Early Relapse Guides Use of CAR T Vs Other Options in LBCL

Chimeric antigen receptor (CAR) T-cell therapy has made a major impact on patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) in the second line of therapy. In a Community Case Forum event in Denver, Colorado, Matthew Lunning, DO, assistant vice chancellor of clinical research and associate vice chair of research of the department of internal medicine at the University of Nebraska Medical Center, discussed the key factors that determine whether patients should receive CAR T-cell therapy, autologous stem cell therapy, or other treatment options. He also examined the typical patient journey to receive CAR T cells from identifying the appropriate patient, to selecting bridging therapy, to monitoring after CAR T-cell infusion.

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Targeted Oncology: How do you define a patient’s eligibility for CAR T in the second line?

Matthew Lunning, DO: R/R LBCL has been flipped upside down with the movement and migration of CAR T-cell therapy truly into the second line, and now in clinical trials going on in the first line. [A diagram] by [Jason Westin, MD, and Laurie H. Sehn, MD], looks at where this divergence happened based upon the ZUMA-7 trial [NCT03391466] as well as the TRANSFORM trial [NCT03575351].¹

One of the things that I’ve started to do in my clinical practice for patients with LBCL is once I get done with either R-CHOP [rituximab (Rituxan), cyclophosphamide, hydroxydaunomycin, vincristine sulfate (Oncovin), and prednisone], Pola-R-CHP [polatuzumab vedotin (Polivy), rituximab, cyclophosphamide, hydroxydaunomycin, or dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine sulfate, cyclophosphamide, and hydroxydaunomycin], I write down when the therapy was completed, because that’s when the clock starts. The vast majority of relapses, if they’re going to occur, occur within the first year from completion of their therapy, [and] that is added to the 10% to 15% who are primary refractory to their disease. Unfortunately, the POLARIX trial [NCT03274492], if you look at the PFS curves, didn’t improve upon that primary refractory population.²

For those who have early relapsed or primary refractory disease, based upon the ZUMA-7 and TRANSFORM data, if eligible for CAR T-cell therapy, they should now be…migrated into that setting. However, if you relapse greater than 1 year from the completion of your induction therapy, and you’re felt to be eligible for stem cell transplant, [you proceed to salvage and transplant].¹ The biggest barrier in getting to your consolidated autologous transplant…still remains the disease. There also may be a whole subset of patients who are not felt to be transplant eligible. They often drop down into [second or third-line options]. Based upon the PILOT trial [NCT03483103] data, CAR T cell is still there with regards to liso-cel. The other therapies that may be offered in the second line for those [who are] not CAR T cell [or] transplant eligible include polatuzumab plus bendamustine and rituximab, tafasitamab [Monjuvi] plus lenalidomide [Revlimid], and other clinical trials.

How do patients transfer from the community setting to receive CAR T cells?

The CAR T cell journey is very complex. When we think about the clinical trials, where it was very regimented on who was eligible and our exclusion criteria…when we moved into the commercial environment, that inherently increased certain things…we couldn’t anticipate within clinical trials. Walking through the landscape of patients who have R/R LBCL, many of the entry points [are] community oncologists referring to academic practices that are authorized treatment centers, or even those community practices now that are authorized treatment centers, but don’t [categorize] themselves as an academic facility. They’re considering CAR T-cell [therapy] either as second line or as third line. In my practice, if I think it’s an intent-to-CAR situation, I will include the line of the pre-apheresis and the post-apheresis bridging therapy not as a line of therapy, but congruent with the CAR T-cell therapy. Just like we do if you’re using platinum-based therapy in an autologous stem cell transplant, you don’t consider R-ICE [rituximab, ifosfamide, carboplatin, etoposide] and then BEAM [carmustine, etoposide, cytarabine, melphalan] as second-line and third-line therapy for your patient with R/R LBCL.

What barriers are there to CAR T-cell center referral?

We know that there can be some barriers even after identifying those patients for second-line or third-line CAR T. There can be a lot of logistical challenges. [In Colorado], getting to the CAR T-cell center may be an issue if you have to pass over the Continental Divide. There can also be the financial ramifications, be it based upon certain insurance carriers, or being underinsured for certain situations, or uninsured, which may present financial challenges. We also know that there’s a time commitment to getting CAR T cells, both with regards to the patient as well as the caregiver, in regards to getting to an authorized treatment center. To prepare for CAR T-cell therapy, there may need to be conversations around pre-apheresis therapy, choosing wisely what you do before you pull the CAR T cells out, as well as post-apheresis bridging therapy, where a lot of the data lives. There aren’t a lot of data in the pre-apheresis period of time from that standpoint. I think the post-apheresis bridging therapy is an evolution.

What else stands out about the real-world CAR T setting?

When we think about in-specification products, we’re doing a lot better in 2025 than I would say we were doing even 3 years ago with getting patients in-specification products, with the relaxation by the FDA of what actually constitutes an in-specification product vs a not-out-of-specification product, yet infusible on expanded access protocols.

Once those products are infused, many patients are doing them as an outpatient infusion, but perhaps being admitted after infusion, or are choosing to stay outpatient. In the PILOT study, even though it was an advanced age or comorbid patient population, 41% of the patients were treated in the outpatient setting.³ That being said, some of those patients did require a hospitalization for cytokine release syndrome [CRS], neurologic events, or complications related to cytopenias—either acute, related to the fludarabine lymphodepleting chemotherapy, or later onset, likely due to manifestation of the immune environment post CAR T cell. We know that early infections can be an issue, often from the lymphodepleting chemotherapy or the amount of steroids that are required to control the CRS and neurologic events.

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_{DISCLOSURES: Lunning previously reported receiving honoraria and/or has served in a consultancy or advisory role for AbbVie, Acrotech, ADC Therapeutics, Astellas, AstraZeneca, Bristol Myers Squibb, Caribou, CRISPR, Daiichi Sankyo, EUSA, Fate Therapeutics, Genentech, Genmab, Instil Bio, Ipsen, Janssen, Kite, Loxo, Miltenyi, MorphoSys, Novartis, Nurix, Pharmacyclics, Regeneron, Sanofi, Seagen, Takeda, and TG Therapeutics; and has received research funding from Bristol Myers Squibb, Curis, FATE Therapeutics, and Sana Therapeutics.}

_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. Morschhauser F, Salles G, Sehn LH, et al. Five-year outcomes of the POLARIX study comparing Pola-R-CHP and R-CHOP in patients with diffuse large B-cell lymphoma. J Clin Oncol. 2025;43(35):3698-3705. doi:10.1200/JCO-25-00925}

_{3. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel for R/R LBCL in patients not intended for HSCT: final results of the phase 2 PILOT study. Blood Adv. 2025;9(15):3694-3705. doi:10.1182/bloodadvances.2024015262}