CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up.

BACKGROUND: Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS: We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded. RESULTS: The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization. CONCLUSIONS: In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).

[Mobilization and conditioning protocols actualization for autologous stem cell transplantation for autoimmune diseases: Guidelines from MATHEC-SFGM-TC]. / Actualisation des protocoles de mobilisation et conditionnement pour la pratique des autogreffes de cellules souches hématopoïétiques chez les patients atteints de maladies auto-immunes : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (MATHEC-SFGM-TC).

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 13th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures in September 2022 in Lille, France. The aim of this workshop is to update the mobilization and conditioning protocols for autologous hematopoietic stem cell transplantation for autoimmune diseases, and to specify contraindications for transplant, conditioning regimen selection, immunosuppressive treatment discontinuation before mobilization and disease-specific surveillance.

Enoxaparin versus dalteparin or tinzaparin in patients with cancer and venous thromboembolism: The RIETECAT study.

Background: Venous thromboembolism (VTE) is a frequent complication in patients with cancer and a leading cause of morbidity and death. Objectives: The objective of the RIETECAT study was to compare the long-term effectiveness and safety of enoxaparin versus dalteparin or tinzaparin for the secondary prevention of VTE in adults with active cancer. Methods: We used the data from the multicenter, multinational RIETE registry to compare the rates of VTE recurrences, major bleeding, or death over 6 months in patients with active cancer and acute VTE using full doses of enoxaparin versus dalteparin or tinzaparin, and a multivariable Cox proportional hazard model was used to analyze the primary end point. Results: From January 2009 to June 2018, 4451 patients with active cancer received full doses of the study drugs: enoxaparin, 3526 patients; and dalteparin or tinzaparin, 925 (754 + 171) patients. There was limited difference in VTE recurrences (2.0% vs 2.5%) and mortality rate (19% vs 17%) between the enoxaparin and dalteparin or tinzaparin subgroups. However, there was a slight numerical increase in major bleeding (3.1% vs 1.9%). Propensity score matching confirmed that there were no differences in the risk for VTE recurrences (adjusted hazard ratio [aHR], 0.81; 95% confidence interval [CI], 0.48-1.38), major bleeding (aHR, 1.40; 95% CI, 0.80-2.46), or death (aHR, 1.07; 95% CI, 0.88-1.30) between subgroups. Conclusions: In RIETECAT, in patients with cancer and VTE receiving full-dose enoxaparin or dalteparin or tinzaparin, no statistically significant differences were observed regarding effectiveness and safety outcomes over a 6-month period.

Outcome of Cancer-Associated Venous Thromboembolism Is More Favorable among Patients with Hematologic Malignancies than in Those with Solid Tumors.

BACKGROUND: The natural history of patients with hematologic cancer and venous thromboembolism (VTE) has not been consistently evaluated. We aimed to compare the rates of symptomatic recurrent VTE, major bleeding, or death during anticoagulant therapy in patients with VTE associated with hematologic versus solid cancers. METHODS: Consecutive patients with active cancer recruited in RIETE were evaluated. Their baseline characteristics, treatments, and outcomes during the course of anticoagulation were compared. Univariate and multivariate competing-risk analyses were performed. RESULTS: As of December 2020, 16,694 patients with cancer and VTE were recruited. Of these, 1,062 (6.4%) had hematologic cancers. Hematologic patients were less likely to initially present with pulmonary embolism (46 vs. 55%) and more likely with upper extremity deep vein thrombosis (25 vs. 18%). They also were more likely to have severe thrombocytopenia at baseline (5.6 vs. 0.7%) or to receive chemotherapy (67 vs. 41%). During the course of anticoagulation (median, 150 vs. 127 days), 1,071 patients (6.4%) developed VTE recurrences, 806 (4.8%) suffered major bleeding, and 4,136 (24.8%) died. Patients with hematologic cancers had lower rates of recurrent VTE (rate ratio [RR]: 0.73; 95% confidence interval [CI]: 0.56-0.95), major bleeding (RR: 0.72; 95% CI: 0.53-0.98), or all-cause death (RR: 0.49; 95% CI: 0.41-0.57) than those with solid cancers. Patients with multiple myeloma showed the best outcomes. CONCLUSION: Patients with hematologic cancers, particularly multiple myeloma, and VTE had better outcomes than those with solid cancers. These findings are relevant for the interpretation of previous clinical trials and the design of future studies.

The Survey on Cellular and Tissue-Engineered Therapies in Europe in 2016 and 2017.

This report describes activity in Europe for the years 2016 and 2017 in the area of cellular and tissue-engineered therapies, excluding hematopoietic stem cell treatments for the reconstitution of hematopoiesis. It is the eighth of its kind and is supported by five established scientific organizations. In 2016 and 2017, a combined 234 teams from 29 countries responded to the cellular and engineered tissue therapy survey; 227 teams reported treating 8236 patients in these 2 years. Indications were categorized in hematology/oncology (40%; predominantly prevention or treatment of graft vs. host disease and hematopoietic graft enhancement), musculoskeletal/rheumatological disorders (29%), cardiovascular disorders (6%), neurological disorders (4%), gastrointestinal disorders (<1%), as well as miscellaneous disorders (20%), which were not assigned to the previous indications. The predominantly used cells were autologous (61%). The majority of autologous cells were used to treat musculoskeletal/rheumatological (44%) disorders, whereas allogeneic cells were mainly used for hematology/oncology (78%). The reported cell types were mesenchymal stem/stromal cells (MSCs) (56%), hematopoietic cells (21%), keratinocytes (7%), chondrocytes (6%) dermal fibroblasts (4%), dendritic cells (2%), and other cell types (4%). Cells were expanded in vitro in 62% of the treatments, sorted in 11% of the cases, and rarely transduced (2%). The processing of cells was outsourced to external facilities in 30% of the cases. Cells were delivered predominantly intravenously or intra-arterially [47%], as suspension [36%], or using a membrane/scaffold (16%). The data are compared with those from previous years to identify trends in a rapidly evolving field. In this edition, the report includes a critical discussion of data collected in the space of orthopedics and the use of MSCs.

Prediction of early mortality in patients with cancer-associated thrombosis in the RIETE Database.

BACKGROUND: Proper risk stratification of patients for early mortality after cancer-associated thrombosis may lead to personalized anticoagulation protocols. Therefore, we aimed to derive and validate a scoring system to predict early mortality in this population. To this end, we selected patients with active cancer and thrombosis from the Computerized Registry of Patients with Venous Thromboembolism database. METHODS: The main outcome was all cause mortality within the month following a thrombotic event. We used a simple random selection to split are data in a derivation and a validation cohort. In the derivation cohort, we used recursive partitioning and binary logistic regression to identify groups at risk and to determine the likelihood of the primary outcome. The risk score was developed based on odds ratios from the final multivariate model, and then tested in the validation cohort. RESULTS: In 10,025 eligible patients, we identified 6 predictors of 30-day mortality: leukocytosis ≥11.5x109/L; platelet count ≤160x109/L, metastasis, recent immobility, initial presentation as pulmonary embolism and Body Mass Index <18.5. The model divided the population into 3 risk categories: low (score 0-3), moderate (score 4-6), and high (score ≥7). The AUC for the overall score was 0.74, and using a cutoff ≥7 points, the model had a negative predictive value of 94.4%, a positive predictive value of 23.1%, a sensitivity of 73.3%, and a specificity of 64.6% in the validation cohort. CONCLUSIONS: Our validated risk model may assist physicians in the selection of patients for outpatient management, and perhaps anticoagulant, considering expanding anticoagulation options.

Anemia and bleeding in patients receiving anticoagulant therapy for venous thromboembolism.

In patients receiving anticoagulant therapy for venous thromboembolism (VTE), the important issue of anemia influence on the risk of bleeding has not been consistently studied. We used the large registry data RIETE (Registro Informatizado Enfermedad Tromboembólica) to compare the rate of major bleeding in patients receiving anticoagulant therapy for VTE according to the presence or absence of anemia at baseline. Patients with or without cancer were separately studied. Until August 2016, 63492 patients had been enrolled. Of these, 21652 (34%) had anemia and 14312 (23%) had cancer. Anemia was found in 57% of the patients with cancer and in 28% without (odds ratio 3.46; 95% CI 3.33-3.60). During the course of anticoagulant therapy, 680 patients with cancer had a major bleeding event (gastrointestinal tract 43%, intracranial 14%, hematoma 12%). Cancer patients with anemia had a higher rate of major bleeding (rate ratio [RR]: 2.52; 95% CI 2.14-2.97) and fatal bleeding (RR 2.73; 95% CI 1.95-3.86) than those without anemia. During the course of anticoagulation, 1133 patients without cancer had major bleeding (gastrointestinal tract 32%, hematoma 24%, intracranial 21%). Patients with anemia had a higher rate of major bleeding (RR 2.84; 95% CI 2.52-2.39) and fatal bleeding (RR 2.76; 95% CI 2.07-3.67) than those without. On a multivariable analysis, anemia independently predicted the risk for major bleeding in patients with and without cancer (hazard ratios: 1.66; 95% CI 1.40-1.96 and 1.95; 95% CI 1.72-2.20, respectively). During anticoagulation for VTE, both cancer- and non-cancer anemic patients had a higher risk for major bleeding than those without anemia. In anemic patients (with or without cancer), the rate of major bleeding during the course of anticoagulant therapy exceeded the rate of VTE recurrences. In patients without anemia the rate of major bleeding was lower than the rate of VTE recurrences.

Analysis of clinical factors affecting the rates of fatal pulmonary embolism and bleeding in cancer patients with venous thromboembolism.

BACKGROUND: In cancer patients with symptomatic venous thromboembolism (VTE) (deep-vein thrombosis (DVT) and/or pulmonary embolism (PE)), clinical factors that influence the benefit-risk balance of anticoagulation need to be identified so treatment intensity and duration can be optimally adjusted for the individual patient. METHODS: Using clinical data for cancer patients with VTE obtained from the RIETE registry, we compared how rates of fatal PE and fatal bleeding during and after anticoagulation vary depending on patients' clinical characteristics. RESULTS: Data were analysed from the 10,962 cancer patients with VTE (5,740 with PE with or without DVT; 5,222 with DVT alone) in RIETE registry as of March 2016. Fatal PE occurred in 2.18% of patients, while fatal bleedings occurred in 1.55%. During the 12 months from initial VTE, fatal PE was the most common cause of death, after disseminating cancer, and bleeding the fourth most common. In patients initially presenting with PE, fatal PE during anticoagulation was 4-fold more frequent than fatal bleeding (204 vs 51 deaths) and occurred mostly during the first month of treatment (196/223, 88%). In patients initially presenting with DVT, fatal PE was 3-fold lower than fatal bleeding during (25 vs 85 deaths) and after anticoagulation treatment (8 vs 37 deaths). During the 12-month follow-up, other characteristics of cancer patients with VTE were identified as more common in fatal cases of PE and/or bleeding than in surviving cases. INTERPRETATION: Baseline clinical characteristics may determine anticoagulation outcomes in cancer patients with VTE and should be further investigated as possible factors for guiding changes in current practices of anticoagulation, such as adjusting anticoagulation intensity and duration in selected patients.

Right heart thrombi in pulmonary embolism.

There is a lack of comprehensive data on the prevalence, predictors and prognostic significance of right heart thrombi (RHT) in pulmonary embolism.In this study of patients with pulmonary embolism from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry, we assessed the prevalence and predictors of RHT, and the association between the presence of RHT and the outcomes of all-cause mortality, pulmonary embolism-related mortality, recurrences, and major bleeding through 30 days after initiation of pulmonary embolism treatment.Of 12 441 patients with pulmonary embolism and baseline echocardiographic data, 2.6% had RHT. The following increased the risk of RHT: younger age, previous bleeding, congestive heart failure, cancer, syncope, systolic blood pressure <100 mmHg, and arterial oxyhaemoglobin saturation <90%. Patients with RHT were significantly more likely to die from any cause (adjusted OR 2.50 (95% CI 1.62-3.84); p<0.001) and from pulmonary embolism (adjusted OR 4.29 (95% CI 2.45-7.48); p<0.001) during follow-up. RHT was associated with an increased risk of recurrence during follow-up (1.8% versus 0.7%; p=0.04). Major bleeding was similar in patients with and without RHT.In patients presenting with pulmonary embolism, RHT is relatively infrequent. Patients with RHT had a worse outcome when compared with those without RHT.

Implementing thrombosis guidelines in cancer patients: a review.

Venous thromboembolism is a frequent and serious complication in patients with cancer. It is an independent prognostic factor of death in cancer patients and the second leading cause of death, but physicians often underestimate its importance, as well as the need for adequate prevention and treatment. Management of venous thromboembolism in patients with cancer requires the coordinated efforts of a wide range of clinicians, highlighting the importance of a multidisciplinary approach. However, a lack of consensus among various national and international clinical practice guidelines has contributed to knowledge and practice gaps among practitioners, and inconsistent approaches to venous thromboembolism. The 2013 international guidelines for thrombosis in cancer have sought to address these gaps by critically re-evaluating the evidence coming from clinical trials and synthesizing a number of guidelines documents. An individualized approach to prophylaxis is recommended for all patients.

Expression of transforming growth factor ß receptor II in mesenchymal stem cells from systemic sclerosis patients.

OBJECTIVES: The present work aimed to evaluate the expression of transforming growth factor-ß (TGF-ß) receptors on bone marrow-derived multipotent mesenchymal stromal cells (MSCs) in patients with systemic sclerosis (SSc) and the consequences of TGF-ß activation in these cells, since MSC have potential therapeutic interest for SSc patients and knowing that TGF-ß plays a critical role during the development of fibrosis in SSc. DESIGN: This is a prospective research study using MSC samples obtained from SSc patients and compared with MSC from healthy donors. SETTING: One medical hospital involving collaboration between an internal medicine department for initial patient recruitment, a clinical biotherapeutic unit for MSC preparation and an academic laboratory for research. PARTICIPANTS: 9 patients with diffuse SSc for which bone marrow (BM) aspiration was prescribed by sternum aspiration before haematopoietic stem cell transplantation, versus nine healthy donors for normal BM. PRIMARY AND SECONDARY OUTCOME MEASURES: TGF-ß, TGF-ß receptor types I (TBRI) and II (TBRII) mRNA and protein expression were assessed by quantitative PCR and flow cytometry, respectively, in MSC from both SSc patients and healthy donors. MSC were exposed to TGF-ß and assessed for collagen 1α2 synthesis and Smad expression. As positive controls, primary cultures of dermal fibroblasts were also analysed. RESULTS: Compared with nine controls, MSC from nine SSc patients showed significant increase in mRNA levels (p<0.002) and in membrane expression (p<0.0001) of TBRII. In response to TGF-ß activation, a significant increase in collagen 1α synthesis (p<0.05) and Smad-3 phosphorylation was upregulated in SSc MSC. Similar results were obtained on eight SSc-derived dermal fibroblasts compared to six healthy controls. CONCLUSIONS: TBRII gene and protein expression defect in MSC derived from SSc patients may have pathological significance. These findings should be taken into account when considering the use of MSC-based therapies in an autologous setting.

Is there a role for TNFα antagonists in the treatment of SSc? EUSTAR expert consensus development using the Delphi technique.

OBJECTIVES: To obtain experiences and expert opinion on treatment of SSc patients with TNF-α antagonists. METHODS: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-α antagonists. Assessment forms on the frequency of TNF-α inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-α inhibitors in SSc. RESULTS: Seventy-nine centres returned information on use of TNF-α antagonists in SSc patients. A total of 65 patients were treated with TNF-α inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-α inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-α antagonists in SSc. Arthritis was suggested as an indication for TNF-α antagonists by 75% of the experts. However, after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-α antagonists decreased and 59% recommended that TNF-α antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-α antagonists for arthritis associated with SSc. CONCLUSIONS: Most of the experts do not recommend the routine use of TNF-α antagonists in systemic sclerosis. Arthritis might be a potential indication in SSc, although controlled clinical trials with TNF-α antagonists are needed before general recommendations can be given.

[Recommendations for venous thromboembolic events treatment and central venous catheter thrombosis management in cancer patients]. / Traitement curatif de la maladie thromboembolique veineuse et prise en charge des thromboses veineuses sur cathéter chez les patients atteints de cancer Méthode SOR.

The "Standards, Options: Recommendations" (SOR) project has been undertaken by the French National Federation of Cancer Centers (FNCLCC) and is now part of the French National Cancer Institute. The project involves the development and updating of evidence-based Clinical Practice Guidelines (CPG) in oncology. In order to answer questions related to venous thromboembolic events (VTE) treatment and to central venous catheter thrombosis (CVCT) management in cancer patients, the SOR elaborated national guidelines, here presented in a short report. It results of a collaborative work with members from three learned societies (<< Société nationale française de médecine interne >> : SNFMI, << Société française de médecine vasculaire >> : SFMV and << Société française d'anesthésie-réanimation >> : SFAR).

[2008 Standards, Options: Recommendations for venous thromboembolic events(VTE)treatment and central venous catheter thrombosis(CVCT) management in cancer patients]. / Standards, Options : Recommandations 2008. Traitement curatif de la maladie thromboembolique veineuse, prevention et traitement des thromboses veineuses sur catheter chez les patients atteints de cancer.

The Standards, Options: Recommendations (SOR) project has been undertaken by the French National Federation of Cancer Centers (FNCLCC) is now part of the French National Cancer Institute. The project involves the development and updating of evidence-based Clinical Practice Guidelines (CPG) in oncology. In order to answer questions related to venous thromboembolic events(VTE) treatment and to central venous catheter thrombosis (CVCT) management in cancer patients, the SOR elaborated national guidelines, here presented in a short report. It results of a collaborative work with members from three learned societies("société nationale française de médicine interne": SNFMI, "société française de médicine vasculaire": SFMV and "société française dEanesthésie-réanimation:SFAR).

[2008 Standards, Options: recommendations for venous thromboembolic events (VTE) treatment and central venous catheter thrombosis (CVCT) management in cancer patients]. / Standards, Options : Recommandations 2008. Traitement curatif de la maladie thromboembolique veineuse, prévention et traitement des thromboses veineuses sur cathéter chez les patients atteints de cancer.

The <> (SOR) project has been undertaken by the French National Federation of Cancer Centers (FNCLCC) is now part of the French National Cancer Institute. The project involves the development and updating of evidence-based Clinical Practice Guidelines (CPG) in oncology. In order to answer questions related to venous thromboembolic events (VTE) treatment and to central venous catheter thrombosis (CVCT) management in cancer patients, the SOR elaborated national guidelines, here presented in a short report. It results of a collaborative work with members from three learned societies ("société nationale française de médicine interne": SNFMI, "société française de médicine vasculaire": SFMV and "société française d'anesthésie-réanimation": SFAR).