who were enrolled in the Lymphovir French National Agency for Research on AIDS and Viral Hepatitis (ANRS)-CO16 cohort and PLWHIV enrolled in the French Hospital Database on HIV (FHDH-ANRS-CO4) with at least one follow-up visit in 2011 (n = 48 186). This cohort has been shown to be representative of PLWHIV under care in France.Lymphovir-ANRS-CO16 cohort enrolled consecutive HIV-infected individuals with lymphoma (NHL or HL) in 32 centers. The histological diagnosis was established using the 2008 WHO classification and was confirmed within the French hematopathology network (LYMPHOPATH). Finally, we analyzed the characteristics and outcomes of lymphomas in coinfected patients. RESULTSBetween 2008 and 2015, 179 patients with HIV-related lymphomas were enrolled, of whom 110 had NHL (61%) and 69 had HL (39%), The HCV serology, available for all the patients, was positive in 38 cases (29 with NHL and 9 with HL). Among 26 HCV+ patients with available data, 15 had detectable HCV RNA load at lymphoma diagnosis, five had Child-Pugh A cirrhosis, two had liver fibrosis, and one had an extrahepatic manifestation (type III cryoglobulinemia). Overall, the HCV seroprevalence was 26% among patients with NHL, a proportion significantly higher than that in the FHDH-ANRS-CO4 cohort (14%) (odds ratio (OR): 2.15, 95% confidence interval [1.35-3.32])(Table). There was no association between HCV and HL (prevalence 13%, OR: 0.90 [0.39-1.82]).The distribution of NHL subtypes among the 29 patients with HCV infection was as follows: DLBCL (n=17), MZL (n=3), plasmablastic lymphomas (n=3), primary effusion lymphoma (PEL) (n=3), BL (n=2), and T-cell lymphoma (n=1). HCV was significantly associated with DLBCL (prevalence 33%, OR: 2.91 [1.53-5.34]). Among the patients with DLBCL, 13/17 HCV+ patients had at least one site of extranodal involvement, compared to 16/34 HCV- patients (p=0.05). Four DLBCL patients received anti-HCV therapy after treatment of their lymphoma, consisting of IFN/ribavirin, either alone (n=1) or direct antiviral agents (n=3). A sustained virological reponse and a durable remission of their lymphoma were obtained in each case. Remarkably, a man with splenic MZL received anti-HCV therapy with interferon and ribavirin with no other lymphoma treatment, leading to long-lasting both virological and hematological complete responses. During follow-up, 10 deaths occurred among HCV+ patients with NHL due to progression of lymphoma (n=8) or solid tumours (n=2). With a median follow-up of 43 months, the 2-year OS among NHL patients tended to be lower in HCV+ patients (Figure).HBV status was available for 177 of the 179 lymphoma patients, of whom 15 had chronic HBV infection based on HBs Ag positivity (n=13) or HBV DNA positivity (n=2). Five patients had NHL (DLBCL (n=2) and BL (n=3)) and 10 had HL. Overall, chronic HBV infection was present in 5% of patients with NHL, which did not differ from the value of the FHDH-ANRS-CO4 cohort (7%) (OR: 0.60 [0.19-1.45]). In contrast, the prevalence of chronic HBV infection was higher among patients with HL than in the FHDH-ANRS-CO4 (14%; OR: 2.16 [0.98-4.27]). CONCLUSIONAs compared with the general cohort of HIV-infected patients, HCV coinfection was associated with an increased risk of NHL, especially DLBCL, and tended to be associated with poorer outcome. While no increase in the risk of NHL was observed among HBV coinfected patients, chronic HBV infection was associated with an increased risk of HL. Our findings suggest that chronic antigenic stimulation induced by HCV or HBV contribute to lymphomagenesis in HIV-infected patients. It paves the way for evaluation of novel therapeutic strategies based on the newest direct antiviral agents for HCV coinfected patients. [Display omitted] DisclosuresCoiffier:Celltrion, Inc: Consultancy, Honoraria. Coppo:Alexion: Consultancy, Research Funding; Ablynx: Consultancy, Research Funding; Octapharma: Consultancy.

Ebv-Mir-BART11-3p, Ebv-Mir-BART9 and Ebv-Mir-BART10 Are Present in the Plasma of HIV-Infected Subjects with Lymphoma and Are Potential Lymphoma Biomarkers

Epstein Barr virus (EBV) has been implicated in the lymphomagenesis, particularly of HIV-related lymphomas. EBV-infected cells are able to share miRNAs with other cells via exosomes and certain EBV-miRNAs were found in cells not infected with the virus but from patients with increased levels of EBV copies in plasma such as HIV-infected individuals. Thus, EBV-miRNAs might be detected in the plasma and might be relevant for the diagnosis and follow-up of HIV-related lymphomas.This case-control study included a group of 26 HIV-infected patients with lymphoma that responded to treatment and a control-group of HIV-infected subjetcs without lymphoma matched for age, gender, CD4-lymphocyte counts, plasma HIV viremia and time from HIV infection. We evaluated the presence of 43 EBV-miRNAs in frozen plasma samples from patients with lymphoma at diagnosis (Dx-group, N=26), one year before diagnosis (Pre-group, N=15) and complete response (CR-group, N=26). RNA was extracted from 200µl of plasma using Trizol LS (Ambion, Carlsbad, CA) and cel-miR-39 was used as spike-in. The detection of EBV-miRNAs was assessed by QRT-PCR in a BioMark™ HD System of Fluidigm (San Francisco, CA) using TaqMan® microRNA assays and TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA). The following clinical and biological parameters were collected from records: age, gender, ECOG score, extranodal and bulky disease, B symptoms, Ann-Arbor stage, serum lactate dehydrogenase (LDH) and beta2-microglobulin, International Prognostic Index (IPI), HCV and HBV serology, history of opportunistic infection and of AIDS-defining illnesses, onset of combination antiretroviral therapy, CD4-lymphocyte counts, plasma HIV viremia. McNemar's and Wilcoxon tests were used for paired comparisons between groups. P-values of less than .05 were considered statistically significant.Overall, 30 EBV-miRNAs were detected in the Dx-group whereas only 8 EBV-miRNAs where found in the control-group and 19 in the CR-group. EBV-miRNAs were detected more frequently in the Dx-group (17 out of 26) than in the control-group (7 out of 26) (P =.002) and in the CR-group (11 out of 26) (P=.02). The presence of 6 EBV-miRNAs (ebv-miR-BART11-3p, ebv-miR-BART9, ebv-miR-BART10, ebv-miR-BART15, ebv-miR-BART31, and ebv-miR-BART19) could be associated with the lymphoma condition, since they were detected significantly different in the Dx-group and the control-group (Figure 1). Importantly, 3 of those EBV-miRNAs (ebv-miRBART11-3p, ebv-miR-BART9 and ebv-miRBART10) were found to be significantly less frequent in the CR group, reinforcing the idea that they could be derived from lymphoma cells and be used as biomarkers for diagnosis and follow up of HIV-related lymphoma. EBV-miRNAs cannot be used as early biomarkers of lymphoma in HIV-infected patients because none of the 3 EBV-miRNAs associated with lymphoma was significantly found in samples before diagnosis. The detection in plasma of ebv-miR-BART11-3p, ebv-miR-BART10 or ebv-miR-BART9 was not associated with having tumor cells infected with EBV (Figure 1). Only the detection of ebv-miR-BART9 was associated with detectable EBV loads [7/14 (50%) vs. 1/12 (8.3%), P=.036] (Figure 1). The following were the statistically significant associations between the presence of the 3 potential EBV-miRNA lymphoma biomarkers and the clinical-biological features studied. The presence of ebv-miR-BART10 in plasma was associated with IPI>2 [8/14 (57.1%) vs. 1/9 (11.1%), P=.004] and ECOG>2 [8/14 (57.1%) vs. 1/11 (9.1%), P=.011]. Also, more patients with ebv-miR-BART11-3p expression in plasma had ECOG>2 than patients without it [7/13 (53.8%) vs. 1/12 (8.3%), P=.030].Ebv-miR-BART11-3p, ebv-miR-BART9 and ebv-miR-BART10 can be detected in the plasma of patients with HIV-related lymphoma, independently of the presence of EBV in tumor cells or of EBV plasma viremia. They are potential biomarkers of lymphoma to be used in the diagnosis and follow up of HIV-infected subjects with the advantage of being easily determined by QRT-PCR employing noninvasive procedures.This work was supported in part by 2014 SGR225 (GRE) from CERCA Programme/Generalitat de Catalunya, and by funds from Josep Carreras International Foundation, “la Caixa” Foundation, DKMS, and Celgene Spain. [Display omitted] DisclosuresBaptista:DKMS: Research Funding; la Caixa Foundation: Research Funding; Carreras International Foundation: Research Funding; CERCA Programme/Generalitat de Catalunya: Research Funding; Celgene Spain: Research Funding. Sancho:Roche: Honoraria; Laboratorios Servier: Consultancy; Mundipharma: Honoraria; Kern Pharma: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Ribera:Celgene: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen Inc.: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; Roche: Honoraria. Navarro:Celgene Spain: Research Funding; DKMS: Research Funding; la Caixa Foundation: Research Funding; Josep Carreras International Foundation: Research Funding; CERCA Programme/Generalitat de Catalunya: Research Funding.

