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There are four conditions caused by Kaposi sarcoma herpesvirus (KSHV): Kaposi sarcoma, KSHV-associated multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and KSHV inflammatory cytokine syndrome (KICS). These KSHV-associated disorders (KADs) often occur in people with HIV and can lead to multiorgan dysfunction requiring admission to the ICU. However, little is known about patient outcomes in this setting.A retrospective study of patients with KADs admitted to the ICU between 2010 and 2021 was conducted, examining KAD admission diagnoses, HIV characteristics, selected cytokine profiles, and ICU interventions. Primary outcomes were 60-day and median overall survival from ICU admission to death from any cause.Forty-seven patients (all but one with HIV coinfection) were included. At ICU admission, 44 patients (94%) were on antiretroviral therapy with a median CD4 + count of 88 cells/μl and HIV viral load of 23 copies/ml. The most common presentation was respiratory failure alone (19%) or with hypotension (17%). Twenty-two (47%) patients had presumed KICS (with or without Kaposi sarcoma) at admission and an additional KAD was diagnosed in 36% of these patients. IL-6 levels did not vary across KAD subtype. Twenty (43%) patients received KAD-directed therapy in the ICU. Sixty-day survival was 70% and median overall survival was 9 months.The majority of patients with HIV and KADs admitted to the ICU had well controlled HIV. Additional KAD were diagnosed during ICU admission in a proportion of patients who presented with presumed KICS. Critical illness did not preclude a subset of patients from receiving KAD-directed therapy in the ICU.

In 1981, a cluster of cases of Kaposi sarcoma (KS), a hitherto rare skin tumor, in previously healthy men who have sex with men in the US, often along with Pneumocystis pneumonia, heralded the onset of the HIV/AIDS pandemic. The frequent occurrence of KS in people with HIV (PWH) remained a puzzle until 1994 when Yuan Chang, Patrick Moore and colleagues showed that this tumor was caused by a novel gammaherpesvirus, Kaposi sarcoma herpesvirus (KSHV), and epidemiologic studies documented the simultaneous spread of KSHV and HIV among men who had sex with men during the early 1980s. Over the next several years, it became apparent that PWH had a substantially increased risk of certain other tumors, including aggressive B cell lymphomas. We now know that most of the tumors associated with HIV are caused by oncogenic viruses, including Epstein Barr virus (EBV), KSHV, and human papillomavirus (HPV). The subsequent development of anti-retroviral drugs, initially spearheaded by NCI scientists and collaborators, and the widespread use of these drugs converted AIDS from an almost universally lethal disease to a manageable condition. It also resulted in a substantial decline in the incidence of those tumors (such as primary central nervous system lymphoma) associated with very low CD4 counts. However, as PWH lived longer and the population of PWH increased, there was a substantial increase in the number of other tumors (such as anal carcinoma) that occur at higher CD4 counts. Also, we continue to see new cases of KS and other tumors associated with severe immunodeficiency. KS is increasingly a disease of minority communities in the US and its incidence is rising in young Black men in the rural South. Moreover, HIV-associated tumors continue to be a major public health issue in sub-Saharan Africa and other low- and middle-income countries (LMIC). In particular, KS continues to be the most common tumor among men 65 or younger in several countries in sub-Saharan Africa. Before the development and use of combination anti-retroviral therapy (cART), PWH who developed cancer often could not tolerate full doses of chemotherapy and treatment regimens employing lower doses of chemotherapy drugs were used, usually with relatively low rates of cure. This has changed, and in general cancers in PWH are best treated with standard-dose regimens that would be used in the general population. For some cancers, such as Hodgkin lymphoma and non-small cell lung cancer, data have shown that when PWH are treated with standard chemotherapy regimens, their outcomes are the same as the general population. In the past several years, there has been a revolution in the development and use of immunologic therapy for various cancers, such as anti-PD-(L)1 monoclonal antibodies. However, there has been a reluctance to enroll PWH on clinical trials using immunotherapy approaches because of concern that the agents may not be tolerated or may not be effective because of the CD4 T cell lymphopenia. Two recent trials, one by the Cancer Immunotherapy Trials Network with the NCI Intramural Program (TS Uldrick et al., JAMA Oncology, 2019) and one by the AIDS Malignancy Consortium (AMC) (TA Rasmussen et al., Clin. Infect. Dis., 2021) showed that these agents could be administered safely to PWH and can have activity. Anti-PD-(L)1 agents are generally most effective in tumors with high mutational burden resulting in neoantigens. Virus-induced tumors tend to have low mutational burdens. However, the oncogenic viruses themselves can provide novel antigens for attack, and these tumors are thus potentially attractive targets for such therapies. A problem, however, is that oncogenic viruses have evolved various mechanisms to suppress expression of surface immune markers (such as MHC-1, B7-2/CD86, or ICAM-1), making the tumor cells invisible to the immune system. Our group recently conducted a clinical trial showing that pomalidomide, a cereblon-binding immunomodulatory drug, was active against KS (MN Polizzotto et al., J. Clin, Oncol. 2016; R. Ramaswami et al., Clin Cancer Res., 2022). Based on this trial, pomalidomide was recently approved by the US Food and Drug Administration for KS. Also, the AMC is studying the feasibility of using pomalidomide against KS in sub-Saharan Africa and other LMIC. In investigating possible mechanisms of its activity, David Davis, Prabha Shrestha et al. in our group found that pomalidomide could reverse or prevent the KSHV-mediated downregulation of surface immune marker expression, at least in lymphoid cells (DA Davis et al, Oncoimmunology, 2018; P Shrestha et al., PLoS Path, 2021). Surprisingly, this upregulation was not found in KSHV-infected endothelial cells (a model for KS), and it isn’t clear if this accounts for the activity of pomalidomide in KS. At the same time, it suggested that this approach might be worth considering in other virus-induced tumors and moreover, that pomalidomide and related drugs might be worth combining with checkpoint inhibition (for example with anti-PD-(L)1 antibodies) in these tumors. We are now testing this in an ongoing study in the NCI HIV and AIDS Malignancy Branch (NCT04902443). In a limited retrospective study, Kathryn Lurain et al. in our group (K Lurain et al., J. Immunotherapy Cancer, 2021) have shown that pembrolizumab with pomalidomide can be effective in HIV-associated lymphomas caused by EBV. Also, we have been exploring the use of other agents that can enhance expression of surface immune markers in virus-infected cells. Yi-Quan Wu et al in our group recently showed that the CDK4/6 inhibitor abemaciclib could upregulate surface immune markers in KSHV-infected endothelial cells as well as in lymphoid cells (Y Wu et al., J. Translational Med., 2022) and we are now studying this in a clinical trial for KS (NCT04941274). In addition to KS, KSHV is the cause of several other severe diseases that occur predominantly in PWH, including a form of multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and KSHV-inflammatory cytokine syndrome (KICS). These diseases often occur together in the same patient. KSHV-MCD and KICS are characterized by severe inflammatory symptoms associated with increased levels of various cytokines, especially human interleukin-6 (IL-6), interleukin-10 (IL-10), and a KSHV-encoded form of IL-6 (vIL-6). Recent studies by our group and others have suggested that a key pathway in these diseases is the induction of human cytokines by vIL-6 and other factors produced by KSHV-infected cells. We are currently exploring mechanisms to specifically target these pathways. Thus, while we have made substantial progress in the prevention and therapy of HIV-associated malignancies, they continue to pose a major health problem. At the same time, our increasing understanding of the pathogenesis of these tumors is leading to novel approaches to their treatment. This work was supported by the Intramural Research program of the NIH, National Cancer Institute. Citation Format: Robert Yarchoan, Kathryn Lurain, Ramya Ramaswami, David A. Davis, Prabha Shrestha. Malignancies in People with HIV: Successes and Challenges at the Intersection of Virology, Immunology, and Oncology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr PL02-04.

