Pediatric Hematopoietic Cell Transplantation Research Articles

Return to school practices after hematopoietic cell transplantation: a survey of transplant centers in the United States.

To understand transplant center recommendations on return-to-school timing and related support for hematopoietic cell transplant (HCT) survivors, we conducted a two-phase, cross-sectional, web-based survey: In Phase I, medical directors of pediatric HCT centers from the National Marrow Donor Program/ Be The Match Registry were asked regarding the availability of a return to school standardized operating procedure (SOP). In Phase II, HCT physician members of the Pediatric Transplantation and Cellular Therapy Consortium were approached to study inter-physician practice variability regarding return to school post-HCT, factors affecting their decision-making, and support provided by HCT centers for return to school. Out of 46 respondents in Phase I (55% response rate), 28 (61%) reported having a SOP. Wide variations in recommendations were noted in 12 received SOPs. In Phase II, 122 physicians (60 centers) responded (30.6% response rate). The majority (60%) recommended autologous HCT recipients return to school within 6 months post-HCT but 65% recommended allogeneic HCT recipients return to school after 6 months or once off immunosuppression. Our findings indicate a lack of consensus within and across HCT centers regarding recommended return to school timing and underscore need for a guideline to standardize this process to ensure patient safety and re-integration into school.

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.

Optimal Rabbit Antithymocyte Pharmacokinetics (PK) Is Associated with Improved Disease-Free Survival (DFS) in TCR-Αβ/CD19-Depleted Pediatric Haploidentical Hematopoietic Cell Transplantation for Hematologic Malignancies

Optimal Rabbit Antithymocyte Pharmacokinetics (PK) Is Associated with Improved Disease-Free Survival (DFS) in TCR-Αβ/CD19-Depleted Pediatric Haploidentical Hematopoietic Cell Transplantation for Hematologic Malignancies

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

Model-Based Dosing of Anti-Thymocyte Globulin in Pediatric Allogeneic Hematopoietic Cell Transplantation Improves Survival Chances: Updated Results from the Single Arm Phase II Parachute-Trial Combined with Real-World Data

Model-Based Dosing of Anti-Thymocyte Globulin in Pediatric Allogeneic Hematopoietic Cell Transplantation Improves Survival Chances: Updated Results from the Single Arm Phase II Parachute-Trial Combined with Real-World Data

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.

Epidemiology of bloodstream infections and the impact of antimicrobial resistance in pediatric hematopoietic cell transplant.

Bloodstream infections (BSI) pose a substantial threat to the well-being and survival of patients undergoing hematopoietic stem cell transplantation (HSCT). Risk factors for these infections vary across the different post-HSCT phases. In the pre-engraftment period, patients are particularly susceptible to infection due to prolonged neutropenia, mucosal damage, and extensive use of central venous line (CVL). In the post-engraftment phase, the emergence of graft versus host diseases further compounds the risk. The epidemiology of these infections has undergone notable changes over the years due to multifactorial reasons, including the evolution of protocols that intensify immunosuppression. In this context, the emergence of multi-drug resistance (MDR) microorganisms can be a challenge due to the elevated risk of mortality in these vulnerable patients. Unfortunately, there is a lack of comprehensive data on this topic, particularly in pediatrics. This article aims to provide a summary of the epidemiology of BSI in the different post-transplant phases and the impact of MDR pathogens. Having knowledge about the local epidemiology of BSI can be instrumental in tailoring targeted therapies, leading to improved survival rates in HSCT 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.

Stopping antibacterial prophylaxis in pediatric allogeneic hematopoietic cell transplantation: An internal audit.

Antibacterial prophylaxis in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) is controversial and not recommended by international guidelines. We analyzed relevant posttransplant outcomes following discontinuation of antibacterial prophylaxis at a major European pediatric transplant center. The single-center retrospective audit included all pediatric allogeneic HCT patients (pts) transplanted between 2011 and 2020 before (≤2014) and after (≥2015) stopping routine antibacterial prophylaxis with penicillin, metronidazole, and ciprofloxacin upon start of the conditioning regimen. The primary endpoint was overall survival until the first hospital discharge. Secondary endpoints included the occurrence of fever; bacterial infections; and cumulative days with antibacterial agents until discharge. A total of 257 HCT procedures were performed in 249 pts (median age: 10 years, range, 0.2-22.5) for leukemia/lymphoma (n = 150) and nonmalignant disorders (n = 107). Of these, 104 procedures were performed before (cohort 1) and 153 after (cohort 2) stopping prophylaxis. Overall survival until discharge was 90.4% in cohort 1 and 96.1% in cohort 2 (p = .06). No differences were observed in the occurrence of fever (92.3vs. 94.1%; p = .57) and bacterial infections (34.6vs. 25.5%; p = .11). The median number of days on antibacterial agents was significantly lower in cohort 2 (39vs. 34; p = .002). Detection rates of resistant organisms were overall low. In this single-center audit, the stop of routine antibacterial prophylaxis had no effect on the occurrence of fever, bacterial infections, resistant organisms, and GVHD. Overall antibiotic use was significantly reduced, and survival was noninferior to the historical control cohort.

