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Jane Kriengkauykiat1,2, James I Ito2, Sanjeet S Dadwal21Department of Pharmacy, 2Division of Infectious Diseases, City of Hope, Duarte, CA, USAAbstract: Over the past 20 years, the number of invasive fungal infections has continued to persist, due primarily to the increased numbers of patients subjected to severe immunosuppression. Despite the development of more active, less toxic antifungal agents and the standard use of antifungal prophylaxis, invasive fungal infections (especially invasive mold infections) continue to be a significant factor in hematopoietic cell and solid organ transplantation outcomes, resulting in high mortality rates. Since the use of fluconazole as standard prophylaxis in the hematopoietic cell transplantation setting, invasive candidiasis has come under control, but no mold-active antifungal agent (except for posaconazole in the setting of acute myelogenous leukemia and myelodysplastic syndrome) has been shown to improve the survival rate over fluconazole. With the advent of new azole and echinocandin agents, we have seen the emergence of more azole-resistant and echinocandin-resistant fungi. The recent increase in zygomycosis seen in the hematopoietic cell transplantation setting may be due to the increased use of voriconazole. This has implications for the empiric approach to pulmonary invasive mold infections when zygomycosis cannot be ruled out. It is imperative that an amphotericin B product, an antifungal that has never developed resistance in over 50 years, be initiated. The clinical presentations of invasive mold infections and invasive candidiasis can be nonspecific and the diagnostic tests insensitive, so a high index of suspicion and immediate initiation of empiric therapy is required. Unfortunately, our currently available serologic tests do not predict infection ahead of disease, and, therefore cannot be used to initiate "preemptive" therapy. Also, the Aspergillus galactomannan test gives a false negative result in patients receiving antimold prophylaxis, ie, virtually all of our patients with hematologic malignancy and hematopoietic cell transplant recipients. We may eventually be able to select patients at highest risk for invasive fungal infections for prophylaxis by genetic testing. However, with our current armamentarium of antifungal agents and widespread use of prophylaxis in high-risk groups (hematologic malignancy, hematopoietic cell transplantation), we continue to see high incidence and mortality rates, and our future hope lies in reversing the immunosuppression or augmenting the immune system of these severely immunocompromised hosts by developing and utilizing immunotherapy, immunoprophylaxis, and vaccines.Keywords: invasive fungal infections, antifungal agents, immunosuppression

Background: Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex.Methods: In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation.Results: From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P<0.001). The frequency and severity of adverse events were similar in the two groups overall. Vomiting was reported in 18.5% of the patients who received letermovir and in 13.5% of those who received placebo; edema in 14.5% and 9.4%, respectively; and atrial fibrillation or flutter in 4.6% and 1.0%, respectively. The rates of myelotoxic and nephrotoxic events were similar in the letermovir group and the placebo group. All-cause mortality at week 48 after transplantation was 20.9% among letermovir recipients and 25.5% among placebo recipients.Conclusions: Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade. (Funded by Merck; ClinicalTrials.gov number, NCT02137772 ; EudraCT number, 2013-003831-31 .). [ABSTRACT FROM AUTHOR]

Sequencing of plasma microbial cell-free DNA (mcfDNA) has gained increased acceptance as a valuable adjunct to standard-of-care testing for diagnosis of infections throughout the body. Here, we report the analytical and clinical validation of a novel application of mcfDNA sequencing, the non-invasive detection of seven common antimicrobial resistance (AMR) genetic markers in 18 important pathogens. The AMR markers include SCC mec , mecA, mecC , vanA, vanB , bla CTX-M , and bla KPC . The AMR markers were computationally linked to the pathogens detected. Analytical validation showed high reproducibility (100%), inclusivity (54 to 100%), and exclusivity (100%). Clinical accuracy was assessed with 114 unique plasma samples from patients at seven study sites with concordant culture results for target bacteria from a variety of specimen types and correlated with available phenotypic antimicrobial susceptibility test results and genotypic results. The positive percent agreement (PPA), negative percent agreement (NPA), and diagnostic yield (DY) were estimated for each AMR marker. DY was defined as the percentage of tests that yielded an actionable result of either detected or not detected. The results for the combination of SCC mec and mecA for staphylococci were PPA 19/20 (95.0%), NPA 21/22 (95.4%), DY 42/60 (70.0%); vanA for enterococci were PPA 3/3 (100%), NPA 2/2 (100%), DY 5/6 (83.3%); bla CTX-M for gram-negative bacilli were PPA 5/6 (83.3%), NPA 29/29 (100%), DY 35/49 (71.4%); and bla KPC for gram-negative bacilli were PPA 0/2 (0%), NPA: 23/23 (100%), DY 25/44 (56.8%). The addition of AMR capability to plasma mcfDNA sequencing should provide clinicians with an effective new culture-independent tool for optimization of therapy., Importance: This manuscript is ideally suited for the Innovative Diagnostic Methods sections as it reports the analytical and clinical validation of a novel application of plasma microbial cell-free DNA sequencing for direct detection of seven selected antimicrobial resistance markers in 18 target pathogens. Clearly, it has potential clinical utility in optimizing therapy and was incorporated into the Karius test workflow in September 2023. In addition, the workflow could readily be adapted to expand the number of target bacteria and antimicrobial resistance markers as needed., Competing Interests: All employees of Karius, which markets the commercial test evaluated in this study, shared responsibilities for study design, analysis of the data, and writing and editing of the manuscript. John Joseph Farrell (OSF Healthcare), Sanjeet Dadwal (City of Hope), Amy L. Carr (AdventHealth Orlando), Arryn Craney (Orlando Health), Matthew Pike (Carle Foundation Hospital), and James B. Wood (Indiana University School of Medicine) received grant support from Karius to support the collection and curation of orthogonal data that were fundamental to the clinical validation and reviewed the manuscript.

