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BK polyomavirus (BKPyV) has been associated with hemorrhagic cystitis (HC) after allogeneic hematopoietic cell transplantation (HCT), but the natural history of HC and factors associated with the clinical course are incompletely understood. We retrospectively analyzed allogeneic HCT patients transplanted from 2007-2017 who presented after platelet engraftment or after day 28 post-HCT with BKPyV-associated HC (BKPyV-HC), which was defined as a positive urine BKPyV PCR, ≥1 plasma BKPyV viral load result, and macroscopic hematuria (Bedi grade ≥2). Factors associated with resolution of macroscopic hematuria and resolution of all cystitis symptoms within 90 days after HC diagnosis were investigated in multivariable models. In 128 patients with BKPyV-HC, the median times from diagnosis to resolution of all symptoms, macroscopic hematuria, and urinary clots (present in 55% [71/128]) were 24 days (15-44), 17 days (10-30), and 14 days (5-26), respectively. Ninety percent of patients had BKPyV viremia at the onset of HC with a median viral load of 1850 copies/mL (interquartile range, 240-8550). In multivariable models, high plasma viral load (≥10 000 copies/mL) and cytopenias at the beginning of BKPyV-HC were significantly associated with longer macroscopic hematuria and cystitis symptoms. Use of cidofovir was not associated with shorter duration of illness. In conclusion, BKPyV-HC after allogeneic HCT is characterized by prolonged and severe symptoms and requires improved management strategies. High-grade viremia and cytopenias were associated with a longer duration of BKPyV-associated HC. Accurate descriptions of disease and factors associated with prolonged recovery will inform end points of future clinical trials.

Adenovirus (AdV) is an increasingly recognized threat to recipients of allogeneic hematopoietic stem cell transplantation (allo-HCT), particularly when infection is prolonged and unresolved. AdVance is the first multinational, multicenter study to evaluate the incidence of AdV infection in both pediatric and adult allo-HCT recipients across European transplantation centers. Medical records for patients undergoing first allo-HCT between January 2013 and September 2015 at 50 participating centers were reviewed. The cumulative incidence of AdV infection (in any sample using any assay) during the 6 months after allo-HCT was 32% (95% confidence interval [CI], 30.9% to 33.4%) among pediatric allo-HCT recipients (n = 1736) and 6% (95% CI, 4.7% to 6.4%) among adult allo-HCT recipients (n = 2540). The incidence of AdV viremia ≥1000copies/mL (a common threshold for initiation of preemptive treatment) was 14% (95% CI, 13.0% to 14.8%) in pediatric recipients and 1.5% (95% CI, 1.1% to 2.0%) in adult recipients. Baseline risk factors for developing AdV viremia ≥1000copies/mL included younger age, use of T cell depletion, and donor type other than matched related. Baseline demographic factors were broadly comparable across patients of all ages and identified by multivariate analyses. Notably, the incidence of AdV infection decreased stepwise with increasing age; younger adults (age 18 to 34 years) had a similar incidence as older pediatric patients (18 years). This study provides a contemporary multicenter understanding of the incidence and risk factors for AdV infection following allo-HCT. Our findings may help optimize infection screening and intervention criteria, particularly for younger at-risk adults.

BACKGROUND Recurrent glioblastoma (rGBM) is rapidly fatal with current therapies. PVSRIPO is an intratumoral immunotherapy targeting CD155 on antigen-presenting and malignant cells of solid tumors. Preclinically, PVSRIPO treatment leads to systemic, tumor antigen-specific, polyfunctional T-cell–mediated anti-tumor response, predominately driven by type I/III interferons. This inflammatory signature generates anti-tumor immunity and upregulates the programmed death (PD)-1 immune checkpoint in the tumor microenvironment. Preclinical models (including GBM) have shown that PVSRIPO+anti-PD-1/L1 therapy was more efficacious than either agent alone, warranting further investigation. METHODS Adults with histologically confirmed rGBM (1-2 prior progressions), Karnofsky performance status (KPS) ≥70, and an active, supratentorial, contrast-enhancing lesion (1-5.5 cm), received PVSRIPO (5x107 TCID50) intratumorally via convection-enhanced delivery (Day 1), followed by 200 mg pembrolizumab IV at week 2, given every 3 weeks for up to 24 months, to evaluate the safety/efficacy of the combination. A safety lead-in period (n=3-6) with a minimum 21–28-day delay before treatment of subsequent patients was planned, with a data safety monitoring board (DSMB) evaluating safety/tolerability prior to expansion (up to N=30). RESULTS The first 3 patients enrolled (ages 55-60, KPS 90-100) all received PVSRIPO followed by pembrolizumab (1-5 cycles), as planned. At cutoff (26-106 days of follow-up), there were no dose-limiting toxicities, treatment-emergent (TE) serious adverse events (SAE), or TEAEs necessitating a delay in initial/subsequent pembrolizumab treatments. All patients experienced a related TEAE, all grade 1 or 2 in severity. One patient experienced an AE of special interest (peritumoral edema, resulting in headache and hemiparesis), successfully managed with low-dose bevacizumab and corticosteroids. The DSMB unanimously recommended the study proceed without modification. CONCLUSIONS Intratumoral PVSRIPO+pembrolizumab was reasonably well tolerated, warranting continued investigation of the safety and efficacy of this combination in patients with rGBM.

Background: PVSRIPO, a novel intratumoral viral immunotherapy, infects cells via CD155, which is widely expressed on solid tumors and antigen-presenting cells (APC). Infection is lethal in malignant cells, but a unique, activating, nonlethal infection of local APCs yields type-I/III interferon (IFN)-dominant inflammation with subsequent anti-tumor T-cell priming and activation. In preclinical models, PVSRIPO-dependent inflammation upregulated the PD-1/L1 pathway, and greater anti-tumor response was observed with PVSRIPO + anti-PD-1/L1 (αPD-1/L1). Promising clinical activity with PVSRIPO monotherapy was observed in patients (pts) with recurrent glioblastoma and advanced αPD-1–refractory melanoma (Desjardins 2018 NEJM, Beasley 2021 JITC). Collectively, these results warrant further clinical investigation of PVSRIPO ± αPD-1/L1. Trial design, objectives, and eligibility criteria: LUMINOS-103 (NCT04690699) is a phase (Ph) 1/2, open-label, multi-center, single-arm basket trial evaluating repeat administration of PVSRIPO ± αPD-1/L1 in adults with solid tumors. Trial objectives are to assess the safety and tolerability of PVSRIPO monotherapy in each cohort in Ph 1 and the safety, tolerability, and antitumor efficacy of PVSRIPO + αPD-1/L1 in each cohort in Ph 2. The first two study cohorts include pts with muscle-invasive bladder cancer being treated in the neoadjuvant setting (A) and pts with metastatic bladder cancer being treated in the 1st/2nd line setting (B); these cohorts have been described previously (Inman 2021 Virtual AACR Annual Meeting). Cohort C includes pts with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) being treated in the neoadjuvant setting; Cohort D includes pts with recurrent/metastatic HNSCC with a PD-L1 Combined Positive Score ≥1 being treated in the 1st line setting. Eligibility: HNSCC pts must have histologically or cytologically proven SCC of the oral cavity, oropharynx, hypopharynx, or larynx. All pts must have prior and boosted PV immunization and tumors amenable to injection and biopsy. Key exclusion criteria: Requirement for oxygen supplementation, systemic or intratumoral therapy ≤6 months prior to the first dose of study drug, CNS metastases requiring immediate treatment, systemic immunosuppressive medications ≤4 weeks prior to the first dose of study drug, and severe active comorbidities. Pts who are HIV+, HBV+ or HCV+ are eligible provided they meet certain criteria. Endpoints: Primary endpoints include safety (all), tolerability (all), surgical complication rate (A, C), pathologic treatment effect/response (A, C), and objective response rate (B, D). Secondary endpoints include overall survival (all), pathologic downstaging and relapse-free survival (A, C), duration of response and progression-free survival (B, D), and assessment of tumor/blood biomarkers (all). Citation Format: Brant A. Inman, Matthew I. Milowsky, Raj S. Pruthi, Marshall Posner, Melissa J. Polasek, Shannon R. Morris, Lori Mixson, Kristin Orr, Elizabeth M. H. Woodson, Andrea T. Kelly, W. Garrett Nichols, Arjun V. Balar. LUMINOS-103: A basket trial evaluating the safety and efficacy of PVSRIPO and PVSRIPO in combination with anti-PD-1/L1 checkpoint inhibitors in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P045.

BACKGROUND Recurrent glioblastoma (rGBM) is rapidly fatal (median overall survival [mOS] of ~9 months; OS at 12 months [OS12] < 35%) with approved therapies (lomustine±bevacizumab). PVSRIPO is an intratumoral immunotherapy targeting CD155 on antigen-presenting and malignant cells of solid tumors. Preclinically, PVSRIPO delivers a systemic, tumor antigen-specific, polyfunctional T-cell mediated anti-tumor response. Interim, single-center, phase (Ph) 1 results showed greater long-term survival with PVSRIPO vs. criteria-matched external control rGBM patients (Desjardins 2018). Updates to Ph1 safety (at the Ph2 dose) and efficacy and interim multicenter (Ph2) results are presented. METHODS Adults with histologically-confirmed rGBM, Karnofsky performance status ≥ 70, and an active, supratentorial, contrast-enhancing lesion (1-5.5cm) received PVSRIPO (5x107 TCID50) intratumorally via convection-enhanced delivery on Day 1, with a planned follow-up of 24 months. Safety (treatment-emergent adverse events [TEAEs]), efficacy (reported as OS12, OS24, mOS), and blood/tissue were assessed. RESULTS 149 patients (>90% with 1-2 prior progressions, including failure of SOC and patients with prior bevacizumab failure) received the Ph2 dose of PVSRIPO (n=30 received other doses in Ph1 with safety summarized previously). Follow-up durations for surviving patients were 51-74 months (Ph1) and 10-44 months (Ph2). No dose-limiting toxicities occurred; up to 97% of patients experienced mostly grade 1-2 related TEAEs; ≤ 23% patients experienced grade ≥ 3 related events. Neurologic symptoms related to peritumoral edema were most common ( > 90% patients) and were effectively managed with low-dose bevacizumab/corticosteroids. Survival estimates were: OS12: 54%, 50%; OS24: 18%, 17%; mOS: 12.3 (95% CI 10,15.3), 12 (10.6,13.7) months, for the Ph1 and Ph2 trials, respectively. Baseline correlates of longer survival included smaller lesions and methylated MGMT-promoter status. CONCLUSIONS The multicenter/Ph2 study replicated the single-center/Ph1 results. Relative to published data with approved therapies, PVSRIPO was associated with greater long-term survival and mOS in patients with rGBM and was generally well-tolerated.

BackgroundPVSRIPO, a novel intratumoral viral immunotherapy, infects cells via CD155, which is widely expressed on solid tumors and antigen-presenting cells (APC). Infection is lethal in malignant cells, but a unique, activating, nonlethal infection of local APCs yields type-I/III interferon (IFN)-dominant inflammation with subsequent anti-tumor T-cell priming and activation resulting in anti-tumor efficacy. In preclinical models, PVSRIPO-dependent inflammation upregulated the PD-1/L1 pathway, and greater anti-tumor response was observed with PVSRIPO + anti-PD-1/L1 (αPD-1/L1). Promising clinical activity with PVSRIPO monotherapy was observed in patients with recurrent glioblastoma and advanced αPD-1–refractory melanoma.1 2 Collectively, these results warrant further clinical investigation of PVSRIPO ± αPD-1/L1.MethodsLUMINOS-103 (NCT04690699) is a phase (Ph) 1/2, open-label, multi-center, single-arm basket trial evaluating repeat administration of PVSRIPO ± αPD-1/L1 in adults with solid tumors. Trial objectives are to assess the safety and tolerability of PVSRIPO monotherapy in each cohort in Ph 1 and the safety, tolerability, and antitumor efficacy of PVSRIPO + αPD-1/L1 in each cohort in Ph 2. The first two study cohorts include patients with muscle-invasive bladder cancer being treated in the neoadjuvant setting (A) and patients with metastatic bladder cancer being treated in the 1st/2nd line setting (B); these cohorts have been described previously.3 Cohort C includes patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) being treated in the neoadjuvant setting; Cohort D includes patients with recurrent/metastatic HNSCC with a PD-L1 Combined Positive Score ≥1 being treated in the 1st line setting. Eligibility: HNSCC patients must have histologically or cytologically-proven SCC of the oral cavity, oropharynx, hypopharynx, or larynx. All patients must have prior and boosted PV immunization and tumors amenable to injection and biopsy. Key exclusion criteria: Requirement for oxygen supplementation, systemic or intratumoral therapy ≤6 months prior to the first dose of study drug, CNS metastases requiring immediate treatment, systemic immunosuppressive medications ≤4 weeks prior to the first dose of study drug, and severe active comorbidities. Patients who are HIV+, HBV+ or HCV+ are eligible provided they meet certain criteria. Primary endpoints include safety (all cohorts), tolerability (all cohorts), surgical complication rate (A, C), pathologic treatment effect/response (A, C), and objective response rate (B, D). Secondary endpoints include overall survival (all cohorts), pathologic downstaging and relapse-free survival (A, C), duration of response and progression-free survival (B, D), and assessment of tumor/blood biomarkers (all cohorts).Trial RegistrationClinicalTrials.gov: NCT04690699ReferencesDesjardins A, et al. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med 2018;379(2):150–161.Beasley GM, et al. Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma. J Immunother Cancer 2021;9(4):e002203.Inman BA, et al. LUMINOS-103: A basket trial evaluating the safety and efficacy of PVSRIPO in patients with advanced solid tumors. Cancer Res 2021;81(13_Suppl):Abstract nr CT242.Ethics ApprovalThe study has been approved by the central Institutional Review Board (IRB), WCG (Study# 1310534) and will be approved by all local IRBs and other required committees, as applicable. The study will be conducted in accordance with the provisions of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization. All patients will provide written informed consent.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

Human herpesvirus 6B (HHV-6B) frequently reactivates after allogeneic hematopoietic cell transplantation (HCT). There are no randomized studies of antiviral treatments to prevent HHV-6B reactivation. Brincidofovir has high in vitro activity against HHV-6B and other DNA viruses, but its in vivo activity for HHV-6B has not been demonstrated. We performed a post hoc analysis of a randomized controlled trial of twice-weekly oral brincidofovir for cytomegalovirus prophylaxis after allogeneic HCT to study the effect of brincidofovir on HHV-6B reactivation. We included patients randomized within 2 weeks of HCT and who received at least 6 consecutive doses of study drug after randomization. We tested plasma for HHV-6B through week 6 post-HCT. The cohort consisted of 92 patients receiving brincidofovir and 61 receiving placebo. The cumulative incidence of HHV-6B plasma detection through day 42 post-HCT was significantly lower among patients receiving brincidofovir (14.2%) compared with placebo (32.4%; log-rank, 0.019). In an adjusted Cox model, brincidofovir exposure remained associated with a lower hazard for HHV-6B plasma detection (hazard ratio, 0.40; 95% confidence interval, 0.20-0.80). In conclusion, brincidofovir prophylaxis reduced HHV-6B reactivation after allogeneic HCT in a post hoc analysis of a randomized controlled trial. These data support the study of intravenous brincidofovir for HHV-6B prophylaxis.

