Background Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.

HDAC1, HDAC2, HDAC6 and acetylated H4 are overexpressed in DLBCL and PTCL relative to normal lymphoid tissue. Furthermore, HDAC6 may be an important prognostic marker associated with favourable outcome in DLBCL and a more aggressive course in PTCL.

No abstract

Traumatic injury to the brain is one of the leading causes of injury-related death or disability. Brain response to injury is orchestrated by cytokines, such as interleukin (IL)-6, but the full repertoire of responses involved is not well known. We here report the results obtained with microarrays in wild-type and IL-6 knockout mice subjected to a cryolesion of the somatosensorial cortex and killed at 0, 1, 4, 8 and 16 days post-lesion. Overall gene expression was analyzed by using Affymetrix genechips/oligonucleotide arrays with 12 400 probe sets corresponding to 10 000 different murine genes (MG_U74Av2). A robust, conventional statistical method (twoway ANOVA) was employed to select the genes significantly affected. An orderly pattern of gene responses was clearly detected, with genes being up-or down-regulated at specific timings consistent with the processes involved in the initial tissue injury and later regeneration of the parenchyma. IL-6 deficiency showed a dramatic effect in the expression of many genes, especially in the 1 day post-lesion timing, which presumably underlies the poor capacity of IL-6 knockout mice to cope with brain damage. The results highlight the importance of IL-6 controlling the response of the brain to injury as well as the suitability of microarrays for identifying specific targets worthy of further study. Keywords: affymetrix, interleukin-6 deficiency, microarray, mouse, traumatic brain injury. Traumatic brain injury is one of the leading causes of injuryrelated death and disability, especially in young people (see Prins and Hovda 2003 for review). The general response of the brain to traumatic injury has been well described pathophysiologically: blood-brain barrier disruption, infiltration and activation of inflammatory cells, death of local neurons and glial cells caused by ischemia and hypoxia along with release of excitatory amino acids, gliosis, recruitment of endothelial cells, angiogenesis, compensatory responses in the surroundings of the most severely affected areas and formation of a glial scar are well-known phenomena. It is generally accepted that these series of responses are orchestrated by a number of cytokines, chemokines and growth factors in a complex manner (for reviews see Giulian et al.

After first-line therapy, patients with Hodgkin lymphoma (HL) and aggressive non-HL are followed up closely for early signs of relapse. The current follow-up practice with frequent use of surveillance imaging is highly controversial and warrants a critical evaluation. Therefore, a retrospective multicenter study of relapsed HL and aggressive non-HL (nodal T-cell and diffuse large B-cell lymphomas) was conducted. All included patients had been diagnosed during the period 2002-2011 and relapsed after achieving complete remission on first-line therapy. Characteristics and outcome of imaging-detected relapses were compared with other relapses. A total of 258 patients with recurrent lymphoma were included in the study. Relapse investigations were initiated outside preplanned visits in 52% of the patients. Relapse detection could be attributed to patient-reported symptoms alone or in combination with abnormal blood tests or physical examination in 64% of the patients. Routine imaging prompted relapse investigations in 27% of the patients. The estimated number of routine scans per relapse was 91-255 depending on the lymphoma subtype. Patients with imaging-detected relapse had lower disease burden (P 5 0.045) and reduced risk of death following relapse (hazard ratio 5 0.62, P 5 0.02 in multivariate analysis). Patient-reported symptoms are still the most common factor for detecting lymphoma relapse and the high number of scans per relapse calls for improved criteria for use of surveillance imaging. However, imaging-detected relapse was associated with lower disease burden and a possible survival advantage. The future role of routine surveillance imaging should be defined in a randomized trial.

