Outcomes in Critically Ill Allogeneic Hematopoietic Stem-Cell Transplantation Recipients.

Rationale: Allogeneic hematopoietic stem-cell transplantation (Allo-HSCT) recipients are still believed to be poor candidates for ICU management. Methods: We investigated outcomes and determinants of mortality in a large multicenter retrospective cohort of Allo-HSCT patients admitted between January 1, 2015, and December 31, 2020, to 14 French ICUs. The primary endpoint was 90-day mortality. Measurements and Main Results: In total, 1,164 patients were admitted throughout the study period. At the time of ICU admission, 765 (66%) patients presented with multiple organ dysfunction, including acute respiratory failure in 40% (n = 461). The median sepsis-related organ failure assessment score was 6 (interquartile range, 4-8). Invasive mechanical ventilation, renal replacement therapy, and vasopressors were required in 438 (38%), 221 (19%), and 468 (41%) patients, respectively. ICU mortality was 26% (302 deaths). Ninety-day, 1-year, and 3-year mortality rates were 48%, 63%, and 70%, respectively. By multivariable analysis, age > 56 years (odds ratio [OR], 2.0 [95% confidence interval (CI), 1.53-2.60]; P < 0.001), time from Allo-HSCT to ICU admission between 30 and 90 days (OR, 1.68 [95% CI, 1.17-2.40]; P = 0.005), corticosteroid-refractory acute graft-versus-host disease (OR, 1.63 [95% CI, 1.38-1.93]; P < 0.001), need for vasopressors (OR, 1.9 [95% CI, 1.42-2.55]; P < 0.001), and mechanical ventilation (OR, 3.1 [95% CI, 2.29-4.18]; P < 0.001) were independently associated with 90-day mortality. In patients requiring mechanical ventilation, mortality rates ranged from 39% (no other risk factors for mortality) to 100% (four associated risk factors for mortality). Conclusions: Most critically ill Allo-HSCT recipients survive their ICU stays, including those requiring mechanical ventilation, with an overall 90-day survival rate reaching 51.8%. A careful assessment of goals of care is required in patients with two or more risk factors for mortality.

Multicenter Retrospective Study of Invasive Fusariosis in Intensive Care Units, France.

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002----2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress-Induced Ferroptosis in FLT3-Mutant Leukemia.

Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)-stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application. SIGNIFICANCE: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501.

Necrotizing soft tissue infections in critically ill neutropenic patients: a French multicentre retrospective cohort study.

BACKGROUND: Necrotizing soft tissue infections (NSTIs) are rare life-threatening bacterial infections. Few data are available regarding neutropenic patients with NSTIs. Our objectives were to describe the characteristics and management of neutropenic patients with NSTIs in intensive care units (ICUs). We conducted a retrospective multicentre cohort study in 18 ICUs between 2011 and 2021. Patients admitted with NSTIs and concomitant neutropenia at diagnosis were included and compared to non-neutropenic patients with NSTIs. The relationship between therapeutic interventions and outcomes was assessed using Cox regression and propensity score matching. RESULTS: 76 neutropenic patients were included and compared to 165 non-neutropenic patients. Neutropenic patients were younger (54 ± 14 vs 60 ± 13 years, p = 0.002) and had less lower limb (44.7% vs 70.9%, p < 0.001) and more abdomino-perineal NSTIs (43.4% vs 18.8%, p < 0.001). Enterobacterales and non-fermenting gram-negative bacteria were the most frequently isolated microorganisms in neutropenic patients. In-hospital mortality was significantly higher in neutropenic than in non-neutropenic patients (57.9% vs 28.5%, p < 0.001). Granulocyte colony-stimulating factor (G-CSF) administration was associated with a lower risk of in-hospital mortality in univariable Cox (hazard ratio (HR) = 0.43 95% confidence interval (CI) [0.23-0.82], p = 0.010) and multivariable Cox (adjusted HR = 0.46 95% CI [0.22-0.94], p = 0.033) analyses and after overlap propensity score weighting (odds ratio = 0.25 95% CI [0.09; 0.68], p = 0.006). CONCLUSIONS: Critically ill neutropenic patients with NSTIs present different clinical and microbiological characteristics and are associated with a higher hospital mortality than non-neutropenic patients. G-CSF administration was associated with hospital survival.

