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1. Development and validation of the post-CAR prognostic index for large B-cell lymphoma patients after CAR-T progression in third or later line treatment

Author

Gloria Iacoboni, Víctor Navarro, Pierre Sesques, Kai Rejeski, Mariana Bastos-Oreiro, Fabio Serpenti, Ana Africa Martin Lopez, Josu Iraola-Truchuelo, Javier Delgado, Ariadna Perez, Manuel Guerreiro, Ana Carolina Caballero, Nuria Martinez-Cibrian, Hugo Luzardo Henriquez, Jose Maria Sanchez Pina, Juan-Manuel Sancho, Hervé Ghesquieres, Alberto Mussetti, Lucia Lopez Corral, Rafael Hernani, Juan Luis Reguera, Anna Sureda, Francesc Bosch, Alejandro Martin Garcia-Sancho, Mi Kwon, Marion Subklewe, Andrea Kuhnl, Emmanuel Bachy, Pere Barba, Guillermo Villacampa, and Pau Abrisqueta

Subjects
CAR-T, Large B-cell lymphoma, Overall survival, Score, Disease progression, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Chimeric antigen receptor (CAR) T-cell therapy fails to achieve durable responses in over 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients in the third or later line setting. After CAR-T failure, survival outcomes are heterogeneous and a prognostic model in this patient population is lacking. A training cohort of 216 patients with progressive disease (PD) after CAR-T from 12 Spanish centers was used to develop the Post-CAR Prognostic Index (PC-PI); primary endpoint was overall survival (OS) from CAR-T progression. Validation was performed in an external cohort from three different European centers (n = 204). The prognostic score incorporated five variables, assessed at time of PD to CAR-T: ECOG (> 0), hemoglobin ( 1) and time from CAR-T to PD (

Published
2024
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2. Treatment outcomes in patients with large B‐cell lymphoma after progression to chimeric antigen receptor T‐cell therapy

Author

Gloria Iacoboni, Josu Iraola‐Truchuelo, Maeve O'Reilly, Víctor Navarro, Tobias Menne, Mi Kwon, Ana África Martín‐López, Sridhar Chaganti, Javier Delgado, Claire Roddie, Ariadna Pérez, Jane Norman, Manuel Guerreiro, Adam Gibb, Ana Carolina Caballero, Caroline Besley, Nuria Martínez‐Cibrián, Alberto Mussetti, Robin Sanderson, Hugo Luzardo, Sunil Iyengar, Jose Maria Sánchez, Ceri Jones, Juan‐Manuel Sancho, Pere Barba, Anne‐Louise Latif, Lucia López‐Corral, Rafael Hernani, Juan Luis Reguera, Anna Sureda, Alejandro Martin Garcia‐Sancho, Mariana Bastos, Pau Abrisqueta, and Andrea Kuhnl

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract Over 60% of relapsed/refractory (R/R) large B‐cell lymphoma (LBCL) patients who receive chimeric antigen receptor (CAR) T cells will experience disease progression. There is no standard next line of therapy and information in this setting is scarce and heterogeneous. We analyzed 387 R/R LBCL patients who progressed after CAR T cells from July 2018 until March 2022 in Spain and the United Kingdom. Median overall survival (OS) was 5.3 months, with significant differences according to the interval between infusion and progression (6 months [not reached]). After progression, 237 (61%) patients received treatment. Focusing on the first subsequent therapy, overall (complete) response rates were 67% (38%) for polatuzumab–bendamustine–rituximab (POLA), 51% (36%) for bispecific antibodies (BsAb), 45% (35%) for radiotherapy (RT), 33% (26%) for immune checkpoint inhibitors (ICIs), 25% (0%) for lenalidomide (LENA), and 25% (14%) for chemotherapy (CT). In terms of survival, 12‐month progression‐free survival and OS was 36.2% and 51.0% for POLA, 32.0% and 50.1% for BsAb, 30.8% and 37.5% for RT, 29.9% and 27.8% for ICI, 7.3% and 20.8% for LENA, and 6.1% and 18.3% for CT. Thirty‐two (14%) patients received an allogeneic hematopoietic cell transplant with median OS not reached after a median follow‐up of 15.1 months. In conclusion, patients with R/R LBCL who progress within the first 2 months after CAR T‐cell therapy have dismal outcomes. Novel targeted agents, such as polatuzumab and BsAbs, can achieve prolonged survival after CAR T‐cell therapy failure.

Published
2024
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3. Quantifying the available capacity and resource needs for provision of CAR-T therapies in the National Health Service in Spain: a survey-based study

Author

Antonio Pérez-Martínez, Carlos Solano, Mi Kwon, Joaquín Martinez, Anna Sureda, Pedro Castro-Rebollo, Lucia López-Corral, Pere Barba-Suñol, Valentín Ortiz, Jaime Sanz-Caballer, Ana Carolina Caballero, and Ángel Cedillo

Subjects
Medicine
Abstract

Objectives To estimate the readiness of Spanish National Health Service (NHS) hospitals to provide chimeric antigen receptor T cell (CAR-T), and to identify and quantify the different resources needed to provide CAR-T considering three scenarios defined by 10, 25 and 50 patients per centre per year.Design Targeted literature review and quantitative study using a questionnaire and telephone interviews. An algorithm was created to determine hospitals’ readiness based on their capacity and capability. All the requirements for quantification were assessed and validated by the steering committee, formed by members of the Spanish Group of Haematopoietic Transplantation and Cell Therapy. A weighting system (from 0 to 1) was established for capability quantification. For resources quantification, a scoring system was established, with 0 points representing the minimum and 3 points the maximum of additional resources that a hospital indicated necessary.Setting 40 Spanish hospital centres that perform allogeneic haematopoietic stem cell transplantation were invited to complete the questionnaire for capacity quantification, 28 of which provided valid responses. Nine hospitals participated in the interviews for resource quantification, eight of which had previously been designated by the Ministry of Health (MoH) to provide CAR-T.Outcome measure Current capacity of NHS Spanish sites to administer CAR-T under different theoretical scenarios with varying numbers of procedures, and the potential healthcare resources that would be needed to realise the theoretical capacity requirements.Results Four hospitals were optimally ready, 17 were somewhat ready and 7 were not ready. The actual extrapolated capacity of the currently designated MoH CAR-T sites would allow treatment of approximately 250 patients per year. Regarding healthcare resource needs, the numbers of haematologists, nurses and beds were the most important limiting factors, and those requiring further growth as patient numbers increased.Conclusions Increasing the number of CAR-T-qualified centres and/or increasing resources in the current designated sites are two potential strategies that should be considered to treat CAR-T-eligible patients in Spain.

Published
2023
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4. CAR T-Cell Therapy Predictive Response Markers in Diffuse Large B-Cell Lymphoma and Therapeutic Options After CART19 Failure

Author

Ana Carolina Caballero, Laura Escribà-Garcia, Carmen Alvarez-Fernández, and Javier Briones

Subjects
CAR-T, DLBCL, lymphoma, antibodies, bispecific, Immunologic diseases. Allergy, RC581-607
Abstract

Immunotherapy with T cells genetically modified with chimeric antigen receptors (CARs) has shown significant clinical efficacy in patients with relapsed/refractory B-cell lymphoma. Nevertheless, more than 50% of treated patients do not benefit from such therapy due to either absence of response or further relapse. Elucidation of clinical and biological features that would predict clinical response to CART19 therapy is of paramount importance and eventually may allow for selection of those patients with greater chances of response. In the last 5 years, significant clinical experience has been obtained in the treatment of diffuse large B-cell lymphoma (DLBCL) patients with CAR19 T cells, and major advances have been made on the understanding of CART19 efficacy mechanisms. In this review, we discuss clinical and tumor features associated with response to CART19 in DLBCL patients as well as the impact of biological features of the infusion CART19 product on the clinical response. Prognosis of DLBCL patients that fail CART19 is poor and therapeutic approaches with new drugs are also discussed.

Published
2022
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5. Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma

Author

Mi Kwon, Gloria Iacoboni, Juan Luis Reguera, Lucía López Corral, Rafael Hernani Morales, Valentín Ortiz-Maldonado, Manuel Guerreiro, Ana Carolina Caballero, María Luisa Guerra Domínguez, Jose Maria Sanchez Pina, Alberto Mussetti, Juan Manuel Sancho, Mariana Bastos-Oreiro, Eva Catala, Javier Delgado, Hugo Luzardo Henriquez, Jaime Sanz, María Calbacho, Rebeca Bailén, Cecilia Carpio, Jose Maria Ribera, Anna Sureda, Javier Briones, Juan Carlos Hernandez-Boluda, Nuria Martínez Cebrián, Jose Luis Diez Martin, Alejandro Martín, and Pere Barba

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
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

Published
2022
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6. Real‐world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B‐cell lymphoma

Author

Gloria Iacoboni, Guillermo Villacampa, Nuria Martinez‐Cibrian, Rebeca Bailén, Lucia Lopez Corral, Jose M. Sanchez, Manuel Guerreiro, Ana Carolina Caballero, Alberto Mussetti, Juan‐Manuel Sancho, Rafael Hernani, Pau Abrisqueta, Carlos Solano, Anna Sureda, Javier Briones, Alejandro Martin Garcia‐Sancho, Mi Kwon, Juan Luis Reguera‐Ortega, Pere Barba, and GETH, GELTAMO Spanish Groups

Subjects
clinical cancer research, clinical observations, hematological cancer, non‐Hodgkin's lymphoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses.

Published
2021
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7. The novel agonistic iNKT-cell antibody NKT14m induces a therapeutic antitumor response against B-cell lymphoma

Author

Laura Escribà-Garcia, Carmen Alvarez-Fernández, Ana Carolina Caballero, Robert Schaub, Jorge Sierra, and Javier Briones

Subjects
inkt cells, nkt14m, b-cell lymphoma, immunotherapy, antibody, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Invariant natural killer T (iNKT) cells are a small population of T lymphocytes that expresses an invariant T cell receptor with a unique specificity for glycolipid antigens. Their activation using the glycolipid α-galactosylceramide (α-GalCer) triggers innate and adaptive immune responses. The use of α-GalCer in preclinical models as a single antitumor treatment showed moderate effect, but its efficacy in cancer patients was less effective. In addition, this glycolipid induces long-term iNKT-cell anergy precluding the possibility of retreatment. Recently, the first murine iNKT-cell agonistic antibody, NKT14m, has been developed. Here, we analyzed, for the first time, the antitumor efficacy of NKT14m in a B-cell lymphoma model. In a therapeutic setting, a single dose of NKT14m had a moderate antitumor efficacy that was associated with an increase of IFN-γ producing iNKT cells even after a second dose of the NKT14m antibody. Importantly, the combination of a single dose of NKT14m with cyclophosphamide had a potent antitumor efficacy and long-lasting immunity in vivo. Our findings provide the first evidence of the in vivo antitumor efficacy of NKT14m antibody, showing that, either alone or in combination with chemotherapy, induces an effective antitumor response. These results open new opportunities for iNKT-cell mediated immunotherapy to treat B-cell lymphoma.

Published
2019
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8. Successful Outcome in Patients with Myelofibrosis Undergoing Allogeneic Donor Hematopoietic Cell Transplantation Using Reduced-Doses of Post-Transplant Cyclophosphamide: challenges and review of the literature.

Author

García-Cadenas, Irene, primary, Redondo, Sara, additional, Esquirol, Albert, additional, Portos, JM, additional, Novelli, Silvana, additional, Saavedra, Silvana, additional, Moreno, Carol, additional, Garrido, Ana, additional, Oñate, Guadalupe, additional, López, Jordi, additional, Ana-Carolina, Caballero, additional, Miqueleiz, Sara, additional, Arguello-Tomas, Miguel, additional, Briones, Javier, additional, Sierra, Jorge, additional, and Martino, Rodrigo, additional

Published
2023
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9. Sequence matters: Total body irradiation (TBI)‐based myeloablative conditioning with post‐transplant cyclophosphamide may reduce the early nonrelapse mortality compared with pretransplant cyclophosphamide plus <scp>TBI</scp>

Author

Sara Redondo, Irene García‐Cadenas, Antonio Vila, Albert Esquirol, J. M. Portos, Silvana Novelli, Silvana Saavedra, Carol Moreno, Ana Garrido, Miguel Arguello‐Tomas, Guadalupe Oñate, Jordi López‐Pardo, Ana‐Carolina Caballero, Sara Miqueleiz, Javier Briones, Jorge Sierra, Gemma Sancho, and Rodrigo Martino

Subjects
Hematology, General Medicine
Published
2023

10. Successful Outcome in Patients with Myelofibrosis Undergoing Allogeneic Donor Hematopoietic Cell Transplantation Using Reduced Doses of Post-Transplantation Cyclophosphamide: Challenges and Review of the Literature

Author

Irene García-Cadenas, Sara Redondo, Albert Esquirol, J.M. Portos, Silvana Novelli, Silvana Saavedra, Carol Moreno, Ana Garrido, Guadalupe Oñate, Jordi López, Ana-Carolina Caballero, Sara Miqueleiz, Miguel Arguello-Tomas, Javier Briones, Jorge Sierra, and Rodrigo Martino

Subjects
Transplantation, Molecular Medicine, Immunology and Allergy, Cell Biology, Hematology
Published
2023

11. Role of allogeneic hematopoietic cell transplant for relapsed/refractory aggressive B-cell lymphomas in the CART era

Author

Alberto Mussetti, Leyre Bento, Mariana Bastos-Oreiro, Blanca Rius-Sansalvador, Carmen Albo, Rebeca Bailen, Pere Barba, Ana Benzaquén, Javier Briones, Ana Carolina Caballero, António Campos, Ignacio Español, Christelle Ferra, Sebastián Garzón López, Pedro Antonio González Sierra, Luisa Maria Guerra, Rafael Hernani, Gloria Iacoboni, Ana Jiménez-Ubieto, Mi Kwon, Lucía López Corral, Oriana López-Godino, Maria Carmen Martinez Munoz, Nuria Martínez-Cibrián, Juan Montoro Gómez, Laura Pérez-Ortega, Guillermo Ortí, Valentín Ortiz-Maldonado, Maria-Jesús Pascual, María Perera, Antonio Perez, Juan Luis Reguera, Jose M. Sanchez, Jaime Sanz, Anna Torrent, Lucrecia Yáñez, Rosario Varela, Izaksun Ceberio Echechipia, Dolores Caballero, and Anna Sureda

Subjects
Transplantation, Hematology
Published
2023

12. Role of Allogeneic Hematopoietic Cell Transplant for Relapsed/Refractory Large B-Cell Lymphomas in the CART Era

Author

Alberto Mussetti, Leyre Bento, Mariana Bastos-Oreiro, Carmen Albo, Rebeca Bailen, Pere Barba, Ana Benzaquén, Javier Briones, Ana Carolina Caballero, António Campos, Ignacio Español, Christelle Ferra, Sebastián Garzón López, Pedro Antonio González Sierra, Luisa Maria Guerra, Rafael Hernani, Gloria Iacoboni, Ana Isabel Jiminez Ubieto, Mi Kwon, Lucía López Corral, Oriana López-Godino, Maria Carmen Martinez Munoz, Nuria Martínez-Cibrián, Juan Montoro Gómez, Laura Pérez-Ortega, Guillermo Ortí, Valentín Ortiz-Maldonado, Maria-Jesús Pascual, María Perera, Antonio Perez, Juan Luis Reguera, Jose M. Sanchez, Jaime Sanz, Anna Torrent, Lucrecia Yáñez, Rosario Varela, Izaksun Ceberio Echechipia, Dolores Caballero, and Anna Sureda

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

13. Outcome Improvement Over Time in Reduced Intensity Conditioning Hematopoietic Transplantation: A 20 Years Experience

Author

Albert Esqu, Irene García-Cadenas, Silvana Novelli, Ana Garrido, Ana Carolina Caballero, Guadalupe Oñate, Jordi López-Pardo, Sara Redondo, Miguel Arquello-Tomas, Silvanna Saavedra Gerosa, Carol Moreno, Javier Briones, Jorge Sierra, and Rodrigo Martino

Abstract

Background: RIC-alloHSCT had been our standard of care for patients more than 50, with comorbidities or previously transplanted. Methods: 484 consecutive RIC-alloHSCT were included. GVHD prophylaxis consisted of CsA-MTX(147), CsA-MMF(124), tacro-siro(145) and PTCy-tacro(68). Results: The median time of overall follow-up in survivors was 8-years (with at least 3-years in all four GVHD prophylaxis groups).Neutrophil and platelet engraftment was longer for PTCy-tacro (p0.0001). CumInc of grade III-IV aGVHD was 17% at 200 days and of moderate-severe cGvHD was 36% at 8-years. GVHD prophylaxis was the only prognostic factor in the MVA(p0.0001). NRM and relapse were 29% and 30%; OS and PFS were 43% and 39% at 8-years. At 3-years, OS was highest in the PTCy-tacro (68%) than in the tacro-siro (61%) and CsA+MTX/MMF (49%) cohorts (PConclusion: This large single institution experience shows the improvement of RIC-alloHSCT over time, mainly due to a better prevention of acute and chronic GVHD. Based on our recent results we strongly support PTCy as the current standard of care since in our hands associates to the best 3-year survival.

Published
2023

14. Real‐world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B‐cell lymphoma

Author

Lucía López Corral, Anna Sureda, Carlos Solano, Pau Abrisqueta, Juan-Manuel Sancho, Pere Barba, Guillermo Villacampa, Javier Briones, Rafael Hernani, Mi Kwon, Geltamo Spanish Groups Geth, Manuel Guerreiro, Gloria Iacoboni, José María Raya Sánchez, Alberto Mussetti, Ana Carolina Caballero, Alejandro Martin Garcia-Sancho, Juan Luis Reguera-Ortega, Rebeca Bailén, Nuria Martínez-Cibrian, Institut Català de la Salut, [Iacoboni G, Abrisqueta P, Barba P] Servei d’Hematologia, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Villacampa G] Oncology Data Science, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Martinez-Cibrian N] Department of Hematology, University Hospital Virgen del Rocio, Sevilla, Spain. [Bailén R] Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. Gregorio Marañón Health Research Institute (IiSGM), Madrid, Spain. [Lopez Corral L] Hematology Department, Hospital Clínico Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain. Centro de Investigación del Cáncer-IBMCC, Salamanca, Spain. [Sanchez JM] Hematology Department, Hospital 12 de Octubre, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, 0301 basic medicine, aminoácidos, péptidos y proteínas::proteínas::proteínas de membranas::receptores de superficie celular::receptores inmunológicos::receptores de antígenos::receptores de antígenos de linfocitos T [COMPUESTOS QUÍMICOS Y DROGAS], Cancer Research, non‐Hodgkin's lymphoma, Best Overall Response, hematological cancer, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Non- Hodgkin's lymphoma, Gastroenterology, 0302 clinical medicine, Medicine research, Other subheadings::/therapeutic use [Other subheadings], Càncer, B-cell lymphoma, RC254-282, Cancer, Original Research, Receptors, Chimeric Antigen, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, non&#8208, Standard of Care, Middle Aged, Patologia, Hodgkin&apos, Progression-Free Survival, Cytokine release syndrome, clinical cancer research, Oncology, neoplasias::neoplasias por tipo histológico::linfoma::linfoma no Hodgkin::linfoma de células B::linfoma de células B grandes difuso [ENFERMEDADES], 030220 oncology & carcinogenesis, Cytokines, Female, Lymphoma, Large B-Cell, Diffuse, non-Hodgkin's lymphoma, medicine.medical_specialty, Receptors, Antigen, T-Cell, Cèl·lules B - Tumors - Tractament, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Investigació mèdica, Real world evidence, 03 medical and health sciences, s lymphoma, Neoplasms::Neoplasms by Histologic Type::Lymphoma::Lymphoma, Non-Hodgkin::Lymphoma, B-Cell::Lymphoma, Large B-Cell, Diffuse [DISEASES], Refractory, clinical observations, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Leukapheresis, Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Antigen::Receptors, Antigen, T-Cell [CHEMICALS AND DRUGS], Aged, Retrospective Studies, Otros calificadores::/uso terapéutico [Otros calificadores], business.industry, Teràpia cel·lular, Clinical Cancer Research, medicine.disease, Malaltia de Hodgkin, Non-Hodgkin's lymphoma, Lymphoma, 030104 developmental biology, Hodgkin's disease, Neoplasm Recurrence, Local, business
Abstract

Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses., This article provides real‐world European data on the results of relapsed/refractory large B‐cell lymphoma patients treated with tisagenlecleucel.

Published
2021

15. High CAR intensity of expression confers enhanced antitumor effect against lymphoma without functional exhaustion

Author

Ana Carolina Caballero, Laura Escribà-Garcia, Paula Pujol-Fernández, Eva Escudero-López, Cristina Ujaldón-Miró, Rosanna Montserrat-Torres, Jorge Sierra, Carmen Alvarez-Fernández, and Javier Briones

Subjects
Cancer Research, Molecular Medicine, Molecular Biology
Abstract

Identifying factors that ameliorates clinical outcomes following CART therapy represents an unmet need. We hypothesized that CAR expression level would have a significant impact on CART efficacy and tested this with CAR30(+) T-SCM(-)LIKE enriched cells. By sorting T-cells according to CAR mean fluorescence intensity in two markedly different populations (CAR(HI) and CAR(LO)), we showed that a high CAR expression enhances antitumor efficacy in vitro, that is sustained after sequential re-exposures to tumor cells and is not associated with T-cell exhaustion or differentiation. Furthermore, we found a correlation between high surface CAR expression and antitumor effect with CAR19(+) T-cells, thus validating our findings with CAR30. Definitive proof of CAR(HI) T-cells improved antitumor efficacy was demonstrated in a human Hodgkin's lymphoma xenograft mouse model, where CAR30-T-SCM(-)LIKE enriched products with high intensity of CAR expression achieved superior tumor control in vivo and longer survival than those with a low intensity of CAR expression. Our data suggest that modulation of CAR intensity of expression represents an additional strategy to increase CART therapy clinical efficacy.

Published
2022

16. Ocular involvement in patients with primary central-nervous-system lymphoma: Analysis of a multicentre study in Spain

Author

Santiago, Mercadal, Mónica, Alañá, María Ines, Barceló, Gema, Bruixola, Patricia, López-Pereira, Sabela, Bobillo, Ivan, Dlouhy, Rocío Caldú, Agud, Estefanía García, Molina, Pilar, Martínez, Purificación, Cacabelos, Ana, Muntañola, Guillermo, García-Catalán, Juan Manuel, Sancho, Iria, Campos, Tamara, Lado, Antonio, Salar, Ana Carolina, Caballero, María, Solé-Rodríguez, and Roser, Velasco

Subjects
Central Nervous System Neoplasms, Lymphoma, Spain, Humans, Hematology, Eye
Published
2022

17. Results of R-ESHAP as salvage therapy in refractory/relapsed follicular lymphoma: a real-world experience on behalf of GELCAB group

Author

A Soler, Ana Carolina Caballero, Olga García, Ana Muntañola, Lourdes Escoda, Armando López-Guillermo, M Canet, Juan-Manuel Sancho, L Iserte, Blanca Sanchez-Gonzalez, Laura Magnano, M T Villalobos, Santiago Mercadal, Marc Sorigue, Tycho Baumann, and Antonio Salar

Subjects
Male, Follicular lymphoma, Salvage therapy, Immunochemotherapy, Gastroenterology, 0302 clinical medicine, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Treatment Failure, Lymphoma, Follicular, Etoposide, Standard treatment, Cytarabine, Hematology, General Medicine, Middle Aged, R-ESHAP, Treatment Outcome, 030220 oncology & carcinogenesis, Disease Progression, Female, Rituximab, medicine.drug, Adult, medicine.medical_specialty, Methylprednisolone, Relapsed, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Aged, Retrospective Studies, Salvage Therapy, business.industry, medicine.disease, Survival Analysis, Transplantation, refractory, Drug Resistance, Neoplasm, Spain, Cisplatin, Neoplasm Grading, ESHAP, business, 030215 immunology
Abstract

There is no standard treatment for relapsed follicular lymphoma (FL). Although platinum-based combinations are one of the most used treatments, few data have been reported in this setting. Our aim was to analyse R-ESHAP efficacy in relapsed FL patients. We retrospectively analysed 80 FL patients treated with R-ESHAP in the first or successive relapses. Responding patients received a stem cell transplantation following R-ESHAP. Seventeen histologically transformed patients were included. Median age was 50 years. At R-ESHAP initiation, 85% of the patients were in an advanced stage, 28% had a bulky disease and 40% had increased LDH. There were no statistically significant differences between POD24 and non-POD24 patients in terms of response to R-ESHAP (ORR 72% vs. 93%, p = 0.109). When analyzing R-ESHAP efficacy according to the response to the immediately previous line, patients achieving CR or PR had better CR rates to R-ESHAP than those who did not respond (CR of 57% vs. 15%, respectively, p = 0.009), as well as differences in OS (7.2 vs. 1.4 years, p < 0.0001) and in PFS (2.1 vs. 0.3 years, p < 0.0001). R-ESHAP is an effective treatment in relapsed FL patients who respond to the previous line and has to be considered as an adequate alternative for some patients.

Published
2020

19. Evolution Over Time of Ventilatory Management and Outcome of Patients With Neurologic Disease

Author

Tejerina E. E., Pelosi P., Robba C., Penuelas O., Muriel A., Barrios D., Frutos-Vivar F., Raymondos K., Du B., Thille A. W., Rios F., Gonzalez M., Del-Sorbo L., Marin M. D. C., Valle Pinheiro B., Soares M. A., Nin N., Maggiore S. M., Bersten A., Amin P., Cakar N., Young Suh G., Abroug F., Jibaja M., Matamis D., Ali Zeggwagh A., Sutherasan Y., Anzueto A., Esteban A, Fernando Ríos, Damian Violi, Marisol Rodríguez-Goñi, Roger Lamoglie, Fernando Villarejo, Norberto Tiribelli, Santiago Ilutovich, Matías Brizuela, Mariana Monllau, Fernando Saldarini, Silvina Borello, Alberto Marino, Mauricio Vinzio, Karina Bonasegla, Julián Hernández, María Belén Yapur, María Eugenia González, Sebastián E Mare, Judith Sagardía, Marco Bezzi, Cecilia Pereyra, Julian Strati, Daniel Vargas, Claudia Diaz, Pablo Gómez, Marcelo Palavecino, Graciela Elizabeth, Aguilera García, M Eugenia, Luis Pablo Cardonnet, Lisandro Betttini, Hernán Nuñez, Lucas Vallejo, Fernando Fernández, Jorge Arroyo, Daniel Duarte, Gerardo Filippa, Cayetano Galetti, Hernan Nunia, Fernando Lambert, Elisa Estenssoro, Marina Busico, Javier Horacio Álvarez, Alejandro Raimondi, Gustavo Badariotti, Martín Lugaro, Fernando Lipovestky, Alan Javier Zazu, Hugo Capponcelli, Patricia Vogl, Cristina Orlandi, Alejandro Gómez, Gustavo Jannello, Alejandro Risso, Leticia Rapetti, Guillermo Chiappero, Juan Domingo Fernández, Rodrigo E Gómez-Paz, Marcos Juan Zec, Pascual Valdez, Jorgelina Guyon, Ariel Chena, Sergio Lasdica, Martin Deheza, Schimdt Alejandra, Francisco Criado, Norma Beatriz Márquez, Pablo Desmery, José Luis Scapellato, Gonzalo Javier Ríos, Cristian Casabella, Jasmin Board, Andrew Davies, Andrew Bersten, Elisha Matheson, Amy Waters, John Santamaria, Jennifer Holmes, Cartan Costello, Manoj K Saxena, John Myburgh, Ellen Kinkel, Forbes McGain, Claire Cattigan, Allison Bone, Ian Seppelt, Leonie Weisbrodt, Cheryl Cuzner, Christopher MacIsaac, Deborah Barge, Tania Caf, Cameron Knott, Graeme Duke, Imogen Mitchell, Helen Rodgers, Rachel Whyte, Elisha Fulton, Alistair Nichol, Hergen Buscher, Priya Nair, Claire Reynolds, Simon J G Hockley, Ian Moore, Katherine Davidson, David Milliss, Raju Pusapati, Helen Wong, Jason Fletcher, Julie Smith, Paul Goldrick, Dianne Stephens, Jane Thomas, Anders Aneman, Sutrisno Gunawan, Tom Cowlam, George Lukas, Rick McAllister, Minka Springham, Joanne Sutton, Jeff Presneill, Tony Sutherland, Dianne Hill, Howard Connor, Jenny Dennett, Tim Coles, Freddy Sandy, Sando Chavarria, Marcelo Choque, Ronald Pairumani, Juan Guerra, Marco Antônio Soares Reis, José Carlos Versiani, Eduardo Fonseca Sad, Maria Aparecida Braga, Dinalva Aparecida Gomes, Fernando Antônio Botoni, Maurício Meireles Góes, Frederico Costa Val Barros, Rogério de Castro Pereira, Hugo Urbano, Valéria de Carvalho Magela, Aline Camile Yehia, Bruno Bonaccorsi Fernandino, Marco Antônio Ribeiro Leão, Rovílson Lara, Rubens Altair Amaral de Pádua, Janine Dias Alves, Aloísio Marques do Nascimento, Bruno do Valle Pinheiro, Carlos Alberto Studart Gomes, Marcelo Alcântara Holanda, Frederico Rodrigues Anselmo, Niall Ferguson, Neill Adhikari, Robert Fowler, Cheromi Sittambalam, Mehar-Un-Nisa Raja, Nicole Marinoff, Lauralyn McIntryre, Shawna Reddie, Laura Jones, Irene Watpool, Jeffrey Singh, Madison Dennis, Andrea Matte, Marc Lipkus, Ryan Albert, Andrew Steel, Emily Stern, Michael Miletin, Antonio Raso, Robyn Klages, Jan Friedrich, Orla Smith, Laura Wilson, Deborah Cook, Mark Bailey, Sangeeta Mehta, Stephen Lapinsky, Hannah Mathers, Cheryl Ethier, Stephanie Lubchansky, Samer Haj-Bakri, Dietrich Henzler, Lisa Julien, Luis Soto-Román, Juan Carlos Maurelia, César Antonio Maquilon, Luis Soto-Germani, Bin Du, Yan Kang, Bo Wang, Fachun Zhou, Fang Xu, Haibo Qiu, Yi Yang, Qingyuan Zhan, Bing Sun, Zhenjie Hu, Bin Yu, Xi Zhu, Yu Bai, Gang Li, Yi Li, Geng Zhang, Jianbiao Meng, Xiaobo Huang, Hong Pu, Daxing Yu, Chuanyun Qian, Wei Zhang, Yongjie Yin, Debiao Song, Yunxuan Yue, Zhengxuan Lv, Chengmin Yu, Qunmei Yao, Xue Wang, Yuan Xu, Wei He, Mian Chen, Zhihua Hu, Dongpo Jiang, Jian Huang, Wei Yu, Juanxian Gu, Yangong Chao, Zhixiang Li, Zhicheng Zhang, Wanxia Li, Zhenyang He, Jianguo Li, Chang Liu, Tiehe Qin, Shouhong Wang, Feng Li, Jun Jin, Jianhong Fu, Hongyang Xu, Hongyuan Lin, Jianying Guo, Yalin Liu, Jinghua Wang, Maoqin Li, Jiaqiong Li, Lei Chen, Qing Song, Liang Pan, Xianyao Wan, Jiuzhi Zhang, Weihai Yao, Yuhong Guo, Pang Wing Yan, Kelly Choy, Kwan Ming Chit, Patricia Leung, Chau Chin Man, Marco González, Ricardo Buitrago, Marcela Granados, Guillermo Ortiz, Cesar Enciso, Mario Gómez, Bladimir Alejandro Gil, Juan Pablo Sedano, Luis Fernando Castro Castro, Carlo Alberto Acosta, Marco Gonzalez, Francisco Molina, Camilo Pizarro, Mario Villabon, Carmelo Dueñas, Carlos Andrés Díaz, Nelson Fonseca, Rubén Camargo, Juan David Uribe, Hans-Henrik Bülow, Simona Beniczky, Jens Brushoj, Mikkel Præst, Birgitte Viebaek, Sine Wichman, Anette Mortensen, Susanne Andi Iversen, Bo Broberg, Edgard Luna, Manuel Jibaja, Leonardo Pazmiño, Katty Trelles, Fabricio Picoita, Gustavo Paredes, Vanesa Ramírez, Guillermo Falconí, Cristian Cevallos, Boris Villamagua, Marco Escobar, Freddy Sánchez, Miguel Llano, Miguel Lazcano, Ramiro Puetate, José Miguel Guerrero, Mijail Játiva, Myriam Montalvo, Franklin Villegas, Luis González Zambrano, Ronnie Mantilla, Gina Quinde, Andrea Gimenez, Luis Gonzalez Mosquera, Henry Caballero, María Fernanda García, Marcelo Ochoa, Soraya Puertas, Jackeline Coello, Mario Acosta, Medhat Soliman, Arnaud W Thille, Achille Kouatchet, Alain Mercat, Laurent Brochard, François Collet, Guillaume Marcotte, Pascal Beuret, Jean-Christophe M Richard, Gaëtan Bedunaeu, Pierre-Gildas Guitard, Fabien Soulis, Frédéric Bellec, Philippe Berger, Dorothée Carpentier, Benoit Veber, Salem Ould Zein, Géraldine Dessertaine, C Canevet, Fabien Grelon, Konstantinos Raymondos, Rolf Dembinski, Rolf Rossaint, Steffen Weber-Carstens, Christian Putensen, Maximillian Ragaller, Michael Quintel, Winfried Schubert, Thomas Bein, Heinrich Paulus, Walter Brandt, Lutz Pfeiffer, Silke Frenzel, Thoralf Kerner, P Kruska, Leila Eckholt, Joachim Hartung, Harald Fritz, Monika Holler, Johannes Busch, Andreas Viehöfer, Jens Buettner, Jörn Schlechtweg, Achim Lunkeit, Roland Schneider, Maria Wussow, Nils Marquardt, Christian Frenkel, Falk Hildebrandt, Tumbass Volker, Thomas Lipp, Cezar Mihailescu, Thomas Moellhoff, Thomas Steinke, Oliver Franke, Marcus Ruecker, Markus Schappacher, Steffen Appel, Heinz Kerger, Andreas Schwartz, Jan Dittmann, Jörg Haberkorn, Wolfgang Baier, Walter Seyde, Dimitros Matamis, Eleni Antoniadou, Pertsas Evangelos, Maria Giannakou, Zoltan Szentkereszty, Zsolt Molnar, Pravin Amin, Farhad N Kapadia, Nagarajan Ramakrishnan, Deepak Govil, Anitha Shenoy, Umesh G, Samir Sahu, Sheila Nainan Myatra, Subhash Kumar Todi, Sanjay Dhanuka, Mayur Patel, P Samaddar, Dhruva Chaudhry, Vivek Joshi, Srinivas Samavedam, Ankur Devendra Bhavsar, Prachee Sathe, Sujoy Mukherjee, Salvatore Maurizio Maggiore, Francesco Idone, Federica Antonicelli, Paolo Navalesi, Rosanna Vaschetto, Arianna Boggero, Rosalba Tufano, Michele Iannuzzi, Edoardo De Robertis, Romano Tetamo, Andrea Neville Cracchiolo, Antonio Braschi, Francesco Mojoli, Ilaria Curro', Mirko Belliato, Chiara Verga, Marta Ferrari, Erika Mannelli, Valerio Mangani, Giorgio Tulli, Francesca Frigieri, Armando Pedulla', Monica Rocco, Giorgia Citterio, Di Russo, Gaetano Perchiazzi, Loredana Pitagora, Antonio Pesenti, Michela Bombino, Davide Chiumello, Federica Tallarini, Serena Azzari, Antonina Pigna, Ivano Aprile, Marco Adversi, Antonio Corcione, Marianna Esposito, Annunziata Mattei, Vito Marco Ranieri, Rosario Urbino, Ilaria Maria Mastromauro, Antonino Giarratano, Maurizio Raineri Santi, Ambrogio Sansone, Younsuck Koh, Moo Suk Park, Je Hyeong Kim, Kyung Chan Kim, Hye Sook Choi, Yun Seong Kim, Jin Hwa Lee, Myung-Goo Lee, Won-Yeon Lee, Jin Young An, Gee Young Suh, Ki-Suck Jung, Asisclo J Villagómez Ortiz, César Cruz Lozano, Zalatiel Maycotte Luna, José Francisco López Baca, José Elizalde, Guillermo Cueto Robledo, Mario Alonso Treviño Salinas, Ricardo Martinez Zubieta, Claudia Olvera-Guzman, Marco Montes De Oca, Silvio A Ñamendys-Silva, José Salvador Martínez Cano, Jose Angel Baltazar Torres, Gustavo Morales Muñoz, Antonio Villa Delgado, Javier Ladape Martinez, Amine Ali Zeggwagh, Tarek Dendane, Abderrahim Azzouzi, Ahmed Sbihi, Wajdi Maazouzi, Mourad Amor, Charki Haimeur, Michael A Kuiper, Matty Koopmans, Uli Strauch, Dennis Bergmans, Serge Heines, Sylvia den Boer, Bas M Kors, Peter van der Voort, Paul J Dennesen, Bert Beishuizen, Ingrid van den Hul, Erna Alberts, Harry P P M Gelissen, Eduard Bootsma, Auke Reidinga, Kim Heus, Diane Mackle, Paul Young, Rachael Parke, Eileen Gilder, Jodi Brown, Lynette Newby, Catherine Simmonds, Jan Mehrtens, Seton Henderson, Tony Williams, Judi Tai, Chantal Hogan, Mary La Pine, John Durning, Sheree Gare, Troy Browne, Shirley Nelson, Jennifer Goodson, Julio Osorio, Chabu Coronado, Rollin Roldán Mori, Rosa Luz López Martínez, Adam Mikstacki, Barbara Tamowicz, Rui Moreno, Eduardo Almeida, Joana Silvestre, Heloisa Castro, Irene Aragão, Susana Alves Ferreira, Nelson Barros, Filomena Faria, Carlos André Correia Casado, Fausto Fialho Moura, Paulo Marcal, Ricardo Matos, Edward Nicolayenko, Mikhail Kirov, Andrey Yaroshetskiy, Andrei Piontek, Valery Subbotin, Yaseen Arabi, Olivia Dulfo, Chafrina Marie Olay, Edgardo E Tabhan, Nicolas Nin, Alfonso Muñoz, César Aragón, Ana Villagrá, Ainhoa Rosselló, Joan Maria Raurich, María Garitacelaya, Miguel Ángel González-Gallego, Francisco Ortuño, Miguel Fernández-Vivas, David Freire, Francisco Guerrero, Francisco Manzano, Juan Carlos, Alfredo Padrón, Pedro Rosa, Rafael Morales, Liliana Caipe, Maurizio Bottiroli, José María Nicolás, Marta Ugalde, Javier Ruiz, Lucia Capilla, Guillermo Muñiz, Jesús Sánchez-Ruiz, Javier Cebrián, Begoña Balerdi, Elena Parreño, Alvaro van Bommel, César Pérez-Calvo, Irene Dot, Javier Blanco, Raquel Manzanedo, José J Blanco, Daniel Fontaneda, Raúl González, Javier Díaz Domínguez, Alfonso Moreno, Antonio Reyes, Ian Carrasco, Itziar Mintegui, Rosa Sebastián, Javier García-Alonso, Carolina Lorencio, Josep Maria Sirvent, Patricia Jimeno, Miguel León, Pedro Galdos, Nuria Alonso, Julia López-Díaz, María Victoria de la Torre, Jorge Vidal Hernández, Nicolás Zamboschi, Francisco Lucena, Gemma Rialp, Raquel Montoiro, Victoria Goñi, María Ángeles Pena, Antonio Maestre, Marc Fabra, Jacinto Baena, Eva Benveniste, Susana Temprano, Jesús Sánchez, Carmen Campos, Sara Cabañes, María Elena Pérez-Losada, José Claudio Leo, Enrique Piacentini, María Del Carmen de la Torre, Laura Álvarez-Montero, Fernando Sánchez, Antonio Viñuales, Bernabé Álvarez, Javier Castañeda, Ángela Alonso, María Isabel Ruiz, Pedro Jesús Domínguez, Marcos Delgado, Eugenio Palazón, Antonio García-Jiménez, Rosa Álvaro, Clara Laplaza Eva Regidor, Enrique Maraví, José María Quiroga, Amalia Martínez de la Gandara, Cecilia Carbayo, María Luisa Navarrete, Manuel Valledor, Raquel Yano, José María Gutiérrez, Javier González-Robledo, Amparo Ferrandiz, Alberto Belenguer, Lidón Mateu, Laura Sayagues, María José Tolón, Nieves Franco, Elena Gallego, Félix Lacoma, Patricia Albert, Vicente Arraez, Mar Gobernado, Susana Moradillo, Carolina Gímenez-Esparza, Teresa Sánchez de Dios, Carlos Marian Crespo, Cecilia Hermosa, Federico Gordo, Genis Carrasco, María Ángeles Alonso, Alejandro Algora, Raúl de Pablo, Sofía García, Ana Carolina Caballero, José María Montón, Teresa Mut, Eva Manteiga, Alejandro de la Serna, Ana Esther Trujillo, Rafael Blancas, Inmaculada Vallverdú, José Manuel Serrano, Miquel Ferrer, Juan Diego Jiménez, Carlos Gallego, Dolores Vila, Luis Marina, Valentín Parra, Juan Ramón Cortés, Chen Chin-Ming, Ai-Chin Cheng, Fekri Abroug, Besbes Mohamed, Imed Chouchene, Mounir Bouaziz, Stambouli Neji, Islem Ouanes, Ayed Samia, Nahit Cakar, Ismail Kati, Ali Aydım Altunkan, Remzi Iscimen, Zafer Dogan, Bilge Çetin, Tayfun Adanir, Sabriye Guvenc, Unase Büyükkoçak, Antonio Anzueto, Ashley Ellis, Gary Kinasewitz, Allan Walkey, Phil Alkana, Gregory A Schmidt, Susan Gillen, Kathleen Lilli, Jennifer Twombley, Denice Wells, Larry Welder, Alejandro Arroliga, Alfredo Vasquez-Sandoval, Vincent John Scott, Craig Cernosek, Christopher Spradley, Dimple Tejwani, Sindhaghatta Venkatram, Gilda Diaz-Fuentes, Amber Monson, Anthony Saleh, Madhav Gudi, George Liziamma, Mohamed A Saad, Crissie De Spirito, Bryan Beatty, Samir Vermani, Crissie Despirito, Zaza Cohen, Amee Patrawalla, Samir Abdelhadi, Rupesh Vakil, Steven Y Chang, Brian Sherman, Rosanna Del Giudice, John Oropell, Timothy D Girard, Cayce Strength, Joyce Okahashi, Leanne Boehm, Matthew Kirchner, Erwin J Oei, Sebastian Circo, Nelson Medina, Mohammed Al-Jagbeer, V J Cardenas Jr, Smyth Smith, Shelby Sutton, Marcela Canola-Mazo, Tim Houlihan, Yogeet Kaur, Travis Parry, Craig A Piquette, Kerry Canady, Rahul Nanchal, Dana K Soetaert, Maria Del Mar Torres-Perez, Carlos Robles-Arias, William Rodriguez-Cintron, Mark Tidswell, Jennifer Germain, Lori-Ann Kozikowski, Erin Braden, Geneva Tatem, Javier Hurtado, Alberto Deicas, Daniel Weiss, Marta Beron, Román Garrido, Cristina Santos, Mario Cancela, Raúl Lombardi, Pedro Alzugaray, Jorge Gerez, Silvia Mareque, Graciela Franca, Oscar Cluzet, Edgardo Nuñez, Julio Pontet, Sergio Cáceres, Elias Caragna, Alberto Soler, Frank Torres, Gastón Pittini, Gabriel D Empaire, Stevens Salva, Fernando Pérez, Clara Pacheco, Zoraida Parra, Ingrid Von der Osten, Luis Williams, José Salinas, Do Danh Quynh, Pham Thi Van Anh, Nguyen Huu Hoang, Nghuyen Ba Tuan, RS: NUTRIM - R2 - Liver and digestive health, MUMC+: MA Arts Assistenten IC (9), Intensive Care, MUMC+: MA Medische Staf IC (9), Tejerina E.E., Pelosi P., Robba C., Penuelas O., Muriel A., Barrios D., Frutos-Vivar F., Raymondos K., Du B., Thille A.W., Rios F., Gonzalez M., Del-Sorbo L., Marin M.D.C., Valle Pinheiro B., Soares M.A., Nin N., Maggiore S.M., Bersten A., Amin P., Cakar N., Young Suh G., Abroug F., Jibaja M., Matamis D., Ali Zeggwagh A., Sutherasan Y., Anzueto A., Esteban A, and Fernando Ríos, Damian Violi, Marisol Rodríguez-Goñi, Roger Lamoglie, Fernando Villarejo, Norberto Tiribelli, Santiago Ilutovich, Matías Brizuela, Mariana Monllau, Fernando Saldarini, Silvina Borello, Alberto Marino, Norberto Tiribelli, Mauricio Vinzio, Karina Bonasegla, Julián Hernández, María Belén Yapur, María Eugenia González, Sebastián E Mare, Judith Sagardía, Marco Bezzi, Cecilia Pereyra, Julian Strati, Daniel Vargas, Claudia Diaz, Pablo Gómez, Marcelo Palavecino, Graciela Elizabeth, Aguilera García, M Eugenia, Luis Pablo Cardonnet, Lisandro Betttini, Hernán Nuñez, Lucas Vallejo, Fernando Fernández, Jorge Arroyo, Daniel Duarte, Gerardo Filippa, Cayetano Galetti, Hernan Nunia, Fernando Lambert, Elisa Estenssoro, Marina Busico, Fernando Villarejo, Javier Horacio Álvarez, Alejandro Raimondi, Gustavo Badariotti, Martín Lugaro, Fernando Lipovestky, Alan Javier Zazu, Hugo Capponcelli, Patricia Vogl, Cristina Orlandi, Alejandro Gómez, Gustavo Jannello, Alejandro Risso, Leticia Rapetti, Guillermo Chiappero, Juan Domingo Fernández, Rodrigo E Gómez-Paz, Marcos Juan Zec, Pascual Valdez, Jorgelina Guyon, Ariel Chena, Sergio Lasdica, Martin Deheza, Schimdt Alejandra, Francisco Criado, Norma Beatriz Márquez, Pablo Desmery, José Luis Scapellato, Gonzalo Javier Ríos, Cristian Casabella, Jasmin Board, Andrew Davies, Andrew Bersten, Elisha Matheson, Amy Waters, John Santamaria, Jennifer Holmes, Cartan Costello, Manoj K Saxena, John Myburgh, Ellen Kinkel, Forbes McGain, Claire Cattigan, Allison Bone, Ian Seppelt, Leonie Weisbrodt, Cheryl Cuzner, Christopher MacIsaac, Deborah Barge, Tania Caf, Cameron Knott, Graeme Duke, Imogen Mitchell, Helen Rodgers, Rachel Whyte, Elisha Fulton, Jasmin Board, Andrew Davies, Alistair Nichol, Hergen Buscher, Priya Nair, Claire Reynolds, Simon J G Hockley, Ian Moore, Katherine Davidson, David Milliss, Raju Pusapati, Helen Wong, Jason Fletcher, Julie Smith, Paul Goldrick, Dianne Stephens, Jane Thomas, Anders Aneman, Sutrisno Gunawan, Tom Cowlam, George Lukas, Rick McAllister, Minka Springham, Joanne Sutton, Jeff Presneill, Tony Sutherland, Dianne Hill, Howard Connor, Jenny Dennett, Tim Coles, Freddy Sandy, Sando Chavarria, Marcelo Choque, Ronald Pairumani, Juan Guerra, Marco Antônio Soares Reis, José Carlos Versiani, Eduardo Fonseca Sad, Maria Aparecida Braga, Dinalva Aparecida Gomes, Fernando Antônio Botoni, Maurício Meireles Góes, Frederico Costa Val Barros, Rogério de Castro Pereira, Hugo Urbano, Valéria de Carvalho Magela, Aline Camile Yehia, Bruno Bonaccorsi Fernandino, Marco Antônio Ribeiro Leão, Rovílson Lara, Rovílson Lara, Rubens Altair Amaral de Pádua, Janine Dias Alves, Aloísio Marques do Nascimento, Bruno do Valle Pinheiro, Carlos Alberto Studart Gomes, Marcelo Alcântara Holanda, Frederico Rodrigues Anselmo, Niall Ferguson, Neill Adhikari, Robert Fowler, Cheromi Sittambalam, Mehar-Un-Nisa Raja, Nicole Marinoff, Lauralyn McIntryre, Shawna Reddie, Laura Jones, Irene Watpool, Jeffrey Singh, Madison Dennis, Andrea Matte, Marc Lipkus, Ryan Albert, Andrew Steel, Emily Stern, Michael Miletin, Antonio Raso, Robyn Klages, Jan Friedrich, Orla Smith, Laura Wilson, Deborah Cook, Mark Bailey, Sangeeta Mehta, Stephen Lapinsky, Hannah Mathers, Cheryl Ethier, Stephanie Lubchansky, Samer Haj-Bakri, Dietrich Henzler, Lisa Julien, Luis Soto-Román, Juan Carlos Maurelia, César Antonio Maquilon, Luis Soto-Germani, Bin Du, Yan Kang, Bo Wang, Fachun Zhou, Fang Xu, Haibo Qiu, Yi Yang, Qingyuan Zhan, Bing Sun, Zhenjie Hu, Bin Yu, Xi Zhu, Yu Bai, Gang Li, Yi Li, Geng Zhang, Jianbiao Meng, Xiaobo Huang, Hong Pu, Bin Du, Daxing Yu, Chuanyun Qian, Wei Zhang, Yongjie Yin, Debiao Song, Yunxuan Yue, Zhengxuan Lv, Chengmin Yu, Qunmei Yao, Xue Wang, Yuan Xu, Wei He, Mian Chen, Zhihua Hu, Dongpo Jiang, Jian Huang, Wei Yu, Juanxian Gu, Yangong Chao, Zhixiang Li, Zhicheng Zhang, Wanxia Li, Zhenyang He, Jianguo Li, Chang Liu, Tiehe Qin, Shouhong Wang, Feng Li, Jun Jin, Jianhong Fu, Hongyang Xu, Hongyuan Lin, Jianying Guo, Yalin Liu, Jinghua Wang, Maoqin Li, Jiaqiong Li, Lei Chen, Qing Song, Liang Pan, Xianyao Wan, Jiuzhi Zhang, Weihai Yao, Yuhong Guo, Pang Wing Yan, Kelly Choy, Kwan Ming Chit, Patricia Leung, Chau Chin Man, Marco González, Ricardo Buitrago, Marcela Granados, Guillermo Ortiz, Cesar Enciso, Mario Gómez, Bladimir Alejandro Gil, Juan Pablo Sedano, Luis Fernando Castro Castro, Carlo Alberto Acosta, Marco Gonzalez, Francisco Molina, Camilo Pizarro, Mario Villabon, Carmelo Dueñas, Carlos Andrés Díaz, Nelson Fonseca, Rubén Camargo, Juan David Uribe, Hans-Henrik Bülow, Simona Beniczky, Jens Brushoj, Mikkel Præst, Birgitte Viebaek, Sine Wichman, Anette Mortensen, Susanne Andi Iversen, Bo Broberg, Edgard Luna, Manuel Jibaja, Leonardo Pazmiño, Katty Trelles, Fabricio Picoita, Gustavo Paredes, Vanesa Ramírez, Guillermo Falconí, Cristian Cevallos, Boris Villamagua, Marco Escobar, Freddy Sánchez, Miguel Llano, Miguel Lazcano, Ramiro Puetate, José Miguel Guerrero, Mijail Játiva, Myriam Montalvo, Franklin Villegas, Luis González Zambrano, Ronnie Mantilla, Gina Quinde, Andrea Gimenez, Luis Gonzalez Mosquera, Henry Caballero, María Fernanda García, Marcelo Ochoa, Soraya Puertas, Jackeline Coello, Mario Acosta, Medhat Soliman, Arnaud W Thille, Achille Kouatchet, Alain Mercat, Laurent Brochard, François Collet, Guillaume Marcotte, Pascal Beuret, Jean-Christophe M Richard, Gaëtan Bedunaeu, Pierre-Gildas Guitard, Fabien Soulis, Frédéric Bellec, Philippe Berger, Dorothée Carpentier, Benoit Veber, Salem Ould Zein, Géraldine Dessertaine, C Canevet, Fabien Grelon, Konstantinos Raymondos, Rolf Dembinski, Rolf Rossaint, Steffen Weber-Carstens, Christian Putensen, Maximillian Ragaller, Michael Quintel, Winfried Schubert, Thomas Bein, Heinrich Paulus, Walter Brandt, Lutz Pfeiffer, Silke Frenzel, Thoralf Kerner, P Kruska, Leila Eckholt, Joachim Hartung, Harald Fritz, Monika Holler, Johannes Busch, Andreas Viehöfer, Jens Buettner, Jörn Schlechtweg, Achim Lunkeit, Roland Schneider, Maria Wussow, Nils Marquardt, Christian Frenkel, Falk Hildebrandt, Tumbass Volker, Thomas Lipp, Cezar Mihailescu, Thomas Moellhoff, Thomas Steinke, Oliver Franke, Marcus Ruecker, Markus Schappacher, Steffen Appel, Heinz Kerger, Andreas Schwartz, Jan Dittmann, Jörg Haberkorn, Wolfgang Baier, Walter Seyde, Dimitros Matamis, Eleni Antoniadou, Pertsas Evangelos, Maria Giannakou, Zoltan Szentkereszty, Zsolt Molnar, Pravin Amin, Farhad N Kapadia, Nagarajan Ramakrishnan, Deepak Govil, Anitha Shenoy, Umesh G, Samir Sahu, Sheila Nainan Myatra, Subhash Kumar Todi, Sanjay Dhanuka, Mayur Patel, P Samaddar, Dhruva Chaudhry, Vivek Joshi, Srinivas Samavedam, Ankur Devendra Bhavsar, Prachee Sathe, Sujoy Mukherjee, Salvatore Maurizio Maggiore, Francesco Idone, Federica Antonicelli, Paolo Navalesi, Rosanna Vaschetto, Arianna Boggero, Rosalba Tufano, Michele Iannuzzi, Edoardo De Robertis, Romano Tetamo, Andrea Neville Cracchiolo, Antonio Braschi, Francesco Mojoli, Ilaria Curro', Mirko Belliato, Chiara Verga, Marta Ferrari, Erika Mannelli, Valerio Mangani, Giorgio Tulli, Francesca Frigieri, Armando Pedulla', Monica Rocco, Giorgia Citterio, Di Russo, Gaetano Perchiazzi, Loredana Pitagora, Antonio Pesenti, Michela Bombino, Davide Chiumello, Federica Tallarini, Serena Azzari, Antonina Pigna, Ivano Aprile, Marco Adversi, Antonio Corcione, Marianna Esposito, Annunziata Mattei, Vito Marco Ranieri, Rosario Urbino, Ilaria Maria Mastromauro, Antonino Giarratano, Maurizio Raineri Santi, Ambrogio Sansone, Younsuck Koh, Moo Suk Park, Je Hyeong Kim, Kyung Chan Kim, Hye Sook Choi, Yun Seong Kim, Jin Hwa Lee, Myung-Goo Lee, Won-Yeon Lee, Jin Young An, Gee Young Suh, Ki-Suck Jung, Asisclo J Villagómez Ortiz, César Cruz Lozano, Zalatiel Maycotte Luna, José Francisco López Baca, José Elizalde, Guillermo Cueto Robledo, Mario Alonso Treviño Salinas, Ricardo Martinez Zubieta, Claudia Olvera-Guzman, Marco Montes De Oca, Silvio A Ñamendys-Silva, José Salvador Martínez Cano, Jose Angel Baltazar Torres, Gustavo Morales Muñoz, Antonio Villa Delgado, Javier Ladape Martinez, Amine Ali Zeggwagh, Tarek Dendane, Abderrahim Azzouzi, Ahmed Sbihi, Wajdi Maazouzi, Mourad Amor, Charki Haimeur, Michael A Kuiper, Matty Koopmans, Uli Strauch, Dennis Bergmans, Serge Heines, Sylvia den Boer, Bas M Kors, Peter van der Voort, Paul J Dennesen, Bert Beishuizen, Ingrid van den Hul, Erna Alberts, Harry P P M Gelissen, Eduard Bootsma, Auke Reidinga, Jasmin Board, Andrew Davies, Kim Heus, Diane Mackle, Paul Young, Rachael Parke, Eileen Gilder, Jodi Brown, Lynette Newby, Catherine Simmonds, Jan Mehrtens, Seton Henderson, Tony Williams, Judi Tai, Chantal Hogan, Mary La Pine, John Durning, Sheree Gare, Troy Browne, Shirley Nelson, Jennifer Goodson, Julio Osorio, Chabu Coronado, Rollin Roldán Mori, Rosa Luz López Martínez, Adam Mikstacki, Barbara Tamowicz, Rui Moreno, Eduardo Almeida, Joana Silvestre, Heloisa Castro, Irene Aragão, Susana Alves Ferreira, Nelson Barros, Filomena Faria, Carlos André Correia Casado, Fausto Fialho Moura, Paulo Marcal, Ricardo Matos, Edward Nicolayenko, Mikhail Kirov, Andrey Yaroshetskiy, Andrei Piontek, Valery Subbotin, Yaseen Arabi, Olivia Dulfo, Chafrina Marie Olay, Edgardo E Tabhan, Nicolas Nin, Alfonso Muñoz, César Aragón, Ana Villagrá, Ainhoa Rosselló, Joan Maria Raurich, María Garitacelaya, Miguel Ángel González-Gallego, Francisco Ortuño, Miguel Fernández-Vivas, David Freire, Francisco Guerrero, Francisco Manzano, Juan Carlos, Alfredo Padrón, Pedro Rosa, Rafael Morales, Liliana Caipe, Maurizio Bottiroli, José María Nicolás, Marta Ugalde, Javier Ruiz, Lucia Capilla, Guillermo Muñiz, Jesús Sánchez-Ruiz, Javier Cebrián, Begoña Balerdi, Elena Parreño, Alvaro van Bommel, César Pérez-Calvo, Irene Dot, Javier Blanco, Raquel Manzanedo, José J Blanco, Daniel Fontaneda, Raúl González, Javier Díaz Domínguez, Alfonso Moreno, Antonio Reyes, Ian Carrasco, Itziar Mintegui, Rosa Sebastián, Javier García-Alonso, Carolina Lorencio, Josep Maria Sirvent, Patricia Jimeno, Miguel León, Pedro Galdos, Nuria Alonso, Julia López-Díaz, María Victoria de la Torre, Jorge Vidal Hernández, Nicolás Zamboschi, Francisco Lucena, Gemma Rialp, Raquel Montoiro, Victoria Goñi, María Ángeles Pena, Antonio Maestre, Marc Fabra, Jacinto Baena, Eva Benveniste, Susana Temprano, Jesús Sánchez, Carmen Campos, Sara Cabañes, María Elena Pérez-Losada, José Claudio Leo, Enrique Piacentini, María Del Carmen de la Torre, Laura Álvarez-Montero, Fernando Sánchez, Antonio Viñuales, Bernabé Álvarez, Javier Castañeda, Ángela Alonso, María Isabel Ruiz, Pedro Jesús Domínguez, Marcos Delgado, Eugenio Palazón, Antonio García-Jiménez, Rosa Álvaro, Clara Laplaza Eva Regidor, Enrique Maraví, José María Quiroga, Amalia Martínez de la Gandara, Cecilia Carbayo, María Luisa Navarrete, Manuel Valledor, Raquel Yano, José María Gutiérrez, Javier González-Robledo, Amparo Ferrandiz, Alberto Belenguer, Lidón Mateu, Laura Sayagues, María José Tolón, Nieves Franco, Elena Gallego, Félix Lacoma, Patricia Albert, Vicente Arraez, Mar Gobernado, Susana Moradillo, Carolina Gímenez-Esparza, Teresa Sánchez de Dios, Carlos Marian Crespo, Cecilia Hermosa, Federico Gordo, Genis Carrasco, María Ángeles Alonso, Alejandro Algora, Raúl de Pablo, Sofía García, Ana Carolina Caballero, José María Montón, Teresa Mut, Eva Manteiga, Alejandro de la Serna, Ana Esther Trujillo, Rafael Blancas, Inmaculada Vallverdú, José Manuel Serrano, Miquel Ferrer, Juan Diego Jiménez, Carlos Gallego, Dolores Vila, Luis Marina, Valentín Parra, Juan Ramón Cortés, Chen Chin-Ming, Ai-Chin Cheng, Fekri Abroug, Besbes Mohamed, Imed Chouchene, Mounir Bouaziz, Stambouli Neji, Islem Ouanes, Ayed Samia, Nahit Cakar, Ismail Kati, Ali Aydım Altunkan, Remzi Iscimen, Zafer Dogan, Bilge Çetin, Tayfun Adanir, Sabriye Guvenc, Unase Büyükkoçak, Antonio Anzueto, Ashley Ellis, Gary Kinasewitz, Allan Walkey, Phil Alkana, Gregory A Schmidt, Susan Gillen, Kathleen Lilli, Jennifer Twombley, Denice Wells, Larry Welder, Alejandro Arroliga, Alfredo Vasquez-Sandoval, Vincent John Scott, Craig Cernosek, Christopher Spradley, Dimple Tejwani, Sindhaghatta Venkatram, Gilda Diaz-Fuentes, Amber Monson, Anthony Saleh, Madhav Gudi, George Liziamma, Mohamed A Saad, Crissie De Spirito, Bryan Beatty, Samir Vermani, Crissie Despirito, Zaza Cohen, Amee Patrawalla, Samir Abdelhadi, Rupesh Vakil, Steven Y Chang, Brian Sherman, Rosanna Del Giudice, John Oropell, Timothy D Girard, Cayce Strength, Joyce Okahashi, Leanne Boehm, Matthew Kirchner, Ashley Ellis, Gary Kinasewitz, Erwin J Oei, Sebastian Circo, Nelson Medina, Mohammed Al-Jagbeer, V J Cardenas Jr, Smyth Smith, Shelby Sutton, Marcela Canola-Mazo, Tim Houlihan, Yogeet Kaur, Travis Parry, Craig A Piquette, Kerry Canady, Rahul Nanchal, Dana K Soetaert, Maria Del Mar Torres-Perez, Carlos Robles-Arias, William Rodriguez-Cintron, Mark Tidswell, Jennifer Germain, Lori-Ann Kozikowski, Erin Braden, Geneva Tatem, Javier Hurtado, Alberto Deicas, Daniel Weiss, Marta Beron, Román Garrido, Cristina Santos, Mario Cancela, Raúl Lombardi, Pedro Alzugaray, Jorge Gerez, Silvia Mareque, Graciela Franca, Oscar Cluzet, Edgardo Nuñez, Julio Pontet, Sergio Cáceres, Elias Caragna, Alberto Soler, Frank Torres, Gastón Pittini, Gabriel D Empaire, Stevens Salva, Fernando Pérez, Clara Pacheco, Zoraida Parra, Ingrid Von der Osten, Luis Williams, José Salinas, Do Danh Quynh, Pham Thi Van Anh, Nguyen Huu Hoang, Nghuyen Ba Tuan

Subjects
Male, medicine.medical_treatment, pulmonary complications, RESPIRATORY-DISTRESS-SYNDROME, Critical Care and Intensive Care Medicine, CASE-FATALITY, 0302 clinical medicine, Risk Factors, Brain Injuries, Traumatic, Multicenter Studies as Topic, Hospital Mortality, Prospective Studies, Simplified Acute Physiology Score, Stroke, POPULATION, Age Factors, ANEURYSMAL SUBARACHNOID HEMORRHAGE, Middle Aged, Hemorrhagic Stroke, Intensive Care Units, Observational Studies as Topic, Anesthesia, Breathing, Female, medicine.symptom, Ventilator Weaning, Cohort study, Adult, TRAUMATIC BRAIN-INJURY, Pressure support ventilation, mechanical ventilation, prognosis factors, ACUTE LUNG INJURY, 03 medical and health sciences, medicine, Humans, Aged, Ischemic Stroke, Mechanical ventilation, Noninvasive Ventilation, business.industry, MORTALITY, neurologic patients, Organ dysfunction, 030208 emergency & critical care medicine, Length of Stay, medicine.disease, TRENDS, Respiration, Artificial, 030228 respiratory system, Etiology, NEUROCRITICAL CARE, Nervous System Diseases, Tracheotomy, business
Abstract

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease.

Published
2021

20. Efficacy and Safety of Ruxolitinib in Steroid-Refractory/Dependent Chronic Graft-versus-Host Disease: Real-World Data and Challenges

Author

Irene García-Cadenas, Guadalupe Oñate, Jordi Mas López, Javier Briones, Carol Moreno, Ana Carolina Caballero, Miquel Granell, Rodrigo Martino, Jorge Sierra, Sara Redondo, Silvanna-Daniela Saavedra, Albert Esquirol, Ana Garrido, and Silvana Novelli

Subjects
medicine.medical_specialty, Ruxolitinib, Anemia, Graft vs Host Disease, Internal medicine, Nitriles, Immunology and Allergy, Medicine, Humans, Retrospective Studies, Transplantation, business.industry, Cell Biology, Hematology, medicine.disease, Confidence interval, Discontinuation, Graft-versus-host disease, Pyrimidines, Toxicity, Molecular Medicine, Pyrazoles, Steroids, business, Steroid refractory, medicine.drug
Abstract

Steroid-refractory (SR) chronic graft-versus-host disease (cGVHD) is a major obstacle in recipients of allogeneic stem cell transplantation (HCT). Ruxolitinib is the first agent to demonstrate superior efficacy to the best available therapy, but real-life data are still lacking. Here we describe the results of ruxolitinib compassionate use for the treatment of SR/steroid-dependent cGVHD in a tertiary care university hospital. In this retrospective single-center study, we evaluated the outcomes of 48 patients diagnosed with SR-cGVHD who were treated with ruxolitinib. Forty-seven (98%) had moderate-severe disease, and 27 (56%) had received ≥2 lines of prior therapy (excluding steroids). Results were analyzed using SPSS version 26.0.01 and R version 3.4.3. The overall response rate was 77% (37 of 48), with 15% (7 of 37) in complete remission. The median time to response was 2 months (range, 0.5 to 8 months). Steroid tapering was achieved in 26 patients (54%) and definitive discontinuation was achieved in 10 patients (21%) after a median of 20 months (range, 1.5 to 60 months). Toxicity was predominantly hematologic, including a 33% rate of anemia and a 17% rate of thrombocytopenia. Overall survival at 2 years was significantly higher in responders compared with nonresponders (88% [95% confidence interval (CI), 65% to 96%] versus 49% [95% CI, 12% to 78%]; P = .01). At last follow-up, tapering of ruxolitinib had been started in 8 of 37 responders (22%). Our experience supports the efficacy of ruxolitinib in the treatment of SR-cGVHD, along with its steroid-sparing effect and manageable toxicity. Gradual tapering of ruxolitinib seems feasible without cases of GVHD flare. More studies and longer follow-up are needed to confirm these data, as well as to identify the ideal dose adjustments in cases of toxicity.

Published
2021

21. Memory stem T cells modified with a redesigned CD30-chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma

Author

Carmen Alvarez-Fernández, Jorge Sierra, Paula Pujol-Fernández, Eva Escudero-López, Ana Carolina Caballero, Javier Briones, Cristina Ujaldón-Miró, Rosanna Montserrat-Torres, and Laura Escribà-Garcia

Subjects
0301 basic medicine, Memory stem T cells, CD30, medicine.medical_treatment, Immunology, Biology, Epitope, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, Antigen, In vivo, immune system diseases, hemic and lymphatic diseases, medicine, Immunology and Allergy, Chimeric antigen receptor, General Nursing, chimeric antigen receptor, integumentary system, Original Articles, Immunotherapy, RC581-607, 030104 developmental biology, memory stem T cells, 030220 oncology & carcinogenesis, Cancer research, Original Article, immunotherapy, Immunologic diseases. Allergy, Ex vivo
Abstract

Objectives Adoptive cell therapy (ACT) with mature T cells modified with a chimeric antigen receptor has demonstrated improved outcome for B‐cell malignancies. However, its application for others such as Hodgkin lymphoma remains a clinical challenge. CD30 antigen, expressed in Hodgkin lymphoma cells, is absent in most healthy tissues, representing an ideal target of ACT for this disease. Despite that, efficacy of CD30‐chimeric antigen receptor (CAR) T cells for Hodgkin lymphoma remains modest. Here, we have developed and tested a novel CD30‐CAR T to improve efficacy of CD30‐CAR therapy, using a targeting epitope within the non‐cleavable part of CD30 receptor, and memory stem T cells (TSCM) to improve engraftment, persistence and antitumor activity. Methods TSCM‐like cultures were generated and expanded ex vivo and transduced at day 1 or 2 with a lentiviral vector encoding the CD30‐CAR. Therapeutic in vivo experiments were performed using NSG mice injected with L540 (sc) or L428 (iv) and treated with CD30‐CAR T cells when the tumor was established. Results CD30‐CAR TSCM‐like cells generated and expanded ex vivo, despite CD30 expression and fratricide killing of CD30+ CAR T cells, were not impaired by soluble CD30 and completely eradicated Hodgkin lymphoma in vivo, showing high persistence and long‐lasting immunity. In addition, highly enriched CD30‐CAR TSCM‐like products confer a survival advantage in vivo, in contrast to more differentiated CAR T cells, with higher tumor infiltration and enhanced antitumor effect. Conclusion This study supports the use of a refined CD30‐CAR T cells with highly enriched TSCM‐like products to improve clinical efficacy of CAR T for Hodgkin lymphoma., We have studied the efficacy of a redesigned CD30‐chimeric antigen receptor (CAR) targeting a proximal epitope to enhance the antitumor efficacy. CD30‐CAR T cells show potent in vivo antitumor effect in different Hodgkin lymphoma models, and overcome inhibition by soluble CD30. CD30‐CAR memory stem T‐cell products show long‐term persistence, improved tumor homing and long‐lasting immunity.

Published
2021

22. Assessment of Confirmed Clinical Hypersensitivity to Rituximab in Patients Affected with B-Cell Neoplasia

Author

L Soto, P Jimeno, Silvana Novelli, M E Moreno, M I Zamora, A Quintas, Ana Carolina Caballero, M J Lara, Jordi Sierra, T Bigorra, Javier Briones, and D Bayo

Subjects
0301 basic medicine, Drug, medicine.medical_specialty, Article Subject, medicine.medical_treatment, media_common.quotation_subject, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, In patient, Diseases of the blood and blood-forming organs, B cell, Desensitization (medicine), media_common, business.industry, Hematology, medicine.disease, Lymphoma, Clinical Practice, 030104 developmental biology, medicine.anatomical_structure, 030228 respiratory system, Clinical Study, Intradermal test, Rituximab, RC633-647.5, business, medicine.drug
Abstract

Rituximab hypersensitivity reactions are rare but are one of the main causes of rituximab elimination from antilymphoma immunochemotherapy treatments. While the clinical picture may be indistinguishable from other infusion-related reactions, hypersensitivity reactions (HSR) do not disappear and instead become more intense with subsequent administrations. Objective. To describe the use of the 12-step protocol for desensitization to intravenous rituximab in clinical practice and the complementary study of a possible IgE-mediated HSR in the context of B-cell lymphoma treatment. Methods. A 12-step rituximab desensitization protocol was performed prospectively within clinical practice in 10 patients with a history of severe infusion reactions or in patients who had a repeated reaction at subsequent doses despite taking more intense preventive measures. Skin prick tests were performed at the time of reaction and at a later time to eliminate false negatives due to possible drug interference. Results. Overall, with the desensitization protocol, 70% of patients were able to complete the scheduled immunochemotherapy. Two patients had to discontinue the therapy due to clinical persistence and the third due to lymphoma progression. Intradermal tests with 0.1% rituximab were positive in only 20% of cases, demonstrating a mechanism of hypersensitivity. Conclusions. The 12-step desensitization protocol is very effective and assumable within healthcare practice. There is a need to determine the mechanism underlying the infusion reaction in a large proportion of cases due to the risk of future drug exposure.

Published
2020

23. Diagnostic delay and outcome in immunocompetent patients with primary central nervous system lymphoma in Spain: a multicentric study

Author

Ana Carolina Caballero, Jordi Bruna, N. Huertas, G García-Catalán, M. Solé-Rodríguez, M J Ibáñez-Juliá, P. Cacabelos, N Barbero-Bordallo, Ivan Dlouhy, Francesc Graus, Santiago Mercadal, A Muntañola, T Lado, M I Barceló, J M Sancho, Roser Velasco, L Gómez-Vicente, Noemi Vidal, Geltamo, J. Estela, R Caldú Agud, P. Martinez, E García Molina, Sabela Bobillo, I Camro, J. Gállego Pérez-Larraya, A Salar, M E Erro, María Concepción Ramírez Barón, Maite Encuentra, M Alañá, Instituto de Salud Carlos III, and European Commission

Subjects
Male, Cancer Research, Multivariate analysis, Neurology, Delayed Diagnosis, medicine.medical_treatment, Central Nervous System Neoplasms, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Primary central nervous system lymphoma, Short survival, Outcome, Aged, 80 and over, medicine.diagnostic_test, Lymphoma, Non-Hodgkin, Cytarabine, Chemoradiotherapy, Middle Aged, Prognosis, Diagnostic delay, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Steroids, Female, Immunocompetence, medicine.drug, Adult, medicine.medical_specialty, Prognostic factors, 03 medical and health sciences, Young Adult, Internal medicine, Biopsy, medicine, Humans, Aged, Retrospective Studies, Chemotherapy, Performance status, business.industry, medicine.disease, Carmustine, Methotrexate, Neurology (clinical), Cranial Irradiation, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

GELTAMO and GENOSEN group., [Introduction] To assess the management of immunocompetent patients with primary central nervous system lymphomas (PCNSL) in Spain., [Methods] Retrospective analysis of 327 immunocompetent patients with histologically confirmed PCNSL diagnosed between 2005 and 2014 in 27 Spanish hospitals., [Results] Median age was 64 years (range: 19–84; 33% ≥ 70 years), 54% were men, and 59% had a performance status (PS) ≥ 2 at diagnosis. Median delay to diagnosis was 47 days (IQR 24–81). Diagnostic delay > 47 days was associated with PS ≥ 2 (OR 1.99; 95% CI 1.13–3.50; p = 0.016) and treatment with corticosteroids (OR 2.47; 95% CI 1.14–5.40; p = 0.023), and it did not improve over the years. Patients treated with corticosteroids (62%) had a higher risk of additional biopsies (11.7% vs 4.0%, p = 0.04) but corticosteroids withdrawal before surgery did not reduce this risk and increased the diagnostic delay (64 vs 40 days, p = 0.04). Median overall survival (OS) was 8.9 months [95% CI 5.9–11.7] for the whole series, including 52 (16%) patients that were not treated, and 14.1 months (95%CI 7.7–20.5) for the 240 (73.4%) patients that received high-dose methotrexate (HD-MTX)-based chemotherapy. Median OS was shorter in patients ≥ 70 years (4.1 vs. 13.4 months; p, [Conclusions] Corticosteroids withdrawal before surgery does not decrease the risk of a negative biopsy but delays diagnosis. In this community-based study, only 73.4% of patients could receive HD-MTX-based chemotherapy and OS remains poor, particularly in elderly patients ≥ 70 years., This work was partially supported by Grant PI1501303 from ISCIII and Fondo Europeo de Desarrollo Regional (FEDER).

Published
2020

24. Axicabtagene Ciloleucel Compared to Tisagenlecleucel for the Treatment of Relapsed or Refractory Large B-Cell Lymphoma in the Real World Setting in Spain

Author

Reyes Maria Martin Rojas, José Luis Díez-Martín, Annalisa Paviglianiti, Pere Barba, Mariana Bastos-Oreiro, María Calbacho, Javier Delgado Serrano, José Morales Sánchez, Manuel Guerreiro, Juan Carlos Hernandez Boluda, Eva Catala, Alejandro Martin Garcia-Sancho, Valentín Ortiz-Maldonado, Javier Briones, Rafael Hernani, Jaime Sanz, Lucía López Corral, Rebeca Bailén, Ana Carolina Caballero, Gillen Oarbeascoa, Juan Reguera, Alberto Mussetti, Gloria Iacoboni, Mi Kwon, and Juan-Manuel Sancho

Subjects
Oncology, medicine.medical_specialty, Refractory, business.industry, Internal medicine, Immunology, medicine, Cell Biology, Hematology, business, B-cell lymphoma, medicine.disease, Biochemistry
Abstract

Introduction: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are the two autologous anti-CD19 chimeric antigen receptors T cells commercially approved in Europe for relapsed/refractory (R/R) DLBCL. We performed a retrospective study to evaluate patients characteristics, efficacy and safety for axi-cel and tisa-cel in a large cohort of patients within the GETH-TC (Spanish Group of Stem Transplantation and Cell Therapy)-GELTAMO (Spanish Group of Lymphoma and Autologous Stem Cell Transplantation). Methods: Ten Spanish centers contributed data. Data were collected retrospectively from consecutive patients with DLBCL in whom apheresis was performed for axi-cel or tisa-cel treatment. CRS and ICANS were graded with the ASTCT consensus criteria. Response was assessed according to the Lugano criteria. Patients included had at least 30 days of follow-up. Results: A total of 268 patients with R/R DLBCL underwent apheresis for axi-cel (n=123) and tisacel (n=145) from Nov-2018 to May-2021, of which 232 (86%) received CART-cell infusion (n=110, 89% and n=122, 84%, respectively). Reasons for not undergoing infusion were progression in 10 cases, tumor lysis syndrome in 1, infection in 1, and CR after bridging therapy in 1 for the axi-cel cohort, and progression in 21 (4 after manufacture failure), psychiatric disorder in 1, and post-apheresis cerebral hemorrhage in 1 case for the tisa-cel cohort. Time between apheresis and infusion was 41 days (IQR 40-56) and 49 days (IQR 46-62) (p=0.006), respectively. Characteristics at baseline, apheresis and at lymphodepletion are summarized in Tables 1 and 2. Median age was 60 (range 19-79), 61% of patients were male, most of them treated for DLBCL NOS (66%). There were no significant differences between patients intended to be treated with axi-cel and tisa-cel. 82% of the infused patients received bridging therapy. At apheresis and at lymphodepletion ECOG performance status score was 0-1 in 93% and 91%, and 7 and 32 patients were in response, respectively. The overall response rates (ORRs) at 1 month and 3 months were 65% and 56%, respectively, with 34% and 45% achieving a complete response (CR), respectively. In the intention-to-treat analysis, with a median follow-up of 9 months (IQR 5-15), EFS and OS at 9 months was 44% (95%CI 38-51)(Figure 1) and 59% (95%CI 53-66) with a median EFS and OS of 6 months and 11 months, respectively. At lymphodepletion, characteristics of infused patients and disease were not significantly different between axi-cel and tisa-cel cohorts. Rates of CRS, CRS grade 3-4, ICANS, ICANS grade 3-4 were 89% and 71% (p=0.001), 10% and 7% (p=0.34), 42% and 16% (p=0.001), 20% and 4% (p=0.001) for the axi-cel and tisa-cel cohorts, respectively. ICU admission was needed in 25% and 15% of patients (p=0.06), respectively. Non-relapse mortality at days 100 were 2.5% and 1.4%, and at day 180, 5.4% and 2.2% (p=0.08) for the axi-cel and tisa-cel groups, respectively. With a median follow-up of 8 months for patients who received infusion with axi-cel and 12 months for patients infused with tisa-cel, EFS and OS at 12 months were 48% and 33% (p=0.33), and 53% and 50% (p=0.27), respectively, with a median EFS of 11 and 6 months and a median OS of 13 and 12 months, respectively. In the multivariate analysis, the only factor associated with poor PFS was having ECOG-PS ≥2 at lymphodepletion (HR13, p=0.03). No factors were identified as associated independently to OS. Factors associated to CRS grade 3-4 were IPI score 4-5 at lymphodepletion (OR 1.4, p=0.03) and ECOG-PS ≥2 at apheresis (OR 1.5, p=0.03). For ICANS grade 3-4, factors associated were the use of axi-cel (OR 8, p=0.04) and diagnosis of HG double/triple hit lymphoma (OR 9, p=0.022). Conclusions:This multicentric analysis describes one of the largest real-life cohorts of patients treated with axi-cel and tisa-cel for R/R aggressive B cell lymphoma in Europe. Results are comparable to those from the pivotal studies and other large real-life experiences. Up to now, patients included for one or other product in Spain do not differ significantly in terms of baseline characteristics, and within this setting, results are comparable between both products in terms of efficacy. The use of axi-cel was associated to higher rates of CRS and especially, severe forms of ICANS. However, mortality associated to toxicity were low and not significantly different between both cohorts. Figure 1 Figure 1. Disclosures Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Lopez Corral: Gilead, Novartis: Consultancy, Honoraria. Guerreiro: Novartis, Gilead: Consultancy, Honoraria. Caballero: Novartis, Gilead: Honoraria. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Sanchez: Janssen, Jazz Pharmaceuticals, Gilead, Novartis, Amgen: Consultancy. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau. Bastos-Oreiro: Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS-Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria; Kite: Speakers Bureau. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Mussetti: Gilead: Other: Unspecified, Research Funding; Novartis: Honoraria, Other: Unspecified; Takeda: Honoraria. Bailen: Gilead, Pfizer: Speakers Bureau. Martin Garcia-Sancho: Takeda: Honoraria; Novartis: Consultancy; Incyte: Consultancy; Celgene/BMS: Consultancy; Celgene: Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Janssen: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Gilead: Consultancy, Honoraria; Morphosys: Consultancy; Kyowa Kirin: Consultancy; Clinigen: Consultancy; Eusa Pharma: Consultancy; Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding.

Published
2021

25. Allogeneic hematopoietic stem cell transplantation for non-Hodgkin’s lymphomas: a retrospective analysis of 77 cases

Author

Albert Esquirol, Javier Briones, Ana M. Picleanu, Jorge Sierra, Anna Monter, Irene García-Cadenas, Silvana Novelli, Ana Carolina Caballero, and Rodrigo Martino

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Poor prognosis, Transplantation Conditioning, medicine.medical_treatment, Graft vs Host Disease, Hematopoietic stem cell transplantation, Disease, Young Adult, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Internal medicine, Retrospective analysis, medicine, Humans, Transplantation, Homologous, Aged, Retrospective Studies, Hodgkin s, Hematology, business.industry, Lymphoma, Non-Hodgkin, Hematopoietic Stem Cell Transplantation, Non-Hodgkin's lymphoma, General Medicine, Middle Aged, medicine.disease, Combined Modality Therapy, Survival Analysis, Surgery, Treatment Outcome, surgical procedures, operative, Increased risk, Histocompatibility, Allo-SCT, 030220 oncology & carcinogenesis, Retreatment, Female, business, human activities, 030215 immunology
Abstract

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a therapeutic option for relapsed, advanced, and otherwise incurable non-Hodgkin's lymphomas (NHL) suggested by the existence of a graft-versus-lymphoma effect. The main complications are graft-versus-host disease and infections. We performed a retrospective analysis of patients with NHL, who received an allo-SCT between January 1995 and December 2014. The parameters that had an impact on overall survival were age aecurrency60 years old, chemosensitive disease pre-allo-SCT, and indolent NHL histology. The parameters that had an impact on progression-free survival were age aecurrency60 years old and chemosensitive disease pre-allo-SCT. Only aggressive NHL histology and refractory disease pre-allo-SCT showed an increased risk of death in the multivariate model. The use of allo-SCT for young patients with multiple relapsed chemosensitive indolent NHL is a suitable option. Despite poor prognosis, young aggressive NHL patients can be considered for allo-SCT provided they have chemosensitive disease.

Published
2017

26. When an HLA identical donor is not available in adults with hematological neoplasms: single-center comparison of single-unit cord blood transplantation and haploidentical-related PBSC transplantation with PTCy using a standardized conditioning platform (thiotepa-busulfan-fludarabine)

Author

Silvana Saavedra, Salut Brunet, Rodrigo Martino, Ana Carolina Caballero, Albert Esquirol, Javier Briones, Miquel Granell, Sergi Querol, Carol Moreno, Irene García-Cadenas, Silvana Novelli, Ana Garrido, and Jorge Sierra

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Transplantation Conditioning, medicine.medical_treatment, ThioTEPA, Hematopoietic stem cell transplantation, Cord blood transplant, Single Center, Umbilical cord, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, Internal medicine, medicine, Humans, TBF conditioning regimen, Busulfan, Aged, Retrospective Studies, Peripheral Blood Stem Cell Transplantation, Hematology, Neutrophil Engraftment, Haploidentical transplant, business.industry, General Medicine, Middle Aged, Allografts, Fludarabine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hematologic Neoplasms, Female, Cord Blood Stem Cell Transplantation, business, Thiotepa, Vidarabine, 030215 immunology, medicine.drug
Abstract

Haploidentical related (Haplo) and umbilical cord blood (UCB) donors are the main "alternative donor" options for allogeneic hematopoietic stem cell transplantation (HCT) for patients without identical donor. At our institution, UCB was the main alternative donor type until 2013, when HaploHCT was introduced as the preferred procedure. A common myeloablative conditioning regimen was used, based on thiotepa, busulfan, and fludarabine. We analyze the outcomes of 47 patients (61%) who received a single UCB transplantation ( UCBT) and 30 patients (39%) who received a HaploHCT with post-transplant cyclophosphamide. No differences were found in the rate of neutrophil engraftment, whereas platelet recovery was earlier with HaploHCT. NRM was higher after UCBT at 3 months and 3 years (13% and 13% vs. 23% and 45% in HaploHCT and UCBT, respectively; p < 0.001 for both time points). The 3-year relapse incidence was 35% after HaploHCT vs. 17% after UCBT, respectively (p = 0.13). The 100-day incidence of grade 3-4 acute GVHD (3% vs. 11%) and the 3-year moderate-to-severe chronic GVHD (4% vs. 15%) did not differ between HaploHCT and UCBT, respectively (p > 0.2). There was a trend for higher overall survival at 1 and 3 years in HaploHCT recipients (69% vs. 45% and 64% vs. 38%, respectively; p = 0.055 for both time points). Despite the small sample sizes, multivariate analysis adjusted for patient age and disease status at transplant showed a better 3-year OS in HaploHCT recipients, mostly due to a lower NRM (p < 0.001). Our results support the use of HaploHCT when feasible when an identical donor is not available.

Published
2019

27. The novel agonistic iNKT-cell antibody NKT14m induces a therapeutic antitumor response against B-cell lymphoma

Author

Robert Schaub, Carmen Alvarez-Fernández, Ana Carolina Caballero, Laura Escribà-Garcia, Jorge Sierra, and Javier Briones

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, medicine.medical_treatment, Immunology, Cell, Population, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Glycolipid, Antigen, antibody, medicine, Immunology and Allergy, nkt14m, education, B-cell lymphoma, Original Research, education.field_of_study, biology, Chemistry, NKT14m, T-cell receptor, Immunotherapy, Inkt cells, b-cell lymphoma, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, inkt cells, immunotherapy, Antibody, lcsh:RC581-607
Abstract

Invariant natural killer T (iNKT) cells are a small population of T lymphocytes that expresses an invariant T cell receptor with a unique specificity for glycolipid antigens. Their activation using the glycolipid alpha-galactosylceramide (alpha-GalCer) triggers innate and adaptive immune responses. The use of alpha-GalCer in preclinical models as a single antitumor treatment showed moderate effect, but its efficacy in cancer patients was less effective. In addition, this glycolipid induces long-term iNKT-cell anergy precluding the possibility of retreatment. Recently, the first murine iNKT-cell agonistic antibody, NKT14m, has been developed. Here, we analyzed, for the first time, the antitumor efficacy of NKT14m in a B-cell lymphoma model. In a therapeutic setting, a single dose of NKT14m had a moderate antitumor efficacy that was associated with an increase of IFN-gamma producing iNKT cells even after a second dose of the NKT14m antibody. Importantly, the combination of a single dose of NKT14m with cyclophosphamide had a potent antitumor efficacy and long-lasting immunity in vivo. Our findings provide the first evidence of the in vivo antitumor efficacy of NKT14m antibody, showing that, either alone or in combination with chemotherapy, induces an effective antitumor response. These results open new opportunities for iNKT-cell mediated immunotherapy to treat B-cell lymphoma.

Published
2018

28. Abstract A023: Highly enriched memory stem T-cell subsets (TSCM) expressing a novel CAR30 have enhanced antitumor effect in Hodgkin lymphoma

Author

Carmen Alvarez-Fernández, Ana Carolina Caballero, Javier Briones, Jorge Sierra, and Laura Escribà-Garcia

Subjects
Cancer Research, Adoptive cell transfer, CD30, Chemistry, T cell, Immunology, medicine.disease, Chimeric antigen receptor, medicine.anatomical_structure, hemic and lymphatic diseases, medicine, Cancer research, B-cell lymphoma, Ex vivo, B cell, CD8
Abstract

Background: Up to 20% of patients with advanced Hodgkin lymphoma (HL) are not cured with current chemo-immunotherapy treatments. Adoptive immunotherapy (AIT) with mature T-cells modified with a chimeric antigen receptor (CAR) holds promise for the treatment of various types of B cell lymphoma. The CD30 antigen, expressed in virtually all HL tumor cells, is absent in most healthy tissues, thus representing an ideal target for AIT of HL. In contrast to CAR19 for B cell malignancies, efficacy of CAR30 T-cells for Hodgkin and other CD30 lymphomas remains modest. Thus, novel approaches are needed to significantly improve the clinical efficacy of this approach. To this end, we used a novel antigen binding domain of a CD30 mAb, unaffected by soluble CD30 protein, as part of a chimeric antigen receptor (CAR) coupled to the 4.1BB and ζ chain endodomains, and transduced memory stem T-cells (TSCM) in an effort to ensure efficient engraftment, prolonged persistence, and enhancement of in vivo antitumor activity. To evaluate the feasibility of ex vivo expansion and antitumor efficacy of genetically-modified TSCM with a novel CD30-specific CAR that recognizes a membrane-proximal epitope of the CD30 molecule for the treatment of HL. Methods: A second-generation CD30-41BBz-EGFRt CAR was developed using a scFv that recognizes a membrane-proximal epitope of the CD30 protein. TSCM cells were generated with IL-7, IL-15 and IL-21, and transduced on day 2 of culture with a third-generation lentiviral vector encoding the CD30-CAR. The HL derived cell line L540 was used as tumor model. Tumor-specific cytotoxicity and cytokines were analysed at 24 hours. The in vivo antitumor efficacy was tested in a NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mouse model of HL xenografted with 2,5x10^6 L450 cells. Results: After 10 days, TSCM represented the majority of T-cells in culture (50.38±5.47 % for CD4+ and 70.84 ± 3.36 % for CD8+ TSCM, respectively) with a very high expression of CD30-CAR (77 ± 3.64 % in CD4+ and 83.12 ± 4.25 % in CD8+ TSCM, respectively). Expression of CD30 protein in TSCM increased over the culture period, peaking at day 8 in both CD4+ (17.5 ± 4.17 %) and CD8+ TSCM (42.37 ± 5.75 %), respectively. Despite these high levels of CD30 expression, TSCM expanded ex vivo very efficiently (CD4+ CD30-CAR: 97.24 ± 26.2 fold expansion, and CD8+ CD30-CAR: 96.79 ± 22.84 fold expansion, respectively), although lower than TSCM transduced with a CD19-CAR (CD4+ CD19-CAR: 161.96±35.9 fold expansion, and CD8+ CD19-CAR: 163.25 ± 26.51, fold expansion, respectively). Bulky CD30-CAR TSCM mediated very efficient in vitro tumor cytotoxicity (tumor cell death at 5:1 ratio: 85.25% vs. 0% with untransduced TSCM), while control CD30- targeT-cells were not killed. In addition, we evaluated the antitumor efficacy of CD30-CAR TSCM in vivo. Upon adoptive transfer of 10x10^6 bulk (CD4+ and CD8+) TSCM into NSG mice engrafted with L540 (2,5x10^6 subcutaneously), complete eradication of HL was observed. In addition, in a stress L540 model where equal numbers of CAR30 T-cells were infused at a low, suboptimal dose (i.e, 50% of effective T-cell dose to induce complete remission), highly enriched CAR30 TSCM (>70% of TSCM) had significantly antitumor effect compared to the infusion of CAR30 T-cells predominantly represented by effector cells ( Citation Format: Carmen Alvarez-Fernández, Laura Escribà-Garcia, Ana Carolina Caballero, Jorge Sierra, Javier Briones. Highly enriched memory stem T-cell subsets (TSCM) expressing a novel CAR30 have enhanced antitumor effect in Hodgkin lymphoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A023.

Published
2019

29. Abstract A028: Memory stem T-cells expressing an optimized CD30-specific chimeric antigen receptor (CAR) efficiently eradicate peripheral T-cell lymphoma in vivo

Author

Carmen Alvarez-Fernández, Laura Escribà-Garcia, Rydzek Julian, Javier Briones, Ana Carolina Caballero, Jorge Sierra, Einsele Hermann, and Michael Hudecek

Subjects
Cancer Research, biology, CD30, business.industry, CD3, medicine.medical_treatment, Immunology, medicine.disease, Chimeric antigen receptor, Lymphoma, Cancer immunotherapy, Antigen, hemic and lymphatic diseases, biology.protein, Cancer research, Medicine, business, Ex vivo, CD8
Abstract

Peripheral T-cell lymphomas (PTCL) represent the most aggressive form among non-Hodgkin lymphomas with a very poor prognosis (5-year survival of 30%), demanding innovative novel treatment strategies. Adoptive immunotherapy with chimeric antigen receptor (CAR) T-cells has demonstrated its therapeutic potential in advanced B-cell hematologic malignancies. However, its application to PTCL remains a formidable challenge mainly due to a lack of truly tumor-specific antigens that are not expressed on normal T-cells. Anaplastic large T-cell lymphomas (ALCL) and several other subtypes of PTCL express CD30, which is also expressed by activated normal T-cells but no other healthy tissues. Indeed, brentuximab-vedotin, an anti-CD30 antibody-drug conjugate, has shown some clinical efficacy in PTCL and ALCL patients although duration of responses is short in the majority of cases. Here, we developed a refined CD30-CAR T-cell approach to target CD30+ PTCL as a potential novel therapeutic strategy. We selected a novel targeting domain that is unaffected by soluble CD30 protein (Nagata S et al., Clin Cancer Res 2002) to prevent blockade of the CD30-CAR. Moreover, we optimized the therapy by using memory stem T-cells (TSCM) to promote engraftment and persistence of CD30-CAR T-cells after transfer.TSCM were generated with CD3/CD28 costimulation in presence of IL-7, IL-15 and IL-21 (Alvarez C et al., J Transl Med 2016). On day 2 of culture, cells were transduced with a third-generation lentiviral vector encoding the CD30-41BBz-EGFRt CAR. The cell line Karpas 299 (ALCL) was used as tumor model. Cytotoxicity assay was performed at 24 hours and the tumor cell death was detected by luminiscence. Mice were injected with Karpas 299 tumor cells (2x10^6 cells/mice; iv) and were treated with CD30-CAR TSCM (1x10^7 cells/mice; iv) when the tumor was established (day 10). Mice were followed daily for survival. The presence of CD30-CAR TSCM in lymphoid organs and their expression of immune checkpoint molecules (i.e., TIM-3, LAG-3) were analyzed at the end of the in vivo study by flow cytometry. TSCM were the most prevalent T-cell subset at day 10 of culture (84±3.1% of total cells), and the CD30-CAR expression was 82.8±1.0% in CD4+ TSCM and 85.2±2.0% in CD8+ TSCM. Although CD30 protein was detected in a fraction of activated T-cells in culture, CD30-CAR TSCM could be expanded ex vivo (CD4+ CD30-CAR TSCM: 96.0±3.2 fold expansion; CD8+ CD30-CAR TSCM: 109.0±4.2 fold expansion). CD30-CAR TSCM conferred specific cytolytic activity against Karpas 299 cells in vitro (tumor cell death 5:1 (effector:target) ratio: 70.2±5.1% vs. 0% with untransduced TSCM; p80% of detected CD4+ and CD8+ T-cells) were still present in lymphoid organs (bone marrow, spleen and lymph nodes) of surviving mice at 50 days after infusion. Tumor-bearing mice also showed CD30-CAR T-cells in their lymphoid organs (80% of total CD4+ and CD8+ T-cells) and in the tumor (67.5% of detected T-cells). Interestingly, a high expression of exhaustion markers TIM-3 (74%±6.8%) and LAG-3 (34%±9.7%) were found on those tumor-infiltrating lymphocytes (TILs). Collectively, our data demonstrate that TSCM cells can be efficiently transduced and ex vivo expanded with a novel CD30-CAR and confer potent antitumor efficacy against CD30+ PTCL in vitro and in vivo, with a potential improvement of the therapy using an immune checkpoint blockade for either TIM-3 or LAG-3. Our findings suggest the potential to improve outcome of patients with CD30+ PTCL through adoptive therapy with CD30-CAR modified T-cells. Citation Format: Laura Escribà-Garcia, Carmen Alvarez-Fernández, Ana Carolina Caballero, Rydzek Julian, Einsele Hermann, Jorge Sierra, Michael Hudecek, Javier Briones. Memory stem T-cells expressing an optimized CD30-specific chimeric antigen receptor (CAR) efficiently eradicate peripheral T-cell lymphoma in vivo [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A028.

