Selection of non-CAR T-Cell therapy in third-line DLBCL R/R

DISCUSSION QUESTIONS

  • How can you sequence the different therapies available for relapsed/refractory third-line diffuse large B-cell lymphoma?​
  • When you think of each, which patient comes to mind as a “perfect fit”?​
  • Would you use any of these therapies, on or off-label, as a second-line treatment?​
  • How do you feel about these therapies compared to CAR (chimeric antigen receptor) T cell therapy?​

JASON WESTIN, MD: Considering clinical trial data for polatuzumab vedotin [Polivy] plus bendamustine and rituximab [Rituxan]tafasitamab [Monjuvi]/lenalidomide [Revlimid]and loncastuximab tesirine [Zynlonta], what are the individual patient characteristics, both clinical and pathological, that might make a difference in your assessment? Is there a patient in particular that you consider an ideal candidate for one of these therapies? Dr. Reddy, tafasitamab was something you were considering. Is there an ideal solution for any of these therapies for a given patient?

BRAMHAM REDDY, MD: Honestly, I don’t know if this is best for every patient because I practice in a small town community practice. [When dealing with patients with] lymphoma after the first and second line, I refer them to a university center. I live about 2.5 hours from Houston, so it’s going to be a tertiary center that will decide. From what I’ve learned, tafasitamab seems to be the easiest therapy I can use. Beyond that, I would probably let the tertiary center decide. It would be very difficult for me to learn how to implement the other agents.

WESTIN: Yes, there is a muscle memory that develops when you don’t have unlimited time to learn all these things. It is useful to [review] some of the data. But getting that experience with 1 or a few therapies and using them as a benchmark is a practice that many of us have.

Dr. Huang, do you have any thoughts on therapy sequencing? Is there a particular agent that you would use as a backup plan? What do you think of how you would structure this processing algorithm?

QUILLAN HUANG, MD: I’ll be honest, I don’t really know. Obviously, CAR T-cell therapy [should be used] if we can, and then I think out of all the CD19 targeting choices, it’s really hard to sequence them. We have used tafasitamab in patients with post-CAR T cells. We checked for CD19, saw it was still positive and gave it a try. It worked occasionally, not surprisingly. Otherwise, we haven’t had a chance to try loncastuximab yet. I think it’s just newer, and we haven’t reached that point yet. Again, the tafasitamab data looks good. I was wondering what you guys think—tafasitamab seems to have a plateau towards the curve.1 It was also the big idea of ​​CAR T-cell therapy, that there was a plateau to the curve.2 They’re different populations in different trials, but I’m just curious to see what you guys think.

WESTIN: I think that’s exactly it. They both look great, but they’re not in the same pool. One of them is a dual impact disease-free population, refractory patients and transplant ineligible population, and the other plays in a more chemotherapy refractory area. So I think it’s hard to know without a direct comparison, but I think if you had a 45-year-old man in your clinic who runs marathons, most of us would consider that person for CAR T therapy -cell , and not for something like tafasitamab/lenalidomide if they could have all the options in front of them.

But real life happens, and sometimes people can’t get to CAR T cell centers, so there’s definitely a role for those who could potentially catch CAR T cells in the future, and I think that there are questions about CD19 loss or targeting CD19 that we don’t yet know about. We don’t have much data on performing these CD19 therapies before CAR T-cell therapy, except for anecdotal experience from the LOTIS-2 trial. [NCT03589469] showing that patients who had previously received CAR T-cell therapy could respond to loncastuximab, and that patients who had previously received loncastuximab could respond to CAR T-cell therapy.3

DISCUSSION QUESTION

  • Under what circumstances would you be most likely to use loncastuximab tesirine as third-line therapy for a patient with DLBCL R/R?​

WESTIN: Is there a patient you consider an ideal candidate for loncastuximab tesirine? Does anyone have an opinion on this, since it is relatively well tolerated, with a response rate of around 50%?3 Is there anyone in particular to whom you would say, “This is the kind of patient I would recommend to loncastuximab?” »

I think the data from the two dual-impact patients that were expressed in the Kaplan-Meier curves, showing that a decent proportion of patients had dual-impact disease, were more heavily pretreated, and received the CAR T- therapy previous cell, all of those I think were unique and might be someone who would be a good candidate to use it. But knowing that you don’t necessarily burn a bridge for CAR T-cell therapy, at least in the stories we’ve seen so far, I’m not sure the idea of ​​reserving loncastuximab just for a no -CAR T- cell patient makes a lot of sense. I think it’s something that as we gain more experience and figure out how to deal with the toxicity profile, doctors will become more comfortable and familiar with it.

DISCUSSION QUESTIONS:

  • If loncastuximab tesirine was covered by insurance, would you use it as a second line for patients who refuse autologous stem cell transplant (ASCT)?​
    • For patients who may be eligible for CAR T-cell therapy?​
    • For patients you consider ineligible for CAR T-cell therapy?​
  • Do you foresee any barriers to using loncastuximab tesirine?​

WESTIN: If loncastuximab is covered by insurance, how would you use it as a second line in patients who refuse transplant? Dr. Lee, if there was a potentially eligible or ineligible patient for CAR T-cell, how would you put loncastuximab in the algorithm?

HUN LEE, MD: My experience with loncastuximab is in the context of post-CAR T cells. I have concerns about targeting CD19 before CAR T. Do you decrease the effectiveness of CD19 CAR T cells if you use them before? We see downregulation of Hodgkin lymphoma when we use brentuximab [Adcetris]. When we re-biopsy these patients who were exposed to brentuximab, they clearly decrease or upregulate CD30.4 So, I’m worried. I use loncastuximab in post-CAR T-cell therapy, as does tafasitamab. I have spoken with many doctors, and we love having a CD19 blank for CAR T-cell therapy, because many patients enter CAR T-cell therapy with the hope and prayer that they will be in this 30 % to 40% of patients with a possibility of cure. So I want to give them the best opportunity to get that 30% to 40% chance of long-term sustainable remission, and a possible cure.

I use polatuzumab for bypass. I agree with you. I don’t like using bendamustine with polatuzumab because I haven’t harvested the T cells at this point. But after harvesting them, I give them bendamustine, but not a lot, because they will soon receive high doses of cyclophosphamide. I’m trying to work on this very fine line of bone marrow toxicity because we have significant cytopenia after CAR T-cell therapy.

WESTIN: It can certainly be a problem, there’s no doubt about it. Dr. Luu, do you foresee any barriers to using loncastuximab? I know it’s new, and maybe you haven’t had a chance to use it yet, but is it something you see as a hindrance in your practice, or is it something who could enter the pantheon of available treatments?

CHU LUU, MD: Yes, I think the biggest hurdle would be knowing how to use it and anticipating the side effects. But I think with better experience, I don’t see any obstacles.

References:

1. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): multicenter, prospective, single-arm phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

2. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagen ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm multicenter phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7

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

4. Al-Rohil RN, Torres-Cabala CA, Patel A, et al. Loss of CD30 expression after treatment with brentuximab vedotin in a patient with anaplastic large cell lymphoma: a new finding. J Cutan Pathol. 2016;43(12):1161-1166. doi:10.1111/cup.12797

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