Open abdominal vacuum pack technique for the management of severe abdominal complications after cytoreductive surgery in ovarian cancer.

INTRODUCTION: The aim of this study was to evaluate the indications and management of grade III-IV postoperative complications in patients requiring vacuum-assisted open abdomen after debulking surgery for ovarian carcinomatosis. METHODS: Retrospective study of prospectively collected data from patients who underwent a cytoreductive surgery by laparotomy for an epithelial ovarian cancer that required postoperative management of an open abdomen. An abdominal vacuum-assisted wound closure (VAWC) was applied in cases of abdominal compartmental syndrome (ACS) or intra-abdominal hypertension, to prevent ACS. The fascia was closed with a suture or a biologic mesh. The primary aim was to achieve primary fascial closure. Secondary outcomes considered included complications of cytoreductive surgery (CRS) and open abdominal wounds (hernia, fistula). RESULTS: Two percent of patients who underwent CRS required VAWC during the study's patient inclusion period. VAWC indications included: (i) seven cases of gastro-intestinal perforation, (ii) three necrotic enterocolitis, (iii) two intestinal ischemia, (iv) three anastomotic leakages and (v) four intra-abdominal hemorrhages. VAWC was used to treat indications (i) to (iv) (which represented 73.7% of cases), to prevent compartmental syndrome. Primary fascia closure was achieved in 100% of cases, in four cases (21.0%) a biologic mesh was used. Median hospital stay was 65 days (range: 18-153). Four patients died during hospitalization, three of these within 30 days of VAWC completion. CONCLUSION: VAWC for managing open abdominal wounds is a reliable technique to treat surgical post-CRS complications in advanced ovarian cancer and reduces the early post-operative mortality in cases presenting with severe complications.

[Management of cytokine release syndrome and macrophage activation syndrome following CAR-T cell therapy: Guidelines from the SFGM-TC]. / Prise en charge du syndrome de relargage cytokinique et du syndrome d'activation macrophagique après traitement par CAR-T cells : recommandations de la SFGM-TC.

The use of chimeric antigen receptor T cells (CAR-T) has increased since their approval in the treatment of several relapsed/refractory B cell malignancies. The management of their specific toxicities, such as cytokine release syndrome (CRS), tends to be better understood and well-defined. During the twelfth edition of practice harmonization workshops of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), a working group focused its work on the management of patients developing CRS following CAR-T cell therapy. A special chapter has been allocated to macrophage activation syndrome (MAS), a rare but life-threatening complication post-CAR-T. In addition to symptomatic measures and preemptive broad-spectrum antibiotics, immunomodulators such as tocilizumab and corticosteroids remain the corner stone for the treatment of CRS. Tocilizumab/corticosteroids-resistant CRS associated with haemophagocytosis markers (spleen and liver enlargement, hyperferritinaemia>10,000ng/mL, hypofibrinogenemia…) should direct the diagnosis towards an overlapping CRS/MAS. An adapted treatment will be based on high-dose IV anakinra and corticosteroids and chemotherapy with etoposide at late refractory stages. These complications and others delignate the need of close collaboration with an intensive care unit.

[Management of neurotoxicity following CAR-T cell therapy: Recommendations of the SFGM-TC]. / Prise en charge du syndrome de neurotoxicité associée au traitement par cellules CAR-T chez l'adulte et l'enfant : recommandations de la SFGM-TC.

The immune effector cell-associated syndrome (ICANS) has been described as the second most frequent specific complication following CAR-T cell therapy. The median time to the onset of neurological symptoms is five days after CAR-T infusion. ICANS can be concomitant to cytokine release syndrome but often follows the resolution of the latter. However, 10 % of patients experience delayed onset after 3 weeks of CAR-T cell infusion. The duration of symptoms is usually short, around five days if an early appropriate treatment is given. Symptoms are heterogeneous, ranging from mild symptoms quickly reversible (alterations of consciousness, deterioration in handwriting) to more serious forms with seizures or even a coma. The ICANS severity is currently based on the ASTCT score. The diagnosis of ICANS is clinical but EEG, MRI and lumbar punction can help ruling out alternative diagnoses. The first line treatment consists of high-dose corticosteroids. During the twelfth edition of practice harmonization workshops of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), a working group focused its work on updating the SFGM-TC recommendations on the management of ICANS. In this review we discuss the management of ICANS and other neurological toxicities in patients undergoing of CAR-T cell therapy. These recommendations apply to commercial CAR-T cells, in order to guide strategies for the management neurological complications associated with this new therapeutic approach.

Prognostic Impact of Unsupervised Early Assessment of Bulk and Leukemic Stem Cell Measurable Residual Disease in Acute Myeloid Leukemia.

PURPOSE: Acute myeloid leukemias (AML) are clonal diseases that develop from leukemic stem cells (LSC) that carry an independent prognostic impact on the initial response to induction chemotherapy, demonstrating the clinical relevance of LSC abundance in AML. In 2018, the European LeukemiaNet published recommendations for the detection of measurable residual disease (Bulk MRD) and suggested the exploration of LSC MRD and the use of multiparametric displays. EXPERIMENTAL DESIGN: We evaluated the performance of unsupervised clustering for the post-induction assessment of bulk and LSC MRD in 155 patients with AML who received intensive conventional chemotherapy treatment. RESULTS: The median overall survival (OS) for Bulk+ MRD patients was 16.7 months and was not reached for negative patients (HR, 3.82; P < 0.0001). The median OS of LSC+ MRD patients was 25.0 months and not reached for negative patients (HR, 2.84; P = 0.001). Interestingly, 1-year (y) and 3-y OS were 60% and 39% in Bulk+, 91% and 52% in Bulk-LSC+ and 92% and 88% in Bulk-LSC-. CONCLUSIONS: In this study, we confirm the prognostic impact of post-induction multiparametric flow cytometry Bulk MRD in patients with AML. Focusing on LSCs, we identified a group of patients with negative Bulk MRD but positive LSC MRD (25.8% of our cohort) with an intermediate prognosis, demonstrating the interest of MRD analysis focusing on leukemic chemoresistant subpopulations.

Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia.

Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte-monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.

When targeted therapy for cancer leads to ICU admission. RETRO-TARGETICU multicentric study.

PURPOSE: To study prevalence of targeted therapy (TT)-related adverse events requiring ICU admission in solid tumor patients. METHODS: Retrospective multicenter study from the Nine-i research group. Adult patients who received TT for solid tumor within 3 months prior to ICU admission were included. Patients admitted for TT-related adverse event were compared to those admitted for other reasons. RESULTS: In total, 140 patients, median age of 63 (52-69) years were included. Primary cancer site was mostly digestive (n=27, 19%), kidney (n=27, 19%), breast (n=24, 17%), and lung (n=20, 14%). Targeted therapy was anti-VEGF/VEGFR for 27% (n=38) patients, anti-EGFR for 22% (n=31) patients, anti-HER2 for 14% (n=20) patients and anti-BRAF for 9% (n=5) patients. ICU admission was related to TT adverse events for 30 (21%) patients. The most frequent complications were interstitial pneumonia (n=7), cardiac failure (n=5), anaphylaxis (n=4) and bleeding (n=4). At ICU admission, no significant difference was found between patients admitted for a TT-related adverse event and the other patients. One-month survival rate was higher in patients admitted for TT adverse event (OR=5.733 [2.031-16.182] P<0.001). CONCLUSIONS: Adverse events related to targeted therapy accounted for 20% of ICU admission in our population and carried a 16% one-month mortality. Outcome was associated with admission for TT related to adverse event, breast cancer and good performance status.

Critically ill patients with severe infections related to Geotrichum species: A French retrospective multicentre study.

OBJECTIVES: Geotrichum spp can be responsible for severe infections in immunocompromised patients. We aim to describe Geotrichum-related infections in the ICU and to assess risk factors of mortality. METHODS: Retrospective multicentre study, conducted in 14 French ICUs between 2002 and 2018, including critically ill adult patients with proven or probable infection related to Geotrichum species. Data were obtained from the medical charts. RESULTS: Thirty-six patients, median age 60 years IQR [53; 66] were included. Most of the patients had haematological malignancies (78%). The reason for ICU admission was shock in half of the patients (n = 19, 53%) and respiratory failure in thirteen patients (36%). Median SOFA score was 8.5 IQR [7; 15]. Time between ICU admission and fungal diagnosis was 2.5 days [-1; 4]. Infection was disseminated in 27 (75%) patients with positive blood cultures in 25 patients (69%). Thirty patients (83%) received curative antifungal treatment in the ICU, in a median time of 1 day [0;1] after ICU admission. Twenty-four patients (67%) died in the ICU and hospital mortality rate was 69%. The number and extent of organ failures, as represented by SOFA score, were associated with mortality. CONCLUSIONS: This study demonstrates poor outcome in critically ill patients with Geotrichum-related infections, which encourages a high level of suspicion.

Nationwide retrospective study of critically ill adults with sickle cell disease in France.

Little is known about patients with sickle cell disease (SCD) who require intensive care unit (ICU) admission. The goals of this study were to assess outcomes in patients admitted to the ICU for acute complications of SCD and to identify factors associated with adverse outcomes. This multicenter retrospective study included consecutive adults with SCD admitted to one of 17 participating ICUs. An adverse outcome was defined as death or a need for life-sustaining therapies (non-invasive or invasive ventilation, vasoactive drugs, renal replacement therapy, and/or extracorporeal membrane oxygenation). Factors associated with adverse outcomes were identified by mixed multivariable logistic regression. We included 488 patients admitted in 2015-2017. The main reasons for ICU admission were acute chest syndrome (47.5%) and severely painful vaso-occlusive event (21.3%). Sixteen (3.3%) patients died in the ICU, mainly of multi-organ failure following a painful vaso-occlusive event or sepsis. An adverse outcome occurred in 81 (16.6%; 95% confidence interval [95% CI], 13.3%-19.9%) patients. Independent factors associated with adverse outcomes were low mean arterial blood pressure (adjusted odds ratio [aOR], 0.98; 95% CI 0.95-0.99; p = 0.027), faster respiratory rate (aOR, 1.09; 95% CI 1.05-1.14; p < 0.0001), higher haemoglobin level (aOR, 1.22; 95% CI 1.01-1.48; p = 0.038), impaired creatinine clearance at ICU admission (aOR, 0.98; 95% CI 0.97-0.98; p < 0.0001), and red blood cell exchange before ICU admission (aOR, 5.16; 95% CI 1.16-22.94; p = 0.031). Patients with SCD have a substantial risk of adverse outcomes if they require ICU admission. Early ICU admission should be encouraged in patients who develop abnormal physiological parameters.

[Prevention and management of infections in patients undergoing CAR T-cell therapy: Recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Prise en charge prophylactique, thérapeutique des complications infectieuses et vaccination des patients traités par CAR-T cells : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Infections occurring after CAR T-cells are a common complication. At the acute phase of treatment following CAR T-cell infusion, the exact incidence of infections is unknown given the overlapping symptoms with cytokine release syndrome. The risk factors for infection include the malignant underlying disease and its multiple treatments, and an immunosuppressive state induced by CAR-T cells themselves and the treatment of their complications. During the twelfth edition of practice harmonization workshops of the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), a working group focused its work on the management of post-CAR infectious complications. In this review we discuss anti-infection prophylaxis and vaccination of patients undergoing CAR T-cell therapy as well as a special chapter for the specific case of COVID-19. These recommendations apply to commercial CAR-T cells, in order to guide strategies for the management and prevention of infectious complications associated with this new therapeutic approach.

[Complications other than infections, CRS and ICANS following CAR T-cells therapy: Recommendations of the Francophone Society of bone marrow transplantation and cell therapy (SFGM-TC)]. / Complications des cellules CAR-T autres que les infections, CRS et ICANS : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

CAR-T cells are an innovative treatment for an increasing number of patients, particularly since the extension of their indication to mantle lymphoma and multiple myeloma. Several complications of CAR T-cell therapy, that were first described as exceptional, have now been reported in series of patients, since its first clinical use in 2011. Among them, cardiac complications, delayed cytopenias, acute and chronic Graft versus Host Disease, and tumoral lysis syndrome are recognized as specific potent complications following CAR T-cells infusion. During the twelfth edition of practice harmonization workshops of the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), a working group focused its work on the management of these complications with focuses the epidemiology, the physiopathology and the risk factors of these 4 side effects. Our recommendations apply to commercial CAR-T cells, in order to guide strategies for the management of complications associated with this new therapeutic approach.

Sinusoidal Obstruction Syndrome in Critically Ill Patients in the Era of Defibrotide: A Retrospective Multicenter Study.

Sinusoidal obstruction syndrome (SOS) is a life-threatening liver complication of high- dose chemotherapy. Defibrotide is the only available therapeutic option approved for SOS. The prognosis of SOS in patients requiring intensive care unit (ICU) admission remains unknown. The primary objective of this study was to assess the outcome of SOS patients in ICU. This retrospective study was conducted between 2007 and 2019 in 13 French ICUs. Seventy-one critically ill adult patients with SOS defined according to European Society for Blood and Marrow Transplantation criteria and treated with defibrotide were included. The main reasons for ICU admission were respiratory failure and acute kidney injury. Mechanical ventilation, vasopressors, and renal replacement therapy were required in 59%, 52%, and 49% of patients, respectively. Twenty-three percent of patients experienced a bleeding event during defibrotide treatment. Hospital mortality was 54%, mainly related to multiorgan failure. Older age (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00 to 1.04), mechanical ventilation (HR, 1.99; 95% CI, 1.00 to 3.99), renal replacement therapy (HR, 2.55; 95% CI, 1.32 to 4.91) were independent predictors of hospital mortality. Defibrotide prophylaxis (HR, 0.35; 95% CI, 0.13 to 0.92) was associated with better outcomes. Critically ill patients with SOS have a high mortality rate in the ICU, especially if organ support is required. Additional studies assessing the impact of defibrotide prophylaxis are warranted.

Outcomes in patients treated with chimeric antigen receptor T-cell therapy who were admitted to intensive care (CARTTAS): an international, multicentre, observational cohort study.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care. METHODS: This international, multicentre, observational cohort study was done in 21 intensive care units in France, Spain, the USA, the UK, Russia, Canada, Germany, and Austria. Eligible patients were aged 18 years or older; had received CAR T-cell therapy in the past 30 days; and had been admitted to intensive care for any reason. Investigators retrospectively included patients admitted between Feb 1, 2018, and Feb 1, 2019, and prospectively included patients admitted between March 1, 2019, and Feb 1, 2020. Demographic, clinical, laboratory, treatment, and outcome data were extracted from medical records. The primary endpoint was 90-day mortality. Factors associated with mortality were identified using a Cox proportional hazard model. FINDINGS: 942 patients received CAR T-cell therapy, of whom 258 (27%) required admission to intensive care and 241 (26%) were included in the analysis. Admission to intensive care was needed within median 4·5 days (IQR 2·0-7·0) of CAR T-cell infusion. 90-day mortality was 22·4% (95% CI 17·1-27·7; 54 deaths). At initial evaluation on admission, isolated cytokine release syndrome was identified in 101 patients (42%), cytokine release syndrome and ICANS in 93 (39%), and isolated ICANS in seven (3%) patients. Grade 3-4 cytokine release syndrome within 1 day of admission to intensive care was found in 50 (25%) of 200 patients and grade 3-4 ICANS in 38 (35%) of 108 patients. Bacterial infection developed in 30 (12%) patients. Life-saving treatments were used in 75 (31%) patients within 24 h of admission to intensive care, primarily vasoactive drugs in 65 (27%) patients. Factors independently associated with 90-day mortality by multivariable analysis were frailty (hazard ratio 2·51 [95% CI 1·37-4·57]), bacterial infection (2·12 [1·11-4·08]), and lifesaving therapy within 24 h of admission (1·80 [1·05-3·10]). INTERPRETATION: Critical care management is an integral part of CAR T-cell therapy and should be standardised. Studies to improve infection prevention and treatment in these high-risk patients are warranted. FUNDING: Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique.