BTK inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): A Systematic Review

Abstract

ImportanceThe Bruton tyrosine kinase (BTK) regulates B cell and macrophage signaling, development, survival, and activation. BTK inhibition was shown to protect against lethal influenza-induced acute lung injury in mice. Inhibiting BTK has been hypothesized to ameliorate lung injury in patients with severe coronavirus disease 2019 (COVID-19). ObjectiveTo evaluate the use of BTK inhibitors (BTKinibs) during COVID-19 and assess how they may affect patient outcomes.Evidence ReviewWe searched PubMed, Embase, and Web of Science: Core on December 30, 2020. Clinical studies with at least 5 COVID-19 patients treated with BTKinibs were included. Case reports and reviews were excluded.FindingsOne hundred twenty-five articles were identified, 6 of which met inclusion criteria. Sample size ranged from 6 to 126 patients. Patient populations included subjects hospitalized with COVID-19 (6/6) and admitted to the intensive care unit (5/6). Patient age ranged between 35 and 98 years. Four studies included patients already receiving BTKinibs for their lymphoproliferative disease, 1 for Waldenstrom’s macroglobulinemia and 3 for chronic lymphocytic leukemia (CLL). The most common clinical outcomes measured were oxygen requirements (4/6) and hospitalization rate or duration (3/6). Differences in standard-of-care reflected the date of study and pre-existing conditions in the various patient cohorts. Full-dose acalabrutinib was evaluated in 2 studies, one study evaluated full-dose ibrutinib, and another study evaluated both ibrutinib and acalabrutinib. The remainder 2 studies described outcomes in CLL patients on multiple BTKinibs and other CLL-targeted treatments. Three studies showed decreased oxygen requirements in patients who started or continued BTKinibs. All three studies that evaluated hospitalization rate or duration found favorable outcomes in those on BTKinibs. Conclusions and RelevanceBTKinib use was associated with decreased oxygen requirements and decreased hospitalization rates and duration. However, randomized clinical trials are needed to validate the beneficial effects of BTKinibs for acute SARS-CoV-2 infection.

Management of patients with chronic lymphocytic leukemia during the SARS‑CoV‑2 pandemic (Review)

“…The analysis included six studies with patients hospitalized for COVID-19 who had malignant lymphoproliferative diseases (some of them with CLL), and who were treated with BTK-inhibitors. This treatment, together with SARS-CoV-2 infection therapy, was associated with a lower oxygen requirement and a shorter stay in hospital ( 17 ). The therapeutic outcome of patients with CLL and COVID-19 is far from expected.…”

B Cells and COVID-19: Lessons From Patients With Agammaglobulinemia and the Study of Functional B-Cell Polymorphisms

“…While we do not currently have a clear explanation, we are excluding the possibility that replacement immunoglobulin treatment had an impact on COVID-19 prognosis, since patients with other antibody deficiencies under replacement treatment displayed a more severe clinical phenotype [5,10]. Therefore, we suggest that BTK signaling may primarily contribute to COVID-19 prognosis, since BTK is also expressed by monocytes and dendritic cells, and the impairment of BTK signaling also results in severe consequences of innate immune responses [12,13]. Thus, BTK-dependent NF-kappaB and NLRP3 activation result in the production of proinflammatory cytokines such as IL-1β and IL-6 (which also contribute to COVID-19 pathogenesis [14,15]), while BTK inhibition dampened the inflammatory response [12,13].…”

“…Therefore, we suggest that BTK signaling may primarily contribute to COVID-19 prognosis, since BTK is also expressed by monocytes and dendritic cells, and the impairment of BTK signaling also results in severe consequences of innate immune responses [12,13]. Thus, BTK-dependent NF-kappaB and NLRP3 activation result in the production of proinflammatory cytokines such as IL-1β and IL-6 (which also contribute to COVID-19 pathogenesis [14,15]), while BTK inhibition dampened the inflammatory response [12,13]. This notion is also supported by recent studies describing the outcomes of patients with B cell malignancies and COVID-19, who were receiving BTK-inhibitors (BTKi) displaying a favorable outcome (reviewed by Stack et al [13]).…”

“…Thus, BTK-dependent NF-kappaB and NLRP3 activation result in the production of proinflammatory cytokines such as IL-1β and IL-6 (which also contribute to COVID-19 pathogenesis [14,15]), while BTK inhibition dampened the inflammatory response [12,13]. This notion is also supported by recent studies describing the outcomes of patients with B cell malignancies and COVID-19, who were receiving BTK-inhibitors (BTKi) displaying a favorable outcome (reviewed by Stack et al [13]). As a result, there are currently active clinical trials investigating BTKi in COVID-19 patients (ClinicalTrials.gov Identifier: J Investig Allergol Clin Immunol 2022; Vol.…”

“…© 2021 Esmon Publicidad doi: 10.18176/jiaci.0726 NCT04528667, NCT04440007, NCT04439006), which will further elucidate their possible therapeutic effects. However, considering that other studies reported that BTK deficiency or inhibition lead rather to enhanced inflammation [13], it is obvious that the exact role of BTKsignaling in innate immune responses needs to be further explored.…”