Background: The prognosis for patients (pts) with recurrent (r) glioblastoma (GBM) is poor, with no highly effective approved therapies. Treatment failure may result from poor penetration of drugs through the blood-brain barrier and the immunosuppressive nature of the tumor microenvironment (TME). PVSRIPO, a recombinant poliovirus (PV):rhinovirus chimera, is a novel, non-neurovirulent, intratumoral immunotherapy. Trial results in rGBM pts showed greater long-term survival with PVSRIPO monotherapy (21%, 36-60 months [mos]) vs. criteria-matched external controls (4%, 36 mos; 2%, 60 mos; Desjardins 2018 NEJM). PVSRIPO targets CD155 (PV receptor), expressed on solid tumors and APC. PVSRIPO IT infection results in inflammatory-mediated destruction of tumor cells but non-lethal lingering infection in TME APC. This leads to a type-I/III interferon-dominant inflammation and ultimately, tumor antigen-specific T cell activation and recruitment (Brown 2017 Sci Transl Med), which is potentiated by immunologic recall to intratumoral replicating virus via prior vaccination. Induction of type-1 IFN dominant inflammation and compensatory activation of the PD-1:PD-L1 immune checkpoint (IC) pathway support investigation of PVSRIPO in combination with PD-1/L1 IC inhibitors. Immunologically cold mouse glioma models showed PVSRIPO+anti-PD-1 therapy resulted in greater anti-tumor response than either agent. Trial design/objectives: LUMINOS-101 (NCT04479241) is a phase 2, multicenter, open-label, single-arm study of intratumoral infusion of PVSRIPO (day 1: 5×107 TCID50) followed by the anti-PD-1 monoclonal antibody pembrolizumab (200mg IV q3w) in adult pts with rGBM. The trial objective is to evaluate the anti-tumor activity, safety, and tolerability of the combination. Eligibility criteria: Pts ≥18 years who had prior PV and boost IPOL® immunizations, histologically confirmed supratentorial rGBM, infusible 1 to ≤5.5cm enhancing disease, confirmed disease progression following prior therapies, and KPS ≥70 will be enrolled. Key exclusion criteria include multifocal disease; discontinuation of prior anti-PD-1/L1 agent for toxicity; prior intratumoral therapy, immunotherapy, or radiotherapy within 12 weeks; high-dose systemic corticosteroids; chemotherapy, anti-VEGF, or TTF therapy ≤1-6 weeks depending on the therapy; serious cerebral herniation syndrome; extensive leptomeningeal, subependymal, or ≥1cm enhancing disease crossing the midline; and severe active comorbidities. Endpoints: Primary endpoints are objective response rate, duration of response, and safety. Secondary endpoints include overall and progression-free survival and disease control rate and duration. Exploratory endpoints include assessment of tumor and blood for biomarkers of response. The study is currently enrolling in the US, and results will inform the design of a randomized phase 3 trial. Citation Format: Andrea True Kelly, Prakash Ambady, Michael Brown, Nicholas Butowski, Robert Cavaliere, William Curry, Annick Desjardins, Lisa Franklin, Henry Friedman, Matthias Gromeier, LeAnn Jackson, Lori Mixson, Shirley Ong, Dina Randazzo, Andrew Sloan, Patrick Wen, Garrett Nichols. LUMINOS-101: Phase 2 study of PVSRIPO with pembrolizumab in recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT240.

Background: The recombinant poliovirus (PV):rhinovirus chimera, PVSRIPO, is a novel non-neurovirulent, intratumoral (IT) immunotherapy showing promising clinical activity in patients (pts) with recurrent glioblastoma and advanced anti-PD-1 refractory melanoma (Desjardins 2018 NEJM, Beasley 2020 SITC). PVSRIPO targets CD155 (PV receptor), expressed on most solid tumors (including bladder cancer [BC]) and antigen presenting cells (APCs) of the tumor microenvironment (TME). PVSRIPO infection results in inflammatory-mediated destruction of tumor cells but non-lethal lingering infection in TME APCs. This leads to a type-I/III interferon-dominant inflammation and ultimately, tumor antigen-specific T cell activation and recruitment (Brown 2017 Sci Transl Med), potentiated by immunologic recall to intratumoral replicating virus via prior vaccination. Induction of type-1 IFN dominant inflammation and compensatory activation of the PD-1:PD-L1 immune checkpoint (IC) pathway support investigation of PVSRIPO in combination with PD-1/L1 IC inhibitors. PVSRIPO+anti-PD-1 therapy resulted in greater anti-tumor response than either agent in immunologically cold mouse tumor models. Trial design, objectives, and eligibility criteria: LUMINOS-103 (NCT04690699) is a phase 1/2, open-label, multi-center, single-arm basket trial evaluating repeat administration of PVSRIPO (2×108 TCID50/mL)±anti-PD-1/L1 therapy in adults with solid tumors. Trial objectives are to evaluate the safety, tolerability, and anti-tumor activity of the combination in pts with solid tumors, beginning with muscle invasive bladder cancer (MIBC). The first arm will include pts in 2 cohorts: MIBC undergoing cystectomy (A); and unresectable locally advanced/metastatic BC (B). Safety/tolerability of PVSRIPO IT injections via cystoscopy will be evaluated in phase 1, Cohort A, and proceed to phase 2, where PVSRIPO+anti-PD-1/L1 therapy will be assessed in both cohorts. Eligible BC pts must refuse/be ineligible for cisplatin (A) or platinum-based therapy (B), have prior and boost PV immunization, and have measurable tumors (B) amenable to injection. Key exclusion criteria: other anti-cancer therapies ≤3 weeks, CNS metastases requiring active radiotherapy or steroids ≤14 days, systemic immunosuppressives ≤4 weeks, and severe active comorbidities. Endpoints: Primary endpoints include safety and tolerability and pathologic complete response (A) or overall response rate (B). Secondary endpoints: overall survival (both cohorts); for A, pathologic downstaging (p≤T2) and relapse-free survival; for B, duration of response and progression-free survival. Exploratory endpoints: assessment of tumor/blood biomarkers; measurement of disease by itRECIST. The trial will open US enrollment ≈ Q2 2021; results will inform later-stage trials in promising indications. Citation Format: Brant A. Inman, Arjun V. Balar, Matthew I. Milowsky, Raj S. Pruthi, Melissa J. Polasek, Shannon R. Morris, Lori Mixson, Kristin Orr, Elizabeth M. Woodson, Andrea True Kelly, Garrett Nichols. LUMINOS-103: A basket trial evaluating the safety and efficacy of PVSRIPO in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT242.

TPS2065 Background: The prognosis for patients (pts) with recurrent (r) glioblastoma (GBM) is poor, with no highly effective approved therapies. Treatment failure may result from poor penetration of drugs through the blood-brain barrier and the immunosuppressive nature of the tumor microenvironment (TME). PVSRIPO, a recombinant poliovirus (PV):rhinovirus chimera, is a novel, non-neurovirulent, intratumoral immunotherapy. Trial results in rGBM pts show greater long-term survival with PVSRIPO monotherapy (21%, 36-60 months [mos]) vs criteria-matched external controls (4%, 36 mos; 2%, 60 mos; Desjardins 2018 NEJM). PVSRIPO targets CD155 (PV receptor), expressed on solid tumors and on APC. PVSRIPO infection results in inflammatory-mediated destruction of tumor cells but non-lethal lingering infection in TME APC. This leads to type I/III interferon-dominant inflammation and, ultimately, tumor antigen-specific T cell activation and recruitment (Brown 2017 Sci Transl Med), which is potentiated by immunologic recall to intratumoral replicating virus via prior vaccination. Induction of type 1 IFN dominant inflammation and compensatory activation of the PD-1:PD-L1 immune checkpoint (IC) pathway support investigation of PVSRIPO in combination with PD-1/L1 IC inhibitors. Immunologically cold mouse glioma models show PVSRIPO+anti-PD-1 therapy resulted in greater anti-tumor response than either agent. Methods: LUMINOS-101 is a phase 2, multicenter, open-label, single-arm study of intratumoral infusion of PVSRIPO (Day 1: 5x107 TCID50) followed by the anti-PD-1 monoclonal antibody pembrolizumab (200mg IV q3w) in adult pts with rGBM. The trial objective is to evaluate anti-tumor activity and safety and tolerability of the combination. Eligibility criteria include pts ≥18 years who had prior PV and boost IPOL® immunizations, histologically confirmed supratentorial rGBM, infusible 1 to ≤5.5cm enhancing disease, confirmed disease progression following prior therapies, and KPS ≥70. Key exclusion criteria include multifocal disease; discontinuation of prior anti-PD-1/L1 agent for toxicity; prior intratumoral therapy, immunotherapy, or radiotherapy within 12 weeks; high-dose systemic corticosteroids; chemotherapy, anti-VEGF, or TTF therapy ≤1-6 weeks depending on the therapy; serious cerebral herniation syndrome; extensive leptomeningeal, subependymal, or ≥1cm enhancing disease crossing the midline; and severe active comorbidities. Primary endpoints are objective response rate, duration of response, and safety. Secondary endpoints include overall and progression-free survival and disease control rate and duration. Exploratory endpoints include assessment of tumor and blood for biomarkers of response. The initially planned safety lead-in period is now fully enrolled. Recruitment is ongoing in the US, and results will inform the design of a randomized phase 3 trial. Clinical trial information: NCT04479241.

2560 Background: Most patients with advanced melanoma (mel) fail/acquire resistance to ICI, including anti-(α) PD-1. PVSRIPO is a novel intratumoral immunotherapy derived from the Sabin type 1 attenuated poliovirus (PV) that targets CD155, widely expressed on solid tumors and antigen-presenting cells (APCs) of the tumor microenvironment. Therapy leads to direct tumor cell death and type I/III interferon-dominant innate inflammation, mediating priming and recruitment of tumor antigen-specific T cells. Inflammation-mediated upregulation of the PD-1/L1 IC suggests greater anti-tumor response could be achieved with PVSRIPO + αPD-1. The aim of this preclinical study was to evaluate the efficacy and safety of murine PVSRIPO (mRIPO) + αPD-1 in an aggressive mel tumor model (B16-F10.9-OVA in human-CD155 transgenic mice [C56BI/6]). Methods: Mice were randomized to 4 groups (G) of 12: (G1 [control]: vehicle [v] + IgG; G2: v + αPD-1; G3: mRIPO + IgG; G4: mRIPO + αPD-1). Tumor cells (5 x 105) were implanted into the right (R) and left (L) flanks. When tumor volume (vol) was ̃25 mm3, 15 µL v or 1 x 107 TCID50 mRIPO was injected into R (Day 1) and L (Day 4) tumors; αPD-1 or IgG (250 µg, 100 µL ip) was given on Days 1 and 4 and q 3 days until termination (Day 13). Weight, hematology, chemistry, and inflammatory cytokines were assessed pre/post-tumor implantation. Tumor vol was assessed every other day, with gross/histologic exam at termination. Results: 47 mice without health issues were euthanized as planned; 1 G1 animal required early euthanasia for tumor ulceration. Microscopic findings: increased mononuclear cell tumor infiltrates (G2 and G4); less severe L tumor growth necrosis in G2, G3, and G4 vs G1. There were no specific treatment-related changes in serum cytokines in G4. See the table below for summary of total tumor vol changes vs control; the most significant reduction was observed in G4. No tumor cells were observed via histopathology at Day 13 in R flanks of 1 mouse in G2; 3 in G3; and 8 in G4; and only G3 (n=1) and G4 (n=5) mice had no evidence of L flank tumor cells, with regression evident before L tumor mRIPO injection (ie, abscopal response). Conclusions: mRIPO + αPD-1 had the greatest overall anti-tumor response, and the combination was well tolerated. These results suggest combination therapy is not associated with untoward immune-mediated toxicity and highlight the potential for enhanced efficacy in injected and uninjected tumors. A phase 2 clinical trial of PVSRIPO ± αPD-1 in unresectable αPD-1 refractory mel is enrolling (LUMINOS-102, NCT04577807).[Table: see text]

Purpose: The logistics of conducting double-blinded phase III clinical trials with participants residing in remote locations are complex. Here we describe the implementation of an interventional trial for the prevention of late cytomegalovirus (CMV) disease in hematopoietic cell transplantation (HCT) subjects in a long-term follow-up environment. Methods: A total of 184 subjects at risk for late CMV disease surviving 80 days following allogeneic HCT were randomized to receive six months of valganciclovir or placebo. Subjects were followed through day 270 post-transplant at their local physician's office within the United States. Anti-viral treatment interventions were based on CMV DNAemia as measured by polymerase chain reaction (PCR) (>1000 copies/mL) and granulocyte colony stimulating factor (G-CSF) was prescribed for neutropenia (absolute neutrophil count (ANC

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2002. Since then, there have been major developments in its diagnosis and management. Therefore, the CMV Drug Development Forum consisting of scientists, clinicians, regulators, and industry representatives has produced an updated version incorporating recent knowledge with the aim to support clinical research and drug development. The main changes compared to previous definitions are the introduction of a "probable disease" category and to incorporate quantitative nucleic acid testing in some end-organ disease categories. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts between scientists, regulators, and industry can provide a platform for this work.

Objective Adenovirus (AdV) infections are potentially life‐threatening for allogeneic hematopoietic stem cell transplant (allo‐HCT) recipients. The AdVance study aimed to evaluate the incidence, management, and outcomes of AdV infections in European allo‐HCT recipients. Methods As part of the study, physician surveys were conducted to determine current AdV screening and treatment practices at their center. Results All of the 28 respondents who treat pediatric patients reported routine AdV screening practices, with 93% screening all allo‐HCT recipients and others screening those with transplant‐related risk factors. Nearly all centers take a pre‐emptive approach to AdV treatment in both high‐ (89%) and low‐risk patients (75%). Among the 14 respondents who treat adult patients, 5 (36%) reported routine screening practices and few (21%) screen all allo‐HCT recipients unless risk factors are present. In adults, pre‐emptive AdV treatment is uncommon and quantitative AdV thresholds are rare. Typical treatment for all patients with symptomatic AdV infection is off‐label intravenous cidofovir. Conclusions Our findings confirm that screening for AdV is more common in pediatric patients. Antiviral treatment is employed in both pediatric and adult patients, although adults are generally treated when AdV disease is diagnosed. The approach to AdV screening and treatment is risk‐based and consistent with clinical guidelines.

This multivariable analysis from the AdVance multicenter observational study assessed adenovirus (AdV) viremia peak, duration, and overall AdV viral burden—measured as time-averaged area under the viremia curve over 16 weeks (AAUC0-16)—as predictors of all-cause mortality in pediatric allo-HCT recipients with AdV viremia. In the 6 months following allo-HCT, 241 patients had AdV viremia ≥ 1000 copies/ml. Among these, 18% (43/241) died within 6 months of first AdV ≥ 1000 copies/ml. Measures of AdV viral peak, duration, and overall burden of infection consistently correlate with all-cause mortality. In multivariable analyses, controlling for lymphocyte recovery, patients with AdV AAUC0-16 in the highest quartile had a hazard ratio of 11.1 versus the lowest quartile (confidence interval 5.3–23.6); for peak AdV viremia, the hazard ratio was 2.2 for the highest versus lowest quartile. Both the peak level and duration of AdV viremia were correlated with short-term mortality, independent of other known risk factors for AdV-related mortality, such as lymphocyte recovery. AdV AAUC0-16, which assesses both peak and duration of AdV viremia, is highly correlated with mortality under the current standard of care. New therapeutic agents that decrease AdV AAUC0-16 have the potential of reducing mortality in this at-risk patient population.

Introduction Acute kidney injury (AKI) is common in hematopoietic cell transplant (HCT) recipients. Few studies have evaluated whether BK polyomavirus (BKV) infections are associated with kidney disease in the HCT population, and results have not been conclusive. Objectives Using retrospectively collected BK plasma viral loads from a large cohort of HCT recipients, we assessed the relationship between plasma BKV replication and AKI through an analysis of BK viral load kinetics, the occurrence of AKI, and change in serum creatinine. Methods Weekly BK viral loads were obtained during the first 100 days after HCT in 403 patients between 2007-2014 (Hill et al., Blood 2017). We defined AKI according to KDIGO (Kidney Disease Improving Global Outcomes) criteria and recovery from AKI as a reduction in serum creatinine to within ten percent of baseline, both sustained for 48 hours. Viral load kinetics of interest included peak viral load, area under the curve (AUC) and cross-sectional BK viral load (log10 BK viral load). Using these weekly longitudinal measures, we estimated the relationships between BKV kinetics and AKI using generalized linear models with robust variance estimates for the outcomes of 1) mean change in serum creatinine (from baseline) and 2) odds of AKI episodes, each adjusted for acute graft versus host disease, use of nephrotoxic medications (cidofovir, foscarnet), bilirubin, conditioning regimen, age, sex, and cell source. Results Fifty-four percent (218/402) of HCT recipients had detection of BKV in at least one sample, and twenty-eight percent (113/403) had at least one BK viral load ≥ 10,000 copies/mL in the first 100 days. Sixty-eight percent (275/403) had at least one AKI episode median onset by day 27 (range 1-98). Logistic regression models did not show significant associations for log10BK viral load, peak viral load and AUC with odds of subsequent AKI (Figure1). In the linear models, BK viral load kinetics were associated with small increases in mean serum creatinine (mg/dL) by 0.025 for each log10 increase (95% CI, 0.01-0.04; p Conclusion Increased plasma BK viral load was associated with small increases in serum creatinine after allogeneic HCT, but the clinical importance of these changes is low. We found no statistically significant association between plasma BKV detection and development of AKI.

