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Background: Infection with SARS-CoV-2 leads to COVID-19, the course of which is highly variable and depends on numerous patient-specific risk factors. Patients with tumor diseases are considered to be more susceptible to severe COVID-19; however, they also represent a heterogeneous group of individuals with variable risk. Identifying specific risk factors for a severe course of COVID-19 in patients with cancer is of great importance., Methods: Patients diagnosed with solid tumors or hematological malignancies and PCR-confirmed SARS-CoV-2 infection were included into the multicentric ADHOK (Arbeitsgemeinschaft der Hämatologen und Onkologen im Krankenhaus e.V.) coronavirus tumor registry. Detailed information about the patients' cancer disease, treatment, and laboratory parameters prior to infection, was collected retrospectively. The outcome of the SARS-CoV-2 infection was graded according to the WHO., Results: A total of 195 patients (68% with solid neoplasms and 32% with hematological malignancies) were included in the registry. Overall, the course of the SARS-CoV-2 infection varied greatly, as 69% of all patients were either asymptomatic or encountered a mild to moderate course, while 23% of the cohort died from COVID-19. In multivariable analysis, preinfection laboratory parameters (determined at least 10 days and a median of 21 days before the first documentation of SARS-CoV-2 infection) significantly correlated with severe course of the disease. Out of these, the absolute neutrophil count prior to infection showed the strongest association with COVID-19-related death., Conclusion: The course of COVID-19 in patients with tumor diseases is highly variable. Preinfection laboratory parameters may aid to identify patients at risk for severe COVID-19 at an early stage prior to infection with the virus. German Clinical Trials Register identification: DRKS00023012., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: The choice of drug treatment in advanced soft tissue sarcoma (STS) continues to be a challenge regarding efficacy, quality of life (QoL) and toxicity. Unlike other cancer types, where integrating patient-reported outcomes (PRO) has proven to be beneficial for QoL, there is no such evidence in patients with STS as of now. The YonLife trial aimed to explore the effect of a tailored multistep intervention on QoL, symptoms and survival in patients with advanced STS undergoing treatment with trabectedin as well as identifying predictors of QoL., Design: YonLife is a cluster-randomised, open-label, proof-of-concept study. The intervention incorporates electronic PRO assessment, a case vignette and expert-consented treatment recommendations., Participants: Six hospitals were randomised to the control arm (CA) or interventional arm (IA). Seventy-nine patients were included of whom 40 were analysed as per-protocol analysis set., Primary and Secondary Outcome Measures: The primary end point was the change of Functional Assessment for Cancer Therapy (FACT-G) total score after 9 weeks. Secondary outcomes included QoL (FACT-G subscales), anorexia and cachexia (Functional Assessment of Anorexia/Cachexia Therapy (FAACT)), symptoms (MD Anderson Symptom Inventory (MDASI)), anxiety and depression (HADS), pain intensity and interference (Brief Pain Inventory (BPI)) and survival assessment., Results: After 9 weeks of treatment, QoL declined less in the IA (ΔFACT-G total score: -2.4, 95% CI: -9.2 to 4.5) as compared with CA (ΔFACT-G total score: -3.9; 95% CI:-11.3 to 3.5; p = 0.765). In almost all FACT-G subscales, average declines were lower in IA, but without reaching statistical significance. Smaller adverse trends between arms were observed for MDASI, FAACT, HADS and BPI scales. These trends failed to reach statistical significance. Overall mean survival was longer in IA (648 days) than in CA (389 days, p = 0.110). QoL was predicted by symptom severity, symptom interference, depression and anxiety., Conclusion: Our data suggest a potentially favourable effect of an electronic patient-reported outcomes based intervention on QoL that needs to be reappraised in confirmatory studies., Trial Registration Number: ClinicalTrials.gov Identifier (NCT02204111)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Primary refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The FLAMSA-reduced intensity conditioning protocol (total body irradiation or treosulfan-based) has been described as an effective approach in patients with refractory leukemia undergoing allogeneic hematopoietic cell transplantation. A modified protocol (without amsacrine) has also recently been used. We retrospectively analyzed the transplantation characteristics and outcomes of all consecutive patients between the years 2003 and 2017 (n=51) diagnosed with primary refractory AML who underwent transplantation at the University of Cologne and the Tel Aviv Medical Center. Median age was 54 years and median follow up was 37 months. Median time to neutrophil and platelet engraftment was 13 (range, 8-19) and 13 (range, 7-30) days, respectively. None of the patients had primary graft failure. Incidences of grade 2-4 and grade 3-4 acute graft-v ersus -host disease (GvHD), overall and moderate-severe chronic GvHD were 50% (95%CI: 41-67%), 12% (95%CI: 3-25%), 61% (95%CI: 47-72%), and 42% (95%CI: 34-51%), respectively. Anti-thymocyte globulin administration was associated with lower incidence of acute GvHD (HR: 0.327; P =0.02). Non-relapse mortality at three months and three years were 6% and 16%, respectively. Relapse incidences were 6% and 29%, respectively. Overall survival rates at three months, three and five years were 90%, 61%, and 53%, respectively. Chronic GvHD disease was associated with a decreased mortality rate (HR: 0.397; P =0.045). We conclude that sequential therapy in patients with primary refractory acute myeloid leukemia is safe and provides a remarkable anti-leukemic effect with durable survival and should be considered for every patient with primary refractory disease., (Copyright© 2019 Ferrata Storti Foundation.)

