Publications by authors named "Francis Ayuk"

127 Publications

Reduced intensity hematopoietic stem cell transplantation for myelofibrosis in accelerated-phase.

Blood Adv 2022 Jan 20. Epub 2022 Jan 20.

University Medical Center Hamburg_Eppendorf, Hamburg, Germany.

Accelerated-phase (AP) myelofibrosis, currently defined by circulating blasts 10-19%, usually confers very high risk for progression and poor outcome. The outcome of hematopoietic stem cell transplantation for AP myelofibrosis has not been evaluated yet. We analyzed the outcome of 349 clinically and genetically annotated patients with primary or secondary myelofibrosis undergoing reduced intensity transplantation, of whom 35 had AP myelofibrosis. In comparison with chronic-phase (CP, <10% blasts), median leukocyte counts were higher, more patients had constitutional symptoms, and RAS mutations were detected more frequently in the AP group. After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% (95% confidence interval, 49-81%) versus 64% (95% confidence interval, 59-69%) for the CP group (P=0.91), and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the AP group was 49% (95% confidence interval, 32-67%) versus 55% (95% confidence interval, 50-61%) for the CP group (P=0.65). Estimated 5-year non-relapse mortality was 20% (95% CI, 8-33%) for the AP group versus 30% (95% confidence interval, 24-35%; P=0.25) for the CP group. In terms of relapse, 5-year incidence was 30% (95% confidence interval, 14-46%) for the AP group versus 15% (95% confidence interval, 11-19%) for the CP group (P=0.02). Results were confirmed in multivariable analysis and propensity score matching. Increase in circulating blasts was associated with increased risk for relapse, showing strongest increase in risk for ≥10% blasts. In conclusion, reduced intensity transplantation showed excellent survival but higher relapse for AP myelofibrosis.
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http://dx.doi.org/10.1182/bloodadvances.2021006827DOI Listing
January 2022

Antibody response after vaccination against SARS-CoV-2 in adults with haematological malignancies: a systematic review and meta-analysis.

Haematologica 2021 Dec 16. Epub 2021 Dec 16.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg.

Vaccines against SARS-CoV-2 have shown remarkable efficacy and thus constitute an important preventive option against COVID-19, especially in fragile patients. We aimed to systematically analyse the outcomes of patients with haematological malignancies who received vaccination and to identify specific groups with differences in outcomes. The primary end point was antibody response after full vaccination (two doses of mRNA or one dose of vector-based vaccines). We identified 49 studies comprising 11086 individuals. Overall risk of bias was low. The pooled response for haematological malignancies was 64% (95% confidence interval [CI], 59-69; I²=93%) vs 96% (95% CI, 92-97; I²=44%) for solid cancer and 98% (95% CI, 96-99; I²=55%) for healthy controls (P<0.001). Outcome was different across haematological malignancies (P<0.001). The pooled response was 50% (95% CI, 43-57; I²=84%) for chronic lymphocytic leukaemia, 76% (95% CI, 67-83; I²=92%) for multiple myeloma, 83% (95% CI, 69-91; I²=85%) for myeloproliferative neoplasms, 91% (95% CI, 82-96; I²=12%) for Hodgkin's lymphoma, and 58% (95% CI, 44-70; I²=84%) for aggressive and 61% (95% CI, 48-72; I²=85%) for indolent non-Hodgkin's lymphoma. The pooled response for allogeneic and autologous haematopoietic cell transplantation was 82% and 83%, respectively. Being in remission and prior COVID-19 showed significantly higher responses. Low pooled response was identified for active treatment (35%), anti-CD20 therapy ≤1 year (15%), Bruton kinase inhibition (23%), venetoclax (26%), ruxolitinib (42%), and chimeric antigen receptor T-cell therapy (42%). Studies on timing, value of boosters, and long-term efficacy are needed. This study is registered with PROSPERO (CRD42021279051).
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http://dx.doi.org/10.3324/haematol.2021.280163DOI Listing
December 2021

Iron Chelation With Deferasirox Increases Busulfan AUC During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation.

Transplant Cell Ther 2021 Nov 11. Epub 2021 Nov 11.

University Medical Center Hamburg-Eppendorf, Department of Stem Cell Transplantation, Hamburg, Germany; University Medical Center Hamburg-Eppendorf, Hospital Pharmacy, Hamburg, Germany. Electronic address:

The negative effects of iron overload caused by repetitive blood transfusions and iron release during cytotoxic chemotherapy might be ameliorated by early treatment with an iron chelator. However, in the setting of allogeneic hematopoietic stem cell transplantation (HSCT), chelation therapy is often postponed until the late post-transplantation period because of potential drug interactions. Therefore we systematically investigated the influence of iron chelation with deferasirox on the pharmacokinetics of intravenous busulfan in adult patients in the context of routine therapeutic drug monitoring (TDM) before HSCT. We conducted a single-center, prospective, observational study in 25 adult patients with planned allogeneic HSCT after myeloablative, busulfan-based, TDM-guided conditioning chemotherapy. Busulfan was administered intravenously over 3 hours with an initial dose of 3.2 mg/kg once daily (based on adjusted ideal body weight [AIBW] in overweight patients). Four consecutive dosages were planned to achieve a cumulative area under the curve (AUC) of 80 mg · h/L. Patients received deferasirox for transfusional iron overload as per approval from the start of conditioning until day 3 after transplantation. Model-based calculation of the busulfan AUC was carried out by means of Bayesian prediction based on a population pharmacokinetic model after the first or second dose of busulfan, and dose adjustments were performed accordingly. Calculated median cumulative AUC before dose adjustment was 93.7 mg · h/L (65.1-151.4 mg · h/L), which was considerably above the target AUC of 80 mg · h/L ± 10%. Median dose adjustment was -17.1% (-50.0% to 18.2%), and patients ultimately received busulfan with a median cumulative dose of 10.60 mg/kg (6.38 - 15.62) mg/kg. A busulfan dose reduction was necessary in 19 patients (76%) whereas a dose increase was only needed in 1 patient. After dose adjustment the median AUC was 79.7 mg/L · h (62.5 - 84.2 mg/L · h). Median busulfan clearance was 0.134 L/h/kg (0.084 - 0.203 L/h/kg), which is significantly lower than the average clearance of 0.2 L/h/kg reported in the literature, whereas volume of distribution was not altered. We were able to demonstrate, that TDM is the key point to facilitate a safe co-administration of both medications, because the intake of deferasirox leads to a considerable increase in the busulfan AUC of about 35% to 40%. The reason for the increase in busulfan AUC is a reduction in busulfan clearance by about one third; therefore a lower initial dose of busulfan followed by TDM could be considered in patients with comedication with deferasirox.
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http://dx.doi.org/10.1016/j.jtct.2021.11.003DOI Listing
November 2021

Evaluation of Elafin as a Prognostic Biomarker in Acute Graft-versus-Host Disease.

Transplant Cell Ther 2021 Dec 30;27(12):988.e1-988.e7. Epub 2021 Aug 30.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT recipients is gastrointestinal (GI) GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. We analyzed serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and compared it with ST2 and REG3α in a large group of patients treated at multiple centers. A total of 526 patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who had received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed. Serum concentrations of elafin, ST2, and REG3α were measured by ELISA in all patients. The patients were divided at random into equal training and validation sets, and a competing-risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3α or the combination of all 3 biomarkers as predictors. Receiver operating characteristic (ROC) curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival (OS), and 4-week treatment response were compared between the risk groups. Unexpectedly, patients in the low-risk elafin group demonstrated a higher incidence of 6-month NRM, although the difference was not statistically significant (17% versus 11%; P = .19). OS at 6 months (68% versus 68%; P > .99) and 4-week response (78% versus 78%; P = .98) were similar in the low-risk and high-risk elafin groups. The area under the ROC curve (AUC) was 0.55 for elafin and 0.75 for the combination of ST2 and REG3α. The addition of elafin to the other 2 biomarkers did not improve the AUC. Our data indicate that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD did not predict 6-month NRM, OS, or treatment response in a multicenter population of patients treated systemically for acute GVHD. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM, and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD.
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http://dx.doi.org/10.1016/j.jtct.2021.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8671218PMC
December 2021

Immune Monitoring Assay for Extracorporeal Photopheresis Treatment Optimization After Heart Transplantation.

Front Immunol 2021 10;12:676175. Epub 2021 Aug 10.

Department of Cardiovascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany.

Background: Extracorporeal photopheresis (ECP) induces immunological changes that lead to a reduced risk of transplant rejection. The aim of the present study was to determine optimum conditions for ECP treatment by analyzing a variety of tolerance-inducing immune cells to optimize the treatment.

Methods: Ten ECP treatments were applied to each of 17 heart-transplant patients from month 3 to month 9 post-HTx. Blood samples were taken at baseline, three times during treatment, and four months after the last ECP treatment. The abundance of subsets of tolerance-inducing regulatory T cells (T) and dendritic cells (DCs) in the samples was determined by flow cytometry. A multivariate statistical model describing the immunological status of rejection-free heart transplanted patients was used to visualize the patient-specific immunological improvement induced by ECP.

Results: All BDCA DC subsets (BDCA1 DCs: p < 0.01, BDCA2 DCs: p < 0.01, BDCA3 DCs: p < 0.01, BDCA4 DCs: p < 0.01) as well as total T p < 0.01) and CD39 T p < 0.01) increased during ECP treatment, while CD62L T decreased (p < 0.01). The cell surface expression level of BDCA1 (p < 0.01) and BDCA4 (p < 0.01) on DCs as well as of CD120b (p < 0.01) on T increased during the study period, while CD62L expression on T decreased significantly (p = 0.04). The cell surface expression level of BDCA2 (p = 0.47) and BDCA3 (p = 0.22) on DCs as well as of CD39 (p = 0.14) and CD147 (p = 0.08) on T remained constant during the study period. A cluster analysis showed that ECP treatment led to a sustained immunological improvement.

Conclusions: We developed an immune monitoring assay for ECP treatment after heart transplantation by analyzing changes in tolerance-inducing immune cells. This assay allowed differentiation of patients who did and did not show immunological improvement. Based on these results, we propose classification criteria that may allow optimization of the duration of ECP treatment.
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http://dx.doi.org/10.3389/fimmu.2021.676175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383491PMC
October 2021

Risk factors for outcome after allogeneic stem cell transplantation in patients with advanced phase CML.

Bone Marrow Transplant 2021 Nov 30;56(11):2834-2841. Epub 2021 Jul 30.

University Medical Center Hamburg Eppendorf, Department of Stem Cell Transplantation, Hamburg, Germany.

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative option for patients with advanced chronic myeloid leukemia (CML). However, outcome is dismal and of short follow-up. The objective of the study was to determine long-term outcome and risk factors in patients with a history of CML Blast Crisis (BC; n = 96) or accelerated phase (n = 51) transplanted between 1990 and 2018. At transplant, patients had a median age of 39 (range 7-76) years and were in ≥CP2 (n = 70), in AP (n = 40) or in BC (n = 37) with a diagnosis-HSCT interval of median 1.9 (range 0.3-24.4) years. Overall survival (OS) amounted 34% (95% CI 22-46) and progression-free survival (PFS) 26% (95% CI 16-36) at 15 years. Adverse risk factors for OS and PFS were low CD34 count in the graft, donor age (>36 years) and BC. Cumulative incidence of Non-Relapse Mortality (NRM) was 28% (95% CI 18-38) and of relapse (RI) 43% (95% CI 33-53) at 15 years. PB-HSCT and HSCT after 2008 were favorable prognostic factors for NRM, while family donor and patient age >39 years were independently associated with higher RI. HSCT resulted in long-term OS in patients with advanced CML. OS was improved in non-BC patients, with donors ≤36 years and with higher CD34 dose in the graft.
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http://dx.doi.org/10.1038/s41409-021-01410-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563424PMC
November 2021

CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma.

Blood 2021 12;138(24):2499-2513

Department of Medicine III, University Hospital, Ludwig Maximilian University (LMU) Munich, Munich, Germany.

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell-related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (absolute neutrophil count [ANC] <100 cells per µL) neutropenia in 72% of patients and prolonged (21 days or longer) neutropenia in 64% of patients. The median duration of severe neutropenia (ANC < 500 cells per µL) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary end point. In the training cohort (n = 58), we observed a significant correlation with baseline thrombocytopenia (r = -0.43; P = .001) and hyperferritinemia (r = 0.54; P < .0001) on univariate and multivariate analysis. Incidence and severity of cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, and peak cytokine levels were not associated with the primary end point. We created the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (eg, platelet count, hemoglobin, and ANC) and baseline inflammation (eg, C-reactive protein and ferritin). This model was validated in independent cohorts, one from Europe (n = 91) and one from the United States (n = 109) and discriminated patients with severe neutropenia ≥14 days to <14 days (pooled validation: area under the curve, 0.89; sensitivity, 89%; specificity, 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs 5.5 days; P < .001) and a higher incidence of severe thrombocytopenia (87% vs 34%; P < .001) and anemia (96% vs 40%; P < .001). The score implicates bone marrow reserve and inflammation prior to CAR T-cell therapy as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.
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http://dx.doi.org/10.1182/blood.2020010543DOI Listing
December 2021

Enhanced Immune Reconstitution of γδ T Cells after Allogeneic Stem Cell Transplantation Overcomes the Negative Impact of Pretransplantation Minimal Residual Disease-Positive Status in Patients with Acute Myelogenous Leukemia.

Transplant Cell Ther 2021 10 9;27(10):841-850. Epub 2021 Jun 9.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Minimal/measurable residual disease (MRD) before allogeneic stem cell transplantation (allo-SCT) in patients with acute myelogenous leukemia (AML) is a poor risk factor for outcome. γδ T cells represent a unique minority lymphocyte population that is preferentially located in peripheral tissues, can recognize antigens in a non-MHC-restricted manner, and plays a "bridging" role between the innate and adaptive immune systems. In this study, we investigated a potential graft-versus-leukemia effect of γδ T cell reconstitution post-transplantation in AML patients with pretransplantation positive MRD status (MRD). MRD assessment was performed in 202 patients using multicolored flow cytometry ("different from normal" strategy); 100 patients were deemed MRD. Analysis for absolute concentrations of CD3, CD4+, CD8, natural killer, and γδ T cells were performed by flow cytometry according to an internal protocol at day +30 and +100 post-transplantation. Differences between categorical and continuous variables were determined using the chi-square and Student t test, respectively. The Mann-Whitney U test was used to compare medians of continuous variables. Spearman's correlation was used for nonparametric assessment of correlation between different cell subsets during immune reconstitution. Kaplan-Meier survival analysis and Cox regression analysis were used to investigate the associations between immune reconstitution and survival outcomes. Gray's analysis was used to compute incidences of relapse, nonrelapse mortality, and graft-versus-host disease (GVHD). The median follow-up of survivors was 28 months (range 3 to 59 months). Younger age (≤58 years) of recipient and donor (<30 years), sex mismatch, use of a matched donor, cytomegalovirus reactivation, and administration of antithymocyte globulin were associated with a faster γδ T cell reconstitution. In multivariable analysis for MRD patients, a higher than median level of γδ T cells on days +30 and +100 resulted in significantly improved leukemia-free survival (hazard ratio [HR], 0.42 [P = .007] and 0.42 [P = .011], respectively) and overall survival (HR, 0.44 [P = .038] and 0.33 [P = .009], respectively). Furthermore, a higher γδ T cell level on day +30 was associated with a significantly reduced risk of relapse (HR, 0.36; P = .019). No impact of γδ T cell level on relapse at days +30 and +100 could be seen in MRD-negative patients, and no correlation with occurrence of GVHD was observed. Our data indicate that enhanced immune reconstitution of γδ T cells post-transplantation may overcome the higher relapse risk of pretransplantation MRD status in patients with AML.
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http://dx.doi.org/10.1016/j.jtct.2021.06.003DOI Listing
October 2021

[Erratum to: Toxicity after chimeric antigen receptor T-cell therapy].

Internist (Berl) 2021 Jun;62(6):694

Klinik I für Innere Medizin, Hämatologie-Onkologie und Internistische Intensivmedizin, Klinikum der Universität Köln, Köln, Deutschland.

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http://dx.doi.org/10.1007/s00108-021-01087-wDOI Listing
June 2021

Axicabtagene ciloleucel in vivo expansion and treatment outcome in aggressive B-cell lymphoma in a real-world setting.

Blood Adv 2021 06;5(11):2523-2527

Department of Stem Cell Transplantation.

Data on the association between chimeric antigen receptor (CAR)-T-cell kinetics and patient outcome in the nontrial setting are missing, mainly due to the lack of broadly available CAR-T-cell diagnostic quantification tools. We performed prospective quantification of axicabtagene ciloleucel (axi-cel) in 21 patients treated for aggressive B-cell lymphoma at our clinic. Median peak CAR-T-cell count was 16.14 CAR-T cells/µL. Patients with 16.14/μL or higher peak CAR-T cells (strong expanders) had more day-30 objective responses (91% vs 40%, P = .02). In univariate analysis, peak CAR-T cell ≥ 16.14 (P < .001), normal platelet counts at start of lymphodepletion (P < .001), no prior stem cell transplant (P = .04), and peak CAR-T cells as continuous variable (P = .03) were associated with better progression-free survival (PFS). After adjusting for platelet counts and prior stem cell transplantation, peak CAR-T cells below median was still associated with shorter PFS (relative risk, 0.15, 95% confidence interval, 0.04-0.59, P = .007). Low platelet counts also maintained significant impact on PFS. Our data demonstrate association of axi-cel levels and outcome in a nontrial setting and for the first time use a cutoff to segregate weak and strong expanders with respective outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2020003959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238487PMC
June 2021

[Toxicity after chimeric antigen receptor T-cell therapy : Overview and management of early and late onset side effects].

Internist (Berl) 2021 Jun 25;62(6):611-619. Epub 2021 May 25.

Klinik I für Innere Medizin, Hämatologie-Onkologie und Internistische Intensivmedizin, Klinikum der Universität Köln, Kerpener Str. 62, 50937, Köln, Deutschland.

Background: The transfusion of chimeric antigen receptor (CAR) T‑cells has become established as a new treatment option in oncology; however, this is regularly associated with immune-mediated side effects, which can also run a severe course and necessitate a specific treatment and intensive medical treatment.

Material And Methods: A literature review was carried out on CAR T-cell therapy, toxicities and the management of side effects.

Results: The cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS) regularly occur shortly after CAR T-cell treatment. The symptoms of CRS can range from mild flu-like symptoms to multiorgan failure. In addition to mild symptoms, such as disorientation and aphasia, ICANS can also lead to convulsive seizures and brain edema. The management of CRS and ICANS is based on the severity according to the grading of the American Society for Transplantation and Cellular Therapy (ASTCT). Tocilizumab and corticosteroids are recommended for CRS and corticosteroids are used for ICANS. In the further course persisting hypogammaglobulinemia and cytopenia are frequent even months after the initial treatment and promote infections even months after CAR T‑cell therapy.

Discussion: Potentially severe complications regularly occur after CAR T-cell therapy. An interdisciplinary cooperation between intensive care physicians, hematologists, neurologists and specialists in other disciplines is of decisive importance for the optimal care of patients after CAR T‑cell therapy.
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http://dx.doi.org/10.1007/s00108-021-01046-5DOI Listing
June 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIb. The 2020 Preemptive Therapy Working Group Report.

Transplant Cell Ther 2021 08 6;27(8):632-641. Epub 2021 Apr 6.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Chronic graft-versus-host disease (GVHD) commonly occurs after allogeneic hematopoietic cell transplantation (HCT) despite standard prophylactic immune suppression. Intensified universal prophylaxis approaches are effective but risk possible overtreatment and may interfere with the graft-versus-malignancy immune response. Here we summarize conceptual and practical considerations regarding preemptive therapy of chronic GVHD, namely interventions applied after HCT based on evidence that the risk of developing chronic GVHD is higher than previously appreciated. This risk may be anticipated by clinical factors or risk assignment biomarkers or may be indicated by early signs and symptoms of chronic GVHD that do not fully meet National Institutes of Health diagnostic criteria. However, truly preemptive, individualized, and targeted chronic GVHD therapies currently do not exist. In this report, we (1) review current knowledge regarding clinical risk factors for chronic GVHD, (2) review what is known about chronic GVHD risk assignment biomarkers, (3) examine how chronic GVHD pathogenesis intersects with available targeted therapeutic agents, and (4) summarize considerations for preemptive therapy for chronic GVHD, emphasizing trial development, including trial design and statistical considerations. We conclude that robust risk assignment models that accurately predict chronic GVHD after HCT and early-phase preemptive therapy trials represent the most urgent priorities for advancing this novel area of research.
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http://dx.doi.org/10.1016/j.jtct.2021.03.029DOI Listing
August 2021

Comparison of immune reconstitution between anti-T-lymphocyte globulin and post-transplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation.

Haematologica 2021 Apr 8. Epub 2021 Apr 8.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg.

Anti T-cell lymphocyte globulin (ATLG) and post-transplant cyclophosphamide (PTCy) are now widely used strategies to prevent graft-versus-host disease after allogeneic stem cell transplantation. Data comparing immune reconstitution (IR) between ATLG and PTCy is scarce. This retrospective study conducted at the University Medical-Center Hamburg- Eppendorf (UKE) compares after myeloablative PBSC allogeneic stem cell transplant between PTCy (n=123) and ATLG (n=476). Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 100 and 180 posttransplant. Incidence of infections, viral reactivations graft-versus-host disease and relapse were collected. Neutrophil engraftment was significantly delayed in the PTCy group (median day 12 vs. 10, p < 0.001) with a high incidence of infection before day+100 in the PTCy arm but a higher EBV reactivation in the ATLG arm and comparable CMV reactivation. Overall incidence of acute GVHD was similar but moderate/severe chronic GVHD was more seen after PTCy (44% vs. 38%, p = 0.005). ATLG resulted in a faster reconstitution of CD8+ T-cells, NK cells, NKT cells, and γδT cells while CD4 T-cells and B-cells reconstituted faster after PTCy. Similar reconstitution was observed for T-regulatory cells and B-cells. NRM, relapse incidence, DFS, and overall survival did not differ significantly between both arms. Even though difference in IR have been translated into decreased incidence of infections and moderate/severe cGVHD in the ATLG group they had no impact on any of the other longterm outcomes. However, it remains undetermined which regimen is better as graft-versushost disease prophylaxis.
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http://dx.doi.org/10.3324/haematol.2020.271445DOI Listing
April 2021

TKI Maintenance After Stem-Cell Transplantation for -ITD Positive Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis.

Front Immunol 2021 12;12:630429. Epub 2021 Mar 12.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

This analysis aimed to systematically review and synthesize the existing evidence regarding the outcome of tyrosine kinase inhibitor (TKI) maintenance therapy after allogeneic stem-cell transplantation for patients with -ITD-mutated acute myeloid leukemia (AML). We searched publicly available databases, references lists of relevant reviews, registered trials, and relevant conference proceedings. A total of 7 studies comprising 680 patients were included. Five studies evaluated sorafenib and 2 studies evaluated midostaurin, compared with control. The incidence of relapse was significantly reduced after TKI therapy, showing an overall pooled risk ratio (RR) of 0.35 (95% confidence interval [CI], 0.23-0.51; < 0.001), with a marked 65% reduced risk for relapse. The overall pooled RR for relapse-free survival and overall survival showed significantly improved outcome after TKI maintenance therapy, being 0.48 (95% CI, 0.37-0.61; < 0.001) and 0.48 (95% CI, 0.36-0.64; < 0.001). The risk for relapse or death from any cause was reduced by 52% using TKI. No difference in outcome was seen for non-relapse mortality, and the risk for chronic or acute graft-vs. -host disease appeared to be increased, at least for sorafenib. In conclusion, post-transplant maintenance therapy with TKI was associated with significantly improved outcome in relapse and survival in patients with -ITD positive AML.
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http://dx.doi.org/10.3389/fimmu.2021.630429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006462PMC
September 2021

Hepatitis E virus persists in the ejaculate of chronically infected men.

J Hepatol 2021 07 20;75(1):55-63. Epub 2021 Jan 20.

I. Department of Medicine, Gastroenterology and Hepatology, with the Sections Infectious Diseases and Tropical Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Heidelberg Partner sites, Germany.

Background & Aims: Hepatitis E virus (HEV) infections are prevalent worldwide. Various viruses have been detected in the ejaculate and can outlast the duration of viremia, indicating replication beyond the blood-testis barrier. HEV replication in diverse organs, however, is still widely misunderstood. We aimed to determine the occurrence, features and morphology of HEV in the ejaculate.

Methods: The presence of HEV in testis was assessed in 12 experimentally HEV-genotype 3-infected pigs. We further tested ejaculate, urine, stool and blood from 3 chronically HEV genotype 3-infected patients and 6 immunocompetent patients with acute HEV infection by HEV-PCR. Morphology and genomic characterization of HEV particles from various human compartments were determined by HEV-PCR, density gradient measurement, immune-electron microscopy and genomic sequencing.

Results: In 2 of the 3 chronically HEV-infected patients, we observed HEV-RNA (genotype 3c) in seminal plasma and semen with viral loads >2 logs higher than in the serum. Genomic sequencing showed significant differences between viral strains in the ejaculate compared to stool. Under ribavirin-treatment, HEV shedding in the ejaculate continued for >9 months following the end of viremia. Density gradient measurement and immune-electron microscopy characterized (enveloped) HEV particles in the ejaculate as intact.

Conclusions: The male reproductive system was shown to be a niche of HEV persistence in chronic HEV infection. Surprisingly, sequence analysis revealed distinct genetic HEV variants in the stool and serum, originating from the liver, compared to variants in the ejaculate originating from the male reproductive system. Enveloped HEV particles in the ejaculate did not morphologically differ from serum-derived HEV particles.

Lay Summary: Enveloped hepatitis E virus particles could be identified by PCR and electron microscopy in the ejaculate of immunosuppressed chronically infected patients, but not in immunocompetent experimentally infected pigs or in patients with acute self-limiting hepatitis E.
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http://dx.doi.org/10.1016/j.jhep.2020.12.030DOI Listing
July 2021

Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin.

Blood Adv 2020 12;4(24):6098-6105

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept "preemptive" treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.
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http://dx.doi.org/10.1182/bloodadvances.2020003336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756981PMC
December 2020

Treosulfan-Based Conditioning Regimen for Second Allograft in Patients with Myelofibrosis.

Cancers (Basel) 2020 Oct 23;12(11). Epub 2020 Oct 23.

Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36-42 g/m) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related ( = 2), unrelated ( = 23), or mismatched unrelated ( = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II-IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease.
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http://dx.doi.org/10.3390/cancers12113098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690833PMC
October 2020

Incidence and Outcome of Late Relapse after Allogeneic Stem Cell Transplantation for Myelofibrosis.

Biol Blood Marrow Transplant 2020 12 17;26(12):2279-2284. Epub 2020 Sep 17.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

In this cross-sectional study, we retrospectively evaluated the files of 227 patients with myelofibrosis who underwent transplantation between 1994 and 2015 for relapse later than 5 years after allogeneic stem cell transplantation (SCT). A total of 94 patients who were alive and in remission at 5 years were identified with follow-up of at least 5 years (median, 9.15 years) after SCT. Thirteen patients (14%) experienced late molecular (n = 6) or hematologic (n = 7) relapse at a median of 7.1 years while 81 patients did not experience relapse. Relapse patients received either donor lymphocyte infusion (DLI) (n = 7) and/or second transplantation (n = 4). Of those, 72.7% achieved again full donor cell chimerism and molecular remission, and after a median follow-up of 45 months, the 3-year overall survival rates for patients with or without relapse were 90.9% (95% confidence interval [CI], 77% to 100%) and 98.8% (95% CI, 96% to 100%), respectively (P = .13). We conclude that late relapse occurs in about 14% of the patients and the majority can be successfully salvaged with DLI and/or second allograft. All patients with molecular relapse are alive and support the long-time molecular monitoring in myelofibrosis patients after allogeneic SCT.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.006DOI Listing
December 2020

1,25-dihydroxyvitamin-D3 but not the clinically applied marker 25-hydroxyvitamin-D3 predicts survival after stem cell transplantation.

Bone Marrow Transplant 2021 02 27;56(2):419-433. Epub 2020 Aug 27.

Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center of Regensburg, Regensburg, Germany.

The serum level of 25-hydroxyvitamin-D3 is accepted as marker for a person's vitamin D status but its role for the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is controversially discussed. The impact of 1,25-dihydroxyvitamin-D3 on HSCT outcome, however, has never been studied. In a discovery cohort of 143 HSCT patients we repeatedly (day -16 to 100) measured 1,25-dihydroxyvitamin-D3 and in comparison the well-established marker for serum vitamin D status 25-hydroxyvitamin-D3. Only lower 1,25-dihydroxyvitamin-D3 levels around HSCT (day -2 to 7, peritransplant) were significantly associated with higher 1-year treatment-related mortality (TRM) risk (Mann-Whitney U test, P = 0.001). This was confirmed by Cox-model regression without and with adjustment for baseline risk factors and severe acute Graft-versus-Host disease (aGvHD; unadjusted P = 0.001, adjusted P = 0.005). The optimal threshold for 1,25-dihydroxyvitamin-D3 to identify patients at high risk was 139.5 pM. Also in three replication cohorts consisting of altogether 365 patients 1,25-dihydroxyvitamin-D3 levels below 139.5 pM had a 3.3-fold increased risk of TRM independent of severe aGvHD compared to patients above 139.5 pM (Cox-model unadjusted P < 0.0005, adjusted P = 0.001). Our data highlight peritransplant 1,25-dihydroxyvitamin-D3 levels but not the commonly monitored 25-hydroxyvitamin-D3 levels as potent predictor of 1-year TRM and suggest to monitor both vitamin D metabolites in HSCT patients.
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http://dx.doi.org/10.1038/s41409-020-01031-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870805PMC
February 2021

Allogeneic Stem Cell Transplantation for Patients with Lower-Risk Myelodysplastic Syndrome.

Biol Blood Marrow Transplant 2020 11 24;26(11):2047-2052. Epub 2020 Jul 24.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The indication for allogeneic stem cell transplantation (SCT) in patients with lower-risk myelodysplastic syndrome (MDS) is controversial. Here we report 60 patients with a low risk (n = 32) or intermediate risk (n = 28) classification according to the revised International Prognostic Scoring System (IPSS-R) who underwent allogeneic SCT with a reduced-intensity conditioning (n = 45) or myeloablative conditioning (n = 15) regimen from an HLA-identical sibling (n = 9), a matched unrelated donor (n = 36), or a mismatched unrelated donor (n = 15). The rates of grade II-IV and grade III-IV acute graft-versus-host disease were 32% and 7%, respectively, resulting in a transplantation-related mortality (TRM) of 17% at 3 years. The cumulative incidence of relapse at 5 years was only 7%, resulting in a 5-year disease-free survival of 72% and overall survival (OS) of 79%. Transplantation from a fully matched donor resulted in significantly improved OS at 5 years (91% versus 70%). Allogeneic SCT in lower-risk MDS (IPSS-R low or intermediate risk) from an HLA-matched donor resulted in excellent OS with a low risk of relapse.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.018DOI Listing
November 2020

Accurate In-Vivo Quantification of CD19 CAR-T Cells after Treatment with Axicabtagene Ciloleucel (Axi-Cel) and Tisagenlecleucel (Tisa-Cel) Using Digital PCR.

Cancers (Basel) 2020 Jul 20;12(7). Epub 2020 Jul 20.

Department of Stem Cell Transplantation, University Medical Centre (UMC) Hamburg-Eppendorf, 20246 Hamburg, Germany.

Immunotherapy with CD19-specific chimeric antigen receptor (CAR-) T cells has shown excellent efficacy in relapsed/refractory B-cell cancers. The in vivo expansion and persistence of CAR-T cells after infusion are important response- and toxicity-determining variables, but diagnostic tools are largely missing. We showed previously for axi-cel that digital PCR (dPCR) is excellently suited to monitoring CAR-T cells in vivo. Here, we aimed to develop an analogous dPCR assay for tisa-cel. To do so, we cloned and sequenced the CAR construct from the lentiviral tisa-cel vector and designed primers and Black hole quencher (BHQ) probes complimentary to sequences present in the FMC63 scFv part of axi-cel (assay A), tisa-cel (T), and both constructs (U = "universal"). In conjunction with excellent specificity, all assays have a detection limit of one single CAR copy, corresponding to a sensitivity of approximately 1 in 5000 cells (0.02%) for 100 ng genomic DNA (for one vector copy per transduced cell). The new universal assay was first validated using patient samples previously quantified with the axi-cel-specific dPCR and thereafter applied to quantify and monitor adoptively transferred axi-cel and tisa-cel T cells in post-infusion samples (peripheral blood, bone marrow, liquor, and ascites). Actual CAR-T counts per µl were calculated, taking into account vector copy and peripheral blood mononuclear cell (PBMC) numbers, and showed very good correlation with flow cytometry results. We conclude that our novel dPCR assay is optimally suited to monitoring tisa-cel and axi-cel CAR-T cells in real-time in various body fluids.
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http://dx.doi.org/10.3390/cancers12071970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409173PMC
July 2020

Development of CAR-T cell therapies for multiple myeloma.

Leukemia 2020 09 22;34(9):2317-2332. Epub 2020 Jun 22.