A biopsy of lymphoid tissue is currently required to diagnose Kaposi sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman disease (KSHV-MCD). Patients showing clinical manifestations of KSHV-MCD but no pathological changes of KSHV-MCD are diagnosed as KSHV inflammatory cytokine syndrome. However, a lymph node biopsy is not always feasible to make the distinction. A pathognomonic feature of lymph nodes in KSHV-MCD is the expansion of KSHV-infected, lambda-restricted but polyclonal plasmablasts. To investigate whether these cells also reside in extra-nodal sites, effusion from 11 patients with KSHV-MCD and 19 with KSHV inflammatory cytokine syndrome was analysed by multiparametric flow cytometry. A distinct, lambda-restricted plasmablastic population (LRP) with highly consistent immunophenotype was detected in effusions in 8/11 patients with KSHV-MCD. The same population was also observed in 7/19 patients with KSHV inflammatory cytokine syndrome. The detection of LRP stratified KSHV inflammatory cytokine syndrome into two clinically distinct subgroups; those with detectable LRP closely resembled KSHV-MCD, showing similar KSHV viral load, comparable severity of thrombocytopenia and hypoalbuminaemia, and similar incidences of hepatosplenomegaly. Collectively, the detection of LRP by flow cytometry can serve as a valuable tool in diagnosing KSHV-MCD. KSHV inflammatory cytokine syndrome with LRP in effusions may represent a liquid-form of KSHV-MCD.

PURPOSE Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS This retrospective study included PWH treated with anti–PD-1- or anti–PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti–PD-1/anti–PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load CONCLUSION Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Purpose:Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes.Patients and Methods:Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes.Results:Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%–87%. Twelve of 18 HIV-positive (67%; 95% CI, 41–87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%–97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6–15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases.Conclusions:Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV.

CD4 Count at baseline and after 6 cycles of combination therapy. . * For all patients, those in cohort 1 and 2, P values test the equality of the matched pair of CD4 counts from baseline to 6 cycles using Wilcoxon signed rank tests. All other P values denote comparison of the change in CD4 count from baseline to 6 cycles in responders as compared with non-responders using Wilcoxon rank sum tests.

Purpose:Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes.Patients and Methods:Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes.Results:Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%–87%. Twelve of 18 HIV-positive (67%; 95% CI, 41–87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%–97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6–15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases.Conclusions:Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV.

Kaplan-Meier curve of duration of response among 9 responders on the study, measured from the date of response (as compared with baseline) till progression or censorship when patient follow-up ended. Median time to progression was not reached. Hatch marks denote time that patients are censored.

Supplementary Table from Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection

Supplementary Figure from Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection

Purpose:VEGF-A is important in the pathogenesis of Kaposi sarcoma, and bevacizumab has a response rate of 31%. We explored the combination of bevacizumab with liposomal doxorubicin in patients with Kaposi sarcoma.Patients and Methods:Patients with Kaposi sarcoma requiring systemic therapy were enrolled in one of two cohorts. Cohort 1 included patients with human immunodeficiency virus (HIV)-negative Kaposi sarcoma or with HIV-associated Kaposi sarcoma who would not be expected to respond to antiretroviral therapy (ART) alone (i.e., either stable or progressive Kaposi sarcoma on ART). Cohort 2 included all other patients with HIV-associated Kaposi sarcoma. Patients were treated with six cycles of liposomal doxorubicin with bevacizumab every 3 weeks followed by up to 11 cycles of bevacizumab alone.Results:Sixteen patients were enrolled: 10 (two HIV negative) in cohort 1 and six in cohort 2. Fourteen patients had advanced disease (AIDS Clinical Trials Group T1). Overall response rate (complete and partial responses) was 56% [80% confidence interval (CI), 38%–74%] for all patients and were similar in the two cohorts. Median progression-free survival was 6.9 months (95% CI, 4.5 months–not estimable). Grade 3 and 4 adverse events attributed to therapy included hypertension (n = 5), neutropenia (n = 6), gastrointestinal hemorrhage (n = 1), and cerebral ischemia (n = 1). There was a significant decrease in VEGF-A levels from baseline to the end of six cycles of combination therapy.Conclusions:Pegylated liposomal doxorubicin in combination with bevacizumab has activity in advanced Kaposi sarcoma, but it is unclear whether the combination yields better outcomes than liposomal doxorubicin used alone.

Supplementary Table 2: Analysis of changes in serum VEGF-A and inflammatory cytokines between responders and non-responders after 6 cycles of treatment with bevacizumab and liposomal doxorubicin. *P values are for the difference between responders and non-responders. Abbreviations: IFN, interferon; IL, interleukin; IQR, interquartile range; VEGF, vascular endothelial growth factor

Diagram to represent the treatment course and responses among patients treated within the study. *Patient had progressive disease of cutaneous KS but continued with treatment due to improvement in symptomatic pulmonary KS.

The report in 1981 of a cluster of cases of Kaposi sarcoma (KS) in homosexual men in New York and California was one of the earliest harbingers of the AIDS pandemic, and association of cancer with HIV/AIDS has been one of the key features of this disease since. Looking back at year 40, the development of anti-retroviral therapy markedly reduced the incidence of AIDS-related cancers that occur at low CD4 counts, and this has been one of the most impressive advances in cancer prevention over the past half-century. There have also been advances in prevention and treatment of various HIV-associated tumors. However, as AIDS patients are living longer, there has been an increase in other cancers. Cancer continues to be one of the most frequent causes of death in persons living with HIV, and further basic, translational, clinical, and epidemiologic research in this area is urgently needed.

OBJECTIVE To assess the cytokine and viral profiles of effusions and peripheral blood among patients diagnosed with HIV and Kaposi sarcoma herpesvirus [KSHV, also known as human herpesvirus 8 (HHV-8)]-associated conditions. DESIGN Retrospective comparative study evaluating clinicopathologic findings in patients with HIV and KSHV-associated conditions presenting with an effusion between 2010 and 2018. METHODS Paired peripheral blood and effusion samples collected at the time of pathological diagnosis of KSHV-associated conditions [Kaposi sarcoma, KSHV-associated multicentric Castleman disease (KSHV-MCD), primary effusion lymphoma (PEL), or KSHV-associated inflammatory cytokine syndrome (KICS)] were evaluated for disease-specific and compartment-specific (effusion vs. blood) characteristics. We assessed 12 cytokines, KSHV viral DNA (KSHV-VL), and Epstein--Barr virus (EBV) viral DNA (EBV-VL). RESULTS Nine patients had PEL, five patients had KSHV-MCD, and eight patients met criteria for KICS; all but one patient had concurrent Kaposi sarcoma in addition to these conditions. PEL effusions had substantially higher levels of IL-13 (median 16.9 pg/ml; interquartile range 9.7--26.9 pg/ml) compared with KSHV-MCD (median

Kaposi sarcoma (KS), caused by Kaposi sarcoma herpesvirus (KSHV), is a multicentric tumor characterized by abnormal vasculature and proliferation of KSHV-infected spindle cells. KS commonly involves the skin but in severe cases KS can also involve the gastrointestinal tract (GI). Here, we sought to compare the cellular and KSHV gene expression signatures of skin and GI KS lesions. Skin and GI KS were compared to normal matched samples using bulk RNA sequencing.Twenty-two paired samples of KS and normal tissue were obtained (skin (10 pairs) and GI (12 pairs)) from 19 patients with KS of whom 17 had concurrent HIV infection. Seven paired samples were from patients who had received prior KS therapy. Three patients provided both skin and GI samples at the same timepoint. These analyses identified 370 differentially expressed genes unique to cutaneous KS and 58 DEGs unique to GI KS compared to normal skin or GI tissues. Twenty-six differentially expressed genes overlapped between skin and GI KS, which included FLT4, which encodes for a VEGF-C and VEGF-D receptor, and STC1. KSHV infection of primary lymphatic endothelial cells (LECs) resulted in increased angiogenesis, and repression of STC1 or FLT4 inhibited angiogenesis. The analyses of KSHV expression from KS lesions identified certain lytic genes, specifically ORF75, that were consistently expressed, and these expression patterns differed from laboratory infection of LECs with KSHV and KSHV gene expression in PEL cell lines. This study demonstrates that complex patterns of gene expression are found in KS tissue that differ from the canonical latent/lytic programs seen in KSHV cell lines and also demonstrates differences in viral gene and clinically relevant host gene expression in skin and GI KS that may offer insights into the pathogenesis of these forms of KS.One sentence summaryKaposi sarcoma that manifests in the skin and gastrointestinal tracts differ by human and viral gene expression.

In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4 + T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti–PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4 + T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4 + T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti–PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti–PD-1 with other interventions to reduce the HIV reservoir.

BackgroundThe Food and Drug Administration recommends that people living with HIV (PWH) with a CD4+ T cell count (CD4) ≥350 cells/µL may be eligible for any cancer clinical trial, but there is reluctance to enter patients with lower CD4 counts into cancer studies, including immune checkpoint inhibitor (ICI) studies. Patients with relapsed or refractory cancers may have low CD4 due to prior cancer therapies, irrespective of HIV status. It is unclear how baseline CD4 prior to ICI impacts the proportion of treatment-emergent adverse events (TEAE) and whether it differs by HIV status in ICI treated patients.MethodsWe conducted a pilot retrospective cohort study of participants eligible for ICI for advanced cancers from three phase 1/2 trials in the USA and Spain. We determined whether baseline CD4 counts differed by HIV status and whether the effect of CD4 counts on incidence of TEAE was modified by HIV status using a multivariable logistic regression model.ResultsOf 122 participants, 66 (54%) were PWH who received either pembrolizumab or durvalumab and 56 (46%) were HIV-negative who received bintrafusp alfa. Median CD4 at baseline was 320 cells/µL (IQR 210–495) among PWH and 356 cells/µL (IQR 260–470) among HIV-negative participants (p=0.5). Grade 3 or worse TEAE were recorded among 7/66 (11%) PWH compared with 7/56 (13%) among HIV-negative participants. When adjusted for prior therapies, age, sex, and race, the effect of baseline CD4 on incidence of TEAE was not modified by HIV status for any TEAE (interaction term p=0.7), or any grade ≥3 TEAE (interaction term p=0.1).ConclusionsThere was no significant difference in baseline CD4 or the proportions of any TEAE and grade ≥3 TEAE by HIV status. CD4 count thresholds for cancer clinical trials should be carefully reviewed to avoid unnecessarily excluding patients with HIV and cancer.

The observation in 1981 of the emergence of Kaposi sarcoma (KS) among young men who had sex with men was one of the first harbingers of the HIV epidemic. With advances in HIV care, the incidence of HIV-associated KS (HIV+KS) has decreased over time in the United States. However, it remains a persistent malignancy among some HIV-infected populations and is one of the most common tumors in sub-Saharan Africa. Because of the relapsing and remitting nature of this cancer, patients with HIV+KS can experience significant, long-term, morbidity. Patients with severe HIV+KS may also have concurrent lymphoproliferative syndromes, malignancies, and/or infections that can contribute to mortality. Several chemotherapy agents were explored in clinical trials for HIV+KS during the early stage of the epidemic. As HIV+KS emerges with CD4 lymphopenia and immunodysregulation, T-cell–sparing options are important to consider. Here, we explore the pathogenesis of HIV+KS and the current evidence for immunotherapy and therapies that potentially target KS pathogenesis. This review provides the current landscape of therapies for HIV+KS and highlights management issues for patients with HIV and cancer.

Purpose [177Lu]DOTATATE prolongs progression free survival (PFS) in metastatic neuroendocrine tumours (NETs). However, objective response rate is low. This, coupled with long duration of therapy and expense suggest need for better selection. We aim to assess whether baseline [68Ga]DOTATATE-PET/CT parameters, and whether response assessment by PET accurately predicts clinical outcome to [177Lu]DOTATATE. Experimental design Retrospective study of patients receiving [177Lu]DOTATATE was conducted. Patients were followed 3-monthly until disease progression. Four [68Ga]DOTATATE-PET parameters (single lesion SUVmax, tumour to spleen and liver SUV ratios, and SUVmax-av using up to five target lesions in multiple organ sites) were determined at baseline and follow-up. The association between these PET parameters either at baseline, or any changes following treatment, and PET response criteria (PERCIST and modified PERCIST) to predict PFS were determined. Patients were followed 3-monthly until disease progression. Response was determined using RECIST 1.1. Baseline SSTR2 expression was assessed and compared with PET parameters. Results 55 patients with metastatic NETs were identified predominantly small bowel (N = 18) and pancreatic (N = 8) in origin. 16 were low grade, 15 intermediate and 3 high grade. Response to PRRT (N = 47): partial response (PR) 28%, stable disease (SD) 60% progressive disease (PD) 13%. Response to PRRT predicted PFS: PR 71.8 months (95%CI: not achieved), SD 29.1 months (95%CI: 15.2–43.1), and PD 9.7 months (95%CI: 0–21.02). Baseline, single lesion SUVmax predicted both response and PFS with SUV cut-off of 13.0 giving high sensitivity and specificity. Tumoural SUVmax correlated with SSTR2 expression, Spearman’s rho – 0.69, p Conclusions Baseline single lesion SUVmax and SUVmax-av predicts response to [177Lu]DOTATATE. Objective response following PRRT defines a subset of patients with markedly improved PFSBaseline SUVmax 13.0 defines a threshold below which patients have poor response to PRRT and worse PFS. SUV threshold analysis should be taken forward into prospective studies.

Purpose: VEGF-A is important in the pathogenesis of Kaposi sarcoma, and bevacizumab has a response rate of 31%. We explored the combination of bevacizumab with liposomal doxorubicin in patients with Kaposi sarcoma. Patients and Methods: Patients with Kaposi sarcoma requiring systemic therapy were enrolled in one of two cohorts. Cohort 1 included patients with human immunodeficiency virus (HIV)-negative Kaposi sarcoma or with HIV-associated Kaposi sarcoma who would not be expected to respond to antiretroviral therapy (ART) alone (i.e., either stable or progressive Kaposi sarcoma on ART). Cohort 2 included all other patients with HIV-associated Kaposi sarcoma. Patients were treated with six cycles of liposomal doxorubicin with bevacizumab every 3 weeks followed by up to 11 cycles of bevacizumab alone. Results: Sixteen patients were enrolled: 10 (two HIV negative) in cohort 1 and six in cohort 2. Fourteen patients had advanced disease (AIDS Clinical Trials Group T1). Overall response rate (complete and partial responses) was 56% [80% confidence interval (CI), 38%–74%] for all patients and were similar in the two cohorts. Median progression-free survival was 6.9 months (95% CI, 4.5 months–not estimable). Grade 3 and 4 adverse events attributed to therapy included hypertension (n = 5), neutropenia (n = 6), gastrointestinal hemorrhage (n = 1), and cerebral ischemia (n = 1). There was a significant decrease in VEGF-A levels from baseline to the end of six cycles of combination therapy. Conclusions: Pegylated liposomal doxorubicin in combination with bevacizumab has activity in advanced Kaposi sarcoma, but it is unclear whether the combination yields better outcomes than liposomal doxorubicin used alone.

Because of tremendous advances in HIV care, the survival of many people living with HIV (PLWH) now approaches that of the general population. This has led to a shift in the types of malignancies diagnosed among PLWH from AIDS-defining cancers during the height of the HIV epidemic toward more non-AIDS−defining cancers and age-related incidental cancers in the last 2 decades. Despite these trends, positive cancer outcomes still lag behind patients without HIV, and many PLWH never receive appropriate cancer therapy. We explore the reasons for the epidemiologic shift that has been observed, as well as the factors that influence treatment disparities. Furthermore, several studies have demonstrated similar cancer survival rates when PLWH and certain cancers receive the same treatment as those who are HIV-negative. Among possible solutions to improve cancer outcomes include increasing the inclusion of PLWH in clinical trials, using guidelines specific for the treatment of HIV-associated malignancies, and incorporating a multidisciplinary approach to cancer management in PLWH.

Background Placental-site trophoblastic (PSTT) and epithelioid trophoblastic tumours (ETT) are the rarest malignant forms of gestational trophoblastic disease (GTD). Our prior work demonstrated that an interval of ≥48 months from the antecedent pregnancy was associated with 100% death rate, independent of the stage. Here, we assess whether modified treatments for these patients have increased survival and identify new prognostic factors. Methods The United Kingdom GTD database was screened to identify all PSTT/ETT cases diagnosed between 1973 and 2014. Data and survival outcomes from our prior patient cohort (1976–2006) were compared to our new modern cohort (2007–2014), when intensified treatments were introduced. Results Of 54,743 GTD patients, 125 (0.23%) were diagnosed with PSTT and/or ETT. Probability of survival at 5 and 10 years following treatment was 80% (95% CI 72.8–87.6%) and 75% (95% CI 66.3–84.3%), respectively. Univariate analysis identified five prognostic factors for reduced overall survival (age, FIGO stage, time since antecedent pregnancy, hCG level, mitotic index) of which stage IV disease (HR 6.18, 95% CI 1.61–23.81, p = 0.008) and interval ≥48 months since antecedent pregnancy (HR 14.57, 95% CI 4.17–50.96, p

Kaposi sarcoma herpesvirus (KSHV)-associated diseases (Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, and KSHV inflammatory cytokine syndrome) are associated with immune suppression and dysregulation and loss of KSHV-specific immunity. These diseases are most frequent in people living with HIV as well as those with primary or iatrogenic immune deficiencies. KSHV itself can modulate the immune system via viral homologs of host cytokines or downregulation of immune-surface markers altering host immune surveillance. These factors make KSHV-associated diseases prime targets for immunotherapy approaches. Several agents have been studied or are under investigation in KSHV-associated diseases, including monoclonal antibodies, immunomodulatory agents, and therapeutic cytokines. Here, we review the role of immunotherapies in KSHV-associated diseases.

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)–associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

2649 Background: PLWH and ca are inadequately represented in clinical trials evaluating ICI especially in the setting of low CD4 counts (ct) and elevated HIV viral loads (VL). We assembled an international cohort of PLWH and ca treated with ICI to evaluate toxicity profiles and clinical outcomes. Methods: We retrospectively collected data on 204 PLWH and ca receiving ≥ 1 cycle of ICI between 2015-2021 at 14 academic medical centers in the US and Europe. Immune-related adverse events (irAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) V5.0. Baseline CD4 ct, CD8 ct and HIV VL were collected within 3 months (mo) of ICI initiation when available. Fisher’s exact test was performed to compare categorical variables. Median (med) Overall Survival (OS) and Objective Response Rate (ORR) were calculated for 186 pts treated in the metastatic (met) setting. Results: Among 204 PLWH treated with ICI, 174 (85%) were cis-gender males. 61 (31%) were Black and 34 (18%) were Hispanic/Latinx. Pts were treated with pembrolizumab (n=93), nivolumab (n=71), atezolizumab (n= 20), nivolumab and ipilimumab (n=13), durvalumab (n=6), or avelumab (n=1). Med number of prior lines of systemic therapy was 1 (range: 0-5). Among pts with available baseline data, 36/133 (27%) had CD4 ct

Background There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly. Methods In an international, multicentre cohort study, outcomes for those aged Results Five thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p p p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p Conclusions Clinical outcomes in the elderly is equivalent to patients aged

Key Points Question Has inclusion of people living with HIV in anti–programmed death 1 and anti–programmed death ligand 1 (anti–PD1/PDL1) immunotherapy trials changed during ongoing Cancer Therapy Evaluation Program advocacy efforts by the National Cancer Institute? Findings In this quality improvement analysis of 87 anti–PD1/PDL1 trials approved by the Cancer Therapy Evaluation Program from January 2014 to May 2019, the proportion of studies including people living with HIV increased from 16% of letters of intent to 70% of approved protocols. Inclusion of people living with HIV on submitted letters of intent increased over time. Meaning This study’s findings suggest that the increasing inclusion rates of people living with HIV in anti–PD1/PDL1 clinical trials are encouraging and that advocacy for these and other underrepresented populations should continue., This quality improvement study evaluates trends in the inclusion of people living with HIV in anti–programmed death 1 and anti–programmed death ligand 1 (anti–PD1/PDL1) clinical trials concurrent with ongoing Cancer Therapy Evaluation Program efforts by the National Cancer Institute to promote inclusion of this patient population., Importance Anti–programmed death 1 and anti–programmed death ligand 1 (anti–PD1/PDL1) immune checkpoint blockade (ICB) constitutes the therapeutic backbone for multiple malignant neoplasms. People living with HIV (PLWH) have routinely been excluded from ICB clinical trials, thus inhibiting broad implementation of ICB to PLWH with cancer. Objective To evaluate trends in the inclusion of PLWH in ICB cancer clinical trials that have occurred in association with ongoing efforts by the Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, to promote inclusion of PLWH. Design, Setting, and Participants This quality improvement study of ICB letters of intent (LOIs) included anti–PD1/PDL1 agents (nivolumab, pembrolizumab, atezolizumab, and durvalumab) submitted to CTEP that proceeded to approved protocols between January 2014 to May 2019. The setting was ICB clinical trial development and inclusion of underrepresented populations, specifically PLWH. All 97 submitted cancer clinical trial LOIs that included the aforementioned ICB agents were eligible for inclusion. Ten proposals were excluded, of which 3 were designed specifically for PLWH and 7 were LOIs that did not advance to approved protocols within the study period. Statistical analysis was performed from April to September 2020. Exposures CTEP advocacy included the requirement for justification of exclusion of PLWH and formal discussion of inclusion criteria during conference calls between CTEP and trial investigators. Main Outcomes and Measures The frequency of inclusion of PLWH in initially submitted LOIs was compared with final approved protocols using descriptive statistics. The probability of inclusion of PLWH in submitted LOIs and approved protocols over time was assessed using logistic regression. Results Eighty-seven studies were included, of which 68 (78%) were pilot, phase 1, phase 1/2, or phase 2 studies and 19 (22%) were phase 2/3 or phase 3 studies. Thirty-nine studies (45%) included nivolumab, 23 (26%) included pembrolizumab, 19 (22%) included atezolizumab, and 6 (7%) included durvalumab. At initial LOI stage, 14 of 87 (16%) included PLWH. Following CTEP advocacy efforts, 61 of 87 protocols (70%) included PLWH. Of 36 LOIs to initially exclude PLWH, 24 (67%) included PLWH in final protocols. Among the 25 protocols to exclude PLWH, 21 (84%) were earlier phase studies (pilot to phase 2) and 4 (16%) were later phase studies (phase 2/3 to phase 3). Only 13 of 25 protocols (52%) provided justification for exclusion of PLWH, with safety being the most frequently cited concern (9 of 13 studies). The inclusion of PLWH on submitted LOIs increased over time (odds ratio, 3.38; 95% CI, 1.14-3.91), whereas inclusion on final protocols did not increase over time (odds ratio, 1.80; 95% CI, 0.81-1.59). Conclusions and Relevance This study identified encouraging trends in the inclusion of PLWH in anti–PD1/PDL1 cancer trials that occurred in the period following the initiation of CTEP advocacy. Work is needed to examine what impact this will have on enrollment of PLWH in such trials. Similar advocacy may help to promote inclusion of other underrepresented populations in cancer clinical trials, including those with organ dysfunction and chronic infections.