Chimeric antigen receptor (CAR) T-cell therapy is rapidly advancing, offering promising treatments for patients with hematological malignancy. However, associated infectious complications remain a significant concern because of their contribution to patient morbidity and non-relapse mortality. Recent epidemiological insights shed light on risk factors for infections after CAR T-cell therapy. However, the available evidence is predominantly retrospective, highlighting a need for further prospective studies. Institutions are challenged with managing infections after CAR T-cell therapy but variations in the approaches taken underscore the importance of standardizing infection prevention and management protocols across different healthcare settings. Therefore, the Infectious Diseases Special Interest Group of the American Society of Transplantation and Cellular Therapy assembled an expert panel to develop best practice considerations. The aim was to guide healthcare professionals in optimizing infection prevention and management for CAR T-cell therapy recipients and advocates for early consultation of Infectious Diseases during treatment planning phases given the complexities involved. By synthesizing current evidence and expert opinion these best practice considerations provide the basis for understanding infection risk after CAR T-cell therapies and propose risk-mitigating strategies in children, adolescents, and adults. Continued research and collaboration will be essential to refining and effectively implementing these recommendations., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The current standard of stethoscope hygiene doesn't eliminate the transmission of harmful pathogens, including multi-drug resistant organisms (MDROs). In the era of the increasing prevalence of MDRO infections, the use of new systems providing touch free barriers may improve patient safety versus traditional stethoscope cleaning practices with chemical agents. Our purpose was to provide a narrative literature review regarding barriers as an improvement over the current standard of care for stethoscope hygiene. Searching PubMed, articles were identified if they were in English and published after 1990, using the search term "stethoscope barrier", or if they were from a previously published stethoscope hygiene article using "author's name + stethoscope". Included articles evaluated or discussed stethoscope barriers. Of 28 manuscripts identified, 15 met the inclusion criteria. Barriers were considered superior to alternatives if they were single use, disposable, applied in a touch free fashion, were impervious to pathogens, provided an aseptic patient contact, and were acoustically invisible. Use of a practitioner's personal stethoscope with a disposable diaphragm barrier should be recommended as a new standard of care as this represents an improvement in patient safety and patient experience when compared to the disposable stethoscope or isopropyl alcohol stethoscope diaphragm cleaning., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: W. Frank Peacock, MD, FACEP, FACC, FESC, has served as the chief medical officer, and the other authors have served as intermittent consultants for Aseptiscope., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Microglia, the resident immune cells of the central nervous system (CNS), have received significant attention due to their critical roles in maintaining brain homeostasis and mediating cerebral immune responses. Understanding the origin of microglia has been a subject of great interest, and emerging evidence suggests that microglia consist of multiple subpopulations with unique molecular and functional characteristics. These subpopulations of microglia may exhibit specialized roles in response to different environmental cues as in disease conditions. The newfound understanding of microglial heterogeneity has significant implications for elucidating their roles in both physiological and pathological conditions. In the context of disease, microglia have been studied rigorously as they play a very important role in neuroinflammation. Dysregulated microglial activation and function contribute to chronic inflammation. Further exploration of microglial heterogeneity and their interactions with other cell types in the CNS will undoubtedly pave the way to novel therapeutic strategies targeting microglia-mediated pathologies. In this review, we discuss the latest advances in the field of microglia research, focusing specifically on the origin and subpopulations of microglia, the populations of microglia types in the brains of patients with neurodegenerative diseases, and how microglia are regulated in the healthy CNS., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of BALs, 49% of which also have HHV-6B mRNA detection. We establish HHV-6B DNA viral load thresholds in BALF that are highly predictive of HHV-6B mRNA detection and associated with increased risk for overall mortality and death from respiratory failure. Participants with HHV-6B DNA in BALF exhibit distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT., (© 2024. The Author(s).)

Background: Cytomegalovirus (CMV) infection is a common opportunistic infection after allogeneic hematopoietic cell transplant (alloHCT). We explored whether a change in CMV cell-mediated immunity during the first month after transplant predicts the risk of development of CMV infection and all-cause mortality., Methods: This follow-up analysis is based on data from the REACT study, a multicenter prospective observational study of recipients of alloHCT who were CMV-seropositive. Production of interferon γ following ex vivo stimulation with CMV antigens IE1 (immediate early 1) and pp65 (phosphoprotein 65) was assessed by CMV ELISPOT assay at baseline and 2 and 4 weeks after transplant. Clinically significant CMV infection (CS-CMVi) was defined as CMV viremia and/or disease necessitating antiviral therapy. We evaluated the impact of CMV CMI changes on the risk of CS-CMVi and post transplant mortality., Results: The analysis included 226 recipients of alloHCT with CMV cell-mediated immunity data at baseline and 2 and/or 4 weeks after transplant. CS-CMVi occurred in 64 patients (28%). On Cox regression analyses, independent predictors of CS-CMVi included a negative Δ change from baseline to week 2 of pp65 spot counts (hazard ratio, 3.65 [95% CI, 1.65-8.04]; P = .001) to week 4 of IE1 spot counts (hazard ratio, 2.79 [95% CI, 1.46-5.35]; P = .002), anti-thymocyte globulin conditioning regimen, type of transplant, female sex, and corticosteroid use. Kaplan-Meir analysis showed a significant association of a negative IE1 change from baseline to week 4 and increased all-cause mortality after transplant (log rank test = 0.041)., Conclusions: A decrease in CMV-specific T-cell responses during the first month after