It is still under debate whether bone marrow (BM) or peripheral blood (PB) should be the preferred stem cell source in adult patients undergoing allogeneic stem cell transplantation for hematological malignancies. After systematic literature search we identified nine randomised controlled trials comparing BM and PB as stem cell source from 2341 total hits. Meta-analysis involving 1521 patients showed a statistically significant reduction in overall and extensive chronic GvHD for patients transplanted with BM (HR 0.72; 95% CI 0.61 to 0.85 and HR 0.69; 95% CI 0.54 to 0.9), but no difference in overall and disease-free survival. In the related donor setting, data from two of eight studies demonstrated a significant increase of relapse incidence for BM (HR 2.73; 95% CI 1.47 to 5.08). This systematic review demonstrates that the current clinical standard to use peripheral blood stem cells instead of bone marrow for allo-SCT is not inferior with regard to the primary outcome overall survival., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant disorders. In the past two decades, peripheral blood stem cells replaced bone marrow as stem cell source due to faster engraftment and practicability. Previous meta-analyses analysed patients treated from 1990 to 2002 and demonstrated no impact of the stem cell source on overall survival, but a greater risk for graft-versus-host disease (GvHD) in peripheral blood transplants. As transplant indications and conditioning regimens continue to change, whether the choice of the stem cell source has an impact on transplant outcomes remains to be determined., Objectives: To assess the effect of bone marrow versus peripheral blood stem cell transplantation in adult patients with haematological malignancies with regard to overall survival, incidence of relapse and non-relapse mortality, disease-free survival, transplant-related mortality, incidence of GvHD and time to engraftment., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE (from 1948 to February 2014), trial registries and conference proceedings. The search was conducted in October 2011 and was last updated in February 2014. We did not apply any language restrictions., Selection Criteria: We included randomised controlled trials (RCTs) comparing bone marrow and peripheral blood allogeneic stem cell transplantation in adults with haematological malignancies., Data Collection and Analysis: Two review authors screened abstracts and extracted and analysed data independently. We contacted study authors for additional information. We used the standard methodological procedures expected by The Cochrane Collaboration., Main Results: We included nine RCTs that met the pre-defined selection criteria, involving a total of 1521 participants. Quality of data reporting was heterogeneous among the studies. Overall, the risk of bias in the included studies was low.For the primary outcome overall survival, our analysis demonstrated comparable results between bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) (six studies, 1330 participants; hazard ratio (HR) 1.07; 95% CI 0.91 to 1.25; P value = 0.43; high-quality evidence).Disease-free survival (six studies, 1225 participants; HR 1.04; 95% CI 0.89 to 1.21; P value = 0.6; moderate-quality of evidence) and non-relapse or transplant-related mortality (three studies, 758 participants; HR 0.98; 95% CI 0.76 to 1.28; P = 0.91; high-quality evidence) were also comparable between transplantation arms.In the related-donor setting, data from two of eight studies with 211 participants (21%) indicated a higher relapse incidence in participants transplanted with bone marrow stem cells rather than peripheral blood stem cells (HR 2.73; 95% CI 1.47 to 5.08; P value = 0.001). There was no clear evidence of a difference in relapse incidence between transplantation groups in unrelated donors (HR 1.07; 95% CI 0.78 to 1.47; P value = 0.66). The difference between the donor-related and -unrelated subgroups (P-value = 0.008) was considered to be statistically significant.BMT was associated with lower rates of overall and extensive chronic GvHD than PBSCT (overall chronic GvHD: four studies, 1121 participants; HR 0.72; 95% CI 0.61 to 0.85; P value = 0.0001, extensive chronic GvHD: four studies, 765 participants; HR 0.69; 95% CI 0.54 to 0.9; P value = 0.006; moderate-quality evidence for both outcomes). The incidence of acute GvHD grades II to IV was not lower (six studies, 1330 participants; HR 1.03; 95% CI 0.89 to 1.21; P value = 0.67; moderate-quality evidence), but there was a trend for a lower incidence of grades III and IV acute GvHD with BMT than with PBSCT (three studies, 925 participants; HR 0.75; 95% CI 0.55 to 1.02; P value = 0.07; moderate-quality evidence).Times to neutrophil and platelet engraftment were longer with BMT than with PBSCT (neutrophil: five studies, 662 participants; HR 1.96; 95% CI 1.64 to 2.35; P value < 0.00001; platelet: four studies, 333 participants; HR 2.17; 95% CI 1.69 to 2.78; P value < 0.00001)., Authors' Conclusions: This systematic review  found high-quality evidence that overall survival following allo-HSCT using the current clinical standard stem cell source - peripheral blood stem cells - was similar to that following allo-HSCT using bone marrow stem cells in adults with haematological malignancies. We found moderate-quality evidence that PBSCT was associated with faster engraftment of neutrophils and platelets, but a higher risk of GvHD (in terms of more overall and extensive chronic GvHD). There was an imprecise effect on relapse and on severe (grades III to IV) acute GvHD. Quality of life, which is severely affected by GvHD, was not evaluated.Against the background of transplantation practices that have clearly changed over the past 10 to 15 years, our aim was to provide current data on the best stem cell source for allo-HSCT, by including the results of recently conducted trials. Our review includes participants recruited up to 2009, a proportion of whom were older, had received reduced-intensity conditioning regimens or had been transplanted with stem cells from unrelated donors. However, only one, large, study included relatively recently treated participants. Nevertheless, our findings are comparable to those of previous meta-analyses suggesting that our results hold true for today's practice.

The introduction of reduced-intensity conditioning regimens has allowed elderly patients with preexisting comorbidities access to the potentially curative allogeneic stem cell transplantation. Patient's comorbidities at the time of treatment consideration play a significant role in transplant outcome in terms of both overall survival (OS) and nonrelapse mortality (NRM). The hematopoietic stem cell transplantation comorbidity index (HCT-CI) quantifies these patient specific risks and has established itself as a major tool in the pretransplant assessment of patients. Many single center and multicenter studies have assessed the HCT-CI score and reported conflicting outcomes. The present study aimed to evaluate the HCT-CI in a single large European transplant centre. 245 patients were retrospectively analyzed and the predictive value of the score was assessed with respect to OS and NRM. We confirm that the HCT-CI predicts outcome for both OS and NRM. Moreover, we identified age of the patient as an independent prognostic parameter for OS. Incorporation of age in the HCT-CI would improve its ability to prognosticate and allow the transplant physician to assess the patient specific risks appropriately at the time of counseling for transplant.

Background: Despite advances made in allogeneic hematopoietic stem cell transplantation (alloSCT), graft versus host disease (GvHD) remains a major problem. The main strategy to combat GvHD is prophylaxis and ATG plays a major role in this arena. Conflicting reports on the effectiveness of ATG on GvHD prevention prompted us to address this question by means of a systematic review and meta-analysis., Methods: Six prospective randomized controlled trials (RCT) comparing the addition of ATG to standard immunosuppressive regimen as GvHD prophylaxis were analyzed. All ATG preparations were considered but homogeneity in type of preparation and dosage had to be observed within each trial., Results: Our meta-analysis reveals that the incidence of grade II-IV GvHD was significantly lower in patients receiving ATG. Addition of ATG had no impact on overall survival, relapse or non-relapse mortality., Conclusions: Based on the current level of the data analyzed in this systematic review, we cannot conclude a general recommendation for the use of ATG for GvHD prophylaxis in alloSCT. In patients who are at high risk for severe GvHD it should be considered individually. However, due to the heterogeneity of the analyzable studies it seems likely that future studies might change the results of the pooled data of this meta-analysis. In order to improve the current level of data, further randomized studies in this topic are therefore urgently warranted., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host disease (GVHD), a condition frequently occurring after HSCT, is the result of host tissues being attacked by donor immune cells. One strategy for the prevention of GVHD is the administration of anti-thymocyte globulins (ATG), a set of polyclonal antibodies directed against a variety of immune cell epitopes, leading to immunosuppression and immunomodulation., Objectives: To assess the effect of ATG used for the prevention of graft-versus-host disease (GVHD) in patients undergoing allogeneic HSCT with regard to overall survival, incidence and severity of acute and chronic GVHD, incidence of relapse, incidence of infectious complications, non-relapse mortality, early mortality within 100 days of transplantation, progression-free survival, quality of life and adverse events., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (January 1950 to February 2012), trials registries and conference proceedings. The search was conducted in October 2010 and was updated in July 2011 and February 2012. We did not apply any language restrictions., Selection Criteria: We included randomised controlled trials (RCTs) investigating the impact of ATG on GVHD prophylaxis in adults suffering from haematological diseases and undergoing allogeneic HSCT. Treatment arms had to differ only in the addition of ATG to the standard GVHD prophylaxis regimen., Data Collection and Analysis: Two review authors screened abstracts, extracted data and analysed the data independently. We contacted study authors for additional information., Main Results: We included in the meta-analysis six RCTs which met the pre-defined selection criteria, involving a total of 568 participants. Quality of data reporting was heterogeneous among these studies with a lack of detailed information in the early studies.The primary outcome of overall survival was not significantly changed by the addition of ATG for the prophylaxis of GVHD (harms ratio (HR) 0.88; 95% CI 0.67 to 1.15, P = 0.33).The incidence of treatment-requiring or severe acute GVHD (grade II to IV) was significantly lower in patients who received ATG (risk ratio (RR) 0.68; 95% CI 0.55 to 0.85, P = 0.009; number needed to treat (NNT) 8). Also, the incidence of severe acute GVHD (grade III to IV) was significantly