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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel virus that spread worldwide from 2019 causing the Coronavirus disease 19 (COVID-19) pandemic. SARS-CoV-2 infection is characterised by an initial viral phase followed in some patients by a severe inflammatory phase. Importantly, immunocompromised patients may have a prolonged viral phase, shedding infectious viral particles for months, and absent or dysfunctional inflammatory phase. Among haematological patients, COVID-19 has been associated with high mortality rate in acute leukaemia, high risk-myelodysplastic syndromes, and after haematopoietic cell transplant and chimeric-antigen-receptor-T therapies. The clinical symptoms and signs were similar to that reported for the overall population, but the severity and outcome were worse. The deferral of immunodepleting cellular therapy treatments is recommended for SARS-CoV-2 positive patient, while in the other at-risk cases, the haematological treatment decisions must be weighed between individual risks and benefits. The gold standard for the diagnosis is the detection of viral RNA by nucleic acid testing on nasopharyngeal-swabbed sample, which provides high sensitivity and specificity; while rapid antigen tests have a lower sensitivity, especially in asymptomatic patients. The prevention of SARS-CoV-2 infection is based on strict infection control measures recommended for aerosol-droplet-and-contact transmission. Vaccinations against SARS-CoV-2 has shown high efficacy in reducing community transmission, hospitalisation and deaths due to severe COVID-19 disease in the general population, but immunosuppressed/haematology patients may have lower sero-responsiveness to vaccinations. Moreover, the recent emergence of new variants may require vaccine modifications and strategies to improve efficacy in these vulnerable patients. Beyond supportive care, the specific treatment is directed at viral replication control (antivirals, anti-spike monoclonal antibodies) and, in patients who need it, to the control of inflammation (dexamethasone, anti-Il-6 agents, and others). However, the benefit of all these various prophylactic and therapeutic treatments in haematology patients deserves further studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Information on incidence, and factors associated with mortality is a prerequisite to improve outcome after hematopoietic stem cell transplantation (HSCT). Therefore, 55'668 deaths in 114'491 patients with HSCT (83.7% allogeneic) for leukemia were investigated in a landmark analysis for causes of death at day 30 (very early), day 100 (early), at 1 year (intermediate) and at 5 years (late). Mortality from all causes decreased from cohort 1 (1980-2001) to cohort 2 (2002-2015) in all post-transplant phases after autologous HSCT. After allogeneic HSCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, increased at 5 years; deaths from relapse increased in all post-transplant phases. Infections of unknown origin were the main cause of infectious deaths. Lethal bacterial and fungal infections decreased from cohort 1 to cohort 2, not unknown or mixed infections. Infectious deaths were associated with patient-, disease-, donor type, stem cell source, center, and country- related factors. Their impact varied over the post-transplant phases. Transplant centres have successfully managed to reduce death after HSCT in the early and intermediate post-transplant phases, and have identified risk factors. Late post-transplant care could be improved by focus on groups at risk and better identification of infections of "unknown origin".

Cytomegalovirus is one of the most important infections to occur after allogeneic haematopoietic stem cell transplantation (HSCT), and an increasing number of reports indicate that cytomegalovirus is also a potentially important pathogen in patients treated with recently introduced drugs for hematological malignancies. Expert recommendations have been produced by the 2017 European Conference on Infections in Leukaemia (ECIL 7) after a review of the literature on the diagnosis and management of cytomegalovirus in patients after HSCT and in patients receiving other types of therapy for haematological malignancies. These recommendations cover diagnosis, preventive strategies such as prophylaxis and pre-emptive therapy, and management of cytomegalovirus disease. Antiviral drugs including maribavir and letermovir are in development and prospective clinical trials have recently been completed. However, management of patients with resistant or refractory cytomegalovirus infection or cytomegalovirus disease is a challenge. In this Review we summarise the reviewed literature and the recommendations of the ECIL 7 for management of cytomegalovirus in patients with haematological malignancies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Donor cell leukaemia (DCL) is a rare complication of allogeneic haematopoietic cell transplantation (HCT). We have investigated the prevalence and outcome of donor cell haematology malignancies within centres registered with the European Society of Blood and Marrow transplantation (EBMT). We have sought to identify risk factors to shed light on the pathogenesis of DCL as a model for leukaemogenesis. DCL cases were identified by questionnaire and a follow-up questionnaire requested detailed data. Control subjects from the EBMT registry who had not developed DCL were used for a matched pair analysis to identify risk factors. We identified 38 patients with DCL; the estimated prevalence was 80.5/100,000 transplants. Patients were predominantly treated for haematological malignancy. A clone was retrospectively identified in 7/25 (28%) donors for whom data was available. Overall survival was poor with 29/38 patients dead a median of 11 (range 0-91) months after DCL diagnosis. Matched case-pair analysis identified three factors on multivariate analysis as significantly associated with an increased risk for DCL: use of growth factors within the first 100 days after transplantation, in vivo T-cell depletion and multiple allografts. The risk factors identified, support reduced immune surveillance and replicative stress as pathogenic in the development of DCL.

