Multicenter Observational Retrospective Study on Febrile Events in Patients with Acute Myeloid Leukemia Treated with Cpx-351 in "Real-Life": The SEIFEM Experience

: In the present study, we aimed to evaluate the absolute risk of infection in the real-life setting of AML patients treated with CPX-351. The study included all patients with AML from 30 Italian hematology centers of the SEIFEM group who received CPX-351 from July 2018 to June 2021. There were 200 patients included. Overall, 336 CPX-351 courses were counted: all 200 patients received the first induction cycle, 18 patients (5%) received a second CPX-351 induction, while 86 patients (26%) proceeded with the first CPX-351 consolidation cycle, and 32 patients (10%) received a second CPX-351 consolidation. A total of 249 febrile events were recorded: 193 during the first or second induction, and 56 after the first or second consolidation. After the diagnostic work-up, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were classifiable as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. The overall 30-day mortality rate was 14% (28/200). The attributable mortality-infection rate was 6% (15/249). A lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis [p-value: 0.004, OR 0.05, 95% CI 0.01-0.39]. Our study confirms the good safety profile of CPX-351 in a real-life setting, with an incidence of infectious complications comparable to that of the pivotal studies; despite prolonged neutropenia, the incidence of fungal infections was low, as was infection-related mortality

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features

The impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%

Psychological Counseling Service “Together” at University of Genoa: Students’ Psychological Profile in Pre and Post Pandemic

none6The present explorative study aims to analyze the profiles of students seeking help in the two areas (emotion/relation or learning areas) of a psychological counseling service for students at the University of Genoa to better understand their request for support in pre- and post-pandemic periods. A total of 229 university students seeking for help from November 2018 to December 2021 completed a psychological battery investigating emotion regulation difficulties and pathological domains of personality (students taken in charge by the emotion/relation area) or motivation issues and anxiety and resilience levels (students taken in charge by the learning area). Regarding the emotion/relation area, results show that problems in emotion dysregulation, and especially in regulating positive emotions, are associated to several pathological domains of personality, such as Psychoticism, Antagonism, Disinhibition, Detachment, and Negative Affectivity. Among the learning area, motivational aspects concerning confidence in one’s intelligence, academic self-efficacy, and learning goals are differently associated with anxiety and resilience above and beyond other aspects, such as attributions. Some limited but significant differences emerge from the comparison between pre- and post-COVID periods: a reduction in detachment in students attending the emotion/relation area, an increase of students with high levels of anxiety in the learning area. These results support the importance of continually operating on emotional and motivational aspects to enhance the students’ well-being and thus sustaining their academic careers.openPace, Cecilia Serena; Usai, Maria Carmen; Bizzi, Fabiola; Minetto, Patrizia; Alcetti, Alberta; Zanobini, MirellaPace, Cecilia Serena; Usai, Maria Carmen; Bizzi, Fabiola; Minetto, Patrizia; Alcetti, Alberta; Zanobini, Mirell

Long-Term Real-World Experience of CPX-351 in Combined French-Italian Cohorts Identified High Rate of Negative Measurable Residual Disease (MRD) and Prolonged Overall Survival

International audienceIntroduction CPX-351 is a liposomal formulation of cytarabine and daunorubicin packaged at a 5:1 molar ratio. This drug has been approved by the FDA and EMEA for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML) according to the WHO 2016 AML classification. Real world experience from several countries (France, Italy, Germany, UK and US) showed similar results of phase 3 clinical registration but with short follow-up. Lancet et al. published a long-term update of phase 3 clinical trial and confirmed long-term remission and improvement of overall survival (OS) ( Lancet Haematology 2021). Thus, the primary objective of this study was to analyze the efficacy of CPX-351 in a real-life setting with a longer follow-up, evaluating the impact of measurable residual disease (MRD) in responding patients. Methods We retrospectively collected data from patients treated with CPX-351 in thirty-six centers in France and Italy. Overall response rate (ORR) was defined by complete remission (CR) and CR with incomplete hematological recovery (CRi). Among the patients in CR or CRi, 62 (61%) had MRD evaluation assessed by next-generation sequencing (NGS) or flow cytometry. OS was calculated from the date of AML diagnosis to the date of death or last follow-up. All statistical analysis were performed using SPSS v.22 software (IBM SPSS Statistics). Results Between April 2018 and October 2019, 170 patients treated with CPX-351 were included in this study. The sex ratio male/female was 80/90 and the median age was 66 years (range 20-83). AML subtypes were MRC-AML in 117 (69%) and t-AML 48 (28%) patients. According to the European LeukemiaNet (ELN) 2017 classification, genetic risk was favorable, intermediate, and adverse in 8 (5%), 61 (36%), and 98 (58%) (missing for 3 patients), respectively. According to the ELN 2022 classification, genetic risk was favorable, intermediate, and adverse in 8 (5%), 16 (9%) and 143 (84%), respectively. Thirty percent and 19% of patients had complex and monosomal karyotypes, respectively. Assessed by NGS the most frequent mutated genes were: TP53 (n=35, 21%), RUNX1 (n=30, 18%), ASXL1 (n=22, 13%) and TET2 (n=18, 11%) among the XX were NGS was available (sinon ca fait des % qui ne tombe pas juste sur les 170 pts). According to a genetic ontogeny-based classifier (Lindsley et al., Blood 2015), 28 %, 39% and 33% had de novo/pan-AML, secondary type mutations AML, and TP53 mutated AML, respectively. The ORR was 102/170 (60%) after one (n=91) or two (n=11) inductions including 53% CR and 6% CRi. Among the 102 CR/CRi patients, 62 (61%) were evaluable for MRD after induction or after first consolidation. Forty (65%) patients had MRD below the threshold of 10 -3. ELN2017 and ELN2022 were identified as factors predicting CR/CRi rate ( P=0.032 and P=0.043, respectivelyà but the Lindsley classifier did not predict response ( P= 0.060). After 3-years of follow-up, in a univariate analysis, only MRD &gt;10 -3 ( P=0.031); ELN 2017 classification ( P=0.027) and presence of TP53 mutation ( P=0.017) but not ELN 2022 or the Lindsley classifier; were associated with a significantly poorer median OS. In a multivariate analysis, only MRD &gt;10 -3 was associated with a poorer OS (hazard ratio [HR]=2.6, 95% CI 1.2-5.5, P=0.013). Median OS was 40.9 months vs. 10.6 months for patients with MRD &lt;10 -3 vs. ≥10 -3, respectively ( P=0.006). Sixty (35%) patients underwent an allogeneic hematopoietic stem cell transplant (HSCT) with an improved median OS compared to non-transplanted patients (not-reached vs. 9.1 months, P&lt;0.0001). We also observed a trend towards a better median OS in transplanted patients who underwent an HSCT with MRD &lt;10 -3 (not reached vs. 26.0 months, P=0.06). Conclusion After 3 years of follow-up, the improved OS with CPX-351 was confirmed in the real- life setting. Achievement of MRD negativity contributed to improvement of OS in the overall population and, maybe, in transplanted patients. These data provide the rationale for the ongoing ALFA-2101 phase III clinical trial evaluating CPX-351 vs. 3+7 (daunorubicin and cytarabine) in non-MRC-AML and non-t-AML using MRD as the primary endpoint

Engagement entrepreneurial et territoires

Les nouvelles technologies de l’information et de la communication ont transformé et rendu caduque la notion même de territoire : dans la réalité, celui-ci n’est plus le résultat d’un découpage administratif, mais coïncide avec l’usage qui lui est prêté. À la notion d’une géographie du territoire spatialement délimitée se substitue celle d’un territoire réticulaire dont les limites deviennent indéfinissables. Penser l’ancrage territorial des entreprises (qui ne doit pas, cependant, apparaître comme antagoniste au concept du nomadisme), permet d’interroger le développement des territoires. Par ailleurs, cet ancrage facilite l’inscription durable de ce type d’organisations dans une réalité locale, en leur octroyant une légitimité dans les questions relevant du social et de l’environnement. L’engagement entrepreneurial en matière d’emploi, de formation, de sensibilisation à la culture, de responsabilité écologique, etc., contribue au développement territorial car les initiatives des entreprises en accompagnant la croissance des acteurs économiques et des partenaires locaux, participent également de la vie citoyenne. Se pose alors la question des moyens financiers, technologiques, humains, etc. Comment repenser la relation entreprise-territoire comme une source de compétitivité et cela à des échelles différentes (locale, régionale, nationale) ? Comment matérialiser l’engagement ? Comment entraîner les « parties prenantes » dans une spirale vertueuse d’aménagement des territoires ? C’est à l’ensemble de ces questions que répondent les contributions publiées dans ce dossier

Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory t-cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study

The outcome of relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T-ALL/T-LBL, but the information to support its use is based on limited available data. The aim of this observational phase 4 study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T-ALL/T-LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post-SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18-74), 73% were male, 77 had a diagnosis of T-ALL and 41 of T-LBL, and 65/118 (55%) had received &gt;2 lines of therapy. The median number of nelarabine cycles was 2 (range 1-4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs. 22 %, log-rank P=0.0001. The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy-five patients (64%) experienced one or more drug-related adverse events (AE). Grade III-IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III-IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T-ALL/T-LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III-IV neurological AE. This article is protected by copyright. All rights reserved

Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T‐cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study

The outcome of relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T-ALL/T-LBL, but the information to support its use is based on limited available data. The aim of this observational phase 4 study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T-ALL/T-LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post-SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18-74), 73% were male, 77 had a diagnosis of T-ALL and 41 of T-LBL, and 65/118 (55%) had received &gt;2 lines of therapy. The median number of nelarabine cycles was 2 (range 1-4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs. 22 %, log-rank P=0.0001. The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy-five patients (64%) experienced one or more drug-related adverse events (AE). Grade III-IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III-IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T-ALL/T-LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III-IV neurological AE. This article is protected by copyright. All rights reserved

CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program

Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p\u2009=\u20090.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p\u2009=\u20090.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT