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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.

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.

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.

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.

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.

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.

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.

11552 Background: Kaposi sarcoma herpesvirus (KSHV, also known as human herpesvirus 8 [HHV-8]), is the causative agent of Kaposi sarcoma (KS), a multicentric angioproliferative tumor, a form of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). KS can be difficult to treat when it occurs with KSHV-MCD or KICS; resulting in high mortality rates. Liposomal doxorubicin (LD) is an FDA-approved treatment for KS. Pomalidomide, an oral immunomodulatory drug, is safe and has demonstrated activity in KS, but the activity of the combination (pomalidomide+LD) in KS alone or with KSHV-associated diseases is unknown. Methods: The primary objective was to evaluate safety and tolerability of pomalidomide+LD in two groups of patients with KS requiring systemic therapy: Group I (GI)- KS alone; Group II (GII)- KS with concurrent KSHV-MCD or KICS. Patients received LD at 20 mg/m2 intravenously on day 1 of a 28-day cycle combined with pomalidomide once daily on days 1 to 21 at escalating dose levels (DL) (I - 2mg, II - 3mg, or III- 4mg) in a 3+3 design until plateau of response or other pre-specified criteria. Patients received 81mg of aspirin daily as thromboprophylaxis. KS responses were evaluated using the modified AIDS Clinical Trial Group criteria. Results: Thirty-four cisgender men, all with T1-stage KS [21 patients (62%) in GI and 13 patients (38%) in GII] were treated; 32 (94%) were HIV-infected and 22 (65%) had prior chemotherapy for KS (15/21 GI and 7/13 GII). There were no dose-limiting toxicities (DLTs) at DLIII for GI, and additional patients were treated at DLIII. In GII, grade 3 rash and pharyngeal edema were DLTs observed at 3mg of pomalidomide. Overall a median of 6 cycles were administered; the most common grade 3/4 toxicity was neutropenia. Among evaluable patients receiving >2 cycles,17/21 patients in GI had a response (all partial) (81% [95% confidence interval (CI) 58-95%]) and 5/10 patients in GII had a response (4 partial and 1 complete) (50% [95% CI 19-81%]). Conclusions: Pomalidomide+LD was well-tolerated and active in heavily pretreated patients with KS alone. In patients with KS and other KSHV-associated diseases, activity was noted but less well-tolerated. Clinical trial information: NCT02659930 .

