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Summary Background Mortality of patients with coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammation is high. In areas of pandemic outbreak, the number of patients can exceed maximum capacity of intensive care units (ICUs), and, thus, these individuals often receive non-invasive ventilation outside of the ICU. Effective treatments for this population are needed urgently. Anakinra is a recombinant interleukin-1 receptor antagonist that might be beneficial in this patient population. Methods We conducted a retrospective cohort study at the San Raffaele Hospital in Milan, Italy. We included consecutive patients (aged ≥18 years) with COVID-19, moderate-to-severe ARDS, and hyperinflammation (defined as serum C-reactive protein ≥100 mg/L, ferritin ≥900 ng/mL, or both) who were managed with non-invasive ventilation outside of the ICU and who received standard treatment of 200 mg hydroxychloroquine twice a day orally and 400 mg lopinavir with 100 mg ritonavir twice a day orally. We compared survival, mechanical ventilation-free survival, changes in C-reactive protein, respiratory function, and clinical status in a cohort of patients who received additional treatment with anakinra (either 5 mg/kg twice a day intravenously [high dose] or 100 mg twice a day subcutaneously [low dose]) with a retrospective cohort of patients who did not receive anakinra (referred to as the standard treatment group). All outcomes were assessed at 21 days. This study is part of the COVID-19 Biobank study, which is registered with ClinicalTrials.gov , NCT04318366 . Findings Between March 17 and March 27, 2020, 29 patients received high-dose intravenous anakinra, non-invasive ventilation, and standard treatment. Between March 10 and March 17, 2020, 16 patients received non-invasive ventilation and standard treatment only and comprised the comparison group for this study. A further seven patients received low-dose subcutaneous anakinra in addition to non-invasive ventilation and standard treatment; however, anakinra treatment was interrupted after 7 days because of a paucity of effects on serum C-reactive protein and clinical status. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein and progressive improvements in respiratory function in 21 (72%) of 29 patients; five (17%) patients were on mechanical ventilation and three (10%) died. In the standard treatment group, eight (50%) of 16 patients showed respiratory improvement at 21 days; one (6%) patient was on mechanical ventilation and seven (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (p=0·009). Mechanical ventilation-free survival was 72% in the anakinra group versus 50% in the standard treatment group (p=0·15). Bacteraemia occurred in four (14%) of 29 patients receiving high-dose anakinra and two (13%) of 16 patients receiving standard treatment. Discontinuation of anakinra was not followed by inflammatory relapses. Interpretation In this retrospective cohort study of patients with COVID-19 and ARDS managed with non-invasive ventilation outside of the ICU, treatment with high-dose anakinra was safe and associated with clinical improvement in 72% of patients. Confirmation of efficacy will require controlled trials. Funding None.

Objectives: Treatment of older patients with acute myeloid leukemia (AML) is still controversial. To facilitate treatment decisions, the “fitness criteria” proposed by Ferrara et al. (Leukemia, 2013), including age > 75 years, performance status and comorbidities, were verified retrospectively in 699 patients with AML (419 de-novo, 280 secondary AML), diagnosed at 8 Hematological Centers (REL). Methods: Patients were categorized in FIT to intensive chemotherapy (i-T) (292, 42.5%), UNFIT to i-T (289, 42.1%), or unfit even to non-intensive therapy (non i-T) (FRAIL) (105, 15.3%). Biological characteristics and treatment actually received by patients [i-T, 274 patients (39.2%); non i-T, 134 (19.2%), best-supportive care (BSC), 291 (41.6%)] were recorded. Results: “Fitness criteria” were easily applicable in 98.1% of patients. Overall concordance between “fitness criteria” and treatment actually received by patients was high (79.4%), 76% in FIT, 82.7% in UNFIT and 80% in FRAIL patients. Fitness independently predicted survival (median survival: 10.9, 4.2 and 1.8 months in FIT, UNFIT and FRAIL patients, respectively; p = 0.000), as confirmed also by multivariate analysis. In FRAIL patients, survival with any treatment was no better than with BSC, in UNFIT non i-T was as effective as i-T and better than BSC, and in FIT patients i-T was better than non i-T or BSC. In addition, a non-adverse risk AML, an ECOG PS

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Incidence and outcome of infections after allogeneic hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis are largely unknown. Study aims were to estimate the incidence of pre-engraftment bloodstream infections (PE-BSIs) and viral infections (VIs; cytomegalovirus [CMV], adenovirus [ADV], human herpes virus 6 [HHV6], and BK-polyomavirus hemorrhagic-cystitis [BKPyV-HC]), their predictive factors, and infection-related mortality (IRM) after HSCT with PT-Cy. We analyzed 235 patients: 62%, 21%, and 17% received haploidentical (haplo), matched-unrelated donor (MUD), and matched-related donor, respectively. Overall, 72 patients had 77 PE-BSI episodes at a median time of 13 days after HSCT: cumulative incidence function (CIF) at 28 days was 32%, without differences among donor types (P = .988). By multivariate analysis, CIF of PE-BSI was higher in patients with severe neutropenia before HSCT (adjusted hazard ratio [AHR] = 2.90) and in multidrug-resistant Gram-negative bacteria rectal carriers (AHR = 2.68). IRM at 30 days was 5%, without differences by donor type (P = .106). Overall, 208 patients experienced ≥1 VIs (first occurrence among CMV, HHV6, ADV, BKPyV-HC) at a median time of 20 days after HSCT: CIF at 90 days was 91%, significantly higher in MUD and haplo (P = .0089). By multivariate analysis, also acute GVHD grade ≥2 (AHR = 1.32) and host/donor CMV-serology mismatch (positive/positive versus negative/negative: AHR = 2.95, positive/negative versus negative/negative: AHR = 2.41, negative/positive versus negative/negative: AHR = 2.35) affected VIs occurrence. IRM at 180 days was 8%, without differences among donor types (P = .106). In conclusion, study results did not show a significant impact of donor type on PE-BSI incidence; conversely, MUD and haploidentical transplants retained a higher occurrence of VIs in the early phase after HSCT.

Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients without an HLA-identical donor, haploidentical (haplo-) HCT is becoming the leading source of stem cell donation. However, data are scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age, 31 years; range, 18 to 68 years) with T-ALL who underwent haplo-HCT with post-transplantation cyclophosphamide (ptCy) between 2010 and 2017. The median duration of follow-up of living patients was 23 months. The 2-year incidences of relapse and nonrelapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS), and graft-versus-host disease, relapse-free survival (GRFS) were 34%, 42%, and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplantation, being 49% and 55%, respectively, for patients in first complete remission (CR1); 34% and 50%, respectively, for those in second CR (CR2); and 8% and 12%, respectively, for patients with active disease. On multivariate analysis, only disease status was found to affect LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at the time of haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in patients in CR. Despite the limitation of the small sample size, our results were not affected by the type of conditioning, calling into question the need for total body irradiation-based myeloablative conditioning in that setting.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before allo-HSCT has not been established. We conducted a Phase II study to evaluate the tolerability and efficacy of clofarabine and treosulfan as conditioning regimen before allo-HSCT. The primary objective was to evaluate the cumulative incidence of nonrelapse mortality (NRM) on day +100. Forty-four patients (36 with acute myelogenous leukemia, 5 with acute lymphoblastic leukemia, 3 with myelodysplastic syndromes) were enrolled. The median patient age was 47 years, and the median duration of follow-up was 27 months. The conditioning regimen was based on clofarabine 40 mg/m2 (days -6 to -2) and treosulfan 14 g/m2 (days -6 to -4). Allogeneic hematopoietic stem cells were derived from a sibling (n = 22) or a well-matched unrelated donor (n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, rituximab, cyclosporine, and a short-course of methotrexate. The regimen allowed for rapid engraftment and a 100-day NRM of 18%, due mainly to bacterial infections. The incidences of grade II-IV acute GVHD and chronic GVHD were 16% and 19%, respectively. The rates of overall survival (OS), progression-free survival, and relapse at 2 years were 51%, 31%, and 50%, respectively. Significantly different outcomes were observed between patients with low-intermediate and patients with high-very high Disease Risk Index (DRI) scores (1-year OS, 78% and 24%, respectively). Our findings show that the use of treosulfan and clofarabine as a conditioning regimen for allo-HSCT is feasible, with a 78% 1-year OS in patients with a low-intermediate DRI score. However, 1-year NRM was 18%, and despite the intensified conditioning regimen, relapse incidence remains a major issue in patients with poor prognostic risk factors.

Background and Purpose: The topotherapy technique was recently suggested as a robust alternative to helical radiation delivery for total body irradiation (TBI). It allows to deliver a discrete number of beams with fixed gantry. A Topotherapy-based low-dose TBI technique was optimized and clinically implemented. Materials and methods: TBI delivery was split in two parts: the first treating from the head to half thigh and the second the remaining legs. An in-silico investigation aimed to optimize plan parameters was first carried out on four patients. For the upper plan, field width and pitch were fixed to 5 cm and 0.5: the combined impact of five modulation factor (MF) values and different field configurations (6/8/12 fields) was investigated. For the lower plan, two anterior/posterior beams (field width: 5 cm; pitch: 0.5; MF:1.5) were used. After assessing the optimal technique, set-up/quality assurance/image-guidance procedures were defined and the technique clinically implemented: 23 patients were treated up to now. Results: The best compromise between treatment time and planning target volume (PTV) coverage/homogeneity was found for MF = 1.5 and 8 fields. All clinical plans were automatically optimized using an “ad-hoc” plan template: excellent PTV coverage (PTV95%>98.5%) and homogeneity (median SD:4%) were found with a median beam-on time of 17/9 min for the upper/lower plan. All patients were successfully treated and transplanted. Conclusions: TBI delivered with the topotherapy approach robustly guarantees adequate coverage and dose homogeneity. Semi-automatic clinical plans can be quickly generated and efficiently delivered. Keywords: TBI, TomoDirect, Tomotherapy, Automatic planning

Highlights • COVID-19, such as other coronaviruses, is associated with psychiatric implication. • 55% of the sample presented a clinical score for at least one mental disorder. • Psychiatric history, setting, and length of hospitalization influenced psychopathology. • Females suffered more than males, scoring higher in all the measures. • There is the need to diagnose and treat psychiatric sequelae in COVID-19 survivors., Infection-triggered perturbation of the immune system could induce psychopathology, and psychiatric sequelae were observed after previous coronavirus outbreaks. The spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID-19) pandemic could be associated with psychiatric implications. We investigated the psychopathological impact of COVID-19 in survivors, also considering the effect of clinical and inflammatory predictors. We screened for psychiatric symptoms 402 adults surviving COVID-19 (265 male, mean age 58), at one month follow-up after hospital treatment. A clinical interview and a battery of self-report questionnaires were used to investigate post-traumatic stress disorder (PTSD), depression, anxiety, insomnia, and obsessive-compulsive (OC) symptomatology. We collected sociodemographic information, clinical data, baseline inflammatory markers and follow-up oxygen saturation levels. A significant proportion of patients self-rated in the psychopathological range: 28% for PTSD, 31% for depression, 42% for anxiety, 20% for OC symptoms, and 40% for insomnia. Overall, 56% scored in the pathological range in at least one clinical dimension. Despite significantly lower levels of baseline inflammatory markers, females suffered more for both anxiety and depression. Patients with a positive previous psychiatric diagnosis showed increased scores on most psychopathological measures, with similar baseline inflammation. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, positively associated with scores of depression and anxiety at follow-up. PTSD, major depression, and anxiety, are all high-burden non-communicable conditions associated with years of life lived with disability. Considering the alarming impact of COVID-19 infection on mental health, the current insights on inflammation in psychiatry, and the present observation of worse inflammation leading to worse depression, we recommend to assess psychopathology of COVID-19 survivors and to deepen research on inflammatory biomarkers, in order to diagnose and treat emergent psychiatric conditions.

Cyclosporine A (CSA) and methotrexate (MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplantation cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients treated with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myelogenous leukemia. In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2 years compared with CSA/MTX (41.1% versus 21.3%; P = .039). The incidences of day +180 grade II-IV acute GVHD and 2-year chronic GVHD were comparable in the PTCy and CSA/MTX arms (25.2% versus 25.4% [P = .90] and 42.6% versus 42.6% [P = .84], respectively). Similarly, 2-year leukemia-free survival (LFS; 54.4% versus 74.32%; P = .052), overall survival (OS; 70.6% versus 79.7%; P = .15), and GVHD-free relapse-free survival (GRFS; 38.1% versus 52.5%; P = .49) were not statistically different in the 2 arms. Our data show that GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS as seen with conventional CSA/MTX in patients undergoing allo-HCT from an MSD. The higher rate of relapse observed with PTCy needs further evaluation in a prospective study. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI)-based versus chemotherapy (CT)-based MAC regimens in patients with acute lymphoblastic leukemia (ALL). The study included 427 patients who underwent first haplo-HCT with post-transplantation cyclophosphamide (PTCy), following TBI-based (n = 188; 44%) or CT-based (n = 239; 56%) MAC. The median patient age was 32 years. Fludarabine-TBI (72%) and thiotepa-busulfan-fludarabine (65%) were the most frequently used TBI- and CT-based regimens, respectively. In the TBI and CT cohorts, 2-year leukemia-free survival (LFS) was 45% versus 37% (P = .05), overall survival (OS) was 51% versus 47% (P = .18), relapse incidence (RI) was 34% versus 32% (P = .44), and nonrelapse mortality (NRM) was 21% versus 31% (P < .01). In the multivariate analysis, TBI was associated with lower NRM (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.33 to 0.86; P = .01), better LFS (HR, 0.71; 95% CI, 0.52 to 0.98; P =.04), and increased risk for grade II-IV acute graft-versus-host disease (GVHD) (HR, 1.59; 95% CI, 1.08 to 2.34; P = .02) compared with CT-based MAC. The type of conditioning regimen did not impact RI, chronic GVHD, OS, or GVHD-free, relapse-free survival after adjusting for transplantation-related variables. TBI-based MAC was associated with lower NRM and better LFS compared with CT-based MAC in patients with ALL after haplo-HCT/PTCy.