CD19-Directed Antibody-Drug Conjugates for DLBCL

Part 3: Third-Line Use of Loncastuximab for Relapsed/Refractory DLBCL

During a live virtual event, Beth A. Christian, MD, discussed data on third-line loncastuximab tesirine treatment in patients with diffuse large B-cell lymphoma and how to sequence treatments for patients who may receive CAR T-cell therapy.

DISCUSSION QUESTIONS

  • Under what circumstances would you be most likely to use loncastuximab tesirine (Zynlonta) as third-line therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL)?
  • What do you view as the pros and cons of loncastuximab as compared with other alternatives such as tafasitamab (Monjuvi)/lenalidomide (Revlimid), polatuzumab (Polivy)/bendamustine (Treanda)/rituximab (Rixutin), and selinexor (Xpovio)?
  • Do you foresee any barriers to using loncastuximab?
  • If loncastuximab were covered by insurance, would you use it in the second line for patients who decline stem cell transplant?
  • Would you use it for patients who may be eligible for chimeric antigen receptor (CAR) T-cell therapy?
  • Would you use it for patients who you consider not to be eligible for CAR T-cell therapy?
  • Consider the 46% response rate to CAR T-cell therapy in the 15 patients who received CAR T-cell therapy after loncastuximab.1 How does that factor into your opinions on sequencing therapeutics?

BETH A. CHRISTIAN, MD: For the participants that have used loncastuximab, what’s your experience like?

YAZAN SAMHOURI, MD: We’ve used loncastuximab in 2 patients who had rapidly progressing disease. This was in the inpatient setting, and we were desperate to gain some control over the disease [to take them to CAR T-cell therapy after failure of other bridging therapies]. But we were unlucky in both patients; 1 patient received 2 cycles [of loncastuximab], and the other patient received 1 cycle before passing away.

CHRISTIAN: It sounds like the patients were on treatment for a relatively short time. Did you encounter any issues with edema or myeloid suppression?

SAMHAHOURI: They experienced myeloid suppression for sure. As for edema, they had already been in the hospital receiving a lot of fluids and had the usual iatrogenic fluid overload. I don’t remember there being any pleural effusion, or anything outstanding that [we could attribute to] loncastuximab.

NEENOS ALNOOR, MD: Did the patients die because of cancer progression or adverse events of the drug?

SAMHOURI: They died from the disease, which was just very refractory to everything, and we couldn’t really control it. It was one of those DLBCLs or high-grade B-cell lymphomas.

CHRISTIAN: In what circumstances would you be most likely to use loncastuximab as third-line therapy for a patient with R/R DLBCL?

ANEEL CHOWDHARY, MD: I haven’t used most of these therapies, and I think the reason for that is that I use R-GemOx [rituximab plus gemcitabine plus oxaliplatin] in most of my patients [who develop refractory disease] after first-line therapy. If the patient has an activated B-cell lymphoma then I am more likely to use zanubrutinib [Brukinsa] or lenalidomide. But the majority of my patients have had germinal cell [GC] disease.

In these patients, I generally use [a combination with] rituximab [Rituxan]. I think a platinum drug is important here. That’s when I go for a second-line [therapy] if the patient is not transplant-eligible. By then I’ve referred the patient for CAR T-cell therapy and they go on to our lymphoma team. But I know that I’m going to be getting some of these patients back. And for various reasons, some of them will go on to third-line or post-CAR T-cell therapy. There are all these [late-line] regimens, and we’ve seen some of the data. I think the polatuzumab vedotin, bendamustine, rituximab is something I lean towards, but I don’t completely grasp where and when to sequence these late-line treatments.

In your decision-making for sequencing, where are your inflection points in terms of using tafasitamab versus a polatuzumab-based regimen? How are you sequencing these in the late-line setting, [both in patients who have and have not received CAR T-cell therapy]?

CHRISTIAN: Some of the things I take into consideration are [the R/R DLBCL setting is] evolving and changing, and it’s really challenging right now to manage this condition.

For my patients who have undergone prior CAR T-cell therapy; [these are usually] younger, fitter patients who weren’t eligible for autologous stem cell transplant or who relapsed after autologous stem cell transplant and received CAR T-cell therapy. One challenge that I encounter with these patients is that they often have prolonged cytopenia, whether that’s from transplant or from CAR T-cell therapy.

In my own practice, I’ve found that [cytopenia] can be somewhat of a barrier to using rituximab plus polatuzumab vedotin. I have had some patients where I started that therapy and then ultimately, I ended up converting it to polatuzumab alone, and I’ve seen some responses there. But I think low blood cell counts can be a challenge with that regimen.

One of the things that I take into account with tafasitamab/lenalidomide is the cell of origin. So, although the data in the phase 2 L-MIND study [NCT02399085] included patients with both non-GC and GC DLBCL, the responses [to lenalidomide] favored non-GC type disease.2 That is something that plays into my decision-making. I also find that the full dose of lenalidomide with tafasitamab/lenalidomide is not necessarily easy on blood counts. That’s something that I also consider when I am making choices about these treatments. And then finally, I think when it comes to loncastuximab, [one has to consider] the tolerability of it, in terms of the dosing schedule, and having to talk with patients and counsel them about the edema [associated with this drug]. There can also be some issues related to myelosuppression, but the dosing schedule does tend to be a little bit kinder [for loncastuximab] than for tafasitamab/lenalidomide.

I don’t think there really is an optimal sequence [for late-line therapies for R/R DLBCL], but [when I make sequencing decisions] I try to take into account patient factors, [such as blood] counts, peripheral neuropathy, prior lines of therapy, [and] cell of origin.

TSUYNOSHI INOSHITA, MD: For the second line patients who are not transplant candidates, how do you select between, R-GemOx versus BR-pola [polatuzumab vedotin plus bendamustine plus rituximab] versus tafasitamab/lenalidomide.

CHRISTIAN: If I have a patient [with non-GC DLBCL] who is elderly and unfit, and I don’t think they’re eligible for transplant or CAR T-cell therapy, that is where tafasitamab/lenalidomide was approved in and has showed good results with sustained responses in some patients.

Patients with high-grade large B-cell lymphoma were excluded from L-MIND of tafasitamab/lenalidomide.2 But these patients were included in other studies, and so that is something I might take into consideration, as well as how rapidly I need a response, or how sick the patient is.

In terms of myeloid suppression, at least in my experience, the BR-pola can be a little bit of a tougher regimen if the patient has baseline cytopenias or is elderly or unfit, and I’m concerned about tolerance.

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. 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. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4