Pediatric Hematopoietic Stem Cell Transplantation Research Articles

The impact of NKG2A and NKG2D receptors and HLA-E and MICA ligands polymorphisms on post-transplant complications after paediatric allogeneic HSCT: a single-centre experience.

Introduction: Natural Killer cells are the first subpopulation of lymphocytes that reconstitute after allogeneic haematopoietic stem cell transplantation (HSCT). Their activity is regulated by various receptor-ligand interactions, including stimulation of the activating NKG2D receptor by the MICA molecule, and inhibitory NKG2A receptor interacting with the HLA-E. In this study the research effort focused on the effect of selected NKG2A and NKG2D receptors and their ligands (HLA-E and MICA molecules) polymorphisms that may affect the pathomechanisms of post-transplant complications after HSCT in children. Methods: One hundred donor-recipient pairs from a single paediatric transplantation centre were investigated. Altogether six single nucleotide substitutions (NKG2A rs7301582; NKG2D rs1049174, rs1154831; HLA-E rs1264457; MICA rs1051792, rs1063635) were genotyped, and the influence of polymorphisms was analysed on acute and chronic graft-versus-host disease (GvHD), cytomegalovirus (CMV) infection incidence, disease relapse and survival. Results: The distribution of the evaluated polymorphisms did not differ between patients and their donors. The results showed a significant influence of HLA-E rs1264457 polymorphism in patients' HLA-E*01:01 allele, which was associated with increased risk of CMV infection (p = 0.050), especially in children positive for CMV IgG before transplantation (p = 0.001). Furthermore, the effect of HLA-E*01:01 allele on CMV infections was more evident in children above the age of 7 years (p = 0.031). Strong tendencies (0.05 < p < 0.10) towards association with the risk of acute GvHD were also observed for the NKG2A or MICA polymorphisms of the recipients. In addition, NKG2D rs1154831 AA and MICA rs1063635 GG might play a protective role as they were not present in any recipient who died after transplantation. Conclusion: In summary, there is emerging evidence that genotyping results of NKG2 receptors and their ligands, may have prognostic value for the outcome of paediatric allogeneic HSCT, but more extensive studies performed on larger groups of donors and transplant recipients are required to confirm these observations.

COVID-19 in Pediatric Cancer Patients and Hematopoietic Stem Cell Transplant Recipients in a Tertiary Care Hospital in Argentina.

The outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer pediatric patients was initially uncertain. The objective of this study was to describe the characteristics and outcome of cancer patients and hematopoietic stem cell transplant recipients from 0 to 19 years with detectable SARS-CoV-2 from April 23, 2020, to April 30, 2022, treated in a tertiary-level hospital in Argentina. A total of 348 cases were registered in 339 patients. The median age was 89.5 (3 to 224) months. The sex was predominantly male: 193 (55.5%). The most common malignant disease was leukemia (42.8%). One hundred four cases (29.9%) had comorbidities. Of the 346 cases with an available blood count, 17.6% had a lymphocyte count <300/mm 3 . Fever was the most common symptom. In most cases (93.1%) presented asymptomatic or mild disease. Twenty-one cases (6%) presented severe or critical status. Eleven of 24 admissions to the intensive care unit were due to COVID-19 (coronavirus disease 2019). Eight patients (2.3%) died. Two deaths were attributable to SARS-CoV-2 (0.6%). Being older, having fever, lymphopenia at diagnosis, and having received hematopoietic stem cell transplant were associated with a more severe disease. Around 90% of the children continued their cancer treatment without any change.

Antifungal Stewardship Programs in Children: Challenges and Opportunities.

Antifungal Stewardship Programs in Children: Challenges and Opportunities.

Karius test as a noninvasive diagnostic tool in pediatric hematopoietic stem cell transplant patients with pneumonia: A case series.

Dr. Frederick Goldman is a scientific advisor for Karius. Other authors declare no conflict of interest. None.

Daratumumab in the treatment of pure red cell aplasia after pediatric allogeneic stem cell transplantation

Pure red cell aplasia (PRCA) is a rare complication of AB0-incompatible allogeneic hematopoietic stem cell transplantation, which manifests as a partial or complete absence of erythroid lineage in recipients with normal function of other hematopoietic lineages. There is a hypothesis, that lysis of erythroid precursors occurs because of antibody formation by population of residual B-lymphocytes and/or long-lived recipient’s plasma cells, which are capable for proliferation and active expression of the CD38 marker. That is why the invention of the IgG1 monoclonal antibody to CD38 presented as a new potentially effective targeted therapeutic option for patients with refractory PPCA. The article summarize clinical data on daratumumab for the therapy of PRCA in pediatric allogeneic hematopoietic stem cell transplantation recipients. The patients' parents gave their consent to the use of their children's data, including photographs, for research purposes and in publications.

Assessment of micafungin dosage regimens against Candida spp. in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation

The objective of this study was to evaluate the efficacy of various micafungin dosing regimens against Candida spp. in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration targets of micafungin. Current standard clinical micafungin dosing regimens of 1 and 2 mg/kg/day were appropriate for the prevention and treatment of Candida glabrata infection in pediatric patients undergoing HSCT, respectively. Moreover, the high-dose prophylactic dosage (2 mg/kg/day) and therapeutic dosage (4 mg/kg/day) should be the preferred option to optimize efficacy against Candida albicans. However, none of the simulated regimens was effective against Candida parapsilosis in pediatric HSCT patients. These PK/PD-based simulations rationalize and optimize the micafungin dosing regimens against Candida spp. in pediatric patients undergoing HSCT.

Pediatric Autologous Hematopoietic Stem Cell Transplantation: Safety, Efficacy, and Patient Outcomes. Literature Review.

Autologous stem cell transplantation (auto-HSCT) is a part of the therapeutic strategy for various oncohematological diseases. The auto-HSCT procedure enables hematological recovery after high-dose chemotherapy, otherwise not tolerable, by the infusion of autologous hematopoietic stem cells. Unlike allogeneic transplant (allo-HSCT), auto-HSCT has the advantage of lacking acute-graft-versus-host disease (GVHD) and prolonged immunosuppression, however, these advantages are counterbalanced by the absence of graft-versus-leukemia. Moreover, in hematological malignancies, the autologous hematopoietic stem cell source may be contaminated by neoplastic cells, leading to disease reappearance. In recent years, allogeneic transplant-related mortality (TRM) has progressively decreased, almost approaching auto-TRM, and many alternative donor sources are available for the majority of patients eligible for transplant procedures. In adults, the role of auto-HSCT compared to conventional chemotherapy (CT) in hematological malignancies has been well defined in many extended randomized trials; however, such trials are lacking in pediatric cohorts. Therefore, the role of auto-HSCT in pediatric oncohematology is limited, in both first- and second-line therapies and still remains to be defined. Nowadays, the accurate stratification in risk groups, according to the biological characteristics of the tumors and therapy response, and the introduction of new biological therapies, have to be taken into account in order to assign auto-HSCT a precise role in the therapeutic strategies, also considering that in the developmental age, auto-HSCT has a clear advantage over allo-HSCT, in terms of late sequelae, such as organ damage and second neoplasms. The purpose of this review is to report the results obtained with auto-HSCT in the different pediatric oncohematological diseases, focusing on the most significant literature data in the context of the various diseases and discussing this data in the light of the current therapeutic landscape.

Acute Complications of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation and Their Effects on Survival: A Single-Center Experience in Korea

Acute Complications of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation and Their Effects on Survival: A Single-Center Experience in Korea

BK Polyomavirus Diversity After Hematopoietic Stem Cell Transplantation.

BK polyomavirus (BKPyV) infection is common after hematopoietic stem cell transplantation (HSCT) and is associated with the development of hemorrhagic cystitis (HC). The role that BKPyV plays in the pathogenesis of HC is not well characterized. We investigated the impact of BKPyV diversity on the development of HC using a previously established cohort of pediatric HSCT patients. There were 147 urine samples with quantifiable BKPyV at month 1 after HSCT; 137 (93.2%) were amplified using our in-house polymerase chain reaction approach and sent for next-generation sequencing. Subtype Ia was most frequent (61.3%), followed by subtype Ib1 (31.4%). The median viral load of subtype Ia samples was higher than for subtype Ib1 at month 1. Across the protein coding regions, APOBEC-induced mutations and signature patterns associated with HC were identified. This is the largest sequencing study of a single cohort of HSCT patients, providing a vast resource of sequence data for future analyses.

