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Letters to the Editor
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Figure 2. Immunological alterations in chronic lymphocytic leukemia patients under ibrutinib therapy during infection by SARS-CoV-2. Chronic lymphocytic leukemia (CLL) peripheral blood mononuclear cells (PBMC) were isolated from CLL patients before and after 3 months of treatment with ibrutinib and stimulated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides (1 mg/ml) for 6 hours. TNF-α and IFN-γ secretion levels have been determined by cytokine secretion assay kit gating CD3+ and CD14+ populations by flow cytometry. (A and B) Bar diagrams show the percentage of TNF-α and IFN-γ secretion by T cells either in the presence or absence of stimulation by SARS-CoV-2 (n=7; *P<0.05). (C and D) Bar diagrams show the percentage of TNF-α and IFN-γ secretion by monocytes either in the presence or absence of stimulation by SARS-CoV-2 (n=7; *P<0.05).
entific debate about the opportunity to maintain or dis- continue treatment in the presence of SARS-CoV-2 infec- tion. In this scenario, some concerns are related to the evidence that an immunosuppressive activity of ibrutinib has been related to the occurrence of early-onset invasive fungal infections in treated-patients. For this reason, the choice of ibrutinib discontinuation may be related to a potentially increased risk of secondary infections and impaired humoral immunity.13 Our results demonstrate how ibrutinib may have protective effects on COVID-19 in CLL patients by limiting the cytokine storm preventing lung injury. On one hand, ibrutinib may influence T-cell function, by skewing T cells from a Th2-dominant to a Th1 and CD8+ cytotoxic population promoting Th1 immunity.9 On the other hand, BTK is involved in the regulation of macrophage lineage commitment towards M1 polarization and ibrutinib is able to skew towards an immunosuppressive phenotype also in response to pro- inflammatory stimuli as fungal infection.12 Inhibition of BTK, expressed by myeloid immune cells, affects the induction of inflammatory cytokines through the NFkB pathway and in mice intratracheal injection of BTK small interfering RNA confers potent protection against sepsis- induced acute lung injury with significant reduction of pulmonary edema, inflammatory cytokines and neu- trophil infiltration in the lung tissues.14 In the setting of influenza A infection, ibrutinib mitigates inflammation and improves resolution of infection.15 Our results seem to strongly support a protective action of ibrutinib miti- gating the feared cytokine storm sustaining the sugges-
tion that there are no evident reasons to prematurely interrupt ibrutinib in these patients as recently suggested.13 In the light of these observations, since ibru- tinib seems to not worsen COVID-19 specific immune response, our study provides a biological rationale for continuation of BTKi in CLL patients who develop COVID-19. Noteworthy, a better overview on the poten- tial use of BTKi against COVID-19 is under evaluation in clinical trials (clinicaltrials.gov Identifier: NCT04439006, NCT04375397) conducted in patients not affected by B-cell malignancies.
Stefania Fiorcari,1* Claudio Giacinto Atene,1* Rossana Maffei,2 Giulia Debbia,1 Leonardo Potenza,1,2 Mario Luppi1,2 and Roberto Marasca1,2
1Department of Medical and Surgical Sciences, Section of
Hematology, University of Modena and Reggio Emilia, Modena and
2
Hematology Unit, Department of Oncology and Hematology,
A.O.U of Modena, Policlinico, Modena, Italy
*SF and CGA contribute equally as co-first authors. Correspondence:
STEFANIA FIORCARI - stefania.fiorcari@unimore.it ROBERTO MARASCA - roberto.marasca@unimore.it doi:10.3324/haematol.2020.277392
Received: December 3, 2020.
Accepted: February 26, 2021.
Pre-published: March 11, 2021.
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