Abstract: The incidence of IFIs during VEN-HMA therapy is low, and the used antifungal prophylaxis approach did not influence the risk of IFIs. The risk of IFIs is higher in nonresponders and those who were treated in the r/r AML setting.

Abstract: CMV recipient seropositivity (R+) and CMVi are independent risk factors for increased mortality after alloHCT. Preemptive therapy (PET) was standard of care until LTV approval by the FDA in November 2017 for CMVi prevention in CMV R+ alloHCT patients (pts). In a registration trial, LTV led to a significant reduction in clinically significant CMVi (CS-CMVi) defined as CMVi requiring PET in both high-risk (HR) or low-risk (LR) recipients. In the HR-group, defined as mismatched related / unrelated donor with at least one mismatch in one of the four HLA-gene loci of HLA-A, -B, -C or -DRB1, haploidentical donor, umbilical cord source or grade ≥2 acute graft-versus-host disease (aGVHD) at randomization, the impact of LTV on CS-CMVi was more robust. Small studies have confirmed the positive impact of LTV on CS-CMVi. Here, we compared the natural history of CMVi and CS-CMVi between the pre-LTV and LTV era in the first 100 days after HR-alloHCT. We also explored the impact on non-relapse mortality (NRM), overall survival (OS), disease free survival (DFS), and incidence of aGVHD between the two eras. In this IRB approved retrospective study, we identified 450 consecutive HR-alloHCT pts who underwent their first HCT from 1/1/2016 to 12/31/2020 at our center. Pre-LTV era was from 1/1/2016 to 2/28/2018 and LTV era was from 3/1/2018 onwards when prophylaxis became standard of care (SOC) for all R+ alloHCT at our institution. In the HR-alloHCT, the uptake of the new SOC was consistent in all HR-R+ pts beginning LTV prophylaxis on day +7 post-HCT. We defined R+ HR-alloHCT pts at high-risk for CMVi or CS-CMVi as described above except for aGVHD (not recorded at time of institution of LTV). CMVi was defined as first time viral load (VL) of & gt;500 genomic copies/ml (gc/ml). CS-CMVi was defined as a VL & gt;500 gc/ml (910 IU/ml) on two consecutive tests done atleast 48 hours apart, that triggered PET (ganciclovir, valganciclovir, foscarnet, cidofovir), or had identification of CMV end organ disease . The incidence of CMVi and CS-CMVi in R+ allo-HCT was compared by LTV era using Gray test. Kaplan-Meier curves and log-rank tests were used for OS and DFS by LTV era. NRM, relapse, acute and chronic GVHD were compared using cumulative incidence curves and Gray test. All tests were 2-sided at 0.05 level. Of the 450 HR-alloHCT pts, 146 were R+ in pre-LTV vs. 246 R+ in LTV era. R+ patient, their eligible underlying disease, and HCT characteristics are shown in Table 1. There was a significant reduction in both CMVi and CS-CMVi in LTV era vs pre-LTV era (24.1% vs 45.2%, and 22.3% vs 44.5% respectively; p & lt;0.001 for both outcomes) in the first 100 days. Compared to pre LTV era, LTV era was associated with significantly reduced CS-CMVi among R+ pts (HR=0.39, 95%CI: 0.26-0.58, p & lt;0.001) in the multivariable Fine and Gray model adjusted for primary diagnosis, donor type and acute GVHD. CMVi was also reduced in the multivariable model (HR=0.41 and 95%CI: 0.28-0.61, p & lt;0.001). Although there were no significant differences in OS, DFS, NRM, relapse, and chronic GVHD between the two eras at 6, 12, and 18 months post-HCT in R+ pts, a trend towards improved OS and DFS in LTV era was noted (p=0.06 and p=0.07) in this patient population. There was a significantly lower rate of grade III-IV acute GVHD in the LTV era (9.2% vs 17.8% at day 100, p=0.012 with HR = 0.49). No case of CMV disease was identified in the first 100 days. LTV has substantially reduced CS-CMVi in the first 100 days post-HCT in HR-R+ pts and resultant burden from PET. We identified a significant reduction in grade III - IV aGVHD in LTV era suggesting that with reduced CMVi, LTV may have a salutary impact on development of aGVHD; this is in agreement with studies showing bidirectional relationship between CMVi and onset of aGVHD. We did not observe a significant difference in OS, DFS, NRM amongst the two eras but there was trend towards higher OS and DFS in LTV era that requires further assessment in a larger multicenter cohort. Lastly, significant burden persists from CS-CMVi in this patient population during the first 100 days of alloHCT that underscores the need of efforts to identify other novel methods to mitigate it. One of the limitations in the LTV era is identifying the clinical scenarios surrounding the CMVi and CS-CMVi that may relate to compliance, absorption from gastrointestinal tract, and affordability or coverage of LTV after discharge from hospital. Figure 1 Figure 1. Disclosures Dadwal: Astellas: Speakers Bureau; Aseptiscope: Consultancy; AlloVir: Research Funding; Shire/Takeda: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Other: Investigator; Karius: Other: Investigator. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Taplitz: Merck: Membership on an entity's Board of Directors or advisory committees. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Al Malki: Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; CareDx: Consultancy; Rigel Pharma: Consultancy; Hansa Biopharma: Consultancy.