Risk factors for acute kidney injury in pediatric patients after hematopoietic stem cell transplantation: a systematic review and meta-analysis.

Risk factors for acute kidney injury (AKI) in pediatric patients after hematopoietic stem cell transplantation (HSCT) remain controversial. This study aimed to identify risk factors for AKI following HSCT in the pediatric population. PubMed, Embase, Web of Science, Cochrane Library, and Scopus databases were searched from inception to February 8, 2023. Studies meeting the following criteria were included: (1) The study was a case-control, cohort study, or cross-sectional design, (2) the study was performed among pediatric and young patients aged 21 years or younger undergoing HSCT, (3) the study measured at least one related factor for AKI after pediatric HSCT, (4) the study included a sample of at least ten patients, and (5) original articles published in English in peer-reviewed scientific journals. Children who were undergoing pediatric HSCT. We assessed the quality of the included studies and analyzed them with a random-effect model. Fifteen studies with a total of 2,093 patients were included. All were cohort studies of high quality. The overall pooled incidence of AKI was 47.4% (95%CI 0.35, 0.60). We found significant associations between post-transplant AKI in pediatric patients and unrelated donor [odds ratio (OR) = 1.74, 95% confidence interval (CI) 1.09-2.79], cord blood stem cell transplantation (OR = 3.14, 95%CI 2.14-4.60), and veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) (OR = 6.02, 95%CI 1.40-25.88). Other controversial factors such as myeloablative conditioning (MAC), acute graft vs. host disease (aGVHD), and the use of calcineurin inhibitors (CNI) were not found to be related to AKI after pediatric HSCT. Results were limited mainly by heterogeneity in the characteristics of patients and transplantation. Posttransplant AKI in children is a common complication. Unrelated donors, cord blood stem cell transplantation, and VOD/SOS might be risk factors for AKI after pediatric HSCT. Further large-scale studies are still needed to draw firm conclusions. CRD42022382361 A higher resolution version of the Graphical abstract is available as Supplementary information.

Effect of Antibiotics and Gut Microbiota on the Development of Sepsis in Children with Hematopoietic Stem Cell Transplants

Abstract Objective To describe the association between antibiotic use, gut microbiota composition, and the development of sepsis in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) to treat acute lymphoblastic leukemia. Methods A cohort of pediatric patients was followed up between days −30 (pre-HSCT) and +30 (post-HSCT), and sequential stool samples were collected for analysis of the taxonomic composition of bacterial communities by comparing the sequences of the 16s ribosomal RNA gene. Clinically, patients were divided into those with or without sepsis according to their clinical and laboratory data. Gut microbiota was categorized as potentially pathogenic or commensal and was described according to antibiotic use in patients with and without sepsis. Results A cohort of eight patients provided 34 stool samples at different time points during their pre- and post-HSCT periods. There was a greater diversity in the microbial composition in patients who did not develop sepsis. In contrast, patients who developed sepsis had low microbiota diversity, a slight dominance of the genus Bacteroides and order Enterobacterales, and a low abundance of the genus Akkermansia. The use of antibiotics was associated with a low relative abundance of commensal bacteria, a high relative abundance of potentially pathogenic microbiota, and a risk of sepsis. Conclusion Our results suggest that gut microbiota sequencing in pediatric HSCT recipients could predict the clinical course and guide direct interventions to improve patient outcomes. Accordingly, short-spectrum, tailored antibiotic therapy could be provided to patients with fever pre- and post-HSCT to prevent dysbiosis and reduce the risk of sepsis.

A Retrospective Review of Revaccination Patterns in Pediatric Hematopoietic Stem Cell Transplantation Recipients.

