42 results on '"Ortiz-Maldonado V"'
Search Results
2. OC 10.5 Endotheliopathy, Innate-Immune Activation and Hemostatic Imbalance Underlying CAR -T Cell Toxicities: Tools for Early and Differential Diagnosis
- Author
-
Moreno-Castaño, A., primary, Fernandez, S., additional, Palomo, M., additional, Martinez-Sanchez, J., additional, Ramos, A., additional, Molina, P., additional, Pino, M., additional, Ortiz-Maldonado, V., additional, Delgado, J., additional, Fernández de Larrea, C., additional, Urbano, Á., additional, Escolar, G., additional, Carreras, E., additional, Fernández-Avilés, F., additional, Castro, P., additional, and Diaz-Ricart, M., additional
- Published
- 2023
- Full Text
- View/download PDF
3. S103: EFFICACY AND SAFETY OF ARI0002H, AN ACADEMIC BCMA-DIRECTED CAR-T CELL THERAPY WITH FRACTIONATED INITIAL THERAPY AND BOOSTER DOSE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
- Author
-
Fernandez De Larrea, C., primary, González-Calle, V., additional, Oliver-Caldés, A., additional, Cabañas, V., additional, Rodríguez-Otero, P., additional, Español-Rego, M., additional, Reguera, J. L., additional, López-Corral, L., additional, Martin-Antonio, B., additional, Paiva, B., additional, Inogés, S., additional, Rosiñol, L., additional, López-Díaz de Cerio, A., additional, Tovar, N., additional, López-Parra, M., additional, Rodríguez-Lobato, L. G., additional, Sánchez-Salinas, A., additional, Varea, S., additional, Ortiz-Maldonado, V., additional, Pérez Simón, J. A., additional, Prósper, F., additional, Juan, M., additional, Moraleda, J. M., additional, Mateos, M. V., additional, Pascal, M., additional, and Urbano-Ispizua, A., additional
- Published
- 2022
- Full Text
- View/download PDF
4. Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies
- Author
-
Garcia-Prieto, C. A., Villanueva, L., Bueno-Costa, A., Davalos, V., Gonzalez-Navarro, E. A., Juan, M., Urbano-Ispizua, A., Delgado, J., Ortiz-Maldonado, V., Del Bufalo, F., Locatelli, Franco, Quintarelli, C., Sinibaldi, M., Soler, M., Castro De Moura, M., Ferrer, G., Urdinguio, R. G., Fernandez, A. F., Fraga, M. F., Bar, D., Meir, A., Itzhaki, O., Besser, M. J., Avigdor, A., Jacoby, E., Esteller, M., Locatelli F. (ORCID:0000-0002-7976-3654), Garcia-Prieto, C. A., Villanueva, L., Bueno-Costa, A., Davalos, V., Gonzalez-Navarro, E. A., Juan, M., Urbano-Ispizua, A., Delgado, J., Ortiz-Maldonado, V., Del Bufalo, F., Locatelli, Franco, Quintarelli, C., Sinibaldi, M., Soler, M., Castro De Moura, M., Ferrer, G., Urdinguio, R. G., Fernandez, A. F., Fraga, M. F., Bar, D., Meir, A., Itzhaki, O., Besser, M. J., Avigdor, A., Jacoby, E., Esteller, M., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
Background: Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods: We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided. Results: We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P <. 001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P =. 002; log-rank P =. 003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P =. 047; log-rank P =. 04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P <. 001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P =. 02; log-rank P
- Published
- 2022
5. CD34(+)CD19(-)CD22(+) B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies
- Author
-
Bueno, C, Barrena, S, Bataller, A, Ortiz-Maldonado, V, Elliott, N, O'Byrne, S, Wang, G, Rovira, M, Gutierrez-Agüera, F, Trincado, JL, Gonzalez, M, Morgades, M, Sorigué, M, Barcena, P, Zanetti, SR, Torrebadell, M, Vega-García, N, Rives, S, Mallo, M, Sole, F, Mead, AJ, Roberts, I, Thongjuea, S, Psaila, B, Juan, M, Delgado, J, Urbano-Ispizua, Á, Ribera, J-M, Orfao, A, Roy, A, Menéndez, P, European Research Council, European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Cancer Research UK, Wellcome Trust, Generalitat de Catalunya, and University of Oxford
- Subjects
B-Lymphocytes ,Lymphoid Neoplasia ,Immunobiology and Immunotherapy ,Sialic Acid Binding Ig-like Lectin 2 ,Immunology ,Antigens, CD19 ,chemical and pharmacologic phenomena ,hemic and immune systems ,Antigens, CD34 ,Cell Biology ,Hematology ,Biochemistry ,Burkitt Lymphoma ,Immunophenotyping ,immune system diseases ,Recurrence ,hemic and lymphatic diseases ,Humans ,Blood Commentary ,Brief Reports ,Free Research Articles ,In Situ Hybridization, Fluorescence - Abstract
CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19− (pre)-leukemic cells represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19−CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19−CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19−CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19−CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19− relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged., The work in P.M. and C.B.’s Laboratory was supported by the European Research Council (CoG-2014-646903, PoC-2018-811220) and the Spanish Ministry of Economy and Competitiveness (SAF2016-80481R, PID2019-108160RB-I00) (P.M.); the ISCIII (ISCIII/FEDER, PI17/01028 and PI20/00822), the Spanish Association against Cancer (AECC), and the FERO Foundation (C.B.). P.M. and J.M.R. acknowledge the support of ISCIII-RICORS within the Next Generation EU program (Plan de Recuperación, Transformación y Resiliencia). N.E. is supported by Cancer Research UK and a Children and Young People’s Cancer Innovation Award (DRCPGM\100058). A.R. is supported by a Wellcome Trust Clinical Research Career Development Fellowship (216632/Z/19/Z). A.O. was supported by ISCIII (PI19/011183). F.S. was supported by AGAUR/Generalitat de Catalunya (SGR288). The single-cell transcriptomic analysis was supported by MRC Discovery award MRCDA 0816-11 and the MRC WIMM Single Cell Facility and MRC-funded Oxford Consortium for Single-Cell Biology (MR/M00919X/1) provided assistance.
- Published
- 2022
6. Manufacturing and Management of CAR T-Cell Therapy in 'COVID-19's Time': Central Versus Point of Care Proposals
- Author
-
Ortiz de Landazuri I, Egri N, Muñoz-Sánchez G, Ortiz-Maldonado V, Bolaño V, Guijarro C, Pascal M, and Manel Juan Otero
- Subjects
good manufacturing practice ,manufacturing process ,chimeric antigen receptor ,adoptive cell immunotherapy ,SARS-CoV-2 coronavirus - Abstract
The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has generated a significant repercussion on the administration of adoptive cell therapies, including chimeric antigen receptor (CAR) T-cells. The closing of borders, the reduction of people transit and the confinement of the population has affected the supply chains of these life-saving medical products. The aim of this mini-review is to focus on how the COVID-19 pandemic has affected CAR T-cell therapy and taking into consideration the differences between the large-scale centralized productions for the pharmaceutical industry versus product manufacturing in the academic/hospital environment. We also review different aspects of CAR T-cell therapy and our managerial experience of patient selection, resource prioritization and some practical aspects to consider for safe administration. Although hospitals have been forced to change their usual workflows to cope with the saturation of health services by hospitalized patients, we recommend centers to continue offering this potentially curative treatment for patients with relapsed/refractory hematologic malignancies. Consequently, we propose appropriate selection criteria, early intervention to attenuate neurotoxicity or cytokine release syndrome with tocilizumab and prophylactic/preventive strategies to prevent infection. These considerations may apply to other emerging adoptive cell treatments and the corresponding manufacturing processes.
