Pediatric Hematopoietic Cell Transplant Recipients Research Articles

Severe Impairment of T-cell Immunity and Pulmonary GvHD Are Major Risk Factors for Nontuberculous Mycobacterial Infection After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplant recipients are prone to infectious complications. Infections caused by nontuberculous mycobacteria have increased in adults but literature in children is scarce. We report 6 episodes of disseminated or pulmonary nontuberculous mycobacteria infection among 5 pediatric hematopoietic stem cell transplant recipients. All but one were caused by Mycobacterium avium complex. Four patients died, 2 related to nontuberculous mycobacteria infection.

The impact of pre-transplant respiratory virus detection on post-transplant outcomes in children undergoing hematopoietic cell transplantation.

Pre-transplant respiratory virus (RV) infections have been associated with negative transplant outcomes in adult hematopoietic cell transplantation (HCT) recipients. In the era of HCT delay due to high-risk RVs, we examined the impact of pre-transplant RV detection on transplant outcomes in a pediatric HCT recipients. This retrospective cohort study included myeloablative allogeneic HCT recipients from 2010 to 2019. All patients were screened for RV at least once within 90 days before HCT using RT-PCR, regardless of symptoms. Post-transplant outcomes included days alive and out of hospital (DAOH) and progression to lower respiratory tract infection (LRTI). Among 310 patients, 134 had a RV detected in the 90 days prior to HCT. In univariable analysis, transplant factors including younger age, total body irradiation, umbilical cord blood transplantation, lymphocyte count less than 100/mm3, and HCT comorbidity index score ≥3, and viral factors including symptomatic infection, human rhinovirus (HRV) as a virus type, and symptomatic pre-transplant upper respiratory tract infection (URTI) were associated with fewer DAOH. In multivariable analysis, transplant factors remained significant, but not viral factors. There was a higher incidence of progression to post-transplant LRTI with the same pre-transplant RV if the last positive PCR before HCT was ≤30 days compared to >30 days (p=0.007). In the setting of recommending HCT delay for high-risk RVs, symptomatic URTI, including HRV infections, may lead to increased duration of hospitalization and early progression to LRTI when transplantation is performed within 30 days of the last positive PCR test.

Approach for defining human adenovirus infection and disease for central review adjudication in clinical studies.

Pediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk for morbidity and mortality from human adenovirus (HAdV). HAdV can be detected in an asymptomatic state, referred to as infection or with signs or symptoms of illness, referred to as disease. Standardized case definitions are needed to distinguish infection from disease and allow for consistent reporting in both observational cohort studies and therapeutic clinical trials. A working group of experts in virology, transplant infectious disease, and HCT was assembled to develop HAdV infection and disease definitions with the degree of certainty (i.e., possible, probable, and proven). Definitions were further refined through an iterative process and independently applied by two central review committees (CRCs) to 20 pediatric allo-HCT recipients with at least one HAdV-positive PCR. Initial HAdV infection and disease definitions were developed and updated through an iterative process after reviewing clinical and virological details for 81 subjects with at least one positive HAdV PCR detected in a clinical specimen. Independent application of final definitions to 20 HAdV positive allo-HCT recipients by two CRCs yielded similar number of HAdV infection or disease events but with variation of degree of certainty for some events. Application of definitions by a CRC for a study of HAdV infection and disease is feasible and can provide consistency in the assignment of outcomes. Definitions need further refinement to improve reproducibility and to provide guidance on determining clinical improvement or worsening after initial diagnosis of HAdV infection or disease.

Presentation, anagement, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients. Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

Treatment-Sensitive and Treatment-Dependent Chronic Graft-versus-Host Disease Yield Superior Failure-Free and Overall Survival Compared to Treatment-Resistant Chronic Graft-versus-Host Disease