Prospective evaluation of blood Epstein-Barr virus DNA load and antibody profile in HIV-related non-Hodgkin lymphomas.

The value of Epstein-Barr virus (EBV) biomarkers on the prognosis of HIV-related non-Hodgkin's lymphoma (NHL) has been poorly explored in the combined antiretroviral therapy (cART) era. We evaluated EBV DNA load and EBV antibodies in HIV-NHL patients enrolled in the French ANRS-CO16 Lymphovir Cohort between 2008 and 2015. Whole blood and plasma EBV DNA load and serological profiles were analyzed in 76 HIV-infected patients at diagnosis of NHL and 6 months after the initiation of chemotherapy. Prechemotherapy whole blood (WB) and plasma EBV DNA loads were positive for 80 and 45% of HIV-NHL patients, respectively. Pretreatment WB EBV DNA positivity was associated with a positive plasma HIV-1 RNA load (relative risk (RR), 4.42 [1.33; 14.72]) and plasma EBV DNA positivity with EBV in situ detection (RR 10.62 [2.38; 47.49]). Following chemotherapy, the proportions of patients with positive WB or plasma EBV DNA declined from 81 to 23% (P < 0.0001) and from 43 to 8% (P < 0.0001), respectively. Estimated 2-year progression-free survival did not differ according to prechemotherapy WB positivity (82% versus 67%, P = 0.15) or plasma EBV DNA positivity (76% versus 81%, P = 0.52). The plasma EBV DNA load correlates with in situ EBV detection. The WB EBV DNA load correlates with HIV load. WB and plasma EBV DNA loads at NHL diagnosis do not constitute prognostic markers for HIV-NHL patients in the modern cART era.

Treatment Efficacy and Outcomes in HIV-Related Plasmablastic Lymphoma: The Results of Multicenter Retrospective Study in Russia

Background Plasmablastic lymphoma (PbL) is a rare and aggressive B-cell malignancy highly associated with HIV. Despite improved understanding of this disease, its prognosis remains poor with short overall survival. There is no standard of care for this entity. Recent advances in the treatment of HIV-associated and aggressive lymphomas have not yet significantly improved the outcomes of patients with PbL. Methods We investigate epidemiological characteristics and the results of the treatment of the HIV-related PbL in large cohort of HIV-related lymphoma patients for a 7-year period (2014-2020). During the observation period, 22 cases of HIV-related PbL were registered in three centers and selected for the analysis from the national multicenter retrospective study database. The median follow-up was 17,8 (4-57,4) months. Results The PbL accounted for 8,9% of lymphomas in HIV-infected patients (22/247). The median age was 42 years (32-61), males - 9 (41%). Most of the patients (n=19, 86%) had III-IV stages and B-symptoms were present in 8 patients (36%). CNS involvement was diagnosed in 8 patients (36%). The median of ECOG score was I (I-III). Half of patients had viral hepatitis as a co-infection including HCV (n=9), HCV and HBV (n=1), HCV, HBV and HDV (n=1). HIV and lymphoma were diagnosed simultaneously in 7 patients (32%). Median time from HIV infection to the lymphoma onset was 4 years (1,5 month - 17,5 years). The only one patient did not receive cART for an unknown reason. The median number of CD4+ cells at the moment of chemotherapy (CT) started was 151 cell/mcl (13 - 374). Frontline CT were following: CHOP±E - 9 (41%), EPOCH - 11 (50%), hyper-CVAD - 1 (4,5%), dexamethasone - 1 (4,5%). Bortezomib was added to frontline treatment in 3 (13,6%) patients, HDC with auto-HSCT had been done as a first line therapy in 2 (9%) patients. A total of 16 patients responded to the first line therapy with the overall response rate (ORR) of 72,7% including CR and PR in 4 (18,2%) and 12 (54,5%) patients respectively. Remaining patients had progression disease (n=5, 22,8%) and stable disease (n=1, 4,5%). The median course to achieve the ORR was 4 (2-6) cycles. Overall (OS) and progression-free survival (PFS) at 2 years after first line treatment was 59,1% and 40,9%, respectively. The median time to progression (TTP) was 7,95 (0,33-23,93) months. The addition of bortezomib and auto-HSCT in first line chemo improved OS (100% vs 47,1%, p=0,027), but non PFS (p=0,1) and TTP (p=0,4). Nine patients received second-line CT: DHAP - 4 (44,4%), ICE - 4 (44,4%), EPOCH - 1 (11,2%). Response was evaluated in 8 patients. CR, PR and progression disease was registered in 1 (12,5%), 2 (25%) and 5 (62,5%) patients respectively. PBSC harvesting was only successful in 1 of 3 cases (33%) and this patient received HDC with auto-HSCT. OS and PFS at 2 years after second line treatment was 44,4% and 22,2%, respectively. Two years after second line CT, 4 patients were still alive, including those after ICE, EPOCH (n=2), HDC with auto-HSCT (n=1) and nivolumab (27 cycles) as a third line therapy (n=1). Conclusions In a large cohort of patients PbL accounted for 8.9% of all HIV-related lymphomas. Bortezomib-containing chemotherapy and first line auto-HSCT show encouraging results, but data are obtained in a small group of patients. Prospective studies are needed for optimization of HIV-related plasmablastic lymphoma therapy. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: The is early clinical date on efficiency of Bortezomib in patients with plasmablastic lymphoma: https://doi.org/10.1111/bjh.15156

RARE CASE OF OVERLAPPING PRIMARY EFFUSION LYMPHOMA AND KAPOSI SARCOMA INFLAMMATORY CYTOKINE SYNDROME IN IMMUNOSUPRESSED PATIENT