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.

Outcomes and Toxicities after Allogeneic Hematopoietic Cell Transplant for Remission Consolidation or Relapse Therapy after CD19 Chimeric Antigen Receptor T Cell Therapy in Children and Young Adults with Acute Lymphoblastic Leukemia

Introduction: CD19-directed chimeric antigen receptor-modified T cells (CART19) induce remarkably high remission rates in relapsed/refractory B-lymphoblastic leukemia (B-ALL), but 50% of children and young adults experience subsequent relapse. Allogeneic hematopoietic cell transplant (HCT) is frequently used after CART19, either for relapse prevention or to treat post-CART19 relapse. However, there is a paucity of safety and outcome data after HCT in this population. This gap is especially relevant because patients often undergo HCT post-CART19 later in their relapsed disease courses (i.e., CR3 or later) than historical patients undergoing HCT for B-ALL. Methods: We conducted a retrospective review of patients aged &amp;lt;30 years with B-ALL who underwent a first HCT for remission consolidation (preemptive cohort) or relapse therapy (relapse cohort) after CART19 at the Children's Hospital of Philadelphia between 2014-2022. The primary outcome was disease-free survival (DFS) from HCT, stratified by cohort. Secondary outcomes included overall survival (OS) and frequency of transplant-related mortality (TRM), graft-versus-host disease (GVHD), sinusoidal obstruction syndrome (SOS), and IgG replacement dependence. Results: The analysis included 41 patients: 19 in the preemptive cohort (pre-planned consolidative HCT, n=5; early loss of B cell aplasia, n=13; positive next-generation sequencing minimal residual disease [MRD], n=1) and 22 in the relapse cohort (morphologic relapse, n=18; detectable flow-based MRD, n=4) (Table 1). With one exception of a patient treated with a CD19/CD28-based product, all patients received investigational or commercial CD19/4-1BB CAR T cells. Median time from CART19 infusion to HCT was 5 months (range, 2-10) for the preemptive and 14 months (range, 5-40) for the relapse cohort. Between CART19 and HCT, 6/19 (32%) preemptive patients received bridging therapy (chemotherapy, n=3; blinatumomab, n=1; inotuzumab, n=2). In the relapse cohort, salvage therapies that successfully induced HCT-acceptable remissions (MRD &amp;lt;0.1%) included inotuzumab (n=11, 50%), cytotoxic chemotherapy (n=5, 23%), blinatumomab (n=2, 9%), CART22 (n=2, 9%), CART19 reinfusion (n=1, 5%), or pembrolizumab (n=1, 5%). At HCT, the majority (79%) of the preemptive cohort was in CR1 or CR2; whereas, the majority (77%) of the relapse cohort was in ≥CR3. All patients received myeloablative conditioning, either total body irradiation-based (n=39) or clofarabine-based (n=2), and 59% received a T cell depleted graft. In the preemptive cohort, with a median follow-up of 36 months, DFS at 1, 2, and 3 years after HCT was 100%, 93% (95% CI, 61-99), and 85% (95% CI, 51-96), respectively (Fig. 1). OS was 100% through 3 years. In the relapse cohort, with a median follow-up of 34 months, DFS was 58% (95% CI, 35-76) and OS was 68% (95% CI, 44-83) by 1 year, and remained the same through 3 years (Fig. 1). When stratified by CD19 immunophenotype at post-CART19 relapse, DFS by 1 year was 67% (95% CI, 34-86) for CD19-positive and 44% (95% CI, 14-72) for CD19-negative disease (p=0.235). Frequently observed toxicities included GVHD and SOS. In the preemptive cohort, 10 patients (53%) developed acute GVHD (3 [16%] were grade ≥3) and 7 (37%) developed chronic GVHD. In the relapse cohort, 11 patients (50%) developed acute GVHD (4 [18%] were grade ≥3) and 6 (27%) developed chronic GVHD. SOS was observed in 1 (5%) preemptive patient and 7 (32%) relapse patients. Four patients (18%), all in the relapse cohort, died of TRM between days +47-65 after HCT. Three had multisystem organ failure in the setting of multiple complications, including severe SOS. One had respiratory failure due to presumed adenoviral pneumonitis. At 1 year post-HCT, 9/18 (50%) preemptive and 8/12 (67%) relapse patients who remained event-free still required IgG replacement. Conclusion: In children receiving their first HCT for post-CART19 remission consolidation, DFS and OS were exceptionally good, without any observed TRM and with comparable rates of GVHD and other major complications to general pediatric HCT populations. For children who were able to undergo HCT following a post-CART19 relapse, of which 77% were in CR3 or later, DFS and OS were also favorable. The majority became long term survivors and all events occurred within 1 year after HCT. However, higher rates of SOS (likely associated with pre-HCT inotuzumab) and TRM were also observed in this cohort.

