COVID-19 Check-Up

What is known and unknown about COVID-19 and patients with hematologic malignancies?

The world has entered the third year of the COVID-19 pandemic, and although the healthcare field has had an unprecedented response in terms of scale and speed of research and discovery, there is still a lot to be learned.

“If there is one thing I think everyone should keep in mind about COVID-19 and hematologic malignancies, it is that everything is constantly changing and there is still so much to be learned,” said Naveen Pemmaraju, MD, Associate Professor in the Department of Leukemia, University of Texas MD Anderson Cancer Center. “The things I say in this article may not be true six months from now.”

One thing that seems to have remained constant is that patients with hematologic malignancies are at greater risk for adverse outcomes from COVID-19.

At the start of the pandemic in 2020, early observational data out of China indicated that patients with cancer and SARS-CoV-2 infection had a higher risk for severe events compared with those without cancer.¹ A larger cohort study also found higher death rates, higher rates of intensive care unit admission, and higher rates of severe or critical symptoms among patients with cancer with SARS-CoV-2 infection compared with those without cancer; this excess risk was highest among patients with hematologic cancers.²

Now, more than two years later, most patients with hematologic malignancies and the people who care for them have access to readily available COVID-19 tests, vaccines, and effective prevention strategies and antiviral therapies. With this in mind, Blood Cancers Today recently spoke with Dr. Pemmaraju and others in the field about what they have learned—and what still needs to be learned—about COVID-19 and hematologic malignancies.

Risk for Infection

At the beginning of the COVID-19 pandemic, there were a lot of unknowns.

“This was a new set of viruses without any preexisting immunity in the population and no knowledge of how best to manage it,” said Sagar Lonial, MD, FACP, Professor and Chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Family Chair in Cancer at Emory University and Chief Medical Officer of Winship Cancer Institute.

Speaking generally, patients with hematologic malignancies have a suppressed immune system as part of the nature of the disease itself, and often the treatments for these diseases—whether chemo­therapy or immunotherapy—can result in further immunosuppression. Clinicians treating patients with hematologic malignancies already had an idea that their patients would be at greater risk for COVID-19, even without the data to back it up.

“If you look at disorders like multiple myeloma (MM) or lymphoma, the cell you need to create antibody-mediated immunity is the same cell we are targeting with our treatments,” Dr. Lonial said. “Almost all drugs used to treat myeloma wipe out plasma cells, which puts those patients at a higher risk than the average patient with a solid tumor.”

One of the best studies that began to confirm this risk was by Passamonti and colleagues, according to Samuel M. Rubinstein, MD, Assistant Professor and Malignant Hematologist at the University of North Carolina at Chapel Hill and an Associate Member of the Lineberger Comprehensive Cancer Center.

“The study showed increased risk for getting sick and increased risk for poor outcomes compared with patients with COVID-19 and no cancer and patients with cancer but no COVID-19,” Dr. Rubinstein said.

The study enrolled 536 patients with hematologic malignancies admitted to 66 Italian hospitals between February 2020 and May 2020 with confirmed COVID-19. Of the included patients, 37% died. Compared with the general Italian population with COVID-19, the standardized mortality ratio was 2.04. Compared with the non-COVID-19 cohort with hematologic malignancies, the standardized mortality ratio was 41.3.³

Since then, similar outcomes have been shown consistently in follow-up studies, including other large cohorts or single-center experiences.

For example, a retrospective study of COVID-19 in patients with hematologic malignancies at Thomas Jefferson University’s Sidney Kimmel Medical College and its associated community sites reported a mortality of 16.1% among patients with hematologic malignancies diagnosed with COVID-19.⁴ This study, conducted by Lindsay Wilde, MD, and colleagues, also looked at mortality rates during waves of COVID-19, with the highest mortality during the first two waves (April 2020: 27.8% and July 2020: 25%) and lower morality during the third wave (November 2020 to January 2021: 10%).

A meta-analysis of 81 studies comparing mortality in patients with cancer and SARS-CoV-2 infection and control patients also showed higher risk of death for patients with cancer (relative risk of mortality=1.69; P<.001). Younger age, lung cancer, and hematologic cancer were all risk factors associated with poor outcomes from COVID-19.⁵

“We must consider all this data, keeping in mind that our ability to recognize and treat COVID-19 is different now than when we started,” said Dr. Wilde, Assistant Professor of Medical Oncology at Sidney Kimmel Medical College.

