Mapping the Full CAR T-Cell Journey in DLBCL From Referral to Survivorship

Chimeric antigen receptor (CAR) T-cell therapy has moved from a later-line rescue option to a guideline-preferred second-line strategy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, translating that guideline preference into consistent real-world referrals depends on how individual physicians weigh relapse timing, product selection, and a set of nonclinical barriers that rarely show up in a treatment algorithm.

In a recent Satellite Session focused on the Banner MD Anderson Cancer Center network in the Phoenix, Arizona, metropolitan area, a multidisciplinary panel worked through the complete CAR T-cell journey in DLBCL, from second-line decision-making through long-term survivorship. The discussion was moderated by Yazan Samhouri, MD, director of the cell therapy program at Banner MD Anderson Cancer Center in Gilbert, Arizona. He was joined by Andrew Baker, PharmD, BCOP, an outpatient cellular therapies and stem cell transplant pharmacist at Banner MD Anderson Cancer Center; Alexandra Farmer, PA-C, physician assistant in Hematology-Oncology at Banner MD Anderson Cancer Center; Laeth George, MD, hematologist and medical oncologist at Arizona Center for Cancer Care in Scottsdale, Arizona; Srivyshnavi Narra, MD, medical oncologist at Banner Cancer Center Specialists LLC in Sun City, Arizona; Anthony Pasquarella, MD, medical oncologist at Ironwood Cancer & Research Centers in Surprise, Arizona; Allison Rosenthal, DO, medical director of the adolescent and young adult cancer program at Mayo Clinic in Phoenix, Arizona; and Misam Zawit, MD, MPH, hematologist and oncologist at City of Hope Phoenix in Goodyear, Arizona.

Decision-Making in the Second Line

Samhouri opened the discussion by walking through how second-line decision-making in DLBCL has shifted: rather than asking only whether a patient is transplant-eligible, the field now asks whether relapse occurred within or beyond 12 months of completing first-line therapy, since early relapse tends to reflect chemotherapy-resistant disease. That distinction underpins the pivotal trials behind both approved second-line CAR T-cell products. The phase 3 ZUMA-7 trial (NCT03391466) randomly assigned patients with primary refractory or early-relapsing (within 12 months) LBCL to axicabtagene ciloleucel (axi-cel; Yescarta) or standard-of-care salvage chemotherapy plus autologous transplant. With extended follow-up, the median event-free survival (EFS) assessed by investigator was 10.8 months with axi-cel vs 2.3 months with standard of care (HR, 0.42), and the 4-year overall survival (OS) rate favored axi-cel, being 54.6% vs 46.0%, respectively.^1,2 The phase 3 TRANSFORM trial (NCT03575351) assessed the same relapse-timing population with lisocabtagene maraleucel (liso-cel; Breyanzi), and reported a median EFS of not reached (NR; 95% CI, 9.5-NR) with liso-cel vs 2.4 months (95% CI, 2.2-4.9) with standard of care (HR, 0.356; 95% CI, 0.243-0.522). Progression-free survival outcomes also favored liso-cel, though OS had not yet reached statistical significance at the data cutoff.³

Regarding when they refer patients for CAR T-cell evaluation, the panel was largely unanimous: at first relapse. George estimated that more than 90% of his patients with relapsed DLBCL are referred at that point, reserving exceptions for patients who are otherwise unsalvageable. Age and performance status were the clinical factors the group most consistently cited as reasons to hold off.

“I have a hard time [envisioning a scenario where I wouldn’t refer]—short of somebody who’s unsalvageable, [such as if] they’re in the hospital [and too unstable to proceed],” explained George.

Narra also raised distance as a practical barrier for patients in the West Valley, asking whether other centers had explored telehealth for initial consultations; Zawit and Samhouri both noted that they do not mandate an in-person visit for an initial cell therapy consult.

For patients relapsing within 12 months, Farmer said she would favor CAR T-cell therapy over transplant given the short interval to refractory disease. Beyond 12 months, Zawit said he would consider immunotherapy in that setting, reasoning that relapse biologically may have begun before the 12-month mark even if it wasn’t detected until later. Rosenthal said she would weigh CAR T-cell therapy against transplant on a case-by-case basis.

On product selection, Rosenthal said they favor axi-cel for patients without central nervous system (CNS) involvement, in part reflecting comfort with a CD28 costimulatory construct in younger patients who are more toxicity-tolerant. Liso-cel, a 4-1BB construct, was preferred for patients with CNS involvement or those less able to tolerate early cytokine release syndrome (CRS) and neurotoxicity. Samhouri walked through the comparative safety data: grade 3 or higher CRS occurred in 6% of patients treated with axi-cel vs 1% with liso-cel, while grade 3 or higher neurologic events occurred in 21% with axi-cel vs 4% with liso-cel.

Bridging Therapy and Referral in Practice

The panelists described the referral process itself as informal and relationship-driven. George said he typically gets a cell therapy specialist’s contact information and texts patient details directly rather than submitting a formal referral, noting, “you have to know somebody there.”

On holding off bridging therapy ahead of apheresis or infusion, preferences varied by physician and clinical scenario rather than following a single protocol. GemOx (gemcitabine-oxaliplatin), ICE (ifosfamide-carboplatin-etoposide), polatuzumab vedotin-piiq (Polivy) plus rituximab (Rituxan) (Pola-R), and involved-site radiation were the most commonly cited options. Several panelists noted growing interest in bispecific antibodies for patients with limited disease sites. Rosenthal said the choice is patient-specific and often depends on insurance type, noting that patients with Medicare tend to move through the process faster than patients with commercial insurance.

She estimated that roughly 85% of her patients likely need some form of bridging, though she does not bridge uniformly, sometimes withholding therapy in asymptomatic patients who have a normal lactate dehydrogenase level and a short anticipated wait time. She also generally avoids platinum-containing regimens because of the risk of renal injury and cytopenias that could delay subsequent therapy. Several panelists, including Baker, said their practice is to confirm the intended holding regimen with the cell therapy team before initiating it, rather than starting bridging therapy independently.

Case Discussion: Product Choice and Nonclinical Barriers

The panel then discussed a case of a 35-year-old patient with de novo stage 4 DLBCL and an International Prognostic Index (IPI) score of 2 who was treated with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) in the first-line setting. Pasquarella said he generally prefers Pola-R-CHP for patients with a high IPI who do not have double- or triple-hit histology, and George noted that, per the phase 3 POLARIX trial (NCT03274492), high IPI and non-germinal center B-cell subtype disease tend to overlap, though this particular case’s lower IPI and germinal center B-cell subtype made it a less clean fit for that pattern.⁴ Rosenthal said her practice does not have a standardized approach to treatment selection based on cell of origin, noting it depends on whether a full or partial mutation panel is sent.

For this patient, panelists agreed CAR T-cell referral would be appropriate regardless of whether relapse occurred before or after the 12-month mark. Rosenthal said she would prefer axi-cel in the absence of CNS disease, citing consistency and reliable product turnaround, while favoring liso-cel if CNS involvement were present:

“From a CAR-T perspective, for those who have known CNS involvement, I’d lean more towards using [liso-cel] when we get there.... I think you can treat people who have had CNS involvement as long as you have some management of it going into CAR-T. I have plenty of patients who have had active CNS disease that had a long-term response to CAR-T,” stated Rosenthal.

Zawit said he uses liso-cel more often than other products generally, and Pasquarella agreed liso-cel was the more appropriate choice with CNS involvement. Samhouri and Pasquarella said they would still refer a patient for CAR T-cell therapy at first relapse even with CNS involvement, noting that CNS disease is not an exclusion criterion for CAR T-cell therapy as long as it is managed prior to treatment.

Nonclinical Barriers to Referral

Nonclinical barriers to referral drew significant discussion. Baker noted patient preference itself can prevent referral. George pointed to the prevalence of naturopathic medicine providers in Arizona, particularly in the Scottsdale area, as a recurring source of delay, with some patients pursuing unconventional treatment from the outset and others turning to it after a difficult experience with conventional therapy. Rosenthal and Samhouri said they had encountered the same pattern. Pasquarella cited financial barriers and social support as additional obstacles, and Samhouri said caregiver support was, in his experience, the single most common nonclinical reason CAR T-cell therapy had not been pursued for an otherwise eligible patient.

“The most common reason I don’t do CAR-T, although the patients reached my door, is caregiver support…. If they don’t have anyone to stay with them for 24 hours—to bring them to appointments, to check on them if they get fevers [or] infections—that’s the most common reason where I had to say no to CAR-T,” Samhouri said.

Finally, the panel agreed that delaying CAR T-cell referral carries real consequences. Samhouri said that it allows disease to worsen and can foreclose the possibility of cure, and Zawit added that delay may simply prolong patient suffering.

References

1. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133
2. 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
3. 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):1675-1687. doi:10.1182/blood.2022018730
4. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304