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Kaposi’s sarcoma-associated herpes virus (KSHV) is a potent oncogenic and immunomodulatory virus. We present a patient with high KSHV viral load with primary effusion lymphoma (PEL) and the rarely reported Kaposi’s sarcoma inflammatory cytokine syndrome (KSICS). CASE PRESENTATION: 31-year-old male with AIDS (CD4 of 45 cell/µL, viral load 170,000) and Kaposi Sarcoma treated with liposomal doxorubicin, admitted for shortness of breath (SOB), lower extremity (LE) and scrotal edema. Physical examination: tachycardia, bibasilar crackles, 3+ pitting edema of LE extending to the sacrum, and violaceous, erythematous KS lesions on the torso. Initial studies notable for anemia (Hgb 9.0 g/dl), otherwise unremarkable including brain natriuretic peptide and microbiology studies. A chest x-ray demonstrated bilateral pleural effusions with loculation on the left, which was later confirmed on a chest computed tomography scan, that also revealed enlarged mediastinal lymph nodes. Echocardiography showed preserved ejection fraction. A doppler ultrasound of LE was negative for deep vein thrombosis. During hospital course, patient became progressively anemic, hemodynamically unstable and profoundly SOB, ultimately requiring transfer to the intensive care unit where he was intubated and started on vasopressors. A thoracentesis with cytology positive for large pleomorphic lymphocytes, CD45+/HHV8+/EBER+ by immunohistochemistry. Flow cytometry showed monotypic B-cell population positive for HLA-DR, CD38, CD45 (dim), and kappa light chain (dim) restricted, consistent with a diagnosis of PEL. Serum studies demonstrated markedly elevated levels of IL6 and IL10 and the clinical presentation suggested a rare condition associated with KSHV, KSICS. The patient unfortunately died despite resuscitative efforts. DISCUSSION: PEL is the least common of all HIV related lymphomas and presents as lymphomatous growth in a liquid phase in a body cavity without extracavitary lesions. The pathogenic mechanism of KSHV is uncertain but almost all cases are associated with this virus. Malignant cells are monoclonal B cells that express CD38 and contain KSHV viral inclusions and the majority demonstrate EBV coinfection . Another disease diagnosed in patient is KSICS, a rarely reported systemic inflammatory syndrome associated with high KSHV viral load and elevated IL6 and IL10, secreted by infected cells. Presentation is similar to sepsis but without obvious source of infection. CONCLUSIONS: This case illustrates varying and overlapping presentations of KSHV infection in immunocompromised patient. Therapy does not exist and KS could not be treated due to the poor condition of patients. Patients have a high mortality rate and often misdiagnosed. Our patient received antibiotics for the presumptive sepsis before a diagnosis was made. It will be important to recognize this syndrome early to support attempts to develop effective therapies. Reference #1: Narkhede M, Arora S, Ujjani C. Primary effusion lymphoma: current perspectives. Onco Targets Ther. 2018;11:3747–3754. Published 2018 Jun 28. doi:10.2147/OTT.S167392 Reference #2: Polizzotto MN, Uldrick TS, Hu D, Yarchoan R. Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome [published correction appears in Front Microbiol. 2017 Aug 21;8:1572]. Front Microbiol. 2012;3:73. Published 2012 Mar 2. doi:10.3389/fmicb.2012.00073 DISCLOSURES: No relevant relationships by Arsenije Kojadinovic, source=Web Response No relevant relationships by Prabhjot Mundi, source=Web Response No relevant relationships by Pahnwat Taweesedt, source=Web Response

HIV-Related Lymphoproliferative Diseases in the Era of Combination Antiretroviral Therapy.

HIV-positive patients have a 60- to 200-fold increased incidence of Non-Hodgkin Lymphomas (NHL) because of their impaired cellular immunity. Some NHL are considered Acquired Immunodeficiency Syndrome (AIDS) defining conditions. Diffuse large B-cell Lymphoma (DLBC) and Burkitt Lymphoma (BL) are the most commonly observed, whereas Primary Effusion Lymphoma (PEL), Central Nervous System Lymphomas (PCNSL), Plasmablastic Lymphoma (PBL) and classic Hodgkin Lymphoma (HL) are far less frequent. Multicentric Castleman disease (MCD) is an aggressive lymphoproliferative disorder highly prevalent in HIV-positive patients and strongly associated with HHV-8 virus infection. In the pre-Combination Antiretroviral Therapy (CART) era, patients with HIV-associated lymphoma had poor outcomes with median survival of 5 to 6 months. By improving the immunological status, CART extended the therapeutic options for HIV positive patients with lymphomas, allowing them to tolerate standard chemotherapies regimen with similar outcomes to those of the general population. The combination of CART and chemotherapy/ immuno-chemotherapy treatment has resulted in a remarkable prolongation of survival among HIV-infected patients with lymphomas. In this short communication, we briefly review the problems linked with the treatment of lymphoproliferative diseases in HIV patients. Combination Antiretroviral Therapy (CART) not only reduces HIV replication and restores the immunological status improving immune function of the HIV-related lymphomas patients but allows patients to deal with standard doses of chemotherapies. The association of CART and chemotherapy allowed to obtain better results in terms of overall survival and complete responses. In the setting of HIV-associated lymphomas, many issues remain open and their treatment is complicated by the patient’s immunocompromised status and the need to treat HIV concurrently.

