ASH 2020: COVID-19 and Hematology

Taking Immunosuppressants? Fauci Says Get the COVID-19 Vaccine

“Patients with compromised immune systems, whether due to chemotherapy or a bone marrow transplant, should plan to be vaccinated against coronavirus disease 2019 (COVID-19) when they have the chance,” Anthony Fauci, MD, the nation’s leading infectious disease expert, said December 5, 2020, less than a week before the FDA approved the first vaccine against COVID-19.

Fauci, who this month counts service to 7 presidents during his tenure as director of the National Institute of Allergy and Infectious Diseases (NIAID), told the online audience gathered for the 62nd annual American Society of Hematology (ASH) meeting that on balance, being vaccinated makes sense for the immunosuppressed, including the patients treated by ASH members.

“It is clear that if you are on immunosuppressant agents, history tells us that you are not going to have as robust a response as if you had an intact immune system that was not being compromised,” Fauci said, in response to a question from ASH President Stephanie Lee, MD, of the Fred Hutchinson Cancer Center, Seattle. “But some degree of immunity is better than no degree of immunity. So, for me, it would be recommended that these people do get vaccinated.”

Fauci’s appearance came days after President-elect Joe Biden announced that he’d asked Fauci to not only stay in the post he’s held for 36 years, but also serve as the chief medical adviser for COVID-19. The longtime NIAID director, whose commitment to public health facts put him at odds with President Donald Trump during 2020, sounded emboldened as he explained the challenge of convincing the public to trust the FDA’s multistep process for approving a vaccine.

“The average person doesn’t realize how many independent scientists are involved at different stages of the approval process,” Fauci said. Lee noted that the vaccines under review were built on scientific gains made over many years, but that “it’s hard when there’s so much emotion and fear and other things going into it.” “That and the mixed signals that have come from Washington,” Fauci interjected. “I mean, let’s face the facts, there have been a lot of mixed signals that have come from Washington.”

Panel on COVID-19 Research

The endorsement for patients with compromised immune systems to get the vaccine made an impression on a panel of scientists who were presenting research related to treating and tracking the effects of COVID-19.

William A. Wood, MD, MPH, of the University of North Carolina School of Medicine; Spyridoula Vasileiou, PhD, of Baylor College of Medicine in Houston; and Eleni Gavriilaki, MD, of George Papanicolaou Hospital, in Thessaloniki, Greece, had varied responses to a question about their reaction to Fauci’s recommendation. The bottom line: a vaccine is great news, but clinicians will need guidelines, and some patients will still get COVID-19 and need therapies.

“This is a question that I get all the time as a malignant hematologist in clinical practice,” said Wood, who sees patients undergoing transplant and cell therapy for leukemia, lymphoma, and multiple myeloma. “It’s a question that many of us are asking in terms of safety advocacy in immunocompromised populations. For me, the bottom line is, I’m pleased that Dr Fauci commented on this issue; I’m going to be looking to leaders like Dr Fauci and others for safe and sound, public health advice and guidance in this on this topic…I’m sure we’ll get more data to inform that recommendation.”

Vasileiou presented research during ASH involving the use of T cells in an allogeneic treatment among patients who have recovered from COVID-19 to prevent severe disease in high-risk, hospitalized patients, such as those who have received a transplant or are being treated for a hematologic malignancy. She said progress in vaccines is “an encouraging development,” but that treatments for high-risk patients are still very much part of the picture.

Even in the general population, a vaccine is not 100% effective; in those with weakened immune systems, the response will be limited. Vasileiou said this is where therapy like the T-cell treatment she is developing “can play a major role” and complement the vaccine. “We need multiple modalities in order to treat this infection and help those particular patients that are in such need,” she said.

Gavriilaki agreed. “COVID-19 will be around for quite a while,” she said, “so there’s plenty of work to be done in understanding how the disease affects thromboinflammation and hypercoagulability. Until everybody’s vaccinated—and until we have concrete guidelines for who will be vaccinated and when—we should keep moving…forward and trying to find therapies for people that might develop severe COVID-19.”

Allogeneic SARS-COV-2–Specific T Cells to Treat High-Risk Patients¹

Vasileiou outlined how she and fellow investigators screened peripheral blood mononuclear cells from patients with mild COVID-19 and then collected T cells that showed activity with prominent proteins on SARS-CoV-2, the virus that causes the disease. The team developed a manufacturing process that would activate the right cytokines to create SARS-CoV-2–specific T cells, which would attack key immune-regulating areas of the virus without hitting off -target antigens, thus creating a safe “off -the-shelf” therapy.

The team performed tests to ensure that these specialized T cells would attack the right antigens. Vasileiou reported that both CD4+ and CD8+ T cells are involved in the immune response, producing gamma interferon and tumor necrosis factor alpha (TNFα), which are involved in infection resistance. Results showed the approach was hitting the desired targets and doing so safely. A clinical trial, sponsored by Baylor College of Medicine and AlloVir, is enrolling patients for a proof-of-concept study for this treatment.

Genetic Variants Linked to COVID-19.²

Why do some patients with COVID-19 recover quickly while others become gravely ill? From the start of the pandemic, researchers have sought biomarkers that would shed light on this, and Gavriilaki’s team has uncovered one of the first clues. She explained that COVID-19 is a disease of endothelial dysfunction, causing platelets to behave as if responding to injury or bringing about cytokine release syndrome, a biological response more associated with certain cellular therapies. Severe COVID-19, her team writes, “shares characteristics with complement-mediated thrombotic microangiopathy (TMA).”

TMA is genetically driven and linked with symptoms seen in the worst cases of COVID-19, such as thrombocytopenia, anemia, damage to the heart and kidneys, and neurological effects. The team conducted a genetic analysis of 60 patients, including 40 with moderate to severe disease; 20 were critical and 11 eventually variant, ADAMTS13, in 28 patients and detected 2 other risk factor variants. Overall, 22 patients had a combination of variants associated with critical disease or hematological effects.

Now, the challenge may be to find a way to target ADAMTS13 in sick patients. “Our findings of variants in complement-regulatory genes and•ADAMTS13•suggest genetic susceptibility and define proof-of-concept for proper selection of patients that would benefit from complement inhibition,” the authors wrote.

Risks for Hematology Patients³

Wood presented data from the first 250 patients with hematological conditions and COVID-19 enrolled on the ASH Research Collaborative Data Hub, created to track characteristics of this high-risk group. (The hub had data from 700 patients as of early December.) There was a strong connection between a patient’s 12-month prognosis following a diagnosis of COVID-19 and a decision whether to accept care in an intensive care unit (ICU) if that became necessary.

Notably, although the overall mortality rate in the data set was 28%, the death rate among those who decided to forgo ICU care was 73% compared with 13% who received ICU care. People with hematological conditions are more likely to be older, and advanced age was also linked to decisions to forgo ICU care. The findings could have implications as health systems become overwhelmed by COVID-19 admissions.

Wood noted that the ASH Collaborative seeks to share data with CDC and public health authorities to protect this medically fragile population. “We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” the authors wrote.

References

1. Vasileiou S, Kuvalekar M, Workineh A, et al. Using allogeneic, off-the-Shelf, SARS-Cov-2-specific T cells to treat high risk patients with COVID-19. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; Virtual, December 5-8, 2020. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper140490.html

2. Gavriilaki E, Asteris PG, Kokoris S, et al. Thrombotic microangiopathy variants are independently associated with critical disease in COVID-19 patients. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; Virtual, December 5-8, 2020. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper139304.html

3. Wood WA, Newberg DS, Thompson JC, et al. Outcomes of patients with hematologic malignancies and COVID-19 infection: a report from the ASH Research Collaborative Data Hub. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; Virtual, December 5-8, 2020. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper141327.html

COVID-19 Vaccine Considerations for the Immunocompromised

Providers and patients alike have asked: should patients with cancer get a vaccine for coronavirus disease 2019 (COVID-19)? Fact sheets from the FDA, recommendations from the CDC, and guidance from a leading cancer research group say yes, with some caveats.

The FDA did not give full approval, but granted emergency use authorization (EUA) to 2 vaccines for COVID-19: the Pfizer-BioNTech vaccine on December 11, 2020, and the Moderna vaccine on December 18, 2020.^1,2 The Pfizer-BioNTech COVID-19 vaccine received its EUA based on data from an ongoing phase 1/2/3 trial in approximately 30,000 participants randomized to receive either the Pfizer-BioNTech vaccine or a saline placebo. The Moderna authorization was based on an ongoing phase 3 trial of about 30,000 participants randomized to receive Moderna vaccine or a saline placebo.

Both vaccines are mRNA-based vaccines that encode the prefusion spike glycoprotein severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. The only contraindication to vaccination for COVID-19 is a history of severe allergic reaction to any of the components of an mRNA COVID-19 vaccine.

The authorization of vaccines for COVID-19 has been extremely fast, relative to typical FDA approvals, leaving many with questions about the vaccines and which populations should be given special consideration before vaccination. The FDA has since provided guidelines for both vaccines, including administration to special populations.

Both vaccines are authorized for use in geriatric patients based on their respective clinical trial results.^3,4 Of special interest are the immunocompromised—including patients with cancer who are disproportionately likely to experience severe complications or die after being infected with COVID-19. Those patients were more likely to develop in-hospital infections or chest distress, or be admitted to the intensive care unit during the pandemic.⁵

Overall, patients with cancer had a higher risk of death (odds ratio [OR], 2.34; 95% CI, 1.15-4.77; P = .03), ICU admission (OR, 2.84; 95% CI, 1.59-5.08]; P <.01), and at least 1 severe complication (OR, 2.79, 95% CI; 1.74-4.41; P <.01) from COVID-19. The most common cancer types in those patients were lung, gastrointestinal, breast, thyroid, and hematological malignancies. Patients with Lung and blood cancers fared the worst, with death rates of 18.18% and 33.33%, respectively.

It stands to reason that those patients should be some of the first to receive a vaccine for COVID-19. But is the vaccine safe in those populations?

Where both vaccines are concerned, the sole FDA warning for immunocompromised patients, including those undergoing immunosuppressant therapy, is the potential for diminished response to the vaccine. The CDC notes that immunocompromised patients may receive the vaccines so long as they have no contraindications to vaccination, but that they should be counseled about the unknown safety profiles of the vaccines in immunocompromised populations.⁶

References

1. Pfizer-BioNTech COVID-19 vaccine. Food and Drug Administration. Updated December 18, 2020. Accessed December 21, 2020. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/pfizer-biontech-covid-19-vaccine

2. Moderna COVID-19 vaccine. Food and Drug Administration. Updated December 21, 2020. Accessed December 21, 2020. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/moderna-covid-19-vaccine

3. Pfizer-BioNTech COVID-19 vaccine EUA fact sheet for healthcare providers. Food and Drug Administration. Revised December 2020. Accessed December 21, 2020. https://www.fda.gov/media/144413/download

4. Moderna COVID-19 vaccine EUA fact sheet for healthcare providers. Food and Drug Administration. Revised December 2020. Accessed December 21, 2020. https://www.fda.gov/media/144637/download

5. Dai M, Lie D, Liu M, et al. Patients with cancer appear more vulnerable to SARS-COV-2: a multi-center study during the COVID-19 outbreak. Cancer Discov. 2020;10(6):783-791. doi: 10.1158/2159-8290.CD-20-0422

6. Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States. Centers for Disease Control and Prevention. Reviewed December 30, 2020. Accessed December 21, 2020. https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fcovid-19%2Finfo-by-product%2Fpfizer%2Fclinical-considerations.html#underlying-conditionsions