Marilyn Bulloch, PharmD, BCPS, FCCM

New evidence is evolving every day on clinical outcomes and different treatment options for patients with underlying medical conditions who test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the coronavirus disease 2019 (COVID-19).

 Currently, there is conflicting primary literature on whether adult patients with a diagnosis of active cancer are at an increased risk of developing severe illness from SARS-CoV-2 infection, and the correlation of the concomitant disease states, as well as treatment, is not well understood.

According to the CDC, having cancer increases your risk of severe illness from COVID-19.

 Severe illness from SARS-CoV-2 infection is defined as hospitalization, admission to the intensive care unit (ICU), intubation or mechanical ventilation, and death.

 Owing to this conflicting evidence, a comprehensive systematic search of 12 cohort study results that assessed cancer comorbidity and risk of mechanical ventilation or death in patients with confirmed COVID-19 found that patients had a lower risk of mechanical ventilation and death than patients without cancer.

 However, the authors felt that because of limited numbers, larger studies that include various malignancies from different centers are needed. In contrast, in a large systematic meta-analysis encompassing 110 studies from 10 countries analyzed pooled in-hospital mortality risk of COVID-19 in patients with cancer, results showed the estimated risk was between 9% and 20% across all settings.

Among 904 patients hospitalized, the pooled mortality risk estimate of 14.1% was at least 5 times higher than the reported mortality risk of COVID-19 in nonelderly patients without underlying predisposing conditions across Europe and North America, which was 0.7% to 2.6%.4 Although there is conflicting primary literature, the CDC’s recent update should caution health care providers to take a closer look at this patient population. 

It is reasonable to presume that patients with concomitant cancer and COVID-19 are at a higher risk of complications because of the systemic immunosuppressive state caused by cancer and the therapy used to treat it.

 Results from a small, retrospective study performed in China evaluated 18 patients with cancer and a diagnosis of SARS-CoV-2 infection found that patients had 3.5 times the risk of requiring mechanical ventilation or ICU admission, compared with the general population without cancer.

 Though the study results showed that patients with cancer are at an increased risk of complications, the small sample size of patients prevented the investigation of specific cancer-associated risk factors for worse outcomes.

A much larger retrospective case-control study comprising 73.4 million patient electronic health records from 360 hospitals across the United States aimed to assess the risk of contracting COVID-19 among 13 common cancer types and the risks associated with adverse outcomes.

 Of the millions of records analyzed, 1200 patients had cancer and received a diagnosis with COVID-19 within 1 year of the study end-date, August 12, 2020. Overall, patients with cancer and COVID-19 had significantly worse outcomes (hospitalization, 47.46%; death, 14.93%) than patients with COVID-19 without cancer (hospitalization, 24.26%; death, 5.26%) (P < .001).

 They concluded that there was a synergistic effect between COVID-19 and cancer on death and hospitalization rates, but the underlying biological mechanisms for this synergy warrants further investigation.

Because the risk of developing severe illness from COVID-19 in patients with different types of cancer is not fully characterized, clinicians are attempting to dig deeper to find nuanced correlations.6 In a large cohort study performed across 14 hospitals in Hubei Province, China, from January 1, 2020, to February 24, 2020, 105 patients with cancer and 536 age-matched patients without cancer with confirmed COVID-19 were assessed for clinical characteristics and outcomes.

 Investigators found that the patients with cancer were more likely to have severe outcomes than the patients without cancer, largely due to the types of tumors. The findings suggested that lung cancer, metastatic disease, and hematologic malignancies may be associated with higher rates of COVID-19-related ICU admissions and mortality.

In terms of cancer therapy, different types of treatments such as immunotherapy, chemotherapy, targeted therapy, and surgery had independent influences on the severity of illness and mortality associated with COVID-19. In the study, patients receiving immunotherapy had the highest severity of illness and death rate. However, because of the wide range of treatments utilized in patients and the small number of patients receiving immunotherapy, conclusions were difficult to draw; therefore, a larger case population is warranted to understand this relationship better.

