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Summary: Background: Monitoring of disease activity in sclerosing dermatoses (SD) can be challenging and tools to support clinical decision‐making are lacking. Aim: To analyse the impact of high‐frequency ultrasonography (HFUS) on the clinical management of SD and to describe the US characteristics of disease activity. Methods: This was a cohort study of patients with various SD [morphoea, systemic sclerosis (SS) and chronic graft‐versus‐host disease (cGvHD)] who underwent HFUS between January 2017 and August 2019. HFUS criteria for diagnosing active SD were increased Doppler vascularity and/or meeting all B‐mode greyscale US signs of activity. Discordance in SD activity between HFUS and clinical examination was evaluated at the time of the first US assessment. Changes in patient management were instituted after HFUS were recorded. Results: In total, 72 patients (31 with morphoea, 19 with SS and 22 with cGvHD), who underwent 163 HFUS sessions in total, were included. All HFUS‐active morphoea lesions exhibited increased vascularity, and all HFUS‐active SS exhibited dermal thickening and dermal hypoechogenicity. HFUS‐active cGvHD displayed increased dermal thickness and loss of definition of the dermal–hypodermal junction, and there were signs of panniculitis in 80% of cases and of increased vascularity in 70%. Discordance in disease activity between clinical and HFUS evaluation was found in 17 (23.6%) patients. Changes in clinical management after HFUS were made for 14 (19.4%) patients: treatment discontinuation for 6 patients (42.9%), treatment initiation for 5 (35.7%), medication change for 2 (14.3%) and skin biopsy taken for 1 (7.1%). Conclusion: HFUS seems an efficacious support tool in the monitoring of SD activity with a notable impact on clinical management. Further studies are warranted to evaluate the impact of HFUS‐supported management changes on SD outcomes. [ABSTRACT FROM AUTHOR]

Background and Aim: Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for refractory Crohn's disease [CD]. However, high adverse event rates related to chemotherapy toxicity and immunosuppression limit its applicability. This study aims to evaluate AHSCT's safety and efficacy using a cyclophosphamide [Cy]-free mobilisation regimen., Methods: A prospective, observational study included 14 refractory CD patients undergoing AHSCT between June 2017 and October 2022. The protocol involved outpatient mobilisation with G-CSF 12-16 μg/kg/daily for 5 days, and optional Plerixafor 240 μg/d [1-2 doses] if the CD34 + cell count target was unmet. Standard conditioning with Cy and anti-thymocyte globulin was administered. Clinical, endoscopic, and radiological assessments were conducted at baseline and during follow-up., Results: All patients achieved successful outpatient mobilisation [seven patients needed Plerixafor] and underwent transplantation. Median follow-up was 106 weeks (interquartile range [IQR] 52-348). No mobilisation-related serious adverse events [SAEs] or CD worsening occurred. Clinical and endoscopic remission rates were 71% and 41.7% at 26 weeks, 64% and 25% at 52 weeks, and 71% and 16.7% at the last follow-up, respectively. The percentage of patients who restarted CD therapy for clinical relapse and/or endoscopic/radiological activity was 14% at 26 weeks, 57% at 52 weeks, and 86% at the last follow-up, respectively. Peripheral blood cell populations and antibody levels post-AHSCT were comparable to Cy-based mobilisation., Conclusions: Cy-free mobilisation is safe and feasible in refractory CD patients undergoing AHSCT. Although relapse occurs in a significant proportion of patients, clinical and endoscopic responses are achieved upon CD-specific therapy reintroduction., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Since 2021 the use of G-CSF was implemented in allo-HCT with PTCY-based prophylaxis with the aim of shortening the aplastic phase and reducing infectious complications. This study investigates the effectiveness of this change in protocol performed at our institution. One-hundred forty-six adults undergoing allo-HCT with PTCY-based prophylaxis were included, and among them, 58 (40%) received G-CSF. The median of days to neutrophil engraftment was shorter in the G-CSF group (15 vs. 20 days, p < 0.001). Patients receiving G-CSF had a lower incidence of day +30 bacterial bloodstream infections (BSI) than the rest (20.7% vs. 47.7%, p < 0.001). GVHD, SOS, and TA-TMA incidences were comparable between groups, and using G-CSF did not impact on survival. Endothelial activation was investigated using EASIX and by the measurement of soluble biomarkers in cryopreserved plasma samples obtained on days 0, +7, +14 and +21 of 39 consecutive patients (10 received G-CSF) included in the study. EASIX, VWF:Ag, sVCAM-1, sTNFRI, ST2, REG3α, TM and NETs medians values were comparable in patients receiving G-CSF and those who did not. Compared with allo-HCT performed without G-CSF, the addition of G-CSF to PTCY-based allo-HCT accelerated neutrophil engraftment contributing on decreasing BSI incidence, and without inducing additional endothelial activation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: To describe the management of haematological patients experiencing prolonged SARS-CoV-2 viral shedding, as the optimal management strategy for this condition remains undetermined., Methods: We conducted a retrospective evaluation of our prospectively followed cohort of haematological patients treated with remdesivir for more than 10 days. Starting January 2023, upon COVID-19 diagnosis, the treatment strategy was based on symptoms and PCR cycle threshold (Ct) as follows: (i) when Ct was 25 or less or if the patient had symptoms, a course of remdesivir for at least 10 days, nirmatrelvir/ritonavir for 5 days (whenever possible) and convalescent plasma was administered; and (ii) when the patient was asymptomatic and had a PCR Ct of more than 25, when possible, a course of 5 days of nirmatrelvir/ritonavir was administered. The patient was considered to have achieved viral clearance and, thus, remdesivir was stopped, in either of these cases: (i) PCR negativity, or (ii) subgenomic RNA negativity., Results: From January to November 2023, 18 patients benefited from a safe extended remdesivir administration, resulting in detection of SARS-CoV-2 viral clearance in a median time of 3.5 weeks (IQR 2.6-3.9) (min-max 1.6-8.0). No clinical or biological side effects were detected. No patient died or needed further treatment for their COVID-19 episode., Conclusions: The extended course of remdesivir, combined with other active therapies for COVID-19 infection, was well tolerated. Cure and virus negativity were obtained in all these high-risk patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Extracorporeal photopheresis (ECP) is a therapy that combines the collection of mononuclear cells by apheresis, the addition of a photosensitizer (8-methoxisoralen), the illumination of the product with ultraviolet A light, and the immediate infusion of the product to the patient. Initially developed and approved to treat T-cell cutaneous lymphomas, soon started to be used to treat graft versus host disease (GvHD) developed after allogeneic hematopoietic-cell transplantation. The high response rate of ECP in skin, ocular, oral, pulmonary, and liver forms of chronic GvHD, the steroid-sparing effect, and the improved overall survival of treated patients, made ECP one of the second-line treatments used to treat steroid-resistant acute and chronic GVHD. Recently, the development of new drugs for treating GVHD has changed the position of ECP in the therapy of GVHD and has started to be used in combination with drugs for increasing the response rate to the treatment in severe or resistant forms of acute and chronic GVHD. ECP remains an essential therapeutic resource in the management of patients with refractory acute and chronic GVHD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This study evaluates the feasibility of using post-transplant cyclophosphamide (PTCY) prophylaxis in allo-hematopoietic cell transplantation (HCT) for adults aged 65 and older. PTCY is increasingly used to prevent graft-versus-host disease (GVHD) across all donor types, but concerns remain about potential risks, especially in older patients. Fifty-seven adults aged 65 or older with hematological malignancies, undergoing their first allo-HCT with PTCY prophylaxis between January 2011 and January 2023 were included. Overall, 94.8% of patients achieved primary engraftment. The median durations for neutrophil and platelet engraftments were 19 and 21 days. The day +30 cumulative incidence of bacterial bloodstream infection was 43.9%. No CMV reactivations occurred within the first 100 days after letermovir implementation. The day +180 cumulative incidences of grade II-IV and III-IV acute GVHD, and the 2-year cumulative incidence of moderate/severe chronic GVHD were 26.3%, 10.5%, and 4.8%. Eighteen patients (31.6%) relapsed, and 30 (52.6%) died, with relapse (16.4%) and infection (11.5%) being the main causes of death. The estimated 2-year overall survival, non-relapse mortality, cumulative incidence of relapse, and GVHD-free relapse-free survival rates were 45.5%, 27.1%, 33.9%, and 37.0%. Adults aged 70 or older had similar outcomes to those aged 65-69. This study confirms the safety and feasibility of PTCY-based allo-HCT in older adults., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

