Myeloneuropathy following intrathecal chemotherapy and craniospinal radiation is multifactorial, especially in post-transplant patients with hematologic malignancies. Superimposed viral infections such as HHV6 further complicate the clinical picture. A 31-year-old woman with secondary AML arising from CML (MECOM rearrangement, complex karyotype) underwent allogeneic stem cell transplant from a 10/10 HLA matched unrelated donor on clinical trial (NCT03802695) following thiotepa, busulfan, and fludarabine conditioning with ex vivo engineered graft (Naive T cell depleted; OrcaQ graft) with no post HCT immunosuppression. She previously received prophylactic craniospinal irradiation pre HCT due to multiple CNS relapses for which she received ITC. Post HCT she achieved full CD3 donor chimerism and >4 log reduction of BCR::ABL PCRs on peripheral blood testing. On around HCT day +7 she developed bilateral lower extremity weakness, sensory loss, and urinary incontinence. Initial MRI showed T2 hyperintensities in the posterior cord from C7–T11. Early CSF analysis revealed elevated myelin basic protein but normal CSF protein without evidence of infection, pleocytosis, autoimmune disease, or relapsed leukemia. She was treated empirically with B12/B9/B6, dextromethorphan, SAM, leucovorin, IVIG, steroids, and plasma exchange without neurological improvement. Subsequent CSF demonstrated high HHV6 viral load and elevated protein and HHV6 viremia. She started on foscarnet. Repeat lumbar puncture confirmed HHV6 clearance. A craniospinal MRI 26 days after foscarnet initiation showed new mesial temporal lobe enhancement consistent with HHV6 encephalitis and progression of spinal cord lesions consistent with worsening myelitis. Foscarnet was discontinued after 28 days after resolution of HHV6 infection in blood/CSF. Nerve conduction studies and somatosensory evoked potentials revealed a superimposed severe axonal motor neuropathy, adding further complexity to her clinical picture. This case highlights a multifactorial neurologic syndrome involving myeloneuropathy and encephalitis, likely due to overlapping neurotoxicity from intrathecal chemotherapy, craniospinal radiation, and HHV6. Serial CSF and imaging studies were essential to clarify etiology. Integrated antiviral and supportive therapies remain critical in managing such complex transplant-associated neurologic syndromes.

Abstract Background Beta-lactam allergy (BLA) is associated with increased broad-spectrum antibiotic (Br-ABX) use, worse clinical outcomes, and higher costs. Our hospital-wide BLA protocol (BLA-P) was launched in 7/2021 with following categories: intolerance, low-risk (urticaria only >5 years ago, mild rash, remote childhood reaction with limited details), and high-risk (angioedema, anaphylaxis, severe rashes). Delabeling was done directly based on antibiotic history/interview alone (direct-delabeling), or via graded challenge for low-risk patients. We evaluated the delabeling rate and its impact on Br-ABX usage. Methods Hospitalized patients ≥ 18 years old with listed BLA during 10/2021-12/2022 were eligible. Exclusion criteria were critically ill, surgical, hospice or comfort care, or non-verbal patients. Assessment was counted each time a pharmacist evaluated BLA; multiple assessments could occur in case of prolonged hospital stay or multiple admissions. Interventions were categorized as no further action (due to high-risk allergy, patient refusal for any update, clinical status), updated allergy label, or delabeled. Missed assessments were reported due to logistical issues. Br-ABX usage was compared in the delabeled patients: the empiric antibiotic use 90 days post-intervention versus pre-intervention using McNemar test (SPSS). Results A total of 700 assessments in 631 unique patients with BLA were identified (Figure 1). 556 assessments in 489 unique patients (median age 63 years, 41% male, 46% hematological cancer) met inclusion criteria. In this cohort, the assessments revealed 8% intolerance, 54% low-risk, 17% high-risk and 21% unknown allergy. Interventions resulted in no further action 7%, updated label 72%, and delabeling 21%. 65% of the delabeling was done via direct-delabeling and 35% via graded challenge (Figure 1). Passing rate with graded challenge was 97%. The use of aztreonam and meropenem decreased significantly in delabeled patients compared to pre-delabeling while cefepime and piperacillin-tazobactam usage increased (Table 1). Conclusion Implementation of BLA-P led to 21% delabeling, which resulted in increased use of preferred Br-ABX and a significant decrease in meropenem and aztreonam use. Disclosures Sanjeet S. Dadwal, MD, FACP, FIDSA, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope, Inc: Stocks/Bonds|Astellas: Honoraria|Karius: Grant/Research Support|Matinas Biopharma: Stocks/Bonds|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer/Amplyx: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Honoraria|Viracor: Honoraria Randy Taplitz, MD, Karius: Advisor/Consultant|Merck: Advisor/Consultant|SNIPR biome: Advisor/Consultant

