A phase II, prospective, randomized, open-label study of defibrotide added to standard-of-care prophylaxis for the prevention of acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Acute graft-versus-host disease (aGvHD) is a life-threatening complication typically occurring within 100 days after allogeneic hematopoietic cell transplantation (allo-HCT). This hypothesis-generating, phase II, prospective, open-label, randomized study (clinicaltrials gov. Identifier: NCT03339297) compared defibrotide added to standard-of-care (SOC) GvHD prophylaxis (defibrotide prophylaxis arm) versus SOC alone (SOC arm) to prevent aGvHD post-transplant. This study estimated incidences of aGvHD and was not statistically powered to assess differences among treatment arms. Patients were randomized 1:1 to defibrotide prophylaxis arm (n=79; median age 57 years; range, 2-69 years) or SOC arm (n=73; median age 56 years; range, 2-72 years). Patient demographics in the two arms were similar except for conditioning regimen type (myeloablative: defibrotide, 76% vs. SOC, 61%) and stem cell source for allo-HCT (bone marrow: defibrotide, 34% vs. SOC, 26%). In the intent-to-treat primary endpoint analysis, the cumulative incidence of grade B-D aGvHD at day 100 post-transplant was 38.4% in the defibrotide prophylaxis arm versus 47.1% in the SOC arm (difference: -8.8%, 90% confidence interval [CI]: -22.5 to 4.9). The difference noted at day 100 became more pronounced in a subgroup analysis of patients who received antithymocyte globulin (defibrotide: 30.4%, SOC: 47.6%; difference: -17.2%; 90% CI: -41.8 to 7.5). Overall survival rates at day 180 post-transplant were similar between arms, as were the rates of serious treatment-emergent adverse events (defibrotide: 42%, SOC: 44%). While the observed differences in endpoints between the two arms were not substantial, these results suggest defibrotide prophylaxis may add a benefit to currently available SOC to prevent aGvHD following allo-HCT without adding significant toxicities.

The American Society of Pediatric Hematology Oncology workforce, productivity, and fellowship assessment: Current state of the workforce.

The American Society of Pediatric Hematology Oncology conducted follow-up workforce surveys in 2017 and 2021 as well as a Pediatric Hematology Oncology Fellowship Program Directors Survey in 2020 to provide an updated review of the current workforce. We provide a comprehensive review and analysis of these results with the goal to provide better understanding of the current landscape in pediatric hematology oncology.

Incorporating Absolute Phagocyte Count With Absolute Neutrophil Count as a Measure for Safe Discharge for Pediatric Oncology Febrile Neutropenia: A Pilot Study.

Adequate bone marrow recovery is a discharge requirement after admission for febrile neutropenia in oncology patients, without specific threshold in consensus guidelines. In January 2016, our institution implemented count recovery criteria of absolute neutrophil count ≥100 cells/µL and absolute phagocyte count ≥300 cells/µL compared with prior criteria of absolute neutrophil count ≥500 cells/µL. Retrospective analysis comparing pre (July 2013 to December 2015, N=68) and post (January 2016 to June 2018, N=30) groups showed no difference in readmissions (P>0.9), no patient deaths, and decreased average length of stay in the post group (P<0.0001). Updated count recovery criteria seem feasible and safe.

Multi-organism gastrointestinal polymerase chain reaction positivity among pediatric transplant vs non-transplant populations: A single-center experience.

