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Blood transfusion is one of the most common procedures in patients in hospital so it is imperative that clinicians are knowledgeable about appropriate blood product administration, as well as the signs, symptoms, and management of transfusion reactions. In this Review, we, an international panel, provide a synopsis of the pathophysiology, treatment, and management of each diagnostic category of transfusion reaction using evidence-based recommendations whenever available.

Development of semi-automated devices that can reduce the hands-on time and standardize the production of clinical-grade CAR T-cells, such as CliniMACS Prodigy from Miltenyi, is key to facilitate the development of CAR T-cell therapies, especially in academic institutions. However, the feasibility of manufacturing CAR T-cell products from heavily pre-treated patients with this system has not been demonstrated yet. Here we report and characterize the production of 28 CAR T-cell products in the context of a phase I clinical trial for CD19+ B-cell malignancies (NCT03144583). The system includes CD4-CD8 cell selection, lentiviral transduction and T-cell expansion using IL-7/IL-15. Twenty-seven out of 28 CAR T-cell products manufactured met the full list of specifications and were considered valid products. cell expansion lasted an average of 8.5 days and had a mean transduction rate of 30.6 ± 13.44%. All products obtained presented cytotoxic activity against CD19+ cells and were proficient in the secretion of pro-inflammatory cytokines. Expansion kinetics was slower in patient's cells compared to healthy donor's cells. However, product potency was comparable. CAR T-cell subset phenotype was highly variable among patients and largely determined by the initial product. T and T were the predominant T-cell phenotypes obtained. 38.7% of CAR T-cells obtained presented a T or T phenotype, in average, which are the subsets capable of establishing a long-lasting T-cell memory in patients. An in-depth analysis to identify individual factors contributing to the optimal T-cell phenotype revealed that cell expansion leads to reduced numbers of T , T , and T cells, while T cells increase, both due to cell expansion and CAR-expression. Overall, our results show for the first time that clinical-grade production of CAR T-cells for heavily pre-treated patients using CliniMACS Prodigy system is feasible, and that the obtained products meet the current quality standards of the field. Reduced expansion may yield CAR T-cell products with increased persistence .

Given the increasing number of older patients undergoing allo-HCT with post-transplant cyclophosphamide (PTCy)-based prophylaxis, a dedicated evaluation of its safety in this population is warranted. We retrospectively analyzed 353 consecutive patients who underwent first allo-HCT with PTCy between 2014 and 2024. Patients were stratified into three age groups: ≤40 (24.4%), 41-64 (51.8%), and ≥65 (23.8%). Median age was 53 years (range 18-75). Older patients mostly received RIC regimens and matched unrelated donors and younger MAC and haplo-HCT. Neutrophil and platelet engraftment occurred at amedian of 18 and 17 days, without differences among age groups. The incidence of grade II-IV aGVHD at day +100 was 22.4% with no differences according to age ranges (Day +100: 16.3%, 24.0% and 25.0%, P = 0.246) and moderate-severe cGVHD in 7.4%, with incidence significantly lower in patients ≥65 years (2-year: 3.1% vs. 12.1% and 4.8%; P = 0.023). At 2-years, OS rates were 79.5% for ≤40, 73.9% for 41-64, and 57.9% for ≥65 years (P = 0.001). NRM rates were 7.1%, 15.6%, and 16.0% (P = 0.128), and relapse incidence rates were, respectively, 26.2%, 24.6% and 40.7% (P = 0.039). Despite higher relapse rates leading to lower OS in older adults, similar NRM and comparable early toxicities support the feasibility of allo-HCT with PTCy in patients ≥65 years.