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

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

Optimizing Vaccine Delivery Among Pediatric Allogeneic Hematopoietic Cell Transplant Recipients: A Quality Improvement Initiative

Abstract Background Pediatric allogeneic hematopoietic cell transplantation (HCT) recipients are at risk for vaccine-preventable infections (VPI). Although evidence-based guidelines recommend starting vaccination efforts between 3-6 months post-HCT, most children remain sub-optimally vaccinated and at-risk for VPI. Our prior work demonstrated that early vaccination starting at 4-6 months post HCT was safe and immunogenic. To reduce potential patient harm from vaccine-preventable infections (VPI), we created a quality improvement (QI) initiative to increase vaccination rates among eligible pediatric allo-HCT recipients, beginning early post-HCT by implementing a best practice immunization strategy at our institution. Methods This QI initiative applied a quasi-experimental design and multiple bundled interventions in Plan-Do-Study-Act (PDSA) cycles to implement and sustain an early immunization strategy among allogeneic HCT recipients in our ambulatory HCT clinic from November 2018-May 2022. The study aimed to increase vaccination rates in eligible patients by providing a core vaccine bundle (pneumococcal conjugate [PCV13], Haemophilus influenzae type b [Hib], inactivated polio [IPV], diphtheria, tetanus, acellular pertussis [DTaP], and hepatitis B vaccines [HBV]) beginning at 6 months [Day+168 to 180] post-HCT, allowing a 30-day grace period for clinic scheduling. The number of subjects who completed a full vaccine series (4 PCV13, 3 DTaP/HBV/IPV and Hib) within the expected time post HCT were recorded. Subjects were ineligible for early vaccination if the indication for HCT was a primary immunodeficiency, and if at screening or vaccination, subjects had relapsed primary disease, graft failure, died, received anti-CD20 therapies in the preceding 6 months and had no evidence of B cell recovery, or were receiving augmented immunosuppression (prednisone-equivalent of ≥ 2 mg/kg/day). The process measure was the proportion of patients screened for vaccine eligibility vs all eligible allo-HCT recipients at 4 months post-HCT. The outcome measure included the proportion of eligible allo-HCT recipients who received the first doses of core vaccines at 6 months (+30 days) among the total number of eligible patients dur for early vaccination. PDSA interventions included creating and implementing a standardized vaccine clinical practice guideline, stakeholder engagement and communication, pre-clinic screening at 4 months post-HCT, creation of a vaccine order set per time post-HCT, and patient-individualized vaccine decision support recommendations. Results Among 72 children who underwent allo-HCT, 37 (51%) were deemed eligible for early vaccination. Review of institutional baseline data revealed that only 43% of eligible allo-HCT received the core vaccines beginning at 6 mos post-HCT. After the first two PDSA cycles, the proportion of eligible patients receiving core vaccines beginning early post-HCT increased from a baseline of 43% to 62%. After implementation of a patient-individualized vaccine decision support recommendation, early immunization rates increased to 92% and were sustained for over 2 years. In total, 33 (90%) patients, predominantly males (55%) with a median age of 9 y [range 0.33-19], received core vaccines at a median of 175 days [range 168-210] post-HCT during the study period. Among children who received early vaccination post-HCT, 82% remained eligible to continue their recommended vaccine roadmap and completed the full vaccine series by the expected 14-16 months post-HCT. Conclusions A multidisciplinary approach applying QI methodology and individualized vaccine decision support allowed for improved and sustained early vaccination after pediatric allo-HCT and completion of vaccine series, thereby reducing potential VPI-associated patient harm. Figure 1. Statistical Process Control Chart (p-chart) of Quality Improvement Initiative to Improve Vaccination Delivery Starting at 6 months After Pediatric Allogeneic Hematopoietic Cell Transplantation (HCT)