HIV Lymphoma and Burkitts Lymphoma.

Despite widely available antiretroviral therapy, lymphoma remains the leading cause of death for human immunodeficiency virus (HIV)-infected persons in economically developed countries. Even a few months of drug interruptions can lead to drops in the CD4 cell count, HIV viremia, and an increased risk of lymphoma. Currently, good HIV control facilitates intensive therapies appropriate to the lymphoma, including autologous and even allogeneic hematopoietic stem cell transplantation. Nonetheless, HIV-related lymphomas have unique aspects, including pathogenetic differences driven by the presence of HIV and often coinfection with oncogenic viruses. Future therapies might exploit these differences. Lymphoma subtypes also differ in the HIV-infected population, and the disease has a higher propensity for advanced-stage, aggressive presentation and extranodal disease. Other unique aspects include the need to avoid potential interactions between antiretroviral therapy and chemotherapeutic agents and the need for HIV-specific supportive care such as infection prophylaxis. Overall, the care of these patients has progressed sufficiently that recent guidelines from the American Society of Clinical Oncology advocate the inclusion of HIV-infected patients alongside HIV-negative patients in cancer clinical trials when appropriate. This article examines HIV lymphoma and includes Burkitt lymphoma in the general population.

Africa calls: A phone-based training program aids a continent's rising stars: A 20-year-old distance learning project has helped to train a generation of African cytopathologists.

Africa calls: A phone-based training program aids a continent's rising stars: A 20-year-old distance learning project has helped to train a generation of African cytopathologists.

Hepatitis C virus or hepatitis B virus coinfection and lymphoma risk in people living with HIV.

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are associated with increased risks of lymphomas in the non-HIV setting. Their impacts on HIV-associated lymphomas deserved further studies in the modern combined antiretroviral therapy (cART) era. We evaluated the associations between HCV, HBV and HIV-related lymphomas in the Lymphovir-ANRS-CO16 cohort. Prevalence of HCV seropositivity and chronic HBV infections were compared with those observed in the French Hospital Database on HIV (FHDH-ANRS-CO4). Between 2008 and 2015, 179 patients with HIV-related lymphomas from 32 French hospitals were enrolled, 69 had Hodgkin's lymphoma (39%), and 110 non-Hodgkin's lymphoma (NHL) (61%). The prevalence of HCV infection was higher in patients with NHL than in the FHDH-ANRS-CO4 [26 versus 14%, odd ratio (OR): 2.15; 95% confidence interval (1.35-3.32)] whereas there was no association between Hodgkin's lymphoma and chronic HCV infection. Chronic HBV infection was not associated with NHL in our cohort with a prevalence of 5 versus 7% in FHDH-ANRS-CO4 but tended to be associated with Hodgkin's lymphoma [prevalence of 14%, OR: 2.16 (0.98-4.27)]. Chronic HCV infection tended to pejoratively impact 2-year overall survival in patients with NHL: 72% [57%, 91%] versus 82% [74%, 91%], hazard ratio: 2.14 [0.95-4.84]. In contrast, chronic HBV infection did not correlate with outcome. In the modern cART era, chronic HCV infection is associated with an increased risk of NHL in PLWHIV and tends to pejoratively impact overall survival. HBV infection is not associated with the risk of NHL but with a borderline increase of Hodgkin's lymphoma risk.