This work aims to review the role of endothelial dysfunction underlying the main complications appearing early after autologous and allogeneic hematopoietic cell transplantation (HCT). The endothelial damage as the pathophysiological substrate of sinusoidal obstruction syndrome (SOS) is well established. However, there is growing evidence of the involvement of endothelial dysfunction in other complications, such as acute graft-versus-host disease (aGVHD) and transplant-associated thrombotic microangiopathy (TA-TMAs). Moreover, HCT-related endotheliopathy is not only limited to the HCT setting, as there is increasing evidence of its implication in complications derived from other cellular therapies. We also review the incidence and the risk factors of the main HCT complications and the biological evidence of the endothelial involvement and other linked pathways in their development. In addition, we cover the state of the art regarding the potential use of the biomarkers of endotheliopathy in the prediction, the early diagnosis, and the follow-up of the HCT complications and summarize current knowledge points to the endothelium and the other linked pathways described as potential targets for the prevention and treatment of HCT-complications. Lastly, the endothelium-focused therapeutic strategies that are emerging and might have a potential impact on the survival and quality of life of post-HCT-patients are additionally reviewed.

Cold agglutinin disease (CAD) is a distinct clinicopathologic entity characterized by clonal B-cell lymphoproliferative disorder in the bone marrow. B-cell gene mutations affect NF-ΚB as well as chromatin modification and remodeling pathways. Clonal immunoglobulins produced by B cells bind to red cells (RBCs) at cold temperatures causing RBC aggregation, complement cascade activation and cold-autoantibody autoimmune hemolytic anemia (cAIHA). The clinical picture shows cold-induced symptoms and cAIHA. Therapeutic options include “wait and watch”, rituximab-based regimens, and complement-directed therapies. Steroids must not be used for treating CAD. New targeted therapies are possibly identified after recent molecular studies.

Acute kidney injury (AKI) increases early mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients and may accelerate chronic kidney disease (CKD) development. We analyzed prospective variables related to AKI and CKD in 422 allo-HCT recipients to establish risk factors of severe acute renal failure and CKD. Renal function and creatinine were periodically assessed from baseline till the last follow-up. Sixty-three patients (14%) developed severe AKI (AKI-3) at 100 days post transplant and 15% at 12 months. Variables associated with AKI-3 were age above 55 years [hazard ratio (HR): 2.4; p = 0.019], total body irradiation (TBI) (HR: 1.8; p = 0.044), high-risk cytomegalovirus reactivation (HR: 1.8; p = 0.041), and methotrexate as GVHD prophylaxis (HR: 2.1; p = 0.024). AKI-3 increased the mortality risk (HR: 2.5, 95% confidence interval: 1.9–3.4). The CKD prevalence in 161 living patients was 10.2% at the last follow-up and in most, CKD developed 1 year post HCT, independent of AKI. The CKD at 1 year post HCT was associated with increased mortality (HR: 3.54; p < 0.001). Interestingly, pretransplant CKD was associated with early mortality (HR: 5.6; p < 0.001). In fact, pre- and posttransplant CKD had independent unfavorable long-term outcomes. These pretransplant factors can potentially be targeted to improve allo-HCT outcomes.