Introduction Allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk of life-threatening viral infections. Objective The objective of the AdVance US practice patterns survey was to characterize current practices in screening and treatment of adenovirus (AdV) infection in the United States (US). Methods Physicians at participating centers were provided with a link to access an online survey. The survey questions addressed current practices around management of AdV infections in allo-HCT recipients at their center, and classified patients with regard to known risks for AdV infection (e.g., T-cell depletion, cord blood, haploidentical, mismatched, GVHD). When necessary, respondents consulted with other physicians in their center to ensure consensus before submitting responses. Results 62 centers were approached, of which 15 (24%) agreed to participate in this survey prior to the first deadline for response. 11 of the participating centers treat pediatric patients and 4 treat adult patients (Figure). According to CIBMTR data and physician interview responses, the pediatric and adult centers conduct an average of 36 and 142 allo HCTs per year, respectively. Almost all (91%) pediatric centers conduct weekly routine screening for AdV after allo-HCT among higher-risk patients, and around half (55%) conduct routine screening for AdV among lower-risk patients. Routine AdV screening is conducted by 25% of adult centers for higher-risk patients, and none routinely screen lower-risk patients. Among those screening higher-risk patients for AdV, all pediatric and adult centers screen blood samples at least once weekly and the majority (90%) of pediatric centers screen blood for at least 3 months post allo-HCT; the one adult center that screens blood does so weekly for up to 6 months post-HCT. Most pediatric centers have a pre-emptive AdV treatment approach for higher-risk patients (91%) and lower-risk patients (82%), using positive blood PCR as the treatment trigger. All adult centers that screen higher-risk patients use a pre-emptive approach. The pre-emptive AdV treatment most frequently reported by pediatric and adult centers is off-label IV cidofovir in spite of well-known toxicity concerns including renal injury. Conclusions The AdVance US practice patterns survey suggests that pediatric centers are more likely than adult centers to screen for AdV, and are also more likely to have a pre-emptive AdV treatment approach compared to adult centers. Perceived risk of AdV infection is a determining factor for whether routine screening and pre-emptive treatment are implemented. For both pediatric and adult centers, AdV viremia was the most common pre-emptive treatment trigger, with off-label IV cidofovir commonly utilized for treatment in spite of toxicity concerns. Treatment practices in the centers surveyed are generally consistent with ASBMT guidelines.

High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count500/μL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 10(9) granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P.99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 10(9) granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.

Objectives Dolutegravir (DTG) has been studied in three trials in HIV treatment-naive participants, showing noninferiority compared with raltegravir (RAL), and superiority compared with efavirenz and ritonavir-boosted darunavir. We explored factors that predicted treatment success, the consistency of observed treatment differences across subgroups and the impact of NRTI backbone on treatment outcome. Design Retrospective exploratory analyses of data from three large, randomized, international comparative trials: SPRING-2, SINGLE, and FLAMINGO. Methods We examined the efficacy of DTG in HIV-infected participants with respect to relevant demographic and HIV-1-related baseline characteristics using the primary efficacy endpoint from the studies (FDA snapshot) and secondary endpoints that examine specific elements of treatment response. Regression models were used to analyze pooled data from all three studies. Results Snapshot response was affected by age, hepatitis co-infection, HIV risk factor, baseline CD4⁺ cell count, and HIV-1 RNA and by third agent. Differences between DTG and other third agents were generally consistent across these subgroups. There was no evidence of a difference in snapshot response between abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) overall [ABC/3TC 86%, TDF/FTC 85%, difference 1.1%, confidence interval (CI) -1.8, 4.0 percentage points, P = 0.61] or at high viral loads (difference -2.5, 95% CI -8.9, 3.8 percentage points, P = 0.42). Conclusions DTG is a once-daily, unboosted integrase inhibitor that is effective in combination with either ABC/3TC or TDF/FTC for first-line antiretroviral therapy in HIV-positive individuals with a variety of baseline characteristics.

Background Improved understanding of double-stranded DNA (dsDNA) virus kinetics after hematopoietic cell transplantation (HCT) would facilitate development of therapeutic strategies. Methods We tested weekly plasma samples from 404 patients through day 100 after allogeneic HCT for cytomegalovirus (CMV), human herpesvirus (HHV) 6A and 6B, BK polyomavirus (BKV), adenovirus (AdV), and Epstein-Barr virus (EBV) using quantitative polymerase chain reaction. Episodes lasting ≤1 week were defined as blips and >1 week as persistent. We described virus-specific kinetics, analyzed the association of virus area under the curve (AUC) with overall mortality, and identified risk factors for persistent episodes. Results We identified 428 episodes of CMV, 292 of BKV, 224 of HHV-6B, 46 of AdV, and 53 of EBV. CMV and BKV had the highest proportions of persistent episodes (68% and 80%, respectively). Detection and kinetics varied by virus. HHV-6B episodes reached maximum levels fastest and had the shortest intervals between detection and end-organ disease. End-organ disease occurred within 14 days of viremia in 68% of cases, generally during persistent episodes. For all viruses, higher viral load AUC increased risk for overall mortality through day 365, persistent episodes had higher viral load than blips, and higher first positive viral load significantly increased risk for persistent episodes. First viral load >2 log10 copies/mL (range, 2.04-3.06 per virus) had high specificity for persistent episodes. Conclusions Persistent high viral load dsDNA viremia episodes after allogeneic HCT predict mortality. Virus-specific kinetics can guide timing and thresholds for early intervention in studies of novel agents.

The efficacy of dolutegravir (DTG) has been demonstrated in 5 randomized studies in integrase inhibitor (INI)-naive adult populations. To date, a detailed safety review of DTG has not been provided in the literature.To describe the safety and tolerability profile of DTG in adults based on 5 randomized, controlled trials and comparison with drugs in 3 major antiretroviral (ARV) classes.Safety data from phase IIb/III/IIIb trials in ART-naive and ART-experienced, INI-naive adults were integrated.In 4 ART-naive (SPRING-1, SPRING-2, SINGLE, FLAMINGO) and 1 ART-experienced, INI-naive study (SAILING), 1,579 individuals received a DTG-containing regimen. The proportion of individuals from DTG treatment arms who withdrew due to adverse events (AEs) was low (≤2%) compared to raltegravir (RAL; 2% SPRING-2, 4% SAILING), efavirenz (EFV)-containing comparator arm (10% SINGLE), and darunavir + ritonavir (DRV/r; 4% FLAMINGO). The most frequently observed AEs (diarrhea, nausea, headache), typically grade 1 or 2 in severity, did not lead to study discontinuation. Psychiatric and nervous system disorders with DTG were comparable to RAL- and DRV/r-containing regimens and favorable to EFV-containing regimens. In hepatitis B and/or C coinfected ART-naive individuals, the incidence of transaminase elevations was lower with DTG versus RAL and EFV comparators, but was similar to DRV/r. In SAILING, transaminase elevations were more commonly observed with DTG, particularly in the setting of inadequate hepatitis B therapy or immune reconstitution. On DTG treatment, mild creatinine elevations occurred and stabilized early. Few cases of hypersensitivity reaction and/or severe rash were seen. Rates of these events were comparable to or lower than with RAL-, EFV-, and DRV/r-containing regimens.The safety profile for DTG 50 mg once daily in INI-naive individuals was comparable to RAL- and DRV/r-containing regimens and generally favorable compared with EFV-containing regimens.

