Neelapu Highlights the Nuances of CAR T-Cell Therapy Administration in Lymphoma

The proper administration of CAR T-cell therapy for the treatment of patients with hematologic malignancies requires careful consideration of several factors by the entire cancer care team and diligent monitoring of both short- and long-term toxicities, according to Sattva S. Neelapu, MD.

“One of the most important ways to get better outcomes in patients with CAR T-cell therapy is to refer them early,” Neelapu said. “The data indicate that patients who have low tumor burden or who get treated early when they have not had multiple chemotherapy regimens tend to have better outcomes because they have better T-cell function. The best time to refer a patient for CAR T-cell therapy is as soon as they relapse after frontline therapy.”

The most recent CAR T-cell therapy to receive an indication from the FDA was in follicular lymphoma; lisocabtagene maraleucel (liso-cel; Breyanzi) received accelerated approval from the agency for the treatment of patients with the disease following at least 2 prior lines of systemic therapy. Data from the phase 2 TRANSCEND-FL study (NCT04245839), which supported the approval, showed that patients treated with liso-cel (n = 94) achieved an overall response rate of 95.7% (95% CI, 89.5%-98.8%) and a median duration of response that was not reached (NR; 95% CI, 18.04-NR).

In an interview with OncLive^®, Neelapu, the deputy department chair and a professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, outlined the optimal processes and remaining unmet needs of CAR T-cell therapy administration for patients with hematologic malignancies.

OncLive: What are some processes that institutions can adopt to streamline the delivery of CAR T-cell therapy?

Neelapu: CAR T-cell therapy is given in dedicated CAR T centers. There are currently over 125 [CAR T] centers across the US, [and each center] requires specially trained personnel. [CAR T-cell therapies] have now been approved for close to 7 years, so a lot of institutions have developed [their own] practices.

At our center, we have a nurse coordinator who is involved from the time we identify a patient who needs CAR T-cell therapy and then guides them through the treatment process. Once we identify a patient, the nurse coordinator makes sure to request an insurance approval. As soon as we get the insurance approval, we schedule the patient for leukapheresis and then coordinate with the referring physician or the physician the patient is being treated by at our center with the primary oncologist [to determine] the bridging therapy that’s required for these patients, because they frequently have rapidly growing disease and approximately 50% require some sort of bridging therapy to hold [or stabilize] the disease while the CAR T [product] is being manufactured.

Once the product has been manufactured––the turnaround time is anywhere between 2 to 4 weeks depending on the manufacturer––we bring the patient back and generally give the lymphodepleting chemotherapy as an outpatient [procedure]. The patient is then admitted for CAR T-cell infusion in the case of axicabtagene ciloleucel [axi-cel; Yescarta]. For products like tisagenlecleucel [tisa-cel; Kymriah] and liso-cel which have less toxicity, we give the option to either [administer the treatment] as an outpatient or inpatient [procedure] depending on the patient’s preference.

What are the best practices to monitor and address the potential adverse effects (AEs) that patients can experience following CAR T-cell infusion?

We generally monitor the patients daily for the first 10 days or so if it’s given as outpatient [treatment] and if they’re in the hospital, we keep them for about 7 days or so, but patients are usually admitted to the regular lymphoma unit at our center. CAR T-cell therapy does not require a transplant unit.

The main part of the care [happens] post-CAR T-cell infusion. These patients can have AEs within the first 2 weeks, generally cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS]. We have trained all our nurses, nurse practitioners, physician assistants, trainees, and faculty [to treat these AEs], as well as the lymphoma oncologist and the oncology consultants, such as infectious disease specialists as well as critical care and emergency room physicians who encounter these patients.

Close monitoring is essential during the first 2 weeks because these patients can develop CRS or ICANS, and we have established guidelines for the management, assessment, and management of these toxicities. We have those [guidelines] available both on a web portal as well as a smartphone app that is freely available to anyone who wants to use it.

We generally restage these patients at the 30-day time point to assess their response. If they have a good response and decide to go back to their home oncologists, we draft a letter with detailed guidelines on how these patients need to be monitored. This is critical because these patients can also have subacute and late toxicities after CAR T-cell therapy, which have been underrecognized. [When] the patient goes back to their primary oncologist in the community, they need to be aware of how to monitor and manage them.

[In terms of] some of the subacute toxicities or cytopenias, these patients can have fluctuating blood counts for the first 3 months or so. They need to be monitored at least once or twice a week, and they may need transfusions as needed. In addition, they can have prolonged lymphopenia, which puts them at risk of infections, including herpes zoster reactivation as well as Pneumocystis pneumonia, [so patients] need to be on prophylaxis for herpes zoster and pneumocystis for at least a year. At that point, we check their CD4 counts and if they’re at [approximately] 200 cells/mm3, we stop the prophylaxis but if they are below 200 cells/mm3 we continue it for a longer period.

What are some unmet needs that persist in terms of CAR T-cell therapy administration and AE management?

There are several areas where there’s room for improvement. We have not fully outlined the different mechanisms of resistance for CAR T-cell therapy. Although loss of CD19 and T-cell dysfunction do play a role, there are still various tumor and intrinsic resistance mechanisms that need to be elucidated. There are several groups that are working in this space, so that might guide us on how to further improve the efficacy of CD19-[directed] CAR T-cell therapy.

The other area that needs a lot of attention is the management of [CAR T-cell–related] toxicities. Although we know CRS can be easily managed with the appropriate therapies that are available now, neurological toxicity is something where there is still room for improvement. There’s room to double-up prophylactic measures, and there are groups that are evaluating various strategies in the space.

[There are also unmet needs] for patients who develop prolonged cytopenias; approximately 30% of patients after CAR T-cell therapy can have prolonged cytopenias that can last weeks to months, during which time they could be at significant risk of infection. There are some recent groups, including ours, that have elucidated the mechanisms of these prolonged cytopenias. Hopefully, that might lead to better strategies on how to reverse that. There are efforts to develop some therapeutic interventions in that space that we’ll see soon.

Lastly, patients who relapse after CAR T-cell therapy have very poor survival. In fact, the median overall survival for patients relapsing after CD19-directed CAR T-cell therapy is only about six months. It’s important that we understand the mechanisms of resistance and develop novel therapies. The best way to treat these patients who relapse after receiving CAR T-cell therapy is not yet clear. In the standard of care setting, probably the most effective treatment appears to be the bispecific T-cell engagers that have been approved in this space. However, only a minority of the patients respond to those therapies. Whenever possible, patients who relapse after CD19-directed CAR T-cell therapy should be referred for clinical trial evaluation.

Reference

FDA grants accelerated approval to lisocabtagene maraleucel for follicular lymphoma. FDA. May 15, 2024. Accessed May 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-follicular-lymphoma