Immunotherapy in patients with relapsed/refractory HIV-related lymphomas

Abstract Background Immune checkpoint inhibitors (ICIs) are a new option for salvage therapy in relapsed/refractory (r/r) Hodgkin lymphoma (HL) and non-Hodgkin lymphoma. Patients with HIV-related lymphoma may benefit not only from the anticancer activity of ICIs, but also from its potential anti-HIV effect. The publications on ICIs in HIV-related lymphomas is limited by a few case reports. Methods Nine patients with r/r HIV-related lymphoma were treated with nivolumab (nivo) between 2017-2019. Median follow-up time was 397 days [45-889]. The end points were response to therapy, immune-related adverse effects (IRAE) and overall survival (OS) at 12 months. LYRIC criteria for assessing FDG-PET/CT were applied. Results The main characteristics of the study population and outcomes are presented in the table. Median number of prior lines of therapy was 3 (range, 2-4). Four patients received low dose of nivo as monotherapy [NCT03343665] with median of 12 courses 12 (7-12), 5 patients in combination with bendamustine and gemcitabine [NCT03259529] with median of 4 courses 4 (3-11). The median of CD4+ was 382 c/mcl (range, 45-560). The only one patient who did not receive cART due to acute renal failure died early from undetermined cause. Overall response rate (ORR) was 89% with the median time 104 days (73-517); complete remission (CR) was 67% with the median time 107 days (75-265). IRAE were not registered. OS at 12 months was 88.9%. Table . 61P Pts. Ds Age HIV load CD4+ cells/mcl cART Nivo N of nivo Response Followed therapy Outcome Follow up 1 HL 33 140 + mono 40 [1] BeGeN 5 CR Auto-HSCT Remission; 882 days 2 HL 41 45 + BeGeN 12 PR Continued [GeN] Relapse; 485 days 889 days 3 HL 36 362 + mono N 40 [1] 10 CR Auto-HSCT Remission; 222 days 4 HL 40 490 + BeGeN 7 CR Auto-HSCT Remission; 427 days 5 HL 37 568 + mono N 40 [1] 6 PR Continued Partial remission; 161 days 6 HL 34 482 + mono N 40 [1] 14 PR Continued Remission; 591 days 7 DLBCL 33 3381 410 + BeGeRN [2] 2 PD - Progression; Died; 45 days 8 DLBCL 38 473 + BeGeRN [2] 7 CR Auto-HSCT Relapse; 266 days 397 days 9 Plasmoblastic Ly 38 174 + mono N 40 [1] 12 CR Continued Remission; 186 days Pts – patients, Ds – diagnose, HL – Hodgkin lymphoma, DLBCL – diffuse large B-cell lymphoma, BeGeR – bendamustine, gemcitabine, rituximab, Nivo/N – nivolumab, CR – complete remission, PR – partial remission, PD – progression disease, auto-HSCT – hematopoietic stem cell transplantation Conclusion Overall response rate to nivo in patients with HIV-related lymphomas was 89%, one-year OS – 88.9%. Immune-related adverse effects were not registered. Preliminary data suggest that nivo seems to be an effective and safety treatment option for r/r HIV-related lymphoma. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Effect of Active Hepatitis C Infection in Relapse-Free Survival Among Patients with HIV‐Related Diffuse Large B‐Cell Lymphoma

Introduction: Diffuse-large B cell lymphoma (DLBCL) is the most common lymphoma associated with Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). During the past decades, the incidence of HIV-related lymphomas has declined; however, it still remains a major cause of morbidity and mortality in this population. Before highly effective antiretroviral therapy for HIV was introduced, individuals with HIV-related DLBCL had worse complete response and survival rates compared to their uninfected counterparts. Additionally, recent studies have shown that relapse rates are lower for DLBCL patients that achieve HCV sustained virological response (SVR). Nevertheless, outcomes in patients with active HCV infection among patients with HIV-related DLBCL have not been reported yet. This study is aimed to compare the clinical outcomes in HIV-related DLBCL among patients with and without active HCV infection. Methods: Patients with HIV infection and newly diagnosed DLBCL between 2005 and 2017 at Montefiore Medical Center/Albert Einstein College of Medicine were identified using the institutional software Clinical Looking Glass. Cases were grouped into concomitant HIV and HCV infection (HIV + HCV) or HIV alone (HIV) based on HCV antibody and viral load counts at DLBCL diagnosis. Patients with active hepatitis B infection were excluded. Data regarding demographics, laboratory parameters, HCV treatment, lymphoma treatment and clinical outcomes including complete response (CR), progression of disease (POD) and relapse were collected by manual chart review and compared among groups. SVR was defined as undetectable HCV RNA level 12 weeks after HCV treatment completion. Clinical outcomes were compared between patients with and without active HCV at the time of outcome evaluation. For this purpose, patients that achieved SVR for HCV were analyzed in the HIV group. Kaplan-Meier curves were plotted to compare 12-months relapse-free survival (RFS) among groups. Statistical analysis was performed using Stata 14.1. Results: A total of 63 patients were identified, of whom 45 (71.4%) had HIV alone (HIV) and 18 (28.6%) had concomitant active HCV and HIV infection (HIV + HCV). The median age was 49 years (IQ: 40-54), there were 39 (61.9%) males, 27 (42.9%) were Non-Hispanic Black and 27 (42.9%) were Hispanic. At DLBCL diagnosis, the majority of cases had advanced stages (stage 3: 15; 25% and stage 4: 40; 66.7%), the median CD4 count was 117 (IQ: 65-217) and 45 (72.6%) had AIDS. Baseline characteristics did not differ among groups. Of 63 patients, 53 (84.1%) were treated for DLBCL. Treatment regimens included DA-EPOCH (28; 50.9%), CHOP (22; 40%) and others (3; 9.1%). Rituximab was given to 33 cases (57.9%). Within the HIV + HCV group, only 3 (16.7%) patients received treatment for HCV; all of them were treated with ledipasvir/sofosbuvir and achieved SVR. In the full cohort, CR was achieved in 17 (32.1%) treated patients and 19 (35.9%) had POD. The CR rate was lower for patients with active HCV + HIV compared to HIV alone (7.1% vs. 41%, p=0.02) and there was no difference in POD among groups (28.6% vs. 38.5%, p=0.37). Patients with active HCV + HIV had a significantly lower 18-month RFS compared to those with HIV (62.9% vs. 87.4%, p=0.035). In a multivariate model adjusted for stage, AIDS and rituximab use; active HCV + HIV was a predictor for relapse (OR:6.36, 95% CI: 1.01 - 39.9, p=0.048). Conclusions: Despite available and effective treatment against HCV infection, only a minority of patients with DLBCL-related HIV received HCV treatment. Active HCV seems to play a role in the outcomes of patients treated for DLBCL and was found to be a predictor for relapse. Hence, HCV treatment should be considered for patients with HIV-related DLBCL. Disclosures Shah: Physicians' Education Resource: Honoraria. Friedman:Incyte pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Plasmablastic lymphoma achieving sustained remission with antiretroviral therapy alone

Despite advances in the treatment of most human immunodeficiency virus (HIV)-related lymphomas, the outcomes for patients with HIV-related plasmablastic lymphoma (PBL) remain poor. While studies have shown an increased survival for patients with most kinds of HIV-related lymphomas since the introduction of highly active antiretroviral therapy (HAART), the impact of HAART on survival in patients with HIV-related PBL is unclear, mainly because the condition is rare and the number of published studies is small. Few case reports have shown regression of PBL after initiation of HAART, however, usually followed by recurrence of PBL or achieved with a need for chemotherapy. We report the first case of PBL in a 38-year-old man with newly diagnosed HIV who achieved sustained remission after the initiation of HAART alone and who remains in remission seven years after diagnosis, without a need for chemotherapy or radiation. We illustrate the importance of initiating HAART therapy under the supervision of infectious disease specialists as soon as the PBL is diagnosed until future studies provide clear evidence in the management of HIV-related PBL.