Background Adenovirus (AdV) infection is an important cause of mortality among allogeneic hematopoietic cell transplant (allo-HCT) recipients. Current European Conference of Infections in Leukemia (ECIL-4) guidelines support weekly AdV screening for those at-risk and pre-emptive antiviral treatment with off-label cidofovir when adenoviremia is detected. However, there is limited understanding of the relative prognostic strength of different dynamic AdV viral load measures. We examined the association between adenovirus viral load dynamics and mortality in pediatric allo-HCT recipients managed under the current standard of care. Methods AdVance was a multinational, multicenter study characterizing the current screening and treatment practices for AdV infection in allo-HCT recipients between January 2013 and September 2015. This analysis focused on pediatric ( Results A total of 241 pediatric allo-HCT recipients had AdV viremia ≥1,000 copies/mL in the 6 months following allo-HCT. Among these, 43/241 (18%) died within 6 months of first AdV ≥1,000 copies/mL. AdV viral load dynamics; whether measured by AdV AAUC0–16, peak viremia, 2-week change in viremia, or days of viremia >1,000 copies/mL, were consistently correlated with all-cause mortality (Figure 2; hazard ratio [HR] range: 1.3–2.3). Most notably, patients with AdV AAUC0–16 in the highest quartile had an HR of 11.6 relative to those in the lowest (confidence interval: 4.7–24.0; Figure 3). Conclusion AdV infection is a significant risk for allo-HCT recipients. The AdVance study has identified several dynamic measures of AdV viral load that correlate with the risk of mortality in pediatric allo-HCT recipients. Results show for the first time, that AdV AAUC0–16 provides the optimal correlation with mortality in this population and serves as a clinically useful indicator of outcome in patients with AdV infection. Disclosures F. Galaverna, Chimerix, Inc.: Investigator, Research support. R. Wynn, Chimerix, Inc.: Scientific Advisor, Grant recipient and Speaker honorarium. Orchard Therapeutics: Scientific Advisor and Shareholder, Consulting fee and Licensing agreement or royalty. Genzyme: Scientific Advisor, Speaker honorarium. P. Comoli, Chimerix, Inc.: Investigator, Research support. A. Chandak, Chimerix, Inc.: Research Contractor, Research support. Analytica Laser: Employee, Salary. E. Vainorius, Chimerix, Inc.: Employee and Shareholder, Salary. T. Brundage, Chimerix, Inc.: Employee and Shareholder, Salary. E. Mozaffari, Chimerix, Inc.: Employee and Shareholder, Salary. G. Nichols, Chimerix, Inc.: Employee and Shareholder, Salary.

Introduction Human herpesvirus 6B (HHV-6) is detected in plasma in ∼40% of allogeneic hematopoietic cell transplant (HCT) recipients and ∼75% of cord blood recipients. HHV-6 viremia, particularly at levels >104 copies/mL, is associated with increased risk for HHV-6 encephalitis. Ganciclovir and foscarnet have antiviral activity against HHV-6, but studies of pre-emptive or prophylactic treatment have not been successful in preventing HHV-6 encephalitis. Prophylaxis for HHV-6 has never been studied in a randomized trial. Brincidofovir (BCV, CMX001) has potent in vitro activity against HHV-6 (EC50=0.007 µM), and unlike cidofovir, has good CNS penetration. Objectives In vivo activity of BCV against HHV-6 has not been demonstrated. We tested plasma from participants in the SUPPRESS clinical trial to explore the potential of BCV to prevent HHV-6 viremia. Methods SUPPRESS was a randomized, double-blind, placebo (PBO)-controlled trial of oral BCV for cytomegalovirus (CMV) prophylaxis after allo-HCT. 452 adult CMV-seropositive HCT recipients without CMV viremia at screening were randomized 2:1 to receive BCV or PBO twice-weekly until week 14 post-HCT. We selected subjects who were randomized within 2 weeks of allo-HCT, who did not have HHV-6 viremia at baseline, and who received at least 6 doses of BCV or PBO within the first 3 weeks of randomization for HHV-6 testing. Plasma samples from the first six weeks post-HCT were tested for HHV-6 with quantitative PCR (Viracor Eurofins, Lee's Summit, MO). We compared HHV-6 viremia between subjects who received BCV and those who received PBO using the Kaplan-Meier method, log rank test, and Cox proportional hazards model. Results 92 subjects in the BCV group and 61 in the PBO group met criteria for inclusion: 64% were male, 84% were white, and median age was 57 years (range: 18-76). 6% of subjects received cord blood grafts, 5% had haploidentical donors, and 8% had mismatched donors. 41% had ex vivo T-cell depletion or received serotherapy with antithymocyte globulin or alemtuzumab. Baseline characteristics were balanced between groups. 15% of BCV subjects vs. 31% of PBO subjects had detectable HHV-6 viremia within 6 weeks after HCT. The cumulative incidence of HHV-6 viremia was significantly lower in BCV subjects (Figure 1). Two subjects (2%) in the BCV group had HHV-6 viremia >103 copies/mL compared to 7 (11%) in the PBO group (Figure 2). In the study overall, no subjects in the BCV group and one in the PBO group developed HHV-6 encephalitis. Conclusion BCV reduced the incidence of detectable HHV-6 viremia in HCT recipients enrolled in a randomized, placebo-controlled clinical trial. BCV prophylaxis could prevent the morbidity and mortality associated with HHV-6 in HCT recipients.

The majority of HIV-1 integrase amino acid sites are highly conserved, suggesting that most are necessary to carry out the critical structural and functional roles of integrase. We analyzed the 34 most variable sites in integrase (>10% variability) and showed that prevalent polymorphic amino acids at these positions did not affect susceptibility to the integrase inhibitor dolutegravir (S/GSK1349572), as demonstrated both in vitro (in site-directed mutagenesis studies) and in vivo (in a phase IIa study of dolutegravir monotherapy in HIV-infected individuals). Ongoing clinical trials will provide additional data on the virologic activity of dolutegravir across subject viruses with and without prevalent polymorphic substitutions.

Michel Foucault teaches us in The Order of Things (1966) that the principle of resemblance guided premodern systems of knowledge and organization. He writes: Up to the end of the sixteenth century, resemblance played a constructive role in the knowledge of Western culture. It was resemblance that largely guided exegesis and the interpretation of texts; it was resemblance that organized the play of symbols, made possible knowledge of things visible and invisible, and controlled the art of representing them. ... And representation--whether in the service of pleasure or of knowledge--was posited as a form of repetition: the theatre of life or the mirror of nature, that was the claim made by all language, its manner of declaring its existence and of formulating its right of speech. (17) Premodern western society relied on resemblance to structure and create discourses of knowledge and truth, providing order to the vast realm of what was "known" to be true. This old order, according to Foucault, started to break down when knowledge took up "residence in a new space" in which identity was no longer based on visibility and similitude but on "the relation between elements (a relation in which visibility no longer plays a role) and of the functions they perform" (218). Modern identity and social ordering began to depend on the functions and internal structures of individuals rather than mere similarities between them. Mark Twain's The Tragedy of Pudd'nhead Wilson (1894) maps a similar transition from an old order of similitude and appearance based on genealogy to one of internal function based on biology. In Pudd'nhead Wilson, Twain's characters must move beyond the visible surface in a power structure based on fluid notions of appearance and behavior to resituate power within individual biological difference. Dawson's Landing, the antebellum Missouri town in which the novel takes place, operates under an older power regime that becomes disrupted when miscegenation threatens to undermine social order and appearance and behavior are no longer sufficient designating race because the system is now openly about biology and the body. Thus, either the social order must change, or new strategies must arise to maintain the old one. The strategic maneuvering by which these changes take place relies on a specific understanding of the social relationship between racism and geography. The novel's thematic tension surrounding the blurring of racial divisions mirrors a similar anxiety about the blurring of social and cultural boundaries separating Dawson's Landing from the outside. Twain positions Dawson's Landing as an antiquated river town populated by residents who quickly dismiss more cosmopolitan outsiders. By the end of the novel, these two parallel tensions--between racial purity and miscegenation and between insider traditions and outsider influences-intersect as a cosmopolitan outsider "solves" the racial confusion resulting from miscegenation. Pudd'nhead Wilson has two central conflicts. The first conflict lies largely at the level of plot and informs the second. The novel's main plot involves Tom Driscoll, born a slave named Valet de Chambers to his mother, Roxy, who switches him at birth with her master's son. Roxy's ruse succeeds because, due to a long history Of miscegenation, she and Tom look white. Tom grows up believing he is a white aristocrat, mistreats his slaves, and pays off gambling debts by disguising himself in drag to rob homes. When Judge Driscoll, his guardian, catches him trying to steal money, Tom stabs him with a knife he has stolen from Luigi and Angelo Capello, two Italian twins with aristocratic ties who recently moved to Dawson's Landing. This plot conflict lies in whether or not David "Pudd'nhead" Wilson, an East Coast-educated lawyer from New York, will discover the real murderer and reveal the switching of the babies. Thematically, the novel's conflict lies less with Tom than it does with the manipulations and machinations of power strategies by Roxy and Wilson. …

