Curci P.

Musto P.

Rizzi R.

Sgherza N.

Strafella V.

English

Archivio istituzionale della ricerca - Università di Bari

Implications of Interleukin-6 (IL-6)-blockade for severe COVID-19 infection in patients with Multiple MyelomaNicola Sgherza, Paola Curci, Vanda Strafella, Rita Rizzi, Pellegrino MustoHematology and Bone Marrow Transplantation Unit - AOUC Policlinico, Department of Emergency and Organ Transplan-tation, “Aldo Moro” University, Bari, ItalyCancer patients are at a higher risk of “Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)” infection than patients without cancer (1). In particular, Multiple Myeloma (MM) patients are at serious risk of contracting this severe infection because of many factors, such as immunosuppression, comor-bidities, immune deregulation and frequent accesses to hospital. At present, there are no proven agents for treatment or prevention of SARS-COV-2 infection, so single or combined therapeutic approaches repur-posing existing anti-viral and anti-inflammatory drugs are currently utilized to treat patients with moder-ate to severe “Coronavirus Disease 2019” (COVID-19) infection. Among these, IL-6 inhibitors seem to be promising for the management of the massive cytokine storm associated with the development of the typical lung damage and consequent acute respiratory distress syndrome occurring in the most aggressive patterns of SARS-COV-2 infection (2-4). While dif-ferent reports have been published about concomitant MM and COVID-19 infection, few data are available about the specific outcome of MM patients treated with IL-6 inhibitors. Available IL-6 inhibitors are sil-tuximab, tocilizumab and sarilumab. Siltuximab binds directly to IL-6, while tocilizumab and sarilumab target its soluble (sIL-6R) and membrane-bound receptors (mIL-6R). To our knowledge, from litera-ture review, including case reports and case series, 49 patients (Table 1), with severe confirmed COVID-19 and MM, were treated with IL-6 inhibitors. The most used IL-6 inhibitor was tocilizumab, FDA approved for the management of CAR T-cell related Cytokine Release Syndrome (CRS) while no patient was reported treated with siltuximab. Clini-cal outcome (alive/deceased) is available for 40 on 49 patients with questionable results: 20 patients (50%) died, 20 patients (50%) survived. Certainly, although this retrospective review includes a quite large cohort of patients (556), providing interesting information, several limitations to generalizability of findings are present. First, the number of patients with MM and COVID-19 infection treated with IL-6 inhibitors in Acta Biomed 2021; Vol. 92, N. 2: e2021205 DOI: 10.23750/abm.v92i2.11395 © Mattioli 1885C o r r e s p o n d e n c eFigure 1. Double-sided of Tocilizumab. Interleukin-6 (IL-6) pro-motes the growth of human myeloma cells via autocrine and pa-racrine mechanisms; tocilizumab, binding to mIL-6R of myeloma cells, inhibits in vitro their proliferation. SARS-CoV-2 infection would cause the release of IL-6 by immune cells, with the deve-lopment of cytokine storm (CS) mediated by macrophages, neu-trophils and T cells; tocilizumab, binding to mIL-6R and sIL-6R, plays an important role in the treatment of CS induced by SARS-CoV-2.Acta Biomed 2021; Vol. 92, N. 2: e20212052the world, is certainly higher than one reported in case reports/case series. Second, data represent experiences of patients from different centers, treated differently in terms of drugs and according to their availability at different hospitals. Third, patients received also addi-tional therapies for COVID-19 including hydroxy-chloroquine and anti-viral agents, so it is no possible distinguish absolutely the efficacy of tocilizumab (or other IL-6 inhibitors) from other drugs. An interest-ing aspect to focus on is the potential use of tocili-zumab against  MM. IL-6 is the major growth factor of human myeloma cells through an autocrine or a paracrine mechanism and tocilizumab was reported to inhibit their proliferation in vitro (5) and to be effec-tive in stabilize serum monoclonal protein in patients with systemic diseases (i.e. rheumatological disorders) and concomitant MM (6). So, in the subset of active MM patients with severe COVID-19 infection, in whom other anti-myeloma treatments could be not administrable, the possibility that tocilizumab could represent a treatment option with a double action (Figure 1) against cytokine storm due to COVID-19 and MM itself would warrant to be verified.Conflicts of interest: Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a con-flict of interest in connection with the submitted article.References1. Liang W, Guan W, Chen R, Wang W, Li J, Xu K, Li C, Ai Q, Lu W, Liang H, Li S, He J. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020 Mar;21(3):335-337. doi: 10.1016/S1470-2045(20)30096-6. Epub 2020 Feb 14. PMID: 32066541; PMCID: PMC71590002. Crisafulli S, Isgrò V, La Corte L, Atzeni F, Trifirò G. Poten-tial Role of Anti-interleukin (IL)-6 Drugs in the Treatment of COVID-19: Rationale, Clinical Evidence and Risks. BioDrugs. 2020 Aug;34(4):415-422. doi: 10.1007/s40259-020-00430-1. PMID: 32557214; PMCID: PMC72992483. Atal S, Fatima Z. IL-6 Inhibitors in the Treatment of Serious COVID-19: A Promising Therapy? Pharmaceut Med. 2020 Aug;34(4):223-231. doi: 10.1007/s40290-020-00342-z. PMID: 32535732; PMCID: PMC7292936. 4. Zhang S, Li L, Shen A, Chen Y, Qi Z. Rational Use of Toci-lizumab in the Treatment of Novel Coronavirus Pneumonia. Clin Drug Investig. 2020 Jun;40(6):511-518. doi: 10.1007/s40261-020-00917-3. PMID: 32337664; PMCID: PMC7183818.Abbreviations: N.S.: not specified; N.A.: not availableTable 1. Summary of studies of IL-6 inhibitors for COVID-19 infection in patients with multiple myeloma. Acta Biomed 2021; Vol. 92, N. 2: e2021205 35. Hirata T, Shimazaki C, Sumikuma T, Ashihara E, Goto H, Inaba T, Koishihara Y, Nakagawa M. Humanized anti-interleukin-6 receptor monoclonal antibody induced apop-tosis of fresh and cloned human myeloma cells in vitro. Leuk Res. 2003 Apr;27(4):343-9. doi: 10.1016/s0145-2126(02)00179-0. PMID: 12531226.6. Matsuyama Y, Nagashima T, Honne K, Kamata Y, Iwa-moto M, Okazaki H, Sato K, Ozawa K, Minota S. Suc-cessful treatment of a patient with rheumatoid arthritis and IgA-κ multiple myeloma with tocilizumab. Intern Med. 2011;50(6):639-42. doi: 10.2169/internalmedicine.50.4636. Epub 2011 Mar 15. PMID: 21422694.Received: 25 February 2021Accepted: 7 April 2021Correspondence: Nicola Sgherza, MD, PhDHematology and Bone Marrow Transplantation Unit - AOUC Policlinico, Department of Emergency and Organ Transplan-tation, “Aldo Moro” University, 70124, Bari, ItalyTel.: +390805594001Fax: +390805428978E-mail: nicolasgherza@libero.it

Implications of interleukin-6 (Il-6)-blockade for severe covid-19 infection in patients with multiple myeloma

https://ricerca.uniba.it/bitstream/11586/370588/1/ACTA-92-205.pdf

Implications of interleukin-6 (Il-6)-blockade for severe covid-19 infection in patients with multiple myeloma

Abstract

Similar works

Full text

Available Versions

Archivio istituzionale della ricerca - Università di Bari