Abstract: First in human trial of Triplex vaccine shows safety and expansion of durable CMV-specific T cells with potential for viremia control. Triplex is immunogenic in both CMV-seronegative and -seropositive healthy adults with or without previous smallpox vaccination.

Abstract: Patients undergoing HCT are at an increased risk of developing primary and/or reactivated CMV infection, although the magnitude of risk of CMV disease has decreased with the widespread use of preemptive ganciclovir. Most episodes of reactivation occur within the first year post-HCT and are associated with risk factors such as CMV serostatus of donor and recipient, development of acute graft vs. host disease (GVHD): and the immunosuppressive therapy used for its management. Because of prolonged periods of immunosuppression post-HCT, patients may be at risk for delayed CMV infection one or more years after HCT. However, the magnitude of risk of delayed CMV infection and characteristics of those at increased risk has not been described. Given the high morbidity and mortality associated with post-HCT CMV infection, identifying patients at high risk of delayed CMV could be useful for effective management. This report includes 2700 consecutive patients who survived more than one year after undergoing HCT at COH between 1976 and 2003; these included 1404 autologous HCT recipients and 1296 allogeneic HCT recipients (1043 related donor; 253 unrelated donor recipients). Median age at HCT was 38 years (range, 0.6 to 79 years) and 59% of the cohort was males. Median follow-up time from HCT until delayed CMV infection/disease, death, or end of study period (12/31/2006), whichever occurred first, was 4.3 years (range:1–26.6 years). Medical records from COH and/or outside facilities were the main source of data for CMV occurrences. In total, 33 patients (1%) developed delayed CMV infection after surviving at least one year post-HCT (1 autologous and 32 allogeneic [20 related donor and 12 unrelated donor HCT] ) developed a total of 40 episodes of delayed CMV that included pneumonia (n=16), gastrointestinal disease (n=8), retinitis (n=2), hepatitis (n=1), concurrent pneumonia and hepatitis (n=1), and asymptomatic reactivation (n=12). The overall cumulative incidence of delayed CMV infection was 1.3% (95% Confidence Interval [CI], 0.9–1.8%) at 5 years from HCT. For autologous HCT recipients, the incidence was 0.07% at 1 year based on 1 event. Among allogeneic HCT recipients, the cumulative incidence at 5 years post-HCT was 2.1% [95%CI, 1.2–3.0%] for related donor HCT recipients; and 5.0% [95%CI, 2.2–7.7%] for unrelated donor HCT recipients. Among allogeneic HCT recipients, the risk factors for the development of delayed CMV infection included unrelated donor HCT (hazard ratio [HR] = 2.5, 95% CI, 1.1–5.7) and CMV seropositive status of the recipient (HR=7.7, 95% CI 1.0–57.0) (Figure). Interestingly, donor CMV status was not associated with increased risk of delayed CMV. All 32 allogeneic HCT recipients experienced chronic GVHD, with prolonged exposures to corticosteroids (median=494 days), and cyclosporine (median=380 days). Thirty patients with delayed CMV infection (94% of the allogeneic HCT recipients with delayed CMV) were receiving immunosuppressive therapy for management of chronic GVHD at onset of delayed CMV. A total of eight patients with delayed CMV did not have a history of CMV infection in the first year, and were characterized by the following clinical and demographic features: 6 (75%) were male; median age at HCT was 35 years; one was an autologous HCT recipient, who relapsed 10 months post-HCT for non-Hodgkin lymphoma, received further chemotherapy and radiation, including Rituximab and then developed late CMV, just over one year post-HCT. The seven allogeneic HCT recipients had chronic GVHD, and were CMV serostatus positive prior to HCT, with 4 also having CMV seropositive donors. Of the 33 patients with delayed CMV in this study, 26 expired; median survival after the development of delayed CMV was 46 days. This study describes the magnitude of risk of delayed CMV infection in autologous and allogeneic HCT recipients and identifies at risk patients as those who are seropositive for CMV, undergoing unrelated HCT, and those with prolonged exposures to immunosuppressive therapy for cGVHD (Figure), suggesting the need for a close surveillance of these patients at high risk. Figure Figure

Abstract: Cytomegalovirus reactivation commonly referred to as CMV infection (CMVi) is a frequent event after allogeneic hematopoietic cell transplantation (HCT), with studies associating CMVi within the first 100 days post-HCT with higher risk of non-relapse mortality (NRM) and decreased overall survival (OS). In addition, understanding the impact of CMVi on resource utilization during the primary HCT admission is critical. Together, this knowledge of epidemiology and resource utilization may be used to inform preventive strategies to minimize CMVi, e.g., use of antiviral agent letermovir. After receiving IRB approval, we retrospectively reviewed institutional electronic medical records and CMVi database from 824 patients who underwent their first allogeneic HCT between 2011 and 2016 at City of Hope (pre-letermovir era). Patients were censored at death, disease relapse or lost to follow up. Data collected: demographics, HCT indication, conditioning regimen, CMV serostatus of the donor and recipient (D/R), length of stay (LOS) for primary HCT admission (all allo HCT were performed as inpatient), readmission rates in first 100 days, and use of supportive care. CMV viral load of & gt;250 genomic copies/ml constituted a diagnosis of CMVi. CMV viral load surveillance in MUD recipients began at engraftment or day +21 post-HCT, whichever occurred earlier. For Haplo and cord blood (CB) HCT, CMV viral load surveillance started on day +14. The primary endpoint of the study was LOS for HCT admission. Supportive care use, transfusions, growth factors and antiviral usage were secondary endpoints. The differences in resource utilization between different groups were examined by CMVi during the primary HCT admission period, using Wilcoxon test or chi-square test whenever appropriate. Median age of patients at the time of HCT was 52 years (range: 1-78), with 57% of patients being male. The most common diagnoses included: AML (39%), ALL (21%) and MDS/MPN (17%). Patients underwent MUD (n=627, 76%), Haplo (n=102, 12%), or CB-HCT (n=95, 12%), and 44% of patients received myeloablative conditioning regimen. Majority of the patients were CMV seropositive (83.7%). Graft source was peripheral blood stem cells in 75% of the recipients. Most commonly used graft-versus-host disease prophylaxis consisted of post-transplant cyclophosphamide (100%), Tacrolimus/sirolimus (83%), and cyclosporine/cellcept (78%) in Haplo, MUD, and CB-HCT recipients, respectively. During the primary HCT admission, rate of CMVi was 7%, 36% and 28% in all of MUD, Haplo, and CB-HCT, respectively (compared to 25%, 71.6%, and 50.5% in MUD, Haplo and CB-HCT respectively in the first 100 days after HCT). Rate of CMVi in CMV+ recipients was 8.2% in MUD, 41.6% Haplo and 34.2% in CB-HCT (Table 1). Majority of patients with CMVi received antiviral therapy (85.8%), with Haplo and CB-HCT more likely to be treated than MUD (p=0.023). LOS was longer among CMVi patients compared to no CMVi patients in each donor type, median of 59 vs. 36 days for the overall cohort (p & lt;0.01). The difference in LOS by CMVi remained significant (p & lt;0.001) in the multivariable regression model including donor type, graft source, primary diagnosis and conditioning intensity (Table 2). Filgastrim use was higher among CMVi patients than no CMVi patients in MUD (p & lt;0.001), but not in Haplo or CB-HCT (p & gt;0.2). Transfusion of packed red blood cells (PRBC) and platelet units were significantly higher among CMVi recipients of MUD and Haplo (p & lt;0.02), but not CB-HCT (p & gt;0.82). There was no significant difference in hospital readmission by CMVi across donor type in the first 100 days (p & gt;0.5). In conclusion, the rate of CMVi during primary HCT admission was high, particularly in the Haplo and Cord HCT ( & gt;50% of the CMVi occurring within 100 days of HCT). Given the relatively high CMV viral load cut-off values and later CMV surveillance initiation, the rate could, in fact, have been underestimated in our cohort. CMVi during primary HCT admission was associated with significantly higher health care resource utilization; longer hospital LOS and supportive care utilization (CMV specific antiviral usage, transfusion and growth factors use). Prophylactic strategies to prevent early CMVi in alloHCT should be considered to decrease NRM and improve value based care delivery. Disclosures Dadwal: Shire/ Takeda: Research Funding; Karius: Research Funding; Astellas: Speakers Bureau; Janssen: Other: Advisory board meeting; Ansun Biopharma: Research Funding; Chimerix: Research Funding; Gilead: Research Funding; Merck: Consultancy, Honoraria, Other: Advisory board meeting, Research Funding, Speakers Bureau. Pullarkat:Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Taplitz:Merck: Other: Immunocompromised Advisory Group. Al Malki:Neximmune: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy. Nakamura:NapaJen Pharma: Consultancy; Magenta Therapeutics: Other: Advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Viracor: Consultancy; Merck: Other: advisory board meeting; Kadmon Corporation: Other: Advisory board meeting.

Abstract: Sepsis and severe sepsis contribute significantly to early treatment-related mortality after hematopoietic cell transplantation (HCT), with reported mortality rates of 30 and 55% due to severe sepsis, during engraftment admission, for autologous and allogeneic HCT, respectively. Since the clinical presentation and characteristics of sepsis immediately after HCT can be different from that seen in general population or those who are receiving non-HCT chemotherapy, detecting early signs of sepsis in HCT recipients becomes critical. Herein, we developed and validated a machine-learning based sepsis prediction model for patients who underwent HCT at City of Hope, using variables within the Electronic Health Record (EHR) data. We evaluated a consecutive case series of 1046 HCTs (autologous: n=491, allogeneic: n=555) at our center between 2014 and 2017. The median age at the time of HCT was 56 years (range: 18-78). For this analysis, the primary clinical event was sepsis diagnosis within 100 days post-HCT, identified based on - use of the institutional sepsis management order set and mention of "sepsis" in the progress notes. The time of sepsis order set was considered as time of sepsis for analyses. To train the model, 829 visits (104 septic and 725 non-septic) and their data were used, while 217 visits (31 septic and 186 non-septic) were used as a validation cohort. At each hour after HCT, when a new data point was available, 47 variables were calculated from each patient's data and a risk score was assigned to each time point. These variables consisted of patient demographics, transplant type, regimen intensity, disease status, Hematopoietic cell transplantation - specific comorbidity index, lab values, vital signs, medication orders, and comorbidities. For the 829 visits in the training dataset, the 47 variables were calculated at 220,889 different time points, resulting in a total of 10,381,783 data points. Lab values and vital signs were considered as changes from individual patient's baselines at each time point. The baseline for each lab value and vital sign were the last measured values before HCT. An ensemble of 20 random forest binary classification models were trained to identify and learn patterns of data for HCT patients at high risk for sepsis and differentiate them from patients at lower sepsis risk. To help the model learning patterns of data prior to sepsis, available data from septic patients' within 24 hours preceding diagnosis of sepsis was used. For 829 septic visits in the training data set, there were 5048 time points, each having 47 variables. Variable importance for the 20 models was assessed using Gini mean decrease accuracy method. The sum of importance values from each model was calculated for each variable as the final importance value. Figure 1a shows the importance of variables using this method. Testing the model on the validation cohort results in an AUC of 0.85 on the test dataset (Figure 1b). At a threshold of 0.6, our model was 0.32 sensitive and 0.96 specific. At this threshold, this model identified 10 out of 31 patients with a median lead time of 119.5 hours, of which 2 patients were flagged as high risk at the time of transplant and developed sepsis at 17 and 60 days post-HCT. The lead time is what truly sets this predictive model apart from detective models with organ failure or dysfunction or other deterioration metrics as their detection criteria. At a threshold of 0.4, our model has 0.9 sensitivity and 0.65 specificity. In summary, a machine-learning sepsis prediction model can be tailored towards HCT recipients to improve the quality of care, prevent sepsis associated-organ damage and decrease mortality post-HCT. Our model significantly outperforms widely used Modified Early Warning Score (MEWS), with AUC of 0.73 in general population. Possible application of our model include showing a "red flag" at a threshold of 0.6 (0.32 true positive rate and 0.04 false positive rate) for antibiotic initiation/modification, and a "yellow flag" at a threshold of 0.4 (0.9 true positive rate and 0.35 false positive rate) suggesting closer monitoring or less aggressive treatments for the patient. Figure 1. Figure 1. Disclosures Dadwal: MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Research Funding; AiCuris: Research Funding; Shire: Research Funding.

Abstract: In the era of preemptive antiviral therapy, cytomegalovirus (CMV) still remains the cause of major health complications, profound defects in immune reconstitution, and significant morbidity in post-transplant recovery of immune-compromised HCT recipients. Substituting antivirals with a vaccine that harnesses the native immune response to CMV may improve outcomes for HCT recipients. Modified Vaccinia Ankara (MVA), a vaccinia virus being investigated as a smallpox vaccine by the Defense Department, is a safe and robust delivery system to treat or prevent a wide range of diseases including HIV and cancer. Replication-defective MVA is safe, well tolerated and strongly immunogenic when given to HCT recipients or AIDS patients. We developed a multiple-antigen recombinant MVA with genes encoding 3 immunodominant CMV proteins: UL83 (pp65), UL123 (IE1-exon4), and UL122 (IE2-exon5) (CMV-MVA-Triplex), and established its pre-clinical safety and immunogenicity using humanized HLA transgenic mouse models and human PBMC from CMV-seropositive healthy volunteers and HCT recipients. Defining safety, persistence of the virus, maximum tolerated dose and immunogenicity of CMV-MVA-Triplex in healthy volunteers is a critical first step in its clinical development for HCT recipients as required by the FDA. In a Phase I trial (NCT01941056), these endpoints were evaluated in 24 healthy volunteers (age: 18-60), with or without prior immunity to CMV and vaccinia. Three escalating dose levels (DL) were administered intramuscularly (DL1=10xE7; DL2=5x10E7; DL3=5x10E8 pfu/dose) in 8 subjects/DL, with a booster injection 28 days later, and follow up for 1 year. As of July 2015, all 24 planned volunteers were enrolled, vaccinated and followed for at least 4 months. Vaccinations at all DL were well-tolerated, with only a few expected injection reactions and no SAE or dose limiting toxicities. Immunogenicity of the vaccine was evaluated by measuring the levels of the CD137 T-cell surface marker representing functional activation of PBL harvested from vaccinees and stimulated 24 hours with full-length pp65, IE-1 and IE2 overlapping peptide libraries, or direct measurement of CMV-specific T-cells using HLA multimers. CMV-MVA-Triplex induced robust expansion of pp65-, IE1- and IE2-specific CD8 and CD4 T-cells in vaccinated CMV-seropositives, at each DL (Cf. plot showing geometric mean with upper lower/limits of the pp65 T-cell levels for DL2 cohort). HLA multimers identified CMV-specific T-cells whose expansion closely followed CD137-activated CMV-specific T-cells in vaccinees with common HLA alleles which have a corresponding known CMV-CTL epitope (data to be presented). A statistical analysis performed using generalized estimated equations indicated that the post-vaccination levels of pp65-, IE1- or IE2-specific CD8 and CD4 T-cells were significantly increased, with p-values ranging from 3x10-5 to 0.025. For example, the pre-/post-vaccination median pp65-reactive CD4+ CD137+ T-cells rose from 1.3 to 4.4 cells/µL (p=3x10-5); and pp65-reactive CD8+ CD137+ T-cells rose from a median of 0.22 to 3.1 cells/µL (p=0.003). Importantly, robust immunity was detected in CMV-seronegatives (as shown in the plot for UPN 14 and 18), as well as in subjects who had received smallpox vaccinations. Elevated frequencies of CMV-specific CD4 and CD8 T cells for all 3 antigens plateaued after day 56, but in most cases remained elevated up to one year post-vaccination (data to be presented). Circulating MVA vector in blood was assessed by real-time PCR post-injection and showed only minimal residual vector DNA [10-30 gc/mL] in just 2 vaccinees in the DL3 cohort that disappeared within 3 months. These results provide evidence that CMV-seropositive HCT recipients, whether they receive stem cell product from CMV-seropositive or -seronegative donors could respond to CMV-MVA-Triplex by generating protective CMV-specific immunity. CMV-MVA-Triplex is the first vaccine against CMV that uses a recombinant MVA incorporating multiple CMV antigens, developed for HCT recipients, who are at risk for CMV reactivation. The safety and marked immunogenicity of CMV-MVA-Triplex in this Phase I trial, warrant testing of the vaccine in the HCT setting. A Phase 2 multicenter, placebo-controlled trial to assess CMV-MVA-Triplex in CMV seropositive recipients, receiving HCT from matched related or unrelated donors will start in Fall 2015. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Diamond: Helocyte, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Abstract: The prevalence of vancomycin-resistance Enterococci colonization (VRE-C) in patients undergoing allogeneic hematopoietic cell transplantation (aHCT) is between 23-40%. Pre-HCT VRE-C is shown to be associated with high risks of VRE bloodstream infection (VRE-BSI), non-relapse mortality (NRM) and lower overall survival. Recent studies investigating the association between VRE-C and risk of acute graft-versus-host disease (aGVHD) after aHCT has demonstrated conflicting results, possibly due to the heterogeneous transplant conditioning and GVHD prophylactic regimens. Here, we sought to examine the VRE-C prevalence and determine its impact on aHCT outcomes, in patients receiving tacrolimus and sirolimus (T/S) as aGVHD prophylaxis. To explore the association between pre-HCT VRE-C and transplant outcomes, we retrospectively reviewed medical records of a cohort of 1074 consecutive patients who underwent aHCT at City of Hope from 2014 to 2017. Patients with stool culture screening within 30 days pre-aHCT (n=862) were identified from the microbiology database and were grouped as VRE-C and non-colonized (VRE-NC). Data was not available on VRE-C in 185 patients and they were not included in analysis. Overall survival (OS) and progression-free survival (PFS) were examined by Kaplan-Meier curves and log-rank tests. Non-relapse mortality (NRM), VRE-BSI, and GVHD rates of the 2 groups were compared by cumulative incidence rates and Gray's test. Multivariate analyses were performed when adjusting for prognostic factors. Two-sided P value of ≤0.05 was considered significant. Of the 862 evaluated patients, 68 had VRE-C (7.9% prevalence). Median age of patients in VRE-C and VRE-NC groups were 53 and 55 years, respectively. Gender distribution, transplant indications, stem cell source, proportion of unrelated donors, GVHD prophylaxis with T/S and other clinical variables including intensity of conditioning regimen and HCT-CI were similar between the two groups (Table 1) . Karnofsky performance status (KPS) of 90-100 and 70-80 were seen in 40% and 53% of patients with VRE-C compared to 47% and 48% of VRE-NC patients (p=0.12). Overall, VRE-BSI episodes were rare (n=7) with 4 patients in VRE-C (6.1%) and 3 patients in VRE-NC (0.4 %); p 〈 0.001. All 3 patients in the VRE-NC group developed bacteremia within the first 100 days (range 2-97) but VRE-BSI was not the eventual cause of death. The median onset of VRE-BSI in the VRE-C group (n=4) was only 6 days (range: 2-12) with 1 surviving patient and 3 who died of non VRE-BSI related causes. No statistical significance was detected in rates of non-VRE BSI (24.1% in VRE-C Vs. 19.2% in VRE-NC; p=0.30) and fungemia (1.5% in VRE-C vs 1.2% VRE-NC; p=0.77). At a median follow-up duration of 19.4 months (range: 2.7-48.4), similar 1-year OS was achieved in both groups (67.4% in VRE-C and 76.5% in VRE-NC; p=0.11) but 1 year PFS was significantly lower in the VRE-C cohort (55.6% Vs. 69.4%; p=0.038). Higher NRM was achieved in the VRE-C cohorts on days +100 and +365 (11.8% Vs. 7.2% and 25.1% Vs. 14.4%, respectively, p=0.041). (Figure 1) There were no differences in rates of day 100 aGVHD (grades II-IV) (Figure 2) and relapse rates at 12 months between the two groups. Conditioning regimen intensity, donor type, KPS, and primary diagnosis were significantly associated with NRM. When these variables were included in the multivariate model, VRE-C was found to be independently associated with higher NRM (HR=1.82, 95%CI: 1.12-2.93; p=0.015). In conclusion, in our cohort of patients receiving predominantly T/S-based aGVHD prophylaxis, no association was detected between VRE-C and aGVHD incidence. Higher rate of VRE-BSI in the VRE-C group is in accordance with published data, albeit lower rates of VRE-BSI was seen in our cohort. VRE-C contributed to higher NRM at days 100 and 365 post-aHCT and was an independent risk factor for poor HCT outcomes Since VRE-C is a potentially modifiable risk factor, our data supports continued efforts for specific interventional strategies (i.e. antimicrobial stewardship) to reduce drug resistant bacterial colonization, and for clinical research to reverse the impact of VRE-C, such as the use of agents, which may modulate gut microbiome. Disclosures Salhotra: Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Dadwal:AiCuris: Research Funding; Gilead: Research Funding; MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding.

Abstract: Background: Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are at high risk of reactivation or de novo infection with double-stranded (ds) DNA viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), adenovirus (AdV), BK virus (BKV), and JC virus (JCV). After allo-HCT, up to 90% patients develop detectable viremia by PCR. EMR data collected between 2018 and April 1, 2021, from over 1400 high-risk allo-HCT patients at 21 US centers suggest that 40-50% develop clinically significant viral infection or disease associated with ≥1 of these dsDNA viruses within 200 days of transplant. Multiple studies demonstrate increased morbidity and mortality associated with viremia, with or without end-organ disease. Prophylactic and preemptive therapies have substantial side effects and can lead to the development of resistance, especially in CMV. HCT donor-derived virus-specific T-cells have shown promise in preventing single virus infections in prior clinical trials but were infeasible for wide-scale use. There is an urgent unmet medical need for preventive strategies targeting multiple viruses in patients undergoing high-risk allo-HCT. Methods: We are conducting a clinical trial (NCT04693637) to evaluate the safety and efficacy of posoleucel (ALVR105, Viralym-M) for preventing clinically significant viral infections due to CMV, EBV, HHV-6, AdV, BKV, and JCV in high-risk allo-HCT recipients. Posoleucel is an ex-vivo expanded, partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product generated from healthy, third-party donors targeting CMV, EBV, HHV-6, AdV, BKV, and JCV. In the open-label portion of the study, patients receive up to seven infusions of 4×10 7 cells of posoleucel administered once every 14 days. High-risk patients are those who received a graft from a sibling or unrelated donor with ≥1 HLA mismatch; from a haploidentical donor; from umbilical cord blood or with T-cell-depletion; as well as patients with lymphocytes & lt;180/mm 3 or CD4 T cells & lt;50/mm 3 at enrollment. Patients must be engrafted and within 15-49 days of allo-HCT. Those with grade ≥3 GVHD as well as those requiring steroids ( & gt;0.5 mg/kg/day prednisone equivalent) at enrollment are ineligible. Patients are tested weekly for viremia using quantitative PCR assays and are monitored every other week for adverse events. The primary endpoint is the number of clinically significant viral infections or episodes of end-organ disease due to CMV, EBV, HHV6, AdV, BKV, or JCV by week 14. Results: Data are available for 12 of 25 planned participants thus far (Table 1). No patient developed a clinically significant infection within 14 weeks, the primary study endpoint. Over the entire study duration, defined as the primary 14-week treatment period plus the additional 12-week follow-up, 11 (92%) patients have remained free of any clinically significant viral infections, the key secondary endpoint. One patient, a 49-year-old female haploidentical transplant recipient, developed clinically significant AdV viremia after receiving over a month of high-dose methylprednisolone exceeding 0.5 mg/kg/day for recurrent aGVHD. This patient was administered IV cidofovir in week 15 of the study. During the primary study efficacy period one participant received 2 doses of valganciclovir following transient CMV viremia deemed not to be clinically significant by the principal investigator. Posoleucel has been well tolerated to date, with no drug-related serious adverse events, new-onset acute GVHD, or cytokine release syndrome. Safety and efficacy data from the entire open-label cohort will be presented. Conclusions: Preliminary results in this open-label cohort show that in high-risk allo-HCT patients receiving off-the-shelf posoleucel, clinically significant viral infections or disease from the 6 targeted dsDNA viruses were uncommon. No clinically significant infections were observed among participants treated in accordance with the protocol. These results, combined with the favorable safety and tolerability profile of posoleucel, support its continued evaluation in high-risk allo-HCT recipients for the prevention of CMV, EBV, HHV6, AdV, BK virus, or JC virus infection and disease. Figure 1 Figure 1. Disclosures Dadwal: Shire/Takeda: Research Funding; Astellas: Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AlloVir: Research Funding; Aseptiscope: Consultancy; Janssen: Other: Investigator; Karius: Other: Investigator. Shuster: Bristol Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Intellisphere: Consultancy, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company; Rafael: Research Funding; Celgene: Consultancy, Current equity holder in publicly-traded company; Incyte: Research Funding; Beigene: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Actinium: Research Funding; GSK: Research Funding; Pharmcyclics: Consultancy, Research Funding, Speakers Bureau; Epizyme: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; AlloVir: Research Funding; Janssen: Consultancy, Speakers Bureau; Astellas: Consultancy, Research Funding, Speakers Bureau; MorphSys: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau. Myers: Novartis: Consultancy, Speakers Bureau; AlloVir: Research Funding; Eliana: Consultancy, Membership on an entity's Board of Directors or advisory committees. Boundy: AlloVir: Current Employment, Current equity holder in publicly-traded company. Warren: AlloVir: Consultancy. Stoner: AlloVir: Current Employment, Current equity holder in publicly-traded company. Hill: Octapharma: Consultancy; OptumHealth: Consultancy; CRISPR therapeutics: Consultancy; CLS Behring: Consultancy; Allogene therapeutics: Consultancy; Gilead: Consultancy, Research Funding; Allovir: Consultancy, Research Funding; Amplyx: Consultancy; Takeda: Consultancy, Research Funding; Karius: Research Funding.

Abstract: Preventing viral infections at an early stage is a key strategy of successfully improving transplant outcomes. Preemptive therapy and prophylaxis using antiviral agents have been used successfully to prevent clinically significant viral infections in hematopoietic cell transplant (HCT) recipients. Major progress has been made over the past decades in preventing viral infections through a better understanding of the biology and risk factors as well as the introduction of novel antiviral agents and advances in immunotherapies. High quality evidence exists for the effective prevention for herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV) infection and disease. Fewer data are available on the effective prevention of human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), Adenovirus (ADV) and BK virus infections. To highlight the spectrum of clinical practice, here we review high-risk situations that we handle with a high degree of uniformity, and cases that feature differences in approaches, reflecting distinct HCT practices such as ex-vivo T cell depletion.