Results of phase 2 randomized multi-center study to evaluate the safety and efficacy of infusion of memory T cells as adoptive therapy in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and/or lymphopenia (RELEASE NCT04578210).

BACKGROUND AIMS: There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)-hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA- memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment. METHODS: Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 106/kg CD45RA- memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2-specific response within the CD45RA- memory T cells and the most frequent human leukocyte antigen typing in the Spanish population. RESULTS: We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events. CONCLUSIONS: Adoptive cell therapy with off-the-shelf CD45RA- memory T cells containing SAR-CoV-2-specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia. TRIAL REGISTRATION: NCT04578210.

Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia: A Randomized, Phase III Clinical Trial (SARTRE Study).

INTRODUCTION: SARS-CoV-2 pneumonia is often associated with hyper-inflammation. The cytokine-storm-like is one of the targets of current therapies for coronavirus disease 2019 (COVID-19). High Interleukin-6 (IL6) blood levels have been identified in severe COVID-19 disease, but there are still uncertainties regarding the actual role of anti-IL6 antagonists in COVID-19 management. Our hypothesis was that the use of sarilumab plus corticosteroids at an early stage of the hyper-inflammatory syndrome would be beneficial and prevent progression to acute respiratory distress syndrome (ARDS). METHODS: We randomly assigned (in a 1:1 ratio) COVID-19 pneumonia hospitalized patients under standard oxygen therapy and laboratory evidence of hyper-inflammation to receive sarilumab plus usual care (experimental group) or usual care alone (control group). Corticosteroids were given to all patients at a 1 mg/kg/day of methylprednisolone for at least 3 days. The primary outcome was the proportion of patients progressing to severe respiratory failure (defined as a score in the Brescia-COVID19 scale ≥ 3) up to day 15. RESULTS: A total of 201 patients underwent randomization: 99 patients in the sarilumab group and 102 patients in the control group. The rate of patients progressing to severe respiratory failure (Brescia-COVID scale score ≥ 3) up to day 15 was 16.16% in the Sarilumab group versus 15.69% in the control group (RR 1.03; 95% CI 0.48-2.20). No relevant safety issues were identified. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia, who were under standard oxygen therapy and who presented analytical inflammatory parameters, an early therapeutic intervention with sarilumab plus standard of care (including corticosteroids) was not shown to be more effective than current standard of care alone. The study was registered at EudraCT with number: 2020-002037-15.

Comparación entre el tratamiento con dexametasona y metilprednisolona en pacientes hospitalizados por COVID-19

RESUMEN Introducción: la dexametasona es un medicamento que demostró una disminución de la mortalidad en la neumonía por SARS-CoV-2. Se desconoce la utilidad de otros corticoides, dosis y su duración para mejorar este resultado clínico. Objetivo: comparar la mortalidad de los pacientes adultos con neumonía por SARS-CoV-2 tratados con dexametasona versus metilprednisolona en el Hospital Nacional, Itauguá, Paraguay. Materiales y métodos: estudio ambispectivo. Se incluyeron 97 pacientes, 52 recibieron dexametasona y 45 metilprednisolona. Se utilizó un muestreo no probabilístico de casos consecutivos. Las variables fueron sometidas a estadística descriptiva y analítica. El protocolo fue aprobado por el Comité de Ética del Hospital Nacional. Los autores no presentan conflictos de interés. Resultados: todos los pacientes ingresaron con neumonía con valoración de 4 (OMS). No se encontraron diferencias significativas en la mortalidad entre ambos grupos. Al aplicar un análisis estratificado por edad, en los pacientes <65 años la mortalidad en los que recibieron dexametasona fue 15,8% mientras que los que recibieron metilprednisolona no fallecieron (p 0,03). En el grupo de ≥65 años la mortalidad n los recibieron dexametasona fue 29,4% vs. 21,4% en los que recibieron metilprednisolona (p 0,7). Conclusiones: en los pacientes <65 años tratados con dexametasona la mortalidad fue mucho más alta que en los que recibieron metilprednisolona, ya que en este último grupo no se registraron fallecimientos.

ABSTRACT Introduction: Dexamethasone is a medication that demonstrated a decrease in mortality in SARS-CoV-2 pneumonia. The usefulness of other corticosteroids, dose and their duration to improve this clinical result is unknown. Objective: To compare the mortality of adult patients with SARS-CoV-2 pneumonia treated with dexamethasone versus methylprednisolone at the Hospital Nacional of Itauguá, Paraguay. Materials and Methods: Ambispective study. Ninety seven patients were included, 52 received dexamethasone and 45 methylprednisolone. A non-probabilistic sampling of consecutive cases was used. The variables were subjected to descriptive and analytical statistics. The protocol was approved by the Ethics Committee of the Hospital Nacional. The authors do not present conflicts of interest. Results: All patients entered with 4 (WHO) vaulting pneumonia. No significant differences were found in mortality between both groups. When applying an age stratified analysis, in patients <65 years who received dexamethasone the mortality was 15.8% while those who received methylprednisolone did not die (p 0.03). In the ≥65 years group, mortality in those who received dexamethasone was 29.4% vs. 21.4% in those who received methylprednisolone (p 0.7). Conclusions: In patients <65 years treated with dexamethasone, mortality was much higher than in those who received methylprednisolone, since in the latter group no deaths were recorded.

A BCR-ABL1 cutoff of 1.5% at 3 months, determined by the GeneXpert system, predicts an optimal response in patients with chronic myeloid leukemia.

In chronic myeloid leukemia (CML) patients, 3-month BCR-ABL1 levels have consistently been correlated with further outcomes. Monitoring molecular responses in CML using the GeneXpert (Cepheid) platform has shown an optimal correlation with standardized RQ-PCR (IS) when measuring BCR-ABL1 levels lower than 10%, as it is not accurate for values over 10%. The aim of the present study was to determine the predictive molecular value at three months on different outcome variables using the Xpert BCR-ABL1 MonitorTM assay (Xpert BCR-ABL1). We monitored 125 newly diagnosed consecutive CML patients in the chronic phase (CML-CP) using an automated method: Xpert BCR-ABL1. Only 5% of patients did not achieve an optimal response at 3 months, and the 10% BCR-ABL1 cutoff defined by RQ-PCR (IS) methods was unable to identify significant differences in the probabilities of achieving a complete cytogenetic response (CCyR) (50% vs. 87%, p = 0.1) or a major molecular response (MMR) (60% vs. 80%, p = 0.29) by 12 months. In contrast, a cutoff of 1.5% more accurately identified differences in the probabilities of achieving CCyR (98% vs. 54%, p<0.001) and MMR (88% vs. 56%, p<0.001) by 12 months, as well as probabilities of treatment changes (p = 0.005). Therefore, when using the Xpert BCR-ABL1 assay, a cutoff of 1.5% at 3 months could with high probability identify patients able to achieve an optimal response at 12 months.