transplant may predict CS-CMVi and is associated with all-cause mortality in recipients of alloHCT., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild-to-moderate COVID-19 at high risk for disease progression., Methods: We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021., Results: Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Four (11%) patients were hospitalized due to COVID-19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID-19 disease. Most patients (n = 34, 89%) ultimately tested negative for SARS-CoV-2, with 34% (n = 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients with hematological malignancies (HM) (n = 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization among patients who received a HCT versus non-HCT (0% n = 0/26 and 36% n = 4/11, respectively; p < 0.01)., Conclusions: This study demonstrates that SARS-CoV-2 specific mAb was safe and may reduce hospitalization compared to what is reported in malignant hematology patients at high risk for disease progression. Our HCT cohort patients had less hospitalization rate compared with HM cohort patients., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Serine proteases (SP), including furin, trypsin, and TMPRSS2 cleave the SARS-CoV-2 spike (S) protein, enabling the virus to enter cells. Here, we show that factor (F) Xa, an SP involved in blood coagulation, is upregulated in COVID-19 patients. In contrast to other SPs, FXa exerts antiviral activity. Mechanistically, FXa cleaves S protein, preventing its binding to ACE2, and thus blocking viral entry and infection. However, FXa is less effective against variants carrying the D614G mutation common in all pandemic variants. The anticoagulant rivaroxaban, a direct FXa inhibitor, inhibits FXa-mediated S protein cleavage and facilitates viral entry, whereas the indirect FXa inhibitor fondaparinux does not. In the lethal SARS-CoV-2 K18-hACE2 model, FXa prolongs survival yet its combination with rivaroxaban but not fondaparinux abrogates that protection. These results identify both a previously unknown function for FXa and an associated antiviral host defense mechanism against SARS-CoV-2 and suggest caution in considering direct FXa inhibitors for preventing or treating thrombotic complications in COVID-19 patients., (© 2023. The Author(s).)

Background: The City of Hope National Medical Center (COH) is the only stand-alone comprehensive cancer center in Los Angeles, a county that was deemed a COVID-19 pandemic epicenter at the height of the 2020 winter surge. The immunocompromised patient population frequently experienced delays in infection control guidelines from local and government bodies due to minimal data available in comparison to the general population. This required COH to make swift, informed decisions for the best interest of the patient population., Aim: Here, we review the comprehensive COVID-19 infection control response conducted at COH within the context of a high-risk patient population, predominately comprised of patients with hematologic malignancies., Methods and Results: This infection control response focused on prevention of COVID-19 transmission on campus, COVID-19 testing, and isolation management. These efforts consisted of COVID-19 screening, limitation of personnel on campus, source control, contact tracing, COVID-19 vaccination, establishment of in-house testing and implementation and management of COVID-19 testing. Between January 2020 and September 2021, COH implemented a robust in-house testing program, completed well over 1000 contact traces, ensured COVID-19 vaccinations were distributed to all eligible staff and patients, and established an algorithm for COVID-19 infection resolution, all without compromising the number of hematopoietic stem cell transplants (HCTs) performed, surgical volume, or healthcare-associated standardized infection ratios (SIR)., Conclusion: Institutional collaboration and attention to infection control was pivotal to minimizing the burden of the COVID-19 pandemic., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Vaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone. Both patients had breast cancer and were on therapy for the malignancy., Methods: The protocol is designed with the primary objective to assess the safety and tolerability of leflunomide in treating severe COVID-19 in patients with cancer. Leflunomide dosing consisted of a loading dose of 100 mg daily for the first three days, followed by daily dosing, at the assigned dose level (Dose Level 1: 40 mg, Dose Level -1, 20 mg; Dose Level 2, 60 mg), for an additional 11 days. At defined intervals, serial monitoring of blood samples for toxicity, pharmacokinetics, and immunologic correlative studies were performed, as well as nasopharyngeal swabs for PCR analysis of SARS-CoV-2., Results: Preclinically, leflunomide impaired viral RNA replication, and clinically, it led to a rapid improvement in the two patients discussed herein. Both patients completely recovered, with minimal toxicities; all adverse events experienced were considered unrelated to leflunomide. Single-cell mass-cytometry analysis showed that leflunomide increased levels of CD8+ cytotoxic and terminal effector T cells and decreased naïve and memory B cells., Conclusions: With ongoing COVID-19 transmission and occurrence of breakthrough infections in vaccinated individuals, including patients with cancer, therapeutic agents that target both the virus and host inflammatory response would be helpful despite the availability of currently approved anti-viral agents. Furthermore, from an access to care perspective, especially in resource-limited areas, an inexpensive, readily available, effective drug with existing safety data in humans is relevant in the real-world setting., Competing Interests: Conflict of Interest The authors declare that they have no competing interests that are relevant to this study.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), disproportionately affects immunocompromised and elderly patients. Not only are hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell recipients at greater risk for severe COVID-19 and COVID-19-related complications, but they also may experience suboptimal immune responses to currently available COVID-19 vaccines. Optimizing the use, timing, and number of doses of the COVID-19 vaccines in these patients may provide better protection against SARS-CoV-2 infection and better outcomes after infection. To this end, current guidelines for COVID-19 vaccination in HCT and CAR T-cell recipients from the American Society of Transplantation and Cellular Therapy Transplant Infectious Disease Special Interest Group and the American Society of Hematology are provided in a frequently asked questions format., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

This document is intended as a guide for diagnosis and management of Coronavirus Disease 2019 (COVID-19), caused by the virus SARS-CoV-2, in adult and pediatric HCT and cellular therapy patients. This document was prepared using available data and with expert opinion provided by members of the (ASTCT) Infectious Diseases Special Interest Group (ID-SIG) and is an update of pervious publication. Since our original publication in 2020, the NIH and IDSA have published extensive guidelines for management of COVID-19 which are readily accessible ( NIH Guidelines , IDSA Guidelines ). This update focuses primarily on issues pertaining specifically to HCT/cellular therapy recipients. Information provided in this manuscript may change as new information becomes available., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Cell-mediated immunity may contribute to providing protection against SARS-CoV-2 and its variants of concern (VOC). We developed COH04S1, a synthetic multiantigen modified vaccinia Ankara (MVA)-based COVID-19 vaccine that stimulated potent spike (S) and nucleocapsid (N) antigen-specific humoral and cellular immunity in a phase 1 clinical trial in healthy adults. Here, we show that individuals vaccinated with COH04S1 or mRNA vaccine BNT162b2 maintain robust cross-reactive cellular immunity for six or more months post-vaccination. Although neutralizing antibodies induced in COH04S1- and BNT162b2-vaccinees showed reduced activity against Delta and Omicron variants compared to ancestral SARS-CoV-2, S-specific T cells elicited in both COH04S1- and BNT162b2-vaccinees and N-specific T cells elicited in COH04S1-vaccinees demonstrated potent and equivalent cross-reactivity against ancestral SARS-CoV-2 and the major VOC. These results suggest that vaccine-induced T cells to S and N antigens may constitute a critical second line of defense to provide long-term protection against SARS-CoV-2 VOC., Competing Interests: While unknown whether the publication of this report will aid in receiving grants and contracts, it is possible that this publication will be of benefit to the City of Hope (COH). COH had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the article. DJD and FW are co-inventors on a patent application covering the design and construction of the synthetic MVA platform (PCT/US2021/016,247). DJD, FW, and FC are co-inventors on a patent application covering the development of a COVID-19 vaccine (PCT/US2021/032,821). DJD is a consultant for GeoVax. All other authors declare no competing interests. GeoVax Labs Inc. has taken a worldwide exclusive license for COH04S1 under the name of GEO-CM04S1., (© 2022 The Author(s).)

Background: COH04S1, a synthetic attenuated modified vaccinia virus Ankara vector co-expressing SARS-CoV-2 spike and nucleocapsid antigens, was tested for safety and immunogenicity in healthy adults., Methods: This combined open-label and randomised, phase 1 trial was done at the City of Hope Comprehensive Cancer Center (Duarte, CA, USA). We included participants aged 18-54 years with a negative SARS-CoV-2 antibody and PCR test, normal haematology and chemistry panels, a normal electrocardiogram and troponin concentration, negative pregnancy test if female, body-mass index of 30 kg/m 2 or less, and no modified vaccinia virus Ankara or poxvirus vaccine in the past 12 months. In the open-label cohort, 1·0 × 10 7 plaque-forming units (PFU; low dose), 1·0 × 10 8 PFU (medium dose), and 2·5 × 10 8 PFU (high dose) of COH04S1 were administered by intramuscular injection on day 0 and 28 to sentinel participants using a queue-based statistical design to limit risk. In a randomised dose expansion cohort, additional participants were randomly assigned (3:3:1), using block size of seven, to receive two placebo vaccines (placebo group), one low-dose COH04S1 and one placebo vaccine (low-dose COH04S1 plus placebo group), or two low-dose COH04S1 vaccines (low-dose COH04S1 group). The primary outcome was safety and tolerability, with secondary objectives assessing vaccine-specific immunogenicity. The primary immunological outcome was a four times increase (seroconversion) from baseline in spike-specific or nucleocapsid-specific IgG titres within 28 days of the last injection, and seroconversion rates were compared with participants who received placebo using Fisher's exact test. Additional secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ClinicalTrials.gov, NCT046339466., Findings: Between Dec 13, 2020, and May 24, 2021, 56 participants initiated vaccination. On day 0 and 28, 17 participants received low-dose COH04S1, eight received medium-dose COH04S1, nine received high-dose COH04S1, five received placebo, 13 received low-dose COH04S1 followed by placebo, and four discontinued early. Grade 3 fever was observed in one participant who received low-dose COH04S1 and placebo, and grade 2 anxiety or fatigue was seen in one participant who received medium-dose COH04S1. No severe adverse events were reported. Seroconversion was observed in all 34 participants for spike protein and 32 (94%) for nucleocapsid protein (p<0·0001 vs placebo for each comparison). Four times or more increase in SARS-CoV-2 neutralising antibodies within 56 days was measured in nine of 17 participants in the low-dose COH04S1 group, all eight participants in the medium-dose COH04S1 group, and eight of nine participants in the high-dose COH04S1 group (p=0·0035 combined dose levels vs placebo). Post-prime and post-boost four times increase in spike-specific or nucleocapsid-specific T cells secreting interferon-γ was measured in 48 (98%; 95% CI 89-100) of 49 participants who received at least one dose of COH04S1 and provided a sample for immunological analysis., Interpretation: COH04S1 was well tolerated and induced spike-specific and nucleocapsid-specific antibody and T-cell responses. Future evaluation of this COVID-19 vaccine candidate as a primary or boost vaccination is warranted., Funding: The Carol Moss Foundation and City of Hope Integrated Drug Development Venture programme., Competing Interests: DJD and FW are co-inventors on a patent application covering the design and construction of the synthetic modified vaccinia Ankara platform (PCT/US2021/016247). DJD, FW, and FC are co-inventors on a patent application covering the development of a COVID-19 vaccine (PCT/US2021/032821). FC, JAZ, PHF, RS, JD, BW, AMA, KFr, RAT, JKD, SD, AGP, DDN, PA, YC, HC, CLR, KT, YP, JM, AI, QZ, VK, DJ, KFa, TK, JN, MK, VHN, SOF, AW, FW, and DJD are employees of City of Hope National Medical Center (Duarte, CA, USA), which developed the vaccine and funded the trial. AS is a consultant for Gritstone, Flow Pharma, Merck, Epitogenesis, Gilead, and Avalia. La Jolla Institute for Immunology has filed for patent protection for various aspects of T-cell epitope and vaccine design work. All other authors declare no competing