PTCY 50 mg/kg/day on days +3/+4 is an excellent strategy to prevent GVHD. However, its use is associated with adverse outcomes such as delayed engraftment, increased risk of infection, and cardiac complications. This pilot study evaluates the efficacy and toxicity of a reduced dose of PTCY (40 mg/kg/day) combined with tacrolimus in 22 peripheral blood HLA-matched alloHSCT patients. At day +100, the cumulative incidences of grade II-IV and III-IV acute GVHD were 18.2% and 4.5%, respectively. No grade IV acute GVHD or steroid-refractory disease was observed. The cumulative incidences of all-grade and moderate-severe chronic GVHD at 1-year were 11.4% and 6.4%, respectively. No patient died from transplant-related complications. Two-year OS and RFS were 77.1% and 58.3%, respectively. All patients engrafted, with neutrophil and platelet recovery occurring at a median of 15 (IQR 14-16) and 16 days (IQR 12-23), respectively. The cumulative incidences of bloodstream bacterial infections, polyomavirus BK hemorrhagic cystitis, HHV6 reactivation, CMV reactivation, and fungal infections were 13.6%, 9.1%, 9.1%, 4.6%, and 6%, respectively. Only one early cardiac event was observed. These results suggest that PTCY 40 mg/kg/day on a +3/+4 schedule provides adequate immunosuppression to allow for engraftment and prevent clinically significant GVHD with a low toxicity profile.

This study investigates the interaction between endothelial activation, indirectly measured using EASIX, and the probability of presenting cardiac adverse events (CAE) during the first year after allo-HCT. The 437 consecutive adults undergoing PB allo-HCT from 2012 and 2021 were included. EASIX was retrospectively calculated before and during the first 6 months after allo-HCT and transformed to log2-base to conduct the statistical analysis. The median age was 53, 46 (10.5%) patients had previous history of cardiac disease, MAC allo-HCTs were performed in 186 (42.6%) patients, and PTCY was administered in 242 (55.5%). The 1-year incidence of CAE was 12.6% (n = 55). The most prevalent cardiac events were heart failure and arrhythmias, 32.7% and 23.6% respectively, and the day +100 mortality rate of these patients was 40.5%. During the first 6 months after allo-HCT, EASIX trends were significantly higher in patients who developed CAE. Regression analyses confirmed that higher log2-EASIX values were predictors for higher risk for CAE during the first year after allo-HCT. This analysis identifies a significant association between higher endothelial activation, indirectly measured using EASIX, and higher risk for cardiac toxicity diagnosed during the first year after allo-HCT and extends the applicability of EASIX for identifying patients at risk for CAE., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

European LeukemiaNet refined their risk classification of acute myeloid leukaemia (AML) in 2022 (ELN 2022) according to the two new myeloid classifications published the same year. We have retrospectively assessed the prognostic value of the ELN 2022 in 120 AML patients undergoing allogeneic haematopoietic cell transplantation (allo-HCT), including 99 in first complete response (CR1) from 2011 to 2021 in our centre. Adverse risk patients (Adv) presented inferior outcome in terms of overall survival (OS) and leukaemia-free survival (LFS) (OS [p = 0.003], LFS [p = 0.02]), confirmed in multivariate analysis (hazard ratio [HR] for OS = 2.00, p = 0.037). These results were also seen in patients allografted in CR1. Further analysis identified a subgroup named adverse-plus (AdvP), including complex karyotype, MECOM(EVI1) rearrangements and TP53 mutations, with worse outcomes than the rest of groups of patients, including the Adv (HR for OS: 3.14, p < 0.001, HR for LFS: 3.36, p < 0.001), with higher 2-year cumulative incidence of relapse (p < 0.001). Notably, within this analysis, the outcome of Adv and intermediate patients were similar. These findings highlight the prognostic value of ELN 2022 in patients undergoing allo-HCT, which can be improved by the recognition of a poor genetic subset (AdvP) within the Adv risk group., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5 * 3 and CYP3A4* 22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C 0 /D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C 0 /dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers ( CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C 0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.

Limited data regarding elevation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in mobilized donors with G-CSF is available. We extended these findings by examining serum NT-proBNP in a cohort study including 35 healthy donors and 69 patients who received G-CSF for CD34+ mobilization as well as 54 patients who did not receive G-CSF but who underwent collection of CD3+ cells for chimeric antigen receptor (CAR) T-cell manufacturing. No donor in the three cohorts experienced significant cardiac adverse events. NT-proBNP levels were measured before and after G-CSF administration and after finishing apheresis procedure. NT-proBNP increase was observed in mobilized healthy donors after G-CSF administration, but was not observed in mobilized or non-mobilized patients. Only in the cohort of healthy donors, pairwise comparisons using Wilcoxon signed ranks test showed a significant increase between the mean serum NT-proBNP level after G-CSF administration and the mean serum NT-proBNP level measured before G-CSF administration (231.09 ± 156.15 pg/mL vs. 58.88 ± 26.84 pg/mL; P < .01). No correlation was observed between NT-proBNP increase and G-CSF dose (r s = 0.09; n = 32; P = .6) and no other variables contributing to predict serum NT-proBNP increase were detected. In conclusion, we observed a statistically, although not clinically, significant increase of NT-proBNP in healthy donors who received G-CSF as CD34+ cell mobilization., Competing Interests: Declaration of competing interest No conflicts of interest exist., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Letermovir for CMV prevention in CMV-seropositive adults undergoing allo-HCT was implemented at our program in 2021. This study investigates the results from the use of letermovir. The study includes all the 140 CMV-seropositive patients who underwent an allo-HCT during the years 2020, 2021, and 2022 at our institution. Thirty-eight (27.4%) of these patients received letermovir, administered from day + 7 to day + 100 and restarted if patients were on treatment with steroids. The day + 180 and 1-year cumulative incidences of CMV reactivation were 5.3% and 12.1% for patients who received letermovir and 52.9% and 53.9% for those who did not (P < 0.001) (HR 0.19, P < 0.001). Four (10.5%) of these thirty-eight patients had a CMV reactivation, but only 2 (5.3%) cases occurred during the administration of letermovir. During the first year after allo-HCT, 13 (9.2%) patients had CMV disease; the day + 180 and 1-year cumulative incidences were 2.6% and 6.0% for patients who received letermovir and 9.9% and 12.3% for those who did not (P = 0.254) (HR 1.01, P = 0.458). Two (4.2%) of the patients included in the letermovir group had CMV disease, but both of them after letermovir discontinuation. Letermovir induced a protective effect on CMV reactivation risk, but its use was not associated with a significant reduction of CMV disease. The fact that the CMV disease in patients who received letermovir occurred after the discontinuation of the drug, questions whether CMV prophylaxis should be used in patients with high risk for CMV reactivation or disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study compared the efficacy of graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy) and tacrolimus (Tac) versus other regimens in 272 adults undergoing peripheral blood (PB) allogeneic hematopoietic cell transplantation (allo-HCT) from HLA-matched donors. Of these 272 patients, 95 (34.9%) received PTCy/Tac. The times to neutrophil and platelet engraftment were longer in the PTCy/Tac group (20 days versus 16 days for neutrophils and 19 days versus 12 days for platelets). The day +30 cumulative incidence (CuI) of bacterial bloodstream infection was higher in the PTCy/Tac group (43.2% versus 13.0%; P < .001). The CuIs of grade II-IV and grade III-IV acute GVHD (aGVHD) at day +180 were 14.7% and 4.2%, and the CuI of moderate/severe cGVHD at 2 years was 2.4% in the PTCy/Tac group and 41.8% (hazard ratio [HR], .29; P < .001), 15.8%, (HR, .24; P = .007), and 47.0% (HR, .05; P < .001), respectively, in the no-PTCy group. The duration of immunosuppression was shorter in patients receiving PTCy/Tac (6.2 months versus 9.0 months; P < .001). PTCy/Tac patients had higher OS (2 years: 74.3% versus 60.9%; HR, .54; P = .012), lower NRM (2 years: 8.6% versus 15.8%; HR, .54; P = .11), comparable CuI of relapse (2 years: 26.0% versus 24.4%; HR, 1.03; P = .89), and higher GRFS (2 years: 59.1% versus 16.7%; HR, .32; P < .001). Using PTCy/Tac in HLA-matched PB allo-HCT improved transplantation outcomes at out institution compared with previous prophylactic regimens, including a higher probability of survival despite more delayed engraftment and a higher rate of bacterial infection., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background Aims: Post-transplant cyclophosphamide (PTCY)-based prophylaxis is becoming widespread for allogeneic hematopoietic cell transplantation (allo-HCT) performed independently of the selected donor source. In parallel, use of the Endothelial Activation and Stress Index (EASIX)-considered a surrogate parameter of endothelial activation-for predicting patient outcomes and clinical complications is gaining popularity in the allo-HCT setting., Methods: We first investigated whether the dynamics of EASIX after allo-HCT differ between patients receiving PTCY and patients receiving other prophylaxis. We then investigated whether the predictive capacity of EASIX persists in PTCY-based allo-HCT. A total of 328 patients transplanted between 2014 and 2020 were included, and 201 (61.2%) received PTCY., Results: EASIX trends differed significantly between the groups. Compared with patients receiving other prophylaxis, patients receiving PTCY had lower EASIX on day 0 and higher values between day 7 and day 100. In patients receiving PTCY, higher EASIX correlated significantly with higher non-relapse mortality (NRM) and lower overall survival (OS) when measured before and during the first 180 days after allo-HCT. In addition, higher EASIX scores measured at specific time points were predictors of veno-occlusive disease (VOD), transplant-associated thrombotic microangiopathy (TA-TMA) and grade 2-4 acute graft-versus-host disease (aGVHD) risk., Conclusions: This study demonstrates how EASIX trends vary during the first 180 days after allo-HCT in patients receiving PTCY and those not receiving PTCY and validates the utility of this index for predicting NRM, OS and risk of VOD, TA-TMA and grade 2-4 aGVHD in patients receiving PTCY., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our hospital designed an at-home FCN administration model to avoid the hospitalization of patients requiring FCN treatment. This study analyzes whether the at-home administration of FCN is as safe and effective as its hospital administration. We collected and compared demographic, clinical, analytical, and economic data of patients with CMV infection post-allo-HCT who received FCN in the hospital ( n = 16, 17 episodes) vs. at-home ( n = 67, 88 episodes). The proportions of patients with cured CMV infections were comparable between the two groups (65.9% vs. 76.5%, p = 0.395). The median duration of FCN treatment was 15 (interquartile range [IQR] 9-23) and 14 (IQR 11-19) days in the HCU and inpatient cohorts, respectively ( p = 0.692). There were no significant differences in the FCN toxicities between groups except for hypocalcemia (26.1% vs. 58.8%, p = 0.007), which was more prevalent in the inpatient cohort. A significant cost-effectiveness was found in the HCU cohort, with a median savings per episode of EUR 5270. It may be concluded that home administration of FCN is a safe, effective, and cost-efficient therapeutic option for patients with CMV infection and disease.

We investigated the predictive capacity of six prognostic indices [Karnofsky Performance Status (KPS), Hematopoietic Cell Transplant-Specific Comorbidity Index (HCT-CI), Disease Risk Index (DRI), European Bone Marrow Transplantation (EBMT) and Revised Pre-Transplantation Assessment of Mortality (rPAM) Scores and Endothelial Activation and Stress Index (EASIX)] in 205 adults undergoing post-transplant cyclophosphamide (PTCy)-based allo-HCT. KPS, HCT-CI, DRI and EASIX grouped patients into higher and lower risk strata. KPS and EASIX maintained appropriate discrimination for OS prediction across the first 2 years after allo-HCT [receiver operating characteristic curve (area under the curve (AUC) > 55 %)]. The discriminative capacity of DRI and HCT-CI increased during the post-transplant period, with a peak of prediction at 2 years (AUC of 61.1 % and 61.8 %). The maximum rPAM discriminative capacity was at 1 year (1-year AUC of 58.2 %). The predictive capacity of the EBMT score was not demonstrated. This study validates the discrimination capacity for OS prediction of KPS, HCT-CI, DRI and EASIX in PTCy-based allo-HCT., Competing Interests: Conflicts of interest The authors declare no relevant conflicts of interest, financial or otherwise., (Copyright © 2023 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: We aimed to describe the clinical outcomes and duration of viral shedding in high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predominance who received early treatment with antivirals., Methods: We conducted a prospective observational study on high-risk haematological patients admitted in our hospital between December 2021 and March 2022. We performed detection techniques on viral subgenomic mRNAs until negative results were obtained to document active, prolonged viral replication., Results: This analysis included 60 consecutive adults with high-risk haematological malignancies and COVID-19. All of these patients underwent early treatment with remdesivir. Thirty-two (53%) patients received combined antiviral strategies, with sotrovimab or hyperimmune plasma being added to remdesivir. The median length of viral replication-as measured by real-time RT-PCR and/or subgenomic RNA detection-was 20 (IQR 14-28) days. Prolonged viral replication (6 weeks after diagnosis) was documented in six (10%) patients. Only two patients had prolonged infection for more than 2 months. Overall mortality was 5%, whereas COVID-19-related mortality was 0%., Conclusions: Current outcomes of high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predminance are good with the use of early antiviral strategies. Persistent viral shedding is uncommon., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study investigates early cardiac events (ECEs) occurring during the first 180 days after allogeneic hematopoietic cell transplant (allo-HCT) in 416 adults receiving posttransplant cyclophosphamide (PTCY) (n = 258) or not receiving PTCY (n = 158). Total body irradiation (TBI) was given to 133 (31.9%) patients, of whom 111 (83.4%) received TBI combined with PTCY. The day +180 cumulative incidence function (CIF) of ECEs was 8.4%, with heart failure (n = 13) and pericardial complications (n = 11) being the most prevalent complications. The incidence of ECEs was higher in patients receiving PTCY, and receiving TBI. ECEs were more prevalent in haploidentical HCTs than in matched sibling donor, 10/10 HLA-matched unrelated donor, and 9/10 HLA-mismatched unrelated donor allo-HCTs. As for the ECE risk from the combination of PTCY and TBI, the multivariate analysis reported that patients receiving PTCY without TBI, TBI without PTCY, and TBI with PTCY were at higher risk for ECEs compared with patients receiving neither PTCY nor TBI. Pre-existing cardiac morbidity predicted ECEs. However, using high-dose CY-containing preparative regimens did not increase the risk for cardiac toxicity at +180 days after allo-HCT. ECEs were associated with higher nonrelapse mortality and lower overall survival. Considering that PTCY and TBI were predictors for ECEs, and the impact of this complication on transplant mortality, the implementation of cardiac monitoring plans could be appropriate in patients receiving these medications., (© 2023 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.)

Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-transplant cyclophosphamide (PTCy) and the effects of Tac IPV on the occurrence of acute GVHD (aGVHD) were analyzed. Tac IPV was calculated from pre-dose concentrations (C0) measured during the first month after Tac initiation. The cumulative rates of grades II-IV and grades III-IV aGVHD at day +100 were 22.7% and 7%, respectively. Higher Tac IPV was associated with a greater risk of developing GVHD, with patients having IPV > 50th percentile having significantly higher rates of grades II-IV (34.9% vs. 10.8%; hazard ratio [HR] 3.858, p < 0.001) and grades III-IV (12.7% vs. 1.5%; HR 9.69, p = 0.033) aGVHD than patients having IPV ≤ 50th percentile. Similarly, patients with IPV > 75th percentile had higher rates of grades II-IV (41.9% vs. 16.5%; HR 3.30, p < 0.001) and grades III-IV (16.1% vs. 4.1%; HR 4.99, p = 0.012) aGVHD than patients with IPV ≤ 75th percentile. Multivariate analyses showed that high Tac IPV (>50th percentile) was an independent risk factor for grades II-IV (HR 2.99, p = 0.018) and grades III-IV (HR 9.12, p = 0.047) aGVHD. Determination of Tac IPV soon after alloHSCT could be useful in identifying patients at greater risk of aGVHD.

This study investigates the incidence and predictors for bacterial bloodstream infection (BSI) in 330 adults undergoing allo-HCT, and explores the effect of post-transplantation cyclophosphamide (PTCY) on the probability of presenting this complication. All patients received levofloxacin during the aplastic phase. Only the first episode of BSI was counted as an event. Patients were classified into 2 groups: PTCY-based (n = 200) versus other prophylaxis (n = 130). One hundred twenty-four patients were diagnosed with a first episode of BSI, most of them during the first 30 days (70.2%). Proportions of BSIs caused by Gram-positive bacteria were comparable to those caused by Gram-negative bacteria (48.3% versus 45.9%). The cumulative incidence of BSI was higher in patients receiving PTCY than in those receiving other prophylaxis (days 30 and 100: 35.0% and 37.0% versus 13.1% and 18.5%, P < .001). At day 30, the likelihood of BSI was 2.41 (P = .012) times higher in the PTCY group than in the non-PTCY group. The 30-day mortality rate in all patients with BSI was 8.0%, lower (P = .002) in the PTCY group (2.3%) than in the non-PTCY group (21.6%). Finally, the overall survival of patients receiving PTCY and diagnosed with BSI was similar to that of patients without presenting this complication. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved., Competing Interests: Conflict of interest statement P.P-A. has received honoraria for talks on behalf of Merck Sharp and Dohme, Gilead, Lilly, ViiV Healthcare and Gilead Science. C.G-V. has received honoraria for talks on behalf of Gilead Science, MSD, Novartis, Pfizer, Janssen, Lilly, as well as a grant from Gilead Science and MSD., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for the treatment of refractory hematopoietic malignancies. Adverse events are common, and neurotoxicity is one of the most important. However, the physiopathology is unknown and neuropathologic information is scarce. Materials and methods: Post-mortem examination of 6 brains from patients that underwent CAR T-cell therapy from 2017 to 2022. In all cases, polymerase chain reaction (PCR) in paraffin blocks for the detection of CAR T cells was performed. Results: Two patients died of hematologic progression, while the others died of cytokine release syndrome, lung infection, encephalomyelitis, and acute liver failure. Two out of 6 presented neurological symptoms, one with extracranial malignancy progression and the other with encephalomyelitis. The neuropathology of the latter showed severe perivascular and interstitial lymphocytic infiltration, predominantly CD8+, together with a diffuse interstitial histiocytic infiltration, affecting mainly the spinal cord, midbrain, and hippocampus, and a diffuse gliosis of basal ganglia, hippocampus, and brainstem. Microbiological studies were negative for neurotropic viruses, and PCR failed to detect CAR T -cells. Another case without detectable neurological signs showed cortical and subcortical gliosis due to acute hypoxic-ischemic damage. The remaining 4 cases only showed a mild patchy gliosis and microglial activation, and CAR T cells were detected by PCR only in one of them. Conclusions: In this series of patients that died after CAR T-cell therapy, we predominantly found non-specific or minimal neuropathological changes. CAR T-cell related toxicity may not be the only cause of neurological symptoms, and the autopsy could detect additional pathological findings., Competing Interests: The authors have no conflicts of interest that relate to the content of this article.

The use of post-transplantation cyclophosphamide (PTCY) for graft-versus-host disease (GHVD) prevention is becoming prevalent in the transplantation community when HLA-identical sibling and 10/10 HLA-matched (MUD) and 9/10 mismatched unrelated donors are selected for alloHSCT. However, reported evidence on outcomes from elderly patients receiving PTCY-containing GVHD prophylaxis remains limited. This study aims to compare the outcomes of PTCY- tacrolimus (TK) prophylaxis and conventional GVHD prophylaxis in patients aged >50 years undergoing peripheral blood alloHSCT from a single institution. A total of 161 consecutive patients aged >50 years undergoing alloHSCT between January 2014 and February 2021 were included. Data were collected retrospectively and updated in December 2021. Patients received grafts from HLA-identical sibling, and from 10/10 and 9/10 HLA matched and mismatched unrelated donors. Overall, median age was 60 years, and 91 (54.8%) received PTCY-TK for GVHD prevention. Time to neutrophil and platelet engraftment was longer in the PTCY-TK group (20 versus 16 days and 19 versus 11 days, P < .001). The cumulative incidences of grade II-IV and III-IV acute GVHD (aGVHD) at day 100 and moderate/severe chronic GVHD (cGVHD) at 2 years were 18.2%, 5.7%, and 9.5% for patients receiving PTCY-TK, and 26.0%, 9.6% and 39.5% for those who did not. The multivariate analysis showed that PTCY-TK reduced the probability of grade II-IV aGVHD (hazard ratio [HR] 0.41, P = .035), of cGVHD (any grade: HR 0.43 [P = .014], and of moderate/severe cGVHD [HR 0.15 {P < .001}]). At 2 years, the overall survival (65.4% versus 65.6%, P = .472), non-relapse mortality (17.4% versus 13.7%, P = .967), and cumulative incidence of relapse rates (24.2% versus 27.5%, P = .712) were comparable between both cohorts; GVHD-free/relapse-free survival (GRFS) was higher in the PTCY-TK group (2 years: 50.2% versus 21.8%; HR 0.42, P = .001). In patients aged ≥50 years. PTCY-TK was safe and a more effective drug combination than non-PTCY containing GVHD prophylaxis, even with the use of matched and mismatched unrelated donors, and resulted in comparable relapse rates and better GRFS., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic cell transplantation (alloHCT) remains the only curative option for relapsed/refractory acute myeloid leukemia and other high-risk myeloid malignancies. To improve alloHCT results in this setting, sequential regimens were designed as a strategy to lower tumor burden and quickly induce the graft-versus-leukemia effect. We analyzed long-term outcomes of a sequential regimen based on IDA-FLAG and high-dose melphalan, as set forth by the CETLAM cooperative group. This protocol yielded a high complete response rate (89%) and a lower cumulative relapse incidence (30% at five years) compared to other regimens. Five-year non-relapse mortality, however, reached 45%, with grade 3-4 acute graft-versus-host disease being the most frequent adverse event (a 100-day incidence of 29%). Altogether, 5-year overall survival was 25% in this group of patients with otherwise dismal prognosis. Long-term survivors enjoyed a good quality of life after a median follow-up of 68 months., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Autologous cell immunotherapy using B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cells is an effective novel treatment for multiple myeloma (MM). This therapy has only been used for relapsed and refractory patients, at which stage the endogenous T cells used to produce the CAR-T cells are affected by the immunosuppressive nature of advanced MM and/or side effects of previous therapies. An alternative pool of "fitter" T cells is found in leukocytoapheresis products that are routinely collected to obtain hematopoietic progenitor cells for autologous stem cell transplantation (ASCT) early in the treatment of MM. However, to mobilize the progenitor cells, patients are dosed with granulocyte colony-stimulating factor (G-CSF), which is reported to adversely affect T cell proliferation, function, and differentiation. Here, we aimed to first establish whether G-CSF treatment negatively influences T cell phenotype and to ascertain whether previous exposure of T cells to G-CSF is deleterious for anti-BCMA CAR-T cells. We observed that G-CSF had a minimal impact on T cell phenotype when added in vitro or administered to patients. Moreover, we found that CAR-T cell fitness and anti-tumor activity were unaffected when generated from G-CSF-exposed T cells. Overall, we showed that ASCT apheresis products are a suitable source of T cells for anti-BCMA CAR-T cell manufacture., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

De novo mutations in the UL56 terminase subunit and its associated phenotypes were studied in the context of cytomegalovirus (CMV) transplant recipients clinically resistant to DNA-polymerase inhibitors, naive to letermovir. R246C was the only UL56 variant detected by standard and deep sequencing, located within the letermovir-resistance-associated region (residues 230-370). R246C emerged in 2/80 transplant recipients (1 hematopoietic and 1 heart) since first cytomegalovirus replication and responded transiently to various alternative antiviral treatments in vivo . Recombinant phenotyping showed R246C conferred an advanced viral fitness and was sensitive to ganciclovir, cidofovir, foscarnet, maribavir, and letermovir. These results demonstrate a low rate (2.5%) of natural occurring polymorphisms within the letermovir-resistant-associated region before its administration. Identification of high replicative capacity variants in patients not responding to treatment or experiencing relapses could be helpful to guide further therapy and dosing of antiviral molecules. IMPORTANCE We provide comprehensive data on the clinical correlates of both CMV genotypic follow-up by standard and deep sequencing and the clinical outcomes, as well as recombinant phenotypic results of this novel mutation. Our study emphasizes that the clinical follow-up in combination with genotypic and phenotypic studies is essential for the assessment and optimization of patients experiencing HCMV relapses or not responding to antiviral therapy. This information may be important for other researchers and clinicians working in the field to improve the care of transplant patients since drug-resistant CMV infections are an important emerging problem even with the new antiviral development.

We analyzed risk factors for mortality in febrile neutropenic patients with bloodstream infections (BSI) presenting with septic shock and assessed the impact of empirical antibiotic regimens. A multicenter retrospective study (2010 to 2019) of two prospective cohorts compared BSI episodes in patients with or without septic shock. Multivariate analysis was performed to identify independent risk factors for mortality in episodes with septic shock. Of 1,563 patients with BSI, 257 (16%) presented with septic shock. Those patients with septic shock had higher mortality than those without septic shock (55% versus 15%, P  < 0.001). Gram-negative bacilli caused 81% of episodes with septic shock, Gram-positive cocci caused 22%, and Candida species caused 5%. Inappropriate empirical antibiotic treatment (IEAT) was administered in 17.5% of septic shock episodes. Empirical β-lactam combined with other active antibiotics was associated with the lowest mortality observed. When amikacin was the only active antibiotic, mortality was 90%. Addition of empirical specific Gram-positive coverage had no impact on mortality. Mortality was higher when IEAT was administered (76% versus 51%, P  = 0.002). Age of >70 years (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.2 to 4.7), IEAT for Candida spp. or Gram-negative bacilli (OR, 3.8; 95% CI, 1.3 to 11.1), acute kidney injury (OR, 2.6; 95% CI, 1.4 to 4.9), and amikacin as the only active antibiotic (OR, 15.2; 95% CI, 1.7 to 134.5) were independent risk factors for mortality, while the combination of β-lactam and amikacin was protective (OR, 0.32; 95% CI, 0.18 to 0.57). Septic shock in febrile neutropenic patients with BSI is associated with extremely high mortality, especially when IEAT is administered. Combination therapy including an active β-lactam and amikacin results in the best outcomes.

The potential role of active CMV infection in promoting acute Graft-versus-Host Disease (aGvHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. We further addressed this issue conducting a retrospective, observational, multicenter study of 632 patients subjected to allogeneic peripheral blood HSCT at 20 Spanish centers. Monitoring of CMV DNA load in plasma or whole blood was performed by real-time PCR assays. Cumulative incidence of CMV DNAemia was 48.9% (95% CI, 45%-52.9%), of any grade aGvHD, 45.6; 95% (CI, 41.3%-50.1%), and of grade II-IV aGvHD, 30.7 (95% CI, 24.9%-36.4%). Overall, development of CMV DNAemia at any level resulted in an increased risk of subsequent all grade (HR, 1.38; 95% CI, 1.08 - 1.76; P = .009) or grade II-IV (HR, 1.58; 95% CI, 1.22 - 2.06; P = .001) aGvHD. The increased risk of aGvHD linked to prior occurrence of CMV DNAemia was similar to the above when only clinically significant episodes were considered for the analyses (HR for all grade aGvHD, 1.48; 95% CI, 1.13 - 1.91; P = .041, and HR for grade II-IV aGvHD, 1.53; 95% CI. 1.13-1.81; P = .04). The CMV DNA doubling time in blood was comparable overall in episodes of CMV DNAemia whether followed by aGvHD or not. Whether CMV replication is a surrogate risk marker of aGvHD or it is causally involved is an important question to be addressed in future experimental research., (© 2021 Wiley Periodicals LLC.)

The optimal prophylaxis regimen for graft-versus-host disease (GVHD) in the setting of single-locus mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation (alloHSCT) is unclear. The use of high-dose post-transplant cyclophosphamide (PTCy) after haploidentical transplantation is effective at overcoming the negative impact of HLA disparity on survival. Limited information is available regarding the efficacy of this strategy in alloHSCT from MMUDs. Most of the published studies have used the triple immunosuppressant model of haploidentical transplant combining PTCy with calcineurin inhibitors and mycophenolate mofetil or methotrexate. In our study, we propose the use of a simpler GVHD prophylaxis protocol comprising PTCy in combination with tacrolimus for MMUD and matched unrelated donor (MUD) alloHSCT. We performed a retrospective analysis of 109 consecutive recipients of alloHSCT from unrelated donors (MMUD, n = 55; MUD, n = 54) in a single center. Graft source was primarily peripheral blood (98%). No differences were observed between the MMUD and MUD groups with respect to 100-day cumulative incidence of grade II to IV acute GVHD (aGVHD; 31% versus 32%, respectively, P = .9), grade III to IV aGVHD (9% versus 7%, P = .7), and moderate/severe chronic GVHD (cGVHD) at 2 years (18% versus 14%, P = .6). Both groups showed similar cumulative incidence of 1 year nonrelapse mortality (13% versus 9%; P = .5) and 3-year relapse rates (24% versus 25%, P = .7). Progression-free survival and overall survival at 3 years for MMUD and MUD were 56% and 57% (P = .9) and 64% and 65% (P = .6), respectively. The 3-year probability of survival free of moderate/severe cGVHD and relapse was 56% and 55%, respectively. GVHD prophylaxis with PTCy and tacrolimus achieves low rates of severe aGVHD and cGVHD, as well as good survival outcomes, in recipients of both MMUD and MUD peripheral blood alloHSCT. This strategy overcomes the negative impact of single-locus HLA disparity., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

In recent years, important epidemiologic changes have been described in hematopoietic stem cell transplantation (HSCT) recipients with bloodstream infection (BSI), with increases in gram-negative bacilli and multidrug resistant (MDR) gram-negative bacilli. These changes have been linked to a worrisome increase in mortality. We aimed to define the risk factors for mortality of HSCT patients experiencing BSI. All episodes of BSI in patients with HSCT between 2008 and 2017 were prospectively collected. Multivariate analyses were performed. A total of 402 BSI episodes were documented in 293 patients who had undergone HSCT (75.4% allogenic, 32.3% autologous, 19.3% second HSCT). The median time from HSCT to BSI was 62 days (interquartile range, 9 to 182 days). Gram-positive cocci accounted for 56.7% of the episodes; gram-negative bacilli, for 42%. The most common microorganisms were coagulase-negative staphylococci (30.6%) and Pseudomonas aeruginosa (15.9%). MDR gram-negative bacilli caused 11.9% of all episodes. Clinical characteristics, source of BSI, etiology, and outcomes changed depending on time since HSCT. Globally, 26.6% of episodes were treated with inappropriate empiric antibiotic therapy, more frequently in BSI episodes caused by P. aeruginosa, MDR P. aeruginosa, and MDR gram-negative bacilli. The 30-day mortality was 19.2%. Independent risk factors for mortality were BSI occurring ≥30 days after HSCT (odds ratio [OR], 11.21; 95% confidence interval [CI], 4.63 to 27.19), shock (OR, 7.10; 95% CI, 2.98 to 16.94), BSI caused by MDR P. aeruginosa (OR, 4.45; 95% CI, 1.12 to 17.72), and inappropriate empiric antibiotic therapy for gram-negative bacilli or Candida spp. (OR, 3.73; 95% CI, 1.27 to 10.89). HSCT recipients experiencing BSI have high mortality related to host and procedure factors, causative microorganism, and empiric antibiotic therapy. Strategies to identify HSCT recipients at risk of MDR P. aeruginosa and reducing inappropriate empiric antibiotic therapy are paramount to reduce mortality., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

There is limited information on the impact of CMV DNAemia episodes developing prior to engraftment (pre-CMV DNAemia) on clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This issue was addressed in the current retrospective multicenter study including 878 patients. All participant centers used preemptive antiviral therapy strategies for prevention of CMV disease. CMV DNA load in blood was monitored by real-time PCR assays. A total of 144 patients (cumulative incidence 16.5%, 95% CI, 14%-19%) had an episode of pre-CMV DNAemia at a median of 10 days after allo-HSCT. Patients who developed pre-CMV DNAemia had a significantly higher (P = < 0.001) probability of recurrent episodes (50%) than those who experienced post-CMV DNAemia (32.9%); Nevertheless, the incidence of CMV disease was comparable (P = 0.52). Cumulative incidences of overall mortality (OM) and non-relapse mortality (NRM) at 1-year after allo-HSCT were 32% (95% CI, 29-35%) and 23% (95% CI 20-26%), respectively. The risk of OM and NRM in adjusted models appeared comparable in patients developing a single episode of CMV DNAemia, regardless of whether it occurred before or after engraftment, in patients with pre- and post-engraftment CMV DNAemia episodes or in those without CMV DNAemia.