PURPOSE OF REVIEW: Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) pathway are a class of anti-cancer immunotherapy agents changing treatment paradigms of many cancers that occur at higher rates in people living with HIV (PLWH) than in the general population. However, PLWH have been excluded from most of the initial clinical trials with these agents. RECENT FINDINGS: Two recent prospective studies of anti-PD-1 agents, along with observational studies and a meta-analysis have demonstrated acceptable safety in PLWH. Preliminary evidence indicates activity in a range of tumors and across CD4(+) T-cell counts. SUMMARY: Safety and preliminary activity data suggest monoclonal antibodies targeting PD-1 or its ligand, PD-L1, are generally appropriate for PLWH and cancers for which there are FDA-approved indications. Ongoing and future trials of anti-PD-1 and anti PD-L1 therapy alone or in combination for HIV-associated cancers may further improve outcomes for this underserved population.

Kaposi sarcoma herpesvirus (KSHV) is the etiological agent of three malignancies, Kaposi sarcoma, primary effusion lymphoma and KSHV-associated multicentric Castelman disease. KSHV infected patients may also have an interleukin six-related KSHV-associated inflammatory cytokine syndrome. KSHV-associated diseases occur in only a minority of chronically KSHV-infected individuals and often in the setting of immunosuppression. Mechanisms by which KSHV genomic variations and systemic co-infections may affect the pathogenic pathways potentially leading to these diseases have not been well characterized in vivo. To date, the majority of comparative genetic analyses of KSHV have been focused on a few regions scattered across the viral genome. We used next-generation sequencing techniques to investigate the taxonomic groupings of viruses from malignant effusion samples from fourteen participants with advanced KSHV-related malignancies, including twelve with primary effusion lymphoma and two with Kaposi sarcoma and elevated KSHV viral load in effusions. The genomic diversity and evolutionary characteristics of nine isolated, near full-length KSHV genomes revealed extensive evidence of mosaic patterns across all these genomes. Further, our comprehensive NGS analysis allowed the identification of two distinct KSHV genome sequences in one individual, consistent with a dual infection. Overall, our results provide significant evidence for the contribution of KSHV phylogenomics to the origin of KSHV subtypes. This report points to a wider scope of studies to establish genome-wide patterns of sequence diversity and define the possible pathogenic role of sequence variations in KSHV-infected individuals.

Noncoding RNAs have substantial effects in host–virus interactions. Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs which can decoy other RNAs or RNA-binding proteins to inhibit their functions. The role of circRNAs is largely unknown in the context of Kaposi’s sarcoma herpesvirus (KSHV). We hypothesized that circRNAs influence viral infection by inhibiting host and/or viral factors. Transcriptome analysis of KSHV-infected primary endothelial cells and a B cell line identified human circRNAs that are differentially regulated upon infection. We confirmed the expression changes with divergent PCR primers and RNase R treatment of specific circRNAs. Ectopic expression of hsa_circ_0001400, a circRNA induced by infection, suppressed expression of key viral latent gene LANA and lytic gene RTA in KSHV de novo infections. Since human herpesviruses express noncoding RNAs like microRNAs, we searched for viral circRNAs encoded in the KSHV genome. We performed circRNA-Seq analysis with RNase R-treated, circRNA-enriched RNA from KSHV-infected cells. We identified multiple circRNAs encoded by the KSHV genome that are expressed in KSHV-infected endothelial cells and primary effusion lymphoma (PEL) cells. The KSHV circRNAs are located within ORFs of viral lytic genes, are up-regulated upon the induction of the lytic cycle, and alter cell growth. Viral circRNAs were also detected in lymph nodes from patients of KSHV-driven diseases such as PEL, Kaposi’s sarcoma, and multicentric Castleman’s disease. We revealed new host–virus interactions of circRNAs: human antiviral circRNAs are activated in response to KSHV infection, and viral circRNA expression is induced in the lytic phase of infection.

