COVID-19 and Blinatumomab Therapy: “First Do No Harm”

Update, 9/16/20: This article refers to the RECOVERY trial, results of which had not been peer reviewed or published when the article was posted in June 2020. Preliminary results from RECOVERY were published in the New England Journal of Medicine on July 20, 2020. They showed that treatment with dexamethasone, at a dose of 6 mg once daily for up to 10 days, reduced 28-day mortality in patients with COVID-19 who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.

More recently, on September 2, 2020, the results of a meta-analysis by the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies Working Group were published in the Journal of the American Medical Association. In this prospective meta-analysis of seven clinical trials of critically ill patients with COVID-19, the administration of systemic corticosteroids (high- and low-dose dexamethasone, high-dose methylprednisolone, and low-dose hydrocortisone) was associated with reduced 28-day all-cause mortality compared with usual care or placebo.

In light of these published findings, Mohammed Bilal Abid, MD, said: "I believe that in patients receiving blinatumomab, the use of corticosteroids may now be considered in select cases – specifically, in those patients who are critically ill with COVID-19, such as those who require mechanical ventilation or higher levels of supplemental oxygen."

Immunocompromised patients face the highest risk of mortality from COVID-19, with those receiving immune-engaging therapy or undergoing stem cell transplants the most vulnerable.

In a recent article published in JAMA Oncology, Muhammad Bilal Abid, MD, and colleagues proposed recommendations for managing conventional immunotherapy and CAR T-cell therapy in patients who are infected with or are at risk for infection with SARS-CoV-2, the novel coronavirus that causes COVID-19.

Dr. Abid, an assistant professor of medicine with the Divisions of Infectious Diseases and Hematology/Oncology at the Medical College of Wisconsin, recently shared with Nucleus his thoughts on factors for clinicians to consider when determining whether to proceed with treatment with the bispecific T-cell engager blinatumomab in the setting of known or possible SARS-CoV-2 infection.

A central concern, he said, is that the virus-induced immune dysfunction and hyperinflammatory state (“cytokine storm”) that is a principal cause of mortality in COVID-19 patients is “almost identical” to cytokine release syndrome (CRS), a major adverse effect of treatment with blinatumomab and other advanced immune-engaging cancer therapies. This raises the fear that the use of blinatumomab in patients who have been exposed to SARS-CoV-2 could result in compounded immune dysregulation.

In the phase III randomized TOWER study in which blinatumomab demonstrated significantly superior overall  survival compared with chemotherapy in adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia, 16% of patients in the blinatumomab arm experienced a CRS event, with 86% of these events occurring in the first treatment cycle.

Among patients receiving blinatumomab, those with a higher burden of underlying disease – for example, patients with MRD-positive disease, multiple prior treatments, or both – are at elevated risk for experiencing more-severe CRS, noted Dr. Abid.

Prior to initiating blinatumomab therapy, patients are premedicated with dexamethasone to reduce the risk of CRS. Corticosteroids are also the first-line treatment for blinatumomab-related adverse events such as CRS and neurotoxicity.

Evidence from previous coronavirus outbreaks has shown, however, that corticosteroids may do more harm than good when used to treat pneumonia associated with coronavirus infections.

“Steroids did not demonstrate efficacy during prior coronaviral outbreaks,” said Dr. Abid. “Moreover, steroids delay viral clearance and result in lymphopenia, which is now emerging as an independent risk factor associated with acute respiratory distress syndrome, intensive care unit admission, and COVID-19–related mortality.”

In its revised interim guidance on COVID-19 clinical management, published in late May, the World Health Organization recommended against the routine use of systemic corticosteroids to treat COVID-19–related viral pneumonia. This followed a similar recommendation in April by a guideline panel of the Infectious Diseases Society of America.  

According to recent press reports, results of the RECOVERY trial show that low-dose dexamethasone (6mg/day for 10 days) reduced mortality in COVID-19 patients who needed mechanical ventilation or supplemental oxygen. The study has not yet been peer reviewed or published.

"Given that this is the first and only signal to date that steroids may offer any benefit to patients with COVID-19 - and that the findings have yet to be peer reviewed - I strongly believe that it would be premature to change practice in any way until we have more data," said Dr. Abid.

