Reviewing Options After CAR T-Cell Therapy Progression in R/R DLBCL

Mehdi H. Hamadani, MD (Moderator)

Professor of Internal Medicine

Division of Hematology & Oncology

Medical College of Wisconsin

Milwaukee, WI

DISCUSSION QUESTIONS

• If a patient relapses after or refractory to chimeric antigen receptor (CAR) T-cell therapy for diffuse large B-cell lymphoma (DLBCL), do you have a preferred regimen?​
• What factors influence your choice for next line of therapy?

MEHDI H. HAMADANI, MD:Let's say a patient was sent to a CAR T-cell therapy center, and the patient didn't benefit from CAR T-cell therapy, either she either relapsed or she was refractory to CAR T. In your practice, do you have a preferred next-line agent after CAR T-cell therapy progression?

VICKI MORRISON, MD: I think part of it depends if they've had a prior autologous stem cell transplant [ASCT] or not, or if they're a candidate for transplant. Otherwise, if they're not a transplant candidate, I don't think there would be a single preferred regimen. A lot would depend on their overall functional status, performance, and what the patient wanted.

HAMADANI: Does anybody have a favorable experience with a given option after CAR T-cell therapy progression?

TAREQ AL BAGHDADI, MD: There are some hypothetical considerations here. CAR T-cell therapy targets CD19. If the disease was absolutely refractory without an initial response, not even a PR [partial response], I'd be reluctant about other CD19-targeting treatments, at least as single agents. A bispecific [T-cell engager] would make sense, and it targets a different epitope, CD20. The real question is which one is best used first in terms of affecting the T cell fitness? Is it better to do CAR T-cell therapy and then bispecific or vice versa?

I suspect CAR T-cell therapy first might be better for the immune system, [since] you don't exhaust the T cells. You collect first and then you leave the bispecific for later. That way you target CD20 [with frontline rituximab (Rituxan)], CD19, and then CD20 again, allowing some time off of CD20 treatment.

We've recently activated a trial [SWOG 2207; NCT05890352] that might change my approach with tafasitamab [Monjuvi] plus lenalidomide [Revlimid] and zanubrutinib [Brukinsa] vs tafasitamab/lenalidomide plus tazemetostat [Tazverik]. A trial is always my preferred option here. We have the epcoritamab trial [NCT05451810] where all treatments are given in the outpatient setting; we've had a few patients on it. It tends to work well and is relatively easy. We've not faced any major problems with epcoritamab yet in the trial, and every treatment is outpatient. My choice depends on how long [CAR T-cell therapy] works, whether it works or not, and what's available.

HAMADANI: Excellent response because you can’t go wrong with a trial. But if a trial is not available, you’re setting the stage perfectly for the questions we want to examine. Should we gravitate to bispecifics if one is available, and can we sequence CD19 therapies? I think the answer may depend on which CD19 agent.

DISCUSSION QUESTION

What is the role of loncastuximab tesirine-lpyl (Zynlonta) in patients who have received prior CAR T-cell therapy?

HAMADANI: We were very interested in [how] the LOTIS-2 trial [NCT03589469] allowed patients with CAR T-cell therapy progression.¹ These are patients who progressed on CAR T-cell therapy with continued expression of CD19, and CD19 loss in lymphomas is not all that common. About 25% of the patients may lose CD19 after CAR T-cell therapy failures. But if you don't lose CD19, does loncastuximab have any hope of working after CAR T-cell therapy? Because it’s an easy-to-give drug in smaller community practices.

Our experience with this drug was that after CAR T-cell therapy progression, the response rates were a respectable 46%, and if you happen to respond, the responses [were durable].² This is not a curative treatment after CAR T-cell therapy progression, but in the real world I'm using loncastuximab as a bridge to an ASCT in the right patients. I have at least 2 patients I've done ASCTs for and those patients only got to an ASCT with loncastuximab as a bridge, so that that is 1 option that is out there. But there is no one-size-fits-all option for all patients after receiving CAR T-cell therapy. I wish something like that existed, but for the right patient, it's an available option.

AL BAGHDADI: I've seen [the LOTIS-2 data] before, and there's a problem with them. The numbers are very small, 13 patients, and duration of response is definitely lower: approximately 13 months [for the overall population] vs 8 months after CAR T-cell therapy.2 The important question is, what was the relationship between response to CAR T-cell therapy vs loncastuximab? Are all patients responding to loncastuximab [also] patients who previously had a complete response [CR] to CAR T-cell therapy? It's not included [in the data]. What is the time difference between [receiving] the CAR T-cell therapy and loncastuximab? Did that affect response? That's also not mentioned. I've seen the data, but it doesn't help me too much other than to say it might work, but it seems inferior.

HAMADANI: It's a very good question. [The published data] shows you…the responses to loncastuximab [as well as] response to CAR T-cell therapy…. I admit that these are small numbers, but among these 13 patients, 54% had a CR after CAR T-cell therapy and then lost that response, 15% were PRs, and then another 31% were refractory to CAR T-cell therapy.

AL BAGHDADI: Which ones of those responded to loncastuximab? That's what it doesn't tell you. Was it the ones with CR, the ones with no response, or a mixture?

HAMADANI: It's a valid question…. I don't know, among the loncastuximab responders, [whether] the responders were patients who were refractory to CAR T-cell therapy, or were those patients who had CR to CAR T-cell therapy and then happen to respond.

But it's an important consideration, because the Memorial Sloan Kettering Cancer Center group presented some very interesting data at the last American Society of Hematology meeting, where they looked at tafasitamab/lenalidomide and CAR T cell progression. There was an important observation was if CAR T cell progression happened within 6 months, virtually nobody responded to tafasitamab/lenalidomide and if the CAR T cell progression was after 6 months, the response rates were [approximately] 30%.³ Maybe the interval from CAR T-cell therapy and the subsequent therapy is important, but it's a very valid question about this agent.

_References:

_{1. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X}

_{2. Caimi PF, Ardeshna KM, Reid E, et al. The antiCD19 antibody drug immunoconjugate loncastuximab achieves responses in DLBCL relapsing after antiCD19 CAR-T Cell therapy. Clin Lymphoma Myeloma Leuk. 2022;22(5):e335-e339. doi:10.1016/j.clml.2021.11.005}

_{3. Qualls D, Buege MJ, Dao P, et al. Tafasitamab and lenalidomide in relapsed/refractory large B cell lymphoma (R/R LBCL): Real world outcomes in a multicenter retrospective study. Blood. 2022;140(suppl_1):787-789. doi:10.1182/blood-2022-167620}