Mary Caffrey

Data gathered by Cardinal Health Specialty Solutions revealed roadblocks community oncology practices encounter when trying to navigate payer approvals for CAR T-cell therapy.

Delays Mean Some Miss Window for CAR T-Cell Therapy, Cardinal Health Data Show

A recent paper in Nature Cancer outlines a novel strategy for overcoming barriers to CAR T-cell therapy in glioblastoma by pretreating the vascular microenvironment.

Moving a Step Closer to Using CAR T-Cell Therapy in Solid Tumors

At the recent meeting of the American Society of Hematology, results from several studies involved the use of chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma. 

Deepu Madduri, MD, Discusses CARTITUDE-1 Data for Multiple Myeloma—and Clinical Trials During COVID-19

Karl Kilgore, PhD, a senior research scientist at Avalere Health, discusses Medicare data that offer insights on the overall costs of CAR T-cell therapy relative to transplants.

Real-World Data Offer Good News for CAR T-Cell Therapy

City of Hope's Dr. Tanya Siddiqi offers an update on a new chimeric antigen receptor (CAR) T-cell therapy awaiting approval from the FDA.

Tanya Siddiqi, MD, Discusses the Promise of Reduced Toxicity With Liso-Cel

Gaining Knowledge of CAR T-Cell Therapy, and CRS, Over Time

The vice president for Clinical Services at OneOncology describes challenges and opportunities for chimeric antigen receptor (CAR) T-cell therapy in the community practice setting.

OneOncology’s Duncan Allen, MHA, Discusses Bringing CAR T-cell Therapy to the Community Setting

From the Academic Center to Community Practice 

Articles

CAR-T Spotlight

President Joe Biden on Thursday said US deaths from the coronavirus disease 2019 (COVID-19) pandemic will reach 500,000 by February, and that it will take months to “turn things around” after nearly a year without nationwide mask mandates and mixed messages from the White House under the former Trump administration.

Biden outlined a new national strategy a day after taking office that included executive actions and a proposed $1.9 trillion request from Congress, which would increase jobless benefits and offer direct cash payments to households. Other elements of the plan are designed to boost the availability to tests and vaccines, get children back into schools, make travel safer, and shore up state governments and small businesses.

Thursday’s actions came on the second day of Biden’s presidency as he sought to move quickly to defeat a pandemic that has killed more 404,000 Americans and infected more than 24 million in the year since it was detected.

, which will allow manufacturing of tests to surge with demand; promote data collection for the government’s response to COVID-19 and research for new treatments, and direct the federal Occupational Safety and Health Administration to enforce guidelines to protect workers.

Among the steps the Biden administration took Thursday:

 that requires people to wear masks in airports and on many planes, trains, and buses. Attendants have said passengers who refuse to follow the airlines’ mask rules have verbally abused workers and fellow passengers, and the airlines need stronger enforcement tools to promote safety;

 to accelerate the development of novel therapies, support research, and create equity in clinical trials, including rural areas;

 to use the National Guard to respond to the COVID-19 pandemic, on a “fully reimbursable basis.” The Federal Emergency Management Agency (FEMA) would fund the National Guard response to COVID-19 until September 30, 2021, including the reopening of schools, child-care centers, and health care facilities, homeless shelters, and transit centers.

Coupled with Biden’s order for masks on federal property, the requirement for masks during travel come close to create a national mask mandate if combined with state and local requirements. The order for masks during flights comes amid news of new variants of the virus reaching the United States.

“In addition to wearing masks, everyone flying to the United States from another country will need to test before they depart and quarantine when they arrive in America,” Biden said.

Despite calls from unions, consumer groups, and airlines themselves for such a mandate, the former Trump administration refused to create such a requirement.

The nation’s long-serving infectious disease expert, Anthony Fauci, MD, started the day by leading the US delegation to the 

, saying he was delivering letters “retracting” the nation’s withdrawal from WHO. Fauci, who is now the nation’s chief medical adviser, said the United States would restore WHO staff and meet its financial obligations.

Later, he appeared in the White House briefing room, and said it was “liberating” to be able to speak his mind on the evidence on COVID-19. “The idea that you can get up here and you can talk about what you know, what evidence, what the science is, and know that’s it – let the science speak,” he said. “It is somewhat of a liberating feeling.”

Fauci was often in a difficult spot when Trump gave incorrect answers on COVID-19, refused to wear a mask, and appeared not to take the pandemic seriously. But he contradicted the idea that there was no vaccine distribution plan when the new administration arrived; Trump’s team left much up to the states but did not offer any additional funding.

"We're coming in with fresh ideas, but also some ideas that were not bad ideas with the previous administration. You can't say it was absolutely not usable at all," Fauci said. "It's taking what's going on, but amplifying it in a big way.”

President Joe Biden issued executive orders to speed up testing and vaccine distribution, and to require masks on planes, trains, and buses.

Biden Says COVID-19 Death Toll Will Soon Top 500,000

In APOLLO, Subcutaneous Daratumumab With Pomalidomide Cuts Progression, Death Risk By 37% in Relapsed MM

A version of daratumumab injected under the skin, when added to the oral medications pomalidomide and dexamethasone (D-Pd), cut the risk of disease progression or death by 37% compared with Pd alone in patients who have had at least 1 relapse with multiple myeloma, according to study results presented during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

Findings from the phase 3 APOLLO trial, which examined the formulation of daratumumab and hyaluronidase-fihj, were presented during ASH, which took place December 5-8, 2020, in a virtual format due to the coronavirus disease 2019 (COVID-19) pandemic.

Daratumumab is an immunotherapy that targets the CD38 protein, which is heavily expressed in multiple myeloma cells. The therapy binds to the protein and blocks tumor cell growth, causing cancerous cells to die. The subcutaneous formulation of daratumumab is approved in various combinations to treat transplant-eligible and refractory multiple myeloma; however, it is not yet approved in combination with pomalidomide (Pomalyst, Celgene), which is anti-angiogenic and acts as antimmunomodulator.

Janssen, which sells daratumumab as Darzalex, filed submissions with FDA and European regulators on November 12, 2020, based on the new results.

The study’s lead investigator, Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Greece, touted the subcutaneous formulation of daratumumab during a press briefing on APOLLO. He said the average time to inject the drug in APOLLO was 5 minutes; Janssen reports that administration can take between 3 and 5 minutes.

Dimopoulos highlighted that using the subcutaneous version can spare a patient 2 hours or more at a hospital or infusion center. “This is an improvement in the quality of life of the patient,” he said, noting this is especially true during the early stretch of the regimen when daratumumab is given weekly.

“Also, it saves valuable time in the chemotherapy or the outpatient treatment unit,” Dimopoulos said.

APOLLO randomized 304 patients to receive either D-Pd or Pd alone; the average age of patients in the D-Pd arm was 67 years and the average age in the Pd arm was 68 years. Patients had multiple myeloma for just over 4 years, and a slightly higher share of patients in the Pd arm was considered high risk. Trial participants had received at least 1 prior line of therapy, including lenalidomide and a proteasome inhibitor, and had responded to the treatment but then progressed. Those with just 1 prior line of therapy were refractory to lenalidomide.

The study achieved its primary end point, significantly improving progression-free survival (PFS), with a hazard ratio (HR) of 0.63 (95% CI, 0.47-0.85;

Patients in the D-Pd arm had a median PFS of 12.4 months, compared with 6.9 months for those in the Pd arm.

Other results showed that patients taking D-Pd had a better rate of overall response (69% vs 46%), very good partial response or better (51% vs 20%) and complete response (25% vs 4%).

A higher share of patients in the D-Pd arm achieved minimal residual disease negativity (9% vs 2%).

Among patients taking the subcutaneous version of daratumumab, 6% had infusion-related reactions, which were all grade 1 or 2, and 2% had local injection site reactions, all grade 1. Dimopoulos said these rates are far less than would be seen with infusion-related reactions, which can include upper respiratory tract reactions, including bronchospasm. An occasional patient develops hypotension; to avoid this, patients are typically premedicated during the first infusion, causing the initial session to last up to 8 hours. This creates a significant burden for patients and caregivers, he said.

In fact, he said, there are very few circumstances when intravenous administration of daratumumab would still be preferred.

Rates of patients who stopped treatment due to treatment-related adverse events were similar: 2% for D-Pd vs 3% for Pd.

Dimopoulous noted that the phase 3 APOLLO results build on what was already known about daratumumab and pomalidomide as single agents in separate trials. He highlighted that the combination of both therapies has now been shown to be even more effective within the context of a randomized trial. “This is a particularly useful regimen for an increasing number of patients with myeloma who progress on lenalidomide maintenance or continuous [therapy],” he said.

