Pediatric Hematopoietic Cell Transplantation Research Articles

Effect of Clofarabine and Fludarabine Exposure on Outcome after Pediatric Allogeneic Hematopoietic Cell Transplantation

Effect of Clofarabine and Fludarabine Exposure on Outcome after Pediatric Allogeneic Hematopoietic Cell Transplantation

Prophylactic use of liposomal amphotericin B in children and adolescents undergoing allogeneic hematopoietic cell transplantation: A 10-years single center experience

BackgroundAzoles are recommended as antifungal prophylaxis in decreasing the incidence of invasive fungal disease (IFD) in high-risk patients in pediatric oncology, including patients receiving allogeneic hematopoietic cell transplantation (HCT). However, azole related toxicity, pharmacological interactions with immunosuppressive medication and conditioning regimen and growing incidence of azole resistance makes this antifungal agent not ideal in the transplant setting. This study reports on the contemporary incidence and outcome of IFD after allogeneic HCT in children with prophylactic liposomal amphotericin B (L-AMB). MethodsThis single-center retrospective study included all patients transplanted between 2012 and 2022. Primary endpoint was the incidence of IFD until hospital discharge post-transplant. Secondary aims were the incidence of IFD and survival 180 days after allogeneic HCT, the evaluation of toxicity of L-AMB and further risk factors for development of IFD during antifungal prophylaxis. Descriptive statistics were performed. Results161 pediatric patients received L-AMB. Incidence of breakthrough IFD post-transplant was 7.5 % (12/161). The 12 cases comprised of three invasive yeast infections (1.9 %), three probable (1.9 %) and six possible (3.7 %) mold infections. Adverse events were in 22.4 % of the patients, most of them mild and reversible. Discontinuation of L-AMB occurred in 2.5 % (4/161) of the patients due to severe hypersensitivity reactions. ConclusionsThe risk of breakthrough IFD in pediatric patients undergoing allogeneic HCT under L-AMB prophylaxis is comparable with the reported risk under first line recommendation drugs for antifungal prophylaxis. If no hypersensitivity reaction occurs, L-AMB is tolerated with manageable side effects. This antifungal agent should therefore be considered as an alternative option to azoles in pediatric allogeneic HCT recipients.

Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation.

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 children's hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung-immune system-microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.

Timing of intubation of pediatric hematopoietic cell transplant patients: an international survey.

Retrospective data suggest that pediatric hematopoietic cell transplant (HCT) patients placed on non-invasive ventilation (NIV) prior to intubation have increased risk of mortality compared to patients who are intubated earlier in their course. The HCT-CI subgroup of the PALISI Network set out to gain a better understanding of factors that influence clinician's decisions surrounding timing of intubation of pediatric HCT patients. We validated and distributed a brief survey exploring potential factors that may influence clinician's decisions around timing of intubation of pediatric HCT patients with acute lung injury (ALI). One hundred and four of the 869 PALISI Network's members responded to the survey; 97 of these respondents acknowledged caring for HCT patients and were offered the remainder of the survey. The majority of respondents were PICU physicians (96%), with a small number of Advanced Practice Providers and HCT physicians. As expected, poor prognosis categories were perceived as a factors that delay timing to intubation whereas need for invasive procedures was perceived as a factor shortening timing to intubation. Concerns for oxygen toxicity or NIV-associated lung injury were not believed to influence timing of intubation. Our survey indicates increased risk of ALI from prolonged NIV and oxygen toxicity in HCT patients are not a concern for most clinicians. Further education of pediatric ICU clinicians around these risk factors could lead to improvement in outcomes and demands further study. Additionally, clinicians identified concerns for the patient's poor prognosis as a common reason for delayed intubation.

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.

Intrapulmonary administration of recombinant activated factor VII in pediatric, adolescent, and young adult oncology and hematopoietic cell transplant patients with pulmonary hemorrhage.

Diffuse alveolar hemorrhage (DAH) is a devastating disease process with 50-100% mortality in oncology and hematopoietic cell transplant (HCT) recipients. High concentrations of tissue factors have been demonstrated in the alveolar wall in acute respiratory distress syndrome and DAH, along with elevated levels of tissue factor pathway inhibitors. Activated recombinant factor VII (rFVIIa) activates the tissue factor pathway, successfully overcoming the tissue factor pathway inhibitor (TFPI) inhibition of activation of Factor X. Intrapulmonary administration (IP) of rFVIIa in DAH is described in small case series with successful hemostasis and minimal complications. We completed a single center retrospective descriptive study of treatment with rFVIIa and outcomes in pediatric oncology and HCT patients with pulmonary hemorrhage at a quaternary hematology/oncology hospital between 2011 and 2019. We aimed to assess the safety and survival of patients with pulmonary hemorrhage who received of IP rFVIIa. We identified 31 patients with pulmonary hemorrhage requiring ICU care. Thirteen patients received intrapulmonary rFVIIa, while eighteen patients did not. Overall, 13 of 31 patients (41.9%) survived ICU discharge. ICU survival (n=6) amongst those in the IP rFVIIa group was 46.2% compared to 38.9% (n=7) in those who did not receive IP therapy (p=0.69). Hospital survival was 46.2% in the IP group and 27.8% in the non-IP group (p=0.45). There were no adverse events noted from use of IP FVIIa. Intrapulmonary rFVIIa can be safely administered in pediatric oncology patients with pulmonary hemorrhage and should be considered a viable treatment option for these patients.

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 treatment of chronic graft-versus-host disease (cGVHD) may help predict prognosis and outcomes. We hypothesized that the response of cGVHD to treatment and the ability to taper immunosuppression define distinct treatment response categories that differ in terms of risk factors and prognosis. Our aim was to determine specific clinical characteristics and outcomes associated with 3 distinct cGVHD treatment response groups based on the response to and duration of immunosuppressive therapy (IST) as treatment-sensitive (TS), treatment-resistant (TR), and treatment-dependent (TD) cGVHD. This retrospective single-institution cohort study included 1142 consecutive adult and pediatric recipients of allogeneic hematopoietic cell transplantation (HCT) performed for malignant and nonmalignant disorders at the University of Minnesota between 2008 and 2016. All donor, graft, conditioning regimen, and GVHD prophylaxis strategies were included, but only patients who commenced systemic treatment within 30 days of cGVHD diagnosis were included. A total of 185 patients who developed cGVHD necessitating IST within 30 days of cGVHD diagnosis were included in this analysis. At 1 year after cGVHD onset, 13% of the patients were TS, 27% were TD, and 60% were TR (including 14% deceased), whereas at 2 years after cGVHD onset, 29% were TS, 5% were TD, and 66% were TR (including 22% deceased). In a landmark analysis starting at 1 year after cGVHD onset, 5-year failure-free survival (FFS) and overall survival (OS) were lowest in the TR group (FFS, 38%; OS, 70%), with comparable outcomes in the TD (74% and 82%, respectively) and TS (79% for both) groups. Compared to no cGVHD, TR cGVHD was associated with worse OS at 5 years after cGVHD (hazard ratio, 2.09 versus no cGVHD; 95% confidence interval, 1.3 to 3.3; P < .01). Our findings suggest that refining cGVHD classification into 3 treatment response states defines important predictors of early and late clinical outcomes and identifies patients needing more effective treatment.

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.

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.

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.