Response to chronic graft-versus-host disease (cGVHD) treatment may help predict prognosis and outcomes. We hypothesized that cGVHD response to treatment and ability to taper immunosuppression defines distinct treatment response categories that differ in risk factors and prognosis. Our aim was to determine specific clinical characteristics and outcomes associated with 3 distinct cGVHD treatment response groups based on response and duration of immune suppression therapy (IST) as: treatment sensitive (TS), resistant (TR) and treatment dependent (TD) cGVHD. This is a retrospective single-institution cohort study including 1142 consecutive adult and pediatric allogeneic hematopoietic cell transplant (HCT) recipients for malignant and non-malignant disorders at the University of Minnesota (2008-2016). All donor, graft, conditioning regimens, and GVHD prophylaxis strategies were included while only patients who commenced systemic treatment within 30 days of diagnosis of cGVHD were included. A total of 185 patients developed cGVHD requiring IST within 30 days of cGVHD diagnosis are included in this analysis. At 1 year after cGVHD onset, 13% were TS, 27% TD, and 60% TR (including 14% deceased), while at 2 years, 29% were TS, 5% TD, and 66% TR (22% deceased). From a landmark analysis starting 1 year after cGVHD onset, 5-year failure free survival (FFS) and OS were lowest in the TR (FFS 38% and OS 70%), with comparable outcomes in the TD (74% and 82%) and TS (79% each) groups, respectively. Compared to those with no cGVHD, TR cGVHD was associated with worse OS at 5 years after cGVHD (HR 2.09 vs. no cGVHD; 95% CI, 1.3-3.3; P < 0.01). Our findings suggest that refining cGVHD classifications into three treatment response states defines important predictors of early and late clinical outcomes and identifies those needing more effective treatments.

Immunophenotypic predictors of influenza vaccine immunogenicity in pediatric hematopoietic cell transplant recipients

AbstractPediatric hematopoietic cell transplant (HCT) recipients exhibit poor serologic responses to influenza vaccination early after transplant. To facilitate the optimization of influenza vaccination timing, we sought to identify B- and T-cell subpopulations associated with influenza vaccine immunogenicity in this population. We used mass cytometry to phenotype peripheral blood mononuclear cells collected from pediatric HCT recipients enrolled in a multicenter influenza vaccine trial comparing high- and standard-dose formulations over 3 influenza seasons (2016-2019). We fit linear regression models to estimate relationships between immune cell subpopulation numbers before vaccination and prevaccination to postvaccination geometric mean fold rises in antigen-specific (A/H3N2, A/H1N1, and B/Victoria) serum hemagglutination inhibition antibody titers (28-42 days, and ∼6 months after 2 doses). For cell subpopulations identified as predictive of a response to all 3 antigens, we conducted a sensitivity analysis including time after transplant as an additional covariate. Among 156 HCT recipients, we identified 33 distinct immune cell subpopulations; 7 significantly predicted responses to all 3 antigens 28 to 42 days after a 2-dose vaccine series, irrespective of vaccine dose. We also found evidence that baseline absolute numbers of naïve B cells, naïve CD4+ T cells, and circulating T follicular helper cells predicted peak and sustained vaccine-induced titers irrespective of dose or timing of posttransplant vaccine administration. In conclusion, several B- and T-cell subpopulations predicted influenza vaccine immunogenicity in pediatric HCT recipients. This study provides insights into the immune determinants of vaccine responses and may help guide the development of tailored vaccination strategies for this vulnerable population.

Nontuberculous Mycobacterial Infections in Pediatric Solid Organ Transplant and Hematopoietic Cell Transplant Recipients.

The diagnosis of nontuberculous mycobacterial infections is challenging in pediatric solid organ transplant and hematopoietic cell transplant recipients due to the absence of specific clinical manifestations, limitations of sampling, prolonged times for culture and identification, and difficulty discerning colonization from clinical disease. Treatment is dependent on the nontuberculous mycobacterial species, disease type, and pattern of drug resistance. Treatment of nontuberculous mycobacterial infections involves prolonged durations of therapy using multiple medications, which are limited by toxicities and drug-drug interactions.

Viral meningoencephalitis in pediatric solid organ or hematopoietic cell transplant recipients: a diagnostic and therapeutic approach.