The role of donor CMV serostatus in the setting of non T-cell depleted haplo-HSCT with post-transplant cyclophosphamide (PT-Cy) has not been specifically addressed so far. Here we analyzed the impact of the donor CMV serological status on the outcome of 983 CMV seropositive (CMV+), acute leukemia patients receiving a first, non T-cell depleted haplo-HSCT registered in the EBMT database. The 1-year NRM was 21.3% (95% CI: 18.4-24.8) and 18.8% (95% CI: 13.8-25.5) in the CMV D+/R+ and D-/R+ pairs, respectively (p = 0.40). Similarly, 1-year OS was 55.1% (95% CI: 50.1-58.0) and 55.7% (95% CI: 48.0-62.8) in the same groups (p = 0.50). The other main outcomes were comparable. No difference in NRM nor OS was observed after stratification for the intensity of conditioning and multivariate anaysis confirmed the lack of significant association with NRM or OS. In conclusion, the choice of a CMV-seronegative donor did not impair early survival of CMV-seropositive patients with acute leukemia after a first, non T-cell depleted haploidentical HSCT and PT-Cy among this series of 983 consecutive patients. Future research may focus on the assessment of the hierarchy of all the donor variables.

Viral hepatitis affects millions of people worldwide, and host immunity is the key determinant of patient outcome. Viral hepatitis can be life threatening in patients with haematological malignancy, including haemopoietic stem cell transplant recipients, because of the virus itself, or through a need to decrease the dose of chemotherapy. A past or currently infected haemopoietic stem cell donor could also transmit viral hepatitis. The burden of viral hepatitis in patients with haematological malignancies and the weak evidence on which previous guidelines are based has prompted the European Conference on Infection in Leukaemia (ECIL-5) to convene a group of experts in the fields of viral hepatitis and of haematological malignancy to specifically address previously unconsidered issues and grade the available quality of evidence according to the Infectious Diseases Society of America grading system. The group recommends that all patients should be screened for hepatotropic viruses before haematological treatment and that patients or haemopoietic stem cell donors with markers of past or current viral hepatitis should be assessed by an expert. Screening, vaccination, and treatment rules are reported in this Review., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Acute and latent human CMV cause profound changes in the NK cell repertoire, with expansion and differentiation of educated NK cells expressing self-specific inhibitory killer cell Ig-like receptors. In this study, we addressed whether such CMV-induced imprints on the donor NK cell repertoire influenced the outcome of allogeneic stem cell transplantation. Hierarchical clustering of high-resolution immunophenotyping data covering key NK cell parameters, including frequencies of CD56(bright), NKG2A(+), NKG2C(+), and CD57(+) NK cell subsets, as well as the size of the educated NK cell subset, was linked to clinical outcomes. Clusters defining naive (NKG2A(+)CD57(-)NKG2C(-)) NK cell repertoires in the donor were associated with decreased risk for relapse in recipients with acute myeloid leukemia and myelodysplastic syndrome (hazard ratio [HR], 0.09; 95% confidence interval [CI]: 0.03-0.27; p < 0.001). Furthermore, recipients with naive repertoires at 9-12 mo after hematopoietic stem cell transplantation had increased disease-free survival (HR, 7.2; 95% CI: 1.6-33; p = 0.01) and increased overall survival (HR, 9.3; 95% CI: 1.1-77, p = 0.04). Conversely, patients with a relative increase in differentiated NK cells at 9-12 mo displayed a higher rate of late relapses (HR, 8.41; 95% CI: 6.7-11; p = 0.02), reduced disease-free survival (HR, 0.12; 95% CI: 0.12-0.74; p = 0.02), and reduced overall survival (HR, 0.07; 95% CI: 0.01-0.69; p = 0.02). Thus, our data suggest that naive donor NK cell repertoires are associated with protection against