TOCLIZUMAB SEEMS TO WORK FOR SERIOUS COVID-19

A case study of one patient with multiple myeloma diagnosed with COVID-19 in Wuhan, China, published by Zhang et al in Blood Advances examined the efficacy of the immunosuppressant tocilizumab as a treatment for this particular patient. The report also suggested that patients with hematologic malignancies may have atypical COVID-19 symptoms.

“Our patients with hematologic malignancies are immunosuppressed, which may put them at higher risk for novel coronavirus infection. What are the characteristics of COVID-19 in patients with blood cancers? What is the optimal treatment approach? Everything is unknown, and that was the motivation for this study,” said lead study author Changcheng Zheng, MD, of the University of Science and Technology of China, in a statement.

Case Study

The patient—a 60-year-old male who had been diagnosed with multiple myeloma in 2015, was treated with two cycles of induction triplet chemotherapy, and was on maintenance thalidomide therapy—was hospitalized in February for chest tightness and shortness of breath. Although he did not show symptoms of cough or fever, he did have decreased oxygen saturation, diminished breath sounds in his lower left lung, and lymphocytopenia. He tested positive for COVID-19, and his illness was classified as severe.

Treatment with antiviral and corticosteroid therapies did not fully resolve his symptoms. On the second day in the hospital, a chest computed tomography (CT) scan showed that the patient had ground glass opacities in his lungs—a characteristic of pneumonia. His levels of interleukin-6 (IL-6), a proinflammatory cytokine, were high.

After one intravenous administration of tocilizumab, the patient’s IL-6 levels decreased. Three days after tocilizumab treatment, his chest tightness had resolved; 10 days later, his CT scan showed decreased range of ground-glass opacities, and he was discharged from the hospital.

Possible Mechanism

Tocilizumab is commonly used to treat cytokine-release syndrome, a systemic inflammatory response that occurs in response to treatment with certain types of immunotherapies. Dr. Zheng and his team suggested the agent may treat COVID-19 by addressing the acute severe inflammatory response, or “cytokine storm,” that the virus can trigger. However, they emphasize the need for more research into the potential mechanisms of action.

Dr. Zheng also suggests that because the patient had chest tightness and shortage of breath without other COVID-19 symptoms—specifically, cough and fever—clinical symptoms of the virus may not be typical in patients who have hematologic malignancies.

“Tocilizumab was effective in the treatment of COVID-19 in this patient with multiple myeloma, but further prospective and randomized clinical trials are needed to verify the findings,” concluded Dr. Zheng.

In March 2020, the U.S. Food and Drug Administration approved a randomized, double-blind, placebo-controlled phase III clinical trial to evaluate the safety and efficacy of intravenous tocilizumab for the treatment of adult patients with COVID-19.

Disclosure: For full disclosures of the study authors, visit ashpublications.org/bloodadvances.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.Dr Alberto

Bassi, a 62-year-old Italian dermatologist, was still hospitalized in the town of Castel San Giovanni in Piacenza, Italy, and on oxygen when he decided to send a message to all his fellow physicians: "I'm now in the hospital with COVID-19 pneumonia. Tocilizumab changed everything."  He posted to Medscape Consult, a crowdsourced social media platform in which clinicians share and discuss real cases, and a frenzy of questions from healthcare providers tackling COVID-19 ensued.  Bassi's case is one of several confirmed and suspected cases of COVID-19 being discussed on Consult. One confirmed case showed classic respiratory symptoms that progressed rapidly in a 43-year-old Italian man. Another showed gastrointestinal symptoms — vomiting and diarrhea — that were resistant to therapy and no pulmonary symptoms. In more than 40 other threads, doctors from around the world are discussing epidemiology, comorbidities, and investigative treatments.    Bassi's symptoms started on March 8: fever, cough, and muscle aches. He suspects he was exposed at a hospital in Correggio, Italy where he underwent retinal surgery 2 weeks before.  Initially, he took acetaminophen and rested, but 2 days later his oxygen saturation "had dropped from 98% to 88% with progressive respiratory failure," he told Medscape by email. On the recommendation of the chief of the local ICU, a close friend, Bassi was hospitalized, and clinicians took a nasal swab to confirm COVID-19. Over the following days he received a treatment regimen of Plaquenil (hydroxychloroquine), lansoprazole, antiretroviral therapy, enoxaparin, and methylprednisolone (intravenous). Then, after one dose of tocilizumab, an immunosuppressant used to treat rheumatoid arthritis, Bassi's breathing improved almost immediately, he said in an email interview. Tocilizumab is an interleukin-6 receptor antagonist, blocking the proinflammatory IL-6 from its binding site and stopping the uncontrolled inflammatory response that may be a cause of mortality in some COVID-19 patients. A recent retrospective study of 150 patients in China suggested virally activated hyperinflammation may be a major cause of COVID-19 mortality.  As one physician commented on Bassi's Consult post, "The second phase of [COVID-19] appears to be immunological. The virus may not even be present anymore and people die from the cytokine storm."  Pranatharthi Chandrasekar, MD, division chief of infectious diseases at Wayne State University in Detroit, Michigan, says that it is still unclear if the virus or host inflammatory response are to blame. But if hydroxychloroquine isn't effective, anti-inflammatories are the next course of action. And when prescribing anti-inflammatory drugs, such as tocilizumab or corticosteroids, for COVID-19, "timing seems to be most critical," he told Medscape. Cytokine storms, the uncontrollable pro-inflammatory reaction that can cause sepsis and organ failure, are also a key factor in cytokine release syndrome (CRS), which tocilizumab is FDA-approved to treat. Immunosuppressive therapies like tocilizumab may be an especially important treatment option, since corticosteroids can exacerbate lung injuries caused by COVID-19, according to a recent study published in The Lancet.   

Σελίδα 2 από 2 If caught in time, steroids may be enough to dampen the inflammatory reaction and prevent further deterioration, Chandrasekar said. "If conditions worsen further, tocilizumab as another, more potent anti-inflammatory drug may be useful."  Bassi was given both — tocilizumab and intravenous corticosteroids. Many physicians responded to his message asking if the two were synergistic. "Of course, methylprednisolone was stopped when [they started] tocilizumab and reintroduced again the day after," he said. But he has no way to be sure there was not a combined effect.  In Italy, current guidelines only allow tocilizumab after the high viral load phase of COVID-19 has passed. Patients must be without fever for 72 hours or have been showing symptoms for at least 7 days. China approved its own tocilizumab clinical trial in mid-February, but the trial is still recruiting. However, a preprintfrom ChinaXiv that followed 20 patients given tocilizumab in early February found that the drug could reduce fever, need for oxygen therapy, blood lymphocytes, C-reactive protein, and lung abnormalities on the CT scan. The drug is not yet approved by the FDA for treating COVID-19. But Bassi's testimony on Consult came just days after the FDA green-lighted phase 3 trialsof tocilizumab (Actemra, Genentech) for COVID-19 pneumonia treatment. Genentech, a subsidiary of Roche, will move forward with the double-blind, placebo-controlled trial evaluating intravenous tocilizumab combined with the standard of care in patients with COVID-19 pneumonia. Bassi remains in the hospital on oxygen therapy, but is "getting better every day." He's no longer on Plaquenil or the retroviral. "This is a very dangerous illness," he wrote to Medscape, "It certainly requires admittance in special intensive critical care units, close follow up is essential, and — as usual — so is a lot of luck."  Donavyn Coffey is a freelance journalist in New York City. She interned for Medscape in the fall of 2019. For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube. Here's how  to send Medscape a story tip.