Primary effusion lymphoma (PEL) is a rare, aggressive B-cell neoplasm with a unique clinical profile that is most frequently associated with HIV infection. It generally presents with malignant effusions but may also present with extracavitary masses. It is caused by the gamma-herpesvirus Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus-8 [HHV-8]), which is also the etiologic agent of Kaposi sarcoma and the plasmablastic form of multicentric Castleman disease (KSHV-MCD). KSHV is known to cause cytokine related severe inflammation associated with elevated human interleukin (IL)-6 and IL-10. There have been no prospective studies in PEL and there is currently no standard therapy for this disease. The prognosis of PEL is poor compared to other HIV-associated lymphomas. PEL has a median survival of 10-22 months when treated with conventional chemotherapy regimens for non-Hodgkin lymphoma according to the most recent retrospective reports. Lenalidomide, a derivative of thalidomide with immunomodulatory activity, has been shown to have in vitro antitumor effects in PEL cell lines. KSHV itself may cause downregulation of immune surface markers as a way to avoid immune detection. Lenalidomide can reverse this and enhance surface expression of major histocompatibility complex-1 and intercellular adhesion molecule-1 in PEL cell lines. Dose-adjusted infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone (DA-EPOCH) is an anthracycline-based regimen that allows for personalization of dose-intensity, and prior anecdotal experience indicates it has activity in PEL. In combination with rituximab, an anti-CD20 monoclonal antibody, DA-EPOCH has been shown to be safe and effective for HIV-associated diffuse large B-cell lymphoma and Burkitt lymphoma. PEL is a CD20 negative tumor; however, many patients have concurrent KSHV-MCD for which rituximab is the standard treatment. In addition, rituximab may aid in eradication of the KSHV B-cell reservoir, a source of inflammatory cytokines that drive the natural history of PEL. Patients of any HIV serostatus with both effusion and extracavitary presentations, including those with concurrent KSHV-associated diseases, such as Kaposi sarcoma and KSHV-MCD, are eligible. Patients with ECOG performance status of ≤4 are eligible for enrollment. The phase I portion of the study will evaluate the safety, tolerability, and maximum tolerated dose of lenalidomide combined with DA-EPOCH and rituximab (DA-EPOCH-R2). The phase II component will evaluate the activity and overall survival. Patients will receive 6, 21-day cycles of DA-EPOCH-R2. Lenalidomide, initially at 25 mg, will be given on days 1 to 10. Patients will receive rituximab on day 1 and DA-EPOCH on days 1 to 5. Patients with HIV will be prescribed antiretroviral therapy as this is central to controlling HIV viremia and managing KSHV-associated malignancies. The lenalidomide dose will be de-escalated in a second dose group if 2 of 6 patients in phase 1 experience a dose-limiting toxicity. In the phase II portion of the study, 15 evaluable patients will be enrolled at the maximal tolerated dose of lenalidomide. At 12 months follow-up after the last patient has enrolled, a 1-tailed 0.10 alpha level test would have 80% power to determine if the overall survival curve would demonstrate a 1-year overall survival consistent with 45% or better and ruling out 20% or worse survival. Secondary outcomes include the evaluation of the pharmacokinetics of lenalidomide in blood, effusions, and CSF and the effect of DA-EPOCH-R2on concurrent KS, KSHV-MCD, and the KSHV-associated inflammatory cytokine syndrome. The study will also examine the effect of lenalidomide alone and in combination with rituximab and DA-EPOCH on the KSHV viral load, serum cytokines, lymphocyte subset reconstitution, HIV latency reversal, cellular measures of HIV, and the pharmacokinetics of tenofovir and tenofovir-diphosphate in plasma and peripheral blood mononuclear cells. The study began enrollment in July 2017, and 5 patients have been enrolled on the phase I portion. All 5 patients have completed treatment without dose limiting toxicities. Disclosures Lurain: Celgene: Other: I receive research support from Celgene through a CRADA at the NCI; Merck: Other: I receive drug for a clinical trial from Merck through a CRADA with the NCI. Ramaswami:Celgene: Other: I receive research support from Celgene through a CRADA at the NCI; Merck: Other: I receive drug for a clinical trial from Merck through a CRADA with the NCI. 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 bio- markers.". Uldrick:Merck: Other: drug for a clinical trial from Merck through a CRADA with the NCI; Roche: Other: commercial research support through a CTA with Fred Hutchinson Cancer Research Center; Celgene: Other: research support from Celgene through a CRADA at the NCI; Patent: Patents & Royalties: co-inventor on US Patent 10,001,483 entitled . Yarchoan:Celgene: Other: I research support from Celgene through a CRADA at the NCI; Merck: Other: I receive drug for a clinical trial from Merck through a CRADA with the NCI; Patent: Patents & Royalties: coinventor on US Patent 10,001,483 entitled ; Patent: Patents & Royalties: coinventor on patents on a peptide vaccine for HIV and on the treatment of Kaposi sarcoma with IL12; Patent: Patents & Royalties: immediate family member is co-inventor on patents related to internal- ization of target receptors, on KSHV viral IL6, and on the use of calreticulin and calreticulin fragments to inhibit angiogenesis.

BACKGROUND: Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a rare lymphoproliferative disorder that occurs primarily in HIV-infected patients and is characterized by inflammatory symptoms with a waxing and waning course. If untreated, it leads to multiorgan failure and death, usually within 2 years. KSHV-MCD symptoms are caused by increased levels of inflammatory cytokines, including human interleukins (IL) 6 and 10, and a KSHV-encoded IL-6 analog (vIL-6). Rituximab is an effective therapy in KSHV-MCD but can result in the development or worsening of Kaposi sarcoma (KS) in those with concurrent diagnoses. Other therapies include rituximab plus liposomal doxorubicin and zidovudine (AZT) plus valganciclovir (VGC). Tocilizumab, a humanized anti-IL-6 receptor (gp80) antibody, has demonstrated benefit in KSHV-negative MCD, although its utility in patients with KSHV-MCD is unknown. We explored the safety and efficacy of tocilizumab in KSHV-MCD and the effect of the addition of AZT and VGC in cases where tocilizumab alone does not lead to clinical benefit. PATIENTS & METHODS: Patients enrolled on this prospective pilot study had symptomatic KSHV-MCD. They received 8mg/kg of tocilizumab every 2 weeks for up to 12 weeks, or 6 cycles. Patients with HIV were required to continue antiretroviral therapy. Treatment responses were assessed using a KSHV-MCD clinical benefit response (CBR) criteria, which consists of 8 indicator abnormalities (4 symptom groups and 4 laboratory parameters) that are closely associated with disease activity. If patients had evidence of progression or lack of improvement with tocilizumab monotherapy, AZT 600mg orally every 6 hours and VGC 900mg orally every 12 hours on days 1-5 of a 14-day cycle could be administered with tocilizumab. Peripheral blood mononuclear cell (PBMC)-associated KSHV viral loads were quantified by PCR using primers to the KSHV gene K6 after each cycle of treatment. The primary objective of the study was to estimate the clinical benefit of tocilizumab in patients with symptomatic KSHV-MCD using a modified KSHV-MCD CBR criteria. RESULTS: Eight HIV positive patients (7 male, 1 female) with a median age of 48.8 years were enrolled. All patients were taking combined antiretroviral therapy and had a baseline CD4+ T cell count of 254 cells/mL. Four patients (50%) had prior KSHV-MCD therapy with rituximab and 3 patients (38%) had KS at the time of enrollment. With tocilizumab alone, the overall response rate (partial and complete responses using the CBR criteria for all patients was 63% (95% confidence interval 25% to 92%). Three patients required the addition of AZT and VGC; one patient required AZT and VGC after 1 cycle and 2 required the combination treatment after 3 cycles of tocilizumab. Two out of 3 patients had a complete response after the addition of AZT and VGC to tocilizumab. Among all patients, 3 patients stopped therapy prior to 6 cycle due to progression of symptoms despite combination therapy, worsening pulmonary KS symptoms and deterioration in performance status due to progressive KSHV-MCD. Two remaining patients with concurrent KS had stable disease at the end of treatment. Among all patients, the median time to next therapy for symptomatic KSHV-MCD was 3.2 months (range 1 - 37 months); subsequent therapies included rituximab alone (3 patients), or in combination with liposomal doxorubicin (2 patients), or treatment with pomalidomide and liposomal doxorubicin (2 patients). One patient had a durable complete response over 3 years of follow-up. Treatment was well tolerated; the most common grade 3 and 4 adverse events included thrombocytopenia and neutropenia as well as hyperuricaemia, which were attributed to KSHV-MCD rather than study therapies. Furthermore, tocilizumab alone or in combination with AZT and VGC did not interfere with the CD4+ T cell count (net increase of 16 cells cells/mL) or HIV viral load. There was an overall decrease in KSHV viral load of 4577 copies/mL from baseline to the final cycle, reflecting clinical response. CONCLUSION: Tocilizumab is safe in patients with HIV and may have a role in the management of symptoms associated with KSHV-MCD. Incomplete responses to tocilizumab may occur because tocilizumab binds to the gp80 IL-6 receptor and KSHV vIL-6 can bind to the gp130 receptor subunit without the requirement for gp80. The addition of AZT and VGC to tocilizumab also showed clinical benefit. Disclosures Uldrick: Celgene: Research Funding; Celgene: Patents & Royalties: 10,001,483 B2; Merck: Research Funding. Yarchoan:NIH: Patents & Royalties: Patents on IL-12 for KS and cereblon-binding drugs for KSHV diseases. Spouse has patent on KSHV IL-6. Patents assigned to DHHS/NIH.; Celgene Corp.: Research Funding.

BACKGROUND: Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus-8) is the causative agent of 3 disorders: primary effusion lymphoma (PEL), Kaposi sarcoma (KS), and a plasmablastic form of multicentric Castleman disease (KSHV-MCD). It also causes KSHV inflammatory cytokine syndrome (KICS), which is characterized by inflammatory symptoms and an elevated KSHV viral load. Multiple KSHV-associated diseases, which usually develop in HIV-infected patients, can present together in the same patient. Effusions can occur in each of these diseases, thereby presenting a diagnostic challenge. Identifying PEL is especially crucial as prompt treatment with multi-agent chemotherapy can be curative. We analyzed effusions from patients with KICS, PEL, and KSHV-MCD to identify distinct immunologic characteristics and virologic profiles that may aid diagnosis, inform treatment and elucidate pathogenesis. PATIENTS AND METHODS: We identified 22 HIV-infected patients with effusions [pleural effusions (20), ascites (1) and pericardial effusion (1)] with diagnoses of PEL (9 patients), KICS (8 patients), or KSHV-MCD (5 patients). All patients had a concurrent diagnosis of KS. We obtained clinical and immunologic characteristics from effusions and paired serum samples at the same timepoint for each patient. Serum and effusion cytokine levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, and IL-12p70; interferon gamma (IFN-g); tumor necrosis factor alpha (TNF-a); vascular endothelial growth factor (VEGF); and inducible protein 10 (IP-10) were evaluated using a commercial multiplex assay. Peripheral blood mononuclear cell (PBMC) and effusion- associated KSHV and Epstein Barr virus (EBV) viral DNA (KSHV-VL, EBV-VL) in PBMC and cells were quantified using PCR with primers to KSHV K6 and EBV pol. Effusion and serum immunologic and virologic characteristics were compared within each disease and separately between diseases using the Wilcoxon sign rank test and Wilcoxon rank sum test, respectively. In these exploratory analyses with few patients, no correction was made for multiple comparisons. RESULTS: In patients with PEL, the median (med) age was 42 years with med CD4+ count of 54 T-cells/μL and HIV viral load (VL) of 325 copies/mL. In those with KICS, the med age was 32 years, with a med CD4+ count of 119 T-cells/μL and HIV VL of 48 copies/mL. In patients with KSHV-MCD, the med age was 31 years, med CD4+ count of 118 T-cells/μL and HIV VL was 75 copies/mL. IL-13 was substantially higher in PEL effusions as compared to serum levels (med 16.9 vs. In analyses comparing serum and cytokine differences among diseases, effusions from patients with PEL had detectable levels of IL-13 (med 16.9 ng/ml; interquartile range 9.7-26.9 ng/ml) compared to patients with KSHV-MCD (med CONCLUSIONS: In HIV-infected patients, effusions can indicate a diagnosis of PEL, KSHV-MCD and/or KICS. Quantifying KSHV VL in the effusion may be useful in the diagnosis of PEL. Effusions in PEL had a distinct profile compared to the circulation or other KSHV-associated diseases, particularly with regard to elevated IL-13, which may aid in diagnosis. In contrast, the inflammatory and virologic findings in KSHV-MCD and KICS effusions roughly paralleled the levels seen in the circulation. This study suggests that KSHV upregulation of IL-13 is a unique feature of PEL, which may contribute to PEL pathogenesis through STAT6 activation and be a potential future therapeutic target. Disclosures Uldrick: Celgene: Patents & Royalties: 10,001,483 B2; Celgene: Research Funding; Merck: Research Funding. Yarchoan:Celgene Corp.: Research Funding; NIH: Patents & Royalties: Patents on IL-12 for KS and cereblon-binding drugs for KSHV diseases. Spouse has patent on KSHV IL-6. Patents assigned to DHHS/NIH..

BACKGROUND: HIV-associated primary central nervous system lymphoma (HIV-PCNSL) is an AIDS-defining cancer. Tumors occur in patients with very low CD4+ counts, and tumors are almost always Epstein-Barr virus (EBV) infected. Overall survival (OS) has improved over time with antiretroviral therapy (ART)-associated immune reconstitution but is still generally less than 1 year. Treatment has traditionally included whole brain radiation, which can lead to devastating long-term neurotoxicity, including cognitive decline. ART has made it possible to treat patients with curative-intent, but radiation-sparing approaches have not been studied prospectively in HIV-PCNSL. METHODS: In a prospective phase II pilot study conducted in the HIV & AIDS Malignancy Branch at the National Cancer Institute, we evaluated curative-intent radiation-sparing immunochemotherapy in patients with untreated HIV-PCNSL (NCT00267865). Patients with HIV-PCNSL received ART, rituximab (375 mg/m2) and HD-MTX (6 g/m2) with leucovorin rescue (R-HD-MTX). Responses were evaluated by modified International Working Group Response Criteria for PCNSL after 6 cycles of induction R-HD-MTX and patients with a complete response (CR) received 2 consolidation cycles of R-HD-MTX. Patients with poor renal or cardiac function who were not eligible to receive HD-MTX at enrollment, received ART, rituximab and best-available radiation-sparing care. The primary objective of the study was to estimate the percentage of patients receiving ART and R-HD-MTX alive without recurrent lymphoma at two years. Response to treatment, immune reconstitution, and OS were evaluated using descriptive statistics and Kaplan-Meier methodology. RESULTS: Twelve patients were enrolled between September 2006 and June 2016. One enrolled patient was initially ineligible to receive HD-MTX due to renal dysfunction and received rituximab with temozolomide (TMZ) 150 mg/m2 for 5 days for one cycle followed by 6 cycles of R-HD-MTX + TMZ and 2 consolidation cycles of R-HD-MTX. Patient characteristics: 9 men, 3 women; median (med) age 33 years (range: 21-55); 8 African-American, 3 Hispanic, 1 white non-Hispanic; med Eastern Cooperative Oncology Group performance status 2 (1-3); med baseline Mini Mental State Examination (MMSE, maximum score = 30) was 22 (range: 5-29). Only 4 patients were on ART prior to diagnosis, and all but 1 had been on ART less than 4 months. Med time from HIV infection to PCNSL diagnosis was 30 weeks (range: 0-23 years). Med CD4+ T-cell count at PCNSL diagnosis was 16 cells/µL (0-409). Diagnosis of PCNSL was biopsy-confirmed (11) or made by 18fludeoxyglucose positron emission tomography/cerebral spinal fluid (CSF) EBV viral load criteria (1). 11/12 tumors were EBV positive. Flow cytometry showed leptomeningeal disease in 4 patients. Three had concurrent CNS infections, including Cryptococcus, histoplasmosis, and CMV retinitis. Ten were evaluable for response to R-HD-MTX induction. Two patients received only 1 cycle of therapy and were not evaluable due to treatment failure (TF). Responses after R-HD-MTX induction: CR (5), partial response (PR) (4) and progressive disease (PD) (1). Two patients with a PR received second-line TMZ at end of R-HD-MTX and obtained a subsequent CR. The patient with PD received second-line therapy with the Cancer and Leukemia Group B 50202 induction regimen and obtained a subsequent CR. There were 4 deaths on study: 1 pulmonary embolism, 1 CNS fungal infection in setting of PD, 2 TF. Eight patients (67%), including 3 patients who received second line therapy, obtained a durable CR. Med CD4+ T-cell increase following R-HD-MTX induction was +35 cells/uL (range: -54 - +369). In surviving patients, med MMSE after R-HD-MTX was 28 (27-30). For all patients, estimated 60-month OS was 66% (95% CI: 32-86%) with med potential follow-up of 82 months. Med OS was not reached. CONCLUSIONS:Treatment with ART and R-HD-MTX is associated with a high response rate, CD4+ immune reconstitution, preserved cognition, and improved OS, even in a high-risk patient population. Disclosures Uldrick: Celgene: Patents & Royalties: 10,001,483 B2; Celgene: Research Funding; Merck: Research Funding. Yarchoan:NIH: Patents & Royalties: Patents on IL-12 for KS and cereblon-binding drugs for KSHV diseases. Spouse has patent on KSHV IL-6. Patents assigned to DHHS/NIH.; Celgene Corp.: Research Funding.