- Published
- 2020
7. P09.05 Immunogenicity induced by the academic chimeric antigen receptor CAR19 (ARI-0001) in patients with CD19-positive relapsed/refractory B-cell malignancies recruited into the CART19-BE-01 clinical trial
- Author
-
Klein-González, N, primary, González-Navarro, EA, additional, Bartoló-Ibars, A, additional, Ortiz-Maldonado, V, additional, Torrebadell, M, additional, Castellà, M, additional, Benítez, D, additional, Caballero-Baños, M, additional, Cabezón, R, additional, Español, M, additional, Baumann, T, additional, Giné, E, additional, Castro, P, additional, Esteve, J, additional, Yagüe, J, additional, Rives, S, additional, Urbano-Ispizua, Á Álvaro, additional, Delgado, J, additional, and Juan, M, additional
- Published
- 2020
- Full Text
- View/download PDF
8. PS1214 INFECTIOUS COMPLICATIONS FOLLOWING ARI-0001 CELL (A3B1:CD8:4–1BB:CD3Z CART19) TREATMENT IN ADULT AND PEDIATRIC PATIENTS WITH CD19+ RELAPSED / REFRACTORY MALIGNANCIES
- Author
-
Ortiz-Maldonado, V., primary, Alonso-Saladrigues, A., additional, Cardozo, C., additional, Baumann, T., additional, Díaz-Beyá, M., additional, Torrebadell, M., additional, Català, A., additional, Caballero-Baños, M., additional, Castro, P., additional, Fernández, S., additional, Jordan, Y., additional, Esteve, J., additional, Yagüe, J., additional, Rovira, M., additional, Urbano-Ispizua, A., additional, Juan, M., additional, Noguera, A., additional, Puerta-Alcalde, P., additional, Soriano, A., additional, García-Vidal, C., additional, Rives, S., additional, and Delgado, J., additional
- Published
- 2019
- Full Text
- View/download PDF
9. S1636 FRACTIONATED DOSING OF ARI-0001 CELLS (A3B1:CD8:4–1BB:CD3Z CAR19) AND EARLY TOCILIZUMAB ADMINISTRATION MAY REDUCE THE INCIDENCE OF SEVERE CYTOKINE RELEASE SYNDROME IN PATIENTS WITH CD19+ MALIGNANCIES
- Author
-
Ortiz-Maldonado, V., primary, Alonso-Saladrigues, A., additional, Caballero-Baños, M., additional, Castella, M., additional, Boronat, A., additional, Garcia-Rey, E., additional, Baumann, T., additional, Díaz-Beyá, M., additional, Torrebadell, M., additional, Català, A., additional, Ramos, F., additional, Pont, S., additional, Cid, J., additional, Lozano, M., additional, Llanos, C., additional, Marzal, B., additional, Moreno, D.F., additional, Castro, P., additional, Fernández, S., additional, Jordan, Y., additional, Esteve, J., additional, Canals, J.M., additional, Trias, E., additional, Yagüe, J., additional, Rovira, M., additional, Urbano-Ispizua, A., additional, Juan, M., additional, Rives, S., additional, and Delgado, J., additional
- Published
- 2019
- Full Text
- View/download PDF
10. Poor outcome of patients with COVID-19 after CAR T-cell therapy for B-cell malignancies: results of a multicenter study on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party and the European Hematology Association (EHA) Lymphoma Group
- Author
-
Adrian Bloor, Nicolaus Kröger, Gloria Tridello, Alvaro Urbano-Ispizua, Roberta Di Blasi, Joaquin Martinez-Lopez, František Folber, Josep-Maria Ribera, Elisabetta Metafuni, Robin Sanderson, Marie José Kersten, Catherine Thieblemont, Friso Calkoen, Livia Giannoni, Pim G.N.J. Mutsaers, Matthew Collin, Arnon Nagler, Emma Nicholson, Emmanuel Bachy, Fiona L Dignan, Valentín Ortiz-Maldonado, Dolores Caballero, Johan Maertens, Per Ljungman, Pere Barba, Carlos Pinho Vaz, Francis Ayuk, Mi Kwon, Fabio Ciceri, Stephan Mielke, Pierre Sesques, Nina Knelange, Anne M. Spanjaart, Rafael de la Cámara, Institut Català de la Salut, [Spanjaart AM] Department of Hematology, Amsterdam University Medical Centers, Cancer Center Amsterdam and LYMMCARE, Amsterdam, The Netherlands. [Ljungman P] Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden. Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. [de La Camara R] Department of Hematology, Hospital Universitario de La Princesa, Madrid, Spain. [Tridello G] Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. [Ortiz-Maldonado V, Urbano-Ispizua A] Department of Hematology, Hospital Clínic, Barcelona, Spain. [Barba P] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Spanjaart, A. M., Ljungman, P., de La Camara, R., Tridello, G., Ortiz-Maldonado, V., Urbano-Ispizua, A., Barba, P., Kwon, M., Caballero, D., Sesques, P., Bachy, E., Di Blasi, R., Thieblemont, C., Calkoen, F., Mutsaers, P., Maertens, J., Giannoni, L., Nicholson, E., Collin, M., Vaz, C. P., Metafuni, E., Martinez-Lopez, J., Dignan, F. L., Ribera, J. -M., Nagler, A., Folber, F., Sanderson, R., Bloor, A., Ciceri, F., Knelange, N., Ayuk, F., Kroger, N., Kersten, M. J., Mielke, S., Graduate School, Clinical Haematology, AII - Cancer immunology, CCA - Cancer Treatment and Quality of Life, and Hematology
- Subjects
Cancer Research ,medicine.medical_specialty ,Letter ,Lymphoma, B-Cell ,Neoplasms::Neoplasms by Histologic Type::Lymphoma::Lymphoma, Non-Hodgkin::Lymphoma, B-Cell [DISEASES] ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,neoplasias::neoplasias por tipo histológico::linfoma::linfoma no Hodgkin::linfoma de células B [ENFERMEDADES] ,Immunotherapy, Adoptive ,Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores] ,SDG 3 - Good Health and Well-being ,Internal medicine ,Leukemia, B-Cell ,virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES] ,Humans ,Medicine ,B cell ,COVID-19 (Malaltia) - Complicacions ,Haematological cancer ,Science & Technology ,Hematology ,business.industry ,Marrow transplantation ,COVID-19 ,diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES] ,Prognosis ,Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,medicine.disease ,Lymphoma ,Europe ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,Multicenter study ,Avaluació de resultats (Assistència sanitària) ,Infectious diseases ,CAR T-cell therapy ,Cèl·lules B - Tumors ,business ,Life Sciences & Biomedicine ,Other subheadings::Other subheadings::/complications [Other subheadings] - Abstract
Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Càncer hematològic; Malalties infeccioses Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cáncer hematológico; Enfermedades infecciosas Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Haematological cancer; Infectious diseases COVID-19 is posing a significant threat to health in vulnerable patients, such as immunocompromised patients. For hematopoietic cell transplantation (HCT) recipients and patients with hematologic malignancies it is known that COVID-19 leads to severe morbidity and high mortality as compared to the general population [1–3]. For patients treated with Chimeric Antigen Receptor T-cell (CAR-T-cell) therapy for B-cell malignancies however, descriptions of the clinical course and outcome are still limited to small case series and case reports [4–8]. CAR-T-cell therapy recipients are believed to be at high risk of poor outcomes from COVID-19 due to their severely immunocompromised state, caused by prior lymphodepleting immunochemotherapy and CAR-T-cell therapy related side effects such as B-cell depletion, hypogammaglobulinemia, and cytopenias. In order to rapidly inform the medical field on the impact of COVID-19 on CAR-T-cell therapy recipients, the EBMT Infectious Diseases Working Party and the EHA Lymphoma Group joined forces and present the clinical course of COVID-19 in the largest European cohort to date.
- Published
- 2021
11. Anti-CD19 CAR-T Cell Therapy in Elderly Patients: Multicentric Real-World Experience from GETH-TC/GELTAMO.
- Author
-
Bailén R, Iacoboni G, Delgado J, López-Corral L, Hernani-Morales R, Ortiz-Maldonado V, Guerreiro M, Caballero AC, Guerra-Domínguez ML, Sánchez-Pina JM, Peña M, Torrent A, Pérez-Martínez A, Bastos-Oreiro M, Reguera-Ortega JL, Martín A, Hernandez-Boluda JC, Martínez-Cibrián N, Sanz J, Briones J, Henriquez HL, Calbacho M, Mussetti A, Sancho JM, Barba P, and Kwon M
- Subjects
- Humans, Aged, Male, Female, Retrospective Studies, Middle Aged, Antigens, CD19 therapeutic use, Antigens, CD19 immunology, Aged, 80 and over, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse immunology, Lymphoma, Large B-Cell, Diffuse mortality, Treatment Outcome, Adult, Biological Products therapeutic use, Receptors, Chimeric Antigen therapeutic use, Receptors, Antigen, T-Cell, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods
- Abstract
Chimeric antigen receptor (CAR)-T cell therapy is approved for the treatment of relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, elderly patients might not be candidates for this therapy due to its toxicity, and criteria for candidate selection are lacking. Our aim was to analyze efficacy and toxicity results of CAR-T cell therapy in the population of patients 70 years and older as compared to those obtained in younger patients in the real-world setting. A multicentric retrospective study was performed including patients with R/R aggressive LBCL who received commercial CAR-T cell therapy with either tisagenlecleucel or axicabtagene ciloleucel within the Spanish Group of Hematopoietic Transplant and Cell Therapy/Spanish Group of Lymphomas and Autologous Transplant (GETH-TC/GELTAMO) centers between 2019 and 2023. As of August 2023, 442 adult patients with aggressive LBCL underwent apheresis for CAR-T cell therapy as third or subsequent line and follow-up data was collected. Of 412 infused patients, 71 (17%) were 70 years or older. Baseline characteristics, product selection, and characteristics at apheresis (including disease status, Ann Arbor stage, revised international prognosis index (R-IPI), bulky disease, lactate dehydrogenase [LDH] and ECOG [Eastern Cooperative Group performance status]) were comparable between groups. Median time from both approval to infusion and apheresis to infusion did not differ. No differences were found between groups in overall and complete response rates at 1 and 3 months. With a median follow-up of 12.2 months (range 1-44), 12-month progression-free survival (PFS) and overall survival (OS) were comparable between groups (35.2% in <70 years vs. 35.9% in ≥70 years (P = .938) and 51.1% and 52.1% (P = .885), respectively). Age ≥70 years did not affect PFS (hazard ratio (HR) 0.98, P = .941) and OS (HR 0.97, P = .890) in the univariate and multivariate analysis. Cytokine release syndrome (CRS) was observed in 82% of patients <70 years old and 84.5% in ≥ 70 years old (P = .408). Grade ≥3 CRS was more frequent in the older group (5% vs. 15%, P = .002). In the multivariate analysis, age ≥70 years was associated with an increased risk of grade ≥3 CRS (OR 3.7, P = .013). No differences were observed in terms of overall neurotoxicity (35% vs. 42%, P = .281) or grade ≥3 (12% vs. 17%, P = .33). The proportion of patients with infections, admission to the intensive care unit within the first month, and non-relapse mortality were similar between both groups. CAR-T cell therapy in patients older than 70 years showed similar efficacy to that observed in younger patients in the real-world setting. However, age ≥70 years was an independent risk factor for grades 3-4 CRS. The need for additional strategies to reduce toxicity in this population should be addressed in future studies., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
12. Chimeric Antigen Receptor T-Cell Postinfusion Fever: Infection Profile, Clinical Parameters, and Biomarkers Trends to Assist Antibiotic Stewardship.
- Author
-
Peyrony O, Garcia-Pouton N, Chumbita M, Teijon-Lumbreras C, Aiello TF, Monzó-Gallo P, Gallardo-Pizarro A, Ortiz-Maldonado V, Martinez-Cibrian N, Delgado J, Fernandez de Larrea C, Mensa J, Puerta-Alcalde P, Soriano A, and Garcia-Vidal C
- Abstract
Background: This study aimed to describe documented infections associated with postinfusion fever after CAR T-cell therapy and to evaluate daily changes in vital signs, laboratory results, and the National Early Warning Score (NEWS) in patients with and without confirmed bacterial infections following fever onset, with the objective of assisting in antibiotic stewardship., Methods: This was a retrospective, observational study including all consecutive adult patients who received CAR T-cell therapy. Documented infection in the first fever episode after infusion, and clinical and analytic trend comparison of patients with bacterial documented infections and those without documented infections, are described., Results: Among 152 patients treated with CAR T-cell therapy, 87 (57.2%) had fever within 30 days of infusion, with a median time from infusion to fever of 3 (interquartile range, 2-5) days. Of these 87 patients, 82 (94.3%) received broad-spectrum antibiotics. Infection was documented in 9 (10.3%) patients and only 4 (4.6%) had bacterial infections. Clinical signs and biomarkers were similar in patients with bacterial documented infection and in those without documented infection at fever onset. Fever, tachycardia, and high C-reactive protein levels remained high during the first 3 days after CAR T-cell infusion, even when no infection was documented., Conclusions: Fever is a common symptom following CAR T-cell infusion and is largely treated with broad-spectrum antibiotics. However, confirmed bacterial documented infections after the first fever post-CAR T-cell infusion are very unusual. Because clinical parameters and biomarkers are not useful for identifying infectious fever, other methods should be assessed to ensure the proper use of antibiotics., Competing Interests: Potential conflicts of interest. C. G.-V. has received honoraria for talks on behalf of Gilead Sciences, MSD, Pfizer, Janssen, Novartis, Basilea, GSK, Shionogi, AbbVie, and Advanz Pharma, and grant support from Gilead Sciences, Pfizer, GSK, MSD, and Pharmamar. A. S. has received honoraria for talks on behalf of Merck Sharp and Dohme, Pfizer, Novartis, Angelini, Menarini, and Gilead Sciences as well as grant support from Pfizer and Gilead Sciences. J. M. has received honoraria for talks on behalf of Merck Sharp and Dohme, Pfizer, Novartis, and Angelini. O. P. has received honoraria for talks on behalf of BMS and Qiagen and consulting for Sanofi. C. F. d. L. declares receiving grants through his institution from BMS, Janssen, and Amgen; honoraria from Amgen, Janssen, BMS, GSK, and Sanofi; support for attending meetings or travel from Janssen, BMS, GSK, and Amgen; and participation in data and safety monitoring boards or advisory boards with Janssen, BMS, Amgen, Pfizer, and Sanofi. All other authors report no potential conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2024
- Full Text
- View/download PDF
13. Cost-Effectiveness Analysis of Axicabtagene Ciloleucel vs. Standard of Care in Second-Line Treatment for Relapsed/Refractory Large B-Cell Lymphoma in Spain.
- Author
-
Martín García-Sancho A, Presa M, Pardo C, Martín-Escudero V, Oyagüez I, and Ortiz-Maldonado V
- Abstract
Purpose: To estimate the cost-effectiveness of axi-cel vs. salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem-cell transplantation (HDT+ASCT) for responders to second-line treatment for relapsed/refractory (R/R) large B-cell lymphoma (LBCL)., Methods: A partitioned survival mixture-cure model comprising three health states was used to estimate the costs, life years gained (LYG), and quality-adjusted life years (QALYs) accumulated over a lifetime horizon. Overall survival, event-free survival, and time to the next treatment with axi-cel and HDT+ASCT were derived from the ZUMA-7 study. The total costs (EUR, 2022) included drug acquisition and administration, ASCT, subsequent treatment, disease and adverse event management, and palliative care. The unitary costs were derived from local databases and the literature. A 3% discount rate was applied to the costs and outcomes., Results: Compared with HDT+ASCT, axi-cel provided higher LYG per patient (10.00 vs. 8.28 LYG/patient) and greater QALYs gained per patient (7.85 vs. 6.04 QALY/patient). The lifetime total costs were 343,581 EUR/patient with axi-cel vs. 257,994 EUR/patient with IQT+ASCT. The incremental cost-effectiveness ratio of axi-cel vs. HDT+ASCT was 49,627 EUR/LYG, and the incremental cost-utility ratio was 47,309 EUR/QALY. Sensitivity analyses confirmed the robustness of the model., Conclusion: Axi-cel is a potentially cost-effective alternative to HDT+ASCT for the treatment of R/R DLBCL in Spain.
- Published
- 2024
- Full Text
- View/download PDF
14. Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.
- Author
-
Oliver-Caldes A, Español-Rego M, Zabaleta A, González-Calle V, Navarro-Velázquez S, Inogés S, de Cerio AL, Cabañas V, López-Muñoz N, Rodríguez-Otero P, Reguera JL, Moreno DF, Martínez-Cibrian N, López-Corral L, Pérez-Amill L, Martin-Antonio B, Rosiñol L, Cid J, Tovar N, Sáez-Peñataro J, López-Parra M, Olesti E, Guillén E, Varea S, Rodríguez-Lobato LG, Battram AM, González MS, Sánchez-Salinas A, González-Navarro A, Ortiz-Maldonado V, Delgado J, Prósper F, Juan M, Martínez-López J, Moraleda JM, Mateos MV, Urbano-Ispizua Á, Paiva B, Pascal M, and Fernández de Larrea C
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Biomarkers, Tumor, Receptors, Chimeric Antigen immunology, Treatment Outcome, Multiple Myeloma therapy, Multiple Myeloma immunology, Multiple Myeloma drug therapy, B-Cell Maturation Antigen immunology, B-Cell Maturation Antigen antagonists & inhibitors, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods
- Abstract
Purpose: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial., Patients and Methods: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes., Results: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse., Conclusions: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes., (©2024 American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
15. The role of chimeric antigen receptor T cells targeting more than one antigen in the treatment of B-cell malignancies.
- Author
-
Brillembourg H, Martínez-Cibrián N, Bachiller M, Alserawan L, Ortiz-Maldonado V, Guedan S, and Delgado J
- Subjects
- Humans, Lymphoma, B-Cell therapy, Lymphoma, B-Cell immunology, Receptors, Antigen, T-Cell genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism, Antigens, CD20 immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Antigens, Neoplasm immunology, Sialic Acid Binding Ig-like Lectin 2 immunology, Receptors, Chimeric Antigen immunology, Immunotherapy, Adoptive methods, Antigens, CD19 immunology
- Abstract
Several products containing chimeric antigen receptor T cells targeting CD19 (CART19) have been approved for the treatment of patients with relapsed/refractory non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukaemia (ALL). Despite very impressive response rates, a significant percentage of patients experience disease relapse and die of progressive disease. A major cause of CART19 failure is loss or downregulation of CD19 expression in tumour cells, which has prompted a myriad of novel strategies aimed at targeting more than one antigen (e.g. CD19 and CD20 or CD22). Dual targeting can the accomplished through co-administration of two separate products, co-transduction with two different vectors, bicistronic cassettes or tandem receptors. In this manuscript, we review the pros and cons of each strategy and the clinical results obtained so far., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
16. Infection epidemiology in relation to different therapy phases in patients with haematological malignancies receiving CAR T-cell therapy.
- Author
-
Garcia-Pouton N, Ortiz-Maldonado V, Peyrony O, Chumbita M, Aiello TF, Monzo-Gallo P, Lopera C, Puerta-Alcalde P, Magnano L, Martinez-Cibrian N, Pitart C, Juan M, Delgado J, Fernandez De Larrea C, Soriano Á, Urbano-Ispizua Á, and Garcia-Vidal C
- Subjects
- Adult, Humans, Immunotherapy, Adoptive adverse effects, Antigens, CD19, Hematologic Neoplasms complications, Hematologic Neoplasms epidemiology, Hematologic Neoplasms therapy, Lymphoma etiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Bacterial Infections epidemiology, Bacterial Infections etiology
- Abstract
Background: We described the real-life epidemiology and causes of infections on the different therapy phases in patients undergoing chimeric antigen receptor (CAR) T-cells directed towards CD19+ or BCMA+ cells., Methods: All consecutive patients receiving CAR T-cell therapy at our institution were prospectively followed-up. We performed various comparative analyses of all patients and subgroups with and without infections., Results: Ninety-one adults mainly received CAR T-cell therapy for acute leukaemia (53%) and lymphoma (33%). We documented a total of 77 infections in 47 (52%) patients, 37 (48%) during the initial neutropenic phase and 40 (52%) during the non-neutropenic phase. Infections during the neutropenic phase were mainly due to bacterial (29, 78%): catheter infections (11 [38%] cases), endogenous source (5 [17%]), and Clostridioides difficile (5 [17%]). Patients receiving corticosteroids after CAR T-cell therapy had a higher risk of endogenous infection (100% vs. 16%; p = .006). During the non-neutropenic phase, bacterial infections remained very frequent (24, 60%), mainly with catheter source (8, 33%). Respiratory tract infections were common (17, 43%)., Conclusions: Infections after CAR T-cell therapy were frequent. During the neutropenic phase, it is essential to prevent nosocomial infections and balance the use of antibiotics to lower endogenous bacteraemia and Clostridial infection rates., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
17. The academic point-of-care anti-CD19 chimeric antigen receptor T-cell product varnimcabtagene autoleucel (ARI-0001 cells) shows efficacy and safety in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma.
- Author
-
Martínez-Cibrián N, Ortiz-Maldonado V, Español-Rego M, Blázquez A, Cid J, Lozano M, Magnano L, Giné E, Correa JG, Mozas P, Rodríguez-Lobato LG, Rivero A, Montoro-Lorite M, Ayora P, Navarro S, Alserawan L, González-Navarro EA, Castellà M, Sánchez-Castañón M, Cabezón R, Benítez-Ribas D, Setoaín X, Rodríguez S, Brillembourg H, Varea S, Olesti E, Guillén E, Sáez-Peñataro J, de Larrea CF, López-Guillermo A, Pascal M, Urbano-Ispizua Á, Juan M, and Delgado J
- Subjects
- Humans, Point-of-Care Systems, Immunotherapy, Adoptive adverse effects, Antibodies, Antigens, CD19, T-Lymphocytes, Receptors, Chimeric Antigen, Lymphoma, B-Cell therapy, Lymphoma, Non-Hodgkin therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Varnimcabtagene autoleucel (var-cel) is an academic anti-CD19 chimeric antigen receptor (CAR) product used for the treatment of non-Hodgkin lymphoma (NHL) in the CART19-BE-01 trial. Here we report updated outcomes of patients with NHL treated with var-cel. B-cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty-five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3-year duration of response was 56%. The 3-year progression-free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression-free survival. The 3-year incidence of B-cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var-cel was manageable, while B-cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
18. Lymphodepletion - an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle.
- Author
-
Lickefett B, Chu L, Ortiz-Maldonado V, Warmuth L, Barba P, Doglio M, Henderson D, Hudecek M, Kremer A, Markman J, Nauerth M, Negre H, Sanges C, Staber PB, Tanzi R, Delgado J, Busch DH, Kuball J, Luu M, and Jäger U
- Subjects
- Adaptor Proteins, Signal Transducing, Alemtuzumab, Antibodies, Cyclophosphamide, Cell- and Tissue-Based Therapy, Receptors, Chimeric Antigen genetics
- Abstract
Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the microenvironment for improved CAR-T expansion and persistence, and reduction of tumor load. However, most LD regimens provide a broad and fairly unspecific suppression of T-cells as well as other hematopoietic cells, which can also lead to severe side effects, particularly infections. We reviewed 1271 published studies (2011-2023) with regard to current LD strategies for approved anti-CD19 CAR-T products for large B cell lymphoma (LBCL). Fludarabine (Flu) and cyclophosphamide (Cy) (alone or in combination) were the most commonly used agents. A large number of different schemes and combinations have been reported. In the respective schemes, doses of Flu and Cy (range 75-120mg/m2 and 750-1.500mg/m2) and wash out times (range 2-5 days) differed substantially. Furthermore, combinations with other agents such as bendamustine (benda), busulfan or alemtuzumab (for allogeneic CAR-T) were described. This diversity creates a challenge but also an opportunity to investigate the impact of LD on cellular kinetics and clinical outcomes of CAR-T. Only 21 studies explicitly investigated in more detail the influence of LD on safety and efficacy. As Flu and Cy can potentially impact both the in vivo activity and toxicity of CAR-T, a more detailed analysis of LD outcomes will be needed before we are able to fully assess its impact on different T-cell subsets within the CAR-T product. The T2EVOLVE consortium propagates a strategic investigation of LD protocols for the development of optimized conditioning regimens., Competing Interests: MH and ML: inventors on patents related to CAR T- cell therapy filed by the University of Würzburg. MH is listed as an inventor on patent applications and granted patents related to CAR-T technologies that have been filed by the Fred Hutchinson Cancer Research Center, Seattle, WA and by the University of Würzburg, Würzburg, Germany. MH is a co-founder and equity owner of T-CURX GmbH, Würzburg, Germany. MH received honoraria from Celgene/BMS, Janssen, Kite/Gilead. VO-M: Travel grants: Kite, Celgene-BMS, Novartis, Roche, Takeda & Janssen; Consultant or advisory fees: Kite, Celgene-BMS, Miltenyi Biomedicine, Pfizer, Novartis & Janssen; Honoraria: Kite, Celgene-BMS & Janssen; Employment: Hospital Clínic de Barcelona. UJ: consultant and advisory fees from Novartis, BMS, Gilead, Janssen, Roche, Honoraria from Miltenyi Biomedicine. DB: research projects with Juno/BMS and Repairon Immuno GmbH; consultant and advisory fees from BMS and Immatics. JD: Employment: Hospital Clínic de Barcelona. DH is an employee and shareholder of Bayer AG. HN and RT: are employees of Servier IRIS. PB: Advisory Board and consultancy from Allogene, Amgen, BMS/Celgene, Kite/Gilead, Incyte, Miltenyi Biomedicine, Novartis, Nektar, Pfizer and Pierre FabreKite/Gilead, Incyte, Miltenyi Biomedicine, Novartis, Nektar, Pfizer and Pierre Fabre. JK: Received grants form Novartis, Miltenyi Biotech and Gadeta. JK is inventor and receives revenues on multiple patents on CAR T and TEG engineering. LC was employed by Takeda. AK was employed by ITTM S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lickefett, Chu, Ortiz-Maldonado, Warmuth, Barba, Doglio, Henderson, Hudecek, Kremer, Markman, Nauerth, Negre, Sanges, Staber, Tanzi, Delgado, Busch, Kuball, Luu and Jäger.)
- Published
- 2023
- Full Text
- View/download PDF
19. Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy.
- Author
-
Gazeau N, Liang EC, Wu QV, Voutsinas JM, Barba P, Iacoboni G, Kwon M, Ortega JLR, López-Corral L, Hernani R, Ortiz-Maldonado V, Martínez-Cibrian N, Martinez AP, Maziarz RT, Williamson S, Nemecek ER, Shadman M, Cowan AJ, Green DJ, Kimble E, Hirayama AV, Maloney DG, Turtle CJ, and Gauthier J
- Subjects
- Humans, Interleukin 1 Receptor Antagonist Protein adverse effects, Cytokine Release Syndrome drug therapy, Cytokine Release Syndrome etiology, Prospective Studies, Retrospective Studies, Plasma Cells, Ferritins, Cell- and Tissue-Based Therapy, Receptors, Chimeric Antigen
- Abstract
Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n = 40) and grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n = 3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P = .069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P = .039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P = .02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings., (Published by Elsevier Inc.)
- Published
- 2023
- Full Text
- View/download PDF
20. Correction: Role of allogeneic hematopoietic cell transplant for relapsed/refractory aggressive B-cell lymphomas in the CART era.
- Author
-
Mussetti A, Bento L, Bastos-Oreiro M, Rius-Sansalvador B, Albo C, Bailen R, Barba P, Benzaquén A, Briones J, Caballero AC, Campos A, Español I, Ferra C, López SG, González Sierra PA, Guerra LM, Hernani R, Iacoboni G, Jiménez-Ubieto A, Kwon M, Corral LL, López-Godino O, Munoz MCM, Martínez-Cibrián N, Gómez JM, Pérez-Ortega L, Ortí G, Ortiz-Maldonado V, Pascual MJ, Perera M, Perez A, Reguera JL, Sanchez JM, Sanz J, Torrent A, Yáñez L, Varela R, Echechipia IC, Caballero D, and Sureda A
- Published
- 2023
- Full Text
- View/download PDF
21. Current outcomes of SARS-CoV-2 Omicron variant infection in high-risk haematological patients treated early with antivirals.
- Author
-
Aiello TF, Puerta-Alcalde P, Chumbita M, Lopera C, Monzó P, Cortes A, Fernández-Avilés F, Suárez-Lledó M, Correa J, Ortiz-Maldonado V, Cuesta G, Martinez-Cibrian N, Esteve J, Marcos MÁ, Mensa J, Soriano A, and Garcia-Vidal C
- Subjects
- Adult, Humans, Antiviral Agents therapeutic use, SARS-CoV-2, Subgenomic RNA, COVID-19, Dermatologic Agents, Hematologic Neoplasms complications, Hematologic Neoplasms drug therapy
- Abstract
Objectives: We aimed to describe the clinical outcomes and duration of viral shedding in high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predominance who received early treatment with antivirals., Methods: We conducted a prospective observational study on high-risk haematological patients admitted in our hospital between December 2021 and March 2022. We performed detection techniques on viral subgenomic mRNAs until negative results were obtained to document active, prolonged viral replication., Results: This analysis included 60 consecutive adults with high-risk haematological malignancies and COVID-19. All of these patients underwent early treatment with remdesivir. Thirty-two (53%) patients received combined antiviral strategies, with sotrovimab or hyperimmune plasma being added to remdesivir. The median length of viral replication-as measured by real-time RT-PCR and/or subgenomic RNA detection-was 20 (IQR 14-28) days. Prolonged viral replication (6 weeks after diagnosis) was documented in six (10%) patients. Only two patients had prolonged infection for more than 2 months. Overall mortality was 5%, whereas COVID-19-related mortality was 0%., Conclusions: Current outcomes of high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predminance are good with the use of early antiviral strategies. Persistent viral shedding is uncommon., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
- Full Text
- View/download PDF
22. Role of allogeneic hematopoietic cell transplant for relapsed/refractory aggressive B-cell lymphomas in the CART era.
- Author
-
Mussetti A, Bento L, Bastos-Oreiro M, Rius-Sansalvador B, Albo C, Bailen R, Barba P, Benzaquén A, Briones J, Caballero AC, Campos A, Español I, Ferra C, López SG, González Sierra PA, Guerra LM, Hernani R, Iacoboni G, Jiménez-Ubieto A, Kwon M, Corral LL, López-Godino O, Munoz MCM, Martínez-Cibrián N, Gómez JM, Pérez-Ortega L, Ortí G, Ortiz-Maldonado V, Pascual MJ, Perera M, Perez A, Reguera JL, Sanchez JM, Sanz J, Torrent A, Yáñez L, Varela R, Echechipia IC, Caballero D, and Sureda A
- Subjects
- Humans, Adolescent, Recurrence, Hematopoietic Stem Cell Transplantation methods, Lymphoma, B-Cell therapy
- Abstract
Anti-CD19 chimeric antigen receptor T cells (CART) has rapidly been adopted as the standard third-line therapy to treat aggressive B-cell lymphomas (ABCL) after failure of second-line therapy despite the lack of direct comparisons with allogeneic hematopoietic cell transplantation (alloHCT)-based strategies. Using the Grupo Español de Trasplante y Terapia Celular (GETH-TC) registry, we selected patients with the following characteristics: CART or alloHCT performed between 2016 and 2021; ≥18 years old; ABCL diagnosis; ≥2 lines of therapy; and either anti-CD19 CART or alloHCT as therapy at relapse. The analysis included a total of 316 (CART = 215, alloHCT = 101) patients. Median follow-up was 15 and 36 months for the CART and alloHCT cohorts, respectively. In the multivariate analysis, CART was confirmed to be similar to alloHCT for the primary study endpoint (progression-free survival) (hazard ratio [HR] 0.92, CI95%:0.56-1.51, p = 0.75). Furthermore, when the analysis was limited to only patients with chemo-sensitive diseases (complete and partial response) at infusion (CART = 26, alloHCT=93), no differences were reported (progression-free survival at month +18: 65% versus 55%, p = 0.59). However, CART had lower non-relapse mortality (HR 0.34, 95% CI: 0.13-0.85, p = 0.02). Given the lower toxicity and similar survival outcomes, these results suggest the use of CART before alloHCT., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
- Full Text
- View/download PDF
23. Chemotherapy resistant Burkitt lymphoma: Possible novel therapies including CAR-T cell infusion.
- Author
-
Geerts PAF, 't Hart N, Visser O, Ortiz-Maldonado V, and Chamuleau MED
- Abstract
Key Clinical Message: The prognosis of patients with relapsed or refractory (R/R) BL is poor with limited response to salvage therapy, especially for patients with early relapse (<6 months) or refractory disease. Novel therapies may be promising but need refinement., Abstract: The prognosis of patients with relapsed or refractory (R/R) BL is poor with a limited response to salvage therapy, especially for patients with early relapse (<6 months) or refractory disease. We present three cases of patients with R/R BL receiving novel therapies followed by a literature review. Amongst others, the patients received inotuzumab ozogamicin, idelalisib, ibrutinib, and CAR-T cell therapy, however, with limited response. In literature, response to several novel agents is described; however, most promising results are seen with CAR-T cell therapy. Concluding from case series, sequential CAR-T cell therapy, targeting multiple B-cell antigens, seems most promising., Competing Interests: The authors report no conflicts of interest., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
24. Characterization of the endotheliopathy, innate-immune activation and hemostatic imbalance underlying CAR-T cell toxicities: laboratory tools for an early and differential diagnosis.
- Author
-
Moreno-Castaño AB, Fernández S, Ventosa H, Palomo M, Martinez-Sanchez J, Ramos A, Ortiz-Maldonado V, Delgado J, Fernández de Larrea C, Urbano-Ispizua A, Penack O, Nicolás JM, Téllez A, Escolar G, Carreras E, Fernández-Avilés F, Castro P, and Diaz-Ricart M
- Subjects
- Humans, T-Lymphocytes, von Willebrand Factor, Diagnosis, Differential, Plasminogen Activator Inhibitor 1, Interleukin-1 Receptor-Like 1 Protein, Hemostasis, Hemostatics, Hematologic Neoplasms therapy, Sepsis
- Abstract
Background: Chimeric antigen receptor (CAR)-T cell-based immunotherapy constitutes a revolutionary advance for treatment of relapsed/refractory hematological malignancies. Nevertheless, cytokine release and immune effector cell-associated neurotoxicity syndromes are life-threatening toxicities in which the endothelium could be a pathophysiological substrate. Furthermore, differential diagnosis from sepsis, highly incident in these patients, is challenging. Suitable laboratory tools could be determinant for their appropriate management., Methods: Sixty-two patients treated with CAR-T cell immunotherapy for hematological malignancies (n=46 with CD19-positive diseases, n=16 with multiple myeloma) were included. Plasma samples were obtained: before CAR-T cell infusion (baseline); after 24-48 hours; at suspicion of any toxicity onset and 24-48 hours after immunomodulatory treatment. Biomarkers of endothelial dysfunction (soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble TNF receptor 1 (sTNFRI), thrombomodulin (TM), soluble suppression of tumorigenesis-2 factor (ST2), angiopoietin-2 (Ang-2)), innate immunity activation (neutrophil extracellular traps (NETs), soluble C5b-9 (sC5b-9)) and hemostasis/fibrinolysis (von Willebrand Factor antigen (VWF:Ag), ADAMTS-13 (A13), α2-antiplasmin (α2-AP), plasminogen activator inhibitor-1 antigen (PAI-1 Ag)) were measured and compared with those in cohorts of patients with sepsis and healthy donors., Results: Patients who developed CAR-T cell toxicities presented increased levels of sVCAM-1, sTNFRI and ST2 at the clinical onset versus postinfusion values. Twenty-four hours after infusion, ST2 levels were good predictors of any CAR-T cell toxicity, and combination of ST2, Ang-2 and NETs differentiated patients requiring intensive care unit admission from those with milder clinical presentations. Association of Ang-2, NETs, sC5b-9, VWF:Ag and PAI-1 Ag showed excellent discrimination between severe CAR-T cell toxicities and sepsis., Conclusions: This study provides relevant contributions to the current knowledge of the CAR-T cell toxicities pathophysiology. Markers of endotheliopathy, innate immunity activation and hemostatic imbalance appear as potential laboratory tools for their prediction, severity and differential diagnosis., Competing Interests: Competing interests: MD-R and EC have been granted by and received honoraria from Jazz Pharmaceuticals. SF and PC have collaborated with Jansen, Gilead, Kite, MSD, Alexion and Pfizer, outside of the submitted work. MP received speaker’s fee from Jazz Pharmaceuticals. The rest of authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
25. Evaluation of cell collection efficiency in non-mobilized adult donors for autologous chimeric antigen receptor T-cell manufacturing.
- Author
-
Piñeyroa JA, Cid J, Vlagea A, Carbassé G, Henao P, Bailo N, Ortiz-Maldonado V, Martínez-Cibrian N, Español M, Delgado J, Urbano-Ispizua Á, and Lozano M
- Subjects
- Humans, Adult, T-Lymphocytes, Retrospective Studies, Blood Donors, Leukapheresis, Receptors, Chimeric Antigen, Hematopoietic Stem Cell Transplantation
- Abstract
Background and Objectives: Data about collection efficiency 1 (CE1), which takes into account blood cell counts before and after collection, thus providing a more accurate estimate, in the collection of autologous T lymphocytes by apheresis for chimeric antigen receptor (CAR) T-cells remain scarce. We evaluated donor- and procedure-related characteristics that might influence the CE1 of lymphocytes., Materials and Methods: We retrospectively reviewed all mononuclear cell (MNC) collections) performed for CAR T-cell manufacturing in our institution from May 2017 to June 2021 in adult patients. Age, gender, weight, total blood volume (TBV), prior haematopoietic cell transplant, diagnosis, days between last treatment and apheresis, pre-collection cell counts, duration of apheresis, TBV processed, vascular access, inlet flow and device type were analysed as potential factors affecting CE1 of lymphocytes., Results: A total of 127 autologous MNC collections were performed on 118 patients diagnosed with acute lymphoblastic leukaemia (n = 53, 45%), non-Hodgkin lymphoma (n = 40, 34%), multiple myeloma (n = 19, 16%), and chronic lymphocytic leukaemia (n = 6, 5%). The median CE1 of lymphocytes was 47% (interquartile range: 32%-65%). In multiple regression analysis, Amicus device was associated with higher CE1 of lymphocytes (p = 0.01) and lower CE1 of platelets (p < 0.01) when compared with Optia device., Conclusion: The knowledge of the MNC and lymphocyte CE1 of each apheresis device used to collect cells for CAR T therapy, together with the goal of the number of cells required, is essential to define the volume to be processed and to ensure the success of the collection., (© 2022 International Society of Blood Transfusion.)
- Published
- 2023
- Full Text
- View/download PDF
26. Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma.
- Author
-
Kwon M, Iacoboni G, Reguera JL, Corral LL, Morales RH, Ortiz-Maldonado V, Guerreiro M, Caballero AC, Domínguez MLG, Pina JMS, Mussetti A, Sancho JM, Bastos-Oreiro M, Catala E, Delgado J, Henriquez HL, Sanz J, Calbacho M, Bailén R, Carpio C, Ribera JM, Sureda A, Briones J, Hernandez-Boluda JC, Cebrián NM, Martin JLD, Martín A, and Barba P
- Subjects
- Humans, Adaptor Proteins, Signal Transducing, Antigens, CD19, Retrospective Studies, Immunotherapy, Adoptive adverse effects, Lymphoma, Large B-Cell, Diffuse therapy
- Abstract
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-targeted chimeric antigen receptor (CAR) T cells approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We performed a retrospective study to evaluate safety and efficacy of axi-cel and tisa-cel outside the setting of a clinical trial. Data from consecutive patients with R/R LBCL who underwent apheresis for axi-cel or tisa-cel were retrospectively collected from 12 Spanish centers. A total of 307 patients underwent apheresis for axi-cel (n=152) and tisa-cel (n=155) from November 2018 to August 2021, of which 261 (85%) received a CAR T infusion (88% and 82%, respectively). Median time from apheresis to infusion was 41 days for axi-cel and 52 days for tisa-cel (P=0.006). None of the baseline characteristics were significantly different between both cohorts. Both cytokine release syndrome and neurologic events (NE) were more frequent in the axi-cel group (88% vs. 73%, P=0.003, and 42% vs. 16%, P<0.001, respectively). Infections in the first 6 months post-infusion were also more common in patients treated with axi-cel (38% vs. 25%, P=0.033). Non-relapse mortality was not significantly different between the axi-cel and tisa-cel groups (7% and 4%, respectively, P=0.298). With a median follow-up of 9.2 months, median PFS and OS were 5.9 and 3 months, and 13.9 and 11.2 months for axi-cel and tisa-cel, respectively. The 12-month PFS and OS for axi-cel and tisa-cel were 41% and 33% (P=0.195), 51% and 47% (P=0.191), respectively. Factors associated with lower OS in the multivariate analysis were increased lactate dehydrogenase, ECOG ≥2 and progressive disease before lymphodepletion. Safety and efficacy results in our real-world experience were comparable with those reported in the pivotal trials. Patients treated with axi-cel experienced more toxicity but similar non-relapse mortality compared with those receiving tisa-cel. Efficacy was not significantly different between both products.
- Published
- 2023
- Full Text
- View/download PDF
27. Post-mortem neuropathologic examination of a 6-case series of CAR T-cell treated patients.
- Author
-
Vidal-Robau N, Caballero G, Archilla I, Ladino A, Fernández S, Ortiz-Maldonado V, Rovira M, Gómez-Hernando M, Delgado J, Suárez-Lledó M, Fernández de Larrea C, Balagué O, Frigola G, Muñoz A, Ortiz E, Ribalta T, Martinez MJ, Angeles-Marcos M, Español-Rego M, González A, Benitez-Ribas D, Martinez-Hernandez E, Castro P, and Aldecoa I
- Abstract
Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for the treatment of refractory hematopoietic malignancies. Adverse events are common, and neurotoxicity is one of the most important. However, the physiopathology is unknown and neuropathologic information is scarce. Materials and methods: Post-mortem examination of 6 brains from patients that underwent CAR T-cell therapy from 2017 to 2022. In all cases, polymerase chain reaction (PCR) in paraffin blocks for the detection of CAR T cells was performed. Results: Two patients died of hematologic progression, while the others died of cytokine release syndrome, lung infection, encephalomyelitis, and acute liver failure. Two out of 6 presented neurological symptoms, one with extracranial malignancy progression and the other with encephalomyelitis. The neuropathology of the latter showed severe perivascular and interstitial lymphocytic infiltration, predominantly CD8+, together with a diffuse interstitial histiocytic infiltration, affecting mainly the spinal cord, midbrain, and hippocampus, and a diffuse gliosis of basal ganglia, hippocampus, and brainstem. Microbiological studies were negative for neurotropic viruses, and PCR failed to detect CAR T -cells. Another case without detectable neurological signs showed cortical and subcortical gliosis due to acute hypoxic-ischemic damage. The remaining 4 cases only showed a mild patchy gliosis and microglial activation, and CAR T cells were detected by PCR only in one of them. Conclusions: In this series of patients that died after CAR T-cell therapy, we predominantly found non-specific or minimal neuropathological changes. CAR T-cell related toxicity may not be the only cause of neurological symptoms, and the autopsy could detect additional pathological findings., Competing Interests: The authors have no conflicts of interest that relate to the content of this article.
- Published
- 2022
- Full Text
- View/download PDF
28. Practical aspects of chimeric antigen receptor T-cell administration: From commercial to point-of-care manufacturing.
- Author
-
Martinez-Cibrian N, Español-Rego M, Pascal M, Delgado J, and Ortiz-Maldonado V
- Subjects
- Antigens, CD19, Humans, Immunotherapy, Adoptive methods, Neoplasm Recurrence, Local, Point-of-Care Systems, T-Lymphocytes, Receptors, Chimeric Antigen
- Abstract
Chimeric antigen receptor T-cells targeting the CD19 antigen have achieved impressive results in patients with relapsed/refractory (R/R) B-cell malignancies, leading to their approval in the European Union and other jurisdictions. In Spain, the 100% academic anti-CD19 CART-cell product varnimcabtagene autoleucel (var-cel, ARI-0001 cells) has been extraordinarily approved under the Hospital Exemption clause for the treatment of patients older than 25 years of age with R/R acute lymphoblastic leukaemia. Var-cel has also been granted PRIority MEdicines designation by the European Medicines Agency for the same indication. In this review we reveal some practical aspects related to the preparation and administration of academic point-of-care CART-cell products, using var-cel as an example, and put them into the context of commercial products., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Martinez-Cibrian, Español-Rego, Pascal, Delgado and Ortiz-Maldonado.)
- Published
- 2022
- Full Text
- View/download PDF
29. CD34+CD19-CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies.
- Author
-
Bueno C, Barrera S, Bataller A, Ortiz-Maldonado V, Elliot N, O'Byrne S, Wang G, Rovira M, Gutierrez-Agüera F, Trincado JL, González-González M, Morgades M, Sorigué M, Bárcena P, Zanetti SR, Torrebadell M, Vega-Garcia N, Rives S, Mallo M, Sole F, Mead AJ, Roberts I, Thongjuea S, Psaila B, Juan M, Delgado J, Urbano-Ispizúa A, Ribera JM, Orfao A, Roy A, and Menendez P
- Subjects
- Antigens, CD34, B-Lymphocytes, Humans, Immunophenotyping, In Situ Hybridization, Fluorescence, Recurrence, Sialic Acid Binding Ig-like Lectin 2, Antigens, CD19, Burkitt Lymphoma
- Abstract
CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19- (pre)-leukemic cells represent an "early progenitor origin-related" mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19-CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19-CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19-CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19-CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19- relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged., (© 2022 by The American Society of Hematology.)
- Published
- 2022
- Full Text
- View/download PDF
30. Results of ARI-0001 CART19 cell therapy in patients with relapsed/refractory CD19-positive acute lymphoblastic leukemia with isolated extramedullary disease.
- Author
-
Ortiz-Maldonado V, Alonso-Saladrigues A, Español-Rego M, Martínez-Cibrián N, Faura A, Magnano L, Català A, Benítez-Ribas D, Giné E, Díaz-Beyá M, Correa JG, Rovira M, Montoro-Lorite M, Martínez-Roca A, Rodríguez-Lobato LG, Cabezón R, Cid J, Lozano M, Garcia-Rey E, Conde N, Pedrals G, Rozman M, Torrebadell M, Setoain X, Rodríguez S, Esteve J, Pascal M, Urbano-Ispizua Á, Juan M, Delgado J, and Rives S
- Subjects
- Adult, Antigens, CD19 therapeutic use, Child, Clinical Trials as Topic, Cytokine Release Syndrome epidemiology, Humans, Multicenter Studies as Topic, Positron Emission Tomography Computed Tomography, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnostic imaging, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with the CD19-directed CAR T cells ARI-0001 in two centers (adult and pediatric), including patients treated in the CART19-BE-01 trial and the consecutive compassionate use program. iEMD was detected by PET-CT in 78% (14/18), and/or by cerebrospinal fluid analysis in 28% (5/18). Patients received cyclophosphamide and fludarabine followed by 1 × 10
6 ARI-0001 cells/kg, initially as a single dose (first patient) and later split into three fractions (10%, 30%, and 60%). Cytokine release syndrome (CRS) occurred in 50% (9/18) of patients, with no cases of grade ≥3 CRS, and 1 case (6%) of grade 1 neurotoxicity. Tocilizumab was used in 6% of patients (1/18). Procedure-related mortality was 0% at 2 years. Objective responses were seen in 94% (95% confidence interval [CI]: 73%-99%) of patients, with complete responses (CR) seen in 78% (95% CI: 52%-94%) of them. Progression-free and overall survival were 49% (95% CI: 30%-79%) and 61% (95% CI: 40%-92%) at 2 years. In conclusion, the use of ARI-0001 cells in patients with R/R ALL and iEMD was associated with a safety and efficacy profile that is comparable with what is observed in patients with marrow involvement and in line with other CART19 products., (© 2022 Wiley Periodicals LLC.)- Published
- 2022
- Full Text
- View/download PDF
31. Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies.
- Author
-
Garcia-Prieto CA, Villanueva L, Bueno-Costa A, Davalos V, González-Navarro EA, Juan M, Urbano-Ispizua Á, Delgado J, Ortiz-Maldonado V, Del Bufalo F, Locatelli F, Quintarelli C, Sinibaldi M, Soler M, Castro de Moura M, Ferrer G, Urdinguio RG, Fernandez AF, Fraga MF, Bar D, Meir A, Itzhaki O, Besser MJ, Avigdor A, Jacoby E, and Esteller M
- Subjects
- Antigens, CD19, Cell- and Tissue-Based Therapy, Epigenesis, Genetic, Humans, Immunotherapy, Adoptive adverse effects, Receptors, Antigen, T-Cell genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Receptors, Chimeric Antigen
- Abstract
Background: Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course., Methods: We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided., Results: We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P < .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P < .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02)., Conclusions: We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2022
- Full Text
- View/download PDF
32. Results of ARI-0001 CART19 Cells in Patients With Chronic Lymphocytic Leukemia and Richter's Transformation.
- Author
-
Ortiz-Maldonado V, Frigola G, Español-Rego M, Balagué O, Martínez-Cibrián N, Magnano L, Giné E, Pascal M, Correa JG, Martínez-Roca A, Cid J, Lozano M, Villamor N, Benítez-Ribas D, Esteve J, López-Guillermo A, Campo E, Urbano-Ispizua Á, Juan M, and Delgado J
- Abstract
CART19 cells are emerging as an alternative therapy for patients with chronic lymphocytic leukemia (CLL). Here we report the outcome of nine consecutive patients with CLL treated with ARI-0001 CART19 cells, six of them with Richter's transformation (RT). One patient with RT never received therapy. The cytokine release syndrome rate was 87.5% (12.5% grade ≥3). Neurotoxicity was not observed in any patient. All patients experienced absolute B-cell aplasia, and seven (87.5%) responded to therapy. With a median follow-up of 5.6 months, two patients with RT experienced a CD19-negative relapse. In conclusion, ARI-0001 cell therapy was feasible, safe, and effective in patients with high-risk CLL or RT., Competing Interests: VO-M: Consultant or advisory role (Kite Gilead, Celgene, Novartis), travel grants (Kite Gilead, Celgene, Novartis, Roche, Takeda, Janssen), honoraria (Kite Gilead). EG: Consultant or advisory role (Kite Gilead, Janssen, Genmab), research funding (Kite Gilead, Janssen, Roche). AM-R: Consultant or advisory role (Bristol Myers Squibb, Abbvie), travel grants (Kite Gilead, Roche, Takeda, Janssen, Abbvie), honoraria (Abbvie). ML: Honoraria (Grifols, Fresenius Kabi), research funding (Terumo BCT, Maco-Pharma). JE: Consultant or advisory role (Abbvie, Novartis, Celgene, Astellas, Jazz, Daiichi Dankyo, Roche, Amgen, Pfizer), travel grants (Celgene, Roche, Astellas, Daiichi Dankyo), research funding (Novartis, Celgene). AL-G: Consultant or advisory role (Roche, Kite Gilead, Celgene/Bristol-Myers, Incyte), honoraria (Roche, Novartis, Takeda, Bayer, Sandoz, Kern), research grants (Roche, Kite Gilead, Celgene/Bristol-Myers, Novartis, Incyte, Janssen, Pfizer, Takeda). ÁU-I: Consultant or advisory role (Kite Gilead, Celgene, Miltenyi), travel grants (Kite Gilead, Celgene). MJ: Consultant or advisory role (Kite Gilead, Grifols), honoraria (Kite Gilead, Grifols). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ortiz-Maldonado, Frigola, Español-Rego, Balagué, Martínez-Cibrián, Magnano, Giné, Pascal, Correa, Martínez-Roca, Cid, Lozano, Villamor, Benítez-Ribas, Esteve, López-Guillermo, Campo, Urbano-Ispizua, Juan and Delgado.)
- Published
- 2022
- Full Text
- View/download PDF
33. First report of CART treatment in AL amyloidosis and relapsed/refractory multiple myeloma.
- Author
-
Oliver-Caldes A, Jiménez R, Español-Rego M, Cibeira MT, Ortiz-Maldonado V, Quintana LF, Castillo P, Guijarro F, Tovar N, Montoro M, Benitez-Ribas D, Bataller A, González-Navarro EA, Cid J, Lozano M, Perez-Amill L, Martin-Antonio B, Mena MP, Moreno DF, Rodríguez-Lobato LG, Campistol JM, Calvo G, Bladé J, Rosiñol L, Juan M, Pascal M, Urbano-Ispizua A, and Fernández de Larrea C
- Subjects
- Female, Humans, Immunoglobulin Light-chain Amyloidosis complications, Immunoglobulin Light-chain Amyloidosis immunology, Middle Aged, Multiple Myeloma complications, Multiple Myeloma immunology, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local pathology, Drug Resistance, Neoplasm, Immunoglobulin Light-chain Amyloidosis therapy, Immunotherapy, Adoptive methods, Multiple Myeloma therapy, Neoplasm Recurrence, Local therapy
- Abstract
Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop an amyloid light-chain (AL) amyloidosis with organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become a promising approach in treating hematological malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA)-CART which is currently being tested in a clinical trial for relapsed/refractory MM.We present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of an MM, successfully treated with CART therapy targeting BCMA. The patient received a fractioned dose of 3×10
6 /kg BCMA-CARTs after lymphodepletion. At 3 months from infusion, the patient had already obtained a deep hematological response with negative measurable residual disease by flow cytometry in the bone marrow. After 12 months, the patient remains in hematological stringent complete remission and has achieved an organ renal response with a decrease of 70% of proteinuria.This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
- Full Text
- View/download PDF
34. Poor outcome of patients with COVID-19 after CAR T-cell therapy for B-cell malignancies: results of a multicenter study on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party and the European Hematology Association (EHA) Lymphoma Group.
- Author
-
Spanjaart AM, Ljungman P, de La Camara R, Tridello G, Ortiz-Maldonado V, Urbano-Ispizua A, Barba P, Kwon M, Caballero D, Sesques P, Bachy E, Di Blasi R, Thieblemont C, Calkoen F, Mutsaers P, Maertens J, Giannoni L, Nicholson E, Collin M, Vaz CP, Metafuni E, Martinez-Lopez J, Dignan FL, Ribera JM, Nagler A, Folber F, Sanderson R, Bloor A, Ciceri F, Knelange N, Ayuk F, Kroger N, Kersten MJ, and Mielke S
- Subjects
- Europe, Humans, Immunotherapy, Adoptive, Leukemia, B-Cell therapy, Lymphoma, B-Cell therapy, Prognosis, Treatment Outcome, COVID-19 complications, Leukemia, B-Cell complications, Leukemia, B-Cell mortality, Lymphoma, B-Cell complications, Lymphoma, B-Cell mortality
- Published
- 2021
- Full Text
- View/download PDF
35. Factors associated with the clinical outcome of patients with relapsed/refractory CD19 + acute lymphoblastic leukemia treated with ARI-0001 CART19-cell therapy.
- Author
-
Ortiz-Maldonado V, Rives S, Español-Rego M, Alonso-Saladrigues A, Montoro M, Magnano L, Giné E, Pascal M, Díaz-Beyá M, Castella M, Català A, Faura A, Rodríguez-Lobato LG, Oliver-Caldes A, Martínez-Roca A, Rovira M, González-Navarro EA, Ortega JR, Cid J, Lozano M, Garcia-Rey E, Fernández S, Castro P, Jordan I, Villamor N, Aymerich M, Torrebadell M, Deyà À, Fernández de Larrea C, Benitez-Ribas D, Trias E, Varea S, Calvo G, Esteve J, Urbano-Ispizua A, Juan M, and Delgado J
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Survival Rate, Young Adult, Antigens, CD19 immunology, Cell- and Tissue-Based Therapy methods, Drug Resistance, Neoplasm, Neoplasm Recurrence, Local therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Receptors, Antigen, T-Cell immunology, Salvage Therapy
- Abstract
Competing Interests: Competing interests: VO-M: Consultant or advisory role (Kite Gilead, Celgene, Novartis), travel grants (Kite Gilead, Celgene, Novartis, Roche, Takeda, Janssen), honoraria (Kite Gilead). SR: Consultant or advisory role (Novartis, Jazz, Shire/Servier, Amgen, Celgene/Bristol-Myers, Kite Gilead), travel grants (Novartis, Jazz, Shire/Servier, Amgen, Celgene/Bristol-Myers, Kite Gilead), honoraria (Novartis, Jazz, Shire/Servier, Amgen, Celgene/Bristol-Myers, Kite Gilead). AA-S: Consultant or advisory role (Novartis), travel grants (Novartis), honoraria (Novartis). EG: Consultant or advisory role (Kite Gilead, Janssen, Genmab), research funding (Kite Gilead, Janssen, Roche). MD-B: Consultant or advisory role (Celgene, Novartis, Jazz, Astellas). AC: Consultant or advisory role (Novartis, Celgene), travel grants (Novartis, Celgene), honoraria (Novartis, Celgene). AF: Consultant or advisory role (Novartis), travel grants (Novartis), honoraria (Novartis). LGR-L: Travel grants (Kite Gilead, Amgen, Janssen). ML: Honoraria (Grifols, Fresenius Kabi), research funding (Terumo BCT, Maco-Pharma). AM-R: Consultant or advisory role (Bristol Myers Squibb, Abbvie), travel grants (Kite Gilead, Roche, Takeda, Janssen, Abbvie), honoraria (Abbvie). EG-R: Honoraria (Novartis). PC: Consultant or advisory role (Kite Gilead, Celgene, Janssen), travel grants (Kite Gilead, MSD, Janssen). MT: Consultant or advisory role (Novartis). CFDL: Consultant or advisory role (Janssen, Celgene/Bristol-Myers, GSK), honoraria (Janssen, Celgene/Bristol-Myers, Amgen, GSK), research funding (Janssen, Celgene/Bristol-Myers, Amgen, Takeda). GC: Consultant or advisory role (Celgene, Novartis). JE: Consultant or advisory role (Abbvie, Novartis, Celgene, Astellas, Jazz, Daiichi Dankyo, Roche, Amgen, Pfizer), travel grants (Celgene, Roche, Astellas, Daiichi Dankyo), research funding (Novartis, Celgene). AU-I: Consultant or advisory role (Kite Gilead, Celgene/Bristol-Myers, Miltenyi), travel grants (Kite Gilead, Celgene/Bristol-Myers). MJ: Consultant or advisory role (Kite Gilead, Grifols), honoraria (Kite Gilead, Grifols).
- Published
- 2021
- Full Text
- View/download PDF
36. CAR-T after Stem Cell Transplantation in B-Cell Lymphoproliferative Disorders: Are They Really Autologous or Allogenic Cell Therapies?
- Author
-
Bartoló-Ibars A, Uribe-Herranz M, Muñoz-Sánchez G, Arnaldos-Pérez C, Ortiz-Maldonado V, Urbano-Ispizua Á, Pascal M, and Juan M
- Abstract
Allogenic hematopoietic stem cell transplantation (allo-HSCT) is one of the standard treatments for B-cell lymphoproliferative disorders; however, deep relapses are common after an allo-HSCT, and it is associated with poor prognosis. A successful approach to overcome these relapses is to exploit the body's own immune system with chimeric antigen receptor (CAR) T-cells. These two approaches are potentially combinatorial for treating R/R B-cell lymphoproliferative disorders. Several clinical trials have described different scenarios in which allo-HSCT and CAR-T are successively combined. Further, for all transplanted patients, assessment of chimerism is important to evaluate the engraftment success. Nonetheless, for those patients who previously received an allo-HSCT there is no monitorization of chimerism before manufacturing CAR T-cells. In this review, we focus on allo-HSCT and CAR-T treatments and the different sources of T-cells for manufacturing CAR T-cells.
- Published
- 2021
- Full Text
- View/download PDF
37. Point-Of-Care CAR T-Cell Production (ARI-0001) Using a Closed Semi-automatic Bioreactor: Experience From an Academic Phase I Clinical Trial.
- Author
-
Castella M, Caballero-Baños M, Ortiz-Maldonado V, González-Navarro EA, Suñé G, Antoñana-Vidósola A, Boronat A, Marzal B, Millán L, Martín-Antonio B, Cid J, Lozano M, García E, Tabera J, Trias E, Perpiña U, Canals JM, Baumann T, Benítez-Ribas D, Campo E, Yagüe J, Urbano-Ispizua Á, Rives S, Delgado J, and Juan M
- Subjects
- Academic Medical Centers, Adolescent, Adult, Automation, Bioreactors, Cell Proliferation, Cells, Cultured, Child, Cytotoxicity, Immunologic, Female, Humans, Immunologic Memory, Male, Point-of-Care Systems, Young Adult, Immunotherapy, Adoptive methods, T-Lymphocyte Subsets immunology, T-Lymphocytes immunology
- Abstract
Development of semi-automated devices that can reduce the hands-on time and standardize the production of clinical-grade CAR T-cells, such as CliniMACS Prodigy from Miltenyi, is key to facilitate the development of CAR T-cell therapies, especially in academic institutions. However, the feasibility of manufacturing CAR T-cell products from heavily pre-treated patients with this system has not been demonstrated yet. Here we report and characterize the production of 28 CAR T-cell products in the context of a phase I clinical trial for CD19+ B-cell malignancies (NCT03144583). The system includes CD4-CD8 cell selection, lentiviral transduction and T-cell expansion using IL-7/IL-15. Twenty-seven out of 28 CAR T-cell products manufactured met the full list of specifications and were considered valid products. Ex vivo cell expansion lasted an average of 8.5 days and had a mean transduction rate of 30.6 ± 13.44%. All products obtained presented cytotoxic activity against CD19+ cells and were proficient in the secretion of pro-inflammatory cytokines. Expansion kinetics was slower in patient's cells compared to healthy donor's cells. However, product potency was comparable. CAR T-cell subset phenotype was highly variable among patients and largely determined by the initial product. T
CM and TEM were the predominant T-cell phenotypes obtained. 38.7% of CAR T-cells obtained presented a TN or TCM phenotype, in average, which are the subsets capable of establishing a long-lasting T-cell memory in patients. An in-depth analysis to identify individual factors contributing to the optimal T-cell phenotype revealed that ex vivo cell expansion leads to reduced numbers of TN , TSCM , and TEFF cells, while TCM cells increase, both due to cell expansion and CAR-expression. Overall, our results show for the first time that clinical-grade production of CAR T-cells for heavily pre-treated patients using CliniMACS Prodigy system is feasible, and that the obtained products meet the current quality standards of the field. Reduced ex vivo expansion may yield CAR T-cell products with increased persistence in vivo ., (Copyright © 2020 Castella, Caballero-Baños, Ortiz-Maldonado, González-Navarro, Suñé, Antoñana-Vidósola, Boronat, Marzal, Millán, Martín-Antonio, Cid, Lozano, García, Tabera, Trias, Perpiña, Canals, Baumann, Benítez-Ribas, Campo, Yagüe, Urbano-Ispizua, Rives, Delgado and Juan.)- Published
- 2020
- Full Text
- View/download PDF
38. Chimeric Antigen Receptor T Cells Targeting CD19 and Ibrutinib for Chronic Lymphocytic Leukemia.
- Author
-
Delgado J, Caballero-Baños M, Ortiz-Maldonado V, Castellà M, Magnano L, Juan M, and Urbano-Ispizua Á
- Published
- 2019
- Full Text
- View/download PDF
39. Development of a Novel Anti-CD19 Chimeric Antigen Receptor: A Paradigm for an Affordable CAR T Cell Production at Academic Institutions.
- Author
-
Castella M, Boronat A, Martín-Ibáñez R, Rodríguez V, Suñé G, Caballero M, Marzal B, Pérez-Amill L, Martín-Antonio B, Castaño J, Bueno C, Balagué O, González-Navarro EA, Serra-Pages C, Engel P, Vilella R, Benitez-Ribas D, Ortiz-Maldonado V, Cid J, Tabera J, Canals JM, Lozano M, Baumann T, Vilarrodona A, Trias E, Campo E, Menendez P, Urbano-Ispizua Á, Yagüe J, Pérez-Galán P, Rives S, Delgado J, and Juan M
- Abstract
Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells in vitro , inducing secretion of pro-inflammatory cytokines and CAR T cell proliferation. In vivo , A3B1 CAR T cells are able to fully control disease progression in an NOD.Cg- Prkdc
scid Il2rdtm1Wjl /SzJ (NSG) xenograph B-ALL mouse model. Based on the pre-clinical data, we conclude that our CART19 is clearly functional against CD19+ cells, to a level similar to other CAR19s currently being used in the clinic. Concurrently, we describe the implementation of our CAR T cell production system, using lentiviral vector and CliniMACS Prodigy, within a medium-sized academic institution. The results of the validation phase show our system is robust and reproducible, while maintaining a low cost that is affordable for academic institutions. Our model can serve as a paradigm for similar institutions, and it may help to make CAR T cell treatment available to all patients.- Published
- 2018
- Full Text
- View/download PDF
40. Is there a role for minimal residual disease monitoring in the management of patients with hairy-cell leukaemia?
- Author
-
Ortiz-Maldonado V, Villamor N, Baumann T, Aymerich M, Magnano L, Mozas P, Rivas-Delgado A, Martínez-Trillos A, Giné E, Campo E, López-Guillermo A, and Delgado J
- Subjects
- Adult, Aged, Cladribine therapeutic use, Disease Management, Female, Humans, Immunophenotyping methods, Male, Middle Aged, Pentostatin therapeutic use, Purines therapeutic use, Rituximab therapeutic use, Leukemia, Hairy Cell pathology, Neoplasm, Residual diagnosis
- Published
- 2018
- Full Text
- View/download PDF
41. Analysis of criteria for treatment initiation in patients with progressive chronic lymphocytic leukemia.
- Author
-
Mozas P, Rivas-Delgado A, Baumann T, Villamor N, Ortiz-Maldonado V, Aymerich M, Costa D, Navarro A, Giné E, López-Guillermo A, Montserrat E, and Delgado J
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Male, Middle Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality
- Published
- 2018
- Full Text
- View/download PDF
42. The biology behind PI3K inhibition in chronic lymphocytic leukaemia.
- Author
-
Ortiz-Maldonado V, García-Morillo M, and Delgado J
- Abstract
Phosphoinositide 3'-kinase (PI3K) is a key component of both chronic active and tonic B-cell receptor-signalling pathways. As such, PI3K inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukaemia. Multiple in vitro experiments and clinical trials have shown efficacy of these agents across all prognostic subgroups with a favourable toxicity profile. Moreover, in vitro studies suggest that combinations with monoclonal antibodies and/or other immune strategies could enhance the effect of PI3K inhibition.
- Published
- 2015
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.