BACKGROUND: Diarrhea is a common problem in the pediatric post-solid organ transplant and post-hematopoietic stem cell transplant populations. Infectious etiology incidences are poorly defined, and the possibility of multi-organism positivity is often uninvestigated. The aim of this study is to utilize stool multiplex GIP assays to compare the PTP and NTP regarding the incidence and profiles of single-organism and multi-organism infectious diarrhea. METHODS: A single-center retrospective review was conducted, investigating stool multiplex GIP panel results over a more than 3-year period, for pediatric patients. Assays test for 23 viral, bacterial, and protozoal organisms. RESULTS: Positive assays in the PTP and NTP were 70/101 (69.3%) and 962/1716 (56.1%), respectively (P = .009). Thirty-two percent (32/101) of assays within the PTP were multi-organism positive, significantly more than 14.8% (254/1716) in the NTP (P < .00001). There was no significant difference in the incidence of single-organism positives, 37.6% (38/101) in PTP and 41.3% (708/1716) in the NTP. The PTP demonstrated a statistically significantly higher incidence of the following organisms within multi-agent positive GIPs (P < .05 for each): Clostridioides difficile, Cryptosporidium, EPEC, norovirus, and sapovirus. CONCLUSIONS: The pediatric PTP demonstrates higher incidence of positive GIPs, higher rate of multi-organism positivity, and unique infectious organism incidence profiles. These data can provide a framework for understanding organism-specific pathogenicity factors, assessing the clinical impact of enteric co-infection, and understanding the utility of this testing modality in this unique population.

Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant: Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression.

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.

The effect of bone marrow graft composition on pediatric bone marrow transplantation outcomes.

Hematopoietic stem cell graft cellular composition has been generally accepted to impact outcomes. Recent studies question this hypothesis. We conducted a single-center retrospective study of sixty-one pediatric BMT recipients for malignant (68%) and nonmalignant diseases (32%) examining effects of graft composition on engraftment, acute GVHD, chronic GVHD, and survival at day 100 and 1 year. Grafts contained a median of 3.63 x  08 TNC/kg (range: 0.031-10.31 x 108 TNC/kg) and 4.09 x 106 CD34+ /kg (range: 0.76-24.15 x 106 CD34+ /kg) with median neutrophil and platelet engraftment times of 17 and 29 days, respectively. A univariate analysis showed a trend for increasing TNC and increasing time to neutrophil engraftment HR: 0.875; CI: 0.075-1.001). Increasing CD34+ counts shortened time to platelet engraftment (HR: 1.085; CI: 1.015-1.161). No significant relationship was found between TNC, CD34+ , or CD3+ and acute or chronic GVHD. TNC or CD34+ did not affect day 100, 1-year survival, or 2-year survival. Increasing CD3+ counts demonstrated a negative trend on day 100 survival (HR: 1.108; CI: 1.001-1.036) but not 1-year survival or 2-year survival. These results add additional data questioning the effect of graft composition on outcomes in pediatric BMT patients with important ramifications for the management of donors.

Autoimmune enteropathy and hepatitis in pediatric heart transplant recipient.

AIE is a rare disorder in children that presents with severe diarrhea and malabsorption, caused by immune-mediated damage to intestinal mucosa. AIE is often associated with various syndromes of immunodeficiency including IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X-linked). Dysfunctional T regulatory cells are the source of pathology in both IPEX syndrome and AIE as they are essential in maintaining tolerance to self-antigens and eliminating autoreactive B cells. This case report describes a 10-year-old cardiac transplant and total thymectomy patient on chronic immunosuppression with tacrolimus that presented with AIE and extraintestinal manifestations of cyclical hepatitis. Transition from tacrolimus to sirolimus successfully increased T regulatory cells and resolved enteritis and hepatitis symptoms. Data support that thymectomy at <1 year of age increases risk of autoimmune disease due to abnormal immune maturation. Studies suggest that the sirolimus promotes the upregulation of the FoxP3 protein that is classically associated with Tregs. In turn, Tregs prevent the maturation of autoreactive B cells that lead to autoimmune reactions.

Phacomatosis Pigmentokeratotica: A Mosaic RASopathy with Malignant Potential.

Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a nevus sebaceous arranged along the lines of Blaschko with a speckled lentiginous nevus (SLN). We report a novel KRAS mutation in a patient with a large nevus sebaceous and an SLN who subsequently developed a vaginal botryoid rhabdomyosarcoma, an association not previously reported in the literature. This case expands our knowledge of the genetic basis for phacomatosis, in which mutations in HRAS have been previously described, although this report provides evidence that activating mutations in KRAS or HRAS may cause PPK. This report confirms that PPK is a mosaic RASopathy with malignant potential and raises the question of whether screening for other RAS-associated malignancies should be performed for all children with PPK.

