Navigating CAR T Therapy Pathways in R/R Large B-Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for patients with relapsed or refractory large B-cell lymphoma (LBCL), offering a potentially curative option in earlier lines of therapy. During a live Case-Based Roundtable event in The Woodlands, Texas, Paolo Strati, MD, associate professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, walked through the currently available anti-CD19 CAR T therapies in this setting, key factors influencing eligibility, and real-world logistical considerations—including referral, manufacturing time, bridging therapy, and evolving FDA requirements—that shape how clinicians deliver CAR T therapy for this patient population.

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Targeted Oncology: What are the CAR T therapies currently available for treatment of relapsed/refractory LBCL?

Paolo Strati, MD: Currently, there are 3 autologous, anti-CD19 CAR T-cell products approved by the FDA: axi-cel [axicabtagene ciloleucel; Yescarta], liso-cel [lisocabtagene maraleucel; Breyanzi], and tisa-cel [tisagenlecleucel; Kymriah].¹ FDA labeling currently allows to utilize 2 of them, axi-cel and liso-cel, in the second line… either for patients with primary chemotherapy-refractory disease—so those who have anything less than a complete response in response to frontline chemoimmunotherapy—or those who relapse within 12 months. Tisa-cel is not currently accessible in second line because the randomized phase 3 trial [NCT03570892] was negative,² but we can utilize tisa-cel along with axi-cel and liso-cel in third line or beyond.

How do you assess and define a patient’s eligibility for CAR T? What clinical and/or patient factors do you consider?

Of course, the big question is: who is CAR T-eligible? It's a little bit easier when it comes to transplant. Transplant has been around for a long time, and there are very clear guidelines on who should be eligible; there are national guidelines and universal consensus on who is transplant eligible. As for CAR T, it's an ongoing conversation. I would say some centers tend to be a little bit more conservative because we don't want to lose our accreditation by giving CAR T to patients who may be too high-risk and having too much CAR T-related mortality, and some others, including the center where I work, are more [open]. As a tertiary center, we will be willing to take the risk of taking a patient who may be considered ineligible in another center. But my point is the following: the eligibility for CAR T may look very different based on this and where you work. …

Age, performance status, social barriers, organ dysfunction, solid organ transplant, all of those are currently subject of discussions when it comes to CAR T eligibility… It's a process, and it may not be feasible for everybody. It’s identification of a relapse, referral to a center that has CAR T ability, even just for evaluation for eligibility, and then you have to go through insurance approval. There's a financial step, there's a medical clearance step… and then the manufacturing based on the product is usually anything between 3 to 4 weeks, but that could be a critical time where you're trying to hold the bridge. And then that's not the end yet. Finally, the CAR T infusion happens, and then the patient usually has to hang around for a couple of weeks or longer. This has changed recently; the REMS [risk evaluation and mitigation strategies] requirements have changed no longer than a year ago, which is very convenient for our patients.

How does the removal of the FDA REMS program impact your overall clinical management of patients and CAR T therapy?

As a reminder, until June of 2025, after CAR T-cell infusions, there was an obligation for patients to stay around for up to 4 weeks, and now it's gone down to 2 weeks. They could not drive for 8 weeks, and now it's down to 2 weeks. And there was a requirement to be monitored daily for about 10 days, and that's down to 7 days. So [the patient’s] ability to drive themselves back and forth definitely was a major barrier before. But I think what happened is that the FDA, over the years, has reviewed all the literature, particularly the long-term follow up from clinical trials, and just realized that—because there is an overall survival benefit, because the intent of treatment is cure—that it was worth to minimize the requirements to address these barriers so that maybe the patient may be encouraged to still undergo a CAR T-cell infusion. At the end of the day, they will need to stay around the academic center for 2 weeks at the longest… To put things in context, even at MD Anderson, we haven't truly started yet to send back patients so early.

CASE SUMMARY

A 60-year-old man presented with fatigue, back pain, and lymphadenopathy.

• Past medical history: Well-controlled hypertension
• Physical exam: left posterior cervical node (1.5 cm); right anterior cervical node (2.5 cm); left supraclavicular node (2.0 cm)
• PET-CT: multiple enlarged mesenteric and retroperitoneal nodes, largest 5.3 x 3.1 cm
• Bone marrow biopsy: Negative
• Lymph node biopsy: confirmed DLBCL, nongerminal center B-cell, double-expresser lymphoma
• Normal complete blood count
• International Prognostic Index: high-intermediate risk; nongerminal center
  • Age ≥ 60 y, elevated LDH, stage III or IV disease
  • ECOG performance status ≥ 2
  • >1 extranodal site

How would you approach treating this patient?

The main difference between axi-cel and liso-cel is the costimulatory domain, which is CD28 for axi-cel and 4-1BB for liso-cel and then translates into different dynamics of growth of CAR T. So, if you look into the way CAR T-cells grow, axi-cel grows after infusion; it will be peaking and be a very tall peak within the first 7 days, and then they go down, then translating to surgery. In the pivotal trials, we’ll see more CRS [cytokine release syndrome], more ICANS [immune effector cell-associated neurotoxicity syndrome], but also potentially more activity. [On the other hand], liso-cel with 4-1BB will not peak as much, would be a “kinder” kinetic, and the [CAR T-cells] may persist for a long time. Now, we don't know whether the long-term persistence gives any benefit, because at the end of the day, what may matter is the ability to eradicate lymphoma within the first 30 to 90 days, and those persistent CAR T-cells months later may be innocent bystanders with no clinical function…but there's never been a head-to-head study, so we don't know which one is better. There's no doubt that liso-cel is not as toxic, so if this patient had any of the big nodes and I had to go with CAR T, I can go with liso-cel. It's a no-brainer in that case, but we haven't answered yet the question whether, in terms of efficacy for cancer toxicity, one is better than the other.

Platinum-based salvage chemotherapy, in my opinion, should be given if you are planning for autologous stem cell transplant subsequently. I don't want you to think that autologous transplant has zero chance of curing somebody with primary chemotherapy; it may still work, but we know there's been a randomized trial comparing this approach with platinum-based chemotherapy followed by transplant to CAR T, and we know the CAR T is better, so I'm going to probably go this route. Polatuzumab vedotin is not formally approved by the FDA in the second line, but it's in the guidelines. Unfortunately, it's combined with bendamustine in the label, and there's now very clear evidence that if we use bendamustine, CAR T-cell activity subsequently may not be as good. So, if you're planning for CAR T in third line, I would use polatuzumab vedotin [Polivy]-rituximab [Rituxan] and drop the bendamustine. I feel like polatuzumab vedotin-rituximab is probably the most commonly utilized holding or bridging treatment before CAR T.

Tafasitamab [Monjuvi]-lenalidomide [Revlimid], in my humble opinion, is for the transplant- and CAR-T–ineligible, so those patients are older and frail. It seems to be working well. The pivotal trial they brought to the approval of tafasitamab-lenalidomide in second line and beyond is called L-MIND [NCT02399085].³ They have a 5-year follow-up, and 20% to 30% of patients were still in remission. But it's a very selective population where you can't do anything else [in terms of treatment]. So if I can’t do transplant or CAR T, I think tafasitamab-lenalidomide is a great option. Bispecifics as single agents are not, even in combination, formally approved by the FDA in the second line. Per NCCN guidelines, you can use in combination…in second line, but most insurances will not look into the guidelines and will look into the FDA label.

DISCLOSURES: Strati previously disclosed a consulting role with Hutchinson MedoPharma and Roche Genentech; memberships on a Board of Directors or advisory committee at Sobi, AstraZeneca Acerta Pharma, Kite Gilead, and ADC Therapeutics; and receipt of research funding from Sobi, AstraZeneca Acerta Pharma, Kite Gilead; ADC Therapeutics, and ALX Oncology.

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REFERENCES

1. Westin J, Sehn LH. CAR T cells as a second-line therapy for large B-cell lymphoma: a paradigm shift? Blood. 2022;139(18):2737-2746. doi:10.1182/blood.2022015789

2‌ .Bishop MR, Dickinson M, Purtill D, et al. Second-Line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med. 2022;386(7):629-639. doi:10.1056/NEJMoa2116596

3. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. The Lancet Oncology. 2020;21(7):978-988. doi:10.1016/s1470-2045(20)30225-4