COVID-19 Outcomes Among Hematopoietic Cell Transplant and Chimeric Antigen Receptor T-cell Recipients in the Era of SARS-CoV-2 Omicron Variants and COVID-19 Therapeutics.

BACKGROUND: Recipients of cellular therapies, including hematopoietic cell transplant (HCT) and chimeric antigen receptor T-cell (CART) therapy, are at risk for poor outcomes from coronavirus disease 2019 (COVID-19). There are limited data describing outcomes among patients in the pre- and early post-cellular therapy period during the Omicron era when multiple antiviral therapeutics were widely available. OBJECTIVES: Describe COVID-19 treatment and outcomes in patients diagnosed with COVID-19 during the pre- or early post-cellular therapy period. STUDY DESIGN: This is a single-center retrospective cohort study of adult HCT and CART recipients diagnosed with COVID-19 in the pre- and early post-cellular therapy period who tested positive for COVID-19 at our cancer center between January 1, 2022 and March 1, 2023. Primary outcomes were 30-day COVID-19-related hospitalization and death. A secondary outcome was development of persistent COVID-19, defined by a positive SARS-CoV-2 polymerase chain reaction (PCR) 31-90 days after COVID-19 diagnosis. RESULTS: Among 65 patients included, 52 (80%) received at least one COVID-19 therapeutic. The most common treatment after initial COVID-19 diagnosis was nirmatrelvir/ritonavir (29%), followed by monoclonal antibody therapy (26%) and remdesivir (11%). Of the 64 patients with at least 30 days of follow-up, 8 (12%) had at least one COVID-19-related hospitalization and one patient died, though cause of death was not due to COVID-19. Of the 8 patients hospitalized for COVID-19, one had severe disease and 7 had mild or moderate infection. Persistent COVID-19 was observed in 13/65 (20%) patients, with 4 patients requiring additional antiviral therapy. Three pre-cellular therapy patients had delays in receiving cellular therapy due to persistent COVID-19. CONCLUSIONS: During the Omicron era, rates of 30-day COVID-19-related hospitalization and death were relatively low in this cohort of pre- and early post-HCT and CART recipients, the majority of whom received treatment with at least one antiviral agent. Persistent COVID-19 occurred in 1 in 5 patients in the peri-cellular therapy period and led to cellular therapy treatment delays in several patients, highlighting the need for new COVID-19 treatment strategies.

Human herpesvirus 6 reactivation and disease are infrequent in chimeric antigen receptor T-cell therapy recipients.

ABSTRACT: Human herpesvirus 6B (HHV-6B) reactivation and disease are increasingly reported after chimeric antigen receptor (CAR) T-cell therapy (CARTx). HHV-6 reactivation in the CAR T-cell product was recently reported, raising questions about product and patient management. Because of overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide 2 lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks after infusion, HHV-6B reactivation occurred in 8 of 89 participants; 3 had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval [CI], 2.2-12.5). HHV-6B detection was low level (median peak, 435 copies per mL; interquartile range, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in the blood and/or cerebrospinal fluid (CSF) within 12 weeks after infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing, with detection in 1. Among 34 patients with CSF HHV-6 testing, 1 patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.

Clinical outcomes and frequency of persistent infection among immunosuppressed patients treated with bebtelovimab for COVID-19 infection at an ambulatory cancer center.

BACKGROUND: There are limited data on clinical outcomes associated with the use of bebtelovimab for the treatment of coronavirus disease 2019 (COVID-19) among cancer patients. We aimed to define the clinical characteristics and outcomes among patients receiving bebtelovimab as part of the COVID-19 therapeutics program at our cancer center. METHODS: This is a retrospective cohort study of immunosuppressed adult patients who received bebtelovimab at Fred Hutchinson Cancer Center between March 2022, and November 2022. We reviewed medical records to capture the date of the first positive COVID-19 test, clinical characteristics, outcomes, and follow-up COVID-19 testing for 60 days after the first positive. Persistent infection was defined as a positive test beyond day 30; these patients were reviewed beyond day 60. RESULTS: Among 93 patients who received bebtelovimab, 64 (69%) had hematologic malignancy. Sixty-nine (74%) patients received bebtelovimab within 2 days after diagnosis. Two (2%) patients were hospitalized, none required ICU care, and one patient died on day 52; although it is unknown if death was directly related to COVID-19. Ten (11%) patients had persistent COVID-19 infection; of these, four received additional COVID-19 therapy with either nirmatrelvir/ritonavir or remdesivir, and five out of six patients with sequencing data available had spike protein mutations associated with bebtelovimab resistance. CONCLUSION: A coordinated systems-based approach led to prompt initiation of bebtelovimab within two days of testing positive in most patients. We observed few hospitalizations or deaths. Persistent infection was noted in 11% of patients with four requiring additional therapies, highlighting a need for novel strategies to manage immunosuppressed patients.

Antiviral Prescribing Among Patients at an Ambulatory Cancer Center With Laboratory-Confirmed Influenza.

Among 133 cancer outpatients diagnosed with influenza between 2016 and 2018, 110 (83%) were prescribed oseltamivir. Among 109 with a known symptom onset date, 53% presented for care and 31% were prescribed oseltamivir within 48 hours. Patient/provider education and rapid diagnostics are needed to improve early oseltamivir use among cancer patients with influenza.

Knowledge and perceptions of antimicrobial resistance and antimicrobial stewardship among staff at a national cancer referral center in Uganda.

Objectives: As access to cancer care has improved throughout sub-Saharan Africa, treatment-associated infections have increased. Assessing healthcare worker knowledge of antimicrobial stewardship and identifying the barriers to infection management will inform the development of contextually appropriate antimicrobial stewardship programs, improving cancer outcomes in sub-Saharan Africa. Design: Cross-sectional survey. Setting: The Uganda Cancer Institute (UCI), a national cancer referral center in Kampala, Uganda. Participants: We surveyed 61 UCI staff: 29 nurses, 7 pharmacists, and 25 physicians. Methods: The survey contained 25 questions and 1 ranking exercise. We examined differences in responses by staff role. Results: All 60 respondents who answered the question had heard the term "antimicrobial resistance." Only 44 (73%) had heard the term "antimicrobial stewardship." Nurses were less likely than pharmacists or physicians to be familiar with either term. Also, 41 respondents (68%) felt that loss of antibiotic susceptibility is a major issue at UCI. Regarding barriers to diagnosing infections, 54 (93%) of 58 thought that it was difficult to obtain blood cultures and 48 (86%) of 56 thought that it was difficult to regularly measure temperatures. Conclusions: Although most recognized the term "antimicrobial resistance," fewer were familiar with the term "antimicrobial stewardship." Inappropriate antibiotic use was recognized as a contributor to antimicrobial resistance, but hand hygiene was underrecognized as a contributing factor. We identified numerous barriers to diagnosing infections, including the ability to obtain blood cultures and consistently monitor temperatures. Educating staff regarding antimicrobial selection, allocating resources for blood cultures, and implementing strategies to enhance fever detection will improve infection management.

Antibiotic prescribing knowledge: A brief survey of providers and staff at an ambulatory cancer center during Antibiotic Awareness Week 2019.

We surveyed healthcare professionals at a cancer center regarding their knowledge and perceptions of antibiotic use. Most knew the term "antimicrobial stewardship." Nurses and other staff were less likely than pharmacists or providers to answer knowledge-based questions correctly. Opportunities exist to improve antibiotic knowledge among cancer center staff.

Exposure to antibiotics with anaerobic activity before respiratory viral infection is associated with respiratory disease progression after hematopoietic cell transplant.

We examined associations between specific antibiotic exposures and progression to lower respiratory tract disease (LRTD) following individual respiratory viral infections (RVIs) after hematopoietic cell transplantation (HCT). We analyzed allogeneic HCT recipients of all ages with their first RVI during the first 100 days post-HCT. For the 21 days before RVI onset, we recorded any receipt of specific groups of antibiotics, and the cumulative sum of the number of antibiotics received for each day (antibiotic-days). We used Cox proportional hazards models to assess the relationship between antibiotic exposure and progression to LRTD. Among 469 patients with RVI, 124 progressed to LRTD. Compared to no antibiotics, use of antibiotics with broad anaerobic activity in the prior 21 days was associated with progression to LRTD after adjusting for age, virus type, hypoalbuminemia, neutropenia, steroid use, and monocytopenia (HR 2.2, 95% CI 1.1-4.1). Greater use of those antibiotics (≥7 antibiotic days) was also associated with LRTD in adjusted models (HR 2.2, 95% CI 1.1-4.3). Results were similar after adjusting for lymphopenia instead of monocytopenia. Antibiotic use is associated with LRTD after RVI across different viruses in HCT recipients. Prospective studies using anaerobe-sparing antibiotics should be explored to assess impact on LRTD in patients undergoing HCT.

Voriconazole in Hematopoietic Stem Cell Transplantation and Cellular Therapies: Real-World Usage and Therapeutic Level Attainment at a Major Transplantation Center.

Voriconazole (VCZ) was one of the first mold-active triazoles available; however, its current use among high-risk hematology populations is unknown as the uptake of posaconazole (PCZ) and isavuconazole (ISZ) increases. We evaluated the usage and therapeutic level attainment of VCZ in hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapy patients at our cancer center. Electronic medical records for all adult HCT or CAR-T patients with an order for VCZ, PCZ, or ISV between January 1, 2018, and June 30, 2020, were extracted. Clinical characteristics, VCZ indication, trough VCZ levels, and frequency of VCZ initiation from 6 months before to 6 months after HCT/CAR-T infusion in consecutive HCT/CAR-T recipients within the study period (infusion between July 1, 2018, and January 1, 2020) were assessed. The association between relevant clinical characteristics and the attainment of subtherapeutic or supratherapeutic levels was also evaluated. Of 468 patients prescribed mold-active triazoles, 256 (54.7%) were prescribed VCZ, 324 (69.2%) PCZ, and 60 (12.8%) ISZ; 152/468 (32.5%) treatment regimens were sequentially modified to alternate mold-active triazoles. Among consecutive HCT and CAR-T recipients at our center, evaluated 6 months pre- or post- HCT/ CAR-T, VCZ was commonly initiated before or after allogeneic HCT (102/381, 26.8%), with most use in the first 30 days after stem cell infusion (40/381, 10.5%); VCZ use was less common in autologous HCT (13/276, 4.7%) and CAR-T (10/153, 6.5%). Of 223 VCZ orders that met inclusion for analysis, indications included empiric treatment in 108/223 (48.4%), directed therapy in 25/223 (11.2%), primary prophylaxis in 69/223 (30.9%) and secondary prophylaxis in 21/223 (9.4%). Of 223 eligible VCZ patients, 144 (64.6%) had at least 1 VCZ level measured during the study period; 75/144 (52.1%) had a therapeutic VCZ level (1.0-5.5 mg/L) at the first measurement (median 2.8mg/L [range 0.1-13.5]) at a median of 6 days of therapy, with 26.4% subtherapeutic and 21.5% supratherapeutic; 46/88 (52.3%) were therapeutic at the second measurement (2.1mg/L [0.1-9.9]) at a median of 17 days of therapy; and 33/48 (68.8%) at the third (2.3mg/L [0.1-7.7]) at a median of 29 days. In multivariable analysis of factors associated with sub- or supratherapeutic levels (body mass index ≥30, concurrent omeprazole use, concurrent letermovir use, indication for VCZ, history/timeframe of HCT), the only significant association was lower odds of a supratherapeutic VCZ level among those undergoing HCT within the previous 30 days compared to those without a history of HCT. VCZ continues to remain an important option in the treatment and prevention of invasive fungal infections in an era when alternative oral mold-active triazoles are available. In spite of long-standing experience with VCZ prescribing, therapeutic level attainment remains a challenge.

Pathogen-Specific Humoral Immunity and Infections in B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy Recipients with Multiple Myeloma.

Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA-CARTx) is an emerging treatment for relapsed or refractory multiple myeloma (R/R MM). Here we characterize the epidemiology of infections, risk factors for infection, and pathogen-specific humoral immunity in patients receiving BCMA-CARTx for R/R MM. We performed a retrospective cohort study in 32 adults with R/R MM enrolled in 2 single-institution phase 1 clinical trials of BCMA-CARTx administered after lymphodepleting chemotherapy alone (n = 22) or with a gamma secretase inhibitor (GSI). We tested serum before and up to approximately 180 days after BCMA-CARTx for measles-specific IgG and for any viral-specific IgG using a systematic viral epitope scanning assay to describe the kinetics of total and pathogen-specific IgG levels pre- and post-BCMA-CARTx. We identified microbiologically documented infections to determine infection incidence and used Poisson regression to explore risk factors for infections within 180 days after BCMA-CARTx. Most individuals developed severe neutropenia, lymphopenia, and hypogammaglobulinemia after BCMA-CARTx. Grade ≥3 cytokine release syndrome (CRS; Lee criteria) occurred in 16% of the participants; 50% of the participants received corticosteroids and/or tocilizumab. Before BCMA-CARTx, 28 of 32 participants (88%) had an IgG <400 mg/dL, and only 5 of 27 (19%) had seropositive measles antibody titers. After BCMA-CARTx, all participants had an IgG <400 mg/dL and declining measles antibody titers; of the 5 individuals with baseline seropositive levels, 2 remained above the seroprotective threshold post-treatment. Participants with IgG MM (n = 13) had significantly fewer antibodies to a panel of viral antigens compared with participants with non-IgG MM (n = 6), both before and after BCMA-CARTx. In the first 180 days after BCMA-CARTx, 17 participants (53%) developed a total of 23 infections, of which 13 (57%) were mild-to-moderate viral infections. Serious infections were more frequent in the first 28 days post-treatment. Infections appeared to be more common in individuals with higher-grade CRS. Individuals with R/R MM have substantial deficits in humoral immunity. These data demonstrate the importance of plasma cells in maintaining long-lived pathogen-specific antibodies and suggest that BCMA-CARTx recipients need ongoing surveillance for late-onset infections. Most infections were mild-moderate severity viral infections. The incidence of early infection appears to be lower than has been reported after CD19-directed CARTx for B cell neoplasms, possibly due to differences in patient and disease characteristics and regimen-related toxicities.

Variation in Clinical Practice and Attitudes on Antibacterial Management of Fever and Neutropenia in Patients With Hematologic Malignancy: A Survey of Cancer Centers Across the United States.

BACKGROUND: Contemporary information regarding fever and neutropenia (FN) management, including approaches to antibacterial prophylaxis, empiric therapy, and de-escalation across US cancer centers, is lacking. METHODS: This was a self-administered, electronic, cross-sectional survey of antimicrobial stewardship physicians and pharmacists at US cancer centers. The survey ascertained institutional practices and individual attitudes on FN management in high-risk cancer patients. A 5-point Likert scale assessed individual attitudes. RESULTS: Providers from 31 of 86 hospitals (36%) responded, and FN management guidelines existed in most (29/31, 94%) hospitals. Antibacterial prophylaxis was recommended in 27/31 (87%) hospitals, with levofloxacin as the preferred agent (23/27, 85%). Cefepime was the most recommended agent for empiric FN treatment (26/29, 90%). Most institutional guidelines (26/29, 90%) recommended against routine addition of empiric gram-positive agents except for specific scenarios. Eighteen of 29 (62%) hospitals explicitly provided guidance on de-escalation of empiric, systemic antibacterial therapy; however, timing of de-escalation was variable according to clinical scenario. Among 34 individual respondents, a majority agreed with use of antibiotic prophylaxis in high-risk patients (25, 74%). Interestingly, only 10 (29%) respondents indicated agreement with the statement that benefits of antibiotic prophylaxis outweigh potential harms. CONCLUSION: Most US cancer centers surveyed had institutional FN management guidelines. Antibiotic de-escalation guidance was lacking in nearly 40% of centers, with heterogeneity in approaches when recommendations existed. Further research is needed to inform FN guidelines on antibacterial prophylaxis and therapy de-escalation.

Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy: a prospective observational study.

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B cell malignancies have profound and prolonged immunodeficiencies and are at risk for serious infections, including respiratory virus infections. Vaccination may be important for infection prevention, but there are limited data on vaccine immunogenicity in this population. We conducted a prospective observational study of the humoral immunogenicity of commercially available 2019-2020 inactivated influenza vaccines in adults immediately prior to or while in durable remission after CD19-, CD20-, or B cell maturation antigen-targeted CAR-T-cell therapy, as well as controls. We tested for antibodies to all four vaccine strains using neutralization and hemagglutination inhibition (HAI) assays. Antibody responses were defined as at least fourfold titer increases from baseline. Seroprotection was defined as a HAI titer ≥40. Enrolled CAR-T-cell recipients were vaccinated 14-29 days prior to (n=5) or 13-57 months following therapy (n=13), and the majority had hypogammaglobulinemia and cellular immunodeficiencies prevaccination. Eight non-immunocompromised adults served as controls. Antibody responses to ≥1 vaccine strain occurred in 2 (40%) individuals before CAR-T-cell therapy and in 4 (31%) individuals vaccinated after CAR-T-cell therapy. An additional 1 (20%) and 6 (46%) individuals had at least twofold increases, respectively. One individual vaccinated prior to CAR-T-cell therapy maintained a response for >3 months following therapy. Across all tested vaccine strains, seroprotection was less frequent in CAR-T-cell recipients than in controls. There was evidence of immunogenicity even among individuals with low immunoglobulin, CD19+ B cell, and CD4+ T-cell counts. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B cell aplasia. However, relatively impaired humoral vaccine immunogenicity indicates the need for additional infection-prevention strategies. Larger studies are needed to refine our understanding of potential correlates of vaccine immunogenicity, and durability of immune responses, in CAR-T-cell therapy recipients.

Association of Physician Orders for Life-Sustaining Treatment With Inpatient Antimicrobial Use at End of Life in Patients With Cancer.

BACKGROUND: Antimicrobial utilization at end of life is common, but whether advance directives correlate with usage is unknown. We sought to determine whether Washington State Physician Orders for Life Sustaining Treatment (POLST) form completion or antimicrobial preferences documented therein correlate with subsequent inpatient antimicrobial prescribing at end of life. METHODS: This was a single-center, retrospective cohort study of adult patients at a cancer center who died between January 1, 2016, and June 30, 2019. We used negative binomial models adjusted for age, sex, and malignancy type to test the relationship between POLST form completion ≥30 days before death, antimicrobial preferences, and antimicrobial days of therapy (DOT) per 1000 inpatient-days in the last 30 days of life. RESULTS: Among 1295 eligible decedents with ≥1 inpatient-day during the last 30 days of life, 318 (24.6%) completed a POLST form. Of 318, 120 (37.7%) were completed ≥30 days before death, 35/120 (29.2%) specified limited antimicrobials, 55/120 (45.8%) specified full antimicrobial use, and 30/120 (25%) omitted antimicrobial preference. Eighty-three percent (1070/1295) received ≥1 inpatient antimicrobial. The median total and intravenous (IV) antimicrobial DOT/1000 inpatient-days were 1077 and 667. Patients specifying limited antimicrobials had significantly lower total antimicrobial DOT (adjusted incidence rate ratio [IRR], 0.68; 95% CI, 0.49-0.95; P = .02) and IV antimicrobial DOT (IRR, 0.57; 95% CI, 0.38-0.86; P = .008) compared with those without a POLST. CONCLUSIONS: Indicating a preference for limited antimicrobials on a POLST form ≥30 days before death may lead to less inpatient antimicrobial use in the last 30 days of life.

Seroprevalence of Measles and Mumps Antibodies Among Individuals With Cancer.

Importance: Although patients with cancer are at an increased risk of infection-related complications, few studies have characterized their vulnerability to measles and mumps. Given the recent outbreaks and increased community vaccine hesitancy, understanding measles and mumps immunity within this population is vital. Objectives: To identify a point prevalence estimate of protective measles and mumps antibodies among ambulatory patients with cancer. Design, Setting, and Participants: In this cross-sectional study, residual clinical plasma samples were obtained from consecutive patients with cancer at Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center in Seattle, Washington, in August 2019. These samples were tested for measles and mumps IgG using a commercial enzyme-linked immunosorbent assay. Patients without cancer were excluded from the analysis. Exposures: Patient age, sex, self-reported race and ethnicity, primary disease, receipt of chemotherapy in the past 30 days before sample collection, hematopoietic cell transplant (HCT) history, and date of most recent intravenous immunoglobulin treatment were abstracted from electronic medical records. Main Outcomes and Measures: Measles and mumps IgG seroprevalence, defined as the proportion of patients with positive antibody test results, was measured overall and among the subgroups. Results: Of the 959 patients included in the analysis, 510 (53%) were male individuals and the mean (SD) age at sample collection was 60 (15) years. Most patients (576 [60%]) had a malignant solid tumor, and 383 patients (40%) had a hematologic malignant neoplasm; 146 patients (15%) had an HCT history. Overall, the seroprevalence of measles antibodies was 0.75 (95% CI, 0.72-0.78), and the seroprevalence of mumps antibodies was 0.62 (95% CI, 0.59-0.65). The lowest seroprevalences were among patients with a hematologic malignant neoplasm (0.63 for measles and 0.48 for mumps), those with a history of HCT (0.46 for measles and 0.29 for mumps), and those aged 30 to 59 years (0.49-0.63 for measles and 0.41-0.58 for mumps). Conclusions and Relevance: In this study, 25% of ambulatory patients with cancer lacked protective antibodies for measles and 38% lacked protective antibodies for mumps. Deficits in protective antibodies underscore patients' increased risk during outbreaks and emphasize the need for community-based efforts to increase herd immunity to protect this population.

Clinical and Virologic Characteristics and Outcomes of Coronavirus Disease 2019 at a Cancer Center.

BACKGROUND: High morbidity and mortality have been observed in patients with cancer and coronavirus disease 2019 (COVID-19); however, there are limited data on antimicrobial use, coinfections, and viral shedding. METHODS: We conducted a retrospective cohort study of adult patients at the Seattle Cancer Care Alliance diagnosed with COVID-19 between February 28, 2020 and June 15, 2020 to characterize antimicrobial use, coinfections, viral shedding, and outcomes within 30 days after diagnosis. Cycle threshold values were used as a proxy for viral load. We determined viral clearance, defined as 2 consecutive negative results using severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction results through July 30, 2020. RESULTS: Seventy-one patients were included with a median age of 61 years; 59% had a solid tumor. Only 3 patients had documented respiratory bacterial coinfection. Empiric antibiotics for pneumonia were prescribed more frequently early in the study period (February 29-March 28, 2020; 12/34) compared to the later period (March 29-June 15, 2020; 2/36) (P = .002). The median number of days from symptom onset to viral clearance was 37 days with viral load rapidly declining in the first 7-10 days after symptom onset. Within 30 days of diagnosis, 29 (41%) patients were hospitalized and 12 (17%) died. Each additional comorbidity was associated with 45% lower odds of days alive and out of hospital in the month following diagnosis in adjusted models. CONCLUSIONS: Patients at a cancer center, particularly those with multiple comorbidities, are at increased risk of poor outcomes from COVID-19. Prolonged viral shedding is frequently observed among cancer patients, and its implications on transmission and treatment strategies warrant further study.

Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy.

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B-cell malignancies are immunocompromised and at risk for serious infections. Vaccine immunogenicity is unknown in this population. We conducted a prospective observational study of the humoral immunogenicity of 2019-2020 inactivated influenza vaccines (IIV) in children and adults immediately prior to (n=7) or 13-57 months after (n=15) CD19-, CD20-, or BCMA-targeted CAR-T-cell therapy, as well as controls (n=8). Individuals post-CAR-T-cell therapy were in remission. We tested for antibodies to 4 vaccine strains at baseline and ≥1 time point after IIV using neutralization and hemagglutination inhibition assays. An antibody response was defined as a ≥4-fold titer increase from baseline at the first post-vaccine time point. Baseline A(H1N1) titers in the CAR-T cohorts were significantly lower compared to controls. Antibody responses to ≥1 vaccine strain occurred in 2 (29%) individuals before CAR-T-cell therapy; one individual maintained a response for >3 months post-CAR-T-cell therapy. Antibody responses to ≥1 vaccine strain occurred in 6 (40%) individuals vaccinated after CAR-T-cell therapy. An additional 2 (29%) and 6 (40%) individuals had ≥2-fold increases (at any time) in the pre- and post-CAR-T cohorts, respectively. There were no identified clinical or immunologic predictors of antibody responses. Neither severe hypogammaglobulinemia nor B-cell aplasia precluded antibody responses. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B-cell aplasia. Larger studies are needed to determine correlates of vaccine immunogenicity and durability in CAR-T-cell therapy recipients. KEY POINTS: Influenza vaccination was immunogenic pre- and post-CAR-T-cell therapy, despite hypogammaglobulinemia and B-cell aplasia.Vaccination with inactivated vaccines can be considered before CAR-T-cell therapy and in individuals with remission after therapy.

Antibodies against vaccine-preventable infections after CAR-T cell therapy for B cell malignancies.

BACKGROUNDLittle is known about pathogen-specific humoral immunity after chimeric antigen receptor-modified T (CAR-T) cell therapy for B cell malignancies.METHODSWe conducted a prospective cross-sectional study of CD19-targeted or B cell maturation antigen-targeted (BCMA-targeted) CAR-T cell therapy recipients at least 6 months posttreatment and in remission. We measured pathogen-specific IgG against 12 vaccine-preventable infections and the number of viral and bacterial epitopes to which IgG was detected ("epitope hits") using a serological profiling assay. The primary outcome was the proportion of participants with IgG levels above a threshold correlated with seroprotection for vaccine-preventable infections.RESULTSWe enrolled 65 children and adults a median of 20 months after CD19- (n = 54) or BCMA- (n = 11) CAR-T cell therapy. Among 30 adults without IgG replacement therapy (IGRT) in the prior 16 weeks, 27 (90%) had hypogammaglobulinemia. These individuals had seroprotection to a median of 67% (IQR, 59%-73%) of tested infections. Proportions of participants with seroprotection per pathogen were comparable to population-based studies, but most individuals lacked seroprotection to specific pathogens. Compared with CD19-CAR-T cell recipients, BCMA-CAR-T cell recipients were half as likely to have seroprotection (prevalence ratio, 0.47; 95% CI, 0.18-1.25) and had fewer pathogen-specific epitope hits (mean difference, -90 epitope hits; 95% CI, -157 to -22).CONCLUSIONSeroprotection for vaccine-preventable infections in adult CD19-CAR-T cell recipients was comparable to the general population. BCMA-CAR-T cell recipients had fewer pathogen-specific antibodies. Deficits in both groups support the need for vaccine and immunoglobulin replacement therapy studies.FUNDINGSwiss National Science Foundation (Early Postdoc Mobility grant P2BSP3_188162), NIH/National Cancer Institute (NIH/NCI) (U01CA247548 and P01CA018029), NIH/NCI Cancer Center Support Grants (P30CA0087-48 and P30CA015704-44), American Society for Transplantation and Cellular Therapy, and Juno Therapeutics/BMS.

Maternal Epstein-Barr Virus-Specific Antibodies and Risk of Infection in Ugandan Infants.

BACKGROUND: Epstein-Barr virus (EBV) infection is a major cause of malignancy worldwide. Maternal antibody is thought to prevent EBV infection because it is uncommon in early infancy. Maternal HIV infection is associated with an increased incidence of EBV infection in exposed infants, which we hypothesized results from impaired transfer of EBV-neutralizing maternal antibodies. METHODS: Among Ugandan infants followed for EBV acquisition from birth, we measured antibody binding to EBV glycoproteins (gp350, gH/gL) involved in B-cell and epithelial-cell entry, as well as viral neutralization and antibody-dependent cellular cytotoxicity (ADCC) activity in plasma samples prior to infection. These serologic data were analyzed for differences between HIV-exposed uninfected (HEU) and HIV-unexposed (HUU) infants, and for associations with incident infant EBV infection. RESULTS: HEU infants had significantly higher titers than HUU infants for all EBV-binding and neutralizing antibodies measured (P < .01) but not ADCC activity, which was similar between groups. No antibody measure was associated with a decreased risk of EBV acquisition in the cohort. CONCLUSIONS: Our findings indicate that in this cohort maternal antibody did not protect infants against EBV infection through viral neutralization. The identification of protective nonneutralizing antibody functions would be invaluable for the development of an EBV vaccine.

Transfusion Challenges in Patients with Hematological Malignancies in Sub-Saharan Africa: A Prospective Observational Study from the Uganda Cancer Institute.

Blood transfusion is fundamental in managing hematologic malignancies. We sought to evaluate the need and availability of blood products for patients with hematological malignancies at Uganda Cancer Institute. We prospectively studied the demand and supply of blood for patients with thrombocytopenia (platelet count ≤50 × 109/L), anemia (hemoglobin ≤10 g/dL), and bleeding (WHO grade ≥2). We used Poisson generalized estimating equation regression models for longitudinal binary outcomes. Among 91 patients, the median age was 26 years (IQR, 11-47). Thrombocytopenia occurred on ≥1 day in 58% of patients and on 49% of hospital days. Platelets were transfused to 39% of patients. The mean number of platelet units requested per day was 16.2 (range 0-30); 5.1 (range 0-15) were received. Anemia occurred on ≥1 day in 90% of patients; on 78% of days; and 68% received at least one blood transfusion. The mean number of blood units requested was 36.3 (range 8-57) units per day; 14 (range 0-30) were received. Bleeding occurred on ≥1 day in 19% of patients on 8% of hospital days. Thrombocytopenia and anemia were common, but product availability was substantially below that requested. We recommend increased blood collection and adherence to strict transfusion triggers as strategies to improve blood availability.

The association between HIV infection and cervical cancer presentation and survival in Uganda.

Our objective was to determine how HIV infection impacts cervical cancer stage at presentation and overall survival (OS) among Ugandan women. This was a prospective study of 149 women diagnosed with cervical cancer from 2013 to 2015 at the Uganda Cancer Institute. Poisson regression models were fit to calculate prevalence ratios (PR) for the association between HIV infection and late stage at cancer diagnosis. The association between HIV infection and OS after cervical cancer diagnosis was evaluated using Cox proportional hazards models. The cohort included 53 HIV-positive and 96 HIV-negative participants. Median age at diagnosis was 44 years for HIV-positive and 54 years for HIV-negative participants. Seventy-seven percent of HIV-positive participants received antiretroviral therapy. Median baseline CD4 count was 373 cells/mm3 for HIV-positive participants versus 926 cells/mm3 for HIV-negative participants. Thirty-two percent of HIV-positive participants were diagnosed with late stage cervical cancer (III-IV) versus 39% of HIV-negative participants. No association was found between late stage at cancer diagnosis and HIV infection (PR adjusted for age, parity and transport cost 1.0, 95%CI 0.6-1.8). Most women presenting for care received cancer treatment, though almost half who received radiotherapy did not complete treatment. The median OS was 13.7 months for HIV-positive participants and 24.3 months for HIV-negative participants. After adjusting for age and stage, HIV infection was weakly associated with OS (HR 1.3, 95%CI 0.8-2.2). In Uganda, cervical cancer is often incompletely treated and survival remains poor. HIV infection was not associated with cervical cancer stage at diagnosis, but may be weakly associated with shorter survival.

Antibiotic Prescribing and Respiratory Viral Testing for Acute Upper Respiratory Infections Among Adult Patients at an Ambulatory Cancer Center.

BACKGROUND: Outpatient antibiotic prescribing for acute upper respiratory infections (URIs) is a high-priority target for antimicrobial stewardship that has not been described for cancer patients. METHODS: We conducted a retrospective cohort study of adult patients at an ambulatory cancer center with URI diagnoses from 1 October 2015 to 30 September 2016. We obtained antimicrobial prescribing, respiratory viral testing, and other clinical data at first encounter for the URI through day 14. We used generalized estimating equations to test associations of baseline factors with antibiotic prescribing. RESULTS: Of 341 charts reviewed, 251 (74%) patients were eligible for analysis. Nearly one-third (32%) of patients were prescribed antibiotics for URIs. Respiratory viruses were detected among 85 (75%) of 113 patients tested. Antibiotic prescribing (P = .001) and viral testing (P < .001) varied by clinical service. Sputum production or chest congestion was associated with higher risk of antibiotic prescribing (relative risk [RR], 2.3; 95% confidence interval [CI], 1.4-3.8; P < .001). Viral testing on day 0 was associated with lower risk of antibiotic prescribing (RR, 0.4; 95% CI 0.2-0.8; P = .01), though collinearity between viral testing and clinical service limited our ability to separate these effects on prescribing. CONCLUSIONS: Nearly one-third of hematology-oncology outpatients were prescribed antibiotics for URIs, despite viral etiologies identified among 75% of those tested. Antibiotic prescribing was significantly lower among patients who received an initial respiratory viral test. The role of viral testing in antibiotic prescribing for URIs in outpatient oncology settings merits further study.