Disclosures: Berger. Ip, Mauro and Rubinstein report no relevant financial disclosures. Wood reports consultant roles with Teladoc/Best Doctors, honoraria from ASH Research Collaborative and research funding from Pfizer.
February 25, 2021
13 min read
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COVID-19 and blood cancer: Evolving science on a dangerous comorbidity

Disclosures: Berger. Ip, Mauro and Rubinstein report no relevant financial disclosures. Wood reports consultant roles with Teladoc/Best Doctors, honoraria from ASH Research Collaborative and research funding from Pfizer.
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More than a year into the COVID-19 pandemic, new information emerges daily about the virus and its effects on various vulnerable populations.

The CDC’s list of underlying medical conditions that elevate risk for severe illness due to COVID-19 is described as a “living document” that will likely remain in flux as knowledge about the virus evolves.

Even less aggressive treatments for blood cancers, such as anti-CD20 monoclonal antibodies, can cause poorer COVID-19 outcomes, according to Samuel M. Rubinstein, MD.
Even less aggressive treatments for blood cancers, such as anti-CD20 monoclonal antibodies, can cause poorer COVID-19 outcomes, according to Samuel M. Rubinstein, MD. “These are widely used drugs for B-cell malignancies,” he said. “It may be the case that these medications impair antibody production.”
Source: UNC Lineberger Cancer Center.

Cancer has been identified as one disease likely to increase risk for poor COVID-19 outcomes.

Because bone marrow plays an essential role in immune function, hematologic malignancies are a particular area of concern. Individuals with blood cancers may have compromised immune systems due to the cancer, its treatment or both.

“Hematologic malignancies are diseases of the blood, the bone marrow and lymphoid organs, and that’s where most immune functions take place,” Nathan A. Berger, MD, Hanna-Payne professor of experimental medicine, professor of medicine, biochemistry and oncology, and director of the Center for Science, Health and Society at Case Western Reserve University School of Medicine, said in an interview with HemOnc Today. “We think the mechanism of that increased susceptibility is because of immune suppression or immune deficiency associated with the disease.”

Nathan A. Berger, MD
Nathan A. Berger

However, the paucity of mechanistic data on this association reflects an overall lack of understanding about the interplay between hematologic malignancies and COVID-19. As the pandemic continues to unfold, researchers strive to make real-time treatment decisions based on limited information.

“It’s tough, because we don’t have much evidence out there,” Andrew Ip, MD, hematologist/oncologist at Hackensack Meridian Health John Theurer Cancer Center, told HemOnc Today. “We think convalescent plasma helps, but it’s still not strongly evidence-based. We’re waiting on larger research trials to publish their data. It’s very hard to make judgments when there’s not much good data.”

Andrew Ip, MD
Andrew Ip

HemOnc Today spoke with hematologist-oncologists about the data gathered so far on incidence and outcomes of COVID-19 among patients with blood cancers, how anticancer treatments and bone marrow transplant may affect COVID-19 outcomes, and how these patients should be treated.

Tracking cases

The need to evaluate the impact of COVID-19 on patients with hematologic malignancies was recognized early in the pandemic, according to William A. Wood, MD, MPH, associate professor in the division of hematology/oncology at The University of North Carolina at Chapel Hill School of Medicine and a HemOnc Today Editorial Board Member.

William A. Wood, MD, MPH
William A. Wood

“In the early days of the COVID-19 pandemic, many hematologists were concerned that our patients could be at increased risk for adverse outcomes from COVID-19 infection for a variety of reasons — many of our patients are older, have underlying or treatment-induced comorbidities, have immune dysregulation or treatment-related immunosuppression, and may already be susceptible to COVID-19-related complications, such as thrombosis,” Wood told HemOnc Today. “With this in mind, the ASH Research Collaborative facilitated the development of a COVID-19 registry.”

The registry, which was launched in April, consists of clinical data contributed voluntarily from more than 100 international study sites.

