Considerations for treatment-free remission in patients with chronic myeloid leukemia: a joint patient-physician perspective

Abstract Treatment-free remission after discontinuation of tyrosine kinase inhibitor therapy is now an emerging treatment goal in patients with chronic myeloid leukemia, who have achieved a deep and stable response to treatment. While guidance are now available, considering patients' questions on this progressive concept have yet to be addressed. The overall aim of this European Steering Group is a patient-centered approach that educates patients on their treatment options, including treatment-free remission, facilitates better patient-physician relationships, and meets patients' emotional and psychological needs. This article outlines five key topic areas on discontinuing tyrosine kinase therapy and the implications of treatment-free remission for patient-physician consideration: what treatment-free remission is and when it is appropriate; which patients may and may not be eligible for treatment-free remission; what patient considerations for discontinuing therapy are, such as tyrosine kinase withdrawal syndrome, potential psychological implications, molecular recurrence and re-treatment. This Steering Group advocates that patients with chronic myeloid leukemia should have access to high quality, frequent molecular monitoring and be managed in a specialist centre with appropriate medical and psychological support. As patient concerns on attempting treatment-free remission become forefront in patient-physician discussions, a greater number of eligible patients may be willing to discontinue therapy

Impaired Cytotoxic Response in PBMCs From Patients With COVID-19 Admitted to the ICU: Biomarkers to Predict Disease Severity

Infection by novel coronavirus SARS-CoV-2 causes different presentations of COVID-19 and some patients may progress to a critical, fatal form of the disease that requires their admission to ICU and invasive mechanical ventilation. In order to predict in advance which patients could be more susceptible to develop a critical form of COVID-19, it is essential to define the most adequate biomarkers. In this study, we analyzed several parameters related to the cellular immune response in blood samples from 109 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centers in Madrid, Spain, during the first pandemic peak between April and June 2020. Hospitalized patients with the most severe forms of COVID-19 showed a potent inflammatory response that was not translated into an efficient immune response. Despite the high levels of effector cytotoxic cell populations such as NK, NKT and CD8+ T cells, they displayed immune exhaustion markers and poor cytotoxic functionality against target cells infected with pseudotyped SARS-CoV-2 or cells lacking MHC class I molecules. Moreover, patients with critical COVID-19 showed low levels of the highly cytotoxic TCRγδ+ CD8+ T cell subpopulation. Conversely, CD4 count was greatly reduced in association to high levels of Tregs, low plasma IL-2 and impaired Th1 differentiation. The relative importance of these immunological parameters to predict COVID-19 severity was analyzed by Random Forest algorithm and we concluded that the most important features were related to an efficient cytotoxic response. Therefore, efforts to fight against SARS-CoV-2 infection should be focused not only to decrease the disproportionate inflammatory response, but also to elicit an efficient cytotoxic response against the infected cells and to reduce viral replication.This work was supported by the Coordinated Research Activities at the Centro Nacional de Microbiología (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr. Inmaculada Casas (WHO National Influenza Center of the CNM); a generous donation provided by Chiesi España, S.A.U. (Barcelona, Spain); the Spanish Ministry of Economy and Competitiveness (PID2019-110275RB-I00); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acciόn Estratégica en Salud, Plan Nacional de Investigaciόn Científica, Desarrollo e Innovaciόn Tecnolόgica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF). The work of ML-H and SR-M is financed by NIH grant R01AI143567. The work of LH is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER).S

Impaired Antibody-Dependent Cellular Cytotoxicity in a Spanish Cohort of Patients With COVID-19 Admitted to the ICU

SARS-CoV-2 infection causes COVID-19, ranging from mild to critical disease in symptomatic subjects. It is essential to better understand the immunologic responses occurring in patients with the most severe outcomes. In this study, parameters related to the humoral immune response elicited against SARS-CoV-2 were analysed in 61 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centres in Madrid, Spain, during the first pandemic peak between April and June 2020. Subjects were allocated as mild patients without hospitalization, severe patients hospitalized or critical patients requiring ICU assistance. Critical patients showed significantly enhanced levels of B cells with memory and plasmablast phenotypes, as well as higher levels of antibodies against SARS-CoV-2 with neutralization ability, which were particularly increased in male gender. Despite all this, antibody-dependent cell-mediated cytotoxicity was defective in these individuals. Besides, patients with critical COVID-19 also showed increased IgG levels against herpesvirus such as CMV, EBV, HSV-1 and VZV, as well as detectable CMV and EBV viremia in plasma. Altogether, these results suggest an enhanced but ineffectual immune response in patients with critical COVID-19 that allowed latent herpesvirus reactivation. These findings should be considered during the clinical management of these patients due to the potential contribution to the most severe disease during SARS-CoV-2 infection.This work was supported by the Coordinated Research Activities at the Centro Nacional de Microbiología (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr Inmaculada Casas (WHO National Influenza Center of the CNM) and a generous donation provided by Chiesi España, S.A.U. (Barcelona, Spain). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. This work was also supported by the Spanish Ministry of Economy and Competitiveness (PID2019 110275RB-I00); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF); Miguel Servet - AESI, MPY 341/21. The work of ML-H and SR is financed by NIH grant R01AI143567. The work of MT is supported by Instituto de Salud Carlos III (COV20_00679). The work of LV is supported by a predoctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER).S

