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Josep Maria Ribera Santasusana,1 Alejandra de Andrés Saldaña,2 Nuria García-Muñoz,3 Joana Gostkorzewicz,2 Diana Martínez Llinàs,3 Cristina Díaz de Heredia4 1Clinical Hematology Department, Catalan Institute of Oncology - Hospital Germans Trias i Pujol, Barcelona, Spain; 2Health Economics and Outcomes Research, Novartis Farmacéutica S.A., Madrid, Spain; 3Oblikue Consulting, S.L., Barcelona, Spain; 4Paediatric Oncology and Hematology Department - Hematopoietic Stem Cell Transplantation, Hospital Universitari Vall d’Hebron, Barcelona, SpainCorrespondence: Diana Martínez LlinàsOblikue Consulting, S.L., C/Comte d’Urgell, 240, 2-D, Barcelona 08036, SpainTel +34 93 252 1377Fax +34 93 737 9984Email diana.martinez@oblikue.comPurpose: Tisagenlecleucel, a chimeric antigen receptor T-cell (CAR-T) therapy, is a promising alternative for the management of children and young adults with relapsed and refractory B-cell acute lymphoblastic leukemia (r/r ALL). The aim of this study was to determine whether treatment with tisagenlecleucel is a cost-effective intervention compared with salvage chemotherapy in paediatric and young adult patients with r/r ALL in Spain.Materials and Methods: A partitioned survival model of monthly cycles with three health states was used (event-free survival, progressive/relapsed disease and death). A lifetime time horizon and the Spanish National Health System perspective were adopted. During the first 5 years, permanence in the different health states was determined according to the results in the clinical studies. In successive years, mortality tables of the Spanish general population adjusted by standardized mortality rate for survivors of childhood cancer were used. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. Only direct health costs (pharmacological costs and the costs derived from health resource use) were included. The robustness of the results was evaluated in a sensitivity analysis.Results: This cost-effectiveness analysis showed a greater benefit (10.10 and 8.97 life-years gained [LYGs] and quality-adjusted life-years [QALYs] gained, respectively) and a higher cost (€ 258,378.40) for tisagenlecleucel compared to salvage chemotherapy. The resulting incremental cost-effectiveness and cost-utility ratios were € 25,576.80 per LYG and € 28,818.52 per QALY gained, respectively. In the sensitivity analysis, all the results were below € 50,000/QALY.Conclusion: Tisagenlecleucel would represent a cost-effective intervention for the treatment of children and young adults with r/r ALL in Spain.Keywords: ALL, cost-effectiveness, tisagenlecleucel, acute lymphoblastic leukaemia, Spain, CAR-T

Introduction: Bacteremia is a life-threatening condition that can progress to sepsis and septic shock, leading to significant mortality in the emergency department (ED). The standard diagnostic method, blood culture, is time-consuming and prone to false positives and false negatives. Although not widely accepted, several clinical and artificial intelligence-based algorithms have been recently developed to predict bacteremia. However, these strategies require further identification of new variables to improve their diagnostic accuracy. This study proposes a novel strategy to predict positive blood cultures by assessing sepsis-induced immunosuppression status through endotoxin tolerance assessment., Methods: Optimal assay conditions have been explored and tested in sepsis-suspected patients meeting the Sepsis-3 criteria. Blood samples were collected at ED admission, and endotoxin (lipopolysaccharide, LPS) challenge was performed to evaluate the innate immune response through cytokine profiling., Results: Clinical variables, immune cell population biomarkers, and cytokine levels (tumor necrosis factor [TNFα], IL-1β, IL-6, IL-8, and IL-10) were measured. Patients with positive blood cultures exhibited significantly lower TNFα production after LPS challenge than did those with negative blood cultures. The study also included a validation cohort to confirm that the response was consistent., Discussion: The results of this study highlight the innate immune system immunosuppression state as a critical parameter for sepsis diagnosis. Notably, the present study identified a reduction in monocyte populations and specific cytokine profiles as potential predictive markers. This study showed that the LPS challenge can be used to effectively distinguish between patients with bloodstream infection leading to sepsis and those whose blood cultures are negative, providinga rapid and reliable diagnostic tool to predict positive blood cultures. The potential applicability of these findings could enhance clinical practice in terms of the accuracy and promptness of sepsis diagnosis in the ED, improving patient outcomes through timely and appropriate treatment., Competing Interests: EH-J, AU, XP, and JS are employees/advisors of the spin-off company Loop Diagnostics related to this biomarker. EH-J, EP-M, XP and JS are shareholders of a spin-off company Loop Diagnostics related to this biomarker. AL and EM have received honoraria from Loop Diagnostics. JS and EH-J are the authors of a PCT patent application to protect against the use of the method and kit for the early detection of sepsis WO2021245025A1. 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 © 2024 Hernández-Jiménez, Plata-Menchaca, Berbel, López de Egea, Dastis-Arias, García-Tejada, Sbraga, Malchair, García Muñoz, Larrad Blasco, Molina Ramírez, Pérez Fernández, Sabater Riera and Ulsamer.)

Background Aims: To describe and analyze whether a hub-and-spoke organizational model could efficiently provide access to chimeric antigen receptor (CAR) T-cell therapy within a network of academic hospitals and address the growing demands of this complex and specialized activity., Methods: The authors performed a retrospective evaluation of activity within the Catalan Blood and Tissue Bank network, which was established for hematopoietic stem cell transplantation to serve six CAR T-cell programs in academic hospitals of the Catalan Health Service. Procedures at six hospitals were followed from 2016 to 2021. Collection shipments of starting materials, CAR T-cell returns for storage and infusions for either clinical trials or commercial use were evaluated., Results: A total of 348 leukocytapheresis procedures were performed, 39% of which were delivered fresh and 61% of which were cryopreserved. The network was linked to seven advanced therapy medicinal product manufacturers. After production, 313 CAR T-cell products were shipped back to the central cryogenic medicine warehouse located in the hub. Of the units received, 90% were eventually administered to patients. A total of 281 patients were treated during this period, 45% in clinical trials and the rest with commercially available CAR T-cell therapies., Conclusions: A hub-and-spoke organizational model based on an existing hematopoietic stem cell transplantation program is efficient in incorporating CAR T-cell therapy into a public health hospital network. Rapid access and support of growing activity enabled 281 patients to receive CAR T cells during the study period., Competing Interests: Declaration of Competing Interest JF and SQ have served on an advisory board for Novartis., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by anti-ADAMTS13 antibodies. Caplacizumab is approved for adults with an acute episode of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. The objective of this study was to analyze and compare the safety and efficacy of caplacizumab vs the standard of care and assess the effect of the concomitant use of rituximab. A retrospective study from the Spanish TTP Registry of patients treated with caplacizumab vs those who did not receive it was conducted. A total of 155 patients with iTTP (77 caplacizumab, 78 no caplacizumab) were included. Patients initially treated with caplacizumab had fewer exacerbations (4.5% vs 20.5%; P < .05) and less refractoriness (4.5% vs 14.1%; P < .05) than those who were not treated. Time to clinical response was shorter when caplacizumab was used as initial treatment vs caplacizumab used after refractoriness or exacerbation. The multivariate analysis showed that its use in the first 3 days after PEX was associated with a lower number of PEX (odds ratio, 7.5; CI, 2.3-12.7; P < .05) and days of hospitalization (odds ratio, 11.2; CI, 5.6-16.9; P < .001) compared with standard therapy. There was no difference in time to clinical remission in patients treated with caplacizumab compared with the use of rituximab. No severe adverse event was described in the caplacizumab group. In summary, caplacizumab reduced exacerbations and refractoriness compared with standard of care regimens. When administered within the first 3 days after PEX, it also provided a faster clinical response, reducing hospitalization time and the need for PEX., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Cryopreservation was recommended to ensure continuity in allogeneic hematopoietic progenitor cells (HPC) transplantation during the COVID-19 pandemic. Several groups have shown no impact on clinical outcomes for patients who underwent HPC transplantation with cryopreserved products during the first months of this pandemic. However, concerns about quality control attributes after cryopreservation have been raised. We investigated, in 155 allogeneic peripheral blood cryopreserved HPC, leukocytapheresis characteristics influencing viable CD34 + and CD3 + cells, and CFU-GM recoveries after thawing. Collection characteristics such as volume, nucleated cells (NC)/mL and hematocrit correlated with viable CD34 + and CD3 + cells recoveries after thawing in univariate analysis but only CD3 + cells remained statistically significant in multivariate analysis (r2 = 0.376; P = < 0.001). Additionally, transit time also showed correlation with viable CD34 + (r2 = 0.186), CD3 + (r2 = 0.376) and CFU-GM recoveries (r2 = 0.212) in multivariate analysis. Thus, diluting leukocytapheresis below 200 × 10 6 NC/mL, avoiding red cells contamination above 2%, cryopreserving below 250 × 10 6 NC/mL and minimizing transit time below 36 h, prevented poor viable CD34 + and CD3 + cells, and CFU-GM recoveries. In summary, optimizing leukocytapheresis practices and minimizing transportation time may better preserve the quality attributes of HPC when cryopreservation is indicated., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Cryopreservation was recommended to ensure continuity of unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) during COVID-19 pandemic. However, its impact on clinical outcomes and feasibility was not well known. We compared 32 patients who underwent UD HSCT using cryopreserved peripheral blood stem cells (PBSC) during the COVID-19 pandemic with 32 patients who underwent UD HSCT using fresh PBSC in the previous period. Median neutrophil engraftment was 17.5 and 17.0 days with cryopreserved and fresh grafts, respectively. Non-significant delays were found in platelet recovery days (25.5 versus 19.0; P = 0.192) and full donor chimerism days (35.0 and 31.5; P = 0.872) using cryopreserved PBSC. The rate of acute graft-versus-host disease at 100 days was 41% (95% CI [21-55%]) in cryopreserved group versus 31% (95% CI [13-46%]) in fresh group (P = 0.380). One-hundred days progression-relapse free survival and overall survival did not differ significantly. During COVID-19 pandemic, six frozen UD donations were not transfused and logistical and clinical issues regarding cryopreservation procedure, packaging, and transporting appeared. In summary, UD HSCT with cryopreserved PBSC was safe during this challenging time. More efforts are needed to ensure that all frozen grafts are transplanted and cryopreservation requirements are harmonized., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)