In an analysis of registry data presented at the virtual ASH Annual Meeting and Exposition in December, Wood and colleagues combined data on 656 patients (77% aged 40 years or older; 60% men; 43% white) with hematologic malignancies and confirmed or presumptive diagnosis of COVID-19 infection. Fifty-seven percent of these patients had known comorbidities, the most common of which were hypertension (50%) and diabetes (30%). More than half (57%) had leukemia, 25% had lymphoma and 18% had plasma cell neoplasms.

Prior to COVID-19 infection, the majority (80%) had an expected survival of more than 12 months.

Overall, 20% of patients died during the study period between April and November, including 33% of those who required hospital-level or ICU-level care. The mortality rate among those with ICU-level care was 65%.

The 33% death rate among hospitalized patients is similar to what has been reported elsewhere for this population, Ip told HemOnc Today at the time the study was presented.

“It is important to note that this was conducted during a 6- to 7-month period, and it’s possible that the mortality rates were higher in April and May than within the last couple of months, for varying reasons,” he said. “This is something that we need to keep in mind when looking at registries spanning the COVID-19 pandemic.”

Wood and colleagues found that the highest risk for death occurred among patients who were older, had more severe infection, chose not to receive more intensive treatment and/or had a poorer cancer prognosis before COVID-19 infection.

Additionally, researchers reported a strong association between COVID-19 severity and the patient’s malignancy status: 69% of patients receiving initial treatment for a hematologic malignancy had moderate or severe COVID-19 compared with 50% of those who were in remission and 79% with relapsed/refractory disease.

Wood noted that the analysis was limited by the registry’s reliance on voluntary reporting, which may lead to estimates that differ from those derived from a true population-based registry.

“This highlights the need for enhanced data-collection systems involving patients with underlying hematologic diseases,” Wood said. “The ASH Research Collaborative Data Hub is building programs that will help to address this gap, starting with sickle cell disease and multiple myeloma, and expanding to other diseases in the future.”

Poorer outcomes

Research conducted by the Italian Hematology Alliance on COVID-19 and published in August in The Lancet Haematology demonstrated that patients with hematologic malignancies had worse COVID-19 outcomes than the general population.

Among 536 patients with a hematologic malignancy and COVID-19 included in the study, 37% died.

Researchers reported standardized mortality ratios of 2.04 (95% CI, 1.77-2.34) for these patients compared with the general Italian population with COVID-19, and 41.3 (95% CI, 38.1-44.9) compared with a cohort of patients with hematologic malignancies but not COVID-19.

Researchers linked shorter OS to older age (HR = 1.03; 95% CI, 1.01-1.05); progressive disease status (HR = 2.1; 95% CI, 1.41-3.12); diagnosis of acute myeloid leukemia (HR = 3.49; 95% CI, 1.56-7.81), indolent non-Hodgkin lymphoma (HR = 2.19; 95% CI, 1.07-4.48), aggressive non-Hodgkin lymphoma (HR = 2.56; 95% CI, 1.34-4.89) or plasma cell neoplasms (HR = 2.48; 95% CI, 1.31-4.69); and severe or critical COVID-19 (HR = 4.08; 95% CI, 2.73-6.09).

Samuel M. Rubinstein, MD
Samuel M. Rubinstein

This study represents “the biggest and most convincing analysis” on the association between hematologic malignancies and poorer COVID-19 outcomes, according to Samuel M. Rubinstein, MD, assistant professor in the division of hematology at The University of North Carolina at Chapel Hill School of Medicine and associate member of UNC Lineberger Comprehensive Cancer Center.

Rubinstein told HemOnc Today that similar findings have been reported in the United States in studies of other data sets, such as the COVID-19 and Cancer Consortium (CCC19) registry.

Data he and colleagues presented at ASH showed that 67% of 757 patients with hematologic malignancies were hospitalized for COVID-19, 25% were admitted to the ICU, 18% required mechanical ventilation and 19% died within 30 days of COVID-19 diagnosis. Rates of severe COVID-19 appeared highest among patients with chronic lymphocytic leukemia (53%) and lowest among patients with Hodgkin lymphoma (23%).

“Preliminarily, in the CCC19 cohort, there is categorically a relatively high mortality rate in patients with hematologic malignancies and COVID-19,” he said. “So, it’s a consistent finding across a variety of COVID-19 registry studies that patients with hematologic malignancies seem to have worse outcomes than those who do not have hematologic malignancies.”

Although researchers have been studying the effects of blood cancers on COVID-19 outcomes, less is known about whether the effects are bidirectional.

Michael J. Mauro, MD
Michael J. Mauro

Michael J. Mauro, MD, leader of the myeloproliferative neoplasms program at Memorial Sloan Kettering Cancer Center, professor at Weill Cornell Medicine and a HemOnc Today Editorial Board Member, said he is particularly concerned with COVID-19 complications and chronic issues.

“Some of the major complications we’re worried about are chronic lung disease and blood clotting issues,” he said. “We have a population that has a higher risk for bleeding and clotting from thrombocytopenia, low platelets and indwelling catheters. Some of the medications we might use for COVID-19 might be dangerous to our population. So, COVID-19 would be harder to manage in the patient with hematologic cancer than in a patient with a solid tumor, for example.”

Some evidence suggests that COVID-19 and hematologic malignancies may interact in ways that can worsen both diseases, according to Berger.

“We showed that if you have a hematologic malignancy alone, you have a death rate of about 5.1%, and if you have COVID-19 alone, your death rate is 5.3%,” he said. “If you have a combination of COVID-19 and a hematologic malignancy, you’d expect to have a 10% death rate, because they add to each other. What we saw, though, was a 15% death rate.”

Risk factors

Some studies have focused on the association between COVID-19 and specific hematologic malignancies to determine who might be at most risk.

Mauro and colleagues presented a study at ASH in which they evaluated patients with chronic myeloid leukemia and COVID-19. The CANDID study represented the largest global cohort study to evaluate COVID-19 in this population.

“We were glad to see that the co-incidence of CML and COVID-19 led to an outcome similar to what we’d expect for COVID in a non-CML population,” Mauro said in an interview. “There was no particular risk factor we identified, like a certain medicine or certain disease state. Age was a predictor, as it is for COVID in the general population.”

A study presented at ASH by Roeker and colleagues assessed COVID-19 outcomes among patients with CLL. This study, which evaluated 411 hospitalized patients with COVID-19 and CLL, identified a case fatality rate of 30% to 34%.

“There have now been a few large series published which show that patients with CLL have relatively high mortality rates with COVID 19, and it seems to correlate with impaired antibody production,” Mauro said.

A study conducted by Ip and colleagues analyzed outcomes of 89 patients with COVID-19 and lymphoma, including CLL, diffuse large B-cell lymphoma, indolent non-Hodgkin lymphoma, Hodgkin lymphoma, T-cell lymphoma and other subtypes.

They found that among patients with lymphoma and COVID-19, survival was poor among those with hypertension or diabetes, as well as those aged 70 years and older.

“We’ve got to sort out the individual risks in the individual hematologic malignancies,” Mauro said. “We also have to consider the effects of medications for these malignancies, such as tyrosine kinase inhibitors for CML. Are they protective, neutral or harmful?”

The duration of a patient’s blood cancer may also affect their susceptibility to COVID-19 infection.

Berger cited a study published in Blood Reviews in which he and colleagues reviewed the IBM Watson Health Explorys database, which included information on 73 million individuals across the country.

“We found that patients who had a diagnosis made within the past year had a much higher risk for developing COVID-19 than those with a longstanding diagnosis,” he said. “Those with a longstanding diagnosis were at least twice as susceptible to COVID-19 as the normal population, [whereas] those with a recent diagnosis were 11 to 12 times more susceptible.”

The impact of treatment

Another area of concern for patients with hematologic malignancies is that the very treatments that are successful in managing their cancer may lead to worse COVID-19 outcomes.

Rubinstein said the added vulnerability to infection associated with some of these treatments was already known.

“Depending on the disease state, high-intensity cytotoxic regimens are oftentimes used,” he said. “Patients with curable lymphoma or acute leukemia may be getting traditional cytotoxic chemotherapy at relatively high intensity, and they’re at risk for a variety of infections,” he said. “COVID-19 is no exception.”

Even less aggressive treatment approaches have potential effects. For instance, Rubinstein cited anti-CD20 monoclonal antibodies, which may deplete a patient’s native antibody production.

“These are widely used drugs for B-cell malignancies,” he said. “It may be the case that these medications impair antibody production.”

In his study of patients with lymphoma and COVID-19, Ip said he and his colleagues found that CD20 antibody therapies were associated with worse COVID-19 outcomes.

“Patients who get B-cell depletion through CD20 antibody therapies, such as rituximab [Rituxan; Genentech, Biogen] or obinutuzumab [Gazyva, Genentech], don’t have a great serologic or humoral response, meaning they don’t create antibodies,” he said. “Therefore, we’ve seen and have been publishing data that these patients have worse outcomes from COVID-19.”

Rubinstein said although some studies have indicated worse outcomes among patients undergoing certain chemotherapy regimens, there are not yet enough data to conclusively show an association.

“Even in the largest case series out there, the numbers of people receiving individual treatments are too small to draw any conclusions,” he said. “With that said, there are biologically plausible reasons that might explain the relatively high mortality in patients with hematologic malignancies that have been seen across a number of peer-reviewed studies.”

Transplant and COVID-19 risk

Hematopoietic stem cell transplant is another treatment associated with immune suppression and increased risk for COVID-19.

According to Berger, the effect of this treatment on a patient’s immune system is potentially more severe than that seen with cytotoxic chemotherapies.

“Patients who undergo bone marrow transplantation usually have an even greater wipeout of hematopoietic cells,” he said. “Bone marrow transplants also purposely create an immune suppression so that the patient doesn’t reject the graft.”

One study presented at ASH by Ljungman and colleagues found that patients with COVID-19 who had undergone allogeneic or autologous HSCT were at increased risk for developing long-term respiratory disease, needing ICU care and mortality vs. the general population.

Rubinstein said in the CCC19 registry, patients with COVID-19 who underwent bone marrow transplantation had a 38% rate of severe disease and 19% mortality rate.

“There also was a slightly higher, but not dramatically higher, mortality rate for patients who were receiving cellular therapy within a year of COVID-19 diagnosis, compared with the remainder of the cohort,” he said. “There are some confounders there. Some of these patients may have had relatively poor control over the primary disease, which is why they were receiving cellular therapy. Poor control over the hematologic malignancy is a consistent risk factor across a lot of these studies, as well.”

Berger noted that in their database study, he and Rong Xu, PhD, found an independent association between hematologic malignancy and increased likelihood of COVID infection, even when adjusting for transplantation.

“We showed that even if we eliminated patients with bone marrow transplantation, there was still this differential,” he said. “This is more than just transplantation now; this is the immunosuppressive aspect of these diseases.”

Treatment considerations

When treating a patient for COVID-19 who has a preexisting diagnosis of a blood cancer, clinicians need to consider whether the treatments may worsen a patient’s outcome from either disease.

Additionally, there is the question of whether these treatments are strong enough to be effective for these patients, Ip said.

“A lot of the treatments out there, like steroids or remdesivir [Veklury, Gilead] may help, but these patients with blood cancers have high risk for poor outcomes or longer infections,” he said. “We’re looking for something more than steroids, which we use as a common treatment, and remdesivir may only be good for the initial antiviral phase, but not for the second half or more severe part of the illness, which is the inflammatory phase.”

High-titer convalescent plasma is one treatment that has shown promise in treating patients with COVID-19 and hematologic malignancies. This treatment approach has yielded positive results among hospitalized patients with COVID-19 who were not on mechanical ventilation.

“There is a plausible mechanism by which convalescent plasma may be effective in patients with hematologic malignancies,” Rubinstein said. “It’s possible that high-titer convalescent plasma would be disproportionately beneficial to a patient population that cannot mount an antibody response.”

Mauro agreed that high-titer convalescent plasma may be suited to patients whose hematologic malignancies have compromised their immune systems.

“Convalescent plasma would be focused on patients with the biggest gaps,” Mauro said, “such as people with low antibody levels or no immune systems from the blood cancers. It’s obviously been given emergency authorization and reviews, but I don’t know if we have very strong confidence in that yet.”

Berger emphasized the importance of vaccination against COVID-19 but added that it is crucial to ensure that it is done safely.

“We have to figure out whether we can immunize patients with hematologic malignancies against COVID-19,” he said. “I think we can, but the question is whether their degree of immunosuppression is going to allow them to respond appropriately to the vaccine.”

Ip said he is currently recommending vaccination for his patients, except for those who have recently undergone a major therapy such as HSCT, chimeric antigen receptor T-cell therapy or intensive chemotherapy.

This recommendation is in line with guidance released by the National Comprehensive Cancer Network. A panel of experts supported vaccination for all patients with cancer, but advised special consideration of the timing based on receipt of anticancer treatment. For instance, they recommend waiting 3 months between receipt of HSCT or cellular therapy and vaccination.

“We may advise these patients to wait a bit, but they should get the vaccine eventually,” Ip said. “We hope to vaccinate a lot of our patients with cancer soon.

“A lot of places have been doing their best to protect patients through masking or distancing,” he added. “One message everyone needs to know is that transmission is mainly in the community, and we have to do our best to listen to public health guidance on preventing transmission of the virus in the first place.”

References:

CDC. Evidence used to update the list of underlying medical conditions that increase a person’s risk of severe illness from COVID-19. Available at: www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/evidence-table.html. Accessed Jan. 25, 2021.

National Comprehensive Cancer Network: Cancer and COVID-19 vaccination. Available at: www.nccn.org/covid-19/pdf/COVID-19_Vaccination_Guidance_V1.0.pdf. Accessed Jan. 25, 2021.

Passamonti F, et al. Lancet Haematol. 2020;doi:10.1016/S2352-3026(20)30251-9.

Wang Q, et al. Blood Rev. 2020;doi:10.1016/j.blre.2020.100775.

The following were presented at ASH Annual Meeting and Exposition (virtual meeting) Dec. 5-8, 2020:

Ip A, et al. Abstract 3553.

Ljungman P, et al. Abstract 2384.

Rea D, et al. Abstract 649.

Roeker LE et al. Abstract 1590.

Rubinstein S et al. Abstract 1632.

Wood WA, et al. Abstract 215.

For more information:

Nathan A. Berger, MD, can be reached at can be reached at Case Comprehensive Cancer Center, 10900 Euclid Ave., Cleveland, OH 44106-4971; email: nab@case.edu.

Andrew Ip, MD, can be reached at John Theurer Cancer Center, 92 Second St., Hackensack, NJ 07601; email: andrew.ip@hmhn.org.

Michael J. Mauro, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: maurom@mskcc.org.

Samuel M. Rubinstein, MD, can be reached at UNC Lineberger Comprehensive Cancer Center, 450 West Drive, Chapel Hill, NC 27514; email: samuel_rubinstein@med.unc.edu.

William A. Wood, MD, MPH, can be reached at UNC Lineberger Comprehensive Cancer Center, Division of Hematology, 101 Manning Drive, Chapel Hill, NC 27514; email: william_wood@med.unc.edu.