Challenges for Non–CAR T-Cell Treatment of Early Relapsed DLBCL

Elizabeth A. Brém, MD

Assistant Clinical Professor, Division of Hematology/Oncology

University of California, Irvine School of Medicine

Irvine, CA

DISCUSSION QUESTIONS

• How do you define primary refractory and early relapsed diffuse large B-cell lymphoma (DLBCL)?
• What therapeutic options would you consider for a patient with early relapsed DLBCL?

ELIZABETH BRÉM, MD: Would anyone want to share what their cutoff is for primary refractory disease? Is it 3 months, 6 months, or 1 year?

ROHIT SUD, MD: [Patients whose disease progressed at] less than 12 months I would consider as primary refractory disease. The prognosis would be bad for those patients, but now we have better options. We’re hoping that things might get a bit better going forward. For a patient who is primary refractory at less than 12 months, I would probably consider chimeric antigen receptor [CAR] T-cell therapy as my preferred option.

BRÉM: I would agree. Would anyone feel differently?

HOLAVANAHALLI KESHAVAPRASAD, MD: To differentiate between primary refractory and early relapse, I would agree that within 12 months or 6 to 12 months is early relapse, but would primary refractory be the same definition? If they grow through chemotherapy—for example, after 2 cycles there’s some response, but then by the time you do another PET scan, it has progressed—I would consider that would be more like primary refractory.

BRÉM: Part of the issue is different studies have used different definitions of primary refractory. That is what makes this complicated. We could probably all agree if [the disease] grew during R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), prednisone], that’s primary refractory. The question becomes if you progress within 3 months or 6 months, do we want to label that? Where do we cut it off?

KESHAVAPRASAD: I would most likely say 6 months.

BRÉM: I think that’s the most common definition. We all agree that in the chemotherapy pre–CAR T-cell era, these are the patients where we would have given chemotherapy to but would have known they were likely going to do very poorly. I think the CORAL study [NCT00137995] would say there’s about a 20% chance of carrying [an early relapsed] patient.¹ Is everybody going to send [such a patient] at least for a CAR T-cell evaluation? Or would anybody offer them anything different?

KESHAVAPRASAD: If CAR T-cell therapy was not available, [we could give] second-line chemotherapy and autologous stem cell transplant. Of course, it’s not the ideal, but if CAR T-cell therapy was not available, would that be reasonable?

BRÉM: Do you mean that there isn’t a center that he could go to? We probably would do it, but not go into it [feeling] optimistic.

JEFF SCHRIBER, MD: Most centers that would do a transplant would look and say, “We’re going to do CAR T-cell therapy,” because most transplant centers are able to do CAR T-cell therapy. It’s not every center, but I would say 80% to 90%, that’s what they would do now. [But] it’s not 0. There are patients who do OK, so in that patient, if they responded to chemotherapy and had responsive disease, then they probably have a 20% survival. It’s certainly better than 0, but it’s not very good.

BRÉM: I agree with you. If you were stuck, you could get chemotherapy and consider taking them to transplant if they went into complete response; it’s just my optimism or expectation of them going into complete response is relatively low.

DISCUSSION QUESTIONS

• What are your clinical goals for a patient who has relapse within 12 months?
• What are key factors that influence your therapeutic recommendation for a patient with primary refractory DLBCL?

BRÉM: When you picked polatuzumab vedotin [Polivy] plus or minus bendamustine plus or minus rituximab [pola-BR], what was in your mind? Were you thinking about what was going to have the best efficacy? Were you thinking about duration of response or duration of therapy? What was at the top of your mind?

PRASHANT SHARMA: I chose pola-BR, not [considering] that the overall survival difference was something like 33 months [for tafasitamab (Monjuvi) plus lenalidomide (Revlimid)] vs 12 months [for pola-BR],^2,3 because I’m familiar with pola-BR from what we used to do before. [Because of] the cytopenias and the synergy with tafasitamab/lenalidomide and the difficulty getting lenalidomide right away a lot of the time, pola-BR might be an option which is reasonable for the patient.

BRÉM: So you’re thinking, “I’ve used polatuzumab; I know it’s effective. I don’t have to wait for the lenalidomide. I’m not going to have to worry about dose-reducing the lenalidomide because of the cytopenias and I feel like there’s a good chance that will help them.” Very reasonable. Does anyone who chose tafasitamab/lenalidomide want to defend [their choice]?

HARRY MENON, DO: I chose tafasitamab/lenalidomide. I know that when we were looking at L-MIND [NCT02399085], with those data using it earlier in sequence led to better responses.² To counterpoint [on accessing] lenalidomide, while it is a challenge to get it, we’re usually able to get it fairly quickly to patients and it’s convenient for patients. They do have to come in weekly for the tafasitamab, but they’ve done pretty well. I’ve liked using it in that setting if we need to.

BRÉM: Do you start patients at 25 mg [lenalidomide] or do you empirically dose reduce?

MENON: I empirically dose reduce because I see such problem with cytopenias.

BRÉM: I do too. I haven’t necessarily had issues getting the lenalidomide, but what I’ve had issues with is the $2000 copay, and then having to scramble for copay assistance. Once or twice patients did not qualify for copay assistance. I don’t know if I’m an outlier in that or if that’s just my patients.

ELISA BOMGAARS, MD: I usually use tafasitamab plus lenalidomide because of the tolerability. I’ve used it in 80-year-old patients, and they tolerate it well.

BRÉM: Do you empirically dose-reduce the lenalidomide, especially in your older patients?

BOMGAARS: Yes, especially since in the relapsed setting I already know how cytopenic they could be.

BRÉM: I’m somebody who’s very comfortable, personally, empirically dose-reducing lenalidomide. I treat some myeloma too, and it’s very rare that I start people on 25 mg of lenalidomide in that setting, either.

REFERENCES:

1. Hagberg H, Gisselbrecht C; CORAL study group. Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: an update of the CORAL study. Ann Oncol. 2006;17(Suppl­­_4):iv31-iv32. doi:10.1093/annonc/mdj996

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

3. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172