reduced (HR 0.53; 95% CI 0.33 to 0.85, P = 0.0005; NNT 7) but comparable data were available for rabbit ATG only. However, pooled study results regarding the incidence of acute GVHD of all grades (I to IV) showed no significant benefit of ATG treatment (RR 0.89; 95% CI 0.74 to 1.06, P = 0.20).Meta-analysis of data regarding the incidence of overall chronic GVHD (both, limited and extensive) was not possible. Nevertheless, studies reporting on extensive chronic GVHD (only studies evaluating rabbit ATG) suggested a lower incidence of extensive chronic GVHD whereas others that only reported on overall chronic GVHD did not show an advantage for ATG.Pooled results regarding the incidence of relapse were not significantly different (RR 1.13; 95% CI 0.75 to 1.68, P = 0.56), as well as pooled results regarding non-relapse mortality (HR 0.82; 95% CI 0.55 to 1.24, P = 0.35).Due to the lack of comparable data, we could not perform meta-analysis of data regarding the incidence of chronic GVHD, relapse-related mortality, progression-free survival, quality of life, adverse events and engraftment., Authors' Conclusions: Our systematic review suggests that the addition of ATG during allogeneic HSCT significantly reduces the incidence of severe grades (II to IV) of acute GvHD, whereas the incidence of overall acute GVHD (grades I to IV) was not significantly lowered. This indicates a reduction of the severity but not the incidence of acute GVHD. However, this effect did not lead to a significant improvement of overall survival, which may be due to the severe potential side effects of the consecutively increased immunosuppression.Furthermore, future research is needed to clarify the effect of ATG on the incidence and severity of chronic GVHD and consequently on all aspects of quality of life.From the currently available data, no recommendation on the general use of ATG in allogeneic HSCT can be supported. Therefore, a careful consideration of the use of ATG based on the patient's condition and the risk factors of the transplantation setting should be made.

A hallmark of various human malignancies is the expression of immunoinhibitory factors within the tumor microenvironment. There is indirect evidence based on in vitro experiments that tumor-infiltrating T cells in human malignancies are suppressed by such factors. Still, direct evidence of the influence of individual inhibitory factors on immune cells in human cancer in vivo is lacking. To address this question, we used Hodgkin lymphoma (HL) as a model because histopathological characteristics of HL are thought to be due mostly to the effects of a wide variety of cytokines, including TGFbeta or membrane-bound receptors such as PD-1 that are suspected to contribute to immune evasion of tumor cells. Using a genome-wide transcriptional approach, we established specific RNA fingerprints of TGFbeta and PD-1 signaling in human T cells in vitro. Applying these specific fingerprints, we directly demonstrate that CD4+ T cells in HL--but not in follicular lymphoma (FL)--are under the inhibitory influence of both TGFbeta and PD-1 in vivo. This approach can be easily generalized to provide direct evidence of the impact of any given soluble or cell-bound factor on any cell type within diseased tissue.

Many tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E(2) (PGE(2)), a known inhibitor of CD4+ T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE(2) might have on primary human CD4+ T cells, we used a whole genome-based transcriptional approach and show that PGE(2) severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE(2) at an early step of T cell receptor signaling: indeed, PGE(2) stimulation of T cells leads to inactivation of lck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE(2)-induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE(2)-treated CD4+ T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27(kip1). Most importantly, CD4+ T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE(2) in T cells from healthy individuals. These data strongly suggest that PGE(2) is an important factor leading to CD4+ T cell impairment observed in Hodgkin's lymphoma.

CTLA-4 and PD-1 are receptors that negatively regulate T-cell activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28-mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4-mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T-cell activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28-mediated activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/AKT activation was dependent upon the immunoreceptor tyrosine-based switch motif located in its cytoplasmic tail, adding further importance to this domain in mediating PD-1 signal transduction. Lastly, PD-1 ligation is more effective in suppressing CD3/CD28-induced changes in the T-cell transcriptional profile, suggesting that differential regulation of PI3K activation by PD-1 and CTLA-4 ligation results in distinct cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms.