Elucidating CAR T-Cell Candidacy for Diffuse Large B-Cell Lymphomas

CAR T-cell therapy has become an increasingly central strategy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), yet significant variation remains in how and when patients are identified, referred, and moved through the treatment pathway. Optimizing that journey, from first relapse through apheresis and infusion, requires alignment across community oncology practices, cellular therapy centers, and the patients themselves.

In a recent Satellite Session focused on the Inova Health System based in Fairfax, Virginia, a multidisciplinary panel examined the full CAR T-cell therapy journey in DLBCL, with a focus on how to improve the proportion of eligible patients who ultimately reach treatment. The discussion was moderated by Stephan Medlin, DO, endowed chair and founding medical director at Inova Schar Cancer, Fairfax, Virginia, and featured Jennifer Kanakry, MD, medical director at MedStar Georgetown University Hospital, Washington, DC, and Ram Trehan, MD, oncologist at Greater Washington Oncology Associates, Silver Spring, Maryland.

The panel reviewed the second-line evidence base supporting early CAR T-cell therapy, worked through a clinical case to evaluate product selection and eligibility, and discussed the operational and patient-level barriers that most commonly impede referral.

What Line of Therapy Are Patients Referred for CAR T-Cell Therapy?

Medlin opened by reviewing the current NCCN Guidelines for relapsed/refractory DLBCL, noting that for patients relapsing within 12 months, axicabtagene ciloleucel (axi-cel; Yescarta) and lisocabtagene maraleucel (liso-cel; Breyanzi) are the Category 1 CAR T-cell therapy options, while bispecifics, including glofitamab-gxbm (Columvi), are listed among alternatives for non-candidates. For patients relapsing beyond 12 months, intention to undergo transplant drives the treatment pathway.

He asked what line of therapy panelists most commonly refer patients for CAR T-cell therapy. Trehan described a clear evolution in his practice.

“There was a time when [I would go] through one of those regimens... after the second line, if they’re not doing well, I would send them to the transplant center,” Trehan explained. Now, for very early relapses, defined as happening within 12 to 18 months, he refers immediately at first relapse. Even for later relapses, he initiates a referral while beginning local treatment simultaneously.

Kanakry agreed, emphasizing the importance of early involvement from the cell therapy team, particularly when bridging therapy is required and the window to CAR T-cell therapy infusion is narrow.

When Medlin asked about the timeline from referral to evaluation, Trehan noted that in his practice, the process typically takes approximately 48 hours, driven by direct physician-to-physician communication. “For me, it's immediately a phone call and sending everything from my OncoEMR right away. I like to do things myself,” he explained. “If the patient doesn't get a call in 24 hours, they call me and I call again. I want to make sure they get there within 2, 3 days.”

Who Is a Candidate for CAR T-Cell Therapy?

Regarding candidacy, Trehan described his patient population as predominantly aged 40 to 70 years, with most patients qualifying unless they are older than 80 or have severe comorbidities. He noted that patients with aggressive early relapses, even those who relapse during or within 2 to 3 months of treatment, should still be referred, as CAR T-cell therapy may represent the only curative option.

Kanakry agreed that age cutoffs are rarely absolute. She noted that central nervous system (CNS) involvement does not alter her decision to offer axi-cel at an experienced center.

“Overall, we’re at a point in the field at an experienced center where [neurotoxicity] can be managed. You have to jump in quickly and make sure that you blunt that response early,” Kanakry explained. “We’ve got good algorithms; we know how to do this now. It’s not 10 years ago when this was all being sorted out.”

Reviewing the ZUMA-7 and TRANSFORM Data

Medlin reviewed the pivotal evidence supporting second-line CAR T-cell therapy, including the phase 3 ZUMA-7 trial (NCT03391466) and TRANSFORM trial (NCT03575351). He highlighted that axi-cel demonstrated significantly improved event-free survival (EFS) and overall survival over standard of care in ZUMA-7, with 62% overall survival at 24 months in patients who were transplant-eligible. Medlin also noted that liso-cel showed improved EFS over standard of care in TRANSFORM and pointed to the lower rates of neurotoxicity with liso-cel relative to axi-cel as a clinically meaningful distinction.

Trehan noted that these data reinforce his practice of referring at first relapse, observing that bispecific antibodies, while increasingly used in myeloma, have not supplanted CAR T-cell therapy as the dominant second-line strategy in lymphoma. Kanakry added that improved neurotoxicity management with axi-cel has expanded her confidence in treating patients with comorbidities such as arrhythmias and CNS involvement.

Impact of CAR T-Cell Therapy: Outcomes From a Patient Case

Medlin presented a clinical case: a 52-year-old man with stage IV de novo DLBCL who had received 6 cycles of polatuzumab vedotin (Polivy), rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) with a Deauville-1 end-of-therapy PET but subsequently relapsed 9 months later with bilateral axillary and retroperitoneal adenopathy, a mediastinal mass, P53 mutation, and MYC, BCL-2, and BCL-6 positivity.

Trehan characterized the case as a clear CAR T-cell therapy candidate given the extremely early and biologically aggressive relapse, recommending immediate referral and concurrent initiation of bridging therapy to control disease while the pathway is established.

Kanakry expressed a preference for axi-cel in this fit patient, citing manufacturing speed and reliability as critical factors.

“I have a personal preference for axi-cel if they’re fit and can withstand it,” Kanakry explained. “We’re going to get your patient in, we’re going to get the [medical authorization], and we’re going to have T cells ready and give essentially 1 dose of interim bridging therapy, and then we’ll be ready to go.”

Both Kanakry and Trehan agreed that relapse beyond 12 months would not fundamentally change their approach. Furthermore, Kanakry noted that the assessment of transplant candidacy becomes relevant in that setting but does not redirect the overall goal toward CAR T-cell therapy.

Holding Vs Bridging Therapy and Coordination of Care

Medlin introduced the conceptual distinction between holding and bridging therapy, highlighting that NCCN guidelines exclude bendamustine from the pre-collection holding phase due to its detrimental effect on T-cell fitness, while post-collection bridging regimens may be more flexible.

Trehan described his approach of proposing a regimen, such as rituximab plus ifosfamide, carboplatin, and etoposide (R-ICE), and confirming alignment with the CAR T-cell center before initiating treatment.

Kanakry noted that the model at her center is collaborative and patient dependent. “A lot of our referrals are internal to begin with,” she said. “Of the subset that are external, it’s probably 50/50 whether the referring doctor just wants the patient fully transferred for bridging and for CAR T-cell therapy.” When patients are clinically unstable or require inpatient apheresis, she noted, consolidating care at the CAR T-cell center, including holding therapy for T-cell collection, becomes important to prevent loss of the patient along the pathway.

Barriers to Referral and Access

When Medlin asked what barriers most commonly impede referral, the panelists identified 2 distinct categories: patient-level and system-level.

From the patient perspective, Kanakry described information overload and logistical overwhelm as primary obstacles.

“I have a lot of patients who come in my clinic and I say, how much did ‘Dr. So-And-So’ say about why you’re here today? Nothing is what they say,” Kanakry said. “Then I start to tell them all the things that they need to know and it’s information overload. People come from far away and it’s a total pain for them to get to a new cancer center and find a parking spot and find my clinic after they’ve driven an hour and a half in [Washington] DC traffic.”

Trehan countered that thorough upfront counseling could address much of this resistance. He noted that when he spends significant time with patients and their families — explaining the urgency, the rationale, and what to expect — patients are generally willing to move forward within a few days.

From a system perspective, Trehan identified geography as a significant determinant of access, noting that while urban and suburban practices in the greater Washington, DC, area see high referral rates, patients located 50 to 70 miles away in more rural areas often decline referral due to travel burdens.

Kanakry added a workforce dimension, noting that the American Society of Transplant and Cellular Therapy (ASTCT) has identified a critical shortage of trained cell therapists relative to projected demand. Even within well-resourced regions, constraints on beds and staffing are beginning to limit the volume of patients who can be accommodated.

“There are not enough cell therapists in the pipeline to meet the demand,” Kanakry said. “There are definitely more patients out there than cell therapists can take care of.”

References

1. Westin JR, Oluwole OO, Kersten MJ, et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665
2. Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023;141(14):1675-1684. doi:10.1182/blood.2022018730