Shortening FDA-Mandated CAR T-Cell Therapy Monitoring Periods Could Improve Access to Treatment in Patients With DLBCL

Two hallmark toxicities of chimeric antigen receptor (CAR) T-cell therapy may be rare after 2 weeks following infusion in patients with diffuse large B-cell lymphoma (DLBCL), supporting a shorter, more flexible toxicity monitoring period.

Background

Currently, three CAR T-cell therapies are approved to treat patients with DLBCL: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. However, patients receiving these therapies are often at high risk of developing either cytokine-release syndrome—characterized by fever as well as low blood pressure and/or oxygen levels in more severe cases—or immune effector cell–associated neurotoxicity syndrome, which can cause temporary effects such as altered mental status and confusion or loss of consciousness and/or seizures in more severe cases. Both toxicities can also result in rapid decline and death.

To monitor and manage these toxicities, the U.S. Food and Drug Administration (FDA) established a Risk Evaluation and Mitigation Strategy (REMS) mandating that recipients of CAR T-cell therapy remain within a 2-hour distance of their authorized treatment center for 4 weeks following therapy and refrain from driving for 8 weeks posttreatment. A majority of authorized treatment centers implement even stricter criteria than those directed by the REMS program, requiring patients to stay within a 30- to 60-minute radius of their center and have a dedicated caregiver. In a recent study of 185 patients receiving CAR T-cell therapy, 65% of them lived more than 30 minutes away from the closest authorized treatment center.

“As a clinician that administers CAR-T, I’ve had many patients who have not been able to receive it because of barriers to access,” stressed lead study author Nausheen Ahmed, MD, Associate Professor of Hematologic Malignancies and Cellular Therapeutics, Assistant Director of Cellular Therapeutics, and Medical Director of the BMT Survivorship Program at the University of Kansas Medical Center. “I have patients who are traveling for 6 or even 8 hours to get treatment,” she added.

Study Methods and Results

In the retrospective study, researchers investigated the onset and duration of cytokine-release syndrome, immune effector cell–associated neurotoxicity syndrome, and other non–relapse-related causes of mortality among 475 patients with DLBCL who received CAR T-cell therapy between March 2018 and May 2023 across nine treatment centers. They sought to determine whether the monitoring period and driving restriction may be shortened to increase treatment accessibility. Among patients involved in the study, 45% (n = 216) of them received axicabtagene ciloleucel, 33% (n = 158) of them received tisagenlecleucel, and 21% (n = 101) of them received lisocabtagene maraleucel. Most of the study participants (69.8%) received CAR T-cell therapy as third-line or later therapy.

The researchers found that the incidence of any grade of cytokine-release syndrome was 60%, whereas the incidence of any grade of immune effector cell–associated neurotoxicity syndrome was 32.4% across all patients. Within the first 7 days post–CAR T-cell therapy infusion, new-onset cytokine-release syndrome occurred in 57.5% of the patients and new-onset immune effector cell–associated neurotoxicity syndrome occurred in 25.4% of them. During the 8- to 12-day period following treatment, 5.4% of patients experienced new-onset cytokine-release syndrome and 9.3% of them experienced new-onset immune effector cell–associated neurotoxicity syndrome. After 12 days postinfusion, there were no recorded cases of new-onset cytokine-release syndrome and only one case of new-onset immune effector cell–associated neurotoxicity syndrome reported in a patient who received tisagenlecleucel.

The findings demonstrated that most patients developed the toxicities within the first 2 weeks following infusion. After this period, no new-onset cytokine-release syndrome cases were reported and only 0.7% of the patients exhibited new-onset immune effector cell–associated neurotoxicity syndrome.

After 2 weeks, infections—which developed in 14.5% of the patients within the 28 days postinfusion—were the most common cause of death. Two infection-related deaths occurred in the first 28 days following CAR T-cell therapy infusion, whereas five deaths were reported between days 29 and 90. Bacterial infections were most common during the period closely following CAR T-cell therapy infusion, whereas viral infections were most prevalent after 4 weeks postinfusion.

Conclusions

The results of the study supported downgrading from the standard 4-week monitoring period to a 2-week period—with the option to extend, dependent on patient status—as well as instituting a shorter driving restriction. Shortening restriction periods could help mitigate the challenges associated with CAR T-cell therapy for both patients and their families as well as prevent patients from having to resort to more accessible therapies when CAR T-cell therapy could be curative. This could make an significant difference in the lives of patients with minority backgrounds and of lower socioeconomic status, who are disproportionately affected by barriers to access. Studies have shown that 25% to 60% of patients eligible for CAR T-cell therapy must relocate during the required REMS monitoring period, depending on their authorized treatment center’s requirements. Further, treatment-adjacent expenses are not always covered by insurance or the authorized treatment center.

“We are learning that infection may be driving a lot of the nonrelapse mortality and toxicity within the first few months after CAR-T infusion, so we have to shift our focus to preventing and managing infections after those 2 weeks,” Dr. Ahmed underscored. To do this, she suggested a hybrid model of care, which would also shorten the restriction periods for patients. “Instead of the [authorized treatment center] trying to keep the patient locally for a long time, we could collaborate with and train community hematologists/oncologists and referring physicians to identify, initiate treatment for, and collaborate with the [center] to manage infections and other less common side effects,” she suggested.

The researchers reported limitations to the study. Each authorized treatment center had individual guidelines that influenced patient eligibility and management of cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome, and some variables were unable to be captured, including late-onset neutropenia and hypogammaglobulinemia, patient-reported outcomes, and caregiver education practices. Additionally, the study was limited to patients with DLBCL and the therapies tested.

The researchers revealed similar results in a study published in Transplantation and Cellular Therapy, involving the CAR T-cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel for the treatment of patients with multiple myeloma.

Source – ASCO