Background Chronic active antibody-mediated rejection (c-aABMR) is an important cause of allograft failure and graft loss in long-term kidney transplants. Methods To determine the efficacy and safety of combined therapy with rituximab, plasma exchange (PE) and intravenous immunoglobulins (IVIG), a cohort of patients with transplant glomerulopathy (TG) that met criteria of active cABMR, according to BANFF’17 classification, was identified. Results We identified 62 patients with active c-aABMR and TG (cg ≥ 1). Twenty-three patients were treated with the combination therapy and, 39 patients did not receive treatment and were considered the control group. There were no significant differences in the graft survival between the two groups. The number of graft losses at 12 and 24 months and the decline of eGFR were not different and independent of the treatment. A decrease of eGFR≥13 ml/min between 6 months before and c-aABMR diagnosis, was an independent risk factor for graft loss at 24 months (OR = 5; P  = 0.01). Infections that required hospitalization during the first year after c-aABMR diagnosis were significantly more frequent in treated patients (OR = 4.22; P  = 0.013), with a ratio infection/patient-year of 0.65 and 0.20 respectively. Conclusions Treatment with rituximab, PE, and IVIG in kidney transplants with c-aABMR did not improve graft survival and was associated with a significant increase in severe infectious complications. Trial registration Agencia Española de Medicametos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTR-INM-2017-01.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy resulting from severe ADAMTS13 deficiency. Caplacizumab accelerates platelet recovery, but ~15% of patients remain refractory, and endothelial/microvascular injury or low ADAMTS13 activity may persist despite remission, highlighting the need for biomarkers. We evaluated the Endothelial Activation and Stress Index (EASIX), an endothelial dysfunction surrogate, dynamics and ability to predict refractoriness and mortality in iTTP. Fifty-five adults receiving ≥2 therapies (corticosteroids, plasma exchange, rituximab, and/or caplacizumab) were studied. Clinical and laboratory data were collected at baseline, days 1-2, 7, 14, 21, 28, 35, and at treatment discontinuation, including clinical or ADAMTS13 relapses. EASIX was calculated at each time point; logistic regression and ROC analyses evaluated its predictive performance for refractoriness and mortality. Median age was 47 years; 13% were refractory, and 7% died. In responders, EASIX dropped below 1 by day 7, earlier than ADAMTS13 recovery (day 21). Clinical relapses showed EASIX spikes (median 13.2), unlike ADAMTS13-only relapses. Baseline EASIX was higher in refractory patients (752 vs. 91; p=0.007), remaining elevated at days 7 and 14. Higher pre-treatment EASIX predicted refractoriness (OR = 1.003; p=0.021; AUC = 0.811; sensitivity 100%; specificity 58.7%) and mortality (OR = 1.004; p=0.027). EASIX may help predict refractoriness and death, improving monitoring in iTTP.

Conventional therapeutic plasma exchange (TPE) is aimed at removing pathological agents from circulation using a medical device which separates out plasma from other components of blood. Usually, 1.0 to 1.5 plasma volumes are removed and replaced with a replacement solution. There is strong clinical evidence for the effectiveness of TPE in a wide spectrum of diseases, such as thrombotic thrombocytopenic purpura, severe acute inflammatory demyelinating polyneuropathy, and Guillain-Barré syndrome, among others. However, therapeutic approaches using lower plasma exchange volumes (LVPE) suggest some degree of effectiveness in a number of pathological conditions, although generally with low level of clinical evidence: hematology disorders (autoimmune hemolytic anemia), neuroimmunological diseases (Guillain-Barré syndrome, neuromyelitis optica, myasthenia gravis, multiple sclerosis), pulmonary disorders, liver failure, dermatology (pemphigus) and metabolic diseases (porphyria, cholesterol). Further or newer studies are needed to confirm LVPE as an alternative to TPE for such groups of pathologies. While plasma volume removed for TPE ranges 3-4.5 L per procedure, for LVPE ranges from 350 mL to 2 L (frequency and duration vary depending on the pathology treated). In the case of Alzheimer‘s disease (AD), the AMBAR trial recently investigated a combined sequence of intensive TPE with human albumin replacement followed by a maintenance phase LVPE (650-880 mL of plasma removed, similar to a plasma donation). The treatment slowed the decline or stabilized the disease symptoms. The AMBAR approach could justify investigating the use of LVPE in chronic conditions where plasma exchange strategies have proven successful.

Therapeutic plasma exchange (TPE) is a therapeutic intervention that separates plasma from blood cells to remove pathological factors or to replenish deficient factors. The use of TPE is increasing over the last decades. However, despite a good theoretical rationale and biological plausibility for TPE as a therapy for numerous diseases or syndromes associated with critical illness, TPE in the intensive care unit (ICU) setting has not been studied extensively. A group of eighteen experts around the globe from different clinical backgrounds used a modified Delphi method to phrase key research questions related to “TPE in the critically ill patient”. These questions focused on: (1) the pathophysiological role of the removal and replacement process, (2) optimal timing of treatment, (3) dosing and treatment regimes, (4) risk–benefit assumptions and (5) novel indications in need of exploration. For all five topics, the current understanding as well as gaps in knowledge and future directions were assessed. The content should stimulate future research in the field and novel clinical applications.