We investigated the outcomes of 179 pediatric patients with severe aplastic anemia (SAA) transplanted upfront (n=87) or after failure of immunosuppressive therapy (IST) (n=92). With a median follow-up of 4.0 years (range 0.2-10.7) after HSCT, 161 patients were alive at last follow-up. The cumulative incidence of graft failure, grade II-IV acute and chronic graft-versus-host-disease (GVHD) was 10%, 18%, and 8%, respectively. Five-year overall survival (OS) and GVHD-free, relapse/rejection-free survival (GRFS) were 89% and 79%, respectively. Patients transplanted upfront from a matched sibling donor (MSD) or ≥9/10 HLA-matched unrelated donor (MUD) both achieved an OS of 95%. OS was superior in patients transplanted upfront compared with those transplanted after failure of IST (upfront 95% [89-100] vs. post-IST failure 83% [75-91], p<0.01). However, OS in the post-IST failure group improved over time, resulting in comparable OS of upfront and post-IST failure HSCT from 2015 (97% vs. 89%, p=0.09). Subgroup analysis of patients transplanted from an MSD revealed no difference in GRFS with different conditioning regimens, including cyclophosphamide (Cy), Cy/anti-thymocyte globulin (ATG), and fludarabine/Cy/ATG (Cy 80% vs. Cy/ATG 84% vs. Flu/Cy/ATG 90%, p=n.s.). Moreover, there was no difference in GRFS of MUD-HSCT comparing patients transplanted upfront or post-IST failure (upfront 77% vs. post-IST failure 76%, p=n.s.). Our data highlight the good transplant outcomes of a consecutive pediatric SAA cohort. While upfront HSCT from a readily available MUD is a viable option if an MSD is not available, HSCT after IST failure from a well-matched unrelated donor also yields favorable outcomes.

Extramedullary disease (EMD) is a rare presentation in Acute Myeloid Leukaemia (AML). On behalf of PDWP/EBMT we studied the effect of EMD compared to isolated BM involvement in the outcomes following non-TBI conditioning hematopoietic stem cell transplantation (HCT) for AML in children. Patients were grouped into three categories: BM involvement only (Group A), BM + CNS involvement only (Group B) and BM+ other EMD+/- CNS (Group C). A total of 958 patients were included, 685 (71.5%) in Group A, 135 (14.1%) in Group B and 138 (14.4%) in Group C. The median post HCT follow-up was 5.4 years. Five years LFS, OS, RI and NRM were 62%, 68.4%, 26.4% and 11.6%, respectively. Multivariate analysis showed higher RI in Group C compared to Group A (HR = 1.45 (1.01-2.06) p = 0.04). In the multivariate analysis patients with EMD had no significant difference in LFS, OS and NRM. Our findings suggest that children with AML and BM with EMD+/- CNS involvement (group C) have a higher incidence of relapse after HCT compared to those with BM only or BM + CNS only disease. However, the presence of EMD did not have an impact on overall, leukaemia-free survival or non-relapse mortality.

Pediatric Hodgkin lymphoma (HL) is highly curable, and reducing the treatment intensity in patients who respond well to induction therapy is a key strategy for minimizing long-term adverse effects. Biomarkers that identify good responders at diagnosis would enable further de-escalation of the treatment. Circulating microRNAs (miRNAs) have shown promise as noninvasive indicators of therapeutic response in hematological cancers, yet their association with early metabolic response on quantitative 18F-Fluorodeoxyglucose-Positron Emission Tomography (18F-FDG-PET) in pediatric HL has not been defined. Here, we investigated the potential of circulating miRNAs to predict the response to induction therapy in pediatric HL. Small RNA sequencing of serum samples from 35 patients revealed 24 Hodgkin lymphoma-associated miRNAs that were differentially expressed between adequate and inadequate responders. Subsequent quantitative reverse transcription-polymerase chain reaction (qRT-PCR) validation demonstrated significantly elevated miR‑148a‑3p levels at diagnosis in inadequate responders to induction therapy than in adequate responders (p=0.009). These results indicate that circulating miR‑148a‑3p may enhance current predictive approaches by identifying high‑risk patients less likely to achieve rapid metabolic remission.

ABSTRACT:Allogeneic hematopoietic stem cell transplantation (HSCT) is used for consolidation in children and adolescents with refractory or early relapsed ALK (anaplastic lymphoma kinase)-positive anaplastic large cell lymphoma (ALCL). The immune system plays a major role in sustained disease control. We retrospectively analyzed whether conditioning, donor type, and in vivo T-cell depletion correlate with outcome in a population-based cohort of 57 children with central nervous system (CNS)-negative ALCL relapse who received HSCT between 2005 and 2022. Progression-free survival (PFS) and overall survival from transplantation were 84% ± 10% and 91% ± 8% at 3 years, respectively. Conditioning was based on total body irradiation (TBI) in 30 patients and on chemotherapy in 27 patients, mainly with reduced-toxicity conditioning (treosulfan, fludarabine, and thiotepa). PFS and graft-versus-host disease (GVHD)-free and event-free survival (GEFS) were comparable between TBI and chemotherapy, 87% ± 6% vs 81% ± 8% (P = .62) and 67% ± 9% vs 74% ± 8% (P = .63), respectively. Patients with transplantation from unrelated donors with rabbit anti-human T lymphocyte globulin (ATLG) had superior PFS and GEFS than those receiving grafts from matched siblings without ATLG: 94% ± 7% vs 67% ± 22% (P = .0007) and 82% ± 13% vs 44% ± 24% (P = .011), respectively. Progression during frontline chemotherapy, minimal residual disease, and remission status at HSCT were not associated with outcome. Nonrelapse mortality was 5.6% for all 65 patients, and cumulative incidence of grade 2 to 4 acute GVHD was 25%. Our data supports the use of TBI-free conditioning and suggest improved outcomes with unrelated donors receiving ATLG prophylaxis.

BACKGROUND:Animal-assisted activities (AAAs) with therapy dogs have shown positive effects on patient well-being and quality of life in various areas of medicine, including pediatric oncology. However, research on this topic is limited. The aim of this study is to present the current status of AAA in pediatric oncology in Germany, Austria, and Switzerland, to identify challenges, and to discuss potential implementation strategies. METHODS:A German-language questionnaire of 43 items was developed by an interdisciplinary team of experts in pediatric oncology, including physicians, nurses, psychosocial staff, physiotherapists, and sports therapists. The survey was made available online to members of 72 institutions in Germany, Austria, and the German-speaking regions of Switzerland. Responses from 60 institutions (Germany, 54; Austria, 3; and Switzerland, 3) were analyzed. RESULTS:Currently, 9/60 centers (15%) offer AAA with therapy dogs in pediatric oncology, 36/60 (60%) are interested in establishing such programs. All centers offering AAA have developed guidelines or regulations for its implementation and report positive feedback from patients. The following challenges were identified: hygiene and safety concepts, legal protection, staff shortage, funding, lack of standardized guidelines, and scientific evidence. CONCLUSION:This study demonstrates strong interest in AAA in pediatric oncology with several institutions already implementing programs responsibly. Perceived benefits contrast with limited availability and structural barriers. Systematic evaluation in registries and appropriately designed studies, standardized guidelines, and collaborative networks are needed for broader, sustainable integration into acute pediatric oncology care. Pediatric oncology societies should play a key role in coordinating research efforts, study networks, and consensus-based standards.