Background: Primary effusion lymphoma (PEL) is a rare, B cell non-Hodgkin lymphoma (NHL) caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8, that is strongly associated with HIV infection. PEL often presents as malignant body cavity effusions but can also present as extracavitary masses. Patients may also have concurrent Kaposi sarcoma (KS) or multicentric Castleman disease (MCD). 80% of PEL is also positive for EBV, and in a cohort of 20 patients we previously showed EBV + PEL had improved overall survival (OS) (Lurain et al. Blood 2019). PEL prognosis is poor compared to other HIV-associated NHL with median survival of 6-10 months. While patients are often treated with chemotherapy regimens used in other NHL, the optimal front-line and subsequent-line treatments are unknown. In this largest cohort of patients with PEL in the United States, we evaluated survival, prognostic markers, and second-line treatments in relapsed/refractory disease. Methods: We analyzed clinical records of all patients with PEL treated in the HIV and AIDS Malignancy Branch at the National Cancer Institute from 2000-2021. We collected demographics, disease characteristics, concurrent KS and MCD, EBV status of tumor by EBER staining, and laboratory data at diagnosis as well as at progression and subsequent lines of therapy. We calculated overall survival (OS) of all patients and progression-free survival (PFS) in those who received front-line EPOCH by Kaplan-Meier method. The survival of extracavitary vs. cavitary PEL was compared using an exact log-rank test. A univariate Cox proportional hazard model was performed to determine prognostic variables associated with OS. Results: We identified 40 patients with PEL: 38 cisgender men, 2 cisgender women; 18 non-Hispanic Black, 6 Hispanic, 16 non-Hispanic White; median age 41 years. At diagnosis of PEL, 29 patients had concurrent KS, and 7 had concurrent MCD. Eight patients had only extracavitary disease, and 5 had leptomeningeal disease. All but 1 had HIV, and all with HIV received antiretroviral therapy. At diagnosis, median HIV viral load (VL) was 50 (IQR: 27-8323) copies/mL, median CD4 + cell count was 100 (IQR:44-395) cells/µL, and median KSHV VL was 4147 copies/10 6 cells (IQR:178-68,526). One patient died prior to receiving treatment. Of the 39 patients who received front-line treatment, 38 received combination chemotherapy (EPOCH [36], CHOP [1], ICE [1]) with rituximab added in 34 patients to treat concurrent MCD or deplete the KSHV-infected B cell reservoir. One patient received pembrolizumab as up-front therapy due to concurrent progressive multifocal leukoencephalopathy. Twenty-three (57%) had complete remission (CR) by Lugano criteria. Median PFS after front-line EPOCH was 16.4 months (Figure 1a), and median OS in all patients was 35.6 months (Figure 1b), with 5-year OS of 44%. Median OS for patients with extracavitary disease was significantly higher than in patients with cavitary disease (p=0.023, Figure 1c). EBER-positive tumors (HR=0.21, p=0.005) were associated with improved survival, while concurrent KS, MCD, leptomeningeal disease, and baseline CD4 and KSHV VL were not associated with OS outcomes. Eleven patients with relapsed/refractory disease received second-line therapy, including combination chemotherapy (3); brentuximab (3); pembrolizumab (1); pembrolizumab and pomalidomide (1); interferon-alpha, ganciclovir, and bevacizumab (1); bortezomib, ganciclovir, and zidovudine (1); and radiation to pelvic lymph nodes (1). Five of these patients received subsequent treatment after disease progression, including 2 patients with leptomeningeal PEL, 1 who received daratumumab and 1 who received pomalidomide and pembrolizumab with ongoing CRs at 12 months and 33 months, respectively. Conclusion: Patients with PEL had a median OS of 35.6 months, which is improved from previous reports. Patients with extracavitary PEL appear to have improved OS, and we confirmed our prior study noting EBER-positive PEL is a positive prognostic marker. Promising chemotherapy-sparing treatment regimens in relapsed/refractory PEL, include pembrolizumab, pomalidomide, and daratumumab. Figure 1 Figure 1. Disclosures Uldrick: Regeneron: Current Employment; Roche: Research Funding; Merck: Other: Receives study drug; Celgene: Research Funding. Yarchoan: Celgene: Research Funding; Merck: Other: Clinical Trial Support; EMD-Serano: Other: Clinical Trial Support; Eli Lilly: Other: Clinical Trial Support; CTI BioPharma: Other: Clinical Trial Support; Janssen Pharmaceuticals: Other: Clinical Trial Support; U.S. Dept of Health and Human Services: Patents & Royalties. Lurain: EMD-Serrono: Research Funding; BMS-Celgene: Research Funding; CTI Biopharma: Research Funding; Merck: Research Funding; Janssen: Research Funding.

// Jessica A. Howell 1, 2, 3, * , David J. Pinato 1, * , Ramya Ramaswami 1 , Tadaaki Arizumi 4 , Carlotta Ferrari 5 , Antonello Gibbin 5 , Michela E. Burlone 5 , Giulia Guaschino 5 , Pierluigi Toniutto 6 , James Black 1 , Laura Sellers 1 , Masatoshi Kudo 4 , Mario Pirisi 5 and Rohini Sharma 1 1 Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK 2 Centre for Population Health, Burnet Institute, Melbourne, Australia 3 Department of Medicine, University of Melbourne, Melbourne, Australia 4 Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan 5 Department of Translational Medicine, Universita degli Studi del Piemonte Orientale “A. Avogadro”, Novara, Italy 6 Department of Experimental and Clinical Medicine, University of Udine, Udine, Italy * These authors have contributed equally to the work Correspondence to: Jessica A. Howell, email: jessica.howell@svha.org.au Keywords: liver cancer, VEGF inhibitor, CLIP score, BCLC, inflammation Received: March 30, 2016 Accepted: October 13, 2016 Published: February 14, 2017 ABSTRACT Background and Aims: Response to sorafenib is highly variable in hepatocellular carcinoma (HCC). Baseline inflammatory parameters and treatment toxicities may improve survival prediction in patients on sorafenib therapy. Results: 442 patients with advanced stage HCC on sorafenib were recruited (follow-up 5096 person-months at risk). 88% had BCLC stage B or greater HCC and 72.3% had Child-Pugh A cirrhosis. On Cox multivariate regression, previously-treated HCC (HR 0.579, 95% CI 0.385-0.872, p=0.009), Cancer of Liver Italian Program (CLIP) score (HR 1.723, 95% CI 1.462-2.047, p