interests., (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Background: Immune checkpoint inhibitors (ICIs) are targeted cancer therapies regarded to have less toxicity than chemotherapy. Immune-related adverse events (irAEs) of ICIs are well described in the literature but limited data exist on their infectious complications. The objective is to describe the spectrum and risk factors for developing serious infections in patients receiving ICIs., Methods: Retrospective review of patients with melanoma, renal cell carcinoma, or nonsmall-cell lung cancer on nivolumab, pembrolizumab, and/or ipilimumab from January 1, 2017 to November 30, 2017. Exclusion: receipt of less than two ICI doses or history of other malignancy. Characteristics: age, sex, prior chemotherapy, steroid use, and temozolomide or infliximab use. Data identified from microbiology, radiography, serology, or physician note documentation. Serious infection is defined as infections requiring hospitalization and/or IV antibiotics from initiation of ICI until the end of the study period., Results: One hundred and eleven pts received ICIs. Suspected or confirmed bacterial infections occurred in 24% (27/111) with 8% (9/111) confirmed bacterial cultures. The overall serious infection rate was 14% (16/111) with 25% (4/16) confirmed bacterial cultures. Suspected or confirmed infection sites: genitourinary 20% (22/111), pneumonia 5% (7/111), skin/soft tissue 7% (8/111). Noninfectious pneumonitis (NIP) occurred in 5% (5/111). No association regarding the risk of infection between the type of malignancy and ICI used. Steroid use was the only risk factor significantly associated with serious infection: 12/16 (75%) on steroids versus 27/95 (28.4%) without steroid use (p = 0.0003)., Conclusion: The rate of serious infection with ICI was higher in our study compared with previous reports of pts treated with melanoma. Infectious complications are encountered with ICIs and correlate with steroid use., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The safety and efficacy of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) emergency-use authorized (EUA) vaccines have been confirmed in the general population. However, there are no data on its safety and tolerability or efficacy in recipients of allogeneic hematopoietic stem cell transplant (HCT). We performed this study to identify the incidence of adverse events following SARS-CoV2 EUA vaccines, the incidence of new-onset graft-versus-host disease (GVHD) or worsening of existing GVHD after EUA vaccine administration, and the incidence SARS-CoV2 positivity in vaccinated HCT patients. We retrospectively reviewed 113 HCT patients who received at least one dose of EUA vaccine to describe the safety and tolerability, any impact on GVHD, and the incidence of SARS-CoV2 PCR positivity after vaccination. Patients received either Pfizer (BNT162b2) or Moderna (mRNA-1273) vaccines. Patients were included if they were 18 years or older and had received at least one dose of vaccine in the post-HCT setting. Most patients presented with myalgias/arthralgias (first dose, 7.7%; second dose, 14.6%), fatigue (first dose, 15.4%; second dose, 29.2%), and injection site pain (first dose, 40.4%; second dose, 43.8%). Other side-effects experienced by patients included nausea, vomiting, diarrhea, headache, and injection-site rash and swelling. Liver function abnormalities occurred in 18.6% of patients. Neutropenia, thrombocytopenia, and lymphopenia occurred in 13.3%, 11.5%, and 8.8% of patients, respectively. Forty percent of patients had active chronic GVHD at the time of vaccination, and worsening chronic GVHD occurred in 3.5% of the patients. New chronic GVHD developed in 9.7% of patients after vaccination. The SARS-CoV2 EUA vaccines were well tolerated in allogeneic HCT recipients., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Currently, there is no consensus on best practices to prevent hemorrhagic cystitis (HC) in patients receiving posttransplant cyclophosphamide (PTCy). We retrospectively reviewed 194 patients undergoing their first hematopoietic cell transplant (HCT) who received PTCy from 2014 to 2018 to describe the incidence and severity of HC, identify potential risk factors, and impact of HC on HCT outcomes. Standard HC prophylaxis was hyperhydration with forced diuresis and mesna at 320% the daily dose of PTCy. Incidence of HC was 31.4% at day +100 of HCT. Median onset of HC was 12 days with 11.5% grade 3 HC and no Grade 4 HC. Patients with chemical HC experienced earlier onset (7 days vs. 34 days, p < 0.001) with a shorter median resolution time (5 days vs. 14 days, p = 0.001) when compared to BK-associated HC. In multivariate analysis, age above 60 years (HR 4.16, p = 0.006) and myeloablative conditioning (HR 2.44, p = 0.054) were associated with higher risk for HC, but overall, HC did not affect nonrelapse mortality or overall survival. In conclusion, hyperhydration with forced diuresis combined with aggressive mesna dosing is an effective strategy in preventing severe PTCy-associated HC, subsequently preventing any negative impact on transplant outcome., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with substantial healthcare resource use, particularly when recipients develop cytomegalovirus (CMV) infection. Letermovir reduced post-HSCT CMV infection risk compared with placebo in a previous phase III trial. This analysis evaluated letermovir's impact on re-hospitalization post-transplant., Methods: Using data from a phase III, multicenter, randomized clinical trial (NCT02137772, registered May 14, 2014), this study assessed CMV-associated and all-cause re-hospitalizations at weeks 14, 24, and 48 post-transplant among recipients of letermovir versus placebo. Unstandardized re-hospitalization rates and days were reported; standardized rates and days were estimated accounting for censoring due to death or early study discontinuation., Results: Unstandardized rates (95% confidence interval [CI]) of all-cause re-hospitalization in letermovir versus placebo recipients at weeks 14, 24, and 48 were 36.6% (31.4-42.1) versus 47.6% (39.9-55.4), 49.2% (43.7-54.8) versus 55.9% (48.1-63.5), and 55.7% (50.1-61.2) versus 60.6% (52.8-68.0), respectively. Unstandardized mean total duration (95% CI) of re-hospitalization with letermovir versus placebo at weeks 14, 24, and 48 were 7.6 (5.9-9.8) versus 11.3 (8.6-14.8), 13.9 (11.2-17.2) versus 15.5 (11.9-20.1), and 18.0 (14.8-21.9) versus 20.7 (15.8-27.1) days, respectively. Similar results were found in CMV-associated re-hospitalization outcomes and standardized rates and days of all-cause re-hospitalizations., Conclusions: In this post-hoc analysis, letermovir was associated with lower rates of CMV-associated and all-cause re-hospitalizations with a shorter length of stay (especially within the first 14 weeks post-transplant)., (© 2021. The Author(s).)

Background: There are no antiviral therapies for parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV., Methods: Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment., Results: A total of 111 patients were randomized to DAS181 (n = 74) or placebo (n = 37). CSS was achieved by 45.0% DAS181-treated patients in the SO stratum compared with 31.0% for placebo (P = .15), whereas patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with placebo (34.5%) at day 28 (P = .17). In a post hoc analysis of solid organ transplant, hematopoietic cell transplantation within 1 year, or chemotherapy within 1 year, more SO stratum patients achieved RTRA on DAS181 (51.8%) compared with placebo (15.8%) by day 28 (P = .012)., Conclusions: The primary endpoint was not met, but post hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation. Clinical Trials Registration. NCT01644877., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: There is a paucity of studies describing the incidence and risk factors for late-occurring (≥1 year) infectious complications in contemporary survivors of hematopoietic cell transplantation (HCT)., Methods: This was a retrospective cohort study of 641 1-year survivors of HCT, transplanted between 2010 and 2013 as adults, and in remission from their primary disease. Standardized definitions were used to characterize viral, fungal, and bacterial infections. Cumulative incidence of infections was calculated, with relapse/progression considered as a competing risk event. Fine-Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained, adjusted for relevant covariates., Results: Median age at HCT was 55.2 years (range 18.1-78.1 years); 54.0% were survivors of allogeneic HCT. The 5-year cumulative incidence of a late-occurring infection for the entire cohort was 31.6%; the incidence of polymicrobial (≥2) infections was 10.1%. In survivors who developed at least one infection, the 5-year incidence of a subsequent infection was 45.3%. Among allogeneic HCT survivors, patients with acute lymphoblastic (HR = 1.82 95% CI [1.12-2.96]) or myeloid (HR = 1.50 95% CI [1.02-2.20]) leukemia, and those with an elevated HCT-Comorbidity index score (HR = 1.09 95% CI [1.01-1.17]) were more likely to develop late-occurring infections; there was an incremental risk associated with severity of graft versus host disease (GVHD) at 1-year post-HCT (mild: HR = 2.17, 95% CI [1.09-4.33]; moderate/severe: HR = 3.78, 95% CI [1.90-7.53]; reference: no GVHD)., Conclusions: The burden of late-occurring infections in HCT survivors is substantial, and there are important patient- and HCT-related modifiers of risk over time. These findings may help guide personalized screening and prevention strategies to improve outcomes after HCT., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Reactivation of human herpesvirus 6 (HHV-6) occurs in 30%-50% of patients (pts) who receive allogeneic (allo) hematopoietic stem cell transplant (HCT). However, the recommendation for post-transplant HHV-6 monitoring and treatment in pediatric pts is not well established., Methods: HHV-6 incidence rates and the clinical outcomes were reported for 139 pediatric pts (≤18 years) undergoing first allo-HCT at City of Hope from July 2011 to July 2017, for whom HHV-6 was monitored weekly throughout HCT hospitalization. For 57 pediatric pts, who underwent first HCT from January 2009 to July 2011, HHV-6 was tested as clinically indicated and only rates of HHV-6 viremia were collected., Results: From July 2011 to July 2017, HHV-6 was detected in 88/139 pts (63%). The frequency of HHV-6 viremia was associated with malignant diagnoses, myeloablative conditioning, and cord blood HCT. Treatment with antiviral agents was offered to symptomatic pts with a higher viral load (VL), for whom the time to VL clearance was longer and the frequency of subsequent recurrences was higher. Pts with a lower VL cleared HHV-6 without treatment. HHV-6 viremia was associated with a higher frequency of grade II-IV acute graft-versus-host disease (GVHD) (P = .022), but did not affect overall survival (OS), disease-free survival (DFS), non-relapsed mortality (NRM), myeloid, or platelet (Plt) engraftment., Conclusions: HHV-6 weekly screening is not necessary for all HCT pts but may be considered for high-risk pts with malignant diagnoses undergoing cord blood HCT; otherwise, HHV-6 should be tested as clinically indicated. Only symptomatic pts (especially with a high VL > 25 000) could benefit from treatment. HHV-6 viremia at the time of initiation and administration of the conditioning regimen cleared promptly without the need to augment the transplant process., (© 2020 Wiley Periodicals LLC.)

The SARS-CoV-2 proteome shares regions of conservation with endemic human coronaviruses (CoVs), but it remains unknown to what extent these may be cross-recognized by the antibody response. Here, we study cross-reactivity using a highly multiplexed peptide assay (PepSeq) to generate an epitope-resolved view of IgG reactivity across all human CoVs in both COVID-19 convalescent and negative donors. PepSeq resolves epitopes across the SARS-CoV-2 Spike and Nucleocapsid proteins that are commonly targeted in convalescent donors, including several sites also recognized in some uninfected controls. By comparing patterns of homologous reactivity between CoVs and using targeted antibody-depletion experiments, we demonstrate that SARS-CoV-2 elicits antibodies that cross-recognize pandemic and endemic CoV antigens at two Spike S2 subunit epitopes. We further show that these cross-reactive antibodies preferentially bind endemic homologs. Our findings highlight sites at which the SARS-CoV-2 response appears to be shaped by previous CoV exposures and which have the potential to raise broadly neutralizing responses., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)

The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Supramolecular nanoassemblies of an AIEE-ICT-active pyrazine derivative (TETPY) having strong absorption in the visible region and excellent transportability have been utilized as an efficient photoredox catalytic system for the synthesis of a variety of benzimidazoles having electron-withdrawing/electron-releasing/aliphatic groups under "metal-free" conditions. The reaction protocol involves the successful harvesting of visible light by TETPY assemblies to catalyze the coupling of o -phenylenediamine/substituted diamines and substituted aromatic/heterocyclic/aliphatic aldehydes under aerial conditions using mixed aqueous media as the reaction solvent. TETPY assemblies could activate aerial oxygen to generate superoxide for completing the vital proton abstraction step without the need for any external metal/base/oxidant. Moreover, all the products are purified by recrystallization from organic solvents. The TETPY assemblies also exhibited high efficiency in catalyzing the synthesis of 2-substituted benzothiazoles and quinazolines in excellent yields.

There are currently limited data on the epidemiology, clinical manifestations, and optimal management of Coronavirus Disease 2019 (COVID-19) in hematopoietic cell transplantation and cellular therapy recipients. Given the experience with other respiratory viruses, we anticipate that patients may develop severe clinical disease and thus provide the following general principles for cancer centers across the nation. These guidelines were developed by members of the American Society for Transplantation and Cellular Therapy Infectious Diseases Special Interest Group. Specific practices may vary depending on local epidemiology and testing capacity, and the guidance provided in this document may change as new information becomes available., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR) = 2.26 (95% CI, 1.28 to 4.00, P = .005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR = 2.18 (95% CI, 1.10 to 4.31, P = .025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR = 0.58 (95% CI, 0.35 to 0.96, P = .034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR = 0.48 (95% CI, 0.23 to 0.98, P = .044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Adenovirus (AdV) is increasingly recognized as a threat to successful outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Guidelines have been developed to inform AdV screening and treatment practices, but the extent to which they are followed in clinical practice in the United States is still unknown. The incidence of AdV in the United States is also not well documented. The main objectives of the AdVance US study were thus to characterize current AdV screening and treatment practices in the United States and to estimate the incidence of AdV infection in allo-HCT recipients across multiple pediatric and adult transplant centers., Methods: Fifteen pediatric centers and 6 adult centers completed a practice patterns survey, and 15 pediatric centers and four adult centers completed an incidence survey., Results: The practice patterns survey results confirm that pediatric transplant centers are more likely than adult centers to routinely screen for AdV, and are also more likely to have a preemptive AdV treatment approach compared to adult centers. Perceived risk of AdV infection is a determining factor for whether routine screening and preemptive treatment are implemented. Most pediatric centers screen higher-risk patients for AdV weekly, in blood, and have a preemptive AdV treatment approach. The incidence survey results show that from 2015 to 2017, a total of 1230 patients underwent an allo-HCT at the 15 pediatric transplant centers, and 1815 patients underwent an allo-HCT at the 4 adult transplant centers. The incidences of AdV infection, AdV viremia, and AdV viremia ≥ 1000 copies/mL within 6 months after the first allo-HCT were 23%, 16%, and 9%, respectively, for patients at pediatric centers, and 5%, 3%, and 2%, respectively, for patients at adult centers., Conclusions: These findings provide a more recent estimate of the incidence of AdV infection in the United States, as well as a multicenter view of practice patterns around AdV infection screening and intervention criteria, in pediatric and adult allo-HCT recipients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Primary objective is to evaluate safety of isavuconazonium sulfate (ISA) in pediatrics below 18 years old. Exploratory endpoint includes mortality due to probable and proven invasive fungal infection (IFI) and overall morality in this population., Patients and Methods: Retrospective review of patients below 18 years receiving ISA for ≥7 days for possible, probable, or proven IFI or prophylaxis between June 2015 and March 2018. Descriptive analysis performed to calculate median, frequency, and percentages., Results: Safety analysis included 18 patients and a subgroup of 11/18 patients were assessed for efficacy. Median age 12.5 years (4 to 17 y), median weight 50.25 kg (19 to 118 kg), 50% male, 77% acute leukemias, 94% hematopoietic cell transplant recipients, 50% matched unrelated donors and 78% in remission. Elevated alanine aminotransferase 3 times baseline within 30 days of ISA occurred in 22% (4/18). No patients had elevated bilirubin or increase in serum creatinine. All-cause mortality at 90 days was 22% (4/18) and 27% (3/11) in patients with probable or proven IFI. Clinical response rates: 14-day: 45% (5/11) partial, 27% (3/11) stable; 30-day: 45% (5/11) partial, 36% (4/11) stable; 90-day: 54% (6/11) had either partial (n=3) or complete (n=3) response to ISA., Conclusions: ISA is safe in pediatric patients for the treatment of IFI. Prospective, randomized controlled trials are warranted to determine efficacy and safety of ISA in pediatric patients with hematologic malignancies and hematopoietic cell transplant.