Neurologic complications, both infectious and non-infectious, are frequent among hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. Up to 46% of HCT and 50% of SOT recipients experience a neurological complication, including cerebrovascular accidents, drug toxicities, as well as infections. Defects in innate, adaptive, and humoral immune function among transplant recipients predispose to opportunistic infections, including central nervous system (CNS) disease. CNS infections remain uncommon overall amongst HCT and SOT recipients, compromising approximately 1% of total cases among adult patients. Given the relatively lower number of pediatric transplant recipients, the incidence of CNS disease amongst in this population remains unknown. Although infections comprise a small percentage of the neurological complications that occur post-transplant, the associated morbidity and mortality in an immunosuppressed state makes it imperative to promptly evaluate and aggressively treat a pediatric transplant patient with suspicion for viral meningoencephalitis. This manuscript guides the reader through a broad infectious and non-infectious diagnostic differential in a transplant recipient presenting with altered mentation and fever and thereafter, elaborates on diagnostics and management of viral meningoencephalitis. Hypothetical SOT and HCT patient cases have also been constructed to illustrate the diagnostic and management process in select viral etiologies. Given the unique risk for various opportunistic viral infections resulting in CNS disease among transplant recipients, the manuscript will provide a contemporary review of the epidemiology, risk factors, diagnosis, and management of viral meningoencephalitis in these patients.

Graft Vs Host Disease (GVHD) in Pediatric Hematopoietic Stem Cell Transplant (HCT) Recipients and Impact on Overall Survival: A CIBMTR Analysis

Graft Vs Host Disease (GVHD) in Pediatric Hematopoietic Stem Cell Transplant (HCT) Recipients and Impact on Overall Survival: A CIBMTR Analysis

Regulatory T Cell Reconstitution Is Associated with Acute Graft-Versus-Host Disease in Pediatric and Young Adult Hematopoietic Cell Transplant Recipients

Regulatory T Cell Reconstitution Is Associated with Acute Graft-Versus-Host Disease in Pediatric and Young Adult Hematopoietic Cell Transplant Recipients

Disparities in Cytomegalovirus Infection Rates by Race and Ethnicity among Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients at a Single Center

Previous literature has reported cytomegalovirus (CMV) infection rate disparities among racial/ethnic groups of hematopoietic cell transplantation (HCT) recipients. Because race and ethnicity categorizations are social constructs unlikely to affect biological systems, it is likely there are covariates on the pathway to CMV detection, known as mediators, that can explain the observed disparity. Recent developments in mediation analysis methods enable the analysis of time-to-event outcomes, allowing an investigation of these disparities to also consider the timing of CMV infection detection relative to HCT. This study aimed to explore whether racial and ethnic CMV infection disparities existed within a population of HCT recipients at our center, and whether clinical covariates explained any observed association. The study cohort included all recipients of allogeneic HCT performed at the Children's Hospital of Philadelphia between January 2004 and April 2017 who were CMV PCR-negative pretransplantation, had known donor/recipient CMV serology, and were under blood CMV PCR surveillance. Subjects were followed for 100 days post-HCT. Accelerated failure time models using subject's reported race/ethnicity, dichotomized into non-Hispanic White (NHW) and non-NHW, and exposure and time to CMV detection as outcomes examined whether selected clinical factors-donor/recipient CMV serostatus, recipient age, indication for HCT, hematopoietic cell source, match quality-mediated any identified exposure-outcome association. The analysis included 348 HCTs performed in 335 subjects, with 86 episodes (24.7%) in which CMV was detected via PCR analysis. The accelerated failure time model without mediators estimated that non-NHW subjects had fewer CMV-free survival days (time ratio, .21; 95% confidence interval, .10 to .44). Any hypothesized mediator mediated at most 5% of the total association between race/ethnicity and time to CMV detection. Non-NHW HCT recipients had fewer CMV-free survival days than NHW recipients; none of the clinical factors hypothesized to mediate this association accounted for a significant component of total association. Further research should focus on nonclinical factors influenced by systemic racism to better understand their effect on CMV infection among HCT recipients.

Intensive care risk and long-term outcomes in pediatric allogeneic hematopoietic cell transplant recipients

AbstractAllogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in intensive care unit (ICU) use and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6995 pediatric patients with HCT aged ≤21 years who underwent first allogeneic HCT between 2008 and 2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years after HCT), and was linked to demographic background, pretransplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7%, but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pretransplant organ function, and alloreactivity risk factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (P<.001). Thus, although ICU management is common and survival to ICU discharge is high, ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in select patients who are at high risk.

Letermovir for CMV Prophylaxis in Very High-Risk Pediatric Hematopoietic Stem Cell Transplantation Recipients for Inborn Errors of Immunity.

The burden of CMV infection and disease is important in pediatric hematopoietic stem cell transplantation (HSCT), notably in the subgroup of patients with inborn errors of immunity (IEIs). Letermovir (LMV) is now a standard of care for CMV prophylaxis in adult sero-positive (R+) recipients, but is not yet labeled for children. Published pediatric studies are still scarce. We report a monocentric real-life use of LMV in 36 HSCT pediatric recipients with IEIs considered at high-risk of CMV infection including 14 patients between 2 and 12 months of age. A homogenous dosage proportional to the body surface area was used. Pharmacokinetic (PK) was performed in 8 patients with a median of 6 years of age (range 0,6;15). The cumulative incidence of clinically significant CMV infections (CS-CMVi) and the overall survival of patients under LMV were compared to a very similar historical cohort under (val)aciclovir prophylaxis. LMV tolerance was good. As compared to the historical cohort, the incidence of CS-CMVi was significantly lower in LMV group (5 out of 36 transplants (13.9%) versus 28 of the 62 HSCT (45.2%)) (p = 0.002). Plasma LMV exposures did not significantly differ with those reported in adult patients. In this high-risk pediatric HSCT cohort transplanted for IEIs, CMV prophylaxis with LMV at a homogenous dosage was well tolerated and effective in preventing CS-CMVi compared with a historical cohort.

Body Surface Area-Based Dosing of Mycophenolate Mofetil in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Prospective Population Pharmacokinetic Study.

Mycophenolate mofetil (MMF) is commonly used for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited population pharmacokinetic (PPK) data are available for pediatric HSCT patients. This study aimed to develop a PPK model and recommend optimal oral MMF dosage in pediatric HSCT patients. This prospective study involved pediatric HSCT patients at a tertiary academic institution. Patients received oral MMF 15-20 mg/kg twice daily for aGVHD prophylaxis and treatment. The PPK analysis was conducted using a nonlinear mixed-effects modeling method. Simulation was performed considering different body surface areas (BSAs) (0.5 m2, 1.0 m2, 1.5 m2) and dosing (400 mg/m2, 600 mg/m2, 900 mg/m2 twice daily). Based on the simulation, an optimal dosage of oral MMF was suggested. A total of 20 patients and 80 samples were included in the PPK model development. A one-compartment model with first-order absorption adequately described the pharmacokinetics of mycophenolic acid (MPA). BSA was a statistically significant covariate on Vd/F. Simulation suggested the optimal dosage of oral MMF as 900 mg/m2 twice daily, respectively. A reliable PPK model was developed with good predictive performance. This model-informed optimal MMF dosage in pediatric HSCT patients can provide valuable dosing guidance in real-world clinical practice.

Surveillance and Outcomes of Pediatric Hematopoietic Stem Cell Transplantation Recipients During the Recent COVID-19 Outbreak in China

Surveillance and Outcomes of Pediatric Hematopoietic Stem Cell Transplantation Recipients During the Recent COVID-19 Outbreak in China

Risk-Adapted Donor Lymphocyte Infusion after Hematopoietic Cell Transplant in Pediatric and Young Adult Patients Is Associated with Low Risk of Graft Versus Host Disease