Background: After a hematopoietic stem cell transplantation (HSCT), patients are left with little to no immunity to prevent infections. Importantly, this includes immunity gained from previous exposures, including vaccinations. This loss of immunity is a direct result of previous chemotherapy, radiation, and conditioning regimens the patients receive. It is critical to revaccinate patients post-HSCT to ensure protective immunity against vaccine-preventable diseases. Before 2017, all patients at our institution were referred to their pediatrician at approximately 12-month post-HSCT to be revaccinated. Clinical concern was raised at our institution regarding nonadherence and errors in vaccine schedules. Methods: To understand the magnitude of the problem with revaccination, we performed an internal audit of post-vaccine adherence in patients who received an HSCT between 2015 and 2017. A multidisciplinary team was developed to review the audit results and make recommendations. Results: This audit revealed delays in the initiation of the vaccine schedule, incomplete adherence to the recommended revaccination schedule, and errors in administration. Discussion: Based on the review of the data, the multidisciplinary team recommended an approach for systematic assessment of vaccine readiness and centralization of the administration of vaccines to be done within the stem cell transplant outpatient center.

Droplet Digital PCR Development for Adenovirus Load Monitoring in Children after Hematopoietic Stem Cell Transplantation

Human adenovirus (AdV) reactivation after hematopoietic stem cell transplantation (HSCT) is associated with life-threatening clinical manifestations. Although real-tme quantitative PCR (qPCR) has been widely used to measure AdV loads, it has not been standardized for AdV. Droplet digital PCR (ddPCR) is a novel pathogen detection technology that enables the absolute quantification of viral loads. ddPCR would enable a more accurate AdV DNA detection compared with qPCR. In this study, ddPCR was developed for AdV DNA and its performance characteristics compared with those of qPCR. AdV DNAemia incidence during the first 12 weeks after allogenic HSCT was then retrospectively examined by qPCR and ddPCR in 97 HSCT procedures using the preserved 545 DNA samples. ddPCR exhibited better reproducibility and sensitivity, as well as equivalent quantifiability, compared with qPCR. AdV DNA among HSCT patients was detected in 11 (2.0%) and 49 (9.0%) of 545 samples by qPCR and ddPCR, respectively. AdV DNA levels >1000 copies/mL were observed in five cases by qPCR and/or ddPCR. However, two patients developed fulminant hepatitis and died; other patients remained asymptomatic with subsequently undetectable AdV DNA. In conclusion, ddPCR was more sensitive and reproducible in detecting AdV DNA among pediatric HSCT recipients than qPCR. ddPCR offers the potential to provide a more accurate DNAemia detection, determine cutoff values for treatment initiation, and enable antiviral efficacy assessment.

Defibrotide impact on the acute GVHD disease incidence in pediatric hematopoietic stem cell transplant recipients.

Despite advances in acute graft-versus-host disease (aGVHD) prophylaxis, current pharmacological approaches fail to prevent aGVHD. The protective effect of defibrotide on GVHD incidence and GVHD-free survival has not been sufficiently studied. 91 pediatric patients included in this retrospective study were divided into two groups based on defibrotide use. We compared the incidence of aGVHD and chronic GVHD-free survival between the defibrotide and control groups. The incidence and severity of aGVHD were significantly lower in patients who received defibrotide prophylactic administration than in the control group. This improvement was observed in the liver and intestinal aGVHD. No defibrotide prophylaxis benefit was observed in the prevention of chronic GVHD. The pro-inflammatory cytokine levels were significantly higher in the control group. Our findings suggest that prophylactic administration of defibrotide in pediatric patients significantly reduces the incidence and severity of aGVHD, with a modification of cytokine pattern, both strongly coherent with the protective drug's action. This evidence adds to pediatric retrospective studies and preclinical data suggesting a possible defibrotide role in this setting.

