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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused high mortality in patients with hematological malignancies (HM). 1 The newly emerged omicron variants of SARS-CoV-2 harbor multiple novel spike protein mutations that raise concerns about vaccine efficiency and antiviral efficacy of the available therapeutic monoclonal antibodies. 2 The first published clinical data in immunocompetent patients have found that infection with omicron variants is associated with reduced vaccine efficiency compared to the delta variants, but decreased hospital admission and mortality. 3,4 Preliminary, prepublished, data from a large case-control study have shown that the vaccine effect against omicron in immunocompromised patients, including HM patients, is even more reduced, but data regarding clinical outcomes are lacking. 5 The aim of this study was to describe risk factors, antiviral treatment and outcomes of SARS-CoV-2 omicron variant infection in 593 HM patients included in the EPICOVIDEHA registry.EPICOVIDEHA is an international open web-based registry for patients with HM infected with SARS-CoV-2. 1,6 Both hospitalized and nonhospitalized patients are eligible for inclusion. The questionnaire includes data on the HM, SARS-CoV-2 vaccination status, risk factors for severe COVID-19 infection, SARS-CoV-2 virus variant, antiviral treatment, and outcomes including mortality (eFigure 1 and eTable 4).

BackgroundThe miR-9 family microRNAs have been identified as a tumor suppressor miRNA in cancers. We postulated that miR-9-1, miR-9-2 and miR-9-3 might be inactivated by DNA hypermethylation in chronic lymphocytic leukemia (CLL).MethodsMethylation of miR-9-1, miR-9-2 and miR-9-3 was studied in eight normal controls including normal bone marrow, buffy coat, and CD19-sorted peripheral blood B-cells from healthy individuals, seven CLL cell lines, and seventy-eight diagnostic CLL samples by methylation-specific polymerase chain reaction.ResultsThe promoters of miR-9-3 and miR-9-1 were both unmethylated in normal controls, but methylated in five (71.4%) and one of seven CLL cell lines respectively. However, miR-9-2 promoter was methylated in normal controls including CD19 + ve B-cells, hence suggestive of a tissue-specific but not tumor-specific methylation, and thus not further studied. Different MSP statuses of miR-9-3, including complete methylation, partial methylation, and complete unmethylation, were verified by quantitative bisulfite methylation analysis. 5-Aza-2′-deoxycytidine treatment resulted in miR-9-3 promoter demethylation and re-expression of pri-miR-9-3 in I83-E95 and WAC3CD5+ cells, which were homozygously methylated for miR-9-3. Moreover, overexpression of miR-9 led to suppressed cell proliferation and enhanced apoptosis together with downregulation of NFκB1 in I83-E95 cells, supporting a tumor suppressor role of miR-9-3 in CLL. In primary CLL samples, miR-9-3 was detected in 17% and miR-9-1 methylation in none of the patients at diagnosis. Moreover, miR-9-3 methylation was associated with advanced Rai stage (≥ stage 2) (P = 0.04).ConclusionsOf the miR-9 family, miR-9-3 is a tumor suppressor miRNA relatively frequently methylated, and hence silenced in CLL; whereas miR-9-1 methylation is rare in CLL. The role of miR-9-3 methylation in the constitutive activation of NFκB signaling pathway in CLL warrants further study.

Summary Masking of the macrocytic expression of megaloblastic anaemia (MA) by coexisting thalassaemia, iron deficiency and chronic illness has been widely reported. We described the haematological and clinical features of 20 Chinese patients with MA presenting with mean corpuscular volume (MCV) ≦99 fl, and analysed the steps leading to the final diagnosis of MA with concomitant thalassaemia trait (n = 11), thalassaemia trait and iron deficiency (n = 3), iron deficiency (n = 4) and chronic illness (n = 2). We also compared the haematological characteristics of this group of patients with a group of normocytic anaemic patients without vitamin B12/folate deficiency, and identified certain laboratory information useful for differentiating the two groups. Statistically significant parameters included the mean values of haemoglobin, MCV, red cell distribution width (RDW), reticulocyte index, platelet count and serum bilirubin. All provided clues to maturation disorders within the marrow. A decision flowchart for the diagnosis of MA without macrocytosis was proposed. In the studied population, by using the parameters of haemoglobin <10 g/dl, MCV 80–99 fl, RDW ≥ 16% and reticulocyte index ≦ 2% as indicators, there was a 58% chance that a patient had MA without macrocytosis if he/she had all the four indicators, and a 2.2% chance of having it if he/she did not have these indicators. We emphasized the importance of including peripheral blood smear examination in the diagnostic procedures for such patients, as well as the importance of paying attention to patients’ medical history, racial background and previous MCV value.

BackgroundTP53 mutation/deletion is uncommon in chronic lymphocytic leukemia (CLL). We postulated that components of TP53-centered tumor suppressor network, miR-34b/c, in addition to DAPK1 and miR-34a might be inactivated by DNA hypermethylation. Moreover, we tested if miR-34b/c methylation might correlate with miR-203 or miR-124-1 methylation in CLL.MethodsmiR-34b/c, miR-34a and DAPK1 methylation was studied in 11 normal controls, 7 CLL cell lines, and 78 diagnostic CLL samples by methylation-specific polymerase chain reaction. MEC-1 cells were treated with 5-Aza-2’-deoxycytidine for reversal of methylation-associated miRNA silencing. Tumor suppressor properties of miR-34b were demonstrated by over-expression of precursor miR-34b in MEC-1 cells.ResultsmiR-34b/c promoter was unmethylated in normal controls, but completely methylated in 4 CLL cell lines. miR-34b/c expression was inversely correlated with miR-34b/c methylation. Different MSP statuses of miR-34b/c, including complete methylation and complete unmethylation, were verified by quantitative bisulfite pyrosequencing. 5-Aza-2’-deoxycytidine treatment resulted in promoter demethylation and miR-34b re-expression in MEC1 cells. Moreover, over-expression of miR-34b resulted in inhibition of cellular proliferation and increased cell death. In primary CLL samples, miR-34a, miR-34b/c and DAPK1 methylation was detected in 2.6%, 17.9% and 34.6% of patients at diagnosis respectively. Furthermore, 39.7%, 3.8% and 2.6% patients had methylation of one, two or all three genes respectively. Overall, 46.2% patients had methylation of at least one of these three genes. Besides, miR-34b/c methylation was associated with methylation of miR-34a (P = 0.03) and miR-203 (P = 0.012) in CLL.ConclusionsTaken together, miR-34b/c is a tumor suppressor miRNA frequently methylated, and hence silenced in CLL. Together with DAPK1 methylation, miR-34b/c methylation is implicated in the disruption of the TP53-centered tumor suppressor network. Moreover, the association of miRNA methylation warrants further study.