Background: For fit CLL patients (pts), continuous BTK inhibitor treatment is replacing CIT as standard of care in frontline setting, particularly in pts with unfavorable prognostic factors. The time limited combinations venetoclax plus obinutuzumab (GVe) and venetoclax plus rituximab (RVe) have produced high rates of undetectable minimal residual disease (uMRD), which strongly associates with long progression-free survival (PFS) both in frontline and relapsed setting. For frontline therapy GVe is approved in this setting based on data from the CLL14 trial in an unfit population. However, data from a fit cohort are not yet available. The GAIA (CLL13) trial evaluated the efficacy and safety of three Ven+CD20 antibody-based regimens in comparison to CIT as a frontline treatment for fit pts with CLL and without TP53 mutation/deletion. Methods: Treatment-naïve fit (CIRS ≤6, normal creatinine clearance with ≥ 70ml/min) CLL pts requiring therapy were eligible. Based on known poor response to CIT, pts with TP53 aberrations were excluded. Pts were randomized in a 1:1:1:1 ratio to receive six courses of CIT (FCR for pt ≤65 years: fludarabine 25 mg/m² d1-3, cyclophosphamide 250 mg/m² d1-3, rituximab 375 mg/m² d1 cycle 1 and 500 mg/m² d1 cycle 2-6; BR for pt &gt;65 years: bendamustine 90mg/m² d1-2, rituximab) or one of three venetoclax (V) combinations (standard ramp-up from cycle 1 d22, 400 mg/d cycle 2-12): V and rituximab (375/500mg/m² d1 cycle 1-6) [RVe], V and obinutuzumab (1000 mg d1, 8, 15 cycle 1 and d1 cycle 2-6) [GVe], or V, obinutuzumab and ibrutinib (420 mg/d cycle 1-12, if MRD-detectable continued until cycle 36) [GIVe] . Pts were stratified according to country, Binet stage and age (≤ 65/&gt; 65 years). The co-primary endpoints of the trial are (1) the rate of uMRD (&lt;10-4) by flow in peripheral blood (PB) at month 15 (MO15, GVe vs CIT) and (2) PFS (GIVe vs CIT), each with a significance level of 2.5%. The co-primary endpoint PFS will be analyzed within a pre-planned interim analysis as soon as 138 (65%) PFS events will have been reported in the GIVe and CIT arm. The co-primary endpoint analysis of uMRD per protocol was performed after the last MO15 MRD sample had been collected. In addition, comparisons regarding uMRD for all study arms were performed using a pre-specified hierarchical test sequence. Bone marrow (BM) was evaluated 3 months after end of treatment (MO9 for CIT, MO15 for all others arms) in pts with clinical CR. Key secondary endpoints as investigator-assessed responses according to iwCLL 2008 guidelines and safety were analyzed. Trial is registered at ClinicalTrials.gov (NCT02950051). Results: A total of 926 pts (CIT: 229 (150 FCR, 79 BR), RVe: 237, GVe: 229, GIVe: 231) with a median age of 61 years (range 27-84) were accrued between 12/2016 and 09/2019. The majority of pts were in advanced Binet stage (B: 37.8%, C: 35.6%) and unmutated IGHV status was present in 56%. Fourteen pts did not receive study treatment (13 FCR, 1 GVe) and were not included in the safety population. The data cut for the first co-primary endpoint analysis was February 28, 2021. The median observation time was 27.9 months. The co-primary endpoint uMRD in PB at MO15 was met as the rate of uMRD in ITT population was significantly higher in GVe compared to CIT: 86.5% (97.5% CI 80.6-91.1) vs 52.0% (CI 44.4-59.5; p&lt;0.0001), respectively. GIVe also showed a superior uMRD rate of 92.2% (CI 87.3-95.7) compared to CIT (p&lt;0.0001), while RVe (57.0%, CI 49.5-64.2) did not (p=0.317) (Figure 1A). Corresponding BM uMRD rates in ITT population were 37.1% (CIT), 43.0% (RVe), 72.5% (GVe) and 77.9% (GIVe), respectively. MO15 overall response rates and complete response rates (CRR) are shown in Figure 1B. The most common grade 3-5 treatment-emergent AE were neutropenia (50.5% of all pts), thrombocytopenia (12.2%), tumor lysis syndrome (7.5%), infusion-related reaction (7.2%), febrile neutropenia (6.5%) and pneumonia (5.3%)). Atrial fibrillation and bleeding events occurred more frequently in GIVe while infusion-related reactions were most common in the GVe arm (Table 1). The absolute numbers of second malignancies were 33, 19, 22 and 21 for CIT, RVe, GVe and GIVe. Fatal AEs occurred in 5, 7, 6 and 9 of the patients. Conclusions: The time-limited therapies of GVe and GIVe provided superior uMRD rates in PB at MO 15 compared to CIT. In addition, uMRD rates in BM and CRR were higher in GVe and GIVe in particular than in CIT. All arms showed a good safety profile in this fit pt population. Figure 1 Figure 1. Disclosures Eichhorst: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Von Tresckow: Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant; AbbVie: Honoraria, Other: advisory board, travel grant. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Sanofi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: Roche: Speakers Bureau; Abbvie,: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Jaeger: Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Hebart: Roche: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Kreuzer: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ritgen: Abbvie: Consultancy, Other: Travel support, Research Funding; Chugai: Consultancy; MSD: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Hallek: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: Ibrutinib in combaintion with Venetoclax + Obinutuzumab is not approved.