Impact of Hematopoietic Cell Transplantation on Cardiovascular Risk Factors and Insulin Sensitivity

The use of hematopoietic cell transplantation (HCT) for treating malignant conditions in children has increased over the past five decades, leading to a growing population of long-term survivors.This population of childhood HCT survivors faces increased risks of adverse medical effects due to cancer treatments, including adverse cardiovascular disease (CVD) risk factors such as metabolic syndrome, insulin resistance. but the impact of exposure to HCT preparative conditioning regimen has not been clearly delineated. These risk factors, including obesity, dyslipidemia, hypertension, and insulin resistance (IR), are significant contributors to premature cardiovascular disease and represent a leading cause of non-relapse deaths in childhood cancer and HCT survivors. This study aimed to assess the early development of CVD risk factors and their relationship to insulin resistance in a large population of pediatric and young adult HCT survivors of childhood hematologic malignancies. The study compared their cardiovascular risk profiles, insulin resistance (measured by euglycemic hyperinsulinemic clamp studies), and body composition (determined by dual X-ray absorptiometry - DXA) with a cohort of sibling controls. We enrolled 151 HCT recipients (26.36 ±0.90 years at study enrollment; time since HCT of 2.6-31.5 years) and 92 sibling controls to complete at cardiovascular risk assessment including insulin sensitivity by hyperinsulinemic euglycemic clamp, anthropometry, body composition by dual X-ray absorptiometry, blood pressure, and serum biomarkers. We used linear models to test for mean differences in all continuous outcomes between survivors and siblings, accounting for intra-family correlations with generalized estimating equations. Recipients of HCT were found to have lower insulin sensitivity and more likely to have adverse CVD risk factors in comparison to their healthy siblings. Significantly higher percent fat mass and visceral adipose tissue, and significantly lower lean body mass were noted in HCT recipients than sibling controls despite having a similar body mass index between the two groups. Total body irradiation in the conditioning regimen was one of the strongest factors associated with lower insulin sensitivity, dyslipidemia and abnormal body composition leading to sarcopenic obesity. This study reveals that pediatric and young adult HCT survivors are more insulin resistant and have a higher prevalence of adverse cardiovascular risk factors compared to sibling controls. The presence of cardiovascular risk factors at a relatively young age raises concerns about an escalating trajectory of cardiovascular disease in this population. Therefore, regular monitoring of HCT survivors for cardiometabolic risk factors and early intervention will be crucial for preventing cardiovascular-related complications in the future. The findings underscore the importance of survivorship care for pediatric and young adult HCT survivors, with a focus on managing cardiovascular risk factors and promoting a healthy lifestyle to mitigate long-term adverse effects. Early identification and targeted interventions can significantly improve the long-term health outcomes of this vulnerable population, reducing the burden of cardiovascular disease and related complications.

Longitudinal Blood Count Analysis Reveals That Poor Graft Function after Pediatric Hematopoietic Cell Transplantation Is a Common Complication Associated with Poor Outcome

