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Emphasizing best practices and a healthy culture rather than focusing narrowly on compensation will help medical groups thrive.

Building a Culture of Resiliency

Seven years ago, when the FDA approved the first-ever chimeric antigen receptor (CAR)-T cell therapy, Novartis’ then-CEO Joseph Jimenez, MBA, said Kymriah (tisagenlecleucel) represented a “paradigm-changing” therapy.

In the years since then, the FDA has approved five more CAR-T therapies, and it is hard to disagree with Jiminez’s assessment. Yet the mainstreaming of CAR-T therapies has changed much more than solely which therapy a physician prescribes. It has also created a unique patient journey, set off a wave of new scientific questions and heightened concerns about the rising cost of care.

Umar Farooq, M.D., a hematologist-oncologist at the University of Iowa (UI) Health Care, has been treating patients with CAR-T cells since 2015, when he began collaborating on a CAR-T clinical trial. His health system now treats between 70 and 80 patients each year with CAR-T cell therapies. “The number of CAR-T cells we’ve been doing every year just continues to increase,” he says.

That’s great news in Farooq’s view because, he says, the therapy has led to dramatic improvements in many of his patients. “With what I’ve seen in the past 10 years, and how drastically it has improved patient outcomes, I’m … very optimistic for the next 10 years.”

As of September 2024, six CAR-T cell therapies covering 16 indications have been approved in the United States, according to the Leukemia & Lymphoma Society. All the therapies have been approved for the treatment of blood cancers, including non-Hodgkin lymphoma, acute lymphoblastic leukemia, multiple myeloma and, as of March 2024, chronic lymphocytic leukemia and small lymphocytic leukemia.

Bethany Lilly, J.D., executive director of public policy at the Leukemia & Lymphoma Society, says the expanding number of indications approved for CAR-T therapy has also increased interest.

“Awareness is growing, so more patients call knowing that they are eligible for the treatment, but [they] often still have questions,” she says.

Farooq says he recommends patients go to an academic medical center once their disease has progressed past one line of treatment.

“If we see you too late and you’re already too frail and the disease has affected your organ function, it would be harder to do,” he says.

Referral speed is important because CAR-T therapy is not a fast process. Farooq says by the time he typically sees a patient, the patient already has insurance authorization for the initial consultation. He and his colleagues will then run tests to ensure the patient’s heart, lungs and other major organs are sufficiently healthy for the therapy. If so, Farooq and colleagues will submit insurance paperwork to get approval for the procedure. Next, they reach out to the cell therapy lab to ensure they are ready to collect the patient’s white blood cells and to the drug manufacturer’s lab to ensure they are ready to receive the cells. It takes a minimum of two weeks from the first patient visit to the time the patient gets the go-ahead, he says.

Then comes the manufacturing itself, which generally takes at least three to four weeks. “Once we know for sure that the cells have been manufactured, meet the quality standards and have arrived at our hospital, it’s only then that we admit the patient to start the low-dose chemotherapy to suppress the immune system,” he says.

In the best-case scenarios, the entire process can take about six weeks in an optimal case, he says, and then the hospitalization is not over. Patients require daily monitoring for adverse events for two to three weeks, usually as an inpatient.

The frequent checkups are necessary because of the significant risk of toxicity from CAR-T therapy, including cytokine release syndrome (CRS) and neurotoxicity.

“And if the patient is … much farther away from the treating center, it would be a very complicated case for a local health facility to deal with,” he says.

Farooq says both CRS and confusion are common, though most of the time the adverse events are not severe.

He sees patients from as far away as Des Moines, which is a little less than two hours from Iowa City, where UI Health Care is based. He says he typically only sees out-of-state patients if it is for a clinical trial.

Still, all that time in the hospital means patients who live far away from their treatment center must plan for things like travel expenses or hotel rooms to undergo the necessary treatment and monitoring. That can create a barrier for many patients, Lilly says.