Abstract T-cell lymphoblastic lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (T-ALL) originate from thymic T-cell precursors, with ongoing debate on whether they are variants of the same disease or distinct entities. For 211 patients, including pediatric and adult T-ALL and T-LBL cases, targeted next-generation sequencing and SNP-arrays were performed, and single-nucleotide variants, indels and copy-number variants (CNVs) were analyzed. We aimed to assess genetic differences between T-ALL and T-LBL across age. Generally, mutational landscape analysis identified mutated PHF6 being associated with higher, NOTCH1 with lower age at diagnosis for both T-LBL and T-ALL. Association of CNVs with higher age was evident for T-ALL, but not T-LBL. Analysis of clonal evolution revealed that CNVs – especially deletions and LOH in chromosome 9 (LOH_in_9p) – were observed as first mutational event in both pediatric T-ALL and T-LBL. The sequence of genetic events, starting with LOH_in_9p followed by mutations in NOTCH1, was significantly more frequent in pediatric T-ALL and T-LBL. Detailed evaluation of the patients’ individual clonal evolution indicated that the proportion of malignant cells without NOTCH MT determines the risk of relapse (hazard ratio 1.032, p = 4.65*10−5). In T-ALL, aside from MRD, validated molecular markers for risk-group stratification remain limited. Our data suggest that molecular metrics analogous to those in T-LBL may help refining risk stratification in T-ALL as well.

High-grade B-cell lymphoma with 11q-aberration (HGBCL-11q) is a rare pediatric non-Hodgkin lymphoma. This study assessed outcome in 90 children with HGBCL-11q. With survival rates ≥95%, patients with HGBCL-11q and no predisposition are candidates for deescalated therapy in future prospective trials.

In the randomized cohort of the international phase-III FORUM trial, which showed the superiority of total-body irradiation (TBI) over chemotherapy-based conditioning prior to hematopoietic stem cell transplantation (HSCT) for pediatric acute lymphoblastic leukemia (ALL), type of conditioning and remission phase, but not pre-HSCT minimal residual disease (MRD), were associated with outcome. We report the impact of MRD within the extended FORUM cohort. Patients (n=1014), 4–21 years old, transplanted from a matched donor who had ≥1 MRD measurement prior to and/or 100 days and/or 1 year after HSCT were eligible. A threshold of 0.01% defined MRD positivity versus negativity. Prior to HSCT, 21% of patients were MRDpos. Three-year event-free survival (EFS) was 0.73 and 0.59 (p<0.001), and 3-year cumulative incidence of relapse (CIR) was 0.20 and 0.33 (p<0.001) in MRDneg and MRDpos patients, respectively. The level of MRD positivity pre-HSCT (<0.1% versus ≥0.1%), did not significantly affect outcome. Pre-HSCT MRDneg and TBI/etoposide conditioning were associated with a 2-fold lower risk of relapse, whereas MRDpos had a 2-fold higher risk of any failure and/or death. No detrimental effect of MRDpos pre-HSCT could be demonstrated in patients with T-cell ALL. MRDpos versus MRDneg patients at day 100 had an EFS of 0.47 versus 0.77 (p<0.001) and a CIR of 0.51 versus 0.17 (p<0.001), respectively, but post-HSCT MRDpos did not necessarily imply relapse. In conclusion, the MRD status pre-HSCT and at day 100 post-HSCT was a strong prognostic factor for children transplanted for ALL in the extended FORUM cohort.

T-cell lymphoblastic lymphoma (T-LBL) is the second most common subtype of non-Hodgkin lymphoma (NHL) in children and adolescents. T-LBL shares considerable biological and clinical features with T-cell acute lymphoblastic leukaemia (T-ALL). The two entities are clinically distinguished by the extent of bone marrow (BM) involvement at diagnosis, with T-ALL defined by ≥25% blasts in the BM. Although the WHO classifies T-LBL and T-ALL as a single entity, emerging data suggest relevant clinical and molecular differences. This review focuses on T-LBL in paediatric patients, summarizing current knowledge on its clinical presentation, immunophenotype and molecular landscape. We further explore age-associated genomic patterns, recurrent mutations and chromosomal aberrations, with a particular focus on their prognostic relevance. Notably, recent studies have identified NOTCH1-fusions as exclusive to paediatric T-LBL, absent in T-ALL, and are associated with an increased risk of relapse. We highlight the limited applicability of measurable residual disease, lack of harmonized risk stratification and the need for T-LBL-specific treatment adaptations. Ultimately, this review emphasizes the urgent need for biologically informed, risk-adapted treatment strategies and collaborative research efforts to advance care and outcomes of paediatric patients with T-LBL.