APOLLO was one of several trials at ASH that featured innovative treatments for multiple myeloma, an incurable blood cancer that affects plasma cells, causing tumors to grow in the bone marrow. Approximately 32,000 people receive a diagnosis of multiple myeloma in the United States this year, and 13,000 people will die from the disease.

 Patients with multiple myeloma sometimes have no symptoms and the first sign of disease is often a bone fracture; symptoms can include fatigue, pain, low red blood cell counts, or renal decline.

1. Dimopoulos MA, Terpos E, Boccadoro M, et al. Apollo: Phase 3 randomized study of subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper135874.html

2. Seeking approval of Darzalex Faspro (daratumumab and hyaluronidase-fihj)/Darzalex (daratumumab) subcutaneous (SC) formulation in combination with pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma. News release. PR Newswire. November 12, 2020. Accessed December 5, 2020. https://www.prnewswire.com/news-releases/janssen-submits-applications-in-us-and-eu-seeking-approvalof-darzalex-faspro-daratumumab-and-hyaluronidase-fihjdarzalex-daratumumabsubcutaneous-sc-formulation-in-combination-with-pomalidomide-and-dexamethasonefor-pat-301171825.html

3. Myeloma. American Cancer Society: Cancer facts and statistics. Accessed November 2020. 

https://cancerstatisticscenter.cancer.org/#!/cancer-site/Myeloma

Zanubrutinib Studies Highlight Efficacy, Tolerability in MZL, CLL, SLL

Zanubrutinib, the second-generation Bruton tyrosine kinase (BTK) inhibitor sold as Brukinsa (BeiGene), fared well in a series of studies presented during the 62nd American Society of Hematology Annual Meeting and Exposition.

Overall, the drug’s selling point—fewer off-target effects—seemed to hold up, as patients were able to stay on the drug for long periods or, as seen in one study, take it successfully after they could not tolerate other BTK inhibitors. However, serious adverse events (AEs) do occur, and a small number of patients stopped taking the drug across the studies due to adverse events.

Results presented on December 6, 2020, demonstrated effectiveness in patients with marginal zone lymphoma (MZL) and treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) with 17p deletion. Additionally, results from a phase 2 study presented December 7, 2020, showed that zanubrutinib was able to maintain or improve clinical outcomes in patients with B-cell malignancies who had stopped taking ibrutinib or acalabrutinib.

Zanubrutinib is FDA-approved in mantle cell lymphoma (MCL) for patients who have received at least 1 prior therapy. Besides MZL and CLL/SLL, it is being studied in other blood cancers including follicular lymphoma, B-cell malignancies, and Waldenström macroglobulinemia (WM).

The phase 2 results presented December 7, 2020, were an outgrowth of a phase 2 study in WM, according to Ian Flinn, MD, PhD, of Tennessee Oncology, the senior author on the new study. In the original study, patients were randomized to take either zanubrutinib or ibrutinib.

“We found that there was much less of the adverse events, such as atrial fibrillation, seen with zanubrutinib than with ibrutinib, and this held true for many of the other adverse events associated with ibrutinib,” Flinn said. “We thought that trying this drug in patients who could no longer take ibrutinib, that maybe we could keep people on therapy with zanubrutinib that could not be on ibrutinib. And that was really the case here,” he continued.

Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute, presented follow-up results from the nonrandomized “Arm C” of the randomized, open-label, phase 3 SEQUOIA trial, which examined zanubrutinib monotherapy in treatment-naïve patients with CLL or SLL with del(17p). As seen in the ASPEN trial for WM, she said, zanubrutinib is “designed to maximize BTK occupancy and minimize off-target inhibition of TEC and EGFR kinases.”

Despite the more favorable safety profile of zanubrutinib, 5 patients in the study stopped treatment due to AEs and 2 patients died, including 1 who developed pneumonia related to therapy.

Results reported at ASH 2019 were based on a follow-up of 10 months, but new results included 21.9 months of follow-up; the complete response (CR) rate increased from 1.9% to 6.4% during that time. Progression-free survival at 18 months (PFS) was 90.6% (95% CI, 83.3-94.9), and the overall response rate (ORR) was 94.5%. The drug’s tolerability remained consistent with what has been reported in previous studies. Overall survival at 18 months was 95.4% (95% CI, 89.3-98.1). PFS at 18 months among patients with unfavorable characteristics was 88% for those with unmutated IGHV and 94% for those with complex karyotype status.

Within the ORR, 6 patients (5.5%) had CRs, 1 (0.9%) had a CR with incomplete bone marrow recovery, 1 (0.9%) had nodular partial response (PR), 94 (86.2%) had PRs, and 1 (0.9%) had PR with lymphocytosis. Additionally, 93.1% maintained response at 12 months, and 87.7% maintained response at 18 months.

The most common AEs were confusion (20.2%), upper respiratory tract infection (19.3%), diarrhea (17.4%), and nausea (14.7%); less common were back pain, constipation, rash, cough, neutropenia, arthralgia, and pneumonia. More than half (52.3%) of patients had an AE of grade 3 or higher, with the most common being neutropenia, pneumonia, falls, and hypertension. More than a third (38.5%) of patients had a serious AE.

Initial results from the single-arm, open-label study showed that zanubrutinib was generally well-tolerated among older, high-risk patients with MZL who had received at least 1 prior line of anti-CD20 treatment. The trial included 68 patients, with an average age of 70 years and a median of 2 prior treatments; more than 30% had refractory disease and nearly 40% had nodal MZL.

Data cut off occurred on August 14, 2020. With a median follow-up time of 10.7 months, 66 patients were eligible for zanubrutinib efficacy evaluation. Results show:

The ORR was 74.2% (95% CI, 62.0-84.2), with 16 complete responses (24.2%) and 33 partial responses (50.0%).

The ORR was strong across high-risk subgroups, including patients who were at least 75 years of age (ORR 88.9%); those with refractory disease (ORR 71.0%); and those with nodal MZL (ORR 84.0%).

Median follow-up time for progression-free survival (PFS) was 9.13 months; PFS rates at 6 and 9 months were 80.0% and 67.0%, respectively.

Nearly all patients (95.6%) had a treatment-related adverse event, with 38.2% having an event of grade 3 or higher. The most common events were neutropenia, diarrhea, pyrexia, thrombocytopenia, anemia, and pneumonia. Two patients stopped taking the drug due to treatment-related AEs, including 1 patient with a pre-existing cardiovascular condition who suffered a fatal heart attack.

Mazyar Shadman, MD, PhD, of the Fred Hutchison Cancer Center and the University of Washington in Seattle, presented phase 2 results of zanubrutinib therapy in patients who had previously taken ibrutinib or and 32 patients reached an assessment milestone in time for the data cutoff: 20 patients with CLL, 5 with SLL, 2 with MCL, and 5 with WM. All but 2 patients had taken ibrutinib previously, either as monotherapy or as part of a combination regimen. The median time on a prior BTK inhibitor ranged from 6.41 months for patients with MCL to 12.91 months for patients with WM, though some were on treatment for less than 2 months.

Of the 66 ibrutinib intolerant events that occurred with the first BTK inhibitor, 58 did not recur with zanubrutinib.

Of the 25 grade 3 intolerant events that occurred on prior therapy, only 2 recurred on zanubrutinib.

None of the four grade 4 events recurred.

Eight intolerant events occurred with zanubrutinib; 7 were at a lower severity than with prior therapy, while 1 was of the same severity. These were all bleeding events.

No patients have developed disease progression. Clinical assessments show that 44% of patients are doing as well as they were on prior therapy, while 50% have experienced improved responses. After a median follow-up of 3.5 months, 31 patients remain in the study. The patient no longer in the study did not drop out due to an AE.

1. Brown JR, Robak T, Ghia P, et al. Efficacy and safety of zanubrutinib in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): follow-up results from arm C of theSEQUOIA (BGB-3111-304) trial. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134280.html

2. Opat S, Tedeschi A, Linton K, et al. Efficacy and safety of zanubrutinib in patients with relapsed/refractory marginal zone lymphoma: initial results of the MAGNOLIA (BGB-3111-214) trial. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134611.html

3. Shadman M, Sharman JP, Levy MY, et al. Phase 2 study of zanubrutinib in patients with relapsed/refractory B-cell malignancies intolerant to ibrutinib/acalabrutinib. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134621.html

NCCN Recommends Zanubrutinib as First-Line, Second-Line Therapy in CLL, SLL

The National Comprehensive Cancer Network (NCCN) has recommended zanubrutinib, a tyrosine kinase inhibitor sold as Brukinsa (BeiGene), for treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

While zanubrutinib is approved by the FDA for the treatment of adult patients with mantle cell lymphoma (MCL), recent NCCN guidelines updated on December 3 now recommend the indication as both a first-line and second-line treatment in CLL/SLL.

First-line therapy of zanubrutinib as a single agent is recommended for the treatment of CLL/SLL with 17p deletion (del 17p) and TP53 mutations in patients with contraindication to other Bruton tyrosine kinase (BTK) inhibitors who have indications for treatment.

For second-line treatment and subsequent therapy, the NCCN recommends the indication as a single agent for the treatment of CLL/SLL with or without del(17p) and TP53 mutations in patients with intolerance or contraindication to other BTK inhibitors who have indications for retreatment.

As payers view the NCCN guidelines as a gold standard for making reimbursement decisions, the question lingers whether to adhere to the NCCN guidelines while the FDA has not approved zanubrutinib for the treatment of CLL/SLL. The distinction of the del(17p) mutation as a high- risk genetic characteristic associated with overall survival may warrant the push for treatment of CLL/SLL as those with CLL have a shorter life expectancy than age- and sex-matched populations.

Findings from the arm C, phase 3 SEQUOIA Trial presented at the 62nd American Society of Hematology Annual Meeting and Exposition indicate that zanubrutinib was well tolerated and effective among patients with CLL/SLL with 17p deletion. Including more than 21.9 months of follow-up, treatment-naïve patients with CLL or SLL with del(17p) administered zanubrutinib as a monotherapy exhibited an increased complete response rate from baseline (1.9% to 6.4%).

Additionally, progression-free survival at 18 months was 90.6% (95% CI, 83.3%-94.9%), and the overall response rate was 94.5%, with the drug’s tolerability remaining consistent with what has been reported in previous studies.

So, how do payers handle a situation when the NCCN updates treatment guidelines ahead of an FDA approval? Erin Lopata PharmD, MPH, vice president, Market Access Experience Team, PRECISIONvalue said in an email that both payers and providers “are challenged with keeping up-to-date with advances and updates in this therapeutic area.”

Most payers, she said, consider the NCCN Guidelines “as a recognized compendium to support coverage decisions for oncology products.” While many will limit coverage to FDA-approved indications, a Category 1 or 2a recommendation for a non-approved indication will generally bring coverage, she wrote.

“The new recommendation may trigger a payer policy change for the drug, where the NCCN-supported indication is added to the pharmacy or medical policy clinical criteria. Other payers may have an overarching policy that allows for authorization based on NCCN guideline recommendations,” she wrote. “Additionally, if the payer utilizes a pathway to manage oncology agents, the pathway may also need to be updated to direct approvals of the NCCN-supported indication.”

Studies have produced conflicting findings. A 2018 analysis published in

 of 113 NCCN recommendations found that the NCCN frequently recommends beyond FDA-approved indications and that the evidence for these recommendations was weak.

 But a later study in the Annals of Oncology,

 examining the levels of evidence used in recommendations within NCCN guidelines formed prior to FDA approvals, found the strength of the evidence supporting these recommendations was “robust, with a significant subset of these drugs later becoming FDA approved or supported by randomized controlled trials.”

1. Wagner J, Marquart J, Julia R, et al. Frequency and level of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond approvals of the US Food and Drug Administration: retrospective observational study. 

2. Kurzrock R, Gurski LA, Carlson RW, et al. Levels of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond Food and Drug Administration approvals. 2019; 

. 30:1647–1652. doi:10.1093/annonc/mdz232.

The 62nd American Society of Hematology (ASH) Annual Meeting and Exposition featured leading experts in hematology and covered some of the most cutting-edge research in the field. 

ASH 2020: Clinical Updates

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.”

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 Patients

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.

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, 

, 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 

 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.

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.

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.

 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.

 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.

Overall, patients with cancer had a higher risk of death (odds ratio [OR], 2.34; 95% CI, 1.15-4.77; 

 = .03), ICU admission (OR, 2.84; 95% CI, 1.59-5.08]; 

 <.01), and at least 1 severe complication (OR, 2.79, 95% CI; 1.74-4.41; 

 <.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.

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. 

. 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

Anthony Fauci gave his insight on the coronavirus disease 2019 (COVID-19) for immunocompromised populations at ASH 2020, and leading organizations released fact sheets and recommendations. 

Mary Caffrey

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