“It can be thousands of dollars, and not every patient can afford it,” she says. “This is especially the case for low-income patients, who also disproportionately live in rural areas and/or are patients of color.”

Of course, those travel costs are typically just the beginning of the extensive fees associated with CAR-T therapy. Most CAR-T treatments run between $300,000 and $400,000, and sometimes upwards of a half-million dollars, Farooq says. That is why one of the first steps his health system takes is to communicate with a patient’s insurer to verify the procedure will be fully paid for and that the patient will not face financial ruin.

“Considering the treatment is so expensive, if we find out that insurance will cover 80% and the patient is responsible for 20%, it’s usually not practical to move forward,” he says.

Farooq points out one particularly thorny problem he faces is when he treats Medicare patients. When patients have commercial insurance or participate in Iowa’s Medicaid program, he is able to get prior authorization that ensures the cost of the procedure will be covered. That’s not the case for patients on Medicare, he says. The lack of a prior authorization requirement saves time at the beginning, but there’s a big — and potentially costly — caveat. “If for any reason we diverged or did not precisely follow the FDA-approved criteria, Medicare can refuse to cover it later,” he says. What makes matters worse is that that refusal might not come until several months or a year following
the treatment.

“It has happened to me,” Farooq recalls, “and I had to write a few letters to highlight that we exactly followed the approved criteria.”

One place patients can turn to when they encounter barriers is a patient advocacy group like the Leukemia & Lymphoma Society. When patients call for help in getting the therapy covered, Lilly says a typical barrier is the novelty of CAR-T.

“Usually, there is a debate between an insurer and a provider about what the reimbursement for the treatment will be,” she says. “Given the rarity of this treatment, it can often be an issue of first impression for insurers, meaning that they haven’t worked out a specific reimbursement rate.” Even if the therapy is covered, caregivers often have to take unpaid leave or partial pay, depending on their state’s paid leave laws, she notes.

Merith Basey, M.Sc., the executive director of Patients for Affordable Drugs, a group that advocates for lower drug prices, says the high-cost CAR-T therapy — and the ways patients and providers have to scramble to pay for it — shows the need for reframing the debate and discussion swirling around
drug costs.

“The conversation is currently about how we [are] going to pay for them,” she says, “and not how we [are] going to lower the price.”

Even in an American health system that is used to paying multiples of the amount other developed countries pay for the same therapies, Basey says CAR-T prices are an urgent problem. She said there are hundreds of CAR-T products in drug company pipelines and other gene therapies as well. If more than a few are approved, they would dramatically impact the cost of care.

“This is something that needs to be tackled because we know that it would essentially bankrupt health care
systems,” she says.

Farooq says one way to cut costs is by lowering the cost of manufacturing. He notes that UI is collaborating with another academic medical center on a trial to investigate a fast-turnaround manufacturing system. Manufacturing doses of CAR-T therapy in 24 hours could bring the price down to as low as $50,000, he says. There are also efforts to create so-called “off-the-shelf” CAR-T cells, which involve making potentially thousands of CAR-T doses from a single donor. They’re still investigational, he says, but they could significantly change the cost structure.

Basey says the issue is not just how CAR-T therapies are manufactured but where. One of the major reasons for the high price tag of CAR-T is the limited number of manufacturing facilities in the U.S., she says. Tight control of manufacturing by pharmaceutical companies creates a situation where patients must wait for their therapies to travel to sometimes distant manufacturing facilities and back. “Because of that, there’s a bottleneck, and it helps to increase the price,” Basey says.

She points out that countries like Spain and Brazil have developed decentralized manufacturing models for CAR-T, lowering prices by approximately one-tenth.
“They don’t have to be priced so excessively … that they’re not able to treat the people who need them,” she says. She notes that much of the research that goes into developing new medical therapies is funded by taxpayers in the form of grants from the National Institutes of Health, Department of Defense and other agencies. “The government and the taxpayers should be entitled to have a voice in the way that publicly funded medicines are priced so that people can afford them,” she says.

Like Basey, Farooq expects CAR-T to become a more common treatment option, perhaps eventually becoming a first-line treatment for some conditions. He is currently involved with a major multi-institutional study designed to gauge the comparative benefits of first-line CAR-T therapy in certain patients with diseases that are difficult to treat. Current first-line therapies for multiple myeloma and lymphoma have strong safety and efficacy track records. “CAR-T cells will need to prove themselves better,” he says.

Another frontier is CAR-T for diseases other than cancer. Investigators have been evaluating CAR-T as a treatment for autoimmune disease, kidney disease and sickle cell disease.

“If you’re deficient in certain genes or have genetic deficiency disorders, that’s another place for cell therapy,” Farooq says. “You can introduce these cells by introducing the gene in cells."

Yet, introducing genes can also create problems. Last year, amid all the optimism about CAR-T, came one stark note of caution. In November 2023, the FDA published a notice saying it was investigating the risk of T-cell malignancies, including CAR-positive lymphoma, in patients who received BCMA- or CD19-directed CAR-T cells. All six approved CAR-T therapies are directed at either BCMA or CD19.

As of December of last year, the FDA said it had become aware of 22 cases of secondary malignancies following CAR-T therapy, the majority of which occurred during the first two years following treatment.

Stella Bouziana, M.D., Ph.D., of King’s College Hospital NHS Foundation Trust in London, notes that the FDA requires that patients receiving therapies involving genetic manipulation, including CAR-T therapy, be monitored for 15 years “due to a theoretical risk of random insertional mutagenesis caused by the viral vectors, potentially leading to secondary cancers.” After the FDA announcement of secondary T cell malignancies, the follow-up period was changed to a life-long requirement, highlighting the need of prolonged surveillance.

Until last year’s announcement, the risk had remained theoretical. The fact that these secondary malignancies were observed sparked surprise, Bouziana says, especially because in some cases the CAR transgene was identified within the secondary T-cell malignancy.

“This was the first time such cases came to light, and although only a handful of cases have been reported so far, a lot of concern has been raised among clinicians and scientists involved in the CAR-T field regarding the safety of the otherwise very promising CAR-T cell therapies,” she says.

Still, Bouziana says there is no reason to slam the brakes on CAR-T. Rather, she says it’s time to do additional research to better understand the risk, if any.

One idea to consider is whether mRNA technologies can be used in place of viral vectors or gene-editing techniques to introduce the therapy. Doing so, she explains, might avoid random transgene integration into host cells and resulting genotoxicities.

Another question pertains to the optimal dose of infused CAR-T cells. Currently, Bouziana says, CAR-T cells are administered empirically without clear criteria on the optimal cell number and composition. “In classical drug pharmacokinetics and pharmacodynamics, this would seem unimaginable,” she says. The effect of a lack of clear dosing criteria is an unpredictable cell composition and effect
in vivo, she says.

Although patient-advocacy groups such as the Leukemia & Lymphoma Society would like to see further expansion of CAR-T into community hospitals, Bouziana advises caution while research into the secondary malignancy risk is ongoing. “Until data is mature and risks fully elucidated, CAR-T cells should continue to be administered as per current recommendations by expert organizations,” she says.

The good news, she notes, is that clinical and translational research appear to be accelerating in the wake of the FDA’s announcement. Farooq says he is optimistic about the technology and its potential to continue positively impacting patients.

“I wouldn’t say that this is the only technology that would make a difference for cancer patients, but it would be a very important part of those tools,” he says.

But there are some concerns: high costs, extended hospitalizations 
and secondary cancers.

The Mainstreaming of CAR-T

Syndax Pharmaceuticals recently announced the FDA approval of Revuforj (revumenib) for the treatment of relapsed or refractory acute leukemia in adult and pediatric patients one year and older. It is indicated for patients with a lysine methyltransferase 2A gene (KMT2A) translocation, according to a 

Onco360 was chosen as a specialty pharmacy partner by Syndax, a seperate 

“Today marks another major milestone in the leukemia community,” Michael Metzger, CEO and director of Syndax said during the investor call. “With the FDA approval in hand, we look forward to launching Revuforj in the United States this month.”

Revuforj is the first and only menin inhibitor approved by the FDA. It works by preventing rearrangements in KMT2A gene, which can lead to the development of leukemia cells. An estimated 95% ofKMT2Ar acute leukemia patients have KMT2A translocation. This abnormality is seen in about 10% of all leukemias.

Only about 5% of patients with this mutation achieve complete remission with current third-line treatment with a median overall survival rate of less than three months, according to the news release. More than half of patients will relapse after first-line treatment.

The approval of Revuforj is based on positive data from the AUGMENT-101 clinical trial in which 21% of patients reached complete remission with partial hematological recovery, meaning that although no was cancer detected, blood cell counts have not fully recovered. This took about six months.

Safety evaluation of Revuforj was based on an analysis of 135 patients. Serious adverse reactions were seen in 73% of patients and 3% of patients died. Two patients died from differentiation syndrome, one hemorrhaged and another “died suddenly,” the news release reports. Differentiation syndrome is a side effect of certain blood cancer drugs that can present as trouble breathing, fever and weight gain. It is fatal within the first few weeks of treatment. 

The most common serious adverse reactions were infection (24%), febrile neutropenia (19%) and bacterial infection (17%). The most common adverse reactions were hemorrhage (53%), nausea (51%) and increased phosphate (50%). As a result, dose interruptions occurred in 42% of patients.

Revuforj will be available as 110 mg and 160 mg tablets to be taken twice daily, depending on weight. It’s expected to be available via specialty pharmacies later this month. There will also be a 25 mg tablet option for patients who weigh less than 40 kg, expected late in the first quarter or early second quarter of 2025. Until then, an oral solution will be available through an expanded access program. The wholesale acquisition price is $39,500 for a 30-day supply of the 110 or 160 mg tablets, according to the investor call.  

Syndax will eventually offer financial assistance via SyndAccess, a newly established support and resource program for patients. 

The FDA previously granted Revuforj Breakthrough Therapy, Fast Track and Priority Review designations. A New Drug Application was granted through FDA's Real Time Oncology Review program.

Relapsed or refractory acute leukemia with a KMT2A translocation currently has an overall survival rate of less than one year when treated with frontline therapies. 

Formulary Watch

Clinical

FDA Approves First-in-Class Drug for Rare Leukemia 

The American Lung Association (ALA) is hoping to lower rates of undiagnosed pulmonary arterial hypertension (PAH) through a new 

The new campaign is a response to the persistent problem of delayed diagnosis among people with PAH, but it also reflects growing attention to the disease by drug developers and scientific investigators.

Left untreated, PAH can be deadly. However, therapy can significantly improve symptoms and extend patient survival. The most recent therapeutic advancement was the FDA’s approval of Winrevair (sotatercept) earlier this year. Merck & Co.’s drug is an activin signaling inhibitor therapy, the first of its kind.

The development of Winrevair was part of a wave of new research clarifying the pathogenesis of the disease and identifying potential new drug targets. Yet, that wave of scientific interest in the disease has not necessarily translated into greater public awareness of the disease.

Harold Wimmer, M.S., the ALA’s president and CEO, said the goal of the campaign is to improve the lives of people with the disease by helping them get earlier access to therapy.

“Through this campaign, we hope to improve awareness and understanding of PAH, promote early diagnosis, and provide valuable resources for patients and caregivers,” he said, in a press release.

The campaign is being supported by Merck, which reported sales of $149 million for Winrevair as of the third quarter of 2024. The company noted that Winrevair was also recently approved in Europe, and has already launched in Germany. Merck said it expects to obtain reimbursement for the drug in most of the other major European markets in the second half of next year.

Patients with pulmonary arterial hypertension often experienced delays in obtaining a correct diagnosis.

Fred Horton, M.H.A.

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