Background: Primary effusion lymphoma (PEL) is a rare, aggressive B-cell neoplasm strongly associated with HIV infection. It generally presents with malignant effusions but may also present with extracavitary (EC) masses. It is caused by the gammaherpesvirus Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus 8), which is also responsible for the development of Kaposi sarcoma (KS) and a form of multicentric Castleman disease (MCD). There are no prospective studies in PEL and no standard therapy. Prognosis is poor compared to other HIV-associated lymphomas with median survival of 10-22 months when treated with conventional lymphoma chemotherapy regimens. In vitro data demonstrate lenalidomide (LEN), an immunomodulatory agent, downregulates IRF4, a cell activation marker overexpressed in PEL, and can reverse KSHV-induced downregulation of MHC-1 and ICAM-1. Dose-adjusted infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone combined with rituximab (EPOCH-R) has been shown to be safe and effective for CD20+ HIV-associated lymphomas. While PEL is generally CD20 negative, rituximab eradicates the KSHV-infected B-cell reservoir, a source of inflammatory cytokines that drive the natural history of PEL; moreover, many patients have concurrent MCD for which rituximab is a standard treatment. Methods: In a prospective phase 1/2 study conducted in the HIV and AIDS Malignancy Branch at the National Cancer Institute (NCI), we are evaluating EPOCH combined with rituximab and LEN (EPOCH-R2) in participants (pts) with untreated PEL. The primary objective was to evaluate safety and tolerability of EPOCH-R2 and determine the recommended phase 2 dose (RP2D) of LEN. PEL was diagnosed/confirmed in the NCI Laboratory of Pathology via cytology and/or flow cytometry of effusions or via biopsy in EC disease. Pts received EPOCH-R days 1-5 and every 21 days for 6 cycles. LEN was administered orally days 1-10 of each cycle starting at 25 mg (with dose de-escalation if toxicity occurred). Dose-limiting toxicities were evaluated during cycles 1-2. Pts with leptomeningeal PEL (CSF-PEL), determined by cytology and/or flow cytometry of cerebrospinal fluid, received intrathecal chemotherapy; intrathecal prophylaxis was given to pts without CSF-PEL. All pts received thromboprophylaxis (aspirin 81 mg daily), opportunistic infection prophylaxis, and antiretroviral therapy (ART). Adverse events (AEs) were evaluated using CTCAEv5 and treatment response was evaluated by Lugano criteria after cycles 2 and 6. Response to treatment, immune reconstitution, and overall survival (OS) were evaluated using descriptive statistics, Wilcoxon signed-rank test and Kaplan-Meier methodology. Results: We are reporting results of the completed Phase I portion of the trial. 6 HIV+ cisgender men (5 Black, 1 White) with stage 4 PEL were enrolled July 2017-August 2019. All received non-boosted integrase inhibitor-based ART. 3 had pleural effusions, 2 had EC disease without effusions, and 1 had both effusions and EC disease. 3 had CSF-PEL and 1 had bone marrow involvement. 4 had concurrent KS; 1 also had concurrent MCD. Median CD4+was 231 cells/µL (IQR: 10, 310) at baseline and 189.5 cell/µL (IQR: 56, 224) at end-of-treatment, which was not a significant decline (p=0.46). The most common AEs were hematologic, including grade (G) 4 neutropenia (100%), leukopenia (100%), thrombocytopenia (67%) and CD4+ lymphopenia (67%). 3 pts (50%) developed G3 pulmonary emboli despite thromboprophylaxis. There were 7 episodes of G3 febrile neutropenia and 2 episodes of sepsis. No pts developed opportunistic infections. There were no dose-limiting toxicities and LEN 25 mg is the RP2D. 4 pts completed all 6 cycles. 2 pts completed 5 cycles: 1 died due to progressive disease and 1 had progressive disease and went on to receive additional therapy. 1 pt who completed all 6 treatment cycles died due to HIV-related complications 5 months after EPOCH-R2 with no evidence of PEL at autopsy. The response rate was 83.3% (95% CI: 36.8-99.6) and 50% (95% CI: 11.8-88.1) after cycles 2 and 6, respectively. 2-year overall survival was 66.7% (95% CI:19.5-90.4). Conclusions: Front-line PEL treatment with EPOCH-R2 is safe, and the most common toxicities were hematologic. This regimen showed preliminary evidence of activity and good OS, which will be further evaluated in the ongoing phase 2. Disclosures Lurain: Celgene: Research Funding; EMD-Serrono: Research Funding; Merck: Research Funding. Ramaswami:Celgene: Research Funding; EMD-Serrono: Research Funding; Merck: Research Funding. Whitby:Patent: Patents & Royalties: Co-inventor on US Patent 10,001,483 entitled "Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers.. Uldrick:Patent: Patents & Royalties: Co-inventor on US Patent 10,001,483 entitled "Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers."; Celgene: Research Funding; Merck: Research Funding; Roche: Research Funding. Yarchoan:Patent: Patents & Royalties: Coinventor on patents on a peptide vaccine for HIV and on the treatment of Kaposi sarcoma with IL12; EMD-Serrono: Patents & Royalties; Patent: Patents & Royalties: Co-inventor on US Patent 10,001,483 entitled "Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers.; Patent: Patents & Royalties: An immediate family member of R. Yarchoan is a co-inventor on patents related to internalization of target receptors, on KSHV viral IL-6, and on the use of calreticulin and calreticulin fragments to inhibit angiogenesis; Celgene: Research Funding; Merck: Research Funding. OffLabel Disclosure: Dose-adjusted infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone combined with rituximab and lenalidomide for the use of primary effusion lymphoma will be discussed.