Purpose: We update a patient series that reported a high incidence of infection with Gram-positive cocci in women treated with the combination of pertuzumab and trastuzumab and further characterize this clinical problem., Patients: Treating physicians and advanced practice partners identified women who developed infections while on treatment with pertuzumab and trastuzumab alone or in combination with chemotherapy and enrolled them onto this registry trial., Results: Between March, 2014 and May, 2017, 48 patients with HER2-positive breast cancers were reported to have 59 individual infections. The median age was 48 years. Twenty-four patients received neoadjuvant therapy, 17 were treated for metastatic disease, and 7 were treated in the adjuvant setting. Pertuzumab and trastuzumab were combined with carboplatin and docetaxel in 24 (49%) patients, docetaxel in 10 (21%), nab-paclitaxel in 12 (24%), and without other agents in 2 (4%). Granulocyte growth factors were administered in 24 (49%) patients and no patients were documented to be neutropenic. Folliculitis developed in 25 (52%) patients and was counted as a single infection. Abscesses developed at a number of sites in 24 (49%) patients, including a septic knee requiring total knee replacement. Paronychia occurred in 7 (15%) patients, and 5 (10%) developed cellulitis. When cultures were obtained, Gram-positive cocci were consistently identified. Hypogammaglobulinemia was documented in 14 (36%) of the 33 patients tested., Conclusions: Our data continue to support an increased risk of infections with Gram-positive cocci as a potentially serious adverse event in women treated with pertuzumab and trastuzumab.

Cyclophosphamide (Cy)/etoposide combined with fractionated total body irradiation (FTBI) or i.v. busulfan (Bu) has been the main conditioning regimens for allogeneic hematopoietic cell transplantation (alloHCT) for young patients with acute myelogenous leukemia (AML) eligible for a myeloablative conditioning (MAC) regimen. Recent data has suggested that i.v. Bu could be the preferred myeloablative regimen in patients with myeloid malignancies. However, Bu-based regimens are associated with higher rates of sinusoidal obstruction syndrome. Here we report long-term survival outcomes of patients with AML receiving FTBI combined with Cy or etoposide before undergoing alloHCT at City of Hope (COH). We obtained a retrospective review of a prospectively maintained institutional registry of clinical outcomes in 167 patients (median age, 41 years; range, 18 to 57 years) with AML in first or second complete remission who underwent alloHCT at COH between 2005 and 2015. Eligible patients received a MAC regimen with FTBI (1320 cGy) and Cy (120 mg/kg) for unrelated donor transplantation or etoposide (60 mg/kg) for related donor transplantation. Graft-versus-host disease (GVHD) prophylaxis was provided with tacrolimus and sirolimus. In this retrospective study, 6-year overall survival was 60% and nonrelapse mortality was 15%. The GRFS rate was 45% at 1 year and 39% at 2 years. We also describe late metabolic effects and report the cumulative incidence of secondary malignancies (9.5%). Overall, in this young adult patient population, our results compare favorably to chemotherapy-based (i.v. Bu) conditioning regimens without significant long-term toxicity arising from TBI-based regimens., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The combination of venetoclax with hypomethylating agents (VEN-HMAs) showed promising activity in newly diagnosed and relapsed/refractory (r/r) acute myeloid leukemia (AML). Treatment with VEN-HMAs results in prolonged cytopenia, thereby exposing patients to invasive fungal infections (IFIs). Here, we retrospectively studied a cohort of 119 AML patients treated with VEN-HMAs and analyzed the occurrence of IFIs, as well as our practice of antifungal prophylaxis, with the aim to identify the nature and risk factors for IFIs and their association with the type of antifungal prophylaxis used. The intended antifungal prophylaxis was micafungin in 38% of patients, azoles in 41% of patients, and none in 21% of patients. Older age was associated with no antifungal prophylaxis or micafungin use and lesser use of azoles (P = .043). We recorded 15 (12.6%) patients who developed probable or proven IFIs, with a median onset of 72 days (range, 35-281) after starting therapy. IFIs were more common among nonresponders compared with responders to VEN-HMA therapy (22% vs 6%, P = .0132) and in r/r compared with newly diagnosed AML (19% vs 5%, P = .0498); however, the antifungal prophylaxis used, patient age, hypomethylating agent schedule, history of prior allogeneic transplant, and initial neutropenia duration did not influence the development of IFIs during therapy. We conclude that the overall risk of IFIs during VEN-HMA therapy is low. The risk of IFIs is higher in nonresponders and in those who were treated in the r/r setting; these patients need reevaluation of their antifungal prophylaxis to minimize the risk of IFIs during therapy., (© 2019 by The American Society of Hematology.)

Pyrazine derivatives DIPY, TETPY and CNDIPY have been designed and synthesized which form fluorescent supramolecular assemblies in mixed aqueous media due to their AIEE and ICT characteristics. Among all the derivatives, the assemblies of TETPY and CNDIPY show strong absorption in the visible region with high absorption coefficients, low HOMO-LUMO gap, and high photostability. Further, the supramolecular nanoassemblies of TETPY and CNDIPY show excellent potential to generate reactive oxygen species (ROS) under the visible light irradiation. Owing to their strong absorption in the visible region and ROS generation ability, the supramolecular nanoassemblies of TETPY and CNDIPY act as efficient photoredox catalytic systems for carrying out (a) oxidative amidation of aromatic aldehydes (b) hydroxylation of boronic acid and (c) oxidative homocoupling of benzylamines under mild conditions such as aqueous media, aerial environment, and natural sunlight as a source of irradiation. All the mechanistic investigations suggest the participation of in-situ generated ROS in the organic transformations upon light irradiation.