Background Poor graft function (PGF) is an important complication of allogeneic hematopoietic cell transplantation (allo-HCT), predisposing to infections, bleeding complications and mortality. The reported incidence and outcome of PGF differ between studies, which may partially be explained by differences in patient cohorts and HCT strategies. Pediatric HCT differs from the adults setting in several aspects, such as the underlying disease and use of relatively young donors, including cord blood. To date, however, information on the incidence and outcome of PGF in pediatric HCT recipients is limited. Aim To determine the incidence, risk factors and outcome of poor graft function in pediatric HCT recipients. Methods Longitudinal blood count and transfusion data from 63.219 measurements were retrieved from the Utrecht Patient Oriented Database (ten Berg et al., Clin Chem Lab Med, 2007) to investigate PGF in pediatric recipients of a first HCT. Patients with less than 5 measurements within the first 30 days or 10 measurements within the first 100 days post-HCT were excluded. In line with published definitions, PGF was defined as cytopenia and/or transfusion dependence for 3 consecutive days after day 28 in ≥2 lineages simultaneously, and patients with relapse, grade III-IV GvHD and/or rejection were excluded (Müskens et al., Blood Reviews, 2023). Cytopenias were defined as thrombocytes &amp;lt;20x10 9/L, neutrophils &amp;lt;0.5x10 9/L and hemoglobin &amp;lt;7 g/dL (Kong et al., Biol Blood Marrow Transplant, 2013). Individual and cohort-wide reconstitution patterns of thrombocytes, neutrophils, and hemoglobin after HCT were analyzed and used to identify patients with PGF. Cumulative incidence and survival analyses were conducted using the {survival} R package. Probability of overall survival (OS) and event-free survival (EFS), defined as retransplantation-free, stem-cell-boost free survival, were calculated using the Kaplan-Meier estimate and compared at one year using the log-rank test. Risk factors for PGF and EFS were assessed in univariable and multivariable Cox proportional hazard models. Results Among 348 pediatric recipients who met the inclusion criteria, we identified 53 patients that fulfilled the criteria for PGF, resulting in a cumulative incidence of 0.15 (95% confidence interval (CI): 0.11-0.18). Risk factors for PGF included HCT for hematological disease (p = 0.03) and from an HLA-mismatched donor (p &amp;lt; 0.01). No difference in PGF incidence was observed between recipients of cord blood and bone marrow donors. The one-year OS (1Y OS) of patients in the PGF group was 71% (95% CI: 59-85%), compared to 91% (95% CI: 87-94%) in the good graft function (GGF) group (p &amp;lt; 0.0001, Figure 1A). Infectious disease was the cause of death in 47% in the PGF group, compared to 27% in the GGF group (p = 0.21). The 1Y EFS was 53% (95% CI: 41-68%) in the PGF group, compared to 90% (95% CI: 86-93%) in the GGF group (p &amp;lt; 0.0001, Figure 1B). Conclusion PGF is a common complication in pediatric HCT recipients. No difference in PGF incidence was observed between bone marrow and cord blood grafts. Both patient-specific (underlying disease) and donor-specific (HLA-matching) may contribute to its pathophysiology. PGF patients show a marked reduction in overall and event-free survival, highlighting the need for therapeutic strategies to prevent and/or treat PGF after HCT.

Clonal Hematopoiesis Is Common in Long-Term Survivors of Pediatric Hematopoietic Cell Transplantation, Including Umbilical Cord Blood Transplantation

Background 1. Approximately 20.000 to 200.000 hematopoietic stem and progenitor cells (HSPCs) contribute to steady-state adult hematopoiesis. During ageing, the overall diversity of the HSPC pool decreases, which is in part driven by the selective expansion of HSPC clones with driver mutations, a process called clonal hematopoiesis (CH). CH is an age-related condition that predisposes to hematologic malignancy, cardiovascular disease, and all-cause mortality. Hematopoietic stem cell transplantation (HCT) recipients are at increased risk of CH, but the mechanisms driving the emergence and expansion of CH clones are largely unknown. Furthermore, the prevalence of CH in pediatric HCT recipients, in whom the long-term consequences of CH are particularly relevant, remains to be defined. Aim To determine the prevalence and risk factors of CH in long-term survivors of HCT at pediatric age. Methods We included survivors of HCT at pediatric age, with a minimum survival of 5 years after HCT. CH was assessed by targeted, error-corrected sequencing of mutations in 27 cancer driver genes in whole blood, at a variant allele frequency detection threshold of 1%. HSC age was calculated by the sum of the age of the donor and the interval after HCT. In case the age of a donor was unknown (n=53), the median age for donors of the same donor relation were used (i.e., 12.6 years for sibling donors and 28.7 for matched unrelated donors). Clinical characteristics were compared using the Wilcoxon signed ranked test for continuous variables and Chi-squared or Fisher's exact test for categorical variables. Results Here, we report the interim results of the first 120 HCT survivors in this study. The median age of the survivors was 20.4 years (range 6.7-51.8), and the median interval after HCT was 11.8 years (range 5.2-38.2). Indications for HCT were hemato-oncology (n=95), bone marrow failure (n=22), or immune deficiency (n=3). The median calculated age of the HSCs was 31 years (range 5.2-61.8). CH was present in 13.3% of survivors (n=16). Mutated genes were DNMT3A (n=15), TET2 (n=4) and MPL (n=1), with three individuals having more than one driver mutation. The median variant allele frequency of the CH clones was 2.2%, but allele frequencies up to 30% were found. No differences were observed in recipient age or interval after HCT between individuals with or without CH (Figure 1A). However, the age of the HSCs was significantly higher in individuals with CH compared to those without (38.6 versus 26.3 years, p = 0.01, Figure 1B). Surprisingly, we detected CH in two recipients of umbilical cord blood grafts, at an interval of 11 and 15 years after HCT. Conclusion Clonal hematopoiesis is common in long-term survivors of pediatric HCT. After HCT, the prevalence of CH is related to the age of the transplanted HSCs, rather than the age of the survivor. The presence of CH in cord blood HSCs within two decades after HCT suggests that HCT-related factors may drive the de novo emergence and/or outgrowth of donor-derived CH. Ongoing research is aimed at investigating how factors such as stem cell source and post-transplant complications affect clonal expansion after HCT. Furthermore, we are investigating the prevalence of CH in an age-matched control cohort using the same detection pipeline, enabling direct comparison of the prevalence of CH in HCT survivors compared to the general population.

