Removal of REMS Requirements Improves Access to CAR T-Cell Therapy Across Hematologic Malignancies

The FDA’s decision to eliminate the Risk Evaluation and Mitigation Strategies (REMS) requirements for all currently approved CD19- and BCMA-directed autologous CAR T-cell immunotherapies in hematologic malignancies reflects growing confidence within the oncology community for identifying and managing associated toxicities.1 The decision is expected to expand access to these therapies by reducing longstanding socioeconomic, geographic, and logistical barriers, according to expert hematologists interviewed by OncLive®

This regulatory decision, announced on June 27, 2025, applies to the following CAR T-cell products in multiple myeloma and select lymphomas/leukemias: idecabtagene vicleucel (ide-cel; Abecma), lisocabtagene maraleucel (liso-cel; Breyanzi), ciltacabtagene autoleucel (cilta-cel; Carvykti), tisagenlecleucel (Kymriah), brexucabtagene autoleucel (Tecartus), and axicabtagene ciloleucel (Yescarta).

Along with the removal of REMS programs for these CAR T-cell therapies, the FDA approved label updates for liso-cel and ide-cel, reducing certain patient monitoring requirements following their administration.2

The removal of REMS eliminates, among other things, requirements for treatment centers to be specially certified and to maintain immediate, on-site access to tocilizumab (Actemra).1

According to the agency, such safeguards are no longer necessary to preserve the favorable benefit-risk balance of these therapies. The FDA cited several factors underlying this decision, including expanded clinical experience; widespread familiarity with, and maturation of, management guidelines; and consistent real-world and clinical trial evidence supporting the predictable safety profile of CAR T-cell therapies.2

Data Driving This Decision

REMS programs were initially implemented to provide structured safety guidelines through which oncologists could determine whether the benefits of certain treatments outweighed their risks. In the case of CAR T-cell therapies, all agents include boxed warnings for cytokine release syndrome (CRS) and neurological toxicities.1,2

The decision to adjust these monitoring requirements was, in part, supported by a growing body of evidence demonstrating the consistent safety profile of CAR T-cell therapies. Research led by Nausheen Ahmed, MD, and her colleagues played a crucial role in generating these data, with 2 key papers published in 2024.3,4

“Our group thought, “Should we re-evaluate the data behind the 4-week [monitoring] restrictions? Where did that come from?” [It seemed like] there were no hard data behind it,” Ahmed, a hematologist-oncologist and associate professor in the Division of Hematologic Malignancies and Cellular Therapeutics at The University of Kansas Cancer Center, explained in an interview with OncLive.

The first was a retrospective study of 475 patients with lymphoma who received axi-cel, tisa-cel, or liso-cel between 2018 and 2023.3 Findings published in Blood Advances demonstrated that the incidence of CRS beyond 2 weeks after infusion was 0% and the incidence of immune effector cell–associated neurotoxicity syndrome (ICANS) was 0.7%. A single case of new-onset ICANS was observed in the third week. Non-relapse mortality (NRM) was driven by ICANS in the early follow-up period (1.1% until day 28) and by infection through the third month (1.2%).

The second study, which evaluated ide-cel and cilta-cel in 129 patients with multiple myeloma across 4 centers, yielded similar findings.4 Results published in Transplantation and Cellular Therapy showed that the incidence of late-onset CRS and ICANS was 0% and 1.6%, respectively, after 2 weeks postinfusion. NRM was primarily due to hemophagocytic lymphohistiocytosis and early infections (1.1% until day 29), and then by infections up to 3 months postinfusion (1.2%). Notably, 25% of patients had to relocate for 4 weeks due to distance from the treatment center.

“These were some of the core data needed to make a shift,” Ahmed noted, adding that, “We did see the [group led by Rahul Banerjee, MD, FACP, of Fred Hutchinson Cancer Center] publish data that a 4-week driving restriction was adequate instead of 8 weeks, but our data still [suggested that] 2 weeks is adequate.”

This evidence was further corroborated by an analysis of over 1,500 patients with B-cell malignancies who were treated with liso-cel across both clinical trial and real-world cohorts.5 Data presented by Manali Kamdar, MD, MBBS, at the 2025 ASCO Annual Meeting, showed that 96% of CRS and ICANS events occurred within the first 2 weeks of administration. In the clinical trial cohorts (n = 702), 98% (n = 374 of 381) of CRS instances occurred on or before day 15, with a median onset of 5 days (range, 1-63); in real-world cohorts (n = 877), 97% (n = 415 of 430) of CRS instances occurred on day 15 or earlier, with a median onset of 4 days (range, 1-554). Regarding neurotoxicities, 88% occurred within the first 2 weeks in clinical trials (n = 702) and 95% occurred by day 15 among real-world patients (n = 877).

“Importantly, late-onset events were exceedingly rare, particularly among patients who remained clinically stable through day 14,” Kamdar, the clinical director of Lymphoma Services at the University of Colorado Anschutz School of Medicine, added in an interview with OncLive.

In line with these findings, the FDA noted that adverse effect reporting for CRS and neurologic toxicity has remained stable, further affirming that the risks could be adequately managed without the additional controls of REMS.1

Collectively, these data indicated that most acute toxicities requiring immediate specialized care occur within the initial 2-week postinfusion period, justifying a shortened monitoring period.

Immediate Impacts: Reduced Monitoring Requirements Remove Barriers to CAR T-Cell Access

These changes are expected to have an immediate effect on patient access to CAR T-cell therapy by easing some of the physical, logistical, and financial barriers associated with administration, experts agreed.

Prior to label adjustments, monitoring requirements mandated that patients treated with liso-cel or ide-cel remain in close proximity to a specialized treatment center for 4 weeks after infusion.2 Additionally, an 8-week driving restriction was in place due to neurotoxicity concerns.

Such requirements were “quite restrictive and limiting for patients who just couldn’t [follow them],” Forat Lutfi, MD, an assistant professor in the Division of Hematologic Malignancies and Cellular Therapeutics at The University of Kansas Cancer Center, shared with OncLive. “Depending on the survey, only a quarter to one-third of our patients who could benefit from CAR T-cell therapy were getting CAR T-cell therapy. Having the REMS restrictions certainly played into this.”

The restrictions also created significant barriers to access for patients with lower socioeconomic status, African Americans, and those living far from treatment centers, Ahmed noted.6

“From clinical experience, we know that some patients are just not able to get these therapies, even though they can improve patient survival, are life-saving, and are curative,” Ahmed added. “All of these factors indicated that something had to be done differently. Either CAR T-cell therapy became more available in centers, or at least some restrictions [should have been] lifted to improve access.”

The FDA’s updates have significantly reduced these patient monitoring requirements: driving restrictions are now shortened to 2 weeks, and the requirement to stay within proximity of the health care facility is reduced to 2 weeks postinfusion.2

Ahmed commented on the swift and positive reception to this change, mentioning that “everyone was really happy about it. It surprised many of us that it came so fast.” Her center has already begun implementing these changes, allowing stable patients to “drive after 2 weeks... and they are able to go back home as long as they’re stable.”

In his interview with OncLive, Omar Nadeem, MD, clinical director of the Myeloma Immune Effector Cell Therapy Program and Center for Early Detection and Interception of Blood Cancers at Dana-Farber Cancer Institute, agreed that the 2-week timeframe makes administration of this therapy “much more doable for the majority of patients and their caregivers.”

Kamdar emphasized that this shift is a “turning point for access, reducing barriers and enhancing access for patients who live far from specialized CAR T centers and alleviating the socioeconomic, caregiver, and logistical burdens that often accompany treatment.”

Increasing Comfort With CAR T-Cell Therapy in Community Practice Could Engender Hybrid Models of Care

The removal of REMS requirements also reflects the oncology community’s increasing familiarity and expertise in managing CAR T-cell toxicities. Oncologists are now more comfortable recognizing and managing CRS symptoms like fever or altered mental status for neurotoxicity, partly due to experience with newer therapies like T-cell engagers and bispecific antibodies, Ahmed explained.

“In practice, I don’t think [this decision] is going to change too much, because most of those toxicities [we are already familiar with] occur within that 2-week window,” Nadeem noted.“CRS usually occurs a week out and is resolved by day 14…the more acute neurological toxicities are [also] usually resolved by that time.”

However, the increased flexibility in monitoring afforded by these updates may also allow referring oncologists to become more comfortable with CAR T-cell therapy, according to Kamdar. As community oncologists continue to gain experience with CAR T-cell therapy, she anticipates that they will become more vocal advocates for its use.

Effective patient and caregiver education will be paramount for accurate symptom identification, and a clear communication pathway with CAR T specialist centers will be essential for community oncologists to manage or refer patients if complications arise.

“It’s going to take some extra guidance [for community oncologists]...but we’re not necessarily discharging those patients from our center entirely,” Nadeem said. “We’ll have regular check-ins with them and will be able to guide the outpatient and the local teams on what to look out for from that point on.”

“The ability and infrastructure [allowing us] to manage low-grade ICANS or CRS will probably be in place as long as we have support from treatment centers,” Ahmed added.

The vision is to transition towards a “hybrid or integrated model of care,” according to both Ahmed and Lutfi. Lutfi’s team at The University of Kansas Cancer Center is moving quickly to adopt these changes and transition aspects of care into affiliated community sites. Although cell infusion and apheresis collection will still be conducted at academic centers, the preparatory phase, including imaging, workup, and lymphodepletion, will be moved into the community.

Lutfi clarified that initial community rollouts will focus primarily on low- or average-risk patients to ensure that high-risk patients, such as those with primary refractory or very high-risk disease, continue to receive care at tertiary centers where complex toxicities can be managed.

Lingering Long-Term Safety Concerns

Despite the removal of REMS, clinical vigilance and long-term monitoring of safety remain paramount. According to current FDA guidelines, manufacturers of CAR T-cell therapies are still required to conduct postmarketing observational safety studies to assess long-term risks, particularly the development of secondary malignancies.1 Patients will be followed for 15 years after product administration to monitor these potential long-term effects.

Although acute CRS and ICANS are now better managed than ever, “patients are still at risk of dying, more so due to infections than any other complication,” Ahmed stated. Her group’s research showed that hemophagocytic lymphohistiocytosis was a main cause of death in the first 4 weeks for patients with myeloma, followed by infections in the first 3 months.4 Similarly, infections were the main cause of death beyond ICANS events 3 months postinfusion in patients with lymphoma.3 Proactive measures, including monitoring immunoglobulin levels, providing intravenous immunoglobulin supplementation if needed, and administering prophylactic antibiotics, are therefore crucial, Ahmed noted.

Lutfi echoed Ahmed’s concerns about infections based on long-term data with CAR T-cell therapy. He added that there also remains a need for additional data on the small number of patients who develop unpredictable, high-grade toxicities with BCMA-targeted CAR T-cell agents. Addressing these unknowns will further inform patient selection and management.

What’s Next for CAR T-Cell Therapy in Clinical Practice?

Overall, the removal of the CAR T-cell REMS program sets a clear precedent for how the FDA and the oncology community can adapt regulatory oversight as clinical experience and data mature and aligns with the broader goal of expanding access to advanced cellular therapies.

As indications for CAR T-cell therapy continue to extend to a broader range of hematologic and non-malignant conditions, experts agree that strengthening collaborative care models between academic and community settings will be essential for ensuring safe, widespread integration.

Lutfi envisions a future where, much like checkpoint inhibitors in solid tumors, CAR T-cell therapy becomes routinely administered in local clinics, lessening the reliance on academic centers. His team is moving swiftly to implement these changes, aiming to “safely reduce the requirements and hoops that patients have to jump through, and their caretakers as well."

“Next steps involve operationalizing these insights by incorporating the day-14 safety algorithm into routine practice at CAR T treating centers,” Kamdar stated. “Standardizing early discharge protocols and ensuring robust communication with referring providers will be essential for safely extending access without compromising outcomes.” Her team is actively developing frameworks that align clinical safety with patient-centered delivery models to ensure that these transformative therapies remain both effective and accessible.

References

1. FDA eliminates Risk Evaluation and Mitigation Strategies (REMS) for autologous chimeric antigen receptor CAR T cell immunotherapies. FDA. June 27, 2025. Accessed August 14, 2025. https://www.fda.gov/news-events/press-announcements/fda-eliminates-risk-evaluation-and-mitigation-strategies-rems-autologous-chimeric-antigen-receptor
2. U.S. Food and Drug Administration approves streamlined patient monitoring requirements and removal of REMS programs within Bristol Myers Squibb’s cell therapy labels. News release. Bristol Myers Squibb. June 26, 2025. Accessed August 15, 2025. https://news.bms.com/news/corporate-financial/2025/U-S--Food-and-Drug-Administration-Approves-Streamlined-Patient-Monitoring-Requirements-and-Removal-of-REMS-Programs-within-Bristol-Myers-Squibbs-Cell-Therapy-Labels/default.aspx
3. Ahmed N, Wesson W, Lutfi F, et al. Optimizing the post-CAR T monitoring period in recipients of axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. Blood Adv. 2024;8(20):5346-5354. doi:10.1182/bloodadvances.2023012549
4. Wesson W, Dima D, Suleman N, et al. Timing of toxicities and non-relapse mortality following CAR T therapy in myeloma. Transplant Cell Ther. 2024;30(9):876-884. doi:10.1016/j.jtct.2024.06.012
5. Kamdar M, Shadman M, Ahmed S, et al. Optimizing post–chimeric antigen receptor (CAR) T cell monitoring: evidence across lisocabtagene maraleucel (liso-cel) pivotal clinical trials and real-world experience. J Clin Oncol. 2025;43(suppl 16):7026. doi:10.1200/JCO.2025.43.16_suppl.7026
6. Ahmed N, Shahzad M, Shippey E, et al. Socioeconomic and racial disparity in chimeric antigen receptor T cell therapy access. Transplant Cell Ther. 2022;28(7):358-364. doi:10.1016/j.jtct.2022.04.008