Two cases of Vici syndrome associated with Idiopathic Thrombocytopenic Purpura (ITP) with a review of the literature.

Vici syndrome is a rare congenital disorder first described in 1988. To date, 31 cases have been reported in the literature. The characteristic features of this syndrome include: agenesis of the corpus callosum, albinism, cardiomyopathy, variable immunodeficiency, cataracts, and myopathy. We report two Hispanic sisters with genetically confirmed Vici syndrome who both developed Idiopathic Thrombocytopenic Purpura. To our knowledge, this is an immunologic process that has been previously undescribed within the phenotype of Vici syndrome and should be added to the spectrum of variable immune dysregulation that can be found in these patients.

Limited Role of Sinus CT in the Management of Febrile Pediatric HSCT Recipients.

Management guidelines have questioned the role of sinus computed tomography (CT). We reviewed 55 febrile episodes with sinus CT during 1 year after admission for hematopoietic stem cell transplant to determine predictive factors for positive sinus CT and the impact on management. Positive sinus CT findings were seen in 42% of febrile episodes. No characteristics were identified as predictors of a positive sinus CT. No other infectious source was identified in 17% of positive sinus CT episodes, with no pharmacotherapy modifications based solely on a positive sinus CT. Sinus CT should be examined in multicenter groups to develop practice guidelines.

Analysis of factors affecting immune recovery and initial response to tetanus after DTaP vaccination in pediatric allogeneic HSCT patients.

Transfer of donor immunity after allo-HSCT is limited, requiring re-vaccination after HSCT. The CDC 2009 guidelines introduced earlier vaccination post-HSCT with a uniform vaccination strategy. This study objective was to describe predictors of immune recovery and initial response to tetanus after DTaP vaccination post-HSCT. We conducted a retrospective chart review of pediatric allo-HSCT patients transplanted between July 1, 2007-June 30, 2012 who survived >1 yr without relapse (N = 27). Response to tetanus one month after the initial dose of DTaP was defined as a ≥4 fold increase in tetanus titers ≥1 month after vaccination. Wilcoxon rank-sum exact test and Kruskall-Wallis tests were used to analyze CD4, CD8, and CD19 counts. Exact conditional logistic regression was utilized to analyze initial tetanus vaccination response. A statistically significant increase in median CD4, CD8, and CD19 counts occurred from six to 12 months post-HSCT (p ≤ 0.0001, 0.005, 0.004). Only 36% of patients had initial tetanus vaccination response at first attempt post-HSCT. None of the variables tested were statistically significant in predicting initial tetanus response to vaccination. There was no association between predictors of immune recovery or transplant variables and initial tetanus response. A uniform vaccination strategy is unlikely to provide protective antibodies for many post-HSCT patients and should be evaluated in larger studies.

Pancytopenia after allogeneic bone marrow transplant due to copper deficiency.

Pancytopenia occurring 1 year or later after allogeneic bone marrow transplantation typically prompts a primary consideration for relapse. We present the case of a 15-year old-girl who underwent transplantation for therapy-related myelodysplasia secondary to Ewing sarcoma treatment who developed pancytopenia with myelodysplasia 1 year after transplant due to copper deficiency. Copper deficiency is an important consideration in the evaluation of pancytopenia and myelodysplasia in pediatric patients.

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.

Standardization of Pediatric Hematopoietic Stem Cell Transplant Patient Discharge to Reduce Readmission Rates.

Background: The time period after a pediatric hematopoietic stem cell transplant (P-HSCT) is tenuous as the patient is severely immunocompromised and awaiting immune reconstitution. Managing activities of daily living and medication administration after discharge from the hospital requires 24-hour care placing a heavy burden on caregivers and patients. Patients who do not adhere to the posttransplant regimen are at a higher risk for hospital readmission within the first 30 days of initial discharge with serious potential for life-threatening complications. The objective of this project was to improve 30-day readmission rates and caregiver readiness for discharge through the implementation of an evidence-based discharge protocol for P-HSCT patients and caregivers. Methods: This quality improvement project included development and implementation of comprehensive Pediatric Blood & Marrow Transplant Guidelines and discharge protocol for patients who received an inpatient autologous or allogeneic HSCT and were scheduled for discharge from a 16-bed inpatient pediatric hematology-oncology unit of a children's hospital in the southeastern United States. Readmission rates were captured through the hospital-monitored system. Results: The comprehensive discharge protocol was implemented for six patients, and 30-day readmission rates decreased from 27.29% to 3.57% following the intervention. Discussion: Results suggest the combination of an evidence-based discharge protocol with a focus on caregiver readiness for discharge and a 24-hour Rooming-In period can influence caregiver confidence and reduce 30-day readmission rates after initial discharge from a P-HSCT.

Prospective PTCTC trial of myeloablative haplo-BMT with posttransplant cyclophosphamide for pediatric acute leukemias.

Promising results have been reported for adult patients with high-risk hematologic malignancies undergoing haploidentical bone marrow transplant (haploBMT) with posttransplant cyclophosphamide (PTCy). To our knowledge, we report results from the first multicenter trial for pediatric and young adult patients with high-risk acute leukemias and myelodysplastic syndrome (MDS) in the Pediatric Transplantation and Cellular Therapy Consortium. Nine centers performed transplants in 32 patients having acute leukemias or MDS, with myeloablative conditioning (MAC), haploBMT with PTCy, mycophenolate mofetil, and tacrolimus. The median patient age was 12 years. Diagnoses included AML (15), ALL (11), mixed-lineage leukemia (1), and MDS (5). Transplant-related mortality (TRM) at 180 days was 0%. The cumulative incidence (CuI) of grade 2 acute graft-versus-host disease (aGVHD) on day 100 was 13%. No patients developed grades 3-4 aGVHD. The CuI of moderate-to-severe chronic GVHD (cGVHD) at 1 year was 4%. Donor engraftment occurred in 27 patients (84%). Primary graft failures included 3 patients who received suboptimal bone marrow grafts; all successfully engrafted after second transplants. The CuI of relapse at 1 year was 32%, with more relapse among patients MRD positive pre-BMT vs MRD negative. Overall survival rates at 1 and 2 years were 77% and 73%, and event-free survival rate at 1 and 2 years were 68% and 64%. There was no TRM or severe aGVHD, low cGVHD, and favorable relapse and survival rates. This successful pilot trial has led to a phase 3 trial comparing MAC haploBMT vs HLA-matched unrelated donor BMT in the Children's Oncology Group. This trial was registered at www.clinicaltrials.gov as #NCT02120157.

Pulmonary microbiome and transcriptome signatures reveal distinct pathobiologic states associated with mortality in two cohorts of pediatric stem cell transplant patients.

Lung injury is a major determinant of survival after pediatric hematopoietic cell transplantation (HCT). A deeper understanding of the relationship between pulmonary microbes, immunity, and the lung epithelium is needed to improve outcomes. In this multicenter study, we collected 278 bronchoalveolar lavage (BAL) samples from 229 patients treated at 32 children's hospitals between 2014-2022. Using paired metatranscriptomes and human gene expression data, we identified 4 patient clusters with varying BAL composition. Among those requiring respiratory support prior to sampling, in-hospital mortality varied from 22-60% depending on the cluster (p=0.007). The most common patient subtype, Cluster 1, showed a moderate quantity and high diversity of commensal microbes with robust metabolic activity, low rates of infection, gene expression indicating alveolar macrophage predominance, and low mortality. The second most common cluster showed a very high burden of airway microbes, gene expression enriched for neutrophil signaling, frequent bacterial infections, and moderate mortality. Cluster 3 showed significant depletion of commensal microbes, a loss of biodiversity, gene expression indicative of fibroproliferative pathways, increased viral and fungal pathogens, and high mortality. Finally, Cluster 4 showed profound microbiome depletion with enrichment of Staphylococci and viruses, gene expression driven by lymphocyte activation and cellular injury, and the highest mortality. BAL clusters were modeled with a random forest classifier and reproduced in a geographically distinct validation cohort of 57 patients from The Netherlands, recapitulating similar cluster-based mortality differences (p=0.022). Degree of antibiotic exposure was strongly associated with depletion of BAL microbes and enrichment of fungi. Potential pathogens were parsed from all detected microbes by analyzing each BAL microbe relative to the overall microbiome composition, which yielded increased sensitivity for numerous previously occult pathogens. These findings support personalized interpretation of the pulmonary microenvironment in pediatric HCT, which may facilitate biology-targeted interventions to improve outcomes.