Mature aggressive B-cell lymphomas, such as Burkitt lymphoma (BL) and Diffuse large B-cell lymphoma (DLBCL), show variations in microRNA (miRNA) expression. The entity of High-grade B-cell lymphoma with 11q aberration (HGBCL-11q) shares several biological features with both BL and DLBCL but data on its miRNA expression profile are yet scarce. Hence, this study aims to analyze the potential differences in miRNA expression of HGBCL-11q compared to BL and DLBCL. We evaluated the expression profiles of 2083 miRNAs in 25 HGCBL-11q, 7 BL, 131 DLBCL, and tonsils using the HTG EdgeSeq miRNA whole transcriptome assay. Uniform manifold approximation and projection (UMAP) and differential gene expression analyses based on DESeq2 were carried out. UMAP analysis of miRNA expression did not reveal distinct groups among the studied lymphomas. However, differential gene expression investigations detected sets of overexpressed miRNAs in HGBCL-11q when compared to BL (miR-9-3p, miR-9-5p, miR-3919, miR-129-1-3p, miR-129-2-3p, miR-331-3p, miR-196b-5p, and miR-28-5p) and DLBCL (miR-3919, miR-1290, miR-4538, and miR-4791), respectively. Notably, miR-3919 showed heterogeneous but significantly higher expression (p-value < 0.001) in HGBCL-11q than in both, BL and DLBCL. We identified a group of differentially expressed miRNAs between HGBCL-11q vs. BL and DLBCL, with miR-3919 as the most commonly and recurrently overexpressed miRNA in HGBCL-11q.

Children undergoing allogeneic stem cell transplantation often receive off-label rituximab treatment for Epstein-Barr virus reactivation, using adult dosing without pediatric evidence. This project aims to develop a clinical decision support tool (CDSS) that provides evidence-based dosing scenarios by analyzing real-world patient data. The CDSS integrates clinical and laboratory data across institutions and includes dynamic models that guide therapy decisions while incorporating feedback to improve over time. It addresses a critical evidence gap for vulnerable populations and represents a scalable approach for individualized care. The project also highlights the need for regulatory and infrastructural adaptations to support data-driven, post-approval evidence generation.

ABSTRACT:Extramedullary plasmacytomas (EMPs) are exceedingly rare in children and adolescents. We describe clinical, pathological, and molecular features of 13 patients with EMP in this age group (8 males and 5 females; age 3-18 years). EMPs presented as localized disease involving the Waldeyer's ring (n = 9), larynx (n = 2), ocular adnexa (n = 1), or epipharynx and conjunctiva simultaneously (n = 1). One patient with EMP of the tonsils had a concurrent Epstein-Barr virus infection. Twelve of 13 patients with follow-up information reached sustained complete remissions after surgical resection (median follow-up, 38 months). However, local relapses were observed in 3 patients. Irradiation was applied in only 1 patient with laryngeal involvement. Histologically, sheets of mature plasma cells with light chain restriction, low proliferation, and predominant expression of immunoglobulin A (11/13 [92%]) were observed. Epstein-Barr virus, CD56, and cyclin D1 were not detected in the plasma cells. Amyloidosis confined to the lesion was observed in 1 case. Clonal, mostly productive immunoglobulin gene rearrangements with somatic hypermutation (3.3%-5.7%) were detectable in all informative cases. Fluorescence in situ hybridization revealed absence of chromosomal abnormalities associated with plasma cell neoplasia (eg, breaks in IGH, MAF, FGFR3, and copy number alterations of 1p32, 1q21, RB1, and TP53). Targeted next-generation sequencing did not reveal any somatic alterations predicted as pathogenic. We conclude that EMP in children and adolescents is a plasma cell neoplasia with low malignant potential lacking systemic dissemination, differing clinically and molecularly from adult plasma cell myeloma.