Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Relapsed/ Refractory Large B-Cell Lymphoma (R/R LBCL): 2-Year Follow-up of Zuma-1 Cohort 6

Background: The ZUMA-1 safety management Cohort 6 (N=40), which evaluated whether prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab could improve safety outcomes, demonstrated an improved safety profile (no Grade >=3 cytokine release syndrome [CRS];15% Grade >=3 neurologic events [NEs]) vs pivotal Cohorts 1+2, without compromising response rate or durability (95% ORR, 80% CR rate, and 53% ongoing response rate with >=1 y of follow-up;Oluwole, et al. ASH 2021. 2832). Here, 2-y updated outcomes are reported. Method(s): Eligible pts with R/R LBCL underwent leukapheresis (followed by optional bridging therapy) and conditioning chemotherapy, then a single axi-cel infusion. Pts received corticosteroid prophylaxis (once-daily oral dexamethasone 10 mg on Days 0 [before axi-cel], 1, and 2) and earlier corticosteroids and/or tocilizumab for CRS and NE management vs Cohorts 1+2 (Oluwole, et al. Br J Haematol. 2021). The primary endpoints were incidence and severity of CRS and NEs. Secondary endpoints included ORR (investigator-assessed), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and chimeric antigen receptor (CAR) T-cell levels in blood. Result(s): As of December 16, 2021, the median follow-up time for the 40 treated pts was 26.9 mo. Since the 1-y analysis, no new CRS events were reported (no pts had Grade >=3 CRS to date). The incidence of Grade >=3 NEs increased from 15% to 18%between the 1-y and 2-y analyses. Two new NEs occurred in 2 pts: 1 pt had Grade 2 dementia (onset on Day 685 and ongoing at time of data cutoff;not related to axi-cel) and 1 had Grade 5 axi-cel-related leukoencephalopathy. Since the 1-y analysis, 6 new infections were reported (Grades 1, 2, and 5 COVID-19 [n=1 each], Grade 3 Pneumocystis jirovecii pneumonia [n=1], Grade 3 unknown infectious episode with inflammatory syndrome [n=1], and Grade 2 herpes zoster [n=1]). In total, 8 deaths occurred since the 1-y analysis (progressive disease [n=5], leukoencephalopathy [n=1], and COVID-19 [n=2]). The ORR was 95% (80% CR), which was unchanged from the 1-y analysis. Median DOR and PFS were since reached (25.9 mo [95% CI, 7.8-not estimable] and 26.8 mo [95% CI, 8.7-not estimable], respectively). Median OS was still not reached. Kaplan- Meier estimates of the 2-y DOR, PFS, and OS rates were 53%, 53%, and 62%, respectively. Of 18 pts (45%) in ongoing response at data cutoff, all achieved CR as the best response. By Month 24, 14/20 pts with evaluable samples (70%) had detectable CAR T cells (vs 23/36 pts [64%] in Cohorts 1+2). Conclusion(s): With 2 y of follow-up, the ZUMA-1 Cohort 6 toxicity management strategy continued to demonstrate an improved long-term safety profile of axi-cel in pts with R/R LBCL. Further, responses remained high, durable, and similar to those observed in Cohorts 1+2 (Locke, et al. Lancet Oncol. 2019).Copyright © 2023 American Society for Transplantation and Cellular Therapy

Increased blood viscosity and red blood cell aggregation in patients with COVID-19

Background: Endothelial injury, hypercoagulability, and decreased blood flow are suspected to play a key role in thrombosis,multiorgan failure, and death of patients with COVID-19. The link between increased blood viscosity and COVID-19- related complications and severity is not formerly established and can only be suspected. Aim(s): The aim of this study was to (1) analyze blood viscosity, red blood cell (RBC) deformability, and aggregation in hospitalized patients with Coronavirus disease 19 (COVID-19);(2) test the associations between impaired blood rheology and blood coagulation;and (3) test the associations between impaired blood rheology and several indicators of clinical severity. Method(s): A total of 172 patients with COVID-19, hospitalized in COVID-unit of the Internal Medicine Department (Lyon, France) participated in this study between January and May 2021. Clinical parameters were collected for each patient. Routine hematological/ biochemical parameters, blood viscosity, RBC deformability and aggregation, and RBC senescence markers were measured on the first day of hospitalization. A control group of 38 healthy individuals was constituted to compare the blood rheological and RBC profile. Rotational thromboelastography was performed in 76 patients to study clot formation dynamics. Result(s): Our study demonstrated that patients with COVID-19 had increased blood viscosity despite lower hematocrit than healthy individuals, as well as increased RBC aggregation. In-vitro experiments demonstrated a strong contribution of plasma fibrinogen in this RBC hyper-aggregation. RBC aggregation correlated positively with clot firmness, negatively with clot formation time, and positively with the length of hospitalization. Patients with oxygen supplementation had higher RBC aggregation and blood viscosity than those without, and patients with pulmonary lesions had higher RBC aggregation and enhanced coagulation than those without. Conclusion(s): This study is the first to demonstrate blood hyper-viscosity and RBC hyper-aggregation in a large cohort of patients with COVID-19 and describe associations with enhanced coagulation and clinical outcomes.