Disseminated neuroendocrine carcinoma in a pediatric patient: a rare case and diagnostic challenge.

A previously healthy 16-year-old female presented with 1-month history of fever, cough, extremity pain, left upper quadrant pain, and night sweats. Imaging studies revealed mediastinal lymphadenopathy, lung and liver masses, and bony lesions. Liver and bone marrow biopsies revealed small tumor cells with a high nuclear cytoplasmic ratio, stippled chromatin, and inconspicuous nucleoli surrounded by bands of collagen. Immunohistochemically, the tumor cells were positive for epithelial (epithelial membrane antigen and cytokeratin AE1/AE3) and neuroendocrine markers (chromogranin and synaptophysin), and negative for other antigens tested, including vimentin, desmin, CD99, and WT-1. The morphologic features and immunohistochemical profile was consistent with neuroendocrine carcinoma. Despite several chemotherapeutic regimens, the patient had progressive disease and enrolled in a phase 1 trial. Thorough histopathologic evaluation, including immunohistochemical stains is a crucial component for diagnosing this rare, aggressive tumor in children and adolescents.

Teriparatide Therapy in a 4-Month-Old With Severe Hypoparathyroidism.

Teriparatide is a human parathyroid hormone analog approved for the treatment of osteoporosis in adult patients. Its use for hypocalcemia and hypoparathyroidism in the pediatric population is described through case reports and small case series; however, larger studies that demonstrate long-term efficacy and safety are limited. At our institution, a 4-month-old premature (gestational age: 32 weeks) infant with multiple congenital anomalies, functional athymia, and severe hypoparathyroidism and receiving calcitriol, vitamin D, and calcium carbonate supplementation was initiated on subcutaneous injection of teriparatide. During the course of treatment, her calcium carbonate, vitamin D, and calcitriol supplementation requirements substantially decreased. Teriparatide effectively increased serum ionized calcium concentrations and decreased serum phosphorus concentrations in the present case-study over a 6-month period. Teriparatide was well tolerated, and no evidence of hypercalcemia was observed throughout treatment.

Decreased Opioid Consumption in Bone Marrow Harvest Patients Using Quadratus Lumborum Blocks in a Standardized Protocol.

Purpose: Bone marrow harvesting is associated with significant postoperative pain that may have potential negative consequences for the patient and health care system. In the current absence of uniform guidelines, there exists considerable variability amongst providers with respect to perioperative analgesia, especially opioid administration. In this initiative, we explored the potential for preoperative bilateral quadratus lumborum blocks in combination with a standardized perioperative analgesic protocol to manage pain with the goal of reducing perioperative narcotic usage and thereby improving opioid stewardship. Methods: Adults who underwent bone marrow donation from 2018 to 2020 were included in this analysis (n = 32). The pre-implementation group (n = 19) was reviewed retrospectively while the implementation group (n = 13) was evaluated prospectively. Patient demographics, pain scores, and opioid consumption were evaluated. Results: Patient characteristics were equivalent except for anesthesia type with an increased number of patients in the implementation group undergoing spinal anesthesia. The implementation group showed significantly reduced median intraoperative (20.0 mg vs. 0.0 mg; p < 0.001) and total opioid consumption (20.5 mg vs. 0.0 mg; p < 0.001). The number of patients who received any opioids decreased from 84.2% (16/19) before implementation to 23.1% (3/13) after implementation. Conclusion: This change in practice suggests that implementation of a standardized perioperative protocol, including bilateral quadratus lumborum blocks, for bone marrow harvest patients leads to reduced perioperative opioid administration without compromising immediate perioperative pain control.