Abstract Background Scant PK data are available with CZA-ATM in combination. Occurrence of ALT/AST elevations are common with ATM, and it is unknown if it is exacerbated by use of CZA-ATM. This analysis of COMBINE sought to describe the popPK of CZA-ATM and to assess the association between ATM exposures and ALT/AST elevations. Methods COMBINE was a Phase I study of 48 healthy subjects aged 18-45 years (NCT03978091). Subjects were enrolled into 1 of 6 Cohorts (Table 1). Drug(s) were administered for 7 D and intensive plasma and urine PK sampling was performed. PopPK models were developed for ceftazidime (CAZ), avibactam (AVI), and ATM. Empirical Bayesian estimates from the ATM PopPK model were used to simulate ATM day 1 (D1) exposures. Associations between D1 ATM exposures and highest observed ALT/AST were assessed with curvilinear regression (CR) and generalized linear models (GLM). Results Of enrolled 48 subjects, 35% had ALT/AST elevations; 94% occurred in ATM/CZA-ATM Cohorts. Two severe study product related ALT/AST AEs were observed with in the continuous infusion (CI) ATM Cohort. All subjects with ALT/ATS elevations were asymptomatic with no other signs of liver injury. In the ATM PopPK model, CZA-ATM administration reduced ATM non-renal clearance (CLNR) by 1 L/hr (16% of total CL) (Table 2). Administration of CAZ-ATM had a negligible effect on total CAZ CL in the CAZ PopPK model and CZA-ATM was not a covariate in final AVI PopPK model. In the CR, no ATM exposure-ALT/AST associations were identified in overall analyses. Associations (R2=0.18-0.22, p< 0.05) between D1 AUC and ALT/AST were observed in CR analyses restricted to the intermittent infusion (II) ATM Cohorts (Figure 1). In GLM, D1 AUC was significantly associated with ALT/AST in the ATM II Cohort analyses. Administration of CZA-ATM was not associated with ALT/AST in the GLM analyses. Figure 1 Conclusion Administration of CZA-ATM was found to reduce ATM CL, resulting in higher daily ATM AUCs, but did not exacerbate AST/ALT elevations relative to ATM alone. The observed association between ATM AUC and ALT/AST elevations in subjects who received II ATM suggest the risks vs benefits of using II of ATM 8 g/daily vs 6 g/daily with CZA should be considered. Use of CI ATM should be used with caution given the 2 severe ALT/ASTs in the CI ATM Cohort. Disclosures Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant J Nicholas O'Donnell, Pharm.D., Merck & Co, Inc: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support Stephen Balevic, MD, Purdue Pharma: Grant/Research Support|UCB: Advisor/Consultant Jeffrey Guptill, MD, argenx: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds henry chambers, MD, Merck: DSMB member|Merck: Stocks/Bonds|Moderna: Stocks/Bonds.

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations.

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

The integrase strand transfer inhibitor (INSTI) dolutegravir is commonly used in combination antiretroviral therapy regimens and retains strong potency even with primary resistance mutations to some other INSTIs. Acquisition of accessory mutations to primary mutations results in significant increases in dolutegravir resistance. Previously, we reported that addition of the secondary mutation T97A can result in rapid treatment failure in individuals with INSTI mutations at positions 140 and 148. Here, we conducted a detailed case study of one of these individuals and find that T97A-containing HIV emerged from a large replicating population from only a few (≤4) viral lineages. When combined with primary INSTI resistance mutations, T97A provides a strong selective advantage; the finding that T97A-containing variants spread by replication and recombination, and persisted for months after discontinuing dolutegravir, has important implications as dolutegravir is rolled out worldwide.

OBJECTIVE: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.METHODS: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.RESULTS: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.CONCLUSION: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.

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 Non-Hodgkin’s lymphoma (NHL) is currently the most common malignancy among people living with HIV (PLWH) in the USA. NHL in PLWH is more frequently associated with oncogenic viruses than NHL in immunocompetent individuals and is generally associated with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less immunosuppressive than chemotherapy may decrease infection risk, improve immune control of oncogenic viruses, and ultimately allow for better lymphoma control.Methods We conducted a retrospective study of patients with HIV-associated lymphomas treated with pembrolizumab±pomalidomide in the HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute.Results We identified 10 patients with stage IV relapsed and/or primary refractory HIV-associated NHL who were treated with pembrolizumab, an immune checkpoint inihibitor, with or without pomalidomide. Five patients had primary effusion lymphoma (PEL): one had germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL); two had non-GCB DLBCL; one had aggressive B cell lymphoma, not otherwise specified; and one had plasmablastic lymphoma. Six patients received pembrolizumab alone at 200 mg intravenously every 3 weeks, three received pembrolizumab 200 mg intravenously every 4 weeks plus pomalidomide 4 mg orally every day for days 1–21 of a 28-day cycle; and one sequentially received pembrolizumab alone and then pomalidomide alone. The response rate was 50% with particular benefit in gammaherpesvirus-associated tumors. The progression-free survival was 4.1 months (95% CI: 1.3 to 12.4) and overall survival was 14.7 months (95% CI: 2.96 to not reached). Three patients with PEL had leptomeningeal disease: one had a complete response and the other two had long-term disease control. There were four immune-related adverse events (irAEs), all CTCAEv5 grade 2–3; three of the four patients were able to continue receiving pembrolizumab. No irAEs occurred in patients receiving the combination of pembrolizumab and pomalidomide.Conclusions Treatment of HIV-associated NHL with pembrolizumab with or without pomalidomide elicited responses in several subtypes of HIV-associated NHL. This approach is worth further study in PLWH and NHL.

Juvenile dermatomyositis (JDM) is a systemic vasculopathy with weakness and rash, frequently exhibiting a chronic/polycyclic course, and treated with broad immunosuppression. An interferon (IFN) signature correlates with disease activity.1 Interferonopathies have been successfully targeted by janus kinase (JAK) inhibitors.2 3 We report the first comprehensive prospective evaluation of JAK inhibition (baricitinib) in JDM. Four patients (5.8–20.7 years old), with chronically active JDM (≥3/6 core set measures)4 who had failed three to six immunomodulatory medications, were enroled on compassionate use study NCT01724580 (online supplementary methods, online supplementary table 1). Biologics other than intravenous immunoglobulin were washed out and other medications continued.### Supplementary data [annrheumdis-2020-218690supp001.pdf] Subjects were assessed before and 4, 8, 12 and 24 weeks after starting baricitinib (4–8 mg/day divided two times per day) dosed by weight and renal function.3 Significant improvement was noted by week 4 in Physician Global Activity, Patient/Parent Global Activity, and Extramuscular Global Activity, and Cutaneous Dermatomyositis Disease Area and Severity Index (figure 1, online supplementary table 2). Two patients with baseline weakness improved by week 4 (ACR/EULAR Myositis Response Criteria) and showed clinically relevant improvement in Manual Muscle Testing-8 by week 8, confirmed by blinded MRI assessment (online supplementary figures 1 and 2). There was no significant change in muscle enzymes (online supplementary table 3), though some had variable elevations with stable/improved strength. Daily corticosteroids were decreased (0.28 to 0.18 mg/kg/day); other immunosuppressive medications were decreased/discontinued (online supplementary table 1). There were no flares/worsening requiring increased immunosuppression. There was no notable change in calcinosis (n=2). Figure 1 Change in disease activity and pharmacodynamic markers on baricitinib treatment. (A–D) Multiple clinical assessments are shown at …

This prospective cohort study enrolled people living with HIV initiating antiretroviral therapy (ART) containing the integrase inhibitors, dolutegravir (DTG) or elvitegravir (EVG) and administered the Montreal Cognitive Assessment (MoCA) at baseline and again after approximately six months to compare changes in MoCA scores. The proportion of patients found to have cognitive impairment, as indicated by a MoCA score <26/30, on each agent were also compared and comparisons were made between changes in each domain assessed by the MoCA (visuospatial/executive, naming, attention, language, abstraction, delayed recall, and orientation). Thirty-five evaluable participants were enrolled, 18 on DTG and 17 on EVG. The median [interquartile range(IQR)] age was 44 (32 to 54) years, 63% were male, 57% were African American. The median (IQR) MoCA score at baseline was 25 (23 to 27) with no difference between groups (p=0.249). The median (IQR) change in MoCA score was 0 (-1 to 2) for DTG and 1 (0 to 3) for EVG (p = 0.183). Of those on DTG, 8 (44%) had MoCA scores <26 on follow-up compared to 11 (65%) on EVG (p = 0.229). There were no significant differences in changes in any of the individual MoCA domains.

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. 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.

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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

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.

The rapid advances in drug discovery and the development of antiretroviral therapy is unprecedented in the history of modern medicine. The administration of chronic combination antiretroviral therapy targeting different stages of the human immunodeficiency virus’ replicative life cycle allows for durable and maximal suppression of plasma viremia. This suppression has resulted in dramatic improvement of patient survival. This article reviews the history of antiretroviral drug development and discusses the clinical pharmacology, efficacy, and toxicities of the antiretroviral agents most commonly used in clinical practice to date.