To further evaluate the effects of immunotherapy as cancer treatment, a multicenter, retrospective analysis of 113 patients with cancer and laboratory-confirmed COVID-19 across North America, Europe, and Australia aimed to shed light on the effects on mortality.

 Immunotherapy, or immune checkpoint inhibitors (ICIs), use substances to stimulate or suppress the immune system.

 In this study, ICIs utilized were PD-1 or PD-L1 inhibitors or a combination of PD-1 or PD-L1 plus a CTLA-4 inhibitor.

 A large percentage of the patient population was from Europe (64%), and about one-third (33%) were from North America. Symptoms, comorbidities, and medications, in addition to investigations and treatments implemented for COVID-19, were analyzed. Investigators sought to look at hospital and ICU admissions and mortalities. Overall, results showed that for hospital and ICU admission, 61% of patients were discharged, 12% stayed in the hospital, and 27% of those admitted died by the data cutoff of May 15, 2020. The analysis results concluded that 9 patients died and this was not attributed to treatment with immunotherapy. Overall, they concluded that patients who received immunotherapy within 12 months of testing positive for COVID-19 did not increase the risk of mortality in patients.

Considering patients with cancer and concomitant SARS-CoV-2 infection are more vulnerable to severe outcomes, managing their cancer therapy during the pandemic can be challenging for clinicians.

 Many patients with cancer may need aggressive treatment due to the nature of their underlying disease; however, the clinical effects of cancer therapy in conjunction with COVID-19 are not fully known, and what data are available provide conflicting results.

 A study performed at a hospital in New York City from March 2020 to April 2020 assessed clinical characteristics and outcomes from 309 patients with cancer who received cytotoxic chemotherapy within 35 days of a COVID-19 diagnosis.

 Results showed that receipt of cytotoxic chemotherapy was not associated with adverse COVID-19 outcomes.

 Further adding to these data, 2 large observational studies were performed in patients with cancer and a confirmed SARS-CoV-2 infection between March 2020 and April 2020. Results of this study found the primary end point of all-cause mortality was not increased due to recent cytotoxic chemotherapy or other anticancer treatment.

On the other hand, results from a study conducted in China of 205 patients with cancer and COVID-19 showed that receiving cytotoxic chemotherapy 4 weeks before symptom onset had a higher mortality rate.

 Study results also found that patients with hematological malignancies had a poorer prognosis than those with solid tumors. The authors concluded that the evidence might not strongly prove that the patients studied have a higher fatality rate than the general patient population, and clinicians should be cautious when deciding whether or not to use cytotoxic chemotherapy in these patients.

 Overall, it is challenging to compare these studies because they vary in their end points and their statistical methods.

In a prospective observational study of 928 patients across the United States, Canada, and Spain from the COVID-19 and Cancer Consortium database, authors expressed that these data strongly indicate that COVID-19 mortality in patients with cancer is mainly driven by advancing age and the presence of other noncancer comorbidities.

 As a result, they do not suggest that chemotherapy or anticancer treatments will necessarily increase the risk of mortality from COVID-19.

 Adding to these data, prospective observational study results in 800 patients with active cancer in the UK Coronavirus Cancer Monitoring Project (UKCCMP) found that mortality from COVID-19 in patients with cancer appears to be mainly driven by age, gender, and comorbidities.

 The study results could not identify evidence that patients with cancer on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment. The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer, so these data are promising.

Overall, the question of whether to continue treatment for cancer in a patient with concomitant COVID-19 should be individualized to that patient, with currently no specific recommendations on whether to continue or discontinue cancer therapy due to the vast array of cancer diagnoses, treatment options, and current comorbidities.

 Currently, the CDC recommends that patients with cancer and COVID-19 have a conversation with their health care provider or care team to discuss the individual level of risk based on the patient’s current condition, treatment, and the level of transmission within their community.

As a pharmacist, it is extremely important to counsel patients with cancer who develop COVID-19 to keep taking medications or not alter their treatment plan without first talking to their health care provider. Although no guidelines are published on oncology pharmacy practice in the COVID-19 context, the French Society for Oncology Pharmacy advocates that hospital and community pharmacists be especially alert to the use of OTC treatments and complementary and alternative medicines, as the pandemic encourages self-medication, which can lead to drug-related problems and herb-drug interactions.

, is a PharmD candidate at Auburn University Harrison School of Pharmacy in Alabama; 

, is an inpatient pharmacist in Tuscaloosa, Alabama, and a faculty member with Auburn University in Arkansas. 

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Articles

The CDC recommends that patients with cancer and COVID-19 have a conversation with their health care provider or care team to discuss the individual level of risk based on the patient’s current condition, treatment, and the level of transmission within their community. 

Treatment and Outcomes Data Are Evolving for Patients With COVID-19 and Cancer

Companies across the United States have been focusing their efforts and resources on developing therapies to modify the outcomes of developing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19).

 Though an initial focus on treatment involved primarily repurposed drugs, research and development on novel therapeutics has moved at an almost unprecedented pace.

There is particular interest in monoclonal antibody agents to determine whether their immune suppressive effects can reduce the immediate and long-term impact of COVID-19. Monoclonal antibodies (mAbs) are engineered versions of antibodies that can be used in the treatment or prevention of infectious diseases. Antibodies are naturally produced by the immune system in response to invading viruses or other pathogens.

The theory behind monoclonal antibody use in COVID-19 is that these agents may mediate the hyperinflammatory state that patients with SARS-CoV-2 undergo, and thus help prevent both short- and long-term damage to the lungs.

There are currently 4 novel mAb agents in phase 3 for the treatment or prevention of COVID-19, which include REGN-CoV-2, lenzilumab, and ravulizumab.

 Two of these agents have been issued Emergency Use Authorizations (EUAs), but are awaiting FDA approval.

As of November 21, 2020, two SARS-CoV-2-specific mAbs, bamlanivimab and REGN-COV2, a combination of casirivimab and imdevimab, have been issued EUAs by the FDA for outpatient use in patients with COVID-19.

An EUA is authorized by the FDA to allow the use of unapproved medical products, to diagnose, treat, or prevent serious or life-threatening diseases when certain criteria are met, and there are inadequate available alternatives.

Based on an FDA review of data from a planned interim analysis of the BLAZE trial, an ongoing randomized, double-blind, placebo-controlled, phase 2 trial of bamlanivimab in 452 patients, the rate of hospitalization on day 29 was lower in the bamlanivimab group (1.6% vs 6.3% in the placebo group).

 FDA review of randomized, placebo-controlled, phase 2/3 trial to evaluate safety, tolerability, and efficacy of a single intravenous (IV) dose for treatment of COVID-19 in ambulatory adults led to its EUA.

A total of 799 patients treated with casirivimab/imdevimab reduced COVID-19-related medical visits by 57% through day 29 compared with placebo.

 Both bamlanivimab and casirivimab/imdevimab were studied in adults and adolescents 12 years and older weighing 40 kilograms or more with mild or moderate COVID-19 at high risk for progressing to severe COVID-19 and/or hospitalization, and outpatient use only.

The EUAs were subsequently approved in this patient population, and are to be administered as IV infusions.

 Bamlanivimab is administered as a single IV infusion of 700 mg over 60 minutes.

Casirivimab/imdevimab is administered as a single IV infusion that consists of 1200 mg of casirivimab and 1200 mg of imdevimab.

 Both bamlanivimab and casirivimab/imdevimab should be administered as soon as possible after positive viral test for SARS-CoV-2 and within 10 days of symptom onset.

Lenzilumab is being studied to neutralize granulocyte-macrophage colony-stimulating factor in hopes to shorten hospital length and improve oxygenation in patients diagnosed with COVID- 19 pneumonia.

 Lenzilumab was approved to be studied as an emergency single-use investigational new drug in a prospective case cohort study of 12 participants compared with a control group of 27 untreated patients.

It was studied at a treatment dose of 600 mg IV given over 1 hour every 8 hours for 3 doses.