Department of Stem Cell Transplantation with Research Department Cell and Gene Therapy University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Currently available data on chimeric antigen receptor (CAR)-T cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated multiple myeloma (MM) patients. The CAR-T field in MM is rapidly evolving with >50 currently ongoing clinical trials across all phases, different CAR-T design, or targets. Most of the CAR-T trials are performed in China and the United States, while European centers organize or participate in only a small fraction of current clinical investigations. Autologous CAR-T cell therapy against B cell maturation antigen shows the best evidence of efficacy so far but main issues remain to be addressed: duration of response, longer follow-up, prolonged cytopenia, patients who may benefit the most such as those with extramedullary disease, outcome prediction, and the integration of CAR-T cell therapy within the MM treatment paradigm. Other promising targets are, i.a.,: CD38, SLAMF7/CS1, or GPRC5D. Although no product has been approved to date, cost and production time for autologous products are expected to be the main obstacles for broad use, for which reason allogeneic CAR-T cells are currently explored. However, the inherent risk of graft-versus-host disease requires additional modification which still need to be validated. This review aims to present the current status of CAR-T cell therapy in MM with an overview on current targets, designs, and stages of CAR-T cell development. Main challenges to CAR-T cell therapy will be highlighted as well as strategies to structurally improve the CAR-T cell product, and thereby its efficacy and safety. The need for comparability of the most promising therapies will be emphasized to balance risks and benefits in an evidence-based but personalized approach to further improve outcome of patients with MM.
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http://dx.doi.org/10.1038/s41375-020-0930-xDOI Listing
September 2020

Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans.

Blood 2020 09;136(12):1442-1455

Department of Medicine I, Faculty of Medicine, Medical Center University of Freiburg (MCUF).

Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2-based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.
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http://dx.doi.org/10.1182/blood.2020005957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498363PMC
September 2020

Ruxolitinib plus extracorporeal photopheresis (ECP) for steroid refractory acute graft-versus-host disease of lower GI-tract after allogeneic stem cell transplantation leads to increased regulatory T cell level.

Bone Marrow Transplant 2020 12 23;55(12):2286-2293. Epub 2020 May 23.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Acute graft-versus-host disease (aGVHD) is a serious complication after stem cell transplantation and is associated with high non-relapse mortality. If steroid treatment as first-line therapeutic approach fails, treatment options are limited. In retrospective studies, ruxolitinib, a selective Janus kinase 1/2 inhibitor as well as extracorporeal photopheresis (ECP) could show high efficacy in treatment of steroid refractory acute and chronic GVHD. Here, we report single-center experience of combining JAK-inhibitor treatment with ECP in 18 patients with severe steroid refractory aGVHD of lower GI-tract. The treatment was well tolerated and no severe cytopenia (grade IV) occurred, in three patients grade III cytopenia could be observed. Response was complete or partial in 44% and 11%, respectively, resulting in an estimated 2 year overall survival of 56%. Steroids were tapered rapidly with a median time of 2 days for halving of dosage avoiding additional steroid-associated side effects. Under treatment with ruxolitinib and ECP, an increased level of regulatory T cells could be observed elucidating direct effects of this treatment on immune response.
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http://dx.doi.org/10.1038/s41409-020-0952-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376644PMC
December 2020

Excellent proliferation and persistence of allogeneic donor-derived 41-BB based CAR-T cells despite immunosuppression with cyclosporine A.

Haematologica 2020 06 2;105(6):322-324. Epub 2020 Apr 2.

Department of Stem Cell Transplantation with Research Department Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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http://dx.doi.org/10.3324/haematol.2019.245969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271598PMC
June 2020

Monocenter study on epidemiology, outcomes, and risk factors of infections in recipients of 166 allogeneic stem cell transplantations during 1 year.

Eur J Haematol 2020 Aug 28;105(2):126-137. Epub 2020 May 28.

Department of Stem Cell Transplantation, University Medical Center Eppendorf, Hamburg, Germany.

Objectives: During allogeneic hematopoietic stem cell transplantation (allo-SCT), infections significantly contribute to morbidity and mortality. A monocentric prospective analysis was performed to assess epidemiology, risk factors, and outcomes of infections during the peri-transplant period.

Methods: Data were recorded prospectively using a predefined questionnaire.

Results: In 2015, 163 consecutive patients, 37.4% female, median age 59 (range 18-79) years received 166 allo-SCT. Median duration of leukopenia <10 /L was 14.5 days (range 4-43 days). Fever of unknown origin (FUO) occurred in 118/166 patients (71.1%). Severe sepsis developed in 95, and septic shock developed in 26 patients. Intensive diagnostic workup helped to identify causative microorganisms only in a small number of infectious courses. All but 13 patients needed antibiotic therapy, each according to the standard operating procedures of the department. Cumulative incidence of death by infection after 1 year was 16.6% (95% CI: 11.3-22.7). The only risk factor for FUO in neutropenia was duration of neutropenia
Conclusion: Results of an elaborate diagnostic workup of infections in the peri-transplant period are scarce. Attention to risk factors might help to identify patients at risk for severe infections.
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http://dx.doi.org/10.1111/ejh.13416DOI Listing
August 2020
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