leukemia relapse after allogeneic HSCT., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Background: The etiology of bacteremia in hematological patients with febrile neutropenia differs geographically and changes over time. Since efficient empirical antibiotic treatment depends on relevant knowledge of the bacterial panorama, the aim of this study was to describe the prevalence of bacteremia, the bacterial spectrum, and the resistance patterns of the isolates in this group today., Methods: In a cross-sectional study, routine blood cultures from febrile episodes occurring in adult patients with hematological disorders and neutropenia presenting to Karolinska University Hospital, Stockholm, Sweden during a 24-month period, were analyzed., Results: A total of 142 febrile neutropenic episodes occurring in 124 hematological patients were included in the study. Bacteremia was documented in 27% of the episodes, and of these, 58% were due to Gram-positive pathogens. The most common isolates were viridans streptococci, coagulase-negative staphylococci, and Escherichia coli. Low levels of antibiotic resistance were detected. The underlying diagnosis of non-Hodgkin's lymphoma (NHL) was independently negatively associated with documented bacteremia (p < 0.01)., Conclusions: The prevalence of bacteremia and the bacterial spectrum were consistent with recent Scandinavian reports. Substantially lower levels of antimicrobial resistance were registered compared to those found in other European centers. Patients with NHL were less likely to have documented bacteremia in this study.

Thirty-one patients treated with mesenchymal stromal cells (MSCs) for acute graft-versus-host disease (aGVHD) or hemorrhagic cystitis between 2002 and 2007 were followed to investigate predictors of outcome, immunologic effects in vivo, and long-term survival. There was no correlation between in vitro suppression by MSCs in mixed lymphocyte cultures and outcome. Soluble IL-2 receptors were measured in blood before and after MSC infusion and declined significantly during the first week after MSC infusion (P = .03). Levels of interleukin-6 and HLA-G were unaffected. Infectious complications occurred several years after recovery from aGVHD. Cytomegalovirus viral load was high, and cytomegalovirus disease was common. Among patients recovering from aGVHD, 54% died of late infections, between 4 months and 2 years after MSC treatment. No increase in leukemia relapse or graft rejection was found. Children had a better survival rate than adults (P = .005). In GVHD patients, 1-year survival was 75% in patients who received early-passage MSCs (from passages 1-2) in contrast to 21% using later passage MSCs (from passages 3-4) (P < .01). We conclude that treatment with early-passage MSCs improved survival in patients with therapy-resistant GVHD. Death from infection was common in MSC-treated patients, but there was no increase in leukemia relapse., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The only way to cure leukemia is by cooperative research. To optimize research, the European LeukemiaNet integrates 105 national leukemia trial groups and networks, 105 interdisciplinary partner groups and about 1,000 leukemia specialists from 175 institutions. They care for tens of thousands of leukemia patients in 33 countries across Europe. Their ultimate goal is to cure leukemia. Since its inception in 2002, the European LeukemiaNet has steadily expanded and has unified leukemia research across Europe. The European LeukemiaNet grew from two major roots: 1) the German Competence Network on Acute and Chronic Leukemias; and 2) the collaboration of European Investigators on Chronic Myeloid Leukemia. The European LeukemiaNet has improved leukemia research and management across Europe. Its concept has led to funding by the European Commission as a network of excellence. Other sources (European Science Foundation; European LeukemiaNet-Foundation) will take over when the support of the European Commission ends.

A retrospective analysis was performed of 118 patients with hematologic malignancies who received donor lymphocyte infusions (DLIs) after allogeneic stem cell transplantation (ASCT). Treatment was either given because of hematologic relapse (n = 44), molecular/cytogenetic relapse (n = 52), or other causes (n = 22). Molecular relapse was in most cases based on leukemia lineage-specific chimerism analysis. Patients with acute leukemia and myelodysplastic syndrome showed a 3-year survival of 42% if DLI treatment was given because of molecular relapse, compared to 16% in hematologic relapse (P < .006). In multivariate analysis, there was a correlation between response to DLI and nonhematologic relapse (risk ratio [RR] 3.36, P = .001), chronic graft-versus-host disease (cGVHD) (RR = 1.51, P = .005), and late relapse (RR = 2.06, P = .017). The overall incidences of acute GVHD (aGVHD) grades I-II and grades III-IV aGVHD were 33% and 8.5%, respectively. Probability of cGVHD was 33%. The development of aGVHD or cGVHD did not significantly influence the response of DLI in patients with molecular/cytogenetic relapse. However, the development of cGVHD was significantly associated with a better response in patients with hematologic relapse because only 4 of 29 patients without cGVHD responded compared to 7 of 12 with cGVHD (P = .007). The development of cGVHD increased significantly if DLI was given >12 months after ASCT (46% versus 27%, P = .04). In contrast, time between ASCT and start of DLI treatment had no significant influence on the risk of developing aGVHD. To conclude, monitoring of leukemia lineage-specific chimerism is of utmost importance for DLI response after ASCT., (Copyright © 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.

BackgroundWe examined the impact of vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) on outcomes of allogeneic hematopoietic cell transplantation (HCT) utilizing the Center for International Blood and Marrow Transplant Research database.MethodsAdult and pediatric patients (N = 7128) who underwent first HCT for acute leukemia or myelodysplastic syndrome from 2008 through 2012 were analyzed as 3 groups-VRE BSI, non-VRE BSI, without BSI-according to BSI status at 100 days (D100) after allogeneic HCT. Multivariable models examined the effect of VRE BSI for overall survival (OS) and nonrelapse mortality (NRM) at 1 year.ResultsOf 7128 patients, 258 (3.2%) had VRE BSI, 2398 (33.6%) had non-VRE BSI, and 4472 (63%) had no BSI. The median time to VRE BSI and non-VRE BSI were D11 and D15, respectively. Compared with non-VRE BSI patients, VRE BSI patients were older, had advanced-stage acute leukemia, and received umbilical cord blood (UCB) allografts. In multivariable models, VRE BSI was associated with lower OS (relative risk [RR], 2.9;(99% confidence interval [CI], 2.2-3.7) and increased NRM (RR, 4.7; 99% CI, 3.6-6.2) (P < .0001) for both. Other predictors for worse OS and increased NRM were non-VRE BSI, older age, advanced disease stage, UCB allograft, - mismatch, comorbidity index ≥3, and cytomegalovirus seropositivity (P < .001 for all variables).ConclusionsVRE BSI is associated with lowest OS and highest NRM compared with patients without BSI or non-VRE BSI. Novel interventions that address the pathophysiology of VRE BSI have the potential of improving survival after HCT.

The European Conference on Infections in Leukaemia (ECIL) updated its guidelines on antifungal prophylaxis for adults using the grading system of IDSA. The guidelines were extended to provide recommendations for other haematological diseases besides AML and recipients of an allogeneic haematopoietic stem cell transplantation (HSCT). Posaconazole remains the drug of choice when the incidence of invasive mould diseases exceeds 8%. For patients undergoing remission-induction chemotherapy for AML and myelodysplastic syndrome (MDS), fluconazole can still offer an alternative provided it forms part of an integrated care strategy that includes screening with biomarkers and imaging. Similarly, aerosolized liposomal amphotericin B combined with fluconazole can be considered for patients at high risk of invasive mould diseases but other formulations of the polyene are discouraged. Fluconazole is still recommended as primary prophylaxis for patients at low risk of invasive mould diseases during the pre-engraftment phase of allogeneic HSCT whereas only a moderate recommendation could be made for itraconazole, posaconazole and voriconazole for patients at high risk. Posaconazole is strongly recommended for preventing invasive mould disease post-engraftment but only when graft-versus-host disease (GvHD) was accompanied by other risk factors such as its severity, use of an alternative donor or when unresponsive to standard corticosteroid therapy. The need for primary prophylaxis for other patient groups was less clear and should be defined by the estimated risk of invasive fungal disease (IFD). [ABSTRACT FROM AUTHOR]