 The primary end-point tested time to clinical improvement as defined as the observation of a 2 point or higher change in the designated 8-point clinical endpoint scale. Lenzilumab showed a significant improvement in this endpoint with a median of 5 days to clinical improvement compared with a median of 11 days in the untreated cohort (P=0.006).

Lenzilumab significantly decreased median hospital length of stay vs control (5 days vs. 11 days) (P=0.006) and significantly improved oxygenation compared with the untreated cohort when observing patients free of acute respiratory distress syndrome (ARDS) (p<0.001). Other data lend to the idea that lenzilumab improves ventilator-free survival, but did not reach significance in this trial.

Lenzilumab also may have a positive impact on reducing the inflammatory response triggered in some patients with COVID-19. It significantly reduced inflammatory biomarkers including CRP and IL-6 from baseline to day 4.

Lenzilumab was well-tolerated in all patients with no observed treatment-related adverse events. The data from the case study have inspired a phase 3, randomized, placebo-controlled study to verify and expand on these findings.

This study started in April 2020 with 300 participants and was designed with specific outcomes to define its role in therapy in addition to remdesivir and dexamethasone for COVID-19.

 Results of this study have not yet been disseminated.

Ravulizumab, also known as Ultomiris, is currently in a phase 3 trial to evaluate the mortality of patients after 29 days who have severe pneumonia due to COVID-19, acute lung injury, acute respiratory distress syndrome, or viral pneumonia.

 This open-label, randomized, controlled trial has 270 patients enrolled, with a 2:1 ratio of patients receiving ravulizumab with supportive care compared to receiving supportive care alone.

The weight-based doses of IV ravulizumab will be administered to patients 18 years or older who meet criteria on days 1, 5, 10, and 15. Inclusion criteria included patients who had confirmed COVID-19 and required hospitalization. 

Furthermore, patients also had to have severe pneumonia, an acute lung injury, or acute respiratory distress syndrome, and the patients had to be mechanically vented. For patients who are 40 kg or greater to less than 60 kg, a 2400 mg dose is used. For patients 60 kg or greater to less than 100 kg, a dose of 2700 mg is used. Finally, for patients greater than or equal to 100 kg, the dose of 3000 mg is to be used.

Depending on the weight of the patient, the day 1 doses were dependent solely on weight; however, patients on days 5 and 10 in the protocol were to receive additional 600 mg (40 kg-60 kg) or 900 mg (60 kg or greater).

 Finally, day 15 was a set dose for all patients with 900 mg being administered.

 Recruitment for this trial started on May 11, 2020, with hopes of recruitment to be finished by November 30, 2020.

In conclusion, SARS-CoV-2 mAbs have shown to be promising pharmacotherapy options for COVID-19 in their phase 3 clinical trials. Looking into the future, with further investigation of these specific therapies, we can hope to better understand the mechanisms behind treating COVID-19 as well as the long-term impact of the therapies on the patients themselves.

With the EUA approved for casirivimab/imdevimab for outpatient use, with more data from the phase 3 trial, there is hope it will receive FDA approval. The data with lenzilumab have set high expectations for EUA consideration or FDA approval, but whether that will occur based on what information is available remains to be determined.

We are expectantly awaiting the results of the ultomiris trial to hypothesis its place in treatment. The completion of these phase 3 trials will help solidify the FDA’s recommendation on their role in the treatment against SARS-CoV-2. 

There is hope that all of these therapies will contribute to improved outcomes when treating COVID-19 as we continue to become more confident and successful in managing this novel pathogen.

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https://covid19.reaganudall.org/companies-developing-covid-19-therapies?f%5B0%5D=mt_phase%3APhase+3%29

World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. [cited December 01, 2020]. Available from: 

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Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibody for Treatment of COVID-1 [Internet]. 2020 Nov 09 [cited November 29 2020].Available at: 

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibody-treatment-covid-19#:~:text=Today%2C%20the%20U.S.%20Food%20and,in%20adult%20and%20pediatric%20patients

Craven, J. COVID-19 therapeutics tracker [Internet]. Rockville, Maryland. Regulatory Affairs Professionals Society. 2020 Nov 23 [cited December 01, 2020]. Available from: 

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Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19 [Internet]. 2020 Nov 21. [Cited Nov 29 2020]. Available at: 

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19

FAQs  on Emergency Use Authorizations for Medical Use During the COVID-19 Pandemic. U.S. Food and Drug Administration. [cited December 13 2020]. Available at: 

https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/faqs-emergency-use-authorizations-euas-medical-devices-during-covid-19-pandemic.

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There is particular interest in monoclonal antibody agents to determine whether their immune suppressive effects can reduce the immediate and long-term impact of COVID-19.

Monoclonal Antibodies Show Promise Treating COVID-19

Influenza has been one of the most common viral infections for centuries. Perhaps the most destructive and well-remembered outbreak occurred in 1918 when approximately 500 million people world-wide were infected with what became known as the Spanish Flu.

The first influenza vaccine was developed in the 1933 for Influenza A, as Influenza B was not isolated until the 1940s. The first bivalent influenza vaccination was developed shortly thereafter in 1942.

Due to the rapidly evolving nature of influenza, an annual flu vaccination is developed to protect against infection from the most prevalent strains of the virus that experts anticipate will be circulating during the upcoming season, including 2 subtypes of Influenza A (H1N1 and H3N2) and 2 lineages of Influenza B (Victoria and Yamagata). A new vaccine is annually developed based on scientific modeling and testing to determine which strains will be most prevalent in the upcoming influenza season.

Vaccination timing depends on geographic location. The Northern Hemisphere’s flu season lasts from approximately October to March, but it is possible to contract influenza at any time. After vaccination, there is approximately a 2-week window where a vaccinated individual is still susceptible while the body forms an immune response due to the vaccine.

Because influenza has a long seasonal cycle, the question regarding whether multiple influenza vaccinations, spaced throughout the season, could provide added protection has arisen. There is validity to this question as previous studies have shown decreasing influenza vaccine protection with increasing time since vaccination.

 The vaccine’s efficacy (VE) against strains of H3N2 (VE 0% 111 days after vaccination) and Influenza B (VE 21.4% at season end) in particular decreased compared to its efficacy against H1N1 (VE 50.3% at season end).

A study by Ferdinands et al. showed a consistent rate of decline in vaccination effectiveness, about 7% decrease per month, in H3N2, H1N1, and Influenza B.

 Several studies agree that vaccination effectiveness declines significantly by 5 to 6 months after vaccination depending on the influenza strain.

Additionally, studies show that in some patient populations a 2-dose regimen of the seasonal influenza vaccination can induce greater seroprotection against influenza.

 A 2-dose regimen is given because a singular dose in these patients does not stimulate the immune system enough to produce a protective number of antibodies.

The first dose of the 2-dose regimen serves to prime the immune system by activating antigen-specific helper T-cells, while the second dose provides the immunity by causing the primed cells to differentiate into effector or memory cells that can mount a stronger response to the vaccine.

 While there is a large amount of consistent evidence for young, vaccine-naïve children receiving a 2-dose regimen, the data for a 2-dose regimen in other patient populations is conflicting. For example, some studies have shown benefit in patients with solid organ transplant,

while other studies did not indicate added benefit.

 However, in these studies the vaccinations were given as contiguous doses with only 2-4 weeks between the 2 doses.

In the past, it has been thought that older adults lost seroprotection associated with influenza vaccination more quickly than younger patients.

 However, recent studies have shown that there is not as much decrease in seroprotection as previously thought.

A study conducted by Skowronski et al. indicates that older adults who achieved seroprotection rates of 70-100% with initial vaccination maintained immunity for 5-6 months, which is comparable to other age demographics.

 A second dose of the influenza vaccine, given 4 weeks after the initial dose, does not significantly improve seroprotective rates overall in geriatrics in studies.

 However, it may have the potential to lengthen the duration of immunity.

A study by Matsushita et al. showed that when given a 2-dose regimen, with doses given 4 weeks apart, seroprotection rates against H3N2 (-4.9%) and Influenza B (-8.8%) did not decline between 4 and 22 weeks after vaccination in older adults; however protection against strain H1N1 (-19.3%) did decline significantly, which should be a consideration in years when H1N1 is the predominant strain circulating.

 Similarly, overall seroprotection rates did not decline significantly differently in adults > 75 years (-20.8%) when compared to adults < 75 years (-17.1%).

Considering the conflicting evidence of these studies, a multi-dose regimen of the yearly influenza vaccine is not recommended at this time except in influenza vaccine naïve children aged 6 months to 8 years old, and in select solid organ transplant patients. A 2-dose regimen for older adults has been explored, but additional data is needed before a conclusive recommendation can be made on whether or not a second dose is warranted. Other specialized patient populations may benefit from a multi-dose regimen, but as with older adults, more studies should be done to determine the efficacy before such a regimen is implemented into practice.

For now, optimizing influenza vaccine coverage is often best addressed with immunization timing. Patients should wait until the recommended time to be vaccinated to ensure immunity will last throughout influenza season.

inpatient pharmacist in Tuscaloosa, Alabama, and a faculty member with Auburn University in Arkansas.

 is a 2022 PharmD candidate at Auburn University, Harrison School of Pharmacy in Arkansas.

Because influenza has a long seasonal cycle, the question regarding whether multiple influenza vaccinations, spaced throughout the season, could provide added protection has arisen.

Studies Examine How Much Protection a Second Flu Shot Provides

Since the 2019 coronavirus disease (COVID-19) emerged, there has been discussion among health care professionals about the role of ACE-inhibitors (ACEIs) and ARBs. This has been of concern knowing that hypertension is one of the comorbidities that appears to predispose patients to the development of more severe disease.

Coronaviruses are known to utilize the ACE2 to help facilitate entry into the host target cell. Some were concerned that this may help promote infection, as ACE2 is known to be upregulated in patients taking ACEIs and ARBs. On the other hand, laboratory data dating back to other coronaviruses suggested that ACEIs and ARBs may be protective against the virus by helping to block viral entry. It has also been suggested that changes in the renin-angiotensin system contribute to the pathogenesis of the inflammatory lung disease caused by the virus and that these drugs could potentially have a role in reducing damage to the lung tissue. Most of the debate has been based on theory because there was minimal clinical data available to evaluate the potential benefit or risk of these medications.

 provides the first clinical data regarding patients with COVID-19 and the impact of these medications. The retrospective study of Chinese patients hospitalized with COVID-19 from January 11, 2020 to February 23, 2020 evaluated the records of 42 patients taking antihypertensives. Of these patients, 17 were taking ACEIs or ARBs and the remaining 25 were treated with other antihypertensives that included calcium channel blockers, beta-blockers, and diuretics. Most of the patients studied had been on antihypertensive therapy for at least 1 year prior to becoming infected. The average age was 64.5 years, and 57.1% of patients were male. Overall, the baseline characteristics between the 2 groups were similar.

Patients in the non-ACEI/ARB group had higher rates of severe infection (48 % [n=12] vs. 23.5% [n=4]). The difference was not significant, but the overall enrollment numbers of the study were small. Patients receiving ACEIs and ARBs were also noted to have lower IL-6 levels, higher CD3+ and CD8+ T cells, and significantly lower peak viral load than the patients receiving other antihypertensives. Finally, the only death occurred in a patient in the non-ACEI/ARB group.

While it may be too early to make definitive conclusions about the impact of ACEI and ARBs on COVID-19 severity or protection, this study provides the first insight into real-world clinical outcomes of infected patients taking these medications. Though more data is needed to determine a correlation, the results of the study are encouraging and may lend support to those advocating for the continued use of ACEI and ARBs for hypertension in the setting of this unprecedented pandemic.

Meng J, Xiao G, Shang J. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. 

Coronaviruses are known to utilize the ACE2 to help facilitate entry into the host target cell.