Effective Prevention Tools

A major difference between today and the beginning of the pandemic is the variety of more effective tools that can be used to prevent or treat COVID-19.

“The pandemic is very different now than it was,” Dr. Rubinstein said. “A plurality of people have had [COVID-19] or have been vaccinated against it.”

People can still get infected, but “outcomes tend to be improving over time, perhaps because of immunity from prior infection or vaccinations” he said.

In a recent study from the COVID-19 and Cancer Consortium, Dr. Rubinstein and colleagues found that calendar time was significantly associated with COVID-19 after adjustment, with the greatest degree of mortality seen during the initial phase of the pandemic.⁶

One of the best tools available for immunocompromised patients has been the vaccines against SARS-CoV-2.

“Among patients with cancer, there were two concerns about vaccines: whether they would cause harm and if patients would mount an antibody response,” Dr. Pemmaraju said.

Although each cancer type and treatment may be slightly different, by and large Dr. Pemmaraju said vaccinating patients with cancer has been successful and safe. However, studies looking at antibody responses have yielded conflicting data, he said.

A recent meta-analysis looked at 44 studies of immunogenicity of COVID-19 vaccines that included 7,064 patients with hematologic malignancies. Overall seropositivity rates were between 62% and 66% after two doses of the COVID-19 vaccine and 37% to 51% after only one dose. The lowest rate was in patients with chronic lymphocytic leukemia and the highest was in patients with acute leukemia. The study found that active, ongoing, or recent treatment with targeted and CD20 monoclonal antibody therapies within 12 months was associated with poor immune responses.⁷

Dr. Lonial participated in another study looking at vaccine-induced neutralizing antibodies in 238 patients with MM undergoing SARS CoV-2 vaccination. These antibodies were detectable “at much lower rates” than in previous seroconversion studies of MM, the study showed. In about a third of patients, vaccine-induced anti-spike receptor-binding domain antibodies lacked detectable neutralizing capacity. The study also showed that patients receiving the Moderna vaccine had significantly greater induction of neutralizing antibodies than those who received the Pfizer vaccine (67% vs 48%; P=.006).⁸

“A lot is still unknown about vaccine efficacy in patients who are immunocompromised, partially because those patients were left out of the original
studies,” Dr. Wilde said. “But making sure that patients are vaccinated and helping them understand that even some level of antibody protection is better than none remains important.”

Another option for prevention of COVID-19 is Evusheld. In December 2021, the U.S. Food and Drug Administration issued emergency authorization for Evusheld (tixagevimab co-packaged with cilgavimab and administered together) for pre-exposure prophylaxis of COVID-19 in certain adults and pediatric individuals, including those who have moderately to severely compromised immune systems due to a medical condition or immunosuppressive medications or treatments.⁹

This authorization was granted based on data from the PROVENT trial, which included adults aged older than 59 years with a prespecified chronic medical condition or with increased risk of SARS-CoV-2 infection. Patients were randomized 2:1 to receive Evusheld (n=3,441) or placebo (n=1,731). Patients assigned to Evusheld had a 77% reduced risk for developing COVID-19 compared with placebo.⁹

Data from a six-month follow-up analysis showed that Evusheld reduced the risk for COVID-19 infection by 83% compared with placebo, and there were no cases of severe disease or COVID-19-related deaths in this group.¹⁰

This prevention method should be embraced for immunocompromised patients, according to Dr. Lonial.

“Evusheld is a way to offer some prevention for patients on B-cell suppressive agents or on anti-CD38 antibodies who we know are not going to mount an immune response to the vaccine,” Dr. Lonial said. “Protecting them with this passive antibody may lower the risk of significant infection, addressing their concerns and allowing them to get back to a more normal life.”

Dr. Rubinstein agreed that patients with B lymphoid malignancies should be prioritized for receipt of Evusheld.

The wider availability of COVID-19 tests has also decreased exposure.

“The number one thing to remember is that you don’t have to wait for symptoms to detect COVID-19,” Dr. Pemmaraju said. “Asymptomatic COVID-19 can be picked up on routine or smart testing; we really need to be paying attention to this.”

All institutions should be testing prior to visits, hospital admissions, surgical procedures, and major courses of chemotherapy.

Finally, in cases where infection occurs, Dr. Rubinstein said that clinicians are better at managing COVID-19 today than they were two years ago.

“Now, there are a number of treatments that have proven benefit both for patients being treated in an outpatient setting and for inpatient levels of COVID-19 severity,” Dr. Rubinstein said.

Decisions about administering available treatments, including antivirals, should be made on a case-by-case basis, as should administering cancer-directed therapy in patients with acute COVID-19.

“On the whole, we are doing less harmful stuff and more helpful stuff,” Dr. Rubinstein said.

Remaining Questions

Looking forward, many questions remain about the relationship between COVID-19 and hematologic malignancies.

Dr. Wilde is particularly interested in ongoing vaccine studies.

“There are hundreds of other vaccines in development worldwide that mechanistically work in different ways,” Dr. Wilde said. “It may be that in the future there are other vaccines that come along that are more effective in our patients.”

Data presented at the American Association for Cancer Research Annual Meeting 2022 showed that a new SARS-CoV-2, peptide-based vaccine called CoVac-1 induced T-cell immune response in 93% of patients with B-cell deficiencies, including many patients with leukemia and lymphoma.¹¹

Researchers at Jefferson and elsewhere are also looking at other effective treatments for COVID-19 in patients with hematologic malignancies, Dr. Wilde said. For example, Jefferson is evaluating modified T cells that can be directed against the SARS-CoV-2 virus.

Dr. Pemmaraju said that the field may have to tackle more issues related to long-COVID or post-COVID conditions.

“That really is the new dominant question in many circles,” Dr. Pemmaraju said. “Why do some patients get it and others don’t? How are we defining these things? We need to learn how to predict it and the prognostics of it all.”

Michael J. Mauro, MD, leader of the Myelo­proliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, said that there will also be a need for even more specific studies related to how COVID-19 affected certain disease types.

“In the area of chronic myeloid leukemia, it will be interesting to look at whether patients missed opportunities for treatment cessation as a result of efforts to decrease risk for COVID-19 exposure,” Dr. Mauro said.

In the area of MM, Dr. Lonial knows that studies will need to be done to evaluate whether patients present with later disease stages because they were not worked up for precursor conditions such as monoclonal gammopathy of undetermined significance or smoldering myeloma.

Finally, the increased use of remote care and telehealth will also need to be examined in the coming years, Dr. Mauro said.

Data from a large commercial insurer published in 2021 indicated that the rate of uptake of tele­medicine visits among newly diagnosed patients with cancer differed by socioeconomic status, with higher uptake among higher socioeconomic quartiles. Results indicated that current telemedicine capabilities were insufficient to reduce disparities and may actually have widened them.¹²

“As a health care system, we need to sort out how this is going to be used as a tool moving forward,” Dr. Mauro said. “Its use during the pandemic has been an eye-opener, and its future is not straightforward.”

Top of Mind

As answers to these questions are awaited, certain things should be kept in mind when managing patients with hematologic malignancies.

“The first is to make sure that your patients have adequate vaccination with the full recommended series of doses,” Dr. Lonial said.

In April, the National Comprehensive Cancer Network released its latest guidance on COVID-19 vaccination for people with cancer or those who are immunocompromised. It recommended that these people get the three primary doses of the vaccine and two booster shots.¹³

Encouraging patients to stay up to date is part of being a good shepherd of public health, which Dr. Mauro encouraged everyone to do.

“It is all of our responsibility—not just our infectious disease and public health colleagues,” Dr. Mauro said. “Our job is to be ambassadors of good health policy as it is given to us by our health care officials.”

Dr. Rubinstein encouraged all practitioners to remember that the vast majority of cancer treatment should not change in this era of the pandemic.

“We want to be doing the most effective things to fight cancer in essentially all situations,” Dr. Rubinstein said. “For the things that we know might only have marginal benefit, we have to consider whether those things might be increasing someone’s risk for COVID-19, and if they are, we have to discuss that with the patient when we get informed consent.”

Dr. Wilde emphasized that the pandemic is not over, especially not for patients.

“Patients are still living with a lot of uncertainty, and that is challenging every day for them,” Dr. Wilde said.

A systematic review of research examining psychological distress among cancer patients during the COVID-19 pandemic found common causes of distress included fear of COVID-19 infection, fear of disease progression, and worry about immunocompromised status. Many patients in the studies examined reported depression, anxiety, insomnia, fatigue, or sleep disorders.¹⁴

“While the rest of the world tries to get back to normal, I think a lot of our patients feel forgotten or left behind,” Dr. Wilde said. “They are still navigating difficult decisions every day.”

Last, but definitely not least, Dr. Pemmaraju reminded his health care colleagues of the importance of self-care.

Surveys of the global oncology workforce conducted in 2020 showed that almost half of respondents had feelings of burnout as a result of the COVID-19 pandemic.¹⁵ The pandemic has exacerbated already high levels of burnout in the specialty, and oncolo­gist well-being must be prioritized.¹⁶

“As health care workers on the front line, you need to make sure you are keeping yourself healthy,” Dr. Pemmaraju said. “This is a shout-out to my fellow providers. We cannot be taking care of other people unless we are also watching out for ourselves.”

Leah Lawrence is a freelance health writer and editor based in Delaware.

References

1. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2022;21(3):335-337.
2. Dai M, Liu D, Liu M, et al. Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak. Cancer Discov. 2020:10(6):783-791.
3. Passamonti F, Cattaneo C, Arcaini L, et al. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Hematol. 2020;7(10):e737-e745.
4. Wang XA, Binder AF, Gergis U, Wilde L. COVID-19 in patients with hematologic malignancies: a single center retrospective study. Front Oncol. 2021;11:740320.
5. Khoury E, Nevitt S, Madsen WR, et al. Differences in outcomes and factors associated with mortality among patients with SARS-CoV-2 infection and cancer compared with those without cancer. A systematic review and meta-analysis. JAMA Network Open. 2022. doi:10.1001/jamanetworkopen.2022.10880
6. Rubinstein SM, Bhutani D, Lynch RC, et al. Patients recently treated for B-lymphoid malignancies show increased risk of severe COVID-19. Blood Cancer Discov. 2022;3(3):181-193.
7. The JSK, Coussement J, Neoh ZCF, et al. Immunogenicity of COVID-19 vaccines in patients with hematologic malignancies: a systematic review and meta-analysis. Blood Adv. 2022;6(7):2014-2034.
8. Nooka AK, Shanmugasundaram U, Cheedarla N, et al. Determinants of neutralizing antibody response after SARS CoV-2 vaccination in patients with myeloma. J Clin Oncol. 2022. doi:10.1200/JCO.21.02257
9. U.S. Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes new long-acting monoclonal antibodies for pre-exposure prevention of COVID-19 in certain individuals. December 8, 2021. Accessed May 6, 2022. www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-long-acting-monoclonal-antibodies-pre-exposure
10. AstraZeneca. Evusheld significantly protected against symptomatic COVID-19 for at least six months in PROVENT phase III trial in high-risk populations. April 20, 2022. Accessed May 6, 2022. www.astrazeneca.com/media-centre/press-
    releases/2022/evusheld-significantly-protected-against-symptomatic-covid-19-for-at-least-six-months-in-provent-phase-iii-trial-in-high-risk-populations1.html
11. Tandler C, Heitmann JS, Marconato M, et al. Interim safety and immunogenicity results of a phase I trial evaluating the multi-peptide COVID-19 vaccine candidate CoVac-1 for induction of SARS-CoV-2 T cell immunity in cancer patients with disease- or treatment-related immunoglobulin deficiency. Abstract CT258. Presented at AACR Annual Meeting 2022.
12. Katz AJ, Haynes K, Du S, et al. Evaluation of telemedicine use among US patients with newly diagnosed cancer by socioeconomic status. JAMA Oncol. 2022;8(1):161-163.
13. National Comprehensive Cancer Network. NCCN COVID-19 vaccination guide for people with cancer. April 27, 2022. Accessed May 6, 2022. www.nccn.org/docs/default-source/covid-19/2021_covid-19_vaccination_guidance_v5-0.pdf?sfvrsn=b483da2b_114
14. Momenimovahed Z, Salehiniya H, Hadavandsiri F, et al. Psychological distress among cancer patients during COVID-19 pandemic in the world: a systematic review. Front Psychol. 2021;12:682154.
15. Burki TK. Burnout among cancer professionals during COVID-19. Lancet Oncol. 2020;21(11):1402.
16. Hlubocky FJ, Symington BE, McFarland DC, et al. Impact of the COVID-19 pandemic on oncologist burnout, emotional well-being, and moral distress: considerations for the cancer organization’s response for readiness, mitigation, and resilience. JCO Oncology Practice. 2021;17(7):365-374.