The acquisition or reactivation of Epstein–Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population.

There is an increased risk of infection in patients with cancer that results in higher morbidity and mortality. Several risk factors can predispose these patients to infectious complications. Some such factors include immunocompromised states like neutropenia, allogeneic hematopoietic cell transplantation, and graft-versus-host disease, while others include immunosuppressive agents like corticosteroids, purine analogs, monoclonal antibodies, and other emerging cancer therapeutics like CAR T-cell therapy. The NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections address infection concerns that may be observed in these immunocompromised populations and characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This paper highlights 2 recently updated sections of the guidelines, namely, infection concerns related to CAR T-cell therapy and antimicrobial prophylaxis recommendations, including vaccination, in patients at high-risk for infections.

There is an increased risk of infection in patients with cancer that results in higher morbidity and mortality. Several risk factors can predispose these patients to infectious complications. Some such factors include immunocompromised states like neutropenia, allogeneic hematopoietic cell transplantation, and graft-versus-host disease, while others include immunosuppressive agents like corticosteroids, purine analogs, monoclonal antibodies, and other emerging cancer therapeutics like CAR T-cell therapy. The NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections address infection concerns that may be observed in these immunocompromised populations and characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This paper highlights 2 recently updated sections of the guidelines, namely, infection concerns related to CAR T-cell therapy and antimicrobial prophylaxis recommendations, including vaccination, in patients at high-risk for infections.

OBJECTIVE:To develop and validate tools for measuring inpatient gastroenterology (GI) consultation quality on oncologic patients. METHODS:A total of 145 inpatient GI consults were analyzed using electronic health records in this cross-sectional study. Essential Consult Elements on oncologic-hospitalized patients (EE-COH) and Hospitalized Oncologic Patients Enhanced Quality of Consult Assessment Tool (HOPE-QCAT) were used for grading. Interrater reliability was assessed. RESULTS:Both EE-COH and HOPE-QCAT showed near-perfect interrater reliability across most measures in the validation cohort. On application of these measures for quality assessment, basic evaluation by the requesting hospitalist was partially complete in 24.8%, the request for GI consultation was inappropriate in 18.6%, while the rationale for recommended studies from the GI consultant was provided in 55.7% of cases suggesting key areas for quality improvement. CONCLUSION:We developed highly reliable quality measures for inpatient GI consults on oncology patients. The EE-COH and HOPE-QCAT tools can be utilized in future studies of inpatient GI consult quality and to form the basis for interventions to improve communication between consultants and hospitalists. Such tools could be adapted for inpatient quality assessment across other specialties and settings.

Background. Continuing antifungal prophylaxis (AFPx) to prevent invasive mold infections (IMIs) in recipients of allogeneic hematopoietic cell transplantation (alloHCT) after primary hospital discharge from alloHCT admission varies among transplant centers despite recommendations to continue prophylaxis through day +75. Characteristics driving AFPx prescribing at hospital discharge and outcomes are unknown. Methods. In this retrospective analysis, we reviewed patients continuing AFPx vs no AFPx at hospital discharge. We included patients with a hospital stay >= 7 days and <= 40 days. We excluded patients with a history of IMI prior to alloHCT, new IMI during admission, or death prior to discharge. Our primary objective was incidence of probable or proven IMI per the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Our secondary objectives were nonrelapse mortality at day +100, overall survival at day +100, and characteristics driving AFPx discontinuation at hospital discharge. Results. Of the 430 patients identified, 387 met inclusion criteria. At discharge, 56% (217/387) continued AFPx, and 44% (170/387) had no AFPx. At day +100, 3 probable IMI cases occurred in the group with continued AFPx vs 1 probable IMI case in the no-AFPx group (no proven IMI). Univariate analysis showed no difference in cumulative incidence of probable IMI (P = .440), nonrelapse mortality (P = .072), and overall survival (P = .855) between groups. Multivariable logistic regression demonstrated that patients were less likely to continue AFPx if they had a diagnosis other than acute myeloid leukemia, a length of stay <= 30 days, acute graft-vs-host disease grade 0 or 1, and corticosteroid use <= 5 days. Conclusions. There was no difference in probable IMI at day +100 after alloHCT based on continuing vs discontinuing AFPx at hospital discharge after alloHCT admission supporting a risk-adapted prophylaxis approach.