Cytokine storm in HSCT for severe combined immunodeficiency infant with SARS-COV-2

Hematopoietic stem cell transplant (HSCT) is the only potentially curative option for severe combined immunodeficiency (SCID) as they are extremely vulnerable to infections. Immunocompromised children are at a higher risk of SARS-CoV-2 infection with prolonged virus shedding, but have a milder disease unlike adults. However, mortality risk increases with neutropenia and in the early transplant period. For these reasons, HSCT is generally deferred when a patient is infected with SARS-COV-2. This decision has to be individualized taking into account the risk of disease progression with delay in transplant. We describe a case of a SCID infant, who had multiple, life-threatening infections (methicillin-resistant Staphylococcus aureus liver abscess, Escherichia coli sepsis, and disseminated Bacillus Calmette-Guerinosis) referred for HSCT. He unfortunately developed SARS-COV-2 infection after the conditioning was commenced for haploidentical stem cell transplant. Foreseeing many challenges with COVID, the transplant was undertaken in the pediatric intensive care unit (PICU) setting. Anticipation, recognition, and timely intervention in the PICU of exaggerated posttransplant cytokine release syndrome and pancreatitis enabled a successful outcome. To the best of our knowledge, this is the youngest pediatric HSCT performed to date with active SARS-COV-2 and first in India.

Is post-transplant day + 14 immature reticulocyte fraction (IRF) a reliable surrogate marker for predicting early platelet engraftment in pediatric hematopoietic stem cell transplant?

BackgroundProphylactic platelet transfusion is given to patients when the platelet count is less than ten thousand to prevent clinically significant bleeding till platelet engraftment is documented. Despite a very low platelet count, if platelet engraftment is confidently predicted, then platelet transfusion can be avoided in an otherwise stable patient.ObjectiveTo determine the role of post-transplant day + 14 immature reticulocyte fraction (IRF) and immature platelet fraction (IPF) as surrogate markers for early prediction of platelet engraftment in pediatric hematopoietic stem cell transplant patients.Material and methodsThis prospective study was done at the National Institute of Blood Diseases and Bone Marrow Transplantation between January 2017 and December 2020. A total of 56 and 31 patients were enrolled in the deviation and validation cohorts respectively. IPF and IRF were tested on a Sysmex XN-1000 hematology analyzer on days + 14 and + 21 of the bone marrow transplant. Platelet count on day + 14 and the day of engraftment was documented. Spearman correlation analysis and receiver operating characteristic curve (ROC) calculation were done using the statistical package STATA version 12, to determine IRF and IPF cut-off values to predict a median platelet engraftment day.ResultsThe derivation and validation cohorts were statistically comparable. The area under the receiver operating characteristic curve (ROC) for IPF and IRF was 0.53 (95% CI: 0.37 – 0.68, p = 0.750) and 0.74 (95% CI: 0.61 – 0.89, p = 0.001) respectively. A weak inverse correlation (rs0.36, p = 0.007) between IRF and platelet engraftment day was found. The ROC demonstrated that the cut-off value for Day + 14 IRF of 13% has a sensitivity and specificity of 92.9% and 37% respectively. This finding was confirmed in the validation group with sensitivity and specificity of 88.2% and 45.2% respectively.ConclusionThis study found that Day + 14 IRF but not IPF value can reliably predict platelet engraftment by day + 17 post-transplant.

Elevated ADA2 Enzyme Activity at the Onset of Chronic Graft-versus-Host Disease in Children

Adenosinergic signaling has potent, context-specific effects on immune cells, particularly on the dysregulation of lymphocytes. This in turn may have a role in immune activation and loss of tolerance in such diseases as chronic graft-versus-host disease (chronic GVHD). We assessed whether changes in the enzymatic activity of adenosine deaminase 2 (ADA2), an enzyme that depletes adenosine in the extracellular space via conversion to inosine, may be associated with the onset of chronic GVHD. ADA2-specific enzyme activity was measured in plasma samples from 230 pediatric hematopoietic stem cell transplantation (HSCT) recipients enrolled on the Applied Biomarkers of Late Effects of Childhood Cancer (ABLE)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) 1202 study and compared between patients developing chronic GVHD and those not developing chronic GVHD within 12 months of transplantation. ADA2 and its relationships with 219 previously measured plasma-soluble proteins, metabolites, and immune cell populations were evaluated as well. Plasma ADA2 enzyme activity was significantly elevated in pediatric HSCT recipients at the onset of chronic GVHD compared to patients without chronic GVHD and was not associated with prior history of acute GVHD or generalized inflammation as measured by C-reactive protein concentration. ADA2-specific enzyme activity met our criteria as a potential diagnostic biomarker of chronic GVHD (effect ratio ≥1.30 or ≤.75; area under the receiver operating characteristic curve ≥.60; P < .05) and was positively associated with markers of immune activation previously identified in pediatric chronic GVHD patients. These results support the potential of ADA2 enzyme activity, in combination with other biomarkers and subject to future validation, to aid the diagnosis of chronic GVHD in children post-HSCT.

Third-Party and Patient-Specific Donor-Derived Virus-Specific T Cells Demonstrate Similar Efficacy and Safety for Management of Viral Infections after Hematopoietic Stem Cell Transplantation in Children and Young Adults

Infections with double-stranded DNA viruses are a common complication after hematopoietic stem cell transplantation (HSCT) and cause significant morbidity and mortality in the post-transplantation period. Both donor-derived (DD) and third-party (TP) virus-specific T cells (VSTs) have shown efficacy and safety in viral management following HSCT in children and young adults. Owing to a greater degree of HLA matching between the recipient and stem cell donor, DD VSTs potentially persist longer in circulation compared to TP VSTs, because they are collected from a well-matched donor. However, TP VSTs are more easily accessible, particularly for smaller transplantation centers that do not have VST manufacturing capabilities, and more economical than creating a customized product for each transplant recipient. We conducted the present study to compare clinical efficacy and safety outcomes for DD VSTs and TP VSTs in a large cohort of pediatric and young adult HSCT recipients and to determine whether DD VSTs are associated with improved outcomes owing to potentially longer persistence in the recipient's circulation. This retrospective cohort study included 145 patients who received VSTs at Cincinnati Children's Hospital Medical Center (CCHMC) between 2017 and 2021 for the treatment of adenovirus, BK virus, cytomegalovirus, and/or Epstein-Barr virus. Viruses were detected using quantitative polymerase chain reaction. Patients received VSTs on a DD (NCT02048332) or TP (NCT02532452) protocol, and VST products for both protocols were manufactured in an identical fashion. The primary study outcome was clinical response to VSTs, evaluated 4 weeks after VST administration, defined as decrease in viral load to under the inclusion thresholds, or resolution of symptoms of invasive viral infection, without the need for additional conventional antiviral medication following VST administration. Secondary outcomes included graft-versus-host-disease, transplant-associated thrombotic microangiopathy, renal function, hospital length of stay, and overall survival at 30 days and 100 days after VST administration and 1 year after HSCT. Statistical analysis was performed using the Fisher exact test or chi-square test. An unpaired t test was used to compare continuous variables. The study group comprised 77 patients in the DD cohort and 68 patients in the TP cohort. Eighteen patients in the TP cohort underwent HSCT at CCHMC, and the other 50 underwent HSCT at other institutions and presented to CCHMC solely for VST administration. There was no statistically significant difference in clinical response rates between DD and TP cohorts (65.6% versus 62.7%; odds ratio [OR], 1.162; 95% confidence interval [CI], .619 to 2.164; P=.747). There were no significant differences in secondary outcomes between the 2 cohorts. The percentage of patients requiring multiple infusions for a clinical response did not differ significantly between the DD and TP cohorts (38.2% versus 32.5%; OR, .780; 95% CI, .345 to 1.805; P=.666). We found no significant difference in clinical response rate between DD VSTs and TP VSTs and a similar safety profile. Our data suggest that TP VSTs may be sufficient to control viral infection until immune reconstitution occurs despite the potential for more rapid VST clearance compared to DD VSTs. The lack of significant differences between DD VSTs and TP VSTs is an important finding, indicating that it is not necessary for every transplant center to manufacture customized DD VSTs, and that TP VSTs are a satisfactory substitute.

194 - Adherence Barriers in Pediatric Hematopoietic Stem Cell Transplant in an Outpatient Setting

194 - Adherence Barriers in Pediatric Hematopoietic Stem Cell Transplant in an Outpatient Setting

429 - BK Polyomavirus after Pediatric Hematopoietic Stem Cell Transplantation

429 - BK Polyomavirus after Pediatric Hematopoietic Stem Cell Transplantation