AimIn 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate adherence to national guidelines and to provide source data for research purposes.Study populationAll patients diagnosed with CLL in Denmark from 2008 onward are included in the registry. Patients are followed in one of nine hematology centers. All centers participate in the registry and are all obliged to collect data.Main variablesPredefined data are collected at the time of diagnosis, and follow-up at the time of significant events: treatment, progression, transplantation, and death. Parameters included in the International Workshop on Chronic Lymphocytic Leukaemia criteria for diagnosis, and for decision on treatment initiation as well as characteristics included in the CLL International Prognostic Index are collected.Descriptive dataTo ensure full coverage of Danish CLL patients in the registry, both continuous queries in case of missing data, and cross-referencing with the Danish National Patient Registry are performed. Data from the registry are published in an annual report summarizing the collected data, the overall survival for yearly cohorts, and the degree of data coverage. Per year approximately 450 new patients with CLL are registered in the registry, cumulative as of July 1, 2015, 3,082 patients have been registered.ConclusionThe Danish National CLL Registry is based within the Danish National Hematology Database. The registry covers a cohort of all patients diagnosed with CLL in Denmark since 2008. It forms the basis for quality assessment of CLL treatment in Denmark and offers a unique opportunity for population-based research.

Summary Cardiotoxicity is a known risk of anthracycline treatment. However, the relative contribution of anthracyclines to the development of congestive heart failure (CHF), when included in a poly‐chemotherapy regimen, is unclear. We examined cardiotoxicity in adult patients with diffuse large B‐cell lymphoma and follicular lymphoma undergoing first‐line immunochemotherapy from 2000–2012. In total, 2440 patients without previous heart disease were identified from the Danish Lymphoma Registry, of which 1994 (81·7%) were treated with anthracycline‐containing chemotherapy [R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R‐CHOEP (R‐CHOP + etoposide)] and 446 (18·3%) were treated without anthracyclines (reference group). Compared to the reference group, the adjusted hazard ratio of CHF after 3–5 cycles of R‐CHOP/CHOEP was 5·0 [95% confidence interval (CI) 1·4; 18·5], 6 cycles 6·8 (95% CI 2·0; 23·3) and >6 cycles 13·4 (95% CI 4·0; 45·0). The cumulative 5‐year risk of CHF with all‐cause mortality as competing risk was 4·6% after 3–5 cycles of R‐CHOP/CHOEP, 4·5% after 6 and 7·9% after more than 6 cycles. Cumulative 5‐year risk for patients treated without anthracyclines was 0·8%. Using anthracyclines in first‐line lymphoma treatment increases risk of CHF in patients without previous history of heart disease. In particular, treatment with >6 cycles of R‐CHOP/CHOEP is associated with a significant increase in CHF rate.