Introduction: Donor lymphocyte infusion (DLI) is a form of adoptive immunotherapy administered to enhance the graft-versus-leukemia (GVL) effect after an allogeneic hematopoietic cell transplantation (HCT). DLI is frequently chosen for its ease of administration and low risk of graft ablation as compared with other chemotherapeutic options in patients experiencing mixed chimerism (MC) or disease relapse. But in patients with acute leukemia experiencing relapse, clinical responses are seen in fewer than 20-30%. Success is also limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). We had previously described our risk-adapted strategy of administering DLIs based on chimerism and donor source (Rujkijyanont P, et al. Blood Cancer J 2013). To determine the efficacy and toxicity of DLIs and to identify potential factors influencing the outcomes, we conducted a retrospective single center study including patients who received DLIs after HCT. Methods: We collected data on all HCTs and conventional DLIs that had been administered to patients from 1993 to 2022 for any indication at our center. Each HCT was considered as an independent event. Numeric variables were represented by median and range and compared using the Wilcoxon-Mann-Whitney test. Categorical variables were compared using the Fisher exact test. Competing-risk regression models using the Fine-Gray method were developed to evaluate risk factors for acute GVHD and chronic GVHD. Death and relapse were considered as competing risk events for these GVHD outcomes. Follow-up data were censored at subsequent HCT, 2 years after the first DLI, 5 years after transplant, or the last follow-up. Logistic regression analysis was performed to assess factors associated with the response to DLI within 180 days after the first DLI. Results: During the study period, 236 patients received 252 HCTs followed by DLIs (median age at HCT 9.2 [range 0.2-25.1] years). An additional 743 patients received 806 HCTs with no subsequent DLI (median age at HCT 10.3 [range 0.1-27.2] years). Dosing most frequently used was 1 × 10 5, 1 × 10 6 and 1 × 10 7 CD3+ cells/kg, for haploidentical donor (HAPLO), matched unrelated donor (MUD) and matched sibling donor (MSD) recipients, respectively. Initial doses were occasionally lower based on risk of GVHD and were escalated as tolerated and based on response. After receiving DLI, 19.4% developed acute GVHD, and 9.2% developed chronic GVHD with no significant differences observed between MSD, MUD and HAPLO recipients. After adjusting for donor source, longer duration between HCT and DLI was associated with a significantly decreased risk of both acute (HR 0.97 P&amp;lt;0.001) and chronic GVHD (HR 0.98 P=0.04). A higher CD3+ cell dose was also significantly associated with an increased risk of acute GVHD (HR 1.03 P&amp;lt;0.001) but not chronic GVHD (HR 0.96 P=0.12). The overall response rate after DLI for treating MC or graft failure was 45.2% for MSD, 32.6% for MUD and 41.4% for HAPLO recipients. Logistic regression analysis revealed leukemia patients had a higher response rate after receiving a DLI for mixed chimerism from MSD (OR=19.5 P=0.002) and HAPLO (OR=9.03 P=0.042), but not from MUD HCT (OR=0.65 P= 0.57), compared to patients with non-malignant disorders. We also evaluated the response to DLI for frank disease relapse in 15 patients. The response rate after DLI for disease relapse was 50% (1/2) for MSD, 44.4% (4/9) for HAPLO, but 0% (0/4) for MUD recipients. Conclusions: In our analysis, the incidence of GVHD was not higher in pediatric and young adult HCT recipients who received DLI as compared to those who did not. Overall, the risk of developing acute and chronic GVHD after DLI was low and comparable between different donor sources. The risk of GVHD decreased further away from HCT and increased with higher DLI dose. The response rate for treating MC and disease relapse remains less than 50%. Thus, DLIs may be safely administered to pediatric and young adult patients after HCT. The therapeutic effect may be modulated by adjusting the dose, timing and frequency of DLI administration.

1100. Cellular Immunophenotypic Predictors of Influenza Vaccine Immunogenicity in Pediatric Hematopoietic Cell Transplant Recipients

Abstract Background Pediatric hematopoietic cell transplant recipients (PHCTRs) have poor serologic responses to influenza vaccination. While absolute numbers of circulating B and T cells are important predictors of response, our goal was to identify B and T cell subpopulations associated with vaccine immunogenicity. Methods We conducted a secondary analysis of PHCTRs enrolled in a multicenter randomized controlled influenza vaccine trial spanning three influenza seasons (2016–2019). Peripheral blood mononuclear cells were collected before vaccination and 28–42 days after the second dose, and they were analyzed using mass cytometry (CyTOF). We fit linear regression models to estimate relationships between strain-specific (A/H3N2, A/H1N1, and B/Victoria) pre- to post-vaccination (28–42 days) serum hemagglutination-inhibition antibody titers vs. log-transformed cell counts, including vaccine dose as a covariate. We used the Benjamini–Yekutieli method to adjust for multiplicity. We conducted a subsequent sensitivity analysis, including time from transplant as an additional covariate, for cell populations identified as predictive of response to all three antigens. Results We included 156 PHCTRs. The median age at first vaccination was 11.8 years (IQR, 6.8–14.3 years), and the median time from transplantation was 7.9 months (IQR, 4.3–13.6 months). High-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine was administered to 79 (50.6%) and 77 (49.4%) PHCTRs, respectively. Mass cytometry revealed 33 distinct cell subpopulations, seven of which were significant predictors of geometric mean titer ratio for all three antigens after two vaccine doses, irrespective of dose (Table 1). We found evidence that subpopulations 1 and 18 (related B cell subpopulations differing by BTLA and CCR6 expression), 8 (CD8+ naïve T cells), and 19 (CD4+ T follicular helper cells) predicted titers irrespective of dose and time from transplantation. Table 1 Figure 1 UMAP from a 32-parameter CyTOF antibody panel generated from 156 PHCTRs at the time of vaccination. Major islands of CD4+ T cells, CD8+ T cells, and B cells are demarcated. Figure 2 Heat map of cell subpopulations identified by CyTOF. The frequency of several cell subpopulations predicted subsequent serological responses to multiple vaccine immunogens, including 1 and 18 (B cells), 5 and 7 (naïve CD4+ T cells), 19 (memory cTfh cells), and 23 (CD8+ memory T cells). Conclusion We identified distinct B and T cell subpopulations predictive of influenza vaccine immunogenicity in PHCTRs. Our findings may improve the identification of PHCTRs at high-risk for influenza due to impaired influenza vaccine immunogenicity and aid in the development of effective vaccine strategies in this population. Disclosures Daniel Dulek, MD, Eurofins Viracor: Research supplies Natasha B. Halasa, MD, MPH, Merck: Grant/Research Support|Quidell: Grant/Research Support|Quidell: donation of kits|Sanofi: Grant/Research Support|Sanofi: vaccine support

2563. Cytomegalovirus (CMV) Prophylaxis with Letermovir (LET) in Pediatric (Birth to &amp;lt; 18 years of age) Allogeneic Hematopoietic Cell Transplant (HCT) Recipients: Pharmacokinetics (PK), Safety and Efficacy Results of a Phase 2b study

Abstract Background LET is a CMV DNA terminase complex inhibitor approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic HCT recipients. This study evaluated PK, safety and efficacy of LET for CMV prophylaxis in pediatric allogeneic HCT recipients. Methods This was a Phase 2b, single-arm, multicenter, open-label study (NCT03940586). Participants (pts) from birth to &amp;lt; 18 years (y) were sequentially enrolled in 3 age groups (AG): AG1, 12 to &amp;lt; 18 y; AG2, 2 to &amp;lt; 12 y; AG3 &amp;lt; 2 y. All pts received LET orally (PO) or intravenously (IV) with/without cyclosporin A (CsA). Pediatric target exposures were based on model-predicted Phase 3 population simulations for adult HCT recipients, ranging from 16,900 ng.h/mL (480 mg PO, no CsA) to 147,800 ng.h/mL (480 mg IV, no CsA). PK parameters were determined by non-compartmental analysis (5 samples over 24 hr, 38/63 pts). Safety was assessed by evaluation of adverse events. Results Of 63 pts administered LET, the majority were White (69.8%) and male (69.8%); median age of 11 (0–17) y; median weight of 32.4 (5.1–95.0) kg. PK (n=36 evaluable pts): AG1 (n=12, LET 480 mg; LET 240 mg + CsA) achieved exposures within safety margins of adult HCT pts. AG2 (n=16, LET 60–240 mg PO/IV; LET 60–120 mg IV + CsA): 14 pts (PO n=6, IV n=8) who received LET alone achieved target range exposures; 2 pts who received IV LET with CsA had exposures slightly lower than target range. AG3 (n=8, LET 40 mg IV; 60 mg PO; LET 20 mg IV + CsA; 40 mg PO; 60 mg PO/IV): 3 pts who received LET with CsA achieved exposures trending lower than median target. Therefore, LET dose was increased for 5 pts (&amp;lt; 10 kg and aged &amp;lt; 2 y) to achieve target range exposures. Safety (n=63): LET was well-tolerated with a safety profile similar to that observed in adults. Efficacy (n=56): The proportion of pts with clinically significant CMV infection (CMV disease/pre-emptive treatment for CMV viremia) through Week 24 post-HCT was similar (25%) to that seen in adults receiving LET in the Phase 3 study (37.5%). Conclusion LET administration for CMV prophylaxis in pediatric HCT recipients at doses used in this study resulted in exposures within development program safety margins and was associated with similar safety and efficacy when compared with LET use in adult HCT recipients. Disclosures Johannes H. Schulte, MD, The German Cancer Consortium (DKTK): Grant/Research Support Andreas H. Groll, MD, Amplyx: Advisor/Consultant|Astellas: Advisor/Consultant|Astellas: sered at the speakers’ bureau|Basilea: Advisor/Consultant|Basilea: served at the speakers’ bureau|F2G: Advisor/Consultant|F2G: served at the speakers’ bureau|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: served at the speakers’ bureau|Merck Sharp &amp; Dohme LLC: Advisor/Consultant|Merck Sharp &amp; Dohme LLC: Grant/Research Support|Merck Sharp &amp; Dohme LLC: served at the speakers’ bureau|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: served at the speakers’ bureau Valerie L. Teal, MS, Merck Sharp &amp; Dohme LLC: Wages and Salary made to Author|Merck Sharp &amp; Dohme LLC: Stocks/Bonds Barbara A. Haber, MD, Merck Sharp &amp; Dohme LLC: Wages and Salary made to Author|Merck Sharp &amp; Dohme LLC: Stocks/Bonds Christopher L. Gilbert, n/a, Merck Sharp &amp; Dohme LLC: Wages and Salary made to Author|Merck Sharp &amp; Dohme LLC: Stocks/Bonds Jacqueline B. McCrea, PharmD, Merck Sharp &amp; Dohme LLC: Wages and Salary made to Author|Merck Sharp &amp; Dohme LLC: Stocks/Bonds Mayankbhai Patel, PhD, Merck Sharp &amp; Dohme LLC: Wages and Salary made to Author|Merck Sharp &amp; Dohme LLC: Stocks/Bonds Karsten Menzel, PhD, Merck Sharp &amp; Dohme LLC: Wages and Salary made to Author|Merck Sharp &amp; Dohme LLC: Stocks/Bonds Cyrus Badshah, MD, PhD, Merck Sharp &amp; Dohme LLC: Wages and Salary made to Author|Merck Sharp &amp; Dohme LLC: Stocks/Bonds

2712. Respiratory syncytial virus (RSV) pre-fusion F antibody titers in hematopoietic cell transplant recipients with upper versus lower respiratory tract infections

Abstract Background Humoral immune responses to respiratory syncytial virus (RSV) infection in hematopoietic cell transplant (HCT) recipients have not been well characterized. We measured RSV pre-fusion F antibody (RSVpreF) titers in HCT recipients in 3 groups: upper respiratory tract infections (URTI) only, lower respiratory tract infections (LRTI) only, and those who progressed from URTI to LRTIs (progressors). Methods We evaluated adult and pediatric allogeneic HCT recipients who acquired RSV from 12/2011 to 12/2019. Prospective and leftover clinical serum specimens were collected from the Fred Hutchinson Cancer Center. Samples included baseline prior to infection, at RSV URTI or LRTI diagnosis, and after infection (both 4-6 and &amp;gt;8 weeks). Quantitative RSVpreF titers were determined using the MesoScale Discovery electrochemiluminescence assay. We compared longitudinal log10 RSVpreF titers among groups using linear mixed effect models with restricted cubic splines. Results A total of 129 samples from 39 patients were analyzed; 24 with URTI only, 8 progressors, and 7 with LRTI only. The median age at infection was 45 years, but HCT recipients with LRTI only had an overall higher median age of 54 (range 23-63) (Table 1). Most had acute leukemia (n=18, 46%) and received peripheral blood stem cells (n=27, 69%) as their cell source (Table 1). Median RSVpreF values were similar across the 3 different groups at each timepoint (Table 2). Trajectories of RSVpreF titers over time for each patient trended towards an increase following RSV diagnosis in all groups (Figure 1a). Predicted curves in RSVpreF titers over time did not differ significantly by group (Figure 1b, p=0.38).Table 2.Summary of RSVpreF titers among allogeneic transplant recipients before and after a post-HCT RSV infection. RSVpreF titers were obtained utilizing Meso Scale Discovery chemiluminescence assays. (A) RSVpreF titers for allogeneic HCT recipients with RSV infection. Each line represents a patient. The top panel shows patients with RSV URTI only, the middle panel shows patients who progressed from URTI to LRTI, and the bottom panel shows patients who presented with RSV LRTI. Open circles represent time points prior to RSV diagnosis, filled circles represent time points just prior to, on or after URTI, and asterisks represent time points just prior to, on, or after LRTI. (B) RSVpreF titers plotted by days from RSV diagnosis. Open circles represent observed values and lines represent model predicted trajectories. Black circles and lines correspond to patients with RSV URTI only, blue corresponds to patients who progressed from RSV URTI to LRTI, and dark orange represents patient who presented with RSV LRTI at diagnosis. An outlying observation at day -53 was excluded. Conclusion Among allogeneic HCT recipients with RSV infection, RSVpreF titers increased in response to RSV infection, but did not differ among patients with URTI only, progressors, or those with LRTI only across pre and post infection time points. Our novel immunoassay results are similar to those from previously described RSV neutralization assays, but extended the observation period beyond 4 weeks after infection, revealing a modest increase in RSVpreF titers. Further characterization of RSV humoral immunity, including mucosal immunity, is needed. Disclosures chikara Ogimi, MD, bioMerieux Japan Ltd.: Honoraria|Horiba: Honoraria|Pfizer: Honoraria Janet A. Englund, MD, Ark Biopharma: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Emily T. Martin, PhD, MPH, Merck: Grant/Research Support Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Symbio: Advisor/Consultant Alpana Waghmare, MD, Allovir: Grant/Research Support|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|GlaxoKlineSmith/Vir: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Pfizer: Grant/Research Support|Vir Biotechnology: Advisor/Consultant

Immunogenicity and Safety of Alternative Influenza Vaccination Strategies in Repeated Seasons in Pediatric Hematopoietic-Cell Transplant Recipients

Abstract Background Pediatric hematopoietic cell transplant (HCT) recipients are at increased risk for morbidity and mortality from influenza infection. Annual influenza vaccination is recommended; however, HCT recipients have diminished immune responses to vaccination. Our recent trial demonstrated that two doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart post-HCT were more immunogenic than two doses of standard dose quadrivalent influenza vaccine (SD-QIV). We assessed the impact of this strategy in a consecutive season post-HCT. Methods The initial trial was a multi-center double-blinded phase II randomized controlled trial comparing two doses of HD-TIV to two doses of SD-QIV in children 3-17 years old given 3-35 months post-allogeneic HCT. Participants completing the initial trial could re-enroll the subsequent influenza season to receive the same two-dose vaccine formulation. Hemagglutinin inhibition (HAI) titers were measured at baseline and 28-42 days following each dose. Injection-site and systemic adverse events were assessed. The immunogenicity endpoints were the post-dose 1 and post-dose 2 geometric mean HAI titers (GMTs) in the second year of participation. Results A total of 170 participants were enrolled in the initial trial, with 65 re-enrolling for a second year (n=33 SD-QIV and n=32 HD-TIV). Post-dose 1 and 2 GMTs were higher for both the SD-QIV and HD-TIV groups in the second year compared the first year (Table 1). In year two, the adjusted geometric mean ratio (aGMR) comparing HD-TIV to SD-QIV was higher post-dose 1 for A/H1N1 (aGMR=1.99, 95% CI:[1.07, 3.68]). The HD-TIV group demonstrated a higher frequency of four-fold titer rise after a single dose compared to two doses of SD-QIV for A/H3N2 (61% vs. 48%) and B/Victoria (77% vs. 65%). Frequency of injection site and systemic reactions were similar between the HD-TIV and SD-QIV groups in year two. Conclusions The post-dose 1 and 2 GMTs were consistently higher for HD-TIV compared to SD-QIV in year two, and aGMR reached statistical significance after a single dose of HD-TIV for A/H1N1. Year two reactogenicity was comparable for both vaccination strategies. Further studies with larger numbers of participants are needed to demonstrate if one or two doses of HD-TIV are needed in subsequent influenza seasons post-HCT when a two-dose vaccination series is given in the first post-HCT season. Table 1. Point estimates and 95% CIs for geometric mean HAI titer, titer ≥1:40, and proportion with ≥4-fold rise from baseline for each vaccine regimen, stratified for each antigen. Also included is the ratio of the observed values (n) to the number of evaluable subjects (N) at each visit. Baseline titers are measured prior to first vaccine dose, post-dose 1 titers are measured 28-42 days following first dose (prior to the second dose), post-dose 2 titers are measured 28-42 days following second dose. Table 1 Note: If 100% achieved seroprotection or seroconversion, “n/a” was entered as a two-sided 95% CI could not be calculated.