Early Cellular and Humoral Responses Developed in Oncohematological Patients after Vaccination with One Dose against COVID-19

Individuals with oncohematological diseases (OHD) may develop an impaired immune response against vaccines due to the characteristics of the disease or to its treatment. Humoral response against SARS-CoV-2 has been described to be suboptimal in these patients, but the quality and efficiency of the cellular immune response has not been yet completely characterized. In this study, we analyzed the early humoral and cellular immune responses in individuals with different OHD after receiving one dose of an authorized vaccine against SARS-CoV-2. Humoral response, determined by antibodies titers and neutralizing capacity, was overall impaired in individuals with OHD, except for the cohort of chronic myeloid leukemia (CML), which showed higher levels of specific IgGs than healthy donors. Conversely, the specific direct cytotoxic cellular immunity response (DCC) against SARS-CoV-2, appeared to be enhanced, especially in individuals with CML and chronic lymphocytic leukemia (CLL). This increased cellular immune response, developed earlier than in healthy donors, showed a modest cytotoxic activity that was compensated by significantly increased numbers, likely due to the disease or its treatment. The analysis of the immune response through subsequent vaccine doses will help establish the real efficacy of COVID-19 vaccines in individuals with OHD.This work was supported by the Strategic Action in Health 2017–2020 of the Instituto de Salud Carlos III (PI21/00877); the Coordinated Research Activities at the National Center of Microbiology (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr Inmaculada Casas (WHO National Influenza Center of the CNM); a generous donation provided by Chiesi España, S.A.U. (Barcelona, Spain). The work of Sara Rodríguez-Mora is financed by NIH grant R01AI143567. The work of Montserrat Torres is financed by the Hematology and Hemotherapy Service of the Hospital Universitario Ramón y Cajal. The work of Fernando Ramos-Martín is financed by the Spanish Ministry of Science and Innovation (PID2019-110275RB-I00). The work of Lorena Vigón is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). The work of Mario Manzanares is supported by a pre-doctoral grant from Instituto de Salud Carlos III (ISCIII-PFIS FI20CIII/00021).S

Strong Cellular Immune Response, but Not Humoral, against SARS-CoV-2 in Oncohematological Patients with Autologous Stem Cell Transplantation after Natural Infection

Oncohematological patients show a low immune response against SARS-CoV-2, both to natural infection and after vaccination. Most studies are focused on the analysis of the humoral response; therefore, the information available about the cellular immune response is limited. In this study, we analyzed the humoral and cellular immune responses in nine individuals who received chemotherapy for their oncohematological diseases, as well as consolidation with autologous stem cell transplantation (ASCT), after being naturally infected with SARS-CoV-2. All individuals had asymptomatic or mild COVID-19 and were not vaccinated against SARS-CoV-2. These results were compared with matched healthy individuals who also had mild COVID-19. The humoral response against SARS-CoV-2 was not detected in 6 of 9 oncohematological individuals prior to ASCT. The levels of antibodies and their neutralization capacity decreased after ASCT. Conversely, an enhanced cytotoxic activity against SARS-CoV-2-infected cells was observed after chemotherapy plus ASCT, mostly based on high levels of NK, NKT, and CD8+TCRγδ+ cell populations that were able to produce IFNγ and TNFα. These results highlight the importance of performing analyses not only to evaluate the levels of IgGs against SARS-CoV-2, but also to determine the quality of the cellular immune response developed during the immune reconstitution after ASCT.This work was supported by the Coordinated Research Activities at the Centro Nacional de Microbiología (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr Inmaculada Casas (WHO National Influenza Center of the CNM), the Spanish Ministry of Science and Innovation (PID2019-110275RB-I00), and AES 2021 grant from Instituto de Salud Carlos III (PI21/00877). The work of Sara Rodríguez-Mora is financed by NIH grant R01AI143567. The work of Montserrat Torres is supported by Instituto de Salud Carlos III (COV20_00679). The work of Lorena Vigón is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER).S

Castell de Castelldefels. Arqueologia, història, art

La recerca en el castell era adreçada a esbrinar els trets generals de l'evolució, però sense exhaurir el jaciment, atesa la inversió econòmica considerable que aquest procediment hagués suposat. En conseqüència, es va realitzar una excavació selectiva en punts ben significatius, la qual s'ha anat ampliant amb altres sondeigs fets paral·lelament a les obres iniciades el 2001, com veurem més endavant en un capítol a part,2 i que actualment continuen en curs. Els punts significatius excavats són els següents: l'indret on se suposava que havia de ser l'entrada principal, entre l'angle nord-est i els lavabos actuals (fig. 68, sondeig VII), els voltants de la porta del pati 1 (fig. 53, 54, 61, 62, sondeig I i fig. 55, sondeig VII) i els àmbits CA2, CA4, CA5 i CA6 (fig. 46, 47, 48, 49, 50, 56, 57, sondeigs IV, Vbis, V i VI, respectivament), tot això dins el cos A. Al cos B només es va dur a terme una rasa estratigràfica a la meitat septentrional de l'espai CB4 (fig. 51, 58, 59, 60, sondeig VIII), la qual va donar dades il·lustratives. A l'església i els edificis adjacents, en canvi, atès que les obres havien de començar ben aviat i que n'afectarien el subsòl, les cobertes i els paraments de manera substancial, hom va dur a terme una excavació extensiva a gairebé tot l'interior, llevat de la capella de la Salut, on només es va treballar a la meitat de llevant. Al mateix temps, es va realitzar una intervenció àmplia a la coberta d'aquest edifici, com també al subsòl i a la volta intermèdia de la sagristia. L'àrea de la rectoria també va ser excavada a fons, tot i que es van deixar alguns testimonis a R3. Totes aquestes recerques es Paral·lelament al treball de camp, es va enllestir l'aplegament de documentació sobre el castell i el temple. De tal manera que posseïm un recull interessant de notícies, sobretot des del segle XIV, mancat, però, d'algunes precisions, a causa de la dispersió notable dels textos i a la dificultat, de vegades insuperable, per accedir als fons particulars.3 També s'han dut a terme estudis d'història de l'art sobre determinats aspectes del conjunt, com ara la decoració de la sala principal del castell, l'ambientació de la resta de les estances o les restauracions portades a terme per Ramon Soriano (1897) i Enric Sagnier (1910)

SARS-CoV-2-reactive antibody detection after SARS-CoV-2 vaccination in hematopoietic stem cell transplant recipients: Prospective survey from the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group

This is a multicenter prospective observational study that included a large cohort (n = 397) of allogeneic (allo-HSCT; (n = 311) and autologous (ASCT) hematopoietic stem cell transplant (n = 86) recipients who were monitored for antibody detection within 3–6 weeks after complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from February 1, 2021, to July 20, 2021. Most patients (n = 387, 97.4%) received mRNA-based vaccines. Most of the recipients (93%) were vaccinated more than 1 year after transplant. Detectable SARS-CoV-2-reactive antibodies were observed in 242 (78%) of allo-HSCT and in 73 (85%) of ASCT recipients. Multivariate analysis in allo-HSCT recipients identified lymphopenia < 1 × 109/ml (odds ratio [OR] 0.33, 95% confidence interval [95% CI] 0.16–0.69, p = .003), active graft versus host disease (GvHD; OR 0.51, 95% CI 0.27–0.98, p = .04) and vaccination within the first year of transplant (OR 0.3, 95% CI 0.15–0.9, p = .04) associated with lower antibody detection whereas. In ASCT, non-Hodgkin's lymphoma (NHL; OR 0.09, 95% CI 0.02–0.44, p = .003) and active corticosteroid therapy (OR 0.2, 95% CI 0.02–0.87, p = .03) were associated with lower detection rate. We report an encouraging rate of SARS-CoV-2-reactive antibodies detection in these severe immunocompromised patients. Lymphopenia, GvHD, the timing of vaccine, and NHL and corticosteroids therapy should be considered in allo-HSCT and ASCT, respectively, to identify candidates for SARS-CoV-2 antibodies monitoring.Peer reviewe

SARS-CoV-2-reactive antibody detection after SARS-CoV-2 vaccination in hematopoietic stem cell transplant recipients: Prospective survey from the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group.

This is a multicenter prospective observational study that included a large cohort (n = 397) of allogeneic (allo-HSCT; (n = 311) and autologous (ASCT) hematopoietic stem cell transplant (n = 86) recipients who were monitored for antibody detection within 3-6 weeks after complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from February 1, 2021, to July 20, 2021. Most patients (n = 387, 97.4%) received mRNA-based vaccines. Most of the recipients (93%) were vaccinated more than 1 year after transplant. Detectable SARS-CoV-2-reactive antibodies were observed in 242 (78%) of allo-HSCT and in 73 (85%) of ASCT recipients. Multivariate analysis in allo-HSCT recipients identified lymphopeni