Background This study was performed to assess the incidence of and risk factors for Candida infection in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT) and the impact on long-term survival. Methods We performed an outcome analysis of 28542 acute leukemia patients who underwent HSCT from 2000 to 2012. There were 347 patients with candidemia by day 100 and 28195 without candidemia or any other type of Candida infection. Results The incidence of candidemia by day 100 was 1.2% and occurred at a median of 22 days after HSCT. Higher 100-day nonrelapse mortality (NRM; hazards ratio [HR], 3.0, P <.0001) and lower 100-day overall survival (OS; HR, 2.5, P <.0001) were observed in patients with candidemia. The case fatality rate by day 100 in patients with candidemia was 22% (76/347). Factors associated with candidemia occurrence were female gender, bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft vs host disease. Among the patients alive at day 100, the 5-year NRM and OS after a median follow-up of 5.6 years (95% confidence interval, 5.5 – 5.7) for patients with and without candidemia were 22.5% vs 13.5%, P <.0001 and 45.6% vs. 53.4%, P =.0003, respectively. In multivariate analysis, the occurrence of a candidemia episode by day 100 was an independent risk factor for higher NRM (HR, 1.7, P =.001) and lower OS (HR, 1.4, P =.001). Conclusions The early occurrence of candidemia after HSCT is still associated with higher NRM and lower short- and-long-term OS. [ABSTRACT FROM AUTHOR]

Bacterial infections were once a major obstacle to the treatment of acute leukaemia. Improvement in management strategies, including the use of broad-spectrum antibacterial drugs targeting Gram-negative bacteria, has reduced the mortality in neutropenic patients developing blood stream infections and other severe infections. In many countries these achievements are threatened by development of multi-resistant bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. This review addresses the epidemiology, clinical importance and possible management of these multi-resistant organisms. [ABSTRACT FROM AUTHOR]

The author reflects on the results of a study by M. L. Green and colleagues on the reactivation of cytomegalovirus (CMV) after allogeneic stem cell transplantation and risk of leukemia relapse. He offers information on CMV, which is considered as an antagonist in transplantation due to the high number of CMV pneumonia deaths. The results reportedly revealed that CMV effectively reduces the risk of relapse after transplantation.

To determine the graft-versus-leukemia effect after hematopoietic stem cell transplantation (HSCT), we studied 199 patients with acute lymphoblastic leukemia who underwent transplantation at Huddinge University Hospital between 1981 and 2001. Seventy-four patients were in first complete remission (CR1), and 125 were in later stages of the disease. Most patients had an HLA-identical sibling donor. Conditioning consisted mainly of total body irradiation and cyclophosphamide, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Acute GVHD developed in 143 patients and chronic GVHD in 67. The 5-year probability of relapse and relapse-free survival (RFS) were 32% and 49%, respectively, in patients in CR1, as compared with 53% and 33% in those with more advanced disease. In the multivariate risk factor analysis of relapse, we found that the absence of chronic GVHD (P < .001), absence of herpes simplex virus infection after HSCT (P = .003), combination prophylaxis with methotrexate and cyclosporine (P = .01), and >6 weeks from the diagnosis to CR (P = .025) were independent risk factors for relapse after HSCT. Factors associated with a better relapse-free survival were chronic GVHD (P < .001), ABO blood group mismatch (P = .006), younger patient age (P = .01), and an HLA-matched donor (P = .01). The association between herpes simplex virus infection and a low frequency of relapse is a new observation and may indicate that viral antigens play a role in the induction of an antileukemic effect. [Copyright &y& Elsevier]