Published
2019

30. Initial management of primary central nervous system lymphoma in Spain in the last decade. The experience of the GELTAMO and Spanish neuro-oncology groups

Author

N. Vidal, Ana Carolina Caballero, Santiago Mercadal, M. Solé, F. Graus, J. Estela, Antonio Salar, L. Gómez, P. Cacabelos, Jaime Gállego, I. Barceló, Roser Velasco, N. Barbero, M. Ibañez, R. Caldú, Ivan Dlouhy, N. Huertas, M. López-Parra, Juan-Manuel Sancho, Eva González-Barca, S. Bobillo, María Concepción Ramírez Barón, E. Erro, P. Martinez, A. Muntañola, and E. García

Subjects
Cancer Research, Pediatrics, medicine.medical_specialty, Oncology, business.industry, Neuro oncology, Primary central nervous system lymphoma, Medicine, Hematology, General Medicine, business, medicine.disease
Published
2017

31. Procalcitonin (PCT) levels for ruling-out bacterial coinfection in ICU patients with influenza: A CHAID decision-tree analysis

Author

Alejandro H. Rodríguez, Francesc X. Avilés-Jurado, Emili Díaz, Philipp Schuetz, Sandra I. Trefler, Jordi Solé-Violán, Lourdes Cordero, Loreto Vidaur, Ángel Estella, Juan C. Pozo Laderas, Lorenzo Socias, Juan C. Vergara, Rafael Zaragoza, Juan Bonastre, José E. Guerrero, Borja Suberviola, Catia. Cilloniz, Marcos I. Restrepo, Ignacio Martín-Loeches, Pedro Cobo, Javier Martins, Cecilia Carbayo, Emilio Robles-Musso, Antonio Cárdenas, Javier Fierro, Dolores Ocaña Fernández, Rafael Sierra, Mª Jesús Huertos, Mª Luz Carmona Pérez, Juan Carlos Pozo Laderas, R. Guerrero, Juan Carlos Robles, Melissa Echevarría León, Alberto Bermejo Gómez, Enrique Márquez, Manuel Rodríguez-Carvajal, José Pomares, José Luis Ballesteros, Olga Moreno Romero, Yolanda Fernández, Francisco Lobato, José F. Prieto, José Albofedo-Sánchez, Pilar Martínez, María Victoria de la Torre, María Nieto, Estefanía Camara Sola, Miguel Angel Díaz Castellanos, Guillermo Sevilla Soler, Carlos Ortiz Leyba, José Garnacho-Montero, Rafael Hinojosa, Esteban Fernández, Ana Loza, Cristóbal León, Samuel González López, Angel Arenzana, Dolores Ocaña, Inés Navarrete, Medhi Zaheri Beryanaki, Ignacio Sánchez, Manuel Pérez Alé, Ana Mª Poullet Brea, Juan Francisco Machado Casas, Carlos Serón, Manuel Luis Avellanas, Arantxa Lander, S. Garrido Ramírez de Arellano, M.I. Marquina Lacueva, Pilar Luque, Elena Plumed Serrano, Juan Francisco Martín Lázaro, Carlos Sánchez Polo, Isabel Gutiérrez Cia, Belén Jiménez Bartolomé, Carlos López Nuñez, Ignacio González, José Ignacio Tomás Marsilla, Clara Jaques Andrés, Pablo Gtiérrez Ibañes, Pilar Araujo Aguilar, Jose Mª Montón, Paloma Dorado Regil, Lisardo Iglesias, Carmen Pascual González, Brígida Quindós Fernández, Lorena Martín Iglesias, Lucía Viña Soria, Raquel Yano Escudero, Mª del Rosario Mtnez Revuelta, null Quiroga, Águeda García-Rodríguez, Marta Martín Cuadrado, Ana Luz Balán Mariño, Pedro Ibánez, Marcío Borges-Sa, A. Socias, A. Del Castillo, Ricard Jordà Marcos, Cristina Muñoz, José M. Bonell, Ignacio Amestarán, M. Angeles González López, Cecilia Vilanova Pàmies, José Ma. Bonell Goytisolo, José Antonio Morales Carbonero, Rossana Pérez Senoff, Marta Generelo López de Medrano, Sergio Ruiz-Santana, Juan José Díaz, Catalina Sánchez Ramírez, Montse Sisón, David Hernández, Ana Trujillo, Luis Regalado, Sonia Rodríguez Fndez, Leonardo Lorente, Judith Cabrera Rivero, Mª Luisa Mora Quintero, Mar Martín, Sergio Martínez, J.J. Cáceres, Manuel Sanchez Palacio, null Marcos, D. García Rodríguez, María Ripoll Leria, P. Ugarte, Fernando García-López, Rafael Sánchez Iniesta, Angel Álvaro Alonso, Antonio Padilla, Basi Martínez Palacios, Mª Luisa Gómez Grande, Ma. Carmen Martín Rodríguez, Hasania Adbel-Hadi Álvarez, Alfonso Ambros Checa, Higinio Martín Hernández, Antonio Albaya, Alberto Silva Obregón, Carlos Marian Crespo, Carlos Armendariz Estrella, Carmen Benito Puncel, Eduardo Quirós Oyargue, Alfonso Canabal, Luis Marina, Ismael López de Toro, Almudena Simón, José María Añón, Juan B. López Messa, Mª Jesús López Pueyo, Ortíz María del valle Sergio Ossa Echeverri, Zulema Ferreras, Juan C. Ballesteros Herraez, Santiago Macias, José Ángel Berezo, Jesús Blanco Varela, Pablo Blanco Schweizer, Angela González Salamanca, Luis Tamayo Lomas, Andaluz Ojeda Anzález, Ramón Cicuéndez Avila, Pérez G. Francisco Javier, Antonio Álvarez Terrero, Fabiola Tena Ezpeleta, Christian Sala, Oliverio López, Zulema Paez, Álvaro García, Demetrio Carriedo Ule, Miriam Riesco Crespo, Jesús Pino Rebolledo, Nicolás Hidalgo Andrés, Ana Carolina Caballero Zirena, Belén Román García, Juan Bautista López Messa, María del Valle Ortiz, Sergio Ossa Echeverri, Rosa Mª Catalán, Miquel Ferrer, Antoni Torres, Catia Cilloniz, Sandra Barbadillo Ansorregui, Lluís Cabré, Ignacio Baeza, Assumpta Rovira, Francisco Álvarez-Lerma, Antonia Vázquez, Joan Nolla, Francisco Fernández, Joaquim Ramón Cervelló, Raquel Iglesia, Rafael Mañéz, J. Ballús, Rosa Mª Granada, Jordi Vallés, Marta Ortíz, C. Guía, Joaquim Páez, Jordi Almirall, Xavier Balanzo, Estel Güell, Juan Carlos Yebenes, Jordi Rello, Elena Arnau, Marcos Pérez, César Laborda, Jesica Souto, Leonel Lagunes, Iñaki Catalán, Josep Mª Sirvent, Nerea López de Arbina, Anna Baró Serra, Adriana Sánchez, Silvia M. Cuenca, Mariona Badía, Begonia Baseda-Garrido, Montserrat Valverdú-Vidal, Fernando Barcenilla, Mercedes Palomar, Xavier Nuvials, Pedro Garrido Benedicto, Ferran Roche Campo, M.F. Esteban, José Luna, Gaspar Masdeu Eixarch, Angels Pascual Diago, Juan Mª Nava, J. González de Molina, Josep Trenado, Ricard Ferrer, Zoran Josic, Montserrat Casanovas, Francisco Gurri, Paula Rodríguez, Alejandro Rodríguez, Laura Claverias, Sandra Trefler, María Bodí, Mónica Magret, Cristina Ferri, Rosa María Díaz, Eduard Mesalles, Fernando Arméstar, Diego de Mendoza, Carmen Lomas Fernández, José Julián Berrade, Alfonso Bonet Saris, Marina Pechkova, Cristina Mora Jiménez, Santiago Picos Gil, José Juliá-Narváez, Manuel Robles Marcos, Vanessa Farje Mallqui, Mª. Angeles Santiago Triviño, Pablo Martínez García, Alberto Fernández-Zapata, Teresa Recio, Abilio Arrascaeta, Mª José García-Ramos, Elena Gallego, Esther Saiz Rodrigo, Fernándo Bueno, Mercedes Díaz, Noemí Gil Pérez, David López Hormigo, Juan Diego Jiménez Delgado, Pérez Frutos, M.J. Rivera Pinna, Mª Lourdes Cordero, José A. Pastor, Luis Álvarez-Rocha, Alexandra Ceniceros Barros, Alejandra Virgós Pedreira, Dolores Vila, Carmen Fernández González, Javier Blanco Pérez, M. Ortiz Piquer, Eleuterio Merayo, Victor Jose López-Ciudad, Juan Cortes Cañones, Eva Vilaboy, José Villar Chao, Francisco Savira Cid López, Pablo Vidal Cortés, Marcos A. Pérez Veloso, Eva Maria Saborido, Enrique Alemparte Pardavila, Ana Ortega Montes, Raul José González, Santiago Freita, Enrique Alemparte, Ana Ortega, Ana María López, Julio Canabal, Enrique Ferres, Santiago Freitas Ramos, Lucas Lage Cendón, Vanesa Gómez Casal, Sabela Vara Adrio, Eva Menor Fernández, Susana González Prado, Antonio Varela Franco, José Luis Monzón, Félix Goñi, Frutos Del Nogal Sáez, M. Blasco Navalpotro, Ricardo Díaz Abad, José Luis Flordelis Lasierra, Mª Carmen García-Torrejón, César Pérez–Calvo, Diego López, Luis Arnaiz, S. Sánchez-Alonso, Carlos Velayos, Francisco del Río, Miguel Ángel González, Mercedes Nieto, Carmen Sánchez Cesteros, María Cruz Martín, José Mª Molina, Juan Carlos Montejo, Mercedes Catalán, Patricia Albert, Ana de Pablo, José Eugenio Guerrero, María Zurita, Jaime Benitez Peyrat, Miriam Díaz Cámara, Enrique Cerdá, Manuel Alvarez, Carlos Pey, Eva Manteiga Riestra, Concepción Martinez-Fidalgo, Montse Rodríguez, Eduardo Palencia, Rafael Caballero, Concepción Vaquero, Francisco Mariscal, S. García, Rico Cepeda, Nieves Carrasco, Isidro Prieto, A. Liétor, R. Ramos, Rosario Cuadra Casas, Cruz Soriano Cuesta, Susana Sánchez Alonso, Beatriz Galván, Juan C. Figueira, M. Cruz Soriano, Bélen Civantos Martín, Alejgandro Robles Caballero, P. Galdós, Bárbara Balandin Moreno, Sara Alcántara Carmona, Fernández del Cabo, Cecilia Hermosa, Federico Gordo, Alejandro Algora, Amparo Paredes, Teodoro Grau Carmona, J.A. Cambroner, Esther López Ramos, Yaiza Ortiz de Zárate, Sonia Gómez-Rosado, Margarita Mas Lodo, Nieves Franco Garrobo, Silvia Álvarez Hernández, Teresa Honrubia, Luis Miguel Prado López, A. Esteban, J.A. Lorente, N. Nin, Carlos Jaramillo Sotomayor, Esperanza Molero Silvero, Eduardo Morales Fdez. de la Reguera, Rosa Mª de la Casa Monje, Fátima Martín Serrano, Mª Victoria Trasmonte Martínez, M. Cruz Martín Delgado, Sofía Martínez, F. Felices Abad, Isabel Cremades Navalon, Martín Vigil Velis, Mariano Martínez, Domingo Martínez Baño, Enriqueta Andreu, Sergio Manuel Butí, Bernardo Gil Rueda, Francisco García, Noemí Llamas Fernández, Luis Herrera Para, Alejandro Ortín Freire, Mª Rosa Nvarro Ruiz, C.R. Hernández Romero, Enrique Maraví-Poma, I. Jimenez Urra, Laura Macaya Redin, A. Tellería, Josu Insansti, Noelia Artesero Garcia, Laura Macaya, Joaquín Lobo Palanco, Nagore González, Pilar Marco, Estibaliz Salas, Ruth Salaberría Udabe, B. Santamaría, Tomás Rodríguez, Juan Carlos Vergara, Jose Ramon Iruretagoyena Amiano, Iratí Garrido Santos, Alberto Manzano, Carlos Castillo Arenal, Pedro María Olaechea, Alejandro Martín López, Fernando Fonseca San Miguel, José Blanquer, Nieves Carbonell, José Ferreres Franco, Roberto Reig Valero, A. Belenger, Susana Altaba, Bernabé Álvarez–Sánchez, José Canovas Robles, Jaime Sánchez Francisco, Mar Ruiz Sánchez, Santiago Alberto Picos, Abilio Arrascaeta Llanes, Eugenio Herrero Gutiérrez, Alberto Fernández Zapata, Ángel Sánchez-Miralles, José Luis Antón Pascual, M. Palamo, Javier Cebrian, José Cuñat, Mónica Gordón Sahuquillo, Belén Romero, Santiago Borrás Pallé, Javier de León Belmar, Constantino Tormo, Susana Sancho Chinesta, Virgilio Paricio, Asunción Marques, S. Sánchez-Morcillo, S. Tormo, J. Latour, M. Ángel García, Manuel Palomo, Francisco Tarín Royo, Pedro Manzano Hinojosa, Mª Salomé Sánchez Pino, Concha Maragues Ribes, Rubén González Luis, Antoli Ribas, and Universitat de Barcelona

Subjects
Male, Procalcitonin, 0302 clinical medicine, Community-acquired pneumonia, Septic shock, Prospective Studies, 030212 general & internal medicine, Coinfection, Bacterial Infections, Middle Aged, Prognosis, Intensive Care Units, Infectious Diseases, Female, Pèptids, Adult, Calcitonin, Microbiology (medical), medicine.medical_specialty, Icu patients, Calcitonin Gene-Related Peptide, CHAID analysis, Respiratory coinfection, Sensitivity and Specificity, Influenzavirus, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, Influenza, Human, parasitic diseases, medicine, Humans, Influenza viruses, Protein Precursors, Intensive care medicine, Influenza A(H1N1)pmd, business.industry, Decision Trees, 030208 emergency & critical care medicine, Influenza a, medicine.disease, CHAID, Observational study, business, Peptides, Biomarkers
Abstract

Objectives: To define which variables upon ICU admission could be related to the presence of coinfection using CHAID (Chi-squared Automatic Interaction Detection) analysis. Methods: A secondary analysis from a prospective, multicentre, observational study (2009 -2014) in ICU patients with confirmed A(H1N1)pdm09 infection. We assessed the potential of biomarkers and clinical variables upon admission to the ICU for coinfection diagnosis using CHAID analysis. Performance of cut-off points obtained was determined on the basis of the bi-nominal distributions of the true (+) and true (-) results. Results: Of the 972 patients included, 196 (20.3%) had coinfection. Procalcitonin (PCT; ng/mL 2.4 vs. 0.5, p < 0.001), but not C-reactive protein (CRP; mg/dL 25 vs. 38.5; p = 0.62) was higher in patients with coinfection. In CHAID analyses, PCT was the most important variable for coinfection. PCT < 0.29 ng/mL showed high sensitivity (Se = 88.2%), low Sp (33.2%) and high negative predictive value (NPV = 91.9%). The absence of shock improved classification capacity. Thus, for PCT < 0.29 ng/mL, the Se was 84%, the Sp 43% and an NPV of 94% with a post-test probability of coinfection of only 6%. Conclusion: PCT has a high negative predictive value (94%) and lower PCT levels seems to be a good tool for excluding coinfection, particularly for patients without shock. (C) 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

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