“Even after you have managed blinatumomab-associated CRS with tocilizumab, patients will continue to have B-cell aplasia and are regularly treated with immunoglobulin infusions,” he said. “Hence, for an unpredictable period of time, blinatumomab recipients will be unable to mount an adequate humoral response to SARS-CoV-2 infection.” 

Dr. Abid recommended that all patients who are candidates for, or are already undergoing, blinatumomab therapy be tested for COVID-19 using the polymerase chain reaction–based nasopharyngeal swab test.

  • If a patient tests positive for SARS-CoV-2, has had recent contact with a person who tested positive, or resides in an area with high prevalence of SARS-CoV-2 infection: Delay or defer blinatumomab treatment until the patient has recovered completely (i.e., has had two consecutive negative nasopharyngeal swab tests conducted at least 24 hours apart and all COVID-19 symptoms have completely resolved for at least 14 days and, if feasible, up to 30 days, given that viral shedding is likely to be prolonged in immunocompromised hosts).
  • If a patient has upper respiratory symptoms but has tested negative for SARS-CoV-2 infection: Perform chest imaging to look for lung lesions. Repeat the nasopharyngeal swab test at least 24 hours after the first test. Clinicians should be aware that, even when correct sampling technique is used, the sensitivity of the nasopharyngeal swab test is unknown.

“A specimen taken from the lower respiratory tract has higher sensitivity than one taken from the upper respiratory tract,” said Dr. Abid. “Additionally, most community-acquired respiratory viruses have a predilection for lung parenchyma over the upper airways, particularly in immunocompromised hosts.”

Delay or defer blinatumomab treatment until the patient has had two consecutive negative nasopharyngeal swab tests conducted at least 24 hours apart and all upper respiratory symptoms have completely resolved for at least 14 days.

Dr. Abid suggested that initiating or continuing blinatumomab therapy may be considered when the following criteria are met:

  • The patient is at a high risk for relapse (e.g., has MRD-positive disease), particularly the patient who is in a first complete remission.
  • The patient has absolutely no symptoms suggestive of COVID-19 or upper-respiratory infection.
  • The patient has had no contact with anyone who is known or suspected to be infected with SARS-CoV-2.
  • The patient has tested negative for SARS-CoV-2 on a nasopharyngeal swab test and, preferably, on a second test conducted at least 24 hours after the first one.
  • The patient lives in a geographic area with a low prevalence of SARS-CoV-2 infection.
  • In the treating oncologist’s judgment, blinatumomab therapy is likely to offer a considerable survival benefit over the standard of care.

Patient visits to healthcare facilities should be limited to the extent possible. For example, after week 1 of the first treatment cycle, deliver treatment via a portable infusion pump whenever possible.

Dr. Abid noted that much remains unknown about SARS-CoV-2, the clinical spectrum of the illness it causes, and the nuances of COVID-19 diagnosis. Furthermore, a clear signal of efficacy and safety is lacking as yet for any of the investigational or repurposed drugs that have thus far been used to treat patients with COVID-19.

“The onus remains on the treating oncologist to exercise best judgment in gauging the additional survival benefit of initiating blinatumomab or other immune-harnessing treatment in the setting of known or possible SARS-CoV-2 infection,” he said. “In balancing the risk-benefit ratio, ‘first do no harm’ ought to prevail.”

Citations for linked articles

[article] Abid MB, Mughal M, Abid MA. Coronavirus Disease 2019 (COVID-19) and Immune-Engaging Cancer Treatment. JAMA Oncol. 2020 May 20. doi: 10.1001/jamaoncol.2020.2367. Online ahead of print.

[phase III randomized TOWER study] Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med 2017;376:836–47. DOI: 10.1056/NEJMoa1609783

[corticosteroids may do more harm than good] Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020 15-21 February; 395(10223): 473–475. doi: 10.1016/S0140-6736(20)30317-2

[revised interim guidance on COVID-19 clinical management] World Health Organization. Clinical management of COVID-19: interim guidance. 27 May 2020. https://www.who.int/publications/i/item/clinical-management-of-covid-19

[similar recommendation] Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. April 11, 2020. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

[news article] Mueller B, Rubin RC. Common Drug Reduces Coronavirus Deaths, Scientists Report. New York Times. 16 June 2020. https://www.nytimes.com/2020/06/16/world/europe/dexamethasone-coronavirus-covid.html?searchResultPosition=1

Tags: COVID-19, patient care, bite

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