PURPOSE:The aim of this study was to assess the cost effectiveness of letermovir prophylaxis with the option for subsequent pre-emptive therapy (PET) for the prevention of cytomegalovirus (CMV) infection compared with a PET-only scenario in adult allogeneic hematopoietic stem cell transplant (allo-HCT) recipients in the United States over a 10-year time horizon.MATERIALS AND METHODS:A publicly available decision tree model was constructed using a commercial third-party payer perspective to simulate an allo-HCT recipient's clinical trajectory in the first-year post-transplant, followed by entry to a Markov model to simulate years 2 through 10. Clinical inputs and utility estimates were derived from published literature. Costs were derived from published literature and US Department of Veterans Affairs Federal Supply Schedule drug pricing. Outcomes assessed included life expectancy, quality-adjusted life-years (QALYs), direct medical costs, and the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the findings.RESULTS:Compared with PET alone, letermovir prophylaxis was projected to increase life-years per person (4.99 vs. 4.70 life-years), and increase QALYs (3.29 vs. 3.08) and costs (US$83.411 vs. US$70,698), yielding an ICER of US$59,356 per QALY gained. One-way sensitivity analyses indicated our model was sensitive to mortality (ICER: $164,771/QALY) and utility (letermovir ICER: $117,447/QALY; PET ICER: $107,290/QALY) in the first-year post-transplant. In 57.1% of the PSA simulations, letermovir was a cost-effective option using a willingness-to-pay threshold of US$100,000 per QALY.CONCLUSIONS:Letermovir prophylaxis is cost effective compared with PET alone with a willingness-to-pay threshold of US$100,000 per QALY gained. Sensitivity analysis results indicate future research is required to understand the impact of mortality and quality of life in the first-year post-transplant to arrive at a conclusive decision on letermovir adoption.

Patients with cancer are increasingly vulnerable to infections, which may be more severe than in the general population. Improvements in rapid and timely diagnosis to optimize management are needed. We conducted a systematic literature review to determine the unmet need in diagnosing acute infections in immunocompromised patients with cancer and identified 50 eligible studies from 5188 records between 1 January 2012 and 23 June 2022. There was considerable heterogeneity in study designs and parameters, laboratory methods and definitions, and assessed outcomes, with limited evaluation of diagnostic impact on clinical outcomes. Culture remains the primary diagnostic strategy. Fewer studies employing molecular technologies exist, but emerging literature suggests that pathogen-agnostic molecular tests may add to the diagnostic armamentarium. Well-designed clinical studies using standardized methodologies are needed to better evaluate performance characteristics and clinical and economic impacts of emerging diagnostic techniques to improve patient outcomes.

Purpose of review Our aim is to review recent literature on antibiotic use in patients with neutropenia. Recent findings Prophylactic antibiotics are associated with risks and have limited mortality benefit. While early antibiotic use in febrile neutropenia (FN) is critical, early de-escalation or discontinuation may be safe in many patients. Summary With an increasing understanding of potential risks and benefits of use and improved risk assessment, paradigms of antibiotic use in neutropenic patients are changing.

Background: Community-acquired respiratory viruses such as influenza (Flu), human metapneumovirus (hMPV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV) are leading causes of morbidity and mortality after hematopoietic cell transplant (HCT) or solid organ transplant (SOT). While these viruses may begin in the upper respiratory tract, ~50% of cases progress to the lower respiratory tract, potentially leading to more severe conditions such as pneumonia, bronchiolitis, bronchiolitis obliterans, and chronic lung allograft dysfunction. ALVR106 is an allogeneic, off-the-shelf, polyclonal, multi-respiratory virus T-cell therapy specific for Flu, hMPV, PIV, and RSV. ALVR106 is generated by exposing peripheral blood mononuclear cells to peptide mixtures followed by ex vivo expansion in presence of activating cytokines. The expanded T cells are Th1-polarized, polyfunctional, and selectively able to kill viral target cells. ALVR106 cells have not shown alloreactivity, attesting to their selectivity and safety for use in HCT or SOT. Methods: In this first-in-human, placebo (PBO)-controlled, dose-ranging trial, HCT or SOT recipients 17 years or older with upper or mild lower respiratory tract infections (URTI/LRTI) caused by Flu, hMPV, PIV, or RSV were randomized in a 3:1 ratio to receive ALVR106 or PBO. Four doses of ALVR106 ranging from 1 × 10 5 cells/kg to 2 × 10 6 cells/kg were planned to be given to 4 cohorts of 4 patients each. Patients receive up to 2 infusions of ALVR106 or PBO once every 14 days and will be followed for up to 1 year. The primary objective was safety as measured by treatment emergent adverse events (AEs), AEs of special interest (acute and chronic graft vs host disease (GvHD), cytokine release syndrome (CRS), infusion related reactions (IRR), and progressive dyspnea), and clinical laboratory abnormalities from baseline (BL) through 12 weeks after the last infusion. Secondary endpoints included evaluation of antiviral activity by qualitative PCR assay by nasal swab and a composite endpoint through D28 which included change from BL in Radiation Therapy Oncology Group Lung Toxicity Scale Grade and viral detection from nasal swab. Patients with an improvement in symptoms or undetectable virus were considered partial responders (PR); those with improved symptoms and undetectable virus were complete responders (CR), and those whose condition did not improve or worsen from BL were non-responders (NR). To assess functional T-cell immune reconstitution and frequency of circulating virus-specific T cells, IFN-g virus-specific ELISpot analysis was performed on serial blood samples over time. ELISpot results will be presented. Preliminary study results presented herein will be unblinded at the time of data presentation. Results: 16 patients were dosed: four in Cohorts (C) 1 and 2, five in C3, and three in C4. Table shows BL demographics, disease characteristics, and blinded results for safety and antiviral activity by composite endpoint. Cohorts 2, 3, and 4 had at least 1 patient with mild LRTI at BL, no patients in C1 had LRTI. All patients received at least 1 infusion. No patients with Flu were enrolled. In these blinded results, no differences were seen in rate or severity of AEs among cohorts. Four patients (25%) had AEs possibly related to treatment (ALVR106 or PBO); all were Grade 1 (mild) in severity. These related events were reported in 1 patient each: diarrhea, ear pressure, neutrophil count decrease, and 1 patient had pyrexia, cGvHD oral, and aGvHD skin. Eight patients (50%) had serious AEs (SAEs), none related to treatment. One patient (6%) in C3 had G2 progressive dyspnea not related to treatment. One patient (6%) in C1 had Grade I aGVHD skin and cGVHD oral; both were considered possibly related to treatment (ALVR106 or PBO). No patients had Grade II-IV aGVHD, cGVHD, IRR, or CRS. No clinically significant changes from BL or trends over time in lab abnormalities or vital signs were seen. At Day 28, all patients in C1 and C2 had undetectable respiratory virus via nasal swab, except 1 patient in C1 who missed D28 visit due to COVID-19; 4/5 (80%) in C3 were undetectable; and 2/3 (67%) in C4 were undetectable. Conclusion: In this ongoing trial-the first-in-human, double-blind, PBO-controlled trial of virus-specific T cell therapy in transplant recipients with respiratory infection-ALVR106 was safe and well tolerated, supporting its continued evaluation in HCT and SOT recipients.

Abstract Background HSV reactivation (HSVr) is frequent in HM and SOM patients while oropharyngeal/ mucocutaneous infections (OP-MCI) and especially HSV pneumonitis (HSVP) are uncommon. BALF-HSV-PCR can identify shedding or disease, however, may result in inappropriate high dose antiviral usage in non-HSVP situations. We report a cohort of patients with positive BALF-HSV-PCR, its impact on antiviral usage and role of IDC on antiviral use. Methods Retrospective chart review of BALF-HSV-PCR positive patients who had IDC between 1/1/2018 and 8/31/2022. Exclusion criteria: No chest imaging (CT scan or chest X-ray imaging within ±7 days of positive test) and no malignancy. Data collection: demographics, laboratory and clinical findings, and antiviral medication dosing before and after each positive BALF-HSV-PCR preceding the IDC. Clinical diagnosis and treatment of HSVP versus non-HSVP was based on IDC. Kruskal-Wallis tests was used for continuous variables and Fisher’s exact test for categorical variables, and p-values reported were 2-sided at significance level of 0.05.Table 3.Impact of BALF HSV PCR and IDC on Antiviral use. PPX=prophylaxis, Y=yes, N=No; ACV=acyclovir Results One-hundred-nine patients met inclusion criteria. Nineteen (17.4%) had HSVP, 90 (82.6%) non-HSVP. In non-HSVP; 83 (92%) had oropharyngeal shedding (HM >SOM), 6 (6%) OP-MCI and 1 (1%) immunotherapy related pneumonitis (IrP). Tables 1-3 provide details on demographics and baseline characteristics, antiviral use, and statistical analysis. HSV shedding/ disease (HSVP and OP-MCI) was more common in HM patients. All HSVP patients received high dose antiviral agents. Of ninety patients determined as non-HSVP, 42% were overtreated with antivirals with a positive test that preceded IDC. Positive PCR led to change in antiviral dose (p < 0.05) with highly significant impact on the dose of acyclovir used (prophylaxis vs. OP-MCI vs. HSPV doses) (p< 0.0001). IDC led to modification of HSVP dosing to either prophylaxis or complete discontinuation in 84.2% of patients (p=0.008). Conclusion BALF-HSV-PCR positive test without HSVP led to overtreatment in both HM and SOM patients that is preventable by IDC, underscoring its value in antiviral stewardship. Diagnostic stewardship can further limit inappropriate use of antivirals. Disclosures Randy Taplitz, MD, Karius: Advisor/Consultant|Merck: Advisor/Consultant|SNIPR biome: Advisor/Consultant Sanjeet S. Dadwal, MD, FACP, FIDSA, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope, Inc: Stocks/Bonds|Astellas: Honoraria|Karius: Grant/Research Support|Matinas Biopharma: Stocks/Bonds|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer/Amplyx: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Honoraria|Viracor: Honoraria

IntroductionPrevious studies suggest that monocytes are an important contributor to tuberculosis (TB)-specific immune signatures in blood. MethodsHere, we carried out comprehensive single-cell profiling of monocytes in paired blood samples of active TB (ATB) patients at diagnosis and mid-treatment, and healthy controls. ResultsAt diagnosis, ATB patients displayed increased monocyte-to-lymphocyte ratio, increased frequency of CD14+CD16- and intermediate CD14+CD16+ monocytes, and upregulation of interferon signaling genes that significantly overlapped with previously reported blood TB signatures in both CD14+ subsets. In this cohort, we identified additional transcriptomic and functional changes in intermediate CD14+CD16+ monocytes, such as the upregulation of inflammatory and MHC-II genes, and increased capacity to activate T cells, reflecting overall increased activation in this population. Single-cell transcriptomics revealed that distinct subsets of intermediate CD14+CD16+ monocytes were responsible for each gene signature, indicating significant functional heterogeneity within this population. Finally, we observed that changes in CD14+ monocytes were transient, as they were no longer observed in the same ATB patients mid-treatment, suggesting they are associated with disease resolution. DiscussionTogether, our study demonstrates for the first time that both intermediate and classical monocytes individually contribute to blood immune signatures of ATB and identifies novel subsets and associated gene signatures that may hold disease relevance.