Shorter monitoring period after CAR-T may be possible, potentially expanding access
Click Here to Manage Email Alerts
Key takeaways:
- Patients with large B-cell lymphoma rarely developed CRS and ICANS more than 2 weeks after CAR T-cell therapy.
- Infections were the main cause of mortality in the period 29 to 90 days after infusion.
An FDA mandate that requires patients who receive chimeric antigen receptor T-cell therapy to stay within a certain radius of their treatment facility for nearly a month for adverse event monitoring may be overly restrictive.
Patients with relapsed or refractory large B-cell lymphoma who received CAR-T rarely developed cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome (ICANS) — the primary adverse events associated with therapy — more than 2 weeks after infusion, retrospective study results showed.
This suggests the monitoring period could be halved, researchers concluded, potentially eliminating a key barrier to CAR-T access.
“There should be no mandate for them to stay in proximity or continue follow-up with just the treatment center [after 2 weeks],” Nausheen Ahmed, MD, associate professor, assistant director of cellular therapeutics and medical director of the blood and marrow transplant survivorship program at The University of Kansas Cancer Center, told Healio. “It should be flexible based on how the patient’s doing, the patient’s infrastructure and where they live. It has to be a more individualized decision beyond 2 weeks.”
Background
The FDA has approved three CAR-T products for treatment of relapsed or refractory large B-cell lymphoma (LBCL) — axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences), often called axi-cel; tisagenlecleucel (Kymriah, Novartis), often called tisa-cel; and lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb), often called liso-cel.
In clinical trials of these therapies, CRS rates ranged from 42% to 93% and ICANS rates ranged from 21% to 64%.
Based on these data, the FDA established a Risk Evaluation and Mitigation Strategy (REMS) that requires individuals who receive these therapies to reside within a 2-hour radius of the treatment facility for 4 weeks. Patients are not allowed to drive for 8 weeks.
Some treatment centers have stricter protocols, requiring patients to stay within a 30- to 60-minute radius and have a designated caregiver for the duration of the monitoring period.
The REMS mandate also requires providers to have at least two doses of tocilizumab (Actemra, Genentech) onsite and within immediate access for each patient undergoing CAR-T. The interleukin-6 receptor antagonist is used as supportive care to help reduce inflammation associated with CAR-T-induced CRS and neurotoxicity.
The safety protocol ensures rapid treatment when adverse events arise, but it also may limit access to CAR-T.
“Only 20% to 30% of patients who are eligible for CAR-T actually are able to get [it],” Ahmed said, noting prior analyses revealed particular access challenges for individuals with lower socioeconomic status, as well as ethnic minorities.
Previous research showed about 30% of CAR-T recipients live within 30 minutes of a treatment facility, Ahmed said. However, 30% live more than 2 hours away, meaning they would have to make considerable life adjustments to meet the FDA mandate.
“Do we really need these requirements?” Ahmed said. “We want to implement restrictions for patient safety, but where’s that balance?”
Study findings
Ahmed and colleagues used the Cell Therapy Consortium registry to identify 475 patients (median age, 65 years, 64.6% men) with relapsed or refractory large B-cell lymphoma who received axi-cel, tisa-cel or liso-cel between March 2018 and May 2023.
Researchers evaluated when CRS and ICANS developed, how long it persisted, and the causes of nonrelapse mortality. Median follow-up was 11 months.
Sixty percent of patients developed CRS, with the highest rate among those who received axi-cel (79.6%) and the lowest rate among those who received tisa-cel (40.5%).
Results showed 57.5% of patients developed CRS in the first week after infusion, and 5.4% developed it in the second week. No CRS cases occurred beyond 14 days after infusion. Median onset of CRS was 3 days after infusion.
Five percent of patients developed grade 3 or higher CRS, with median onset of 6 days after infusion.
Overall, median time to CRS resolution was 4 days. CRS persisted beyond 2 weeks for 7% of patients.
About one-third (32.4%) of patients developed ICANS, with the highest rate among those who received axi-cel (51.8%) and the lowest rate among those who received tisa-cel (10.1%).
Results showed 25.3% of patients developed ICANS in the first week after infusion, and 9.3% developed it in the second week.
Median onset of ICANS was 5 days after infusion.
One patient — a 71-year-old man who received tisa-cel — developed ICANS in the third week after infusion, and it persisted until day 34.
Grade 3 or higher ICANS occurred among 17.9% of patients, with median onset of 7 days.
Median time to ICANS resolution was 5 days, though it persisted beyond 2 weeks for 34% of patients.
In the 28-day post-infusion period, seven deaths unrelated to disease progression occurred — four due to ICANS, one due to CRS and ICANS, and two due to infection.
Nine patients died between 29 days and 90 days after infusion. Five died due to infection, one died due to isolated ICANS and one died of cardiac-related causes. Causes of the other two deaths were unknown.
“We were expecting these results,” Ahmed said. “When I tell patients that they can’t drive for 8 weeks, in the back of my mind, I’m [thinking] it’s very unlikely that something will happen — maybe less than a 1% chance. [Now] I have the data now to go behind that.”
The mortality rates due to infection did highlight the need for better communication between treatment facilities and community health practices to manage post-infusion infections, Ahmed said.
Guidelines exist for monitoring immunoglobulin levels, CD4 counts and white blood cells, but those follow-ups may not always be conducted, she said.
“We have identified infections as being a main driver of deaths for those who don’t progress,” Ahmed said. “Community centers or physicians may not be as up to date with infection risks. There has to be more communication and education, especially beyond 28 days.”
Not always an emergency
Results of this study — as well as previous findings from Ahmed and colleagues that showed low risk for CRS or ICANS beyond 2 weeks of CAR-T infusion for patients with relapsed or refractory multiple myeloma — underscore the improvements in managing these toxicities, Ahmed said.
“[Several years ago], if a patient developed fever within 2 hours, they would get a dose of tocilizumab,” Ahmed said. “However, we are realizing that we don’t need to be doing that. The patterns have evolved for treating CRS and ICANS over the years. We are now more comfortable dealing with it. We have a better idea of some preventive measures, as well as early intervention. In some cases, it’s not an emergency.
“For example, if a patient went home and was living 4 hours away and developed a fever, they don’t need tocilizumab right away, [even though that] is why the FDA wanted them to stay close,” Ahmed added. “Sometimes we let the patient have a fever for several hours before we give them anything. Ideally, we would be in communication with the community doctor who’s seeing the patient, and we would either get the patient transferred here or co-manage the patient with them.”
The data on CRS and ICANS incidence and timing suggest mandates should be revised to improve access to CAR-T, Ahmed said.
“This risk is now comparable to the risk with some of the drugs that don’t even have a REMS program, such as bispecific therapies,” Ahmed said. “If the risk with CAR-T is equal to that of bispecifics, the FDA may want to reconsider.”
For more information:
Nausheen Ahmed, MD, can be reached at nahmed5@kumc.edu.
References:
- Ahmed N, et al. Blood Adv. 2024;doi:10.1182/bloodadvances.2023012549.
- Wesson W, et al. Transplant Cell Ther. 2024;doi:10.1016/j.jtct.2024.06.012.
Collapse
Click Here to Manage Email Alerts