Early Relapsed DLBCL Outcomes Have Changed Drastically Due to CAR T

Natalie Galanina, MD

Associate Professor of Medicine, Malignant Hematology and Medical Oncology

University of Pittsburgh School of Medicine

Physician

UPMC Hillman Cancer Center

Pittsburgh, PA

Targeted Oncology: Could you describe the treatment landscape for patients with diffuse large B-cell lymphoma?

Natalie Galanina, MD: We treat large cell lymphoma with standard-of-care induction chemotherapy, be that R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate (Oncovin), and prednisone] or R-EPOCH [rituximab, etoposide phosphate, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride, and prednisone], or more recently, pola-R-CHP [polatuzumab vedotin (Polivy), rituximab, cyclophosphamide, doxorubicin hydrochloride, and prednisone] is indicated for patients with activated B-cell subtype and advanced International Prognostic Index score between 2 and 5 and bulky disease.¹

In the relapsed/refractory setting, normally we resort to chimeric antigen receptor [CAR] T-cell therapy, particularly in patients with refractory disease and early relapse, but there's still a role for autologous hematopoietic cell transplant [HCT], particularly for those who suffer a relapse after 1 year, and there is a variety of different salvage regimens that are pretty much equivalent in terms of their efficacy. For patients who are ineligible for transplant, we do either polatuzumab/bendamustine/rituximab, tafasitamab [Monjuvi] plus lenalidomide [Revlimid] or a combination.

[Looking at the third-line options] CAR T-cell treatment is reserved for the second line these days. However, sometimes patients who relapse following HCT, for example, would be good candidates if eligible for CAR T. We also have a variety of other agents, such as loncastuximab tesirine [Zynlonta] and selinexor [Xpovio]… and pembrolizumab [Keytruda], primarily in primary mediastinal B-cell lymphoma, ibrutinib for activated B-cell subtype large cell lymphoma, and bispecifics such as epcoritamab [Epkinly] and glofitamab [Columvi].

How do you determine what patients should receive as second-line therapy?

This is the general algorithm that we normally use: depending on whether it's early or late relapse, we normally would do CAR T-cell therapy for the former and perhaps HCT would be a consideration for late relapsed disease.² In terms of outcomes, for chemotherapy-refractory disease, the outcomes post–salvage chemotherapy are fairly poor, and overall projected cure rates in that setting are on the order of 5%. CAR T cell outcomes are much better for the relapsed/refractory setting. There are now data that suggest that about 40% of patients on CAR T-cell therapy could be cured at 7-year follow up.^2,3

I think the vast majority of relapses occur within the first 2 years. In my experience, it's about 20% to 30% of patients who suffer relapse. So, [over] two-thirds are in durable condition with induction chemotherapy, and about one-third unfortunately suffer a relapse.

In my experience, primary refractory disease is defined as the patients who have evidence of residual disease, meaning Deauville score of 4 or 5 following the completion of induction chemotherapy, or those patients who will relapse early within the first 6 months. I don’t think it makes a big difference if the definition is 6 months or 12 months. The prognosis for these patients, prior to CAR T, was historically very poor, with cure rates of roughly 7%, and median survival of about 6 months.⁴ The therapeutic options for the patient like this have been much improved with the introduction of CAR T treatment.

[Data were] published back in 2017 [showing that] the timing of relapse correlates with response rates to additional therapy, and the survival also correlated with outcomes, whether or not the patient is eligible for transplant.⁴ Patients who relapsed within 12 months were the majority of these. Those patients who are eligible for autologous HCT are just a minority, about 20% of patients, and only half of them will relapse. So overall survival data are much worse for patients with early relapsed or refractory disease, as compared with those who will relapse later.

What considerations are there for giving CAR T-cell therapy in the second line?

We have a number of different products that we could use for large B-cell lymphoma, including axicabtagene ciloleucel [axi-cel; Yescarta] or lisocabtagene maraleucel [liso-cel; Breyanzi]. I think they're pretty much equivalent in terms of their efficacy. There are differences in terms of adverse events. Axi-cel has a more rapid expansion in vivo and therefore is associated with greater incidence of cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS]. Whereas liso-cel, because of the 4-1BB costimulatory molecule, has more of a gradual expansion, and therefore I hardly ever see any neurotoxicity with liso-cel. The incidence of CRS is low, and a lot of my patients just hang out for about a week, and then they get discharged, and they have no evidence of CRS whatsoever. That's very encouraging.

In terms of the bridging therapy, some of our patients do require that, simply because it takes time to get the products back. I've found gemcitabine/oxaliplatin creates a lot of cytopenia and makes it harder, especially as you see some cytopenias with CAR T-cell therapy, so it exacerbates that problem. But we also use polatuzumab. Sometimes I use polatuzumab, then apheresis, then followed by rituximab afterwards. We can use tafasitamab with lenalidomide, which I have not used. Or we can sometimes even use bispecific T-cell engagers such as glofitamab or epcoritamab.

I refer everyone who is eligible for CAR T. I would say all of my patients get CAR T in the second-line setting, those who are willing to come [and do] all the required assessments. In my personal experience, I [have had] one patient who said that she was unwilling to come, and she had a number of social [commitments] and she did not want to be too far away. But more than 90% are willing to commute, even in some cases 2 or 3 hours.

In terms of referring to academic centers, the earlier we start the process, the better, because this way we sometimes can obviate the need for bridging therapy, if things go smoothly. The potential roadblocks are probably housing, accommodation, and transportation.

I don't typically start the referral process before relapse. Usually, we confirm a relapse and then we start the CAR T treatment. We have a PET scan machine that is sensitive…then there’s a dilemma, is it a real uptake or not so? I've had at least 3 patients who had uptake that is not trivial, but then we did a biopsy, and it was negative.

How does minimal residual disease (MRD) assessment assist in the relapsed/refractory setting?

I have patients with positive PET scans but negative MRD, and then we would confirm with [a negative] biopsy.The other thing is that we normally do MRD assessment before treatment starts, and then after cycle 1 or 2. If the MRD remains positive, then it’s very likely that the patient will have refractory disease. It helps me get ready and potentially plan for this earlier.

DISCLOSURE: Dr Galanina had no known relevant disclosures.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 2.2025. Accessed March 6, 2025. http://tinyurl.com/4tnnkr68}

_{2. 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}

_{3. Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20(6):359-371. doi:10.1038/s41571-023-00754-1}

_{4. Farooq U, Maurer MJ, Thompson CA, et al. Clinical heterogeneity of diffuse large B cell lymphoma following failure of front-line immunochemotherapy. Br J Haematol. 2017;179(1):50-60. doi:10.1111/bjh.14813}