Adverse reaction reporting and inquiries about COVID-19 vaccines from general practitioners

Introduction: Since the beginning of 2021, general practitioners (GPs) have been massively confronted with adverse drug reactions (ADRs) reported by their patients vaccinated against COVID-19. They were also greatly solicited by their patients, and they had themselves numerous questions about COVID-19 vaccines. Material and methods: Between January and August 2021, we retrospectively analyzed (i) the requests for information concerning COVID-19 vaccines addressed by GPs to the Regional Centre of Pharmacovigilance (CRPV) of Montpellier France, and (ii) the ADRs related to COVID-19 vaccines reported to the French pharmacovigilance system by GPs at the national level. Results: During this period, the CRPV of Montpellier received 121 requests concerning COVID-19 vaccines from GP (6% of the total requests sent to the CPRV). Compared to previous years, requests from GPs increased threefold in 2021. More than 50% of the requests concerned the indication, with 39% concerning the indication of the second dose in the case of ADR reported after the first dose. The questions were mainly about COMIRNATY (63%) (the most administered vaccine) and VAXZEVRIA (27%) (the vaccine whose serious risks such as atypical thrombosis were most discussed). After increasing until May, the number of monthly requests decreased. At the national level, up to August 2021, 28,115 AEs were reported by French GPs (30% of total reports). Nearly 20% concerned serious and unexpected ADR. The most frequently reported serious ADR were similar to other reporters. Reporting rate varied from 0.15 to more than 0.4 reports per GP across the country. With more than 2000 reports, the number ADRs reported by GPs to the CRPV of Montpellier was multiplied by more than 50 compared to previous years. Discussion/Conclusion: The centrality of GPs in the vaccine campaign and their proximity to patients largely explains their increased requests to the pharmacovigilance system and their high involvement in COVID-19 vaccine surveillance.

Preliminary results of the FILO phase 2 trial for untreated fit patients with intermediate risk chronic lymphocytic leukemia comparing ibrutinib plus venetoclax (IV) vs. FCR

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate-risk CLL defined by either unmutated IGHV status, 11q deletion, or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, i.e. FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from the month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9;if bone marrow (BM) MRD was <0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped;if BM MRD at M9 was ≥0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD <0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy, and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well-balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV), and Binet stage (A, B, and C 15, 64, 21% for FCR;8.5, 59, and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for all cohort was 12.7 [4.5.9-21.4] months. The frequency of patients presenting all grades adverse events (AE) so far was 90% (grade ≥3: 45%) in the FCR arm and 80% (grade ≥3: 45%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4);for the IV arm, 5% of patients experienced tumor lysis syndrome (TLS) (grade 3 for 1 patient). Ibrutinib doses were reduced for seven patients (four permanently stopped and three resumed at a lower dose because of toxicities (digestive, hepatic, or hematological). Venetoclax was permanently discontinued before M9 in four patients (digestive toxicities and grade 4 neutropenia). Fifty-two serious adverse events were reported of which 22 were in the IV arm (among them one sudden death, one ischemic stroke, one acute coronary syndrome, two atrial fibrillations, two TLS, two acute renal failures, one hepatitis, one neutropenia, two COVID pneumonitis, and one osteoporotic fracture) and 30 in the FCR arm (among them five febrile neutropenia, one hemolytic anemia, one thrombocytopenia, three IRR, three TLS, three COVID pneumonitis, one acute myeloid leukemia, one myelodysplasic syndrome). All patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for three of them. The first 85 patients included in the study have reached M9 and among them, nine prematurely discontinued the study, (one active hemolysis, one ischemic stroke, one TLS, one hepatitis, and one sudden death in the IV arm;three hematologic toxicities and one early progression in the FCR arm). In the evaluated patients (n=74), 69% of patients in the FCR arm and 43% of patients in the IV arm achieved bone BM MRD <0.01%. The complete (CR, CRi) and partial response rates were 56 and 44% in the FCR arm and 74 and 26% in the IV arm, respectively. In conclusion, preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate may improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy.

Preliminary Results of the Filo Phase 2 Trial for Untreated Fit Patients with Intermediate Risk Chronic Lymphocytic Leukemia Comparing Ibrutinib Plus Venetoclax (IV) Versus FCR

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate risk CLL defined by either unmutated IGHV status, 11q deletion or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, ie FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9;if bone marrow (BM) MRD was < 0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped;if BM MRD at M9 was ≥ 0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD < 0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV) and Binet stage (A, B and C 15%, 64%, 21% for FCR;8.5%, 59% and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for the all cohort was 11 [2.9 - 19.8] months. The frequency of all grades adverse events (AE) observed so far was 53% (grade 3-4, 24%) in the FCR arm and 47% (grade 3-4, 17%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4);for the IV arm, 6% of patients experienced tumor lysis syndrome (TLS) (grade 4 for 4 patients). ibrutinib doses were reduced for 7 patients (4 permanently stopped and 3 resumed at a lower dose because of toxicities (digestive, hepatic or haematological)). Venetoclax was permanently discontinued before M9 in 4 patients (digestive toxicities and grade 4 neutropenia). Forty serious adverse events were reported of which 15 in the IV arm (1 sudden death, 1 ischemic stroke, 2 atrial fibrillations, 2 clinical TLS, 1 hepatitis, 1 neutropenia, 4 COVID pneumonitis and one osteoporotic fracture) and 25 in the FCR arm (2 neutropenias, 1 anemia, 1 thrombocytopenia, 1 autoimmune haemolytic anemia, 3 IRR, 4 TLS, 2 COVID pneumonitis, 4 fever episodes of undetermined origin, 1 community-acquired pneumonia, 1 gastrointestinal toxicity, 1 confusion, 2 chest pains, 1 acute myeloid leukemia, 1 myelodysplasic syndrome). The patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for 3 of them. The first 60 patients included in the study have reached M9 and among them, 6 prematurely discontinued the study, 3 in each arm (active hemolysis, ischemic stroke and sudden death in the IV arm;2 grade 4 hematologic toxicities and 1 early progression in the FCR arm). In the evaluated patients (n=54), 71% of patients in the FCR arm and 48% of patients in the IV arm achieved bone BM MRD < 0.01%. The complete (CR, CRi) and partial response rates were 54% and 46% in the FCR arm and 76% and 24% in the IV arm respectively. In conclusion, the preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with a toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate should improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy. Disclosures: Quinquenel: Abbvie: Honoraria;Jansse : Honoraria;AstraZeneca: Honoraria. Laribi: Le Mans Hospital: Research Funding;Novartis: Other: Personal Fees, Research Funding;Takeda: Other: Personal Fees, Research Funding;BeiGene: Other: Personal Fees;IQONE: Other: Personal Fees;AbbVie: Other: Personal Fees, Research Funding;Astellas Phama, Inc.: Other: Personal Fees;AstraZeneca: Other: Personal Fees;Jansen: Research Funding. Cymbalista: Lilly-LOXO: 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;ASTRA ZENECA: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: 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. Leblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Lilly: Consultancy;AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support;Roche: Honoraria;Amgen: Honoraria;Beigene: 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. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress;Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress;Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Ferrant: Janssen: Other: Travel, Accommodations, Expenses;AbbVie: Honoraria, Other: Travel, Accommodations, Expenses;AstraZeneca: Honoraria. de Guibert: Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria;Gilead: Consultancy, Honoraria. Feugier: Astrazeneca: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Amgen: Honoraria;Janssen: Consultancy, Honoraria. Cartron: Roche, Celgene-BMS: Consultancy;Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding.

Dietary obesity in mice is associated with lipid deposition and metabolic shifts in the lungs sharing features with the liver.

Obesity is associated with both chronic and acute respiratory illnesses, such as asthma, chronic obstructive pulmonary disease (COPD) or increased susceptibility to infectious diseases. Anatomical but also systemic and local metabolic alterations are proposed contributors to the pathophysiology of lung diseases in the context of obesity. To bring perspective to this discussion, we used NMR to compare the obesity-associated metabolomic profiles of the lung with those of the liver, heart, skeletal muscles, kidneys, brain and serum from male C57Bl/6J mice fed with a high-fat and high-sucrose (HFHSD) diet vs. standard (SD) chow for 14 weeks. Our results showed that the lung was the second most affected organ after the liver, and that the two organs shared reduced one-carbon (1C) metabolism and increased lipid accumulation. Altered 1C metabolism was found in all organs and in the serum, but serine levels were increased only in the lung of HFHSD compared to SD. Lastly, tricarboxylic acid (TCA)-derived metabolites were specifically and oppositely regulated in the serum and kidneys but not in other organs. Collectively, our data highlighted that HFHSD induced specific metabolic changes in all organs, the lung being the second most affected organ, the main alterations affecting metabolite concentrations of the 1C pathway and, to a minor extend, TCA. The absolute metabolite quantification performed in this study reveals some metabolic specificities affecting both the liver and the lung, that may reveal common metabolic determinants to the ongoing pathological process.