Despite Potential Benefits, Barriers to CAR T-Cell Therapy for DLBCL Persist


Chimeric antigen receptor (CAR) T-cell therapies have shown efficacy and safety for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), but barriers to referral may obstruct patient access to them.

Chimeric antigen receptor (CAR) T-cell therapy has shown efficacy and safety for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), but barriers to referral for CAR T-cell therapy may obstruct patient access to it, according to a review published in Transplantation and Cellular Therapy.

Patients who are refractory to or relapse after first-line therapy for DLBCL typically experience poor outcomes, and research has shown that patients treated with additional lines of cytotoxic chemotherapy often succumb to their disease, the study authors wrote. CAR T-cell therapy is a novel approach that was initially approved for third-line treatment but was recently greenlit by the FDA for second-line treatment of R/R DLBCL.

CAR T-cell therapy entails removing and engineering a patient’s own T cells to target cancer cells, then reinfusing those cells. Two CD19-directed CAR T-cell therapies, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), are approved for the treatment for patients who are primary refractory or relapse within 12 months of initiation of first-line therapy. A third CD19-directed CAR T-cell therapy, tisagenlecleucel (tisa-cel), is FDA approved as a third-line option for R/R DLBCL.

“When novel cancer therapies are first approved, there can be a steep learning curve and time required to understand the intricacies of the clinical trial data and how to identify patients who are most likely to benefit from treatment,” the authors wrote. “Given the variety of current treatment options for R/R DLBCL in the third line and beyond and the anticipated approvals of bispecific antibodies for DLBCL, making informed treatment decisions will be more challenging in the near future.”

While CAR T-cell therapy has shown a favorable risk-to-benefit profile in R/R DCBCL, an array of patient-related and physician-related barriers to referral for CAR T-cell therapy exist, according to the study authors.

There are numerous potential causes of patient hesitancy to receive CAR T-cell therapy, from financial concerns to safety concerns.

A key concern is the cost of CAR T-cell therapy, with infusions priced at up to $475,000, the study authors noted. Adverse events (AEs), which are common, can also add to the cost. Depending on the type of insurance a patient has, there may be a lack of coverage for these therapies, making their cost a significant barrier.

“It has been the authors’ experience that some patients who have already incurred large costs associated with receiving several lines of therapy for DLBCL may be averse to trying innovative/expensive treatment options that may require further financial burden,” the authors wrote. While resources for cost assistance exist, many patients may not be aware of them prior to consulting with a treatment center.

The risk of serious AEs such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which could potentially lead to intensive care unit admission, may also be a concern for patients. However, the authors noted that data from clinical trials and real-world settings have shown that low-grade AEs typically resolve with time and supportive care, and serious AEs can be managed with established protocols.

Additional costs can come from required travel to treatment centers, as well as receiving care away from home. Caregiver support is important for those undergoing CAR T-cell therapy who require constant monitoring for symptom changes and to ensure medications are taken, so those without caregivers may not be able to receive CAR T-cell therapy, the authors wrote.

There are also barriers from the provider perspective, including knowledge gaps surrounding efficacy, safety, and AE management that may be a bigger concern for referring physicians in the community oncology setting.

“Patient referrals for CAR T-cell therapy may be challenging if community oncologists are unfamiliar with the effect of prior therapies on T-cell fitness prior to leukapheresis and the potential impact on CAR T-cell manufacturing,” the authors wrote. Patient selection is also complex, requiring consideration of previous therapy lines, patient fitness, comorbidities, and functional status.

While there are defined inclusion and exclusion criteria on product labels, the authors also noted that multidisciplinary discussion among oncologists and colleagues at local CAR-T cell therapy meetings could supplant borderline inclusion or exclusion criteria for therapy.

“Overall, patient referrals for CAR T-cell therapy in the real-world setting have expanded beyond the strict criteria used in clinical trials and have maintained clinical efficacy while demonstrating improved safety,” the authors wrote. Referring patients earlier than later in their disease progression is also advantageous, they added.

The authors stress the importance of patient awareness and referring physician education around CAR T-cell therapies in R/R DLBCL. Effective collaboration between community oncologists and CAR T-cell therapy treatment centers is also crucial. This includes direct communication, ideally via personal cell phone, between treatment centers and physicians for referrals, follow-up, and virtual patient visits. Referring physicians should also receive clear follow-up information for effective patient monitoring post-infusion.

Finally, long-term monitoring plans should be in place to ensure treatment efficacy and prevent further relapse, the authors wrote.

“Barriers to CAR T-cell therapy obstruct patient access to essential treatment, and it is imperative to reduce these perceived obstacles to maximize the number of patients who receive standard-of-care lymphoma therapy,” the authors concluded.


Hoffmann MS, Hunter BD, Cobb PW, Varela JC, Munoz J. Overcoming barriers to referral for chimeric antigen receptor T-cell therapy in patients with relapsed/refractory diffuse large B-cell lymphoma. Transplant Cell Ther. 2023;S2666-6367(23)01234-4. doi:10.1016/j.jtct.2023.04.003

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