Brincidofovir (BCV, CMX001) is an orally available, long-acting, broad-spectrum antiviral that has been evaluated in healthy subjects in Phase I studies and in hematopoietic cell transplant recipients and other immunocompromised patients in Phase II/III clinical trials for the prevention and treatment of cytomegalovirus and adenovirus infections. BCV has also shown in vitro activity against orthopoxviruses such as variola (smallpox) virus, and is under advanced development as a treatment for smallpox under the US FDA's 'Animal Rule'. The anticipated treatment regimen for smallpox is a total weekly dose of 200 mg administered orally for 3 consecutive weeks. To assess the benefit-to-risk profile of BCV for the treatment of smallpox, we evaluated short-term safety data associated with comparable doses from Phase I studies and from adult and pediatric subjects in the cytomegalovirus and adenovirus clinical programs. When administered at doses and durations similar to that proposed for the treatment of smallpox, BCV was generally well tolerated in both adults and pediatric subjects. The most common adverse events were mild gastrointestinal events and asymptomatic, transient, and reversible elevations in serum transaminases. The data presented herein indicate a favorable safety profile for BCV for the treatment of smallpox, and support its continued development for this indication.

Strategies to prevent active infection with certain double-stranded DNA (dsDNA) viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple viruses and association of viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Risk factors for detection of multiple viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease (P values < .01). Absolute lymphocyte count of

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2002. Since then, there have been major developments in its diagnosis and management. Therefore, the CMV Drug Development Forum consisting of scientists, clinicians, regulators, and industry representatives has produced an updated version incorporating recent knowledge with the aim to support clinical research and drug development. The main changes compared to previous definitions are the introduction of a "probable disease" category and to incorporate quantitative nucleic acid testing in some end-organ disease categories. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts between scientists, regulators, and industry can provide a platform for this work.

APV102002 was an open-label study comparing a dual-boosted HIV-1 protease inhibitor (PI) [fosamprenavir/lopinavir/ritonavir (FPV/LPV/RTV; 1400 mg/533 mg/133 mg twice daily)] and a high dose of FPV/RTV 1400 mg/100 mg twice daily (HD-FPV/RTV) versus the standard FPV/RTV 700 mg/100 mg twice-daily (STD-FPV/RTV) regimen for 24 weeks.Adult patients with prior failure to two or more PI-based regimens and on a failing PI regimen were randomized to STD-FPV/RTV (n = 24), HD-FPV/RTV (n = 25) or FPV/LPV/RTV (n = 25). The primary aim was to test week 24 superiority of HD-FPV/RTV and FPV/LPV/RTV over STD-FPV/RTV as measured by plasma HIV-1 RNA average area under the curve minus baseline (AAUCMB).There was no difference in the week 24 AAUCMB between the regimens. The proportion of patients with50 copies/mL of plasma HIV RNA was 21%, 24% and 20%, respectively, by time to loss of virological response (TLOVR) analysis. High baseline drug resistance provided some explanation for the low efficacy. A lower baseline background drug resistance and higher fosamprenavir genotypic inhibitory quotient led to better antiviral responses. The plasma amprenavir trough concentartion (C(tau)) was 49% higher in the HD-FPV/RTV arm than in the STD-FPV/RTV arm and similar in the FPV/LPV/RTV and STD-FPV/RTV arms. The plasma lopinavir C(tau) was similar to historical data with standard LPV/RTV 400 mg/100 mg twice daily. All regimens were relatively well tolerated, although diarrhoea was more frequent in the HD-FPV/RTV and FPV/LPV/RTV arms, and hypertriglyceridaemia and increased total cholesterol were more common in the FPV/LPV/RTV arm.While the strategies of higher dose FPV/RTV and dual FPV/LPV/RTV were relevant at the time of study initiation, new therapies for antiretroviral-experienced patients make such strategies of limited interest. In addition, this study failed to demonstrate antiviral superiority of the HD-FPV/RTV or FPV/LPV/RTV regimen over the STD-FPV/RTV twice-daily regimen in highly treatment-experienced patients.

Background Between August 1 and October 30, 1998 (outbreak period), an increased incidence of central venous catheter (CVC)-associated gram-negative bacterial bloodstream infection (GN-BSI) was detected in hematopoietic stem cell transplantation (HSCT) candidates and recipients in an outpatient HSCT unit. The objectives of the present study were to determine strategies for controlling the outbreak and identify risk factors for GN-BSI. Methods Two case-control studies, an assessment of infection control practices, microbiologic studies, and water quality analysis were conducted. A case was defined as any outpatient with a CVC and a primary GN-BSI during the outbreak period. Results All of the 31 case patients identified had needleless intravenous (IV) access devices. Independent risk factors for CVC-associated GN-BSI were self-administered IV infusion (odds ratio [OR] = 6.2; P = .02), lower frequency of needleless device changes (OR = 15.2; P = .03), and more frequent baths (OR = 1.4; P = .05). Interventions included increased frequency of needleless device change, recommending showers rather than baths, and use of CVC protection during showering/bathing. After these interventions, the CVC-associated GN-BSI rate declined to below the preoutbreak period rate (2.1/1000 vs 0.3/1000 CVC-days; P Conclusions This study demonstrated an increased risk of CVC-associated GN-BSIs related to self-IV infusion, bathing habits, and frequency of needleless device change. Infection control practices associated with the use of needleless devices may expose susceptible patients to increased risk for BSI.

In an environment where (i) potential risks to subjects participating in clinical studies need to be managed carefully, (ii) trial costs are increasing, and (iii) there are limited research resources available, it is necessary to prioritize research projects and sometimes re-prioritize if early indications suggest that a trial has low probability of success. Futility designs allow this re-prioritization to take place. This paper reviews a number of possible futility methods available and presents a case study from a late-phase study of an HIV therapeutic, which utilized conditional power-based stopping thresholds. The two most challenging aspects of incorporating a futility interim analysis into a trial design are the selection of optimal stopping thresholds and the timing of the analysis, both of which require the balancing of various risks. The paper outlines a number of graphical aids that proved useful in explaining the statistical risks involved to the study team. Further, the paper outlines a decision analysis undertaken which combined expectations of drug performance with conditional power calculations in order to produce probabilities of different interim and final outcomes, and which ultimately led to the selection of the final stopping thresholds.

SUMMARYThough several antivirals have been developed and marketed to treat influenza virus infections, the development of antiviral agents with clinical activity against other respiratory viruses has been more problematic. Here we review the epidemiology of respiratory viral infections in immunocompetent and immunocompromised hosts, examine the evidence surrounding the currently available antivirals for respiratory viral infections other than influenza, highlight those that are in the pipeline, and discuss the hurdles for development of such agents.

Background. Oseltamivir is safe and effective in immunocompetent persons, and prophylactic use is recommended during influenza outbreaks. However, no data exist regarding the use of oseltamivir as prophylaxis among patients undergoing hematopoietic stem cell transplantation (HSCT). Methods. In January 2002, an influenza A outbreak was identified when 4 cases occurred within 1 week at an outpatient residential facility for patients undergoing HSCT. Oseltamivir prophylaxis (75 mg per day) was initiated for all asymptomatic patients living in the housing facility. Retrospectively, 45 patients (25 of whom had undergone HSCT, and 20 of whom were pre-HSCT candidates) who received oseltamivir prophylaxis were evaluated for adverse events. These 45 patients were matched 1:1 with control subjects who received transplants during the period 1994-2003 and did not receive prophylaxis; they were matched according to donor type, conditioning regimen, cytomegalovirus serostatus, time after HSCT, and recipient age (± 5 years). The frequency of clinical and laboratory adverse events was determined by chart review and graded using National Cancer Institute Common Terminology Criteria. Results. Forty-five residents received oseltamivir for a median of 17 days (range, 10-81 days). No new cases of influenza A occurred in the facility. Seven weeks after initiation of prophylaxis, 1 resident who had been noncompliant to prophylaxis developed an influenza B infection, followed by an additional case of influenza B that occurred in a patient who had not received prophylaxis. No deaths occurred that were attributable to prophylaxis. The proportions of clinical and laboratory adverse events meeting common terminology criteria grades 2-4 or 3-4 were not significantly different between the case patients who received oseltamivir prophylaxis and control subjects. Conclusion. Oseltamivir prophylaxis appeared to be safe and well tolerated in managing an influenza outbreak in an HSCT outpatient residence.

We conducted a 12-year retrospective study to determine the effects that the community respiratory-virus species and the localization of respiratory-tract virus infection have on severe airflow decline, a serious and fatal complication occurring after hematopoietic cell transplantation (HCT). Of 132 HCT recipients with respiratory-tract virus infection during the initial 100 days after HCT, 50 (38%) developed airflow decline < or =1 year after HCT. Lower-respiratory-tract infection with parainfluenza (odds ratio [OR], 17.9 [95% confidence interval {CI}, 2.0-160]; P=.01) and respiratory syncytial virus (OR, 3.6 [95% CI, 1.0-13]; P=.05) independently increased the risk of development of airflow decline < or =1 year after HCT. The airflow decline was immediately detectable after infection and was strongest for lower-respiratory-tract infection with parainfluenza virus; it stabilized during the months after the respiratory-tract virus infection, but, at < or =1 year after HCT, the initial lung function was not restored. Thus, community respiratory virus-associated airflow decline seems to be specific to viral species and infection localization.

Background. Community-acquired respiratory viruses, such as influenza virus, are thought to be major causes of morbidity and mortality in patients who had undergone hematopoietic stem cell transplantation (HSCT). Risk factors for acquisition, progression to pneumonia, and the effect of antiviral therapy are unknown. Methods. We reviewed records from patients with documented influenza over 12 consecutive respiratoryvirus infection seasons at a single transplantation center. Results. From 1 September 1989 through 31 March 2002, influenza virus was isolated from 62 of 4797 persons undergoing HSCT (1.3%); 44 patients had upper respiratory tract infections (URIs) alone, and 18 developed pneumonia. Among patients with influenza virus infection, pneumonia developed more commonly among those infected earlier after transplantation (median, 36 vs. 61 days, ) and those with concurrent lymphopenia. P p .04 Of the 51 cases that were initially diagnosed as URIs, 17 were treated with antivirals, and 34 were not treated. Six untreated patients (18%) developed pneumonia, whereas 1 (13%) of 8 patients treated with rimantadine and 0 of 9 treated with oseltamivir developed pneumonia. The duration of influenza virus shedding was longer in patients treated with steroid doses of 11 mg/kg than among those treated with doses of !1 mg/kg (mean, 15 vs. 9 days); there was a trend towards decreased shedding with oseltamivir therapy (but not rimantadine therapy) after controlling for steroid use ( ). The 30-day mortality rate was highest among patients who had progression to P ! .08 pneumonia (5 [28%] of 18 patients); pulmonary copathogens (such as Aspergillus fumigatus) were commonly isolated. Conclusions. Influenza virus infection is an important cause of mortality early after HSCT. Our nonrandomized data suggest that early antiviral therapy with neuraminidase inhibitors may prevent progression to pneumonia and decrease viral shedding, which may prevent both influenza-related death in index patients and nosocomial transmission to others.

In the current era of effective prophylactic and preemptive therapy, cytomegalovirus (CMV) is now a rare cause of early mortality after hematopoietic stem cell transplantation (HSCT). However, the ultimate goal of completely eliminating the impact of CMV on survival remains elusive. Although the direct effects of CMV (ie, CMV pneumonia) have been largely eliminated, several recent cohort studies show that CMV-seropositive transplant recipients and seronegative recipients of a positive graft appear to have a persistent mortality disadvantage when compared with seronegative recipients with a seronegative donor. Recipients of T-cell–depleted allografts and/or transplants from unrelated or HLA-mismatched donors seem to be predominantly affected. Reasons likely include both incomplete prevention of direct and indirect or immunomodulatory effects of CMV as well as consequences of drug toxicities. The effect of donor CMV serostatus on outcome remains controversial. Large multicenter cohort studies are needed to better define the subgroups of seropositive patients that may benefit from intensified prevention strategies and to define the impact of CMV donor serostatus in the era of high-resolution HLA matching. Prevention strategies may require targeting both the direct and indirect effects of CMV infection by immunologic or antiviral drug strategies.

Prophylactic fluconazole prevents candidiasis; however, this drug has no activity against molds. We performed a randomized trial to determine whether prophylactic itraconazole prevents invasive mold infections (IMIs). A total of 304 patients receiving allogeneic stem cell transplants (SCT) were randomized to receive fluconazole (400 mg/d) or itraconazole (oral solution 2.5 mg/kg 3 times daily, or intravenous 200 mg daily) for 180 days after SC transplantation, or until 4 weeks after discontinuation of graft-versus-host disease (GVHD) therapy. Proven or probable invasive fungal infections (IFI) were evaluated by intent-to-treat and “on-treatment” analyses. More patients in the itraconazole arm developed hepatotoxicities, and more patients were discontinued from itraconazole because of toxicities or gastrointestinal (GI) intolerance (36% versus 16%, P < .001). Intent-to-treat analysis demonstrated no difference in the incidence of IFI during the intended study period (fluconazole 16% versus itraconazole 13%, P = .46); however, fewer patients in the itraconazole arm developed IFI on treatment (fluconazole 15% versus itraconazole 7%, P = .03). Itraconazole provided better protection against IMI (fluconazole 12% versus itraconazole 5%, P = .03), but similar protection against candidiasis (3% versus 2%, P = .69). There was no difference in overall or fungal-free survival. Itraconazole appears to prevent IMI in the subset of patients who tolerate the drug; however, toxicities and poor tolerability limit its success as prophylactic therapy.

Human parainfluenza virus type 3 (hPIV3) infections cause considerable morbidity and mortality after stem cell transplantation, and inpatient nosocomial outbreaks are common. From September 1998 to July 1999, 93 stem cell transplantation recipients at our institution contracted hPIV3, of which 66 (71%) were being followed up in our outpatient department (OPD). The peak incidence was in September and October, when 39 cases were identified; thereafter, hPIV3 incidence decreased to approximately 5 cases per month. Nucleotide sequences (778 nucleotides from variable regions of the hemagglutinin-neuraminidase gene) from 46 patient and 8 community hPIV3 isolates were compared to determine epidemiologic relatedness. Sequence analysis of OPD isolates revealed that 18 of 19 isolates from September and October and 11 of 15 isolates from November 1998 to July 1999 were genetically similar. In contrast, 2 of 3 community isolates from September and October and 0 of 5 from November to July were linked to this cluster. Symptomatic surveillance and isolation were ineffective in terminating the outbreak, suggesting asymptomatic shedding among patients, staff, or visitors or viral persistence on environmental surfaces as possible explanations. The concept of nosocomial transmission should be expanded to include the OPD for immunosuppressed patients.