Expert Perspectives in the Evolving Treatment Landscape of Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Supplements And Featured Publications, Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma, Volume 1, Issue 1

Faculty debate the definitions of chemotherapy resistance, sensitivity, and refractoriness and discussed appropriate management strategies based on how patients would be classified in DLBCL.

OncLive®: Could you provide some considerations for MOR208 as a second-line therapy in patients with diffuse large B-cell lymphoma (DLBCL) who have previously received a regimen that contains chemotherapy and rituximab?

Flinn: I think decisions about second-line therapies always begin with the goal. Patients with a curative approach generally receive a salvage chemotherapy such as RICE [rituximab, ifosfamide, carboplatin, and etoposide] and, if sensitive, an autologous peripheral blood stem cell transplant. But in some patients, that’s not a suitable goal; maybe their comorbidities are too high and prevent them from receiving such an aggressive approach, or maybe they’re a person in their late 70s or 80s where that’s not an approach. I think MOR208 combinations, such as with lenalidomide, are appropriate in that second-line setting.

Kahl: Well, the MOR208 data are pretty impressive. The patient population with relapsed/refractory DLBCL is always difficult. These patients don’t have a ton of great treatment options, so we’re always interested in finding treatments that have high activity and good tolerability.

Tafasitamab [MOR208], a monoclonal antibody that targets CD19, and lenalidomide [Revlimid] can be given in combination. The lenalidomide is given for a year. The tafasitamab is given weekly for the first 3 months and then every other week, indefinitely. Overall, it looks to be a pretty well-tolerated regimen. The response rate was nice at 60%, with a complete response rate of around 40%. What was most impressive was the durability of those responses. Well over 50% of patients were still in remission at 18 months.

Abdulhaq: Results of the phase 2 L-MIND trial [NCT02399085] that combined MOR208 with lenalidomide, which included patients who were not eligible for stem cell transplant, showed a really promising overall response rate (ORR), 60%, and complete response rate, 40%. The median duration of response was about 21 months. To me, this seems to be really good activity of this combination in this population of patients with a significant unmet need. These patients actually have a poor prognosis, and at the same time this combination showed a reasonable adverse eveffect (AE) profile, and the toxicities were reasonable for such a regimen. I believe the infection rate was [about] 10%, with neutropenic fever rate of about 5%. It seems like most patients, about 70%, were able to be maintained on a dose of lenalidomide of more than 20 mg. Given all of that, I think it is a reasonable regimen to consider in the second-line setting in patients with relapsed or refractory DLBCL who are not eligible for stem cell transplant.

Would MOR208 be considered for those patients who are ineligible for chimeric antigen receptor (CAR) T-cell therapy and who are not candidates for polatuzumab?

Flinn: MOR208 would be considered for anybody after relapse in DLBCL who is not suitable for a variety of other things. For instance, CAR T cells are a very aggressive treatment option; people need to be almost as fit as for a stem cell transplant to see CAR T cells. I don’t think it’s the same with patients receiving polatuzumab. Polatuzumab is given in combination with bendamustine and rituximab. Those patients have to have good hematologic function to be a candidate, and for some patients, that is not a realistic scenario. Perhaps they have cytopenias or they’ve received multiple chemotherapy before; getting more chemotherapy such as bendamustine and polatuzumab is not an appropriate approach. So MOR208 in combination with lenalidomide is a very appropriate treatment option for that group of patients.

Kahl: If you’re treating patients with CAR T-cell therapy, you’re really still in a curative intent mindset, but many patients can’t make it to CAR T cell because they can’t get their disease under control. Some patients are just not appropriate for CAR T-cell therapy; others relapse after CAR T-cell therapy. All those patients would be appropriate for this combination of tafasitamab and lenalidomide.

In that same space would be the polatuzumab vedotin plus bendamustine/rituximab combination that has FDA approval in relapsed/refractory DLBCL. That regimen hasn’t been compared head-to-head with the tafasitamab/lenalidomide combination, so it is hard to know how the 2 stack up against each other. Response rates look similar. The durability, on paper, perhaps looks a little better with [the] tafasitamab/ lenalidomide combination. For most patients, I do think the tafasitamab/lenalidomide combination would be better tolerated than a polatuzumab-based therapy. I could see a lot of investigators choosing the lenalidomide/tafasitamab as their regimen of choice for patients in this setting.

Abdulhaq: Yes, absolutely. I think it is a very reasonable option in this situation. I think obviously in this patient population there is something to be said about the AE profile, maintaining quality of life. If we’re look at patients who have relapsed or refractory DLBCL and are not eligible for transplant, that means we’re looking at patients who are older or who have comorbidities, and that’s where we need to have that balance between efficacy and a reasonable AE profile. That’s where I see a value in using this regimen. The other thing is that obviously lenalidomide is an oral drug and it is also not a chemotherapy, so that, too is of value for these patients.

Could you highlight some of the benefits of using a chemotherapy-free regimen such as MOR208?

Flinn: I think chemo-free regimens are very popular with patients in general. We know from other diseases, such as chronic lymphocytic leukemia and low-grade lymphoma, that using these targeted agents that are chemo free are extremely popular. If you ask someone, “Would you rather receive a cytotoxic chemotherapy, or would you rather receive a targeted agent?” pretty much everyone chooses a targeted agent because you don’t have nearly as much off-target toxicity or as much collateral damage as you do with cytotoxic chemotherapy. [Avoiding] those adverse events (AEs) is an important treatment goal for many of my patients.

From a patient perspective, do other benefits exist aside from the favorable toxicity profile of MOR208?

Flinn: I think MOR208 [tafasitamab] is an attractive treatment option for many patients because it doesn’t have all the problems with cytopenias, or the nausea, vomiting, and all the [other] collateral damage that we see with cytotoxic chemotherapy. Giving it in combination with lenalidomide, which is an oral agent, is a benefit for many patients who are trying to avoid all the AEs that you see with traditional cytotoxic chemotherapy or even to a certain extent just with polatuzumab. Polatuzumab basically works like a targeted chemotherapy, so [by using MOR208] you’re avoiding some of the AEs you’d see with cytotoxic chemotherapy.

Kahl: In general, a chemotherapy-free regimen tends to be better tolerated. That’s not always true, but often it is. One appealing part is [avoiding] the mechanism of action in which patients start exhibiting resistance to chemotherapy drugs. Often it doesn’t matter which other chemotherapy drugs you’d [change] to—they still have resistance, at least relative resistance. Even if they respond, the responses are pretty brief. So we’re always interested in finding agents that attack the cancer cells with a different mechanism, beyond the genotoxic damage of DNA-damaging chemotherapy.

The appeal of lenalidomide/tafasitamab is that it’s trying to kill the cells in a fundamentally different way from a chemotherapy-based regimen, and it is generally more tolerable as well.

Abdulhaq: From the L-MIND study, it seems that MOR208 was very well tolerated. We would expect the AEs of monoclonal antibody–like allergic reactions, which probably showed up more in the patients after 12 cycles when lenalidomide was stopped, but otherwise it was well tolerated. We didn’t see significant toxicity in these patients after those 12 cycles, and we didn’t see a significant rate of infections.

In another study, the drug has shown promising activity as a single agent also, although my preference would be to use it in combination. But in a very frail patient, if I felt that they might not be even able to tolerate a combination, I might consider it as a single drug.

Say a patient has cycled rituximab after a drug holiday, with limited evidence of the efficacy of rituximab. Could MOR208 be considered next? Why or why not?

Flinn: We traditionally use rituximab in combination with chemotherapy because we don’t really know whether rituximab helps or not, but [we do know] that it probably doesn’t add much in the way of AEs. If you add it to yet another chemotherapy or another regimen, it [again] seems to add little in the way of AEs. [But] if you think about it, that’s not really the most rational approach, right? We don’t reuse other chemotherapy. We wouldn’t reuse adriamycin or [cyclophosphamide] or gemcitabine if someone was not responding to it anymore. We’re probably not adding all that much to chemotherapy or to regimens by continuing to use rituximab or other CD20 antibodies. Using other targeting antigens, such as CD19, or using MOR208, I think, is an attractive option for patients who’ve already been through treatment with another monoclonal antibody that targets CD20 or another target.

Kahl: Certainly, most patients with relapsed DLBCL have been exposed to quite a bit of rituximab. It’s given in virtually every salvage chemotherapy regimen in combination, and a lot of patients have either absolute or relative rituximab resistance at that point. So going to a regimen that isn’t based on rituximab at all has a lot of appeal. Tafasitamab targets a different antigen, CD19 instead of CD20. So, again, the tafasitamab/lenalidomide combination [avoids] a strategy that patients have already been exposed to and has probably had diminishing returns at that point.

Abdulhaq: Yes, I would consider it. It just makes sense, logically, to use a different drug that targets a different antibody rather than cycling the same drug we used before. In another trial, a phase 2 trial that looked at the use of rituximab and lenalidomide in patients with relapsed/refractory DLBCL, the ORR was somewhere around, I believe, 35% to 40%, so it doesn’t seem to me [to be] very different from the response rate to just [the] single agent [of] lenalidomide. That being said, obviously we’re not supposed to compare across trials, but I think somehow we cannot afford to not think about it.