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Background/objectives: This work aimed to analyze pediatric Post-Authorization Studies (PASs) registered in the European Union electronic Register of Post-Authorization Studies (EU PAS Register) from September 2010 to April 2023 to identify trends in terms of timing, age groups, and therapeutic areas and to discuss pediatric specificities and sources of funding for the PASs., Methods: A screening process identified PASs conducted exclusively on the pediatric population, and instructions were provided to ensure standardized data collection from the EU PAS Register. A univariate linear regression descriptive analysis was performed to assess trends over time, while a multivariate linear regression analysis helped explore additional characteristics of these studies., Results: Of the 2574 PASs extracted from the EU PAS Registry, 165 were included in this analysis. The majority of pediatric PASs were observational studies (86%), and most of them utilized secondary data (53%). The annual number of PASs increased significantly between 2010 and 2023. As envisaged, the largest part was funded by pharmaceutical companies (62%). Anti-infectives for systemic uses (25%), medicines for the nervous system (18%), and antineoplastic and immunomodulating agents (15%) resulted in the most studied drugs., Conclusions: Our findings show that post-marketing observational research in pediatric populations has increased over time. Nevertheless, industry-academia collaboration should be encouraged, and regulatory guidance is needed to prioritize research in areas of unmet therapeutic need.

Post-transplant high-dose cyclophosphamide (PTCy) is effective in overcoming the negative impact of HLA disparity in the haploidentical setting. In the light of these results, we investigated the efficacy and safety of PTCy, with a calcineurine inhibitor and mycophenolate mofetil, in improving clinical outcomes of haematopoietic cell transplantation (HCT) from mismatched unrelated donor (MMUD) in patients with acute myeloid malignancies by reducing aGvHD incidence and severity. A prospective single arm, phase II study (PHYLOS - NCT03270748) was conducted by the Italian GITMO. The primary objective was the cumulative incidence (CI) of grade II-IV aGvHD. Conditioning regimen for all patients was busulfan (total dose 12.8mg/kg) and fludarabine (total dose 160mg/m2). The ethical committees of the participating centers approved the study (EURODRACT 2017-003530-85). Seventy-seven consecutive patients (AML: 64; MDS: 13) were enrolled at 26 Italian transplant centers (January 2020-November 2022). Median age was 53 years (range 19-65). The 100-day cumulative incidence (CI) of grade II-IV aGvHD was 18.2% (95%CI: 10.6-27.6) and 6.5% (95%CI: 3.1-15.1) for grade III-IV. Seventy-one patients (92%) had full-donor chimerism with complete neutrophil engraftment by day +30.One-year CI of chronic GvHD (cGvHD) was 13.4% (95%CI: 6.9-22.1). One-year CI of non-relapse mortality was 9.1% (95%CI: 4.0-16.9), and the relapse rate was 23.8% (95%CI: 14.9-33.9). One-year overall survival and graft-relapse-free survival were 78.6.% (95%CI: 67.4-86.3) and 55.3% (95%CI: 43.4-65.7), respectively. Our study in a homogeneous patient cohort suggests that PTCy leads to a low rate of aGvHD and improves clinical outcomes of MMUD transplantation., (Copyright © 2025 American Society of Hematology.)

Brexucabtagene autoleucel (brexu-cel) has revolutionized the treatment of patients affected by mantle cell lymphomas. In this prospective, observational multicentre study, we evaluated 106 patients, with longitudinal brexu-cel kinetics in peripheral blood monitored in 61 of them. Clinical outcomes and toxicities are consistent with previous real-world evidence studies. Notably, beyond established poor prognostic factors-such as blastoid variant and elevated lactate dehydrogenase-Bruton tyrosine-kinase inhibitors (BTKi) refractoriness and platelet count emerged as significant predictors of survival. Specifically, the 1-year overall survival was 56% in BTKi-refractory patients compared to 92% in BTKi-relapsed patients (p = 0.0001). Our study also demonstrated that in-vivo monitoring of brexu-cel expansion is feasible and correlates with progression-free survival and toxicities. Progression-free survival at 1 year was 74% in patients categorized as strong expanders, based on brexu-cel peak concentration, versus 54% in poor expanders (p = 0.02). Furthermore, in-vivo expansion helped identify a high-risk group of non-responders, those with progressive or stable disease at the 90-day post-infusion evaluation (OR = 4.7, 95% CI = 1.1-34, p = 0.04) characterized by dismal outcomes. When integrated with other clinical factors, monitoring brexu-cel expansion could assist in recognizing patients at high risk of early relapse., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: In paediatrics, medicines repurposing is a particularly advantageous approach, offering a route to address unmet medical needs and turn off-label use into evidence-based treatments for paediatric populations. This study analysed the effects of funds provided under the Seventh Framework Programme for Research (FP7-FRP), issued by the European Commission from 2007 to 2013 according to the European Paediatric Regulation, in terms of new paediatric marketing authorisations (MAs) including paediatric Use Marketing Authorisations (PUMAs). Additionally, we investigated which funded projects included repurposing initiatives., Methods: Data was collected on paediatric Investigation Plans (PIPs), new MAs, and MAs variations from the EMA website, national medicine registers, and final project reports. A survey to project coordinators was also conducted to explore the challenges faced during paediatric drug development plans., Results: The 20 FP7-funded projects studied 24 off-patent active substances. Eighteen substances had agreed PIPs with the European Medicines Agency paediatric Committee (PDCO). Positive compliance checks were granted for three PIPs, resulting in three new PUMAs. According to the adopted definition, 22 out of 24 (91.6%) paediatric development plans could be classified as repurposing. New conditions were proposed for eight substances, while 16 aimed to extend existing indications to broader paediatric populations. Additionally, 18 development plans included new age-appropriate formulations. The survey revealed that primary challenges in paediatric development plans included budgeting, lengthy regulatory processes, and recruitment., Discussion: Taken together, these results highlighted on one hand that the FP7 programme had a positive impact, as three new PUMAs were effectively obtained, representing one third of the nine PUMAs obtained since the paediatric Regulation entered into force, and three out of 18 agreed PIPs were successfully completed within 3-10 years. In addition, repurposing existing drugs for paediatric use significantly contributed to addressing unmet medical needs in paediatrics. On the other hand, the gap between the number of agreed PIPs and those that have led to PUMAs is still considerable, due to regulatory barriers and financial constraints. This underscores the need for continued support and further initiatives to streamline public-private partnerships for paediatric drug development, ensuring that off-patent medicines can be safely and effectively repurposed for paediatric use., Competing Interests: VG is a member of the Paediatric Committee at the European Medicines Agency. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Ruggieri, Torretta, Giannuzzi, Natale, Felisi, Ceci and Bonifazi.)

Background: Antibodies directed against donor-specific HLA allele(s)/antigen(s) (DSAs) represent a known risk factor for hematopoietic stem cell transplantation (HSCT) engraftment. Still, the overall management needs to be standardized., Material and Methods: GITMO and AIBT ran a survey on DSAs in Italian Transplant Programs including mismatched HSCT performed between January 2014 and June 2017., Results: One-thousand-thirty-three patients were proposed for the study, 804 were evaluable. Overall, 355 (44%) were screened: 91/355 (25.6%) showed anti-HLA antibodies, 23 DSAs (6.5%). Female gender and at least 4 previous pregnancies showed an impact on alloimmunization. Eleven patients with DSAs underwent desensitization. In seven cases no desensitization was employed. An alternative donor was selected for five patients. Neutrophil and platelet engraftment were obtained in 93.6% and 86.6% of the whole population, respectively, and were statistically associated with the absence of anti-HLA antibodies, ABO match, a higher number of infused nucleated cells and lack of a-GvHD. In addition, significant factors for platelet engraftment were the use of leuco-depleted transfusions, HLA match, younger age of the patient. Graft failure (GF) was associated with bone marrow stem cell source, and a lower number of infused CD34+. The detection of antibodies directed against both HLA classes, donor and patient age, the hematologic and molecular remission at HSCT, HLA match, ANC and PLTS engraftment, full donor engraftment within 28 days after HSCT, early and late GF, grade>II a-GVHD showed an impact on OS., Discussion: Anti-HLA antibodies and DSAs were confirmed as risk factors affecting OS. DSAs were managed with various approaches resulting in stable engraftment in 81.9% of patients. Our study supports the clinical relevance of DSAs detection and management in mmHSCT. A standardized approach of DS is warranted.

Background: Anti-CD19 CAR T-cells have revolutionized outcomes in relapsed/refractory large B-cell lymphomas. Long-term follow-up underscored the role of hematological toxicity in nonrelapse mortality, largely driven by infections, leading to the development of the CAR-HEMATOTOX (HT) score for predicting neutropenia. The European scientific community (EHA/EBMT) later reached a consensus, defining a new entity: immune effector cell-associated hematotoxicity (ICAHT)., Aims: To validate the ability of the HT score to predict ICAHT and survival., Methods: The CART-SIE is an ongoing multicenter prospective observational study collecting data on patients affected by B-cell lymphoma treated with commercial anti-CD19 CAR T-cells (ClinicalTrials.gov ID: NCT06339255)., Results: Since 2019 to 2024, 1002 consecutive patients were enrolled. Out of 746 patients infused, the HT score at infusion was evaluable in 389. Median age was 59 years (48-66). Patients with high HT score had greater disease burden and a greater need for bridge therapy. Patients with a HT HIGH score had a 4-fold higher risk of experiencing late ICAHT of grade≥3 (OR = 3.99, 95% CI = 1.16-13.77, P = .03). Patients with a HT HIGH score also showed lower overall response rates (ORR) and complete response rates (CRR) at 90 days (CRR at 90 days: 59% HT LOW versus 38% HT HIGH , OR = 0.42, 95% CI = 0.27-0.66, P = .0002; ORR at 90 days: 67% HT LOW versus 49% HT HIGH , OR = 0.47, 95% CI = 0.29-0.74, P = .001). Adjusted logistic models confirmed that the effect of HT score was independent from baseline characteristics. With a median follow-up of 18 months, patients with a HT HIGH score have lower OS and PFS (1-year OS: 78% HT LOW versus 62% HT HIGH , P = .0002; 1-year PFS: 49% versus 39%, P = .003). Adjusted Cox models confirmed that HT was an independent prognostic factor for OS. A high HT-score was found to be associated with higher risk of secondary primary malignancy (HR=2.8, 95% CI = 1.03-7.8, P = .04). A simplified version of HT (simpleHT), based solely on the platelet count and C-reactive protein at infusion, was calculated for 560 patients and proved significant in predicting both OS and PFS (1-year was 72% simpleHT LOW versus 37% simpleHT HIGH , P < .0001, 1-year PFS was 48% simpleHT LOW versus 22% simpleHT HIGH , P < .0001)., Conclusion: In our prospective real-world study, we validated the ability of the HT score to predict ICAHT and survival. SimpleHT identified a population at very high risk with an impaired progression free and overall survival., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)