Reduction of acute kidney injury in pediatric patients after bone marrow transplant: A prospective analysis after quality improvement implementation.

371 Background: Hematopoietic cell transplantation (HCT) is a curative therapy for malignant and non-malignant diseases. Acute kidney injury (AKI) is a common complication after HCT secondary to use of nephrotoxic medications (NTMx) prescribed for conditioning and prophylaxis. A recently published meta-analysis estimates the incidence of AKI after HCT to be 55.1%, with Stage 3 occurring in 8.3% of patients. Nephrotoxic medication–associated AKI (NAKI) affects 19%–31% of children who receive an intravenous aminoglycoside, with NAKI rates doubling with receipt of ≥ 3 nephrotoxic medications on the same day. We hypothesized that reducing NTMx exposure in pediatric HCT patients would be associated with lower all causes AKI incidence in the HCT unit. Methods: Single-center harm-preventing measures have been implemented at our center since 2019 to 2023. A multi-phased approach was used to increase education and recognition surrounding NTMx exposures in the HCT unit and role in subsequent AKI. We identified champions in the Pediatric HCT and Infectious Disease Host Defense teams. Five educational sessions took place from November 2022-June 2023 and an informational handout was created and distributed to HCT providers. Notifications to attending physicians of patients meeting NTMx exposure criteria, with acceptable alternatives to commonly used nephrotoxic drugs, and suggestions for AKI monitoring took place during daily rounds by the clinical pharmacist. Data on exposures and NAKIs’ was collected and reviewed every 3 months. Results: The cohort included 79 unique patients with 3547 patient days admitted to the HCT unit at Nationwide Children’s Hospital between January 1 2022 and March 31 2023. A total of 210 NTMx exposures were identified and resulted in 22 NAKI events. We reduced the rates of nephrotoxic medication exposure by 51% from 14.36 to 7 per month per 1000 patient days and NAKIs by 21% from to 1.27 to 1 per month per 1000 patient days since the start of our interventions. Conclusions: Successful interventions to decrease AKI in patients admitted to the HCT unit require a multi-disciplinary, iterative, and continuous approach, including recurrent education efforts to providers and pharmacy-driven daily physician alerts. Organizational implementation of these interventions is still ongoing.

Busulfan and subsequent malignancy: An evidence-based risk assessment.

The incidence of secondary malignancies associated with busulfan exposure is considered low, but has been poorly characterized. Because this alkylating agent is increasingly utilized as conditioning prior to gene therapy in nonmalignant hematologic and related disorders, more precise characterization of busulfan's potential contribution to subsequent malignant risk is warranted. We conducted a literature-based assessment of busulfan and subsequent late effects, with emphasis on secondary malignancies, identifying publications via PubMed searches, and selecting those reporting at least 3years of follow-up. We identified eight pediatric and 13 adult publications describing long-term follow-up in 570 pediatric and 2076 adult hematopoietic cell transplant (HCT) recipients. Secondary malignancies were reported in 0.5% of pediatric HCT recipients, with no cases of myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). Fatal secondary malignancies were reported in 0.8% of 1887 evaluable adult HCT recipients, and an overall incidence of secondary malignancies of 4.8% was reported in a subset of 389 evaluable adult patients. We also reviewed long-term results from eight publications evaluating lentiviral- and human promotor-based HSC-targeted gene therapy in 215 patients with nonmalignant conditions, in which busulfan/treosulfan monotherapy or busulfan/fludarabine was the only conditioning. Two malignancies were reported in patients with sickle cell disease (SCD), one of which was potentially busulfan-related. No additional malignancies were reported in 173 patients with follow-up of 5-12years. The incidence of busulfan-related secondary malignancies is low, and likely to be substantially less than 1% in pediatric transplant recipients, especially those receiving busulfan monotherapy for nonmalignant conditions other than SCD.