Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients undergoing chemotherapy—evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO)

We found convincing evidence from numerous randomised controlled trials that G-CSF, biosimilar G-CSF and pegfilgrastim reduce the risk to develop febrile neutropenia and infections. As a rule of thumb, it seems the relative benefit is highest for patients with an intermediate risk of infections. Compared to other guidelines, we rated the evidence for growth factors during AML induction chemotherapy and pegfilgrastim use in haematological malignancies lowe

Acute Graft-vs.-Host Disease-Associated Endothelial Activation in vitro Is Prevented by Defibrotide

Altres ajuts: This study was supported in part by Jazz Pharmaceuticals Plc (IST-16-10355), German Jose Carreras Leukaemia Foundation (11R/2016 and 03R/2019).Angiogenesis and endothelial activation and dysfunction have been associated with acute graft-vs.-host disease (aGVHD), pointing to the endothelium as a potential target for pharmacological intervention. Defibrotide (DF) is a drug with an endothelium-protective effect that has been approved for the treatment of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Clinical data suggest that DF also reduces the incidence of aGVHD; however, the mechanisms of DF-mediated aGVHD regulation have not been examined. To investigate possible DF-mediated prophylactic and therapeutic mechanisms in aGVHD, we performed in vitro studies using endothelial cell (EC) lines. We found that DF significantly and dose-dependently suppressed EC proliferation and notably reduced their ability to form vascular tubes in Matrigel. To explore whether DF administered prophylactically or therapeutically has a significant effect on aGVHD endothelial dysfunction, ECs were exposed to media containing sera from patients with aGVHD (n = 22) in the absence or presence of DF and from patients that did not develop aGVHD (n = 13). ECs upregulated adhesion molecules (vascular cell adhesion molecule 1, intercellular adhesion molecule 1), the adherence junction protein VE-cadherin, von Willebrand factor (VWF), and Akt phosphorylation in response to aGVHD sera. These responses were suppressed upon treatment with DF. In summary, DF inhibits vascular angiogenesis and endothelial activation induced by sera from aGVHD patients. Our results support the view that DF has notable positive effects on endothelial biology during aGVHD

EASIX and severe endothelial complications after CD19-directed CAR-T Cell therapy-a cohort study

BACKGROUND: Endothelial dysfunction is associated with two main complications of chimeric antigen receptor T (CAR-T) cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This study evaluates the Endothelial Activation and Stress Index (EASIX) as a prognostic marker for high-grade CRS and ICANS in patients treated with CD19-directed CAR-T cells. METHODS: In this retrospective study, a training cohort of 93 patients from the ZUMA-1 trial and a validation cohort of 121 patients from two independent centers (University Hospital Heidelberg, Charité University Medicine Berlin) were investigated. The primary objective was to assess the predictive capacity of EASIX measured immediately before the start of lymphodepletion (EASIX-pre) for the occurrence of grade =3 CRS and/or ICANS. To explore a possible endothelial link, serum levels of endothelial stress markers (angiopoietin-2, suppressor of tumorigenicity-2, soluble thrombomodulin, and interleukin-8) were determined before lymphodepletion and on day 7 after CART infusion in the validation cohort (n = 47). RESULTS: The prognostic effect of EASIX-pre on grade =3 CRS and/or ICANS was significant in the training cohort [OR 2-fold increase 1.72 (1.26-2.46)] and validated in the independent cohort. An EASIX-pre cutoff >4.67 derived from the training cohort associated with a 4.3-fold increased odds ratio of severe CRS/ICANS in the independent cohort. Serum endothelial distress markers measured on day+7 correlated with EASIX-pre and associated with severe complications. CONCLUSIONS: EASIX-pre is a powerful predictor of severe CRS/ICANS after CD19-directed CART therapy and might be used as a basis for risk-adapted prevention strategies

Paired donor and recipient immunophenotyping in allogeneic hematopoietic stem cell transplantation: a cellular network approach

Success and complications of allogeneic hematopoietic stem cell transplantation (alloHSCT) are closely connected to the transferred graft and immune reconstitution post alloHSCT. Due to the variety of immune cells and their distinct roles, a broad evaluation of the immune cellular network is warranted in mobilization and reconstitution studies in alloHSCT. Here, we propose a comprehensive phenotypic analysis of 26 immune cell subsets with multicolor flow cytometry from only 100µl whole blood per time point. Using this approach, we provide an extensive longitudinal analysis of almost 200 time points from 21 donor-recipient pairs. We observe a broad mobilization of innate and adaptive immune cell subsets after granulocyte-colony stimulating factor (G-CSF) treatment of healthy donors. Our data suggest that the relative quantitative immune cell subset composition in recipients approaches that of healthy donors from day +180 post alloHSCT onwards. Correlation of donor and recipient cell counts reveals distinct association patterns for different immune cell subsets and hierarchical clustering of recipient cell counts identifies distinct reconstitution groups in the first month after transplantation. We suggest our comprehensive immune subset analysis as a feasible and time efficient approach for a broad immune assessment for future clinical studies in the context of alloHSCT. This comprehensive cell composition assessment can be a critical step towards personalized graft composition strategies and individualized therapy management in areas such as GvHD prophylaxis in the highly complex immunological setting of alloHSCT

Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT - A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party

Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies. This prospective multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point was determined at 1500 mu g/l (median of measured ferritin levels). In alloSCT recipients with ferritin levels above cut off measured before the start of conditioning, overall survival (HR = 2.5, CI = 1.5-4.1, p = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6-3.8, p <0.0001) were inferior. Excess mortality in the high ferritin group was due to both higher relapse incidence (HR = 2.2, CI = 1.2-3.8, p = 0.007) and increased non-relapse mortality (NRM) (HR = 3.1, CI = 1.5-6.4, p = 0.002). NRM was driven by significantly higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6-9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.Peer reviewe

Diagnosis and management of secondary HLH/MAS following HSCT and CAR-T cell therapy in adults; a review of the literature and a survey of practice within EBMT centres on behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP)

Introduction: Secondary haemophagocytic lymphohistiocytosis (sHLH) or Macrophage Activation Syndrome (MAS) is a life-threatening hyperinflammatory syndrome that can occur in patients with severe infections, malignancy or autoimmune diseases. It is also a rare complication of haematopoetic stem cell transplantation (HSCT), with a high mortality. It may be associated with graft vs. host disease in the allogeneic HSCT setting. It is also reported following CAR-T cell therapy, but differentiation from cytokine release syndrome (CRS) is challenging. Here, we summarise the literature and present results of a survey of current awareness and practice in EBMT-affiliated centres of sHLH/MAS following HSCT and CAR-T cell therapy. Methods: An online questionnaire was sent to the principal investigators of all EBMT member transplant centres treating adult patients (18 years and over) inviting them to provide information regarding: number of cases of sHLH/MAS seen in their centre over 3 years (2016–2018 inclusive); screening strategies and use of existing diagnostic/classification criteria and treatment protocols. Results: 114/472 centres from 24 different countries responded (24%). We report estimated rates of sHLH/MAS of 1.09% (95% CI = 0.89–1.30) following allogeneic HSCT, 0.15% (95% CI = 0.09–5.89) following autologous HSCT and 3.48% (95% CI = 0.95–6.01) following CAR-T cell therapy. A majority of centres (70%) did not use a standard screening protocol. Serum ferritin was the most commonly used screening marker at 78% of centres, followed by soluble IL-2 receptor (24%), triglycerides (15%), and fibrinogen (11%). There was significant variation in definition of “clinically significant” serum ferritin levels ranging from 500 to 10,000 μg/mL. The most commonly used criteria to support diagnosis were HLH-2004 (43%) and the H score (15%). Eighty percent of responders reported using no standard management protocol, but reported using combinations of corticosteroids, chemotherapeutic agents, cytokine blockade, and monoclonal antibodies. Conclusions: There is a remarkable lack of consistency between EBMT centres in the approach to screening, diagnosis and management. Further research in this field is needed to raise awareness of and inform harmonised, evidence-based approaches to the recognition and treatment of sHLH/MAS following HSCT/CAR-T cell therapy

Single-cell clonal tracking of persistent T-cells in allogeneic hematopoietic stem cell transplantation

The critical balance between intended and adverse effects in allogeneic hematopoietic stem cell transplantation (alloHSCT) depends on the fate of individual donor T-cells. To this end, we tracked αβT-cell clonotypes during stem cell mobilization treatment with granulocyte-colony stimulating factor (G-CSF) in healthy donors and for six months during immune reconstitution after transfer to transplant recipients. More than 250 αβT-cell clonotypes were tracked from donor to recipient. These clonotypes consisted almost exclusively of CD8+ effector memory T cells (CD8TEM), which exhibited a different transcriptional signature with enhanced effector and cytotoxic functions compared to other CD8TEM. Importantly, these distinct and persisting clonotypes could already be delineated in the donor. We confirmed these phenotypes on the protein level and their potential for selection from the graft. Thus, we identified a transcriptional signature associated with persistence and expansion of donor T-cell clonotypes after alloHSCT that may be exploited for personalized graft manipulation strategies in future studies