Flexible CAR-T Monitoring Period Could Help With Post-Treatment Barriers

In the seven years since the approval of the first chimeric antigen receptor T-cell (CAR-T) therapy, the agents have proved to be effective in the treatment of non-Hodgkin lymphoma. But the one-time-use agents come with risks, including the potentially fatal cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), so the FDA requires patients remain near their treatment center for four weeks after administration, which can be onerous for patients. But a recent study finds that side effects were rare after the first two weeks post-infusion, perhaps helping lead to less of a burden for patients.

An article in Blood Advances, a journal of the American Society of Hematology, revealed the findings of a retrospective study of 475 patients who received three CD19-directed CAR-Ts at nine different centers: Yescarta (axicabtagene ciloleucel) from Gilead Sciences Inc. subsidiary Kite Pharma, Inc., Novartis Pharmaceuticals Corp.’s Kymriah (tisagenlecleucel) and Breyanzi (lisocabtagene maraleucel) from Juno Therapeutics, Inc., a Bristol Myers Squibb company.

Bristol Myers Squibb and Novartis were two of the entities that helped fund the research.

Patients were undergoing treatment for relapsed/refractory large B-cell lymphoma between March 2018 and May 2023. Forty-five percent of the patients were treated with Yescarta, 33% with Kymriah, and 21% received Breyanzi. Most of them were being treated as third line or later.

Researchers examined the onset and duration of CRS and ICANS and reasons for non-relapse mortality (NRM), or death not related to disease progression.

In the first seven days after treatment, 57.5% of patients experienced new-onset CRS. That percentage dropped to 5.4% of patients in days eight to 14; there were no cases of new-onset CRS after the 14th day.

In the first seven days after administration, 25.3% of the population experienced new-onset ICANS, which declined to 9.3% in days eight to 14. One person developed ICANS on day 21, a 71-year-old male who had four previous lines of therapy.

Seven people died within 28 days of treatment from causes other than their disease progressing, as did another nine between days 29 and 90.

“While differences were noted in the incidence and duration of CRS and ICANS between CAR T products, new-onset CRS and ICANS are exceedingly rare after two weeks following infusion (0% and 0.7% of patients, respectively),” wrote researchers. “No new cases of CRS occurred after two weeks and a single case of new-onset ICANS occurred in the third week following infusion.… This study provides valuable insights into optimizing CAR T therapy monitoring and our findings may provide a framework to reduce physical and financial constraints for patients.”

“A flexible monitoring period beyond 14 days appears safe,” they said. “NRM beyond day 28 is largely driven by infection and highlights the need to monitor for late effects and complications.”

REMS Requires Patients Stay Within Two Hours

The CAR-Ts are available only at certain treatment centers across the country. An FDA Risk Evaluation and Mitigation Strategy (REMS) requires patients to remain within two hours of their treatment center so they can be evaluated and treated within two hours of the onset of CRS and ICANS symptoms.

According to the researchers, the REMS requirements are to ensure patient safety, but “they were implemented with a relative paucity of real-world data on the onset, incidence, and duration of CRS and ICANS following CAR T administration.”

They noted that “limited patient access” is a barrier to CAR-T treatment, and only 20% to 30% of eligible patients are able to receive it. More than half of patients must relocate during and after treatment, and although “insurance and industry may help defray some of the relocation costs,…much will fall directly to the patient.”

Researchers suggested “a framework for late toxicity monitoring and management” that uses community oncology centers, not only treatment centers, for patients stable after two weeks. “A flexible monitoring period may help to decrease financial and geographic limitations for patients and make CAR T more accessible and feasible,” they maintained.

Findings May Not Be Applicable to All CAR-Ts

That conclusion, says Avalere principal Kolton Gustafson, “certainly seems promising — the No. 1 priority is safety, and if studies can clearly demonstrate that patients can stay safe with a shorter monitoring period, it would generally be to the benefit of patients and their caregivers, as a shorter monitoring period could be less financially burdensome for patients that don’t live in the immediate vicinity of a treatment site.”

Those findings are reasonable for the three CAR-Ts studied but not necessarily for all six of the CAR-T agents currently approved, says Caron Jacobson, M.D., associate professor of medicine at Harvard Medical School. “Some of the newer CARs with rapid manufacturing do their expansion in vivo after administration, and so toxicities start late and extend late, and so the peak toxicity window may be 10 to 30 days after treatment,” she tells AIS Health, a division of MMIT. “This also appears to be true for Carvykti. So I think this is a CAR-specific recommendation.”

Madeline L. Waldron, Pharm.D., vice president of oncology clinical solutions at Precision AQ, agrees that the products have “slightly different toxicity window[s],…but the growing body of evidence to support a shortened monitoring window is promising for all CAR-Ts.”

Gustafson points out that some treatment centers may ask patients to stay closer after administration than the two hours dictated by the REMS. “For example, if a CAR-T treating site wanted a patient to stay within 15 to 20 minutes of the hospital, that could require many patients to identify a lodging option. In a prior analysis, we found that only about a quarter of potential CAR-T patients live within 30 minutes of a treatment site.”

Waldron tells AIS Health that for many years she practiced at a large referral center “that routinely cared for patients outside our one-hour commute window. Housing was often a challenge for both CAR-T and bone marrow transplant, as we required both the patient and a 24-hour caregiver to be within one hour of the facility at all times,” which could sometimes stretch to 100 days post-treatment depending on the patient.

The center often worked with medical housing resources such as Hope Lodge, Transplant House and Ronald McDonald House, which are “great because they are relatively controlled environments with patients in similar situations, strict hygiene protocols and high awareness for the needs of immunocompromised or otherwise at-risk patients.”

When those were not available, on-site hotels offered discounted rates. Organizations such as the Leukemia and Lymphoma Society offer grants that can be used to cover housing costs, she explains. When patients stay with friends or family, this “becomes a challenge because it becomes difficult for the patient to control the environment such as pets, kids with daycare germs, etc.”

“Every cancer center will have their own relationships for housing and food coverage, and each sponsor has their own reimbursement policies,” says Jacobson, who also is chairperson of the Association of Cancer Care Centers’ advisory committee for the program Early Patient Identification for CAR T-Cell Therapy and Care Continuity with Community Providers.

Medicaid May Help With Some Costs

For patients enrolled in Medicaid, their state program may help shoulder some of the costs, Gustafson says. In addition to lodging programs, treatment centers may help with transportation support, such as shuttles, and patient groups may have travel-assistance programs. “Manufacturers have also been permitted to provide some assistance — the Office of Inspector General has approved certain travel assistance programs offers by manufacturers for low-income CAR-T patients. This mix of support might not cover all the costs that patients face, but they can help reduce the burden.”

Jacobson notes that patients cannot work during that time, so treatment centers help them apply for disability. Caregivers, she says, often take time off via the Family and Medical Leave Act (FMLA).

But being granted short-term disability is based on a patient’s employment status, and many people treated with CAR-Ts often “have had many previous lines of therapy and may have had to reduce their working time or may have already used up their disability or sick time,” states Waldron.

Additional expenses include food, transportation and gas, Gustafson points out, and caregivers accompanying patients may need to take vacation time from work or not get paid. If a patient must hire a 24-hour caregiver, that’s another cost as well. Many centers will provide monitoring tools such as a blood pressure monitor or pulse oximeter, says Waldron, but if they don’t, patients may have to purchase and maintain them.

“This can easily add up to hundreds or thousands of dollars,” says Gustafson.

In addition, points out Waldron, “one thing I think often gets overlooked is all the expenses back home don’t cease to exist — so mortgage/rent payments, utilities, childcare, pet care for their primary residence continue to pile up as they are living away from home.”

Several personal, clinical and financial factors can play into a patient's decision on whether to pursue CAR-T treatment, says Gustafson, and the four-week post-treatment stay could be an obstacle for some patients.

Jacobson says that being required to remain near the treatment center for four weeks “is a barrier for sure, but getting rid of it doesn't overcome the barrier of just being able to travel to the cancer center in the first place — so it solves some of the problem but probably not the major problem.”

According to Waldron, however, the requirement “can be a huge barrier — especially for facilities in areas with high-cost housing or highly populated areas. We recently assessed about 70 cancer centers on the biggest barriers to cellular therapy, and outside of clinical resources (inpatient hospital beds and access to 24/7 call coverage), housing was the No. 1 response for barriers to care.